text stringlengths 8 5.77M |
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Seeing the Royal Pony Sisters enjoying a beautiful flight in their shared sky is as heartwarming as it is gorgeous. Amazing work bringing the princesses to life in all of their glory, and you did such beautiful work on the details in all of their textures and effects. Their feathers are outstanding, with the brilliant glow and soft colors creating more majesty for the pair.
Their action poses carry more than a hint of playfulness, and their energy is unbounded. Their smiles shine brighter than the skies. The dichotomy of skies is fantastic too, giving each a bit of her own element while also bringing them together. The birds joining them for their happy morning routine make it even sweeter. Thanks for sharing. |
Biography
July 29 A false-color photograph of NGC 1097, a barred spiral galaxy about 45 million light-years away in the constellation Fornax. The galaxy was discovered by William Herschel on 9 October 1790. It has a supermassive black hole at its center, which is 140 million times the mass of the Sun, as well as two satellite galaxies. The photograph was taken in infrared light by the Spitzer Space Telescope. Photograph: NASA/JPL-Caltech Wikipedia is hosted by the Wikimedia Foundation, a non-profit organization that also hosts a range of other projects: This Wikipedia is written in English. Started in 2001 (2001), it currently contains 4,930,244 articles. Many other Wikipedias are available; some of the largest are listed below. |
#include <string>
#include <BWAPI/UpgradeType.h>
#include <BWAPI/Race.h>
#include <BWAPI/UnitType.h>
namespace BWAPI
{
template <>
const std::string Type<UpgradeType, UpgradeTypes::Enum::Unknown>::typeNames[UpgradeTypes::Enum::MAX] =
{
"Terran_Infantry_Armor",
"Terran_Vehicle_Plating",
"Terran_Ship_Plating",
"Zerg_Carapace",
"Zerg_Flyer_Carapace",
"Protoss_Ground_Armor",
"Protoss_Air_Armor",
"Terran_Infantry_Weapons",
"Terran_Vehicle_Weapons",
"Terran_Ship_Weapons",
"Zerg_Melee_Attacks",
"Zerg_Missile_Attacks",
"Zerg_Flyer_Attacks",
"Protoss_Ground_Weapons",
"Protoss_Air_Weapons",
"Protoss_Plasma_Shields",
"U_238_Shells",
"Ion_Thrusters",
"",
"Titan_Reactor",
"Ocular_Implants",
"Moebius_Reactor",
"Apollo_Reactor",
"Colossus_Reactor",
"Ventral_Sacs",
"Antennae",
"Pneumatized_Carapace",
"Metabolic_Boost",
"Adrenal_Glands",
"Muscular_Augments",
"Grooved_Spines",
"Gamete_Meiosis",
"Metasynaptic_Node",
"Singularity_Charge",
"Leg_Enhancements",
"Scarab_Damage",
"Reaver_Capacity",
"Gravitic_Drive",
"Sensor_Array",
"Gravitic_Boosters",
"Khaydarin_Amulet",
"Apial_Sensors",
"Gravitic_Thrusters",
"Carrier_Capacity",
"Khaydarin_Core",
"",
"",
"Argus_Jewel",
"",
"Argus_Talisman",
"",
"Caduceus_Reactor",
"Chitinous_Plating",
"Anabolic_Synthesis",
"Charon_Boosters",
"",
"",
"",
"",
"",
"Upgrade_60",
"None",
"Unknown"
};
// LOCALIZATION
std::string upgradeLocalNames[UpgradeTypes::Enum::MAX];
// DEFAULTS
static const int defaultOreCostBase[UpgradeTypes::Enum::MAX] = // same as default gas cost base
{
100, 100, 150, 150, 150, 100, 150, 100, 100, 100, 100, 100, 100, 100, 100, 200, 150, 100, 200, 150, 100, 150, 200, 150, 200, 150, 150, 100, 200,
150, 150, 150, 150, 150, 150, 200, 200, 200, 150, 150, 150, 100, 200, 100, 150, 0, 0, 100, 100, 150, 150, 150, 150, 200, 100, 0, 0, 0, 0, 0, 0, 0, 0
};
static const int defaultOreCostFactor[UpgradeTypes::Enum::MAX] = // same as default gas cost factor
{
75, 75, 75, 75, 75, 75, 75, 75, 75, 50, 50, 50, 75, 50, 75, 100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,
0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0
};
static const int defaultTimeCostBase[UpgradeTypes::Enum::MAX] =
{
4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 4000, 1500, 1500, 0, 2500,
2500, 2500, 2500, 2500, 2400, 2000, 2000, 1500, 1500, 1500, 1500, 2500, 2500, 2500, 2000, 2500, 2500, 2500, 2000,
2000, 2500, 2500, 2500, 1500, 2500, 0, 0, 2500, 2500, 2500, 2500, 2500, 2000, 2000, 2000, 0, 0, 0, 0, 0, 0, 0, 0
};
static const int defaultTimeCostFactor[UpgradeTypes::Enum::MAX] =
{
480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 480, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,
0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0
};
static const int defaultMaxRepeats[UpgradeTypes::Enum::MAX] =
{
3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 1, 1, 0, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,
1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 1, 0, 1, 0, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0
};
// ACTUAL
int oreCostBase[UpgradeTypes::Enum::MAX], gasCostBase[UpgradeTypes::Enum::MAX], timeCostBase[UpgradeTypes::Enum::MAX];
int oreCostFactor[UpgradeTypes::Enum::MAX], gasCostFactor[UpgradeTypes::Enum::MAX], timeCostFactor[UpgradeTypes::Enum::MAX];
int maxRepeats[UpgradeTypes::Enum::MAX];
namespace upgradeInternalWhat
{
using namespace UnitTypes::Enum;
static const int whatUpgrades[UpgradeTypes::Enum::MAX] =
{
Terran_Engineering_Bay, Terran_Armory, Terran_Armory, Zerg_Evolution_Chamber, Zerg_Spire, Protoss_Forge, Protoss_Cybernetics_Core, Terran_Engineering_Bay,
Terran_Armory, Terran_Armory, Zerg_Evolution_Chamber, Zerg_Evolution_Chamber, Zerg_Spire, Protoss_Forge, Protoss_Cybernetics_Core, Protoss_Forge, Terran_Academy,
Terran_Machine_Shop, None, Terran_Science_Facility, Terran_Covert_Ops, Terran_Covert_Ops, Terran_Control_Tower, Terran_Physics_Lab, Zerg_Lair, Zerg_Lair, Zerg_Lair,
Zerg_Spawning_Pool, Zerg_Spawning_Pool, Zerg_Hydralisk_Den, Zerg_Hydralisk_Den, Zerg_Queens_Nest, Zerg_Defiler_Mound, Protoss_Cybernetics_Core, Protoss_Citadel_of_Adun,
Protoss_Robotics_Support_Bay, Protoss_Robotics_Support_Bay, Protoss_Robotics_Support_Bay, Protoss_Observatory, Protoss_Observatory, Protoss_Templar_Archives,
Protoss_Fleet_Beacon, Protoss_Fleet_Beacon, Protoss_Fleet_Beacon, Protoss_Arbiter_Tribunal, None, None, Protoss_Fleet_Beacon, None, Protoss_Templar_Archives,
None, Terran_Academy, Zerg_Ultralisk_Cavern, Zerg_Ultralisk_Cavern, Terran_Machine_Shop, None, None, None, None, None, None, None, None
};
}
namespace upgradeInternalReqs
{
using namespace UnitTypes::Enum;
static const int requirements[3][UpgradeTypes::Enum::MAX] =
{
// Level 1
{ None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, Zerg_Hive, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, None, None, None, Terran_Armory, None, None, None, None, None, None, None, None },
// Level 2
{ Terran_Science_Facility, Terran_Science_Facility, Terran_Science_Facility, Zerg_Lair, Zerg_Lair, Protoss_Templar_Archives, Protoss_Fleet_Beacon,
Terran_Science_Facility, Terran_Science_Facility, Terran_Science_Facility, Zerg_Lair, Zerg_Lair, Zerg_Lair, Protoss_Templar_Archives,
Protoss_Fleet_Beacon, Protoss_Cybernetics_Core, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, None, None, None, None },
// Level 3
{ Terran_Science_Facility, Terran_Science_Facility, Terran_Science_Facility, Zerg_Hive, Zerg_Hive, Protoss_Templar_Archives, Protoss_Fleet_Beacon,
Terran_Science_Facility, Terran_Science_Facility, Terran_Science_Facility, Zerg_Hive, Zerg_Hive, Zerg_Hive, Protoss_Templar_Archives,
Protoss_Fleet_Beacon, Protoss_Cybernetics_Core, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None, None,
None, None, None, None, None, None, None, None, None },
};
}
namespace upgradeInternalUsage
{
using namespace UnitTypes::Enum;
static const int Infantry_Armor[] = { Terran_Marine, Terran_Ghost, Terran_SCV, Hero_Gui_Montag, Terran_Civilian, Hero_Sarah_Kerrigan,
Hero_Jim_Raynor_Marine, Terran_Firebat, Terran_Medic, Hero_Samir_Duran, Hero_Alexei_Stukov };
static const int Vehicle_Plating[] = { Terran_Vulture, Terran_Goliath, Terran_Siege_Tank_Tank_Mode, Hero_Alan_Schezar, Hero_Jim_Raynor_Vulture,
Hero_Edmund_Duke_Tank_Mode, Hero_Edmund_Duke_Siege_Mode, Terran_Siege_Tank_Siege_Mode };
static const int Ship_Plating[] = { Terran_Wraith, Terran_Science_Vessel, Terran_Dropship, Terran_Battlecruiser, Hero_Tom_Kazansky, Hero_Magellan,
Hero_Arcturus_Mengsk, Hero_Hyperion, Hero_Norad_II, Terran_Valkyrie, Hero_Gerard_DuGalle };
static const int Carapace[] = { Zerg_Larva, Zerg_Egg, Zerg_Zergling, Zerg_Hydralisk, Zerg_Ultralisk, Zerg_Broodling, Zerg_Drone, Zerg_Defiler,
Hero_Torrasque, Zerg_Infested_Terran, Hero_Infested_Kerrigan, Hero_Unclean_One, Hero_Hunter_Killer, Hero_Devouring_One,
Zerg_Cocoon, Zerg_Lurker_Egg, Zerg_Lurker, Hero_Infested_Duran };
static const int Flyer_Carapace[] = { Zerg_Overlord, Zerg_Mutalisk, Zerg_Guardian, Zerg_Queen, Zerg_Scourge, Hero_Matriarch, Hero_Kukulza_Mutalisk,
Hero_Kukulza_Guardian, Hero_Yggdrasill, Zerg_Devourer };
static const int Protoss_Armor[] = { Protoss_Dark_Templar, Protoss_Dark_Archon, Protoss_Probe, Protoss_Zealot, Protoss_Dragoon, Protoss_High_Templar,
Protoss_Archon, Hero_Dark_Templar, Hero_Zeratul, Hero_Tassadar_Zeratul_Archon, Hero_Fenix_Zealot, Hero_Fenix_Dragoon,
Hero_Tassadar, Hero_Warbringer, Protoss_Reaver, Hero_Aldaris };
static const int Protoss_Plating[] = { Protoss_Corsair, Protoss_Shuttle, Protoss_Scout, Protoss_Arbiter, Protoss_Carrier, Protoss_Interceptor, Hero_Mojo,
Hero_Gantrithor, Protoss_Observer, Hero_Danimoth, Hero_Artanis, Hero_Raszagal };
static const int Infantry_Weapons[] = { Terran_Marine, Hero_Jim_Raynor_Marine, Terran_Ghost, Hero_Sarah_Kerrigan, Terran_Firebat, Hero_Gui_Montag,
Special_Wall_Flame_Trap, Special_Right_Wall_Flame_Trap, Hero_Samir_Duran, Hero_Alexei_Stukov, Hero_Infested_Duran };
static const int Vehicle_Weapons[] = { Terran_Vulture, Hero_Jim_Raynor_Vulture, Terran_Goliath, Hero_Alan_Schezar, Terran_Siege_Tank_Tank_Mode,
Terran_Siege_Tank_Siege_Mode, Hero_Edmund_Duke_Tank_Mode, Hero_Edmund_Duke_Siege_Mode, Special_Floor_Missile_Trap,
Special_Floor_Gun_Trap, Special_Wall_Missile_Trap, Special_Right_Wall_Missile_Trap };
static const int Ship_Weapons[] = { Terran_Wraith, Hero_Tom_Kazansky, Terran_Battlecruiser, Hero_Hyperion, Hero_Norad_II, Hero_Arcturus_Mengsk,
Hero_Gerard_DuGalle, Terran_Valkyrie };
static const int Zerg_MeleeAtk[] = { Zerg_Zergling, Hero_Devouring_One, Hero_Infested_Kerrigan, Zerg_Ultralisk, Hero_Torrasque, Zerg_Broodling };
static const int Zerg_RangeAtk[] = { Zerg_Hydralisk, Hero_Hunter_Killer, Zerg_Lurker };
static const int Zerg_FlyerAtk[] = { Zerg_Mutalisk, Hero_Kukulza_Mutalisk, Hero_Kukulza_Guardian, Zerg_Guardian, Zerg_Devourer };
static const int Protoss_GrndWpn[] = { Protoss_Zealot, Hero_Fenix_Zealot, Protoss_Dragoon, Hero_Fenix_Dragoon, Hero_Tassadar, Hero_Aldaris, Protoss_Archon,
Hero_Tassadar_Zeratul_Archon, Hero_Dark_Templar, Hero_Zeratul, Protoss_Dark_Templar };
static const int Protoss_AirWpn[] = { Protoss_Scout, Hero_Mojo, Protoss_Arbiter, Hero_Danimoth, Protoss_Interceptor, Protoss_Carrier, Protoss_Corsair, Hero_Artanis };
static const int Shields[] = { Protoss_Corsair, Protoss_Dark_Templar, Protoss_Dark_Archon, Protoss_Probe, Protoss_Zealot, Protoss_Dragoon, Protoss_High_Templar,
Protoss_Archon, Protoss_Shuttle, Protoss_Scout, Protoss_Arbiter, Protoss_Carrier, Protoss_Interceptor, Hero_Dark_Templar,
Hero_Zeratul, Hero_Tassadar_Zeratul_Archon, Hero_Fenix_Zealot, Hero_Fenix_Dragoon, Hero_Tassadar, Hero_Mojo, Hero_Warbringer,
Hero_Gantrithor, Protoss_Reaver, Protoss_Observer, Hero_Danimoth, Hero_Aldaris, Hero_Artanis, Hero_Raszagal };
static const int Shells[] = { Terran_Marine };
static const int Ion_Thrusters[] = { Terran_Vulture };
static const int Titan_Reactor[] = { Terran_Science_Vessel };
static const int Ghost_Upgrades[] = { Terran_Ghost };
static const int Apollo_Reactor[] = { Terran_Wraith };
static const int Colossus_Reactor[] = { Terran_Battlecruiser };
static const int Overlord_Upgrades[] = { Zerg_Overlord };
static const int Zergling_Upgrades[] = { Zerg_Zergling };
static const int Hydralisk_Upgrades[] = { Zerg_Hydralisk };
static const int Gamete_Meiosis[] = { Zerg_Queen };
static const int Metasynaptic_Node[] = { Zerg_Defiler };
static const int Singularity_Charge[] = { Protoss_Dragoon };
static const int Leg_Enhancements[] = { Protoss_Zealot };
static const int Reaver_Upgrades[] = { Protoss_Reaver };
static const int Gravitic_Drive[] = { Protoss_Shuttle };
static const int Observer_Upgrades[] = { Protoss_Observer };
static const int Khaydarin_Amulet[] = { Protoss_High_Templar };
static const int Scout_Upgrades[] = { Protoss_Scout };
static const int Carrier_Capacity[] = { Protoss_Carrier };
static const int Khaydarin_Core[] = { Protoss_Arbiter };
static const int Argus_Jewel[] = { Protoss_Corsair };
static const int Argus_Talisman[] = { Protoss_Dark_Archon };
static const int Caduceus_Reactor[] = { Terran_Medic };
static const int Ultralisk_Upgrades[] = { Zerg_Ultralisk };
static const int Charon_Boosters[] = { Terran_Goliath };
static const int Upgrade60[] = { Terran_Vulture_Spider_Mine, Critter_Ursadon, Critter_Scantid, Critter_Rhynadon, Critter_Ragnasaur, Critter_Kakaru, Critter_Bengalaas,
Special_Cargo_Ship, Special_Mercenary_Gunship, Terran_SCV, Protoss_Probe, Zerg_Drone, Zerg_Infested_Terran, Zerg_Scourge };
#define TSET(x) {std::begin(x), std::end(x)}
#define TSETEMPTY {}
static const UnitType::set upgradeWhatUses[UpgradeTypes::Enum::MAX] =
{
TSET(Infantry_Armor), TSET(Vehicle_Plating), TSET(Ship_Plating), TSET(Carapace), TSET(Flyer_Carapace), TSET(Protoss_Armor), TSET(Protoss_Plating),
TSET(Infantry_Weapons), TSET(Vehicle_Weapons), TSET(Ship_Weapons), TSET(Zerg_MeleeAtk), TSET(Zerg_RangeAtk), TSET(Zerg_FlyerAtk), TSET(Protoss_GrndWpn),
TSET(Protoss_AirWpn), TSET(Shields), TSET(Shells), TSET(Ion_Thrusters), TSETEMPTY, TSET(Titan_Reactor), TSET(Ghost_Upgrades), TSET(Ghost_Upgrades),
TSET(Apollo_Reactor), TSET(Colossus_Reactor), TSET(Overlord_Upgrades), TSET(Overlord_Upgrades), TSET(Overlord_Upgrades), TSET(Zergling_Upgrades),
TSET(Zergling_Upgrades), TSET(Hydralisk_Upgrades), TSET(Hydralisk_Upgrades), TSET(Gamete_Meiosis), TSET(Metasynaptic_Node), TSET(Singularity_Charge),
TSET(Leg_Enhancements), TSET(Reaver_Upgrades), TSET(Reaver_Upgrades), TSET(Gravitic_Drive), TSET(Observer_Upgrades), TSET(Observer_Upgrades),
TSET(Khaydarin_Amulet), TSET(Scout_Upgrades), TSET(Scout_Upgrades), TSET(Carrier_Capacity), TSET(Khaydarin_Core), TSETEMPTY, TSETEMPTY,
TSET(Argus_Jewel), TSETEMPTY, TSET(Argus_Talisman), TSETEMPTY, TSET(Caduceus_Reactor), TSET(Ultralisk_Upgrades), TSET(Ultralisk_Upgrades),
TSET(Charon_Boosters), TSETEMPTY, TSETEMPTY, TSETEMPTY, TSETEMPTY, TSETEMPTY, TSET(Upgrade60), TSETEMPTY, TSETEMPTY
};
#undef TSETEMPTY
#undef TSET
}
namespace upgradeInternalRace
{
using namespace Races::Enum;
static const int upgradeRaces[UpgradeTypes::Enum::MAX] =
{
Terran, Terran, Terran, Zerg, Zerg, Protoss, Protoss, Terran, Terran, Terran, Zerg, Zerg, Zerg, Protoss, Protoss, Protoss, Terran, Terran, Terran, Terran, Terran,
Terran, Terran, Terran, Zerg, Zerg, Zerg, Zerg, Zerg, Zerg, Zerg, Zerg, Zerg, Protoss, Protoss, Protoss, Protoss, Protoss, Protoss, Protoss, Protoss, Protoss,
Protoss, Protoss, Protoss, None, None, Protoss, None, Protoss, None, Terran, Zerg, Zerg, Terran, None, None, None, None, None, None, None, Unknown
};
}
namespace UpgradeTypeSet
{
using namespace UpgradeTypes::Enum;
const UpgradeType::set upgradeTypeSet = { Terran_Infantry_Armor, Terran_Vehicle_Plating, Terran_Ship_Plating,
Zerg_Carapace, Zerg_Flyer_Carapace, Protoss_Ground_Armor, Protoss_Air_Armor,
Terran_Infantry_Weapons, Terran_Vehicle_Weapons, Terran_Ship_Weapons,
Zerg_Melee_Attacks, Zerg_Missile_Attacks, Zerg_Flyer_Attacks,
Protoss_Ground_Weapons, Protoss_Air_Weapons, Protoss_Plasma_Shields,
U_238_Shells, Ion_Thrusters, Titan_Reactor, Ocular_Implants,
Moebius_Reactor, Apollo_Reactor, Colossus_Reactor, Ventral_Sacs,
Antennae, Pneumatized_Carapace, Metabolic_Boost, Adrenal_Glands,
Muscular_Augments, Grooved_Spines, Gamete_Meiosis, Metasynaptic_Node,
Singularity_Charge, Leg_Enhancements, Scarab_Damage, Reaver_Capacity,
Gravitic_Drive, Sensor_Array, Gravitic_Boosters, Khaydarin_Amulet,
Apial_Sensors, Gravitic_Thrusters, Carrier_Capacity, Khaydarin_Core,
Argus_Jewel, Argus_Talisman, Caduceus_Reactor, Chitinous_Plating,
Anabolic_Synthesis, Charon_Boosters, None, Unknown };
}
Race UpgradeType::getRace() const
{
return upgradeInternalRace::upgradeRaces[this->getID()];
}
int UpgradeType::mineralPrice(int level) const
{
return defaultOreCostBase[this->getID()] +
std::max(0, level-1) * this->mineralPriceFactor();
}
int UpgradeType::mineralPriceFactor() const
{
return defaultOreCostFactor[this->getID()];
}
int UpgradeType::gasPrice(int level) const
{
// Gas price is exactly the same as mineral price
return mineralPrice(level);
}
int UpgradeType::gasPriceFactor() const
{
// Gas price factor is the same as mineral price factor
return mineralPriceFactor();
}
int UpgradeType::upgradeTime(int level) const
{
return defaultTimeCostBase[this->getID()] +
std::max(0, level-1) * this->upgradeTimeFactor();
}
int UpgradeType::upgradeTimeFactor() const
{
return defaultTimeCostFactor[this->getID()];
}
UnitType UpgradeType::whatUpgrades() const
{
return upgradeInternalWhat::whatUpgrades[this->getID()];
}
const UnitType::set& UpgradeType::whatUses() const
{
return upgradeInternalUsage::upgradeWhatUses[this->getID()];
}
int UpgradeType::maxRepeats() const
{
return defaultMaxRepeats[this->getID()];
}
UnitType UpgradeType::whatsRequired(int level) const
{
if ( level >= 1 && level <= 3)
return upgradeInternalReqs::requirements[level-1][this->getID()];
return UnitTypes::None;
}
const UpgradeType::set& UpgradeTypes::allUpgradeTypes()
{
return UpgradeTypeSet::upgradeTypeSet;
}
}
|
Ride-Hailing App Geared Toward Women Debuts In Boston
A new ride-hailing service in Boston called Safr is aimed at getting female customers and employing female drivers. Some women drivers and passengers felt unsafe using other ride-hailing apps.
DAVID GREENE, HOST:
So there's a ride-hailing company that's now up and running in Boston, and it is geared toward women. The company wants women to be less worried about sexual harassment when they are riding. Another goal is to open this industry to more women drivers. From member station WABE, Zeninjor Enwemeka reports.
ZENINJOR ENWEMEKA, BYLINE: About 20 women gather at a training session just north of Boston for the new ride-hailing company Safr, spelled S-A-F-R. Many of the women share stories about driving for other companies. Danielle Maree Langley tells about a night she picked up two men.
DANIELLE MAREE LANGLEY: One of them kept on really getting in my face, and he didn't understand - why don't you want to come home with me?
ENWEMEKA: Langley says she tried to stay calm and changed the subject. But the passenger just got more menacing.
LANGLEY: I mean, I was so scared, and these two men said they were firefighters. So I said if you're such great firefighters, then I will drop you off at the police station and the police can take you home.
(LAUGHTER)
ENWEMEKA: Many women in the group drive for other ride-hailing companies. They say this work allows them to make their own hours and earn extra money outside their other jobs. But many won't drive at odd times to avoid uncomfortable situations. Safr CEO Syed Gilani says his company wants to change that.
SYED GILANI: We want to make sure that women feel safe during any time of the day or night as a rider and as a driver. And in the end, they feel empowered and new and new women join the ride-sharing market.
ENWEMEKA: Safr works like other ride-hailing companies. There's an app to summon a ride, but then there are the safety features. The passenger is assigned a color - so is the driver - and the colors must be verified before a ride can start. This is to make sure drivers pick up the right passengers. If you do run into trouble, Safr has a feature that will dial 911, your emergency contacts or the company's call center.
COMPUTER-GENERATED VOICE: You are on the best route despite usual traffic. You should reach your destination by 4:31 p.m.
ENWEMEKA: I tested out the app and caught a ride from Safr driver Tracey Ozel. She also drives for Uber and Lyft.
TRACEY OZEL: Lots of women ask me, what is it like to drive? And what they're really asking is, like, are you, like, afraid of picking up strangers in the car? That's what they're really trying to find out, and I'm like, I'm totally used to it now.
ENWEMEKA: But she says more of her passengers have expressed the desire for female drivers.
OZEL: It'll be more of a niche market, that's for sure, but there's definitely a market out there for it.
ENWEMEKA: Safr wanted to be exclusive to women, but then it would be vulnerable to discrimination lawsuits. So men can sign up to be drivers and passengers, too. CEO Syed Gilani says Safr wants to shift the imbalance of women in the industry, which right now is about 14 percent for Uber.
GILANI: Instead of 14 percent drivers in other ride-sharing as women, we want 99 percent drivers on our side as women.
ENWEMEKA: Gilani says safety is the company's priority. Safr conducts numerous background checks and meets face to face with every driver. Uber and Lyft say they also use their technology to ensure the safety of both passengers and drivers. Their new competitor, Safr, plans to expand beyond Boston to other cities and hopes to go global, too. For NPR News, I'm Zeninjor Enwemeka in Boston.
(SOUNDBITE OF WATER FAI'S "TO THE GREEN TOWN")
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The Definitive Guide To Saying Hello To (Almost) Everyone
Handshakes, fist bumps, high fives and kisses. Our guide to greetings and small talk in different countries.
The handshake has never been simple. It was, after all, born of mistrust; an overt demonstration that one is unarmed. Nowadays the main concern isn’t whether your counterpart is packin’ - it’s whether you’re going to meet his or her hand at the right pace, trajectory and with due firmness.
Hand-wringing experts have detonated a cluster bomb of categories from the teacup to the bone crusher to the politician. Each of these categories gives way to a cascade of personality traits, an understanding of which could reduce the average duration of a job interview to a mere five seconds. Teacuppers, for example, are conniving little devils that avoid palm-to-palm contact by cupping their hands. They are not to be trusted. Bone crushers are out to intimidate you in a macho display of a weak ego. The politician will enact a sleight, swift move of his second hand to cover yours. He’s trying to win you over with false sincerity. Don’t vote for him.
And these categorizations are just in the English speaking world. In Morocco and Turkey, a gentle shake is much preferred to the stout, assuring, firm handshake favored in the US. And one shouldn’t be too quick about it either. Let the hand linger. Unless you’re in France, of course, in which case shake quickly and lightly.
But how true is all of this? Globalization irons out the creases of cultural idiosyncrasy and the humble handshake is by no means immune. It’s now more likely that a twenty-something German male will greet a twenty-something French male on the streets of Berlin with an Obama-approved fist bump, and depart with a wide five, arms outstretched and swooping to meet in a fleeting clasp in the middle.
But what would happen if our twenty-something German male were to meet a sixty-something Italian at a formal business lunch? Would they fist bump? Most probably not. These variants of the handshake are copied and choreographed in order to impute familiarity, whether authentic or not. Judging the formality of a situation, and thereby the kind of greeting one should give and may receive, is becoming ever more complex. Add layers of intercultural complexity and we enter a minefield of explosive etiquette. Would you know how to greet a Spanish girl, or a Bulgarian senior, or a German native to Hamburg? And would your natural topics of small talk be met with enthusiasm or bemusement? What happens when different cultures of small talk collide? Let’s take a whistlestop tour of a few cultural norms of which you should be aware.
A few weeks after moving to Spain, I had my first experience as a lone foreigner in a multitude of Spanish speakers. I was listening attentively, trying to decipher sentences and contributing with clumsy, slapstick self-deprecation. Three girls arrived and, on being introduced, I remained nonchalantly in my wicker chair. Never had I been so reprimanded by someone I had known so briefly. Like drill sergeants whose authority had been questioned, they ordered me to stand and bestow a kiss on either cheek. A formality can be so much more than just a formality if it isn’t fulfilled.
In Spain men and women greet others with two kisses, delivered from left to right, often taking hold of a shoulder while doing so. Shaking hands isn’t something the Spanish are keen on – “you might be contagious!”
The weather and fútbol are considered small talk staples, but I found the most common intro when unexpectedly encountering an acquaintance in the street was, ¿a dónde vas? - where are you going? An achingly simple, slightly interrogatory opener that launches one into moderately more purposeful small talk. It’s worth noting that there are some significant variations across Spanish speaking countries when it comes to greetings. In the Dominican Republic, for example, men greet each other with a fist bump. This is accompanied by a ¿Qué dicen?, to which one responds to ta bien.
When I rolled up in Perugia at the beginning of this year to study Italian, I was bursting with confidence. I’d been studying avidly on the train down from Munich, and half the words seemed virtually identical to their Spanish counterparts. This was going to be easy. I ventured out onto the streets on the first evening and started headbutting the locals. You heard me. Headbutting.
“Ciao” reigns supreme in Italy. Regardless whether you meet someone during the day, night, or whether you’re saying hello or goodbye (one-word-fluency!). However, make sure you respect the distinction between the formal and informal ways to greet and address.
What had they done to deserve such persecution? After two years of diligently delivering two kisses from left to right in Spain, the Italians had the temerity to greet me with kisses from the right to the left. Reprogramming one’s mind to accommodate for this is tantamount to driving on the wrong side of the road - it takes a few scrapes and near misses before it becomes second nature. If you’re a creature of habit, stick to holidays in Bulgaria - they also kiss from left to right, although they have the odd custom of using different languages for simple exchanges; the Italian ciao to say goodbye and the French merci for thank you, for example.
German is an angry, harsh, jagged language born from the vocal chords of angsty Barbarians after a winter deprived of sausages and Glühwein, right? It’s a stereotype that is promptly obliterated when you first bump into a friend who greets you with a short na? delivered on a cushion of velvet charm. Learn the word, for there is a world in this grain of sand; how are you? … it’s nice to see you … what’s up? … everything ok? … tell me what you’ve been up to … Despite this web of meaning, or perhaps because of it, the most common response is … na? … with just a little more inflexion. The unabashedly, adorably camp tchüssi is challenged only by the Dutchdoei doei for the most saccharine goodbye in Europe.
Greetings often depend on where exactly you are in Germany. In the north you’ll be greeted with a moin moin while in the south you may be on the receiving end of a servus. A hallo or a guten Tag will get you started everywhere, however.
Young people often greet one another with a hug, but in large groups a simple nod of the head and a hallo zusammen (hello together) suffices. Interestingly, greetings remain stubbornly conventional within traditional companies with employees greeting one another formally with a firm shake of the hand and addressing one another by title and surname; guten Tag Herr Wowereit. I once taught English in a cigarette factory just outside Hannover and broke the record for hands shaken within two minutes. No adjudicators were present.
In Austria one greets with a servus, and they’re very attentive to titles, so pay attention, Doctor Doe. Women often say hello with two kisses, one on each cheek and always starting on the right and then moving to the left (they border Italy, after all). Men will normally shake hands.
In France people greet with a bonjour or the more informal salut. And if you thought the formalities of kissing were somewhat novel, be prepared for the bise, planting up to four kisses on the cheeks of the French. The number is dependent upon region, so you’ll need to brush up on some local knowledge before mingling with the haute société. Pay strict attention to the formal vous form for older people and strangers. Incidentally, Brazilians haven’t agreed on the number of kisses either, but numbers vary less dramatically between one and three. Further to the well-known tudo bem?, greetings include the joyously concise oi and e ai. Romanians, like their Bulgarian neighbors, sometimes add a touch of continental flair to their informal greetings with a salut! salut! or a servus for hello.
Are we giving the kiss too much lip service? Then you’ll be glad for the Swedes and the Greeks. These two nationalities often go in for the back pat-slap-clap. The Greeks use it as a follow-up to two kisses, while it’s the successor to a short handshake or hug for the Swedes.
If all of the above greetings are too touchy-feely for you, you’ll find respite in Japan where the standard gesture is a reverential bow. No physical contact required. If a handshake does occur, make sure to still lower your gaze as a sign of respect to the other person. Small talk can be about anything, but make sure to save it until after work.
In Sweden one greets with a hej or a longer heeeeej if you’re particularly pleased to see whoever has just entered audible territory. And then you speak about the weather and Eurovision.
And so it would seem that even faced with the normalizing powers of globalization, there is no such thing as a simple hello. The dissolution of distinct gradations of formality where certain behaviors are prudent is a common trend, but knowing each country’s etiquette is the first step to navigating this little gauntlet of intercultural communication.
Connect with Babbel
Ed M. Wood is originally from Wells, the smallest city in England, and now lives in Berlin. He studied Psychology at the University of Southampton before working as a teacher and translator in Spain, England and Germany. He then undertook a MA in Political Science in Bath, Berlin and Madrid. His main interests lie in the areas of language, culture and travel, and it is these three things which ultimately led him to Babbel towers, where he currently resides. Follow him on Twitter. |
Antagonistic effect of sodium ascorbate on ethanol-induced changes in swimming of mice.
Swimming behavior in the mouse was used to study the motor disturbances induced by alcohol, and the effects of vitamin C upon these disturbances were assessed. High doses of vitamin C (125 and 500 mg/kg) prevented any swimming impairment due to ethanol; however, lower doses of vitamin C (62.5 mg/kg) had no significant effect. When given 1 h before alcohol, the protective effect of vitamin C was reduced. The alcohol-induced intoxication lasted beyond alcohol's elimination from the blood, suggesting that the intoxication is maintained by a metabolite of ethanol or by an effect of ethanol, or a metabolite, on another metabolic system. |
Challow Hurdle Preview and Tips
With such an aray of top class racing coming from Kempton, Leopardstown and Chepstow; Newbury is unfortunately overlooked by many over the festive period. This is an obvious shame as they host the Challow Hurdle, a top quality Grade 1 race with the likes of Denman and Reve De Sivola winning the event in the year’s gone by. Always influential for the Cheltenham novice hurdle races here are my thoughts on the likliest winner!
This year’s contest looks like being run on desperate ground and will suit the future staying chasing types in the field. KAKI DE LA PREE(15/2 BetVictor) fits the bill well having shown that stamina is his forte when comfortably on top at the finish over an extended three miles at Carlisle. That handicap win was impressive as it came off a mark of 127 and twenty lengths separated the runner up and the third. Tom Symond’s exciting six year-old began the season when only going down by a length to Kings Palace who has been mightily impressive twice since. The step down in trip is probably not in Kaki De La Pree's favour but he has already shown his ability to handle plenty of cut and his stamina could prove very useful here.
Timesremembered(3/1 Betfred) is another proven on soft ground, winning a Grade 2 race at Chepstow. He was never quite able to reel in Creepy at Cheltenham last time but has a seven pound pull for just a length beating and the ground may have been a little quicker than ideal for him there. Creepy(11/2 Stan James) has shown improvement on good ground this season and while this trip looks ideal, the ground looks a definite concern.
Oscar Rock(5/2 BetVictor) has shown a liking to ground with plenty of cut and looks more likely to give his running in these conditions.
Nicky Henderson has an interesting hand with Captain Cutter(8/1 Stan James). This horse has a bit to find with a few of these on official ratings over hurdles having won two weak novices at prohibitive odds, but his debut win last December over Kings Palace is very strong form.
Shantou Magic(11/2 BetVictor) is an interesting contender for Charlie Longsdon. Both of his hurdle wins have been on soft ground; firstly at Fontwell when eased down to beat a half decent field with a number of runners rated in the early 120's. He followed that up at Market Rasen with another facile success. The third that day beaten 19 lengths in receipt of 7lbs is now rated 110, both bits of form would give him a massive chance here.
A case can be made for all 6 runners in what looks an ultra competitive renewal. I marginally prefer KAKI DE LA PREE over Timesremembered and Shantou Magic as I believe his proven extra stamina is going to be vital in these conditions. Whatever the result, it's a race to keep in mind for the rest of the season and beyond, as this group of horses are going to be winning an awful lot more races between them. |
Today we finish analyzing Rich’s hypothetical root beer business with Porter’s Five Forces Model.Yesterday we examined the impact of industry competitors, suppliers, and buyers.
#4—Substitutes
This category deals with the threat of substitute products or services.
Q: Is there a feature of your root beer that will compel consumers to drink yours over other soft drinks?
A: GRB includes vitamins and minerals, and tastes great! (+)
Q: Can your customers drink something other than root beer?
A: Yes. There are gallons of other options. (-)
Although this seems to even out, it’s not quite as cut-and-dried as that. The truth is there are thousands of substitutes for your product: other root beer, other soda, juice, milk, water, or even nothing at all. Because of the weight of this negative aspect, the overall score for this force is negative as well. (-)
#5—Potential Entrants
How difficult is it to enter the space? Do you have an advantage over the competition? Once in, how do you plan to keep others out? Of all the factors to consider, this is the most important. I call it “Barriers to Entry.” Also, when I draw the model I include another box: “Channel.” I always pay particular attention to the power of the distribution channel, or lack thereof. The following questions will help you understand the concept more fully.
Q: Can anyone make root beer?
A: Yes.
Q: How expensive is it for someone else to enter the GRB space?
A: Not expensive at all. (-)
Q: Is it expensive for your buyers to switch from GRB to another brand?
A: No. The store just has to clear the shelf and replace my brand with my competitors’ product. (-)
Q: Do you have access to an established distribution channel?
A: Yes, I have an exclusive agreement with all distribution channels in my target region. In fact, my brother-in-law controls the beverage distribution for all the food chains in my area. (+)
The overall score for this force is a negative. (-) But you must take into consideration your exclusive channel agreement. The power of this positive may be enough to convince you to enter anyway.
On your whiteboard diagram, write a “+” next to Potential Entrants.
Tallying up the overall scores, we come up with a grand score of 2 positive, 3 negative. Do these results mean you should avoid the venture? Not necessarily. The information you’ve gained from this exercise is a valuable assessment of the competitive landscape–you know where you are vulnerable, where you need to apply focus, and what your strengths are. You now have a wide variety of things to consider. Perhaps your assessment ended up all negatives except for one area: but if that one area is powerful enough, your idea may still be worth the effort!
I have colleagues who have made millions on a venture that scored all negatives. They had to work very hard and very long before they were able to make a profit, but they did it! If you look at your whiteboard and see a plethora of pluses scattered across the boxes, it’s indicative of a wave! It will be easier and faster to get the venture up and running. Conversely, the more negatives you have, the more time it will take to make a profit.
Porter’s Points – The Five Forces Model
The Five Forces Model is fast. Use it during your idea stage to test what you plan.
Just because an idea scores mostly negatives doesn’t make it a bad idea. Negatives mean you will have to work harder, smarter, and longer. Decide if you are up to it; if not, test some other ideas to find a wave.
Use the Five Forces Model with the Competitive Matrix in the next section to really get a grip on your market and make plans for success.
Now that you know how powerful, yet simple, this model is, try using it to analyze your own business idea. |
Influenza epidemics and pandemics continue to claim human lives and impact the global economy. In the United States alone, influenza causes an estimated 50,000 deaths annually (Thompson et al., 2003), while global pandemics can result in millions of influenza-related deaths. A classic example is the so-called ‘Spanish influenza’, which killed an estimated 40-50 million people worldwide in 1918-1919 (Potter, 1998). The threat imposed by influenza virus has been further elevated with the recent introductions of avian influenza viruses into the human population. Avian influenza viruses were long thought not to be directly transmissible to humans and cause lethal outcomes. However, this perception changed in 1997, when 18 Hong Kong residents were infected by a wholly avian influenza virus of the H5N1 subtype, that resulted in 6 deaths (Subbarao et al., 1998; Claas et al., 1998). Over the next few years, several other cases of direct avian-to-human transmission were reported (Peiris et al., 2004; Fouchier et al., 2004; Koopsman et al., 2004), including the ongoing outbreak of highly pathogenic H5N1 influenza viruses in several Asian countries that has claimed 41 lives of 54 infected individuals as of Jan. 26, 2005 (WHO, 2004). The increasing numbers of human H5N1 virus infections, together with a high mortality rate and possible human-to-human transmission, make the development of vaccines to these viruses essential.
In the United States, two influenza vaccines are licensed for human use: an inactivated vaccine and a live attenuated vaccine virus. The production of influenza virus vaccines relies on reassortment (Gerdil, 2003), which requires coinfection of cells with a circulating wild-type strain that provides the hemagglutinin (HA) and neuraminidase (NA) segments and either A/PR/8/34 (PR8) virus (an attenuated human virus that provides high-growth properties in eggs) or a live attenuated virus that provides the attenuated phenotype. The selection of the desired “6+2” reassortants (i.e., those containing the HA and NA gene segments of the circulating wild-type strain in the genetic background of PR8 or live attenuated virus) is time-consuming and cumbersome. Moreover, the need for reassortment and selection, as well as the inability of some reassortant viruses to grow to high titers, have resulted in delays in vaccine production.
The artificial generation of influenza A and B viruses entirely from cloned cDNA in plasmid-transfected cells, the so-called “plasmid-based reverse genetics system” (Fodor et al., 1999; Neumann et al., 1999; Neumann et al., 2004; Neumann et al., 2002; Neumann et al., 1999; Hoffmann et al., 2002; Fodor et al., 1999; Hoffmann et al., 2000), represents an important advance for influenza virology. This technology has advanced both basic and applied research of influenza virus; most notably, the development of vaccine seed strains for highly pathogenic influenza viruses, including the currently circulating H5N1 viruses (Horimoto et al., 2006; Subbarao et al., 2003; Takada et al., 1999; Webby et al., 2004; Wood et al., 2004).
In one system (Neumann et al., 1999), eight plasmids encoding the eight influenza viral RNA segments under the control of the RNA polymerase I (PolI) promoter and terminator sequences are transfected into eukaryotic cells together with four RNA polymerase II (PolII)-driven plasmids for the expression of the three viral polymerase subunits and the nucleoprotein NP; these four proteins are required to initiate viral replication and transcription. An alternative system has been developed (Hoffmann et al., 2000) that relies on eight plasmids in which the viral cDNAs are flanked by an RNA polymerase I promoter on one site and an RNA polymerase II promoter on the other site, which permits the vRNA and mRNA to be derived from the same template. These systems have allowed 6+2 reassortants to be engineered without the need for reassortment and screening procedures.
Since at least eight plasmids have to be transfected into a single cell for virus generation, the limiting factor for plasmid-based reverse genetics is the transfection efficiency of the cells. In general, 293T cells, which are readily transfected with plasmids (Goto et al., 1997), have been used for plasmid-based systems (Hoffmann et al., 2000; Neumann et al., 1999). However, 293T cells cannot be used for the development of human vaccine seed strains because they are not validated for such use. African green monkey kidney (Vero) cells, which have been used for the production of rabies and polio virus vaccines (Montagnon et al., 1999), are the WHO-recommended cell line for vaccine production (Wood et al., 2004). Although these cells are not readily transfected (Kistner et al., 1998; Kistner et al., 1999a; Kistner et al., 1999b; Bruhl et al., 2000), the generation of influenza virus in Vero cells has been demonstrated (Fodor et al., 1999; Nicolson et al., 2005). Madin-Darby canine kidney (MDCK) cells (Brands et al., 1999; Palache et al., 1999; Halperin et al., 2002) are available for the production of influenza virus vaccine cells, but the cell line cannot be transfected with high efficiencies. It is, therefore, difficult to efficiently generate influenza viruses by using plasmid-based systems in influenza virus vaccine cells. |
NORWICH are closing in on Cuban-born German winger Onel Hernandez.
The Canaries, who sold Alex Pritchard to Huddersfield for £11.9million, have made a £1.7m offer to Eintracht Braunschweig.
3 Onel Hernandez is set to join Norwich City for £1.7million Credit: Getty - Contributor
Hernandez, 24, moved to Germany aged six and has played for Werder Bremen.
He also featured in a Wolfsburg’s second teams before joining Braunschweig in Germany’s second division in 2016.
Wolves and Huddersfield have previously watched Hernandez, who is keen to try English football.
Both reportedly made offers in the summer.
3 The German winger previously interested Huddersfield and Wolves Credit: Getty - Contributor
3 Now Hernandez could solve a long-term Norwich problem on the flanks Credit: Getty - Contributor
Boss Daniel Farke has had issues out wide so far with Norwich.
Josh Murphy started well but has hit a run of bad form, and Marley Watkins has struggled to make an impact since joining from Barnsley.
Yanic Wildschut has also struggled to get into the team.
Hernandez would add pace and strength out wide for Norwich, something that has been noticeably lacking so far this season.
Chelsea 1-1 Norwich AET (5-3 on Pens): Blues pull through tough test from the Canaries to win on penalties
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Despite this likely arrival, Norwich still expect to keep hold of star man James Maddison.
Marcus Edwards has also arrived on loan from Spurs. |
Zune exec bails ahead of player's upcoming HD launch
Knowing when to iTune out
Chris Stephenson is understood to be leaving the software giant to join Universal Music Group.
According to the Wall Street Journal, Stephenson has turned his back on MS, whose Zune execs are undergoing a tough time following an appalling 54 per cent drop in sales of the music player.
Microsoft confirmed in January that $100m had been cut from revenues in the last quarter of 2008, with sales of $85m compared to the same period in 2007, when Redmond notched up $185m for its Zune hardware.
The Zune team is also rejigging how it punts the business, by shifting its focus from the device to the service Microsoft can offer. It is understood to be considering making Zune available on a range of devices, including its own Windows mobile phones.
According to WSJ, Stephenson’s final day at Microsoft is 4 September. Three days later he will rock up at Universal-owned record label Interscope Geffen A&M Records, where he will take on the role of chief marketing officer.
The British-born exec joined Microsoft in 2006 as the company’s media biz boss. He previously held down roles at Jaguar, Ministry of Sound and MTV. ® |
#pragma once
#include <memory>
#include <vector>
#include "optimizer/operator_node_contents.h"
namespace terrier::optimizer {
/**
* Class defining a Pattern used for binding
*/
class Pattern {
public:
/**
* Creates a new pattern
* @param op Operator that node should match
*/
explicit Pattern(OpType op) : type_(op) {}
/**
* Destructor. Deletes all children
*/
~Pattern() {
for (auto child : children_) {
delete child;
}
}
/**
* Adds a child to the pattern.
* Memory control of child passes to this pattern.
*
* @param child Pointer to child
*/
void AddChild(Pattern *child) { children_.push_back(child); }
/**
* Gets a vector of the children
* @returns managed children of the pattern node
*/
const std::vector<Pattern *> &Children() const { return children_; }
/**
* Gets number of children
* @returns number of children
*/
size_t GetChildPatternsSize() const { return children_.size(); }
/**
* Gets the operator this Pattern supposed to represent
* @returns OpType that Pattern matches against
*/
OpType Type() const { return type_; }
private:
/**
* Target Node Type
*/
OpType type_;
/**
* Pattern Children
*/
std::vector<Pattern *> children_;
};
} // namespace terrier::optimizer
|
Longitudinal studies of immunological parameters in Farmer's lung.
A group of patients with serum precipitins against M. faeni culture filtrate antigens and with clinically proven farmer's lung disease was examined. A group of precipitin-negative farmers with comparable antigen exposure and with unrelated forms of pulmonary disease served as control. Immunoglobulins G and A were elevated at first consultation in the majority of the acute cases of farmer's lung. Immunological parameters normalized during corticosteroid medication and antigen avoidance. Autologous complement (C) consumption by M. Faeni antigens proved valuable for diagnostic purposes. Despite normalizing immunological factors and subsiding symptomatology, C-consuming antibody levels remained constant. |
Analytical and clinical performance of a new point of care LABGEOIB D-dimer test for diagnosis of venous thromboembolism.
LABGEO(IB) D-dimer Test is a newly developed POC D-dimer assay and the first commercially available POC immunoassay instrument that exploits the disk rotation method for extraction of plasma. Citrate plasma was obtained from 201 apparently healthy subjects and 91 patients suspected for VTE, and their D-dimer level was measured by the LABGEO(IB) D-Dimer Test (LABGEO D-dimer) and HemosIL D-dimer test as a comparative method. To examine the effect of blood cells and anticoagulant, paired blood samples anticoagulated by heparin and citrate were obtained from various postoperative patients. The overall diagnostic performance of LABGEO(IB) D-dimer and HemosIL was comparable with similar area under ROC curve (p=0.79). The cut-off levels recommended by manufacturers (LABGEO D-dimer: 0.45 μg/ml fibrinogen equivalent unit (FEU), HemosIL: 0.23 μg/ml D-dimer unit (DDU)) and those yielding highest diagnostic efficiency (LABGEO D-dimer: 1.41 μg/ml FEU; HemosIL: 0.85 μg/ml DDU), were chosen for the evaluation. For LABGEO D-dimer negative predictive value (NPV), positive predictive value (PPV), sensitivity, specificity, and negative likelihood ratio (LR-neg) were 93-100%, 67-89%, 93-100%, 53-89% and 0.00-0.08. For HemosIL D-dimer, NPV, PPV, sensitivity, specificity and LR-neg were 90 - 100%, 76-95%, 89-100%, 70-96% and 0.00-0.12, all comparable to results for LABGEO D-dimer. LABGEO D-dimer test demonstrated acceptable performance when used for the VTE diagnostic work-up. |
Q:
applescript Calculator not working
I have made a calculator which should work but doesn't. The only part that works is the addition. this is my code:
my Calculator()
on Calculator()
display dialog "Calculator" buttons {"Add", "Multiply", "Divide"}
if button returned of the result is "Add" then
display dialog "What plus What?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a + b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
end if
if button returned of the result is "Multiply" then
display dialog "What times what?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a * b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
end if
if button returned of the result is "Divide" then
display dialog "What divided by what?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a / b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
end if
end Calculator
end
end
it is an applescript code. I'm sorry if it is a nooby question but I need help. Thanks!
A:
You are using three if/end if statements to process the button returned, you should only use a single if/end, and utilize else if in between. I have edited your code to fix it, and commented out the incorrect regions.
e.g.:
my Calculator()
on Calculator()
display dialog "Calculator" buttons {"Add", "Multiply", "Divide"}
if button returned of the result is "Add" then
display dialog "What plus What?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a + b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
else if button returned of the result is "Multiply" then
display dialog "What times what?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a * b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
else if button returned of the result is "Divide" then
display dialog "What divided by what?" default answer ""
set a to (text returned of result)
if a is equal to "q" then
return
end if
display dialog "Next number" default answer ""
set b to (text returned of result)
set c to a / b
display dialog "The answer is " & c buttons {"Start Again", "Quit"}
if button returned of the result is "Quit" then
return
else
my Calculator()
end if
end if
end Calculator
end
end
|
Private home on 2+ acres in the Pine Mountain Estates with gated driveway and sweeping views of Willits Valley. House features just over 4300 square feet of living space that consists of 5 bedrooms, 4 full baths and 2 half baths, sun room, in-ground pool and much more. Kitchen is upgraded with granite counter tops, sub-zero fridge and limestone floors. Attached 2-car garage plus a separate oversized 2+ car garage/shop on bottom of property.
Horse? Of course! You'll adore this perfectly charming vintage farmhouse on 4+/- acres. Enjoy the cozy fireplace and original wood floors. 3 bedrooms, 1 and a 1/2 bath with den and a rocking chair front porch. 4 stall barn and flat pasture right in town. Plenty of parking for those great family BBQ's with your above ground pool and play area for the kids. Relax on the porch or nap in the hammock in a perfectly groomed yard. City water and well.
This is a very hard-to-find property for recreation or ranchette. Close to town with good access. Small pond. Lots of fir, pine, oak and madrone trees. Rock pit. Very private, secluded property with great valley views.
Wonderful 4.5 +/- acre ranch property. Bring your horses, chickens and even the in-laws! Live comfortably in the spacious main home and use the detached apartment as a guest retreat or rental....there are so many possibilities! Main house has 2 bedrooms, 2.5 baths, beautiful sunken living room with fireplace and deck to enjoy the summer evenings. Amenities include detached garage, barn, round-pen, chicken coop and much more.
Beautiful artistic 3 bedroom 3 bath home with solar power located on approximately 25.5 acres. The kitchen is tastefully done with concrete and slate counters. Eye catching detailed use of wood and tile throughout home. Plenty of room on the property to build a 2nd unit. The property has a spring and a well with plenty of storage tanks. Enjoy hiking around the seasonal creek or just kick back and relax to the sound of nature.
This golden opportunity won't last long! 20 private, gentle acres. 15 minutes from town and 5 minutes from elementary school. Mix of forest and meadow. Spring with pump, 2 holding tanks, 2 ponds. Building pad with partial foundation and breathtaking views. Small residence on slab foundation with solar, propane and phone to live in while you build. Power at property line. Gated with coded entry. Surveyed with property corners. OMC with 30% down
Move right in and put your feet up and take in the awesome views or go outside and enjoy the Zen Garden with a beautiful Koi pond. This 3 bedroom, 2 bath home boasts open open beam pine ceilings, tile flooring with passive solar in living room area. There is a detached workshop for an additional get away spot. |
Q:
Is it possible to find if the connection has been established in active mq in c#
Here is my code
private Connection _connection;
private ISession _session;
private const String QUEUE_DESTINATION = "DotNet.ActiveMQ.Test.Topic";
ConnectionFactory factory;
Transpo
public void TestInitialize()
{
factory = new ConnectionFactory("tcp://localhost:61616");
_connection = factory.CreateConnection("system", "manager") as Connection;
bool x=_connection.TransportFailed;
_connection.ClientId = "LFV";//Exception when connection not estab
_connection.Start();//Exception when connection not estab
_session = _connection.CreateSession();
}
I get an exception at _connection.ClientId and _connection.Start. Is there any way i can avoid this exception by finding if the connection has been established or not before calling the start method and assigning the client ID.
A:
If you're not setting a unique client ID then the exception would be expected as only one client can be connected to the broker for any given client Id. If you fix your code such that each client app has it's own unique client Id then the problem should resolve itself. You can of course also set an exception listener on the Connection to get notified of errors.
There is no way to test the connection as it's waiting for you to either set a ClientId or start the connection in order to behave as a JMS client. The actual connection handshake doesn't happen until the start call or any call that would require a fully established connection such as createSession etc. You should code you application to respond to failures from connection start.
Oh and FYI, setting client ID after calling start will have no effect as it is only allowed prior to the start of the Connection.
|
AVENTURA, Fla. — Sen. Amy Klobuchar, D-Minn., a member of the Senate Agriculture Committee, could provide a strong challenge to President Donald Trump in the key Midwestern states that a Democrat needs to win in order to win the presidency, a prominent political analyst told agribusiness executives here today at the International Sweetener Colloquium.
David Wasserman of The Cook Political Report said he had been impressed with Klobuchar’s performance on a CNN Town Hall, and that she could appeal to voters in Wisconsin, Michigan and Pennsylvania. Klobuchar recently announced she is running for the Democratic nomination.
Trump won those three states by a combined total of 78,000 votes. They delivered the presidency to him even though former Secretary of State Hillary Clinton, the Democratic nominee, won the national popular vote.
Wasserman praised Klobuchar’s potential in comparison with candidates he considers frontrunners: former Vice President Joe Biden, Sen. Bernie Sanders, I-Vt., Sen. Elizabeth Warren, D-Mass., and Sen. Kamala Harris, D-Calif.
Wasserman noted that Biden and Sanders are both elderly. Warren’s problems with past declarations that she is part American Indian and her long history as a professor at Harvard Law School will not play well in the Midwest, he said, and Harris spoke in “platitudes” during her CNN Town Hall appearance.
Sen. Kirsten Gillibrand, D-N.Y., and Sen. Cory Booker, D-N.J., are more long-shot candidates, he said.
Wasserman acknowledged that Klobuchar had gotten negative coverage over the issue of how she treat her staff, but said she can turn the issue to her advantage if she “owns” it, and also that it has gotten her more press attention.
To confront Trump, Wasserman said, voters would rather have a candidate who pushes her staff hard. (On CNN, Klobuchar said she has been a demanding boss.)
Wasserman, who specializes in House races for the Cook Report, is a popular speaker among farm groups, devoted most of his speech to an analysis of the 2018 midterm elections and the political relationship between urban and rural America.
He said Republicans lost the House in 2018 because Trump did not attempt to broaden his appeal beyond the 46 percent of Americans who voted for him. Trump could have broadened his base by convincing Congress to pass infrastructure and comprehensive immigration bills, he said.
“As a result of catering to the 46 percent, Trump’s approval rating has been 39 to 41 percent, and he lost control of the House,” Wasserman said.
The turnout in the 2018 elections was “historic,” he noted, the highest percentage in 104 years. Usually 40 percent of the people who vote in the presidential election do not turn out for the midterms, but the fall off in 2018 was only 15 percent because voters were so strongly motivated, he said.
The main issue in the election, Waserman said, was not the Russia investigation or Trump, but opposition to the Republican attempt to overturn the Affordable Care Act, particularly the provision that would end mandatory coverage for pre-existing conditions.
The Democrats won 40 House seats that had been held by Republicans and might have won even more and done better in Senate races if the controversy over the Supreme Court nomination of Brett Kavanaugh close to Election Day had not motivated Republican voters, he added.
Wasserman stressed that the gap between urban and suburban voters, on one hand, and rural and small town voters on the other, has never been so great. He noted that voters in northern small towns and rural areas are voting more Republican like the South, but that voters in the southern suburbs “are beginning to vote like northern ones,” which vote Democratic.
Democratic women did so well in the House races that he has concluded “the best way to send a message against Donald Trump is to send a woman,” he said.
Wasserman noted he had tweeted on Dec. 9 that there are now huge gaps in the types of people and areas that Republicans and Democrats represent.
The Senate Republican majority represents only 18 percent of the American people, he said. Democrats have the majority in the House, but represent only 20 percent of the land area of the United States. (See link)
Wasserman, whose prominence is due partly to an article he wrote two months before the election in 2016 titled “How Trump Could Win the White House While Losing the Popular Vote,” said he sees a pathway for Trump to win in 2020, but that there are too many wild cards to predict the outcome of the race at this time.
The number of Democratic candidates running for the nomination for president is so large that the Democrats could end up with a brokered convention, he said.
But one critic that Trump won’t have to worry about running against him is Rep. Alexandria Ocasio-Cortez, D-N.Y., who has become famous as the youngest woman ever elected to the House. Ocasio-Cortez, born in 1989, will be too young to run in 2020 and “barely eligible” in 2024 to meet the Constitutional requirement that American presidents be 35 years old, Wasserman noted. |
The present invention relates generally to desks and desking systems.
A conventional desk for supporting a computer includes a main desktop, various drawers and cupboards, and possibly one or more drawers and/or stands for supporting a computer keyboard and/or viewing screen (VDU). Some computer desks also include a drawer, rack or stand for the central processing unit (CPU) chassis, to position the CPU toward the rear of the desk or beside a desk leg, rather than on the desktop or the floor beside or beneath the desk. Typically, a VDU, a mouse, and often the keyboard are positioned on top of the main desktop, and often one or more peripheral devices are also placed on top of the desktop.
In an environment including several computer desks, for example, in an office of networked computers, each desk is typically separate from the others and the power and electronics cabling is supplied to each desk individually from power and cable connection points on the floor or walls. In an education institution, for example, classrooms are set up with one or more rows of desks, each desk carrying one or more respective computers, and desks are often placed side-by-side, or otherwise adjacent one another.
Convention computer desks (or environments including several computer desks, e.g., offices, classrooms) require: (i) power cabling to a computer processor and various computer peripheral devices (e.g., VDU, keyboard, mouse, printer, scanner); (ii) cabling between the processor and peripheral devices, and between various peripheral devices; (iii) a telephone connection for Internet access; and (iv) in some cases, network cabling connecting two or more computers to each other and to other devices. Systems for handling these cables include tying them together with plastic cable ties, string, or plastic “Cable Zip” tubes, taping the cabling to the floor, placing the cabling under rubber cable protectors that form ridges on top of the floor, or placing the cabling in trunking under the floor.
Conventional computer desks are not made to connect to one another. In environments including several computer desks, they are generally simply placed side by side, and can be moved about, or they are tied together using a crude system such as cable ties, which typically still allow some movement. Existing desking systems are not designed to provide a flexible arrangement of desk placement when one or more desks are connected together in some fashion. |
Purification and characterization of a heat-stable wheat substrate for wheat embryo calcium-dependent protein kinase.
A heat-stable wheat protein (WP) that is a good substrate for wheat embryo Ca(2+)-dependent protein kinase (CDPK) was purified from wheat embryo by a procedure involving batchwise anion exchange chromatography on DEAE-cellulose (DE52), passage through Phenyl-Sepharose CL-4B, heat and acid treatment and anion exchange HPLC on a DEAE-5PW column. WP is phosphorylated by CDPK to a stoichiometry of about 0.8 mol phosphoryl per mol WP. The Km for WP is 3.5 microM. WP is phosphorylated by CDPK on Ser residues. [32P]phosphoWP exactly copurifies on SDS-PAGE with WP (59 kDa). Phosphorylation of WP by CDPK is largely Ca(2+)-dependent. The N-terminal amino acid sequence of WP has homology with bacterial azurins. Evidence for two serine phosphorylation sites was obtained from sequencing of phosphopeptides derived from tryptic and chymotryptic digests of phosphoWP. One major site of phosphorylation is inferred to be on a serine within the sequence KKMASMK. WP is one of the best endogenous protein substrates yet found for wheat embryo CDPK. A 59kDa protein is phosphorylated in vivo in sprouting wheat. |
-68 + 142. Let d = r - s. What is the remainder when d is divided by 16?
14
Suppose 0 = -5*c + l + 24, -3*l = 4*c + 2 - 6. Let p(g) = -g**3 - 15*g**2 + 7. What is the remainder when p(-15) is divided by c?
3
Suppose -4*n + 3*y + 28 = 0, -5*y - 28 = 5*n - 7*n. Let t = 13 - 11. Suppose 0 = -2*i - t*i + n. Calculate the remainder when i is divided by 1.
0
Let p be (-2)/(-7) + 75/7. Let m be 2 + (-2)/2 + -9. Let y = p + m. What is the remainder when 5 is divided by y?
2
Suppose 4*c = 9*c - 40. Let k(p) = -p**2 + 8*p + 5. Let w be k(c). Suppose -35 = -4*t + w. Calculate the remainder when 18 is divided by t.
8
Suppose -2*k - 60 = -6*k. What is the remainder when k is divided by 5?
0
Let j be (0 + -2)/(1/2). Let o(g) = 11*g - 6. Calculate the remainder when o(4) is divided by j/8*(-42 - -2).
18
Suppose 3*d - 5*l = -2*d + 60, 3*d = -l + 24. Let y = -3 + 6. Calculate the remainder when d is divided by y.
0
Let x = 181 - 164. Calculate the remainder when 134 is divided by x.
15
Suppose 0 = 3*s + 4*c - 222, 4*c + 159 = 2*s + 31. Suppose 7*g = 2*g + s. Let p(f) = -f**3 + 4*f**2 + f + 4. What is the remainder when g is divided by p(4)?
6
Let f = 97 + -44. Let l(m) = 1 - m**3 - 2 - 2*m**2 - 3*m**3 - 2*m. Calculate the remainder when f is divided by l(-2).
26
Let r be (-48)/(-10) + 11/55. Suppose -9 = -5*w + 3*t, -2*w + t - r = -3*w. Calculate the remainder when 5 is divided by w.
2
Let h = -159 - -162. Let a = 18 + -10. What is the remainder when a is divided by h?
2
Let h(y) = -8*y + 7. Let x(c) = c**3 - 5*c**2 - 6*c - 6. Let j be x(6). Suppose -3*l + 2*l + 19 = 0. What is the remainder when h(j) is divided by l?
17
Let u = 3 + 9. What is the remainder when u/66 - (-108)/11 is divided by 3?
1
Suppose 2*v - 39 = h + 22, -35 = -v - h. What is the remainder when v is divided by (-4)/(1 - 9)*22?
10
Suppose 3*n - 51 = -3*h, 0*h - 46 = -2*h + n. What is the remainder when 61 is divided by h?
19
Suppose r = -5*r + 126. Calculate the remainder when r is divided by 5.
1
Suppose -48 = 5*g - 188. Let v(a) = a - 2. Let j be v(6). Calculate the remainder when g is divided by ((-10)/j)/(3/(-18)).
13
What is the remainder when (3/(-9))/((-1)/9) is divided by 2?
1
Suppose 7*s - 3*s = 2*d - 20, s - 2 = 0. Let v = 37 + 3. Calculate the remainder when v is divided by d.
12
Let c = 58 + -19. Calculate the remainder when 114 is divided by c.
36
What is the remainder when (1162/(-21))/(6/(-9)) - 3 is divided by 9?
8
Suppose -2*r - 32 = -5*h, 2*r + 4*h = h. Let u(d) = d**3 + 7*d**2 + 4*d + 3. Calculate the remainder when 42 is divided by u(r).
12
Let p = 198 + -119. What is the remainder when p is divided by 5?
4
Let n = -14 - -76. Let q be (-3 - -4) + 0 + 32. Let u = n - q. What is the remainder when u is divided by 10?
9
Let h be (-1)/(-1)*15 - 0. Suppose -4*j = -y - h, 4*j + 3*y - 19 = -0*j. Suppose j*s - 54 = -z, 3*s - s - z = 24. What is the remainder when 25 is divided by s?
12
Let z = -41 - -51. What is the remainder when 37 is divided by z?
7
Let l be ((-15)/(-2))/((-9)/(-24)). Let j = l + -10. Calculate the remainder when j is divided by 3.
1
Let g(z) = 4*z**2 - z + 2. Let x(c) = c**3 + 6*c**2 - 4*c - 6. Let o be x(-6). Let k = 29 - o. What is the remainder when g(-2) is divided by k?
9
Calculate the remainder when (66/4)/((-2)/(-12)) is divided by 17.
14
Let u = 346 - 328. Let o = 147 - 319. Let y = -120 - o. Calculate the remainder when y is divided by u.
16
Suppose 4*j - 37 = -5*l, -5*l - 14 = 3*j - 48. Let q be (j - (0 + 2))/(-1). Let z = 20 - q. Calculate the remainder when 39 is divided by z.
18
Let k(h) = h**2 + h. Let q(g) = -2*g - 1. Let b(x) = x - 7. Let a be b(6). Calculate the remainder when k(-2) is divided by q(a).
0
Suppose -5*o = 25, 0 = -5*n + 4*o - 0*o + 120. Suppose 0 = -5*p - 96 + 386. What is the remainder when p is divided by n?
18
Suppose -f - 2*f = -51. Let h = 41 + 8. What is the remainder when h is divided by f?
15
Suppose 0*k = -3*v + k + 53, -4*k = -16. Let y = 69 - 33. Suppose 0 = d - 3*t - 39, -4*d - 2*t = -178 + y. Calculate the remainder when d is divided by v.
17
Suppose -l + 116 - 37 = 0. Calculate the remainder when l is divided by 20.
19
Suppose -4*r + 2*y = -2*y - 28, 0 = -r + 2*y + 8. Calculate the remainder when 12 is divided by r.
0
Suppose -4*x + 5*h + 2 = 0, 5*h - 9 = -x + 4. Calculate the remainder when 9 is divided by x.
0
Let g(v) = 4*v + 1. Let x be g(7). Let k = x - 44. Calculate the remainder when 546/10 - 6/k is divided by 19.
17
Let b(a) = a + 15. Calculate the remainder when 32 is divided by b(3).
14
Let l = 1 + 16. Calculate the remainder when 44 is divided by l.
10
Let g = 214 + -428. Calculate the remainder when 4/(-14) + g/(-14) is divided by (-6)/4 - 95/(-10).
7
Suppose 2*c - 4*y + 12 = 0, 3*c - 2*y + 3 = -15. Let v = c - -23. What is the remainder when 50 is divided by v?
16
Suppose 0 = 4*q - 2*p - 90, -5*q + 4*p = -4*q - 40. Calculate the remainder when 98 is divided by q.
18
Let r(v) = 2*v**2 + 5*v - 10. Calculate the remainder when 27 is divided by r(-5).
12
Let q = 8 - -1. Let x = 26 - -14. Let b = x - 14. What is the remainder when b is divided by q?
8
What is the remainder when -61*(1 - 8/4) is divided by 8?
5
Let y be (1 - -9)/(2/(-7)). Let h = y + 60. What is the remainder when 73 is divided by h?
23
Let y(q) = q**2 + q - 10. Let l be y(0). Let z = -3 - l. What is the remainder when 12 is divided by z?
5
What is the remainder when 54 is divided by 5*((-87)/(-15) + -3)?
12
What is the remainder when 31 is divided by (-11 + 5)/(-6)*6?
1
Let f = 79 + 89. Calculate the remainder when f is divided by 10.
8
Suppose 0*n = -n + 4. Let s(d) = d**3 + 4*d**2 - 7*d. Let c be s(-5). What is the remainder when 2/4*(c + n) is divided by 4?
3
Suppose -a - 6 = -13. What is the remainder when a is divided by 2?
1
Let d be (-38)/(-14) - (-4)/14. Let h be ((-62)/(-6) - 2)*d. Suppose 0*i = -5*o - 5*i + 25, -i = -4*o + h. Calculate the remainder when 10 is divided by o.
4
Let x(v) = v**3 - 3*v**2 + 4. Let d be x(3). Suppose -5*h = 5*u + 5, 0*u - 16 = d*u. What is the remainder when h is divided by 3?
0
Let f(p) = -p**2 - 3 + p - p**2 + p + p**2. Let z be f(3). Calculate the remainder when 3 is divided by 4/z - (-16)/6.
1
Let o = -29 - -57. What is the remainder when 81 is divided by o?
25
Let h(p) = p + 4. What is the remainder when 8 is divided by h(3)?
1
Let a be (1 - -2)/(9/(-6)). Let k be 0/(-3) - a - 2. Let l = k - -1. Calculate the remainder when 1 is divided by l.
0
Let m = 49 + -26. Calculate the remainder when m is divided by 13.
10
Let y = -27 - -61. What is the remainder when y is divided by 5?
4
Let f(i) = -i + 9. Let l be f(-5). Let w = l - 7. Calculate the remainder when 13 is divided by w.
6
Let g be (-1 + (-15)/(-3))/2. What is the remainder when g/10 - (-208)/10 is divided by 12?
9
Let q(l) be the first derivative of -70*l**2 + 2*l - 1. Let g be q(-2). Calculate the remainder when g/5 + 4/(-10) is divided by 19.
18
Suppose 0 = -2*m + 13 + 9. What is the remainder when 10/(-25) - (414/(-10) - 0) is divided by m?
8
Let d = -20 + 34. Let b = 35 + d. Calculate the remainder when b is divided by 17.
15
Suppose g - 2*g = 0. Suppose k - 6 = -g*k. What is the remainder when 17 is divided by k*((-3)/6 + 2)?
8
Let k = -3 + 12. Let v(g) = -g**3 + 9*g**2 + 7*g - 12. What is the remainder when v(k) is divided by 13?
12
Let b(o) = o**2 - 2*o. Let v be b(-5). Let w be (0 + 4)/(2/1). Suppose -3*z + v = -k, -z + 4*z + w*k = 20. What is the remainder when z is divided by 4?
2
Suppose 60 = -2*j + 7*j - 5*x, j = -2*x + 27. Let l be (3 - 6)/(2/(-6)). What is the remainder when j is divided by 3/l - (-52)/6?
8
Suppose s + u = 2*s, -3*s + 5*u = 0. Suppose s = -3*y - 36 + 117. What is the remainder when y is divided by 6?
3
Let g(s) = s**3 - 6*s**2 - s + 8. Let x be g(6). Calculate the remainder when (3/6)/(x/44) is divided by 4.
3
Suppose 0 = -2*u + 6*u - 124. Calculate the remainder when 122 is divided by u.
29
Suppose 0 = 2*r + c - 32, -5*r + 5*c = -13 - 67. What is the remainder when r is divided by 6?
4
Let n(z) = -4*z + 3. Suppose m = -3*h - 23, -4 = -h + 5*m - 3*m. What is the remainder when n(h) is divided by 7?
6
Let h(m) = 3*m + 3. What is the remainder when 22 is divided by h(2)?
4
Let m(u) = -3 - 3 + 3*u - 43*u. Let |
Spencer and Heidi wedding pictures
The two douchebags known as Spencer Pratt and Heidi Montag finally tied the knot this time. Despite faking a wedding last year, the two made sure this one was legitimate. TMZ reported the couple got a legit marriage license last week.
It is also reported that their Hills costar Lauren Conrad attended the wedding. |
Human immunodeficiency virus infection in emergency department patients. Epidemiology, clinical presentations, and risk to health care workers: the Johns Hopkins experience.
In a study to assess the impact of the human immunodeficiency virus epidemic on The Johns Hopkins Hospital Emergency Department, we found 152 (6.0%) of 2544 consecutive patients to have human immunodeficiency virus infection, an absolute increase of 0.8% from the previous year. Of the 57 patients with a known history of infection, 49.1% had no insurance vs 36.0% of seronegative patients. Infected patients were three times more likely to be admitted as seronegative patients. Overall, health providers followed universal precautions during 44.0% of interventions. In patients with profuse bleeding, adherence fell to 19.5%. The most common reasons given by providers for not following precautions were insufficient time to put on protective attire and interference with procedural skills. We conclude that the human immunodeficiency virus epidemic has a major impact on emergency services and that strategies need to be developed for appropriate use of emergency resources and also for maximizing provider protection. |
"Tonight we commemorate the crucifixion. Tomorrow we vote and realize the resurrection," Jesse Jackson told a crowd of thousands outside the Capitol in Madison, Wisconsin, gathered on a blustery late afternoon April 4 to remember the assassination of Martin Luther King, Jr., and the April 5 election in Wisconsin.
Sanitation workers who marched with King when he joined their historic strike in Memphis, Tennessee, in April 1968 stood with Jackson on stage, as he linked their struggle to the current struggles of union workers, the poor, and working people all over the nation.
Rank and file union members carried signs saying "I Am a Man" and "I Am a Worker."
Michelle Shocked rocked the crowd, singing spirituals and union songs and was joined on stage by a spontaneous chorus of firefighters with bagpipes, dressed in full Scottish regalia, for "Joy in the Morning."
The bagpipes returned to stand with Jackson as he offered a prayer for King.
After a moment of silence, he said, "We reflect upon the America he found, the America he left, and the dream." He prayed that "men and women in high places with hard hearts will hear our plea. Amen. Bagpipes."
And then the bagpipes played "Amazing Grace," as the crowd joined in, humming.
Jackson reminded everyone that King stood against the "triple evils of racism, militarism, and economic exploitation."
He preached: "Multiracial democracy: that's King democracy. Multicultural democracy: that's king democracy. Stop war and invest in peace: that's King democracy."
"One bullet cannot kill a dream or a movement," he said. "Dr. King is alive today because he lives in us."
He reminded the crowd how democracy and the struggle for economic justice and labor rights were intertwined in King's dream. And then he urged teachers to register their students to vote and lead them to the polls on April 5.
"Come alive April 5!" he got everyone chanting.
The rally, organized by We Are Wisconsin, was the culmination of a day of 30 events around the state and more than 1,000 around the nation to commemorate the 43rd anniversary of King's death and the struggle that continues today.
"Martin Luther King was assassinated on April 4, 1968 while supporting striking AFSCME sanitation workers in Memphis who were fighting for the right to collectively bargain for a better life," Karen Hickey of the Wisconsin AFL-CIO said in a statement. "Yet 43 years later, in Wisconsin and across the country, well-funded, right-wing corporate politicians are trying to take away the rights King gave his life for: the right to collectively bargain, to vote, to afford a college education and justice for all workers, immigrant and native-born. This year to commemorate his sacrifice, Wisconsinites organized throughout the state to revive the King's dream."
Dennis Dattlaff, a respiratory therapist from the UW hospital came in hospital scrubs with a Partnership for Quality Care logo -- a project of SEIU and AFSCME unions. "I'm concerned about care of patients. The way things are going, the more people come into the ER that don't have any insurance, that's going to raise insurance rates for everyone," he said.
Wisconsin history professor Will Jones spoke out about Wisconsin's progressive labor history, and how public employee unions "didn't just fight for their own members," in many cities, as union membership declined, "they were the only advocates for people of color."
Protecting labor rights means protecting the middle class and economic justice, speaker after speaker declared. Despite Walker's divisive appeal to private sector workers who have seen their own benefits decline along with union membership, it is the public sector employee unions he is attacking who are fighting for a decent life for everyone. One woman carried a sign: "Don't like your benefits? Join a union!"
Tuesday's Supreme Court election, which pits corporate-financed, pro-Walker Republican David Prosser against JoAnne Kloppenburg is the next stop in the battle in Wisconsin.
Some teachers across the state, as part of an April 4 day of action, held a massive civics lesson on MLK and labor rights. Teachers at Malcolm Shabazz, an alternative high school in Madison, began registering students to vote after Jackson's last visit, when he came to the school and talked about the civil rights movement and the importance of mobilizing young voters for change.
Madison East High School students, who held a teach-in outside M&I bank before the rally, plan to wear red on election day to show their support for Wisconsin workers.
If you liked this article by Ruth Conniff, the political editor of The Progressive, check out her story "Wisconsin Leads the War on Public Schools."
× Follow Ruth Conniff
Follow Ruth Conniff @rconniff on Twitter. |
Michigan in the News
Anne Petersen, research professor at the Center for Human Growth and Development, was quoted in The Washington Post about the long-term effects of child abuse and neglect.
The Huffington Post featured comments by Lennard Fisk, professor of physics and atmospheric, oceanic and space sciences, in an article about NASA's Voyager I probe leaving the solar system, 36 years after launch.
Michigan Radio interviewed Helen Levy, research associate professor at the Institute for Social Research and the schools of Public Health and Public Policy, about the possibility that some Detroit retirees could lose their current health insurance, but be moved to health care exchanges instead.
Marc Gershwin, nephew of George and Ira Gershwin, speaks during Sunday's announcement of the U-M George and Ira Gershwin Critical Edition. Looking on are, from left, University Musical Society President Ken Fischer, Associate Professor of Musicology Mark Clague, President Mary Sue Coleman, and School of Music, Theatre & Dance Dean Christopher Kendall. (Photo by Austin Thomason, Michigan Photography)
U-M to become epicenter of research on work of George and Ira GershwinThe School of Music, Theatre & Dance has entered a new partnership with the estates of George and Ira Gershwin to provide U-M music scholars access to all of the Gershwins' papers, compositional drafts and original scores to create the first-ever critical edition of the brothers' works, which will, in turn, catalyze a campus effort known as the Gershwin Initiative.
Third Century Initiative funds new round of learning projectsAnne Mondro, associate professor in the Stamps School of Art & Design, has spent a decade at U-M learning how creativity impacts health care, with particular emphasis on aging and memory loss. As one of the latest faculty teams to receive funding from the Third Century Initiative, Mondro and her university and community colleagues will expand the experience to include undergraduate and graduate students from across campus.
SECURITY BULLETIN: Solicitation scam alertTwo university academic units have been contacted by people reporting a fundraising scam. The people were approached in different southeast Michigan communities by individuals requesting donations for U-M class trips.
The Michigan Difference
Math in Africa
A two-week summer school that was part of a mathematics conference in the African nation of Cameroon last spring helped share knowledge across the region. Co-sponsored by U-M and made possible largely through the efforts of Nkem Khumbah, lecturer of mathematics with the Comprehensive Studies Program, the biennial Buea International Conference on the Mathematical Sciences brought global experts to Africa, where they discussed their research with peers across the continent. |
1. Field of the Invention
This invention relates generally to highway construction machinery and, more particularly, but not by way of limitation, to machinery for crushing asphalt removed from paved roadways for reuse of such asphalt.
2. Description of the Prior Art
Machines for planing the surface of a paved roadway are known in the art. For example, an apparatus suitable for planing asphalt from a paved roadway is disclosed in the aforementioned co-pending United States Patent Application, Ser. No. 672,326. It is also known to crush material removed from a roadway and to redeposit such material on the roadway. Machines constructed for this purpose have been disclosed in United States Pat. No. 1,938,755, issued to Swearingen on Dec. 12, 1933, and in Russian Authors Certificate No. 505,767 issued to Samuilov, et al., publication date Mar. 5, 1976.
A problem which occurs when asphalt removed from a roadway is redeposited is that the apparatus for planing the roadway can produce large fragments of asphalt which are not suitable for reuse in resurfacing the roadway. |
Dads2Dads: Teach the value of diversity
3:34 PM,
Oct. 25, 2013
Written by
Tom Tozer and Bill Black
A high-school World Studies class recently went on a field trip and visited a mosque and Hindu temple. It was all part of a three-week examination of world religions. You may have seen the story in the news.
Public and parental reaction was fast and furious. Several people thought the teacher who organized the trip should be fired. Others, including one teenage student who was interviewed, were surprised at the negative reaction and defended the role of education as a means of exposing students to other cultures and practices. The teenager also responded with a chuckle and a shake of the head to ... |
Outback Game Day......... I think these Picts call for some captions...... After eating all the Bloomin Onions for Ryan.....my pick are the Coconut Shrimp.....yum! And their dipping sauce is the best.......
Drum roll for our @outbackbowl Team Captains...@KevinHarvick & @DeLanaHarvick. Follow them on Game Day for some fun. pic.twitter.com/1JYz0q8VjA
December 27, 2013
TAMPA, Fla. - Outback Bowlofficials announced today that 23-time NASCAR Sprint Cup Series race winner Kevin Harvick will perform the official coin toss atthis year's Outback Bowl college football game in Raymond James Stadium. Harvick is the driver of the No. 4Outback Steakhouse Chevrolet SS for Stewart-Haas Racing (SHR) and aperennial Sprint Cup championship contender.The Outback Bowl will kick off at 1p.m. EST on New Year's Day as the No. 14 LSU Tigers square off against the IowaHawkeyes. Tickets are on sale through Ticketmaster at (813) 287-8844 or 1-800-745-3000 and can be purchasedonline at http://www.ticketmaster.com. Tickets can also be purchased at anyTicketmaster outlet in the state of Florida.For information on limited priorityseating call the Outback Bowl office directly at (813) 874-BOWL or go to thebowl web site at http://www.outbackbowl.com for details.Outback Steakhouse and SHR haveteamed up for a third consecutive NASCAR season. Outback will serve as primarysponsor of Harvick for tworaces each in 2014 and 2015, and when not serving as a primary sponsor, will bean associate sponsor with placement on the B-post of the No. 4 Chevrolet SS.Outback's popular Bloomin' Monday promotion will continue in 2014, where whenever Harvick finishes among thetop-10 in a Sprint Cup race, a free Bloomin' Onion will be offered to customerson the Monday following the race. Customers have been treated to over 400,000 free Bloomin' Onions sincethe first Bloomin' Monday in 2012. Find out more at http://www.Outback.com\racingAbout Outback Steakhouse:At Outback Steakhouse, our flavorsrun wild - where it's not only OK to sit back, relax and forget your manners -it's encouraged. "No Rules, Just Right," is the spirit of the Outback thatdelivers a delicious and no worries dining experience. Outback Steakhouse wasvoted No. 1 Best Steak in the 2012 Zagat Survey of National Full-ServiceRestaurant Chains for the fourth consecutive year. For more information, pleasevisit http://www.Outback.com, http://www.Facebook.com/Outback, or http://www.Twitter.com/Outback.About Stewart-Haas Racing:Stewart-HaasRacing is the title-winning NASCAR Sprint Cup Series team co-owned bythree-time Sprint Cup champion Tony Stewart and Gene Haas, founder of HaasAutomation - the largest CNC machine tool builder in the western world. Theteam fields four entries in the elite Sprint Cup Series - the No. 14 Bass ProShops/Mobil 1 Chevrolet for Stewart, the No. 10 GoDaddy Chevrolet for DanicaPatrick, the No. 4 Outback Steakhouse Chevrolet for Kevin Harvick and the No.41 Haas Automation Chevrolet for Kurt Busch. Based in Kannapolis, N.C.,Stewart-Haas Racing operates out of a 140,000-square-foot facility withapproximately 250 employees. For more information, please visit us on the Webat http://www.StewartHaasRacing.com, onFacebook at http://www.Facebook.com/StewartHaasRacingand follow on Twitter @StewartHaasRcng.More News...Teams Devour More Than 5,000 lbs of Food at Outback Welcome Dinner
outbackbowl #TeamCoconutShrimp https://vine.co/v/hVIKbt5JF27Here is Kevin's intro to coin toss.......hope this works he drove on the field with his car..... Got an email message that Outback is giving a FREE Bloomin onion tomorrow....was so hoping for coconut shrimp! I think you have to mention Kevin's name and the winning team....... |
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Posts tagged "sexism"
David Letterman, we haven't forgotten about you and your staff member-diddling ways! Nell Scovell, the second female ever hired to write for "Late Night with David Letterman" recently penned a piece for Vanity Fair's website alleging that sex between high-level male and lower-level female staffers led to a "hostile" work environment: "Without naming…
Hey, big news! Abercrombie & Fitch has a few T-shirts in its "New College" line that are, like, way sexual and sexist and not particularly funny. (The shirts above say "Show the Twins," "Female Students Wanted for Sexual Research,"and "Female streaking encouraged.") And people are mad about it! The American Family Association (AFA), a religiou…
You've probably heard of Tucker Max, blogger and author of the memoir I Hope They Serve Beer In Hell, who regaled the bestseller list with stories of sex with many, many women and excessive drinking. (The charming cover illustration is of a man holding a beer bottle and pointing to a blonde…
A new law in Afghanistan permits men who are Shia Muslims to deny food for their wives if she won't satisfy his sexual longings. According to the Guardian, the law states:"Tamkeen is the readiness of the wife to submit to her husband's reasonable sexual enjoyment, and her prohibition from going out of the house, except…
A PETA billboard in Jacksonville, FL, calls larger women "whales" and urges them to "lose the blubber" by going vegetarian. PETA's press release on the billboard says "going vegetarian can be an effective way to shed those extra pounds that keep [women] from looking good in a bikini." Oh, God, now…
We love the idea, in theory, of a porn magazine for women. Unfortunately, Filament, a British for-women-by-women porn mag, is having a lot of troubles. First, the above-the-waist photos of "feminine" male models, which Filament's editors said academic research proved women are attracted to, were not pornographic enough for us. Sorry, but Rufu…
If Secretary of State Hillary Clinton had been invited to the Obama's "beer summit," she should have knocked back a bottle of Mad Bitch beer, said Dana Milbank, a columnist for The Washington Post, in a video on the WaPo web site. [Politico] — Because insinuating a powerful woma…
Come on, Double X, you're just baiting us: With a headline like "The Appallingly Sexist Origins of Facebook," we were expecting to be served some juicy dish that made Mark Zuckerberg, the 25-year-old founder of Facebook, look like a pig. But Double X pulled snippets of purported douchebaggery from The…
A male blogger named Anthony Michael Rojas posted a little list entitled "How To Treat A Woman On A Date: The Basics" on his Tumbler blog this week and it got quite a few angry reblogs from women who felt like his suggestions were sexist. Rojas clearly believe his suggestions to be basic…
Jamie Lynn Spears gives us the finger, and parties it up. [TMZ] -- We’re glad the girl is finally acting her age, but we’re a little scared about what’s in the cup. Miley Cyrus and Justin Gaston have reportedly split up. [Us Magazine] -- He was too cute for her, anyway.
Historically, if that's a word that can be used in relationship to blogging, Gawker Media ladyblog Jezebel has dedicated much its blog's space to pointing out sexism in advertising -- or what they deem "badvertising." So, if the Jezebels are the self-proclaimed policewomen of what they perceive to be rampant advertising…
This morning, I flew back to New York and caught up on my pop music by listening to the Top 20on20 on XM radio, the one perk Airtran provides. Most of the music was expected -- Lady GaGa, Miley Cyrus, Black Eyed Peas -- but I'd never heard one of the songs that made it…
In the most recent issue of Vice, Chris Nieratko lists 10 inventions he wishes, you know, inventors would make already. He desires a cell phone with lasers, a "titty-milk-catching bag," and seven others things. That adds up to nine, if you're counting. The 10th annoyed me. A Mouthless Woman: A mouthless woman gives me no…
These ads caught my eye -- which I suppose is exactly what their creators at Brazilian ad agency Publicis had in mind when they created them. The image is arresting, isn't it? In this provocative ad series, the women appear to be holding their own lopped off heads. The tagline is an odd fit, though.
Over on AskMen.com there’s this article all about the importance of asking a father’s permission for his daughter’s hand in marriage, a tradition I guess I wrongly assumed was as relevant as outhouses and chastity belts. According to the article, “while the traditional reasons for asking are now obsolete, popping the question to…
Some folks have gotten their panties in a bunch over Beyonce's cover for the "Shape Issue" of Vogue. Beyonce is one of only five black women to grace the cover of Vogue since it was founded in 1892, but blogs like Jezebel and Sociological Images think the magazine was being sexist…
Behold the European beer giant’s latest ad that’s been airing all over Holland. You don’t need to speak Dutch to get the gist. The scene takes place at a couple’s new home, where the woman is giving her friends a grand tour. The situation quickly turns into a screaming contest between men and women, beer…
Simply Irresistible
Taking a page out of those girls you went to high school with who can't stop smugly posting every detail of their perfect lives on Facebook, Lady Gaga shaded America's youngest grandma Taylor Swift just perfectly on Twitter yesterday. It all started when Jaime King's unborn child's godmother tweeted about Gaga, using the preferred…
Oh look, it's hottest DILF alive, Ryan Gosling, making a rare appearance in public grabbing lunch in LA today. And what's that I see? In addition to his perfectly worn T-shirt (that collar is stretched just so), hoodie and leather jacket, the Gos is rocking a few faint letters on his knuckles, spelling out the… |
11. DETROIT LIONS (LAST WEEK: 12)
Even with Calvin Johnson playing sparingly, Matthew Stafford threw four touchdown passes as the Lions pulled away from those plucky Browns after halftime. Big test coming up against the Bengals.
Even with Calvin Johnson playing sparingly, Matthew Stafford threw four touchdown passes as the Lions pulled away from those plucky Browns after halftime. Big test coming up against the Bengals. (Matt Sullivan, Getty Images)
Even with Calvin Johnson playing sparingly, Matthew Stafford threw four touchdown passes as the Lions pulled away from those plucky Browns after halftime. Big test coming up against the Bengals. |
The Connectivity Premium
Commercial real estate’s guiding principles are changing.
In fact, according to real estate technology strategist James Carlini, the industry’s new mantra is “location, location, connectivity.”
There’s no mystery to it; ABI Research’s latest data shows that there are more than 10 billion wirelessly connected devices in the market today, with over 30 billion devices expectedby2020. Moreover, thanks to the proliferation of mobile work applications and bring-your-own-device (BYOD) policies, experts now believe 70 to 80 percent of the world’s mobile usage is happening in-doors, often inside commercial properties.
But thanks to that unprecedented, unrelenting rise in wireless data traffic, today’s outdoor networks can barely handle the data demand; they’re overloaded by outside traffic, while at the same time powerless—due to signal loss caused by building materials—on the inside. Which puts a tremendous strain on in-building networks, and makes delivering any form of wireless communication (especially cellular or Wi-Fi) less reliable, more expensive, and ever more complex.
Fortunately, commercial real estate developers can profit from this unpleasant reality by making decisions—today—that will alleviate the access, bandwidth, and throughput issues of tomorrow.
In this article, Corning and RF Connect will analyze the ins and outs of “future-ready” data networks from a developer’s perspective—including methods for choosing the right components, selecting the right sources, and ensuring future service readiness for maximum profitability and return-on-investment.
Data: The Fourth Utility
According to Intel, 10 billon applications have been downloaded from iTunes, 200,000 text messages are sent every second, and 35 hours of video are uploaded to YouTube every minute.
There’s no end in sight; not only is our extraordinary demand for person-to-person data communications likely to continue unabated, but we’re on the verge of a Renaissance in what Cisco calls the “Internet of Everything.”
Think, for example, of office security cameras (equipped with real-time analytics) alerting a building’s security manager that they’ve detected a threat. That’s digital information— sent wirelessly, via the Internet—to an individual’s smart device. And it’s a massive amount of digital information, too. According to Cisco, if you’re streaming video to a local area network (LAN) file server or storage unit, a single camera might need 11 Mbps of bandwidth; with five cameras, it could take
53 Mbps.
What’s more, data is increasingly being driven by machine-to-machine communications, without any human involvement whatsoever. (Think, for instance, of that same security camera communicating—autonomously—with a building’s HVAC system to aid with the detection of water leaks. Or consider that camera using motion detection software to determine
a room’s occupancy level, then sending that information to the HVAC system to help make real-time heating and cooling decisions.)
All told, companies like Bosh estimate that more than six billion “things” will be connected to the Internet by 2015. Already, with a myriad of digital, wireless, and IP-based systems taking root—many of which are now central to the operation of commercial buildings—broadband data has become an unofficial “fourth utility,” as crucial as electricity, water and gas.
To real estate strategists like James Carlini, “the need for [data infrastructure today] is as important to commerce and urban development as the need for good roads, bridges and public transportation.” In fact, according to a recent report from Deloitte, attracting tenants and buyers is requiring the “commercial real estate industry to fundamentally change [its] business practices, including re-designing existing space to suit new tenant demands and the growing use of automation.”
Today’s building occupants are demanding wireless data and cellular communications without restriction—every time, at full speed, and with the dependability of a landline. But beyond that, they’re demanding to work with the newest available applications and devices, which means a need for ever-increasing bandwidth.
Traditionally, real estate developers and management companies have addressed this need for bandwidth reactively; as technology evolves, they attempt to “catch up” with the building infrastructure by creating multiple parallel networks that in many cases demand higher capacity than the existing cable structure can provide.
Operating like this—by perpetually adding new networks and running new cabling—is a tremendously expensive and unsustainable practice. Tomorrow’s tenants will demand a much more scalable bandwidth infrastructure, and developers will need an inexpensive and efficient way to meet this crucial requirement.
Fortunately, the solution is not uncharted. Gas, water,
and electricity are all purchased and installed based on specifications intended to last the lifetime of a commercial building. If we consider data access to be a true “fourth utility,” why wouldn’t we design and budget its infrastructure in the same way?
Building for the Future – All Fiber
So what does a future-ready data network actually
look like?
For starters, we know that in-building communications networks have undergone substantial changes over the past decade. Many businesses have transitioned from twisted copper pair voice lines to either VoIP connections or cellular service. For security personnel, we’ve seen a shift from two-way radios to IP cameras and closed circuits. And thanks to growing trends like BYOD, secure remote email access, and Web-based tools for asset tracking and conferencing, more and more wireline services have been replaced by wireless.
In this emerging world of all-digital, all-wireless communications, it’s safe to say that copper cabling—though it has served us well over the years—is very quickly running out of the capacity to efficiently support our soaring bandwidth needs.
Rather, at this point in time, we must look to fiber; only all-fiber (passive optical LAN) infrastructures have the capacity for unlimited bandwidth. And while fiber is already the industry’s standard for intrabuilding riser cabling, today’s forward-looking commercial developers are taking the next logical step—installing fiber in the horizontal. As data traffic increases, the copper cabling used in horizontal networking will become an infrastructure’s primary “choke point.” Hence, the shift from copper to fiber in the horizontal will be a crucial component of future-ready network planning.
For years, the knock on fiber has been its perceived cost. But in today’s business climate, tenants and developers are increasingly finding that fiber actually reduces their costs over time.
Not only are the prices of fiber cable, components, and hardware steadily decreasing, but most fiber installations now cost less to install and to maintain, suffer less downtime, and require less networking hardware than copper cabling systems. At one
tenth the size and weight of copper, fiber allows for a much cleaner, simpler cabling infrastructure. (What’s more, the availability of pre-terminated fiber cables can drastically reduce both installation costs and deployment times.)
Building for the Future – Convergence
Another way the forward-looking network reduces costs and improves performance is through convergence—extending the core network to support multiple in-building applications, including cellular (via cost-effective Distributed Antenna Systems), Wi-Fi, and other IP-based services.
Already, there are hundreds of systems and applications
that buildings must support (public safety, security, building automation, WI-FI, LAN, DAS, and PON, to name but a few) with more arising frequently. Through convergence, developers can save CAPEX and OPEX by eliminating the need for parallel network structures. Instead of managing an unwieldy set of separate networks, the single converged infrastructure transports all of a building’s voice, video and data with the convenience of a one-stop-shop.
Moreover, that shop must be fully equipped. For too long, network planners have neglected to provide fast, reliable cellular service throughout an office building’s dense, labyrinthine interior. Perhaps yesterday’s tenants were willing to forego in-building cellular service; rest assured, today’s tenants will demand it. With the number of cellular devices expected to exceed the world’s population, sophisticated tenants can no
longer abide the potential for missed calls, opportunities or revenue.
Fortunately, robust cellular service through cost-effective distributed antenna system (DAS) technology—once reserved only for large-scale public venues—is now available to everyone. And with new converged solutions and shared cost models, in-building cellular voice and data service needn’t be complex or costly.
Selecting a Source
An additional cost driver for commercial real estate developers is the number of subcontractors (and the amount of specialized labor) needed to complete an in-building networking project.
Having a single-source integrator—instead of hiring separate consultants, low-voltage contractors and cable contractors—can reduce time, cost and project delivery risk. But when it comes to choosing an integrator with the requisite expertise, commercial developers should consider several criteria.
First and foremost, the integrator should be highly familiar with fiber-based networking solutions that can deliver a truly future-ready infrastructure. Second, the integrator should have experience fielding converged solutions that support multiple services and applications, and that can easily be modified (via telecom closet or head-end in the building) to adjust or add services.
Next, the integrator should be familiar architecting solutions that can provide flexibility to tenants when they inevitably change floor plans or the locations of services.
In-building wireless implementations are multifaceted and complex, with multiple stakeholders and a myriad of details. At a minimum, these projects require a well-coordinated effort, performed by experienced RF engineers with specialized tools, analytics, testing and problem solving methodologies.
Last but not least, an integrator must be able to deal effectively with wireless carriers—negotiating, coordinating, scheduling secure design approval and rebroadcast rights, and getting the system tested and commissioned to the carrier’s satisfaction.
Commanding a Premium
With the commercial real estate industry anticipating continued market improvements to rent and occupancy levels, as well as asset prices, transactions and capital availability, now is the perfect time for investing in future profitability.
As such, developers will be examining projects carefully to ensure their potential for return, with a special emphasis on building assets—particularly in major metropolitan markets that are seeing prices move closer to 2007 peaks—and ensuring that those assets are competitively positioned to command appropriate premiums.
Network infrastructure planning—designed for the future, not the present—will be essential to this pursuit, and successful developers must be forward thinking in their efforts to attract sophisticated future tenants and buyers.
More specifically, commercial developers can benefit from taking the specific actions outlined in this article:
1. Treating data access as a core utility, and
accordingly, choosing a data infrastructure based on specifications intended to last the lifetime of the commercial building.
Overall, developers must be wary of cheap imitators—focusing on long-term profits instead of short-term savings. And they must be creative in achieving new future-ready solutions and intelligent infrastructures and amenities, supporting the next generation of devices, services, and networks. |
Q:
Relationship between Wien's law and Stefan-Boltzmann's law
I'm studying Quantum mechanics by Bransden and Joachain and in the introduction chapter it says:
Wien showed that the spectral distribution function had to be on the form
$$\rho(\lambda,T)=\lambda^{-5}f(\lambda T)$$
where $f(\lambda T)$ is a function of the single variable $\lambda T$. It is a simple matter to show that Wien's law includes Stefan-Boltzmann law $R(T)=\sigma T^4$.
One of the exercises is to show this and I cannot understand how to.
This is what I've tried:
The relationship between spectral emittance and spectral distribution is
$$\rho(\lambda,T)=\frac{4}{c}R(\lambda,T),$$
where c is the speed of light, which inserted in the above equation gives
$$R(\lambda,T)=\frac{c}{4}\lambda^{-5}f(\lambda T).$$
Now, the total spectral emittance is the integral of $R$ over all wavelengths so
$$
R(T)=\frac{c}{4}\int\limits_0^\infty \lambda^{-5}f(\lambda T)d\lambda
$$
This is where I'm stuck. Can anyone help me figure this out?
A:
The solution to your problem(1) is this :
\begin{align}
R(T) & =\frac c4 \int\limits_{\lambda=0}^{\lambda=\infty} \lambda^{-5}f(\lambda T)\mathrm{d}\lambda=\frac c4 \int\limits_{\lambda=0}^{\lambda=\infty} T^{4}\dfrac{f(\lambda T)}{(\lambda T)^{5}}\mathrm{d}(\lambda T)\qquad \Longrightarrow
\nonumber\\
R(T) & =\frac c4 \underbrace{\left(\:\:\int\limits_{\mu=0}^{\mu=\infty} \dfrac{f(\mu)}{\mu^{5}}\mathrm{d}\mu\right)}_{A=\text{constant}}T^{4}=
\underbrace{\left(\frac c4 A\right)}_{\sigma}\, T^{4}=\sigma\, T^{4}
\tag{01}
\end{align}
But, sincerely, trying to find this directly you are missing important facts about the "before Planck" adventure of the blackbody radiation theory. For example, you must try to find from Wien's Law (your first equation) why if you know the function $\;\rho(\lambda,T_{1})\;$ for a given temperature $\;T_{1}\;$ then you know it for any temperature $\;T\;$ or that $\;\lambda_{\rm max}\cdot T=b=\rm constant\;$ (Wien's Displacement Law), see Emilio Pisanty answer therein : Showing Wien's Displacement Law from Wien's Law.
(1)
"Quantum Mechanics" B. H. Bransden-C. J. Joachain, 2nd Edition 2000, Pearson Education Limited (Problem 1.3, page 45)
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Be sure to check out our website, EWBArmentaProgram.org, for field updates!
THE NEED
Homes in the village of Armenta, Honduras only receive water one day a week.In addition the medical center that treats both people and animals often goes without water for days, greatly hampering their ability to adequately serve the community. The people we visited are allowed to fill up their pillas (home water storage facility) one day a week. They draw all water for drinking, preparing food, laundry, bathing, sanitation, etc, from that single home storage source throughout the week.
PROJECT SCOPE
The goal of our site assessment trip will be to gather all information necessary to develop a Master Water Plan for the community. This will include recommended enhancements to their existing Water Program including things like; developing ways to improve maintenance and capital fund generation, improved water distribution layout and monitoring practices, maintenance education and a physical implementation of a phased-in improved water distribution system to meet their current water needs as well as make provision for future expansion.
FUTURE INVOLVEMENT
We have already built a pedestrian bridge for this community over another waterway that previously divided the community in half. We eagerly look forward to working with them to fund, develop and implement a reliable clean water system. Beyond this project we anticipate looking into ways to effectively handle all the “grey water” this project produces. We recognize this as a “good challenge” to have and one we eagerly look forward to. |
Lack of familial predisposition to cardiovascular disease in type 1 (insulin-dependent) diabetic patients with nephropathy.
A familial predisposition has been proposed as a major determinant of the increased morbidity and mortality from cardiovascular disease demonstrated in Type 1 (insulin-dependent) diabetic patients with nephropathy. We assessed this concept by studying 91 parents of Type 1 diabetic patients with nephropathy and 94 parents of aged-matched Type 1 diabetic patients with normoalbuminuria. The two groups of parents were of a similar age (58 +/- 8 vs 58 +/- 7 years). The prevalence (%) of death and cardiovascular diseases (World Health Organisation questionnaire) was 10 (4-18)% and 12 (6-21)% in parents of nephropathic patients compared to 8 (3-16)% and 13 (6-23)% in parents of normoalbuminuric Type 1 diabetic patients. The frequency of risk factors for cardiovascular disease were about the same in both groups of parents. Microalbuminuria was found in 5% and 11%, hypercholesterolaemia (greater than 6.5 mmol/l) in 25% and 26% and smokers constituted 40% and 34% of parents of patients with and without proteinuria, respectively. A familial predisposition to cardiovascular disease cannot explain the increased morbidity and mortality from cardiovascular disease in young patients with diabetic nephropathy. |
i am here like everyone else because i like anime/manga and i'm also in too other things like games:) i like kingdom hearts, harvest moon, final fantasy , league of legends, world of warcraft , tera, dota2, etc.... if anyone ever wants reccomends for animes or manga just msg me :) i have a pretty good knowlege on many hidden gems :)
What is anime-planet?
Founded in 2001 as the first anime & manga recommendation database.
Create lists for what you've seen & read, watch over 40,000 legal streaming episodes online via
Crunchyroll, Hulu & Viki, and meet other anime fans just like you. |
Feasibility of a virtual health and wellness center for the Oregon Air National Guard.
A cross-sectional survey of members was used to examine the feasibility of developing a virtual health and wellness center in the Oregon Air National Guard. The survey asked about the health behaviors members wanted to change and explored their current access to, and potential use of, the Internet to make these changes. Surveys were mailed to 1,368 members, and 521 (38%) were returned. Most respondents (92.5%) had contemplated making one or more health behavior changes in the past year, which included becoming more physically active (94.6%), improving eating habits (86%), losing weight (81%), improving stress management (62%), and reducing tobacco use (46%). Popular sources of health behavior change information used included reading material (95.5%) and the Internet (91.3%). Many respondents had Internet access (82%), and average computer self-efficacy, rated on a scale of 1 to 5, was very high (mean = 4.05, SD = 0.91). Use of the Internet by health professionals to promote health behavior change among Oregon Air National Guard personnel seems feasible and desirable. |
Q:
Is $\bigwedge^{p,0}M$ a holomorphic vector bundle?
I have difficulties in understanding how to show that a vector bundle is holomorphic. For instance, how can I prove that $\bigwedge^{p,0}M$ is a holomorphic vector bundle, where $M$ is a complex manifold ? I think I should determine the transition maps and show that they are holomorphic. However, it is unclear to me how to do this in a correct way.
Thanks in advance.
A:
A complex rank r vector bundle $E$ over $M$ is given by a cocycle $$\{\varphi_{ij}\colon U_i\cap U_j \longrightarrow {\rm GL}(r,\mathbb{C}) \}.$$ $E$ is holomorphic if the $\varphi_{ij}$ are holomorphic. Then we can apply "any linear algebra construction" such as exterior and symmetric powers to $E$ (fiberwise) and the result will be also a holomorphic bundle. For example, the determinant of $E$ will have a cocycle given by $\det(\varphi_{ij})$.
See page 67 of Huybrecht's book https://www.math.uh.edu/~shanyuji/Complex/Complexgeometry.pdf
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The compounds of the formula (I) of the invention can be considered as analogs of prostacyclin (PGI.sub.2), a physiologically very important natural substance, which are stable and possess a selective pharmacological action.
Prostacyclin (PGI.sub.2) as a metabolite of arachidonic acid, which is wide-spread in mammalian organisms, was discovered in 1976. This substance possesses a number of therapeutically valuable biological effects: e.g. inhibits the aggregation of the blood platelets, lowers the blood pressure, dilatates the airways and diminishes the gastric juice secretion. In addition, prostacyclin shows a cyto-protective action in various organs, e.g. in the stomach, liver, heart and kidney. This means that the destructive consequences of various organ-damaging effects can be prevented or remedied by prostacyclin.
A large number of review articles have been published on the above-mentioned advantageous pharmacologic effects of prostacyclin (see e.g. Flohe et al.: Arnzeimittelforschung 33, 1240 (1983); S. Moncada and J. R. Vane: J. Med. Chem. 23, 591 (1980); W. Bartman et al.: Angewandte Chemie, Int. Ed. Engl. 21, 751 (1982); R. F. Newton et al.: Synthesis 1984, 449).
Today, the advantageous pharmacological actions of prostacyclin are also utilized clinically. The sodium salt has been commercialized by the Wellcome company under the trade name Flolan and by the Upjohn company under the trade name Cycloprostin in 1983 (Drugs of Today 19, 605 (1983)) for cardiopulmonary bypass proceses, perfusion in the course of liver deficiency and kidney haemolysis as areas of indication.
However, severe problems with the use of prostacyclin are induced by the extraordinary unstability of this substance (A. J. Kresge et al.: J. Chem. Soc. Chem. Comm. 1979, 129). The most sensitive moiety of the molecule is the ethanolether functional group. The main principles of the chemical and biological stabilization of the molecule are reported in the above-cited review articles. |
The alert security personnel, however, foiled the move of the rebels. The rebels had struck at the place at about 7pm and opened indiscriminate fire from different corners at the station ó about 500km from the state capital.
Sources said a huge deployment of security personnel in the station foiled the attempt of the rebels who faced strong retaliation.
Besides jawans of the Special Task Force, personnel of Special Armed Force and District Force were present in the station that also adjoins a relief camp, housing some 1,000 villagers, who had deserted their homes in Maoist terror.
Inspector general of police R.K. Vij said the rebels were camping in the area and had been firing at the station in intermittently. There is sufficient force in the station, said Vij, adding that there was no casualty reported. |
The Ministry of Coal has identified seven big coal blocks for allotment to power generation companies of six states. The blocks on offer include Deocha Pachami with 2,102 million tonne (mt) of coal reserves in West Bengal, Ghograpalli with 1,163 mt, Jaduanathpur with 525 mt in Odisha, Pokharia Paharpur with 584 mt and North Kathara with 305 mt in Jharkhand. |
---
abstract: |
A neutral vector boson can possess static electromagnetic properties provided that the associated field is no self-conjugate. This possibility is explored in the $SU_C(3)
\times SU_L(3)\times U_N(1)$ model with right-handed neutrinos, which predicts a complex neutral gauge boson $Y^0$ in a nontrivial representation of the electroweak group. In this model the only nonvanishing form factors are the CP-even ones, which arise from both the quark and gauge sectors, and contribute to the magnetic dipole and the electric quadrupole moments of this neutral particle.
author:
- 'G. Tavares-Velasco'
- 'J. J. Toscano'
title: 'Static quantities of a neutral bilepton in the 331 model with right-handed neutrinos'
---
Introduction {#int}
============
The electromagnetic properties of neutral particles have been the source of great interest since they are generated at the loop level, thereby opening up the possibility for the detection of new physics effects. Considerable attention has been paid to the electromagnetic properties of neutrinos and the neutral $Z$ boson of the standard model (SM). In particular, the impact of new physics effects on the trilinear couplings of the $Z$ boson has been studied in a model-independent manner using the effective Lagrangian technique [@Belanger]. As far as neutral fermions are concerned, it was long realized that the off-shell electromagnetic vertex of a massless Dirac neutrino is a gauge-dependent quantity [@Marciano]. On the other hand, a massive Dirac neutrino does have static electromagnetic properties which characterize its magnetic and electric dipole moments. This is to be contrasted with the case of a Majorana neutrino, which only has off-shell electromagnetic properties [@Majorana], which in turn is a consequence of the fact that a Majorana neutrino is identical to its antiparticle. A more recent model-independent study of the electromagnetic form factors of Majorana particles with higher spin was presented in Ref. [@Boudjema]. The situation for neutral spin-1 particles is similar as for neutrinos: a neutral vector boson characterized by a self-conjugate field, for which the particle is identical to its antiparticle, cannot have static electromagnetic properties. This fact has been already discussed in the case of the neutral $Z$ boson [@Barroso]. On the contrary, a no self-conjugate field do can have static electromagnetic properties.
The possibility that neutral particles have nonzero static electromagnetic properties was explored in a general context using arguments of gauge invariance and transformation under the discrete symmetries $C$, $P$ and $T$ [@nieves]. Several extensions of the SM, such as grand unified theories (GUTs), predict the existence of at least one new complex neutral gauge boson with nonzero content of quantum numbers from the global or local symmetries of the theory. The purpose of this work is to present a calculation in a specific version of the $331$ model [@Fra-Ple] which predicts the existence of a no self-conjugate neutral gauge boson in a nontrivial representation of the electroweak group.
The $331$ model is based on the simplest non-Abelian extension of the SM group, namely, $SU_c(3)\times SU_L(3)\times U_N(1)$ [@Fra-Ple]. This model is appealing and has been the source of interest recently [@Tavares-331] because it requires that the number of fermion families be a multiple of the quark color number in order to cancel anomalies, which suggest a path to the solution of the flavor problem. Another important feature of this model is that the $SU_L(2)$ group is totally embedded in $SU_L(3)$. As a consequence, after the first stage of spontaneous symmetry breaking (SSB), when $SU_L(3)\times U_N(1)$ is broken down to $SU_L(2)\times U_Y(1)$, a pair of massive gauge bosons associated with four broken generators of $SU_L(3)$ emerge in a doublet of the electroweak group. Contrary to what happens in other theories, the couplings between the new and the SM gauge bosons do not involve any mixing angle, which means that they are expected to be similar in magnitude to the ones existing between the SM gauge bosons themselves.
Apart from the minimal 331 model, another version including right-handed neutrinos has been considered in the literature more recently [@Long; @Long-1]. Its main feature is that it requires a more economic Higgs sector to break the gauge symmetry and generate the fermions masses. This model predicts the existence of a singly-charged boson $Y^\pm$ along with a no self-conjugate neutral boson $Y^{0*}$. Both of these new gauge bosons can be classified as bileptons since they carry lepton number $L =\pm
\,2$, and thus are responsible for lepton-number violating interactions [@Cuypers]. The neutral bilepton is a very promising candidate in accelerator experiments since it may be the source of neutrino oscillations [@Long-Inami]. The dynamical behavior of the $Y^0$ boson is somewhat similar to that of the $W$ gauge boson, due to the nontrivial quantum number assignment. For instance, the $Y^0 Y^+W^+$ coupling resembles those existing between the electroweak gauge bosons. In the fermionic sector, the $Y^0$ also couples to the quark pairs $(d,D_1)$, $(s,D_2)$, and $(t,T)$, with $D_1$, $D_2$ and $T$ three new quarks predicted by the model. These couplings induce nonzero static electromagnetic properties for the neutral bilepton.
This presentation has been organized as follows. In Sec. \[mod\], we present a brief review of the $331$ model with right-handed neutrinos, with special emphasis on the current and Yang-Mills sectors. Sec. \[cal\] is devoted to the calculation of the on-shell vertex $Y^0Y^{0*}\gamma$. In Sec. \[num\] we analyze the behavior of the $Y^0$ form factors, and the conclusions are presented in Sec. \[con\].
The 331 model with right-handed neutrinos {#mod}
=========================================
$331$ models are based on the $SU_C(3)\times
SU_L(3)\times U_N(1)$ gauge group. In the version with right-handed neutrinos [@Long] the leptons are arranged as $$f^i_L=\left( \begin{array}{ccc} \nu^i_L \\
e^i_L\\
(\nu^c_L)^i
\end{array}\right) \sim (1,3,-1/3), \ \ e^i_R \sim (1,1,-1),\ \
i=1,\,2,\,3,$$ where $i$ stands for the family index. In the quark sector, a new quark for each family is necessary. The first two quark families transform as $${Q_a}_L=\left( \begin{array}{ccc} {d_a}_L \\
-{u_a}_L\\
{D_a}_L
\end{array}\right) \sim (3,\bar{3},0), \ \
{u_a}_R \sim (3,1,2/3), \ \ {d_a}_R \sim (3,1,-1/3),\, \ {D_a}_R
\sim (3,1,-1/3),$$ for $a=1,\,2$, whereas the third family transforms differently $${Q_3}_L=\left( \begin{array}{ccc} {u_3}_L \\
{d_3}_L\\
T_L
\end{array}\right) \sim (3,3,1/3),\ \
{u_3}_R\sim (3,1,2/3),\ \ {d_3}_R\sim (3,1,-1/3),\ \ T_R\sim
(3,1,2/3).$$
As far as the scalar sector is concerned, only three triplets of $SU_L(3)$ are required to achieve the SSB mechanism: $$\begin{aligned}
\chi=\left( \begin{array}{ccc} \chi^0 \\
\chi^-\\
\chi^{'0}
\end{array}\right)\sim (1,3,-1/3),\ \
\rho=\left( \begin{array}{ccc} \rho^+ \\
\rho^0\\
\rho^{'+}
\end{array}\right)\sim (1,3,2/3),\ \
\eta=\left( \begin{array}{ccc} \eta^0 \\
\eta^-\\
\eta^{'0}
\end{array}\right)\sim (1,3,-1/3).\end{aligned}$$ In contrast, the minimal version requires three triplets and one sextet. The vacuum expectation values $<\chi>^T=(0,0,w/\sqrt{2})$, $<\rho>^T=(0,u/\sqrt{2},0)$, and $<\eta>^T=(v/\sqrt{2},0,0)$ yield the following SSB pattern $$\begin{aligned}
SU_C(3)\times SU_L(3)\times U_N(1)\ \
\begin{array}{c}
w\\ \to
\end{array}\ \
SU_C(3)\times SU_L(2)\times U_Y(1)\ \
\begin{array}{c}
u,\,v \\ \to
\end{array}\ \
SU_C(3)\times U_e(1).\end{aligned}$$ Notice that in order to break $SU_C(3)\times SU_L(3)\times U_N(1)$ into $SU_C(3)\times SU_L(2)\times U_Y(1)$, only the scalar triplet $\chi$ is required. The covariant derivative in the triplet representation is given by $${\cal
D}_\mu=\partial_\mu-ig\frac{\lambda^a}{2}A^a_\mu-ig_NN\frac{\lambda^9}{2}N_\mu,$$ where $\lambda^9=2\,{\rm diag}\{1,1,1\}/3$, and $\lambda^a$ ($a=1\cdots 8$) are the Gell-Mann matrices. The generators are normalized as ${\rm Tr}(\lambda^a \lambda^b)=2\delta^{ab}$ and ${\rm Tr}(\lambda^9 \lambda^9)=2$. In the first stage of SSB, five generators of $SU_L(3)$ along with the one associated with $U_N(1)$ are broken, [*i.e.*]{} $\lambda^a <\chi>_0\neq 0$, for $a=4, \ldots, 9$. The linear combination $Y=(3\sqrt{2}N\lambda^9-\lambda^8)/\sqrt{3}$ annihilates the vacuum and can be identified with the hypercharge operator. In this stage the three exotic quarks and the gauge bosons associated with the broken generators of the $331$ group $Y^0$, $Y^\pm$, and $Z^\prime$ acquire mass. The exotic quarks have the same electric charge as the SM quarks, namely, $Q_{D_{1,\,2}}=-1/3$ and $Q_T=2/3$. As for the massive gauge bosons, both $Y^0$ and $Y^\pm$ are complex, whereas $Z^\prime$ is a real field with no quantum numbers from the electroweak group.
At the Fermi scale, when $SU_C(3)\times SU_L(2)\times U_Y(1)$ is broken down to $SU_C(3)\times U_e(1)$, the masses of the heavy particles receive new contributions. The diagonalization of the complete Higgs kinetic-energy sector leads to the following mass-eigenstate fields: $$\begin{aligned}
Y^{0(*)}_\mu &=&\frac{1}{\sqrt{2}}\left(A^4_\mu \mp iA^5_\mu\right), \\
Y^\mp_\mu&=&\frac{1}{\sqrt{2}}\left(A^6_\mu \mp iA^7_\mu\right),\\
W^\pm_\mu&=&\frac{1}{\sqrt{2}}\left(A^1_\mu \mp iA^2_\mu\right),\end{aligned}$$ with $m^2_{Y^0}=g^2(w^2+u^2)/4$, $m^2_{Y^\pm}=g^2(w^2+v^2)/4$, and $m^2_W=g^2(u^2+v^2)/4$. The symmetry-breaking hierarchy yields a splitting between the bilepton masses:
$$\label{splitting} |m^2_{Y^0}-m^2_{Y^\pm}|\leq m^2_{W}.$$
It is straightforward to obtain the explicit Lagrangian for the current sector. We will concentrate only on those terms involving the complex field $Y^0$, which in the lepton sector only couples to neutrinos, whereas in the quark sector it couples to both SM and exotic quarks as follows: $$\label{l1} {\cal
L}^{NC}_{Y^0}=\frac{g}{\sqrt{2}}\left(-\sum_{i=1,\,2}\bar{d}_{iL}\gamma^\mu
D_{iL}+\bar{u}_{3L}\gamma^\mu T_L\right)Y^0_\mu +{\rm H.c.}$$ This is the only term of the fermion sector that contributes to the one-loop induced $Y^0Y^{0*}\gamma$ vertex, whereas in the bosonic sector there are contributions from both gauge and charged scalar fields. In this work we will not consider those contributions arising from the latter and concentrate only on the Yang-Mills sector.
The Yang-Mills sector of 331 models
------------------------------------
In order to calculate the gauge-sector contributions to the $Y^0Y^{0*}\gamma$ vertex, it is necessary to introduce the gauge-fixing term. We found it convenient to use the unitary gauge for our calculation. Since the Yang-Mills sector was discussed to a certain extent in the case of the minimal version of the model [@Tavares-331], we refrain from presenting a more detailed discussion and focus on those points relevant for the present discussion. The Yang-Mills sector associated with the group $SU_L(3)\times U_N(1)$ is given by $${\cal L}_{YM}=-\frac{1}{4}F^a_{\mu \nu}F^{\mu
\nu}_a-\frac{1}{2}N_{\mu \nu}N^{\mu \nu},$$ where $F^a_{\mu \nu}=\partial_\mu A^a_\nu-\partial_\nu
A^a_\mu+f^{abc}A^b_\mu A^c_\nu$ and $N_{\mu \nu}=\partial_\mu
N_\nu-\partial_\nu N_\mu$, being $f^{abc}$ the structure constants of the group $SU_L(3)$. We can write this Lagrangian as $$\label{L_YM} {\cal L}_{YM}={\cal L}^{SM}_{YM}+{\cal
L}^{SM-NP}_{YM}+{\cal L}^{NP}_{YM},$$ where the first term represents the Yang-Mills sector associated with the electroweak group: $${\cal L}^{SM}_{YM}=-\frac{1}{4}F^i_{\mu \nu}F^{\mu
\nu}_i-\frac{1}{4}B_{\mu \nu}B^{\mu \nu}, \ \ \ \ \ i=1,\,2,\,3.$$ The term ${\cal L}^{SM-NP}_{YM}$ represents the interactions between the SM gauge fields and the heavy ones. It can be written in the following $SU_L(2)\times U_Y(1)$-invariant form $$\begin{aligned}
\label{15} {\cal L}^{SM-NP}_{YM}&=&-\frac{1}{2}\left(D_\mu
Y_\nu-D_\nu Y_\mu\right)^\dag \left(D^\mu Y^\nu-D^\nu
Y^\mu\right)-iY^\dag_\mu\left( g{\bf F}^{\mu
\nu} +g'{\bf B}^{\mu \nu}\right)Y_\nu \nonumber \\
&&-\frac{ig}{2}\frac{\sqrt{3-4s^2_W}}{c_W}Z^\prime_{\mu}\left(Y^\dag_\nu
\left(D^\mu Y^\nu-D^\nu Y^\mu\right)-\left(D^\mu Y^\nu-D^\nu
Y^\mu\right)^\dag Y_\nu\right),\end{aligned}$$ where $Y^\dag_\mu=(Y^{0*}_\mu, Y^+_\mu)$ is a doublet of the electroweak group with hypercharge $-1$ and $D_\mu=\partial_\mu-ig{\bf A}_\mu +ig'{\bf B}_\mu$ is the covariant derivative associated with this group. In addition, we have introduced the definitions ${\bf F}_{\mu
\nu}=\sigma^iF^i_{\mu \nu}/2$, ${\bf A}_\mu=\sigma^iA^i_\mu/2$, and ${\bf B}_\mu=YB_\mu/2$, with $\sigma^i$ the Pauli matrices. Finally, the last term in Eq. (\[L\_YM\]) is also invariant under the electroweak group and comprises the interactions between the heavy gauge fields: $$\begin{aligned}
{\cal L}^{NP}_{YM}&=&-\frac{1}{4}Z^\prime_{\mu \nu}{Z^\prime}^{\mu
\nu}+\frac{g^2}{4}\left(Y^\dag_\mu \frac{\sigma^i}{2}Y_\nu
-Y^\dag_\nu \frac{\sigma^i}{2}Y_\mu\right)\left(Y^{\dag \mu}
\frac{\sigma^i}{2}Y^\nu
-Y^{\dag \nu} \frac{\sigma^i}{2}Y^\mu\right)\nonumber \\
&&+\frac{3g^2}{16}\left(Y^\dag_\mu Y_\nu-Y^\dag_\nu
Y_\mu\right)\left(Y^{\dag \mu} Y^\nu-Y^{\dag \nu} Y^\mu
\right)-\frac{3g^2}{4}Z^\prime_{\mu}Y^\dag_\nu
\left(Z^\mu_2 Y^\nu-Z^\nu_2 Y^\mu \right)\nonumber \\
&&-\frac{ig}{2}\frac{\sqrt{3-4s^2_W}}{c_W}\,Y^\dag_\mu
Y_\nu\,{Z^\prime}^{\mu \nu}.\end{aligned}$$
From these Lagrangians we have derived the Feynman rules shown in Table \[tab1\], which are necessary for the calculation of the gauge boson contribution to the $Y^0Y^{0*}\gamma$ vertex. These results are in agreement with Ref. [@Long-1]
--------------------------------------------------------------------------------------------------------------------
Vertex Feynman rule
------------------------------------------------ -------------------------------------------------------------------
$Y^0_\alpha $ ig\left((p-k_2)_\lambda
(p)W^-_\lambda (k_1)Y^+_\rho (k_2)$ g_{\rho \alpha}+(k_2-k_1)_\alpha g_{\lambda \rho}+(k_1-p)_\rho
g_{\alpha
\lambda}\right)/\sqrt{2}$
$A_\mu (q)V^+_\lambda(k_1) V^-_\rho (k_2)$ $
-ie\left((k_2-k_1)_\mu g_{\lambda \rho}+(q-k_2)_\lambda g_{\mu
\rho} +(k_1-q)_\rho g_{\mu \lambda}\right)$
$Y^0_\alpha Y^{0*}_\beta Y^+_\lambda Y^-_\rho$ $
ig^2\left(2g_{\alpha \rho}g_{\beta \lambda}-g_{\alpha
\lambda}g_{\beta \rho}-g_{\alpha \beta}g_{\lambda \rho}\right)/2$
$Y^0_\alpha Y^{0*}_\beta W^+_\lambda W^-_\rho$ $
ig^2\left(2g_{\alpha \lambda}g_{\beta \rho}-g_{\alpha
\beta}g_{\lambda \rho}-g_{\alpha \rho}g_{\beta \lambda}\right)/2$
$A_\mu Y^0_\alpha Y^+_\lambda W^-_\rho$ $ ige\left(g_{\alpha
\lambda}g_{\rho \mu}-2g_{\alpha \mu}g_{\lambda \rho}+g_{\alpha
\rho}g_{\lambda \mu}\right)/\sqrt{2}$
--------------------------------------------------------------------------------------------------------------------
: \[tab1\]Feynman rules necessary for the calculation of the gauge boson contribution to the $Y^0Y^{0*}\gamma$ vertex. $V^\pm$ stands for $Y^\pm$ or $W^\pm$. All the 4-momenta are directed inward.
The static electromagnetic properties of the $Y^0$ boson {#cal}
========================================================
We turn now to the calculation of the static electromagnetic properties of the no self-conjugate neutral boson $Y^0$. In the usual notation, the most general on-shell $Y^0_\alpha Y^0_\beta A_\mu$ vertex can be written as [@Hagiwara; @nieves] $$\label{elecprop} \Gamma_{\alpha \beta \mu}=i\,e\left(2\Delta
\kappa (q_\beta g_{\alpha \mu}-q_\alpha g_{\beta
\mu})+\frac{4\,\Delta Q}{m^2_{Y^0}}\,p_\mu q_\alpha
q_\beta+2\Delta \widetilde{\kappa}\,\epsilon_{\alpha \beta \mu
\lambda}q^\lambda+\frac{4\,\Delta
\widetilde{Q}}{m^2_{Y^0}}\,q_\beta \epsilon_{\alpha \mu \lambda
\rho}p^\lambda q^\rho\right).$$ Note that the $p_\mu g_{\alpha \beta}$ term, which is present for a charged particle, is absent as it would violate gauge invariance. This term can only arise through the electromagnetic covariant derivative. The magnetic (electric) dipole moment $\mu_{Y^0}$ ($\widetilde {\mu}_{Y^0}$) and the electric (magnetic) quadrupole moment $Q_{Y^0}$ ($\widetilde{Q}_{Y^0}$) are given in terms of the electromagnetic form factors as follows $$\begin{aligned}
\label{mu}
\mu_{Y^0}&=&\frac{e}{2\,m_{Y^0}}(2+\Delta \kappa), \\
\label{Q}
Q_{Y^0}&=&-\frac{e}{m^2_{Y^0}}(1+\Delta \kappa+\Delta Q),\\
\label{mutilde}
\widetilde{\mu}_{Y^0}&=&\frac{e}{2\,m_{Y^0}}\Delta \widetilde{\kappa},\\
\label{Qtilde} \widetilde{Q}_{Y^0}&=&-\frac{e}{m^2_{Y^0}}(\Delta
\widetilde{\kappa}+\Delta \widetilde{Q}).\end{aligned}$$
The CP-violating form factors $\Delta \widetilde{\kappa}$ and $\Delta \widetilde{Q}$ are not induced in the $331$ model with right-handed neutrinos. In the fermionic sector, $\Delta
\widetilde \kappa$ can be induced at the one-loop level, but it requires that the neutral boson couples to both left- and right-handed fermions simultaneously [@Burgess; @TTU].
In order to compute the contributions to the on-shell $Y^0Y^{0*}\gamma$ vertex, we used the method described in Refs. [@Tavares-331; @Stuart], which is a generalization of the Passarino-Veltman reduction scheme [@Passarino]. Since the gauge invariant form (\[elecprop\]) is obtained once all the contributions are summed over, the absence of the $p_\mu g_{\alpha
\beta}$ term and the cancellation of ultraviolet divergences will serve as a test to check the correctness of our results. Below we will present separately the fermionic and gauge boson contributions to the $\Delta Q$ and $\Delta \kappa$ form factors.
Fermion contribution
--------------------
![\[Fermion-diag\] Feynman diagrams for the fermion contributions to the static quantities of the $Y^0$ boson.](Y0-fermion.eps){width="3.5in"}
The contribution of this sector comes from the Feynman diagrams shown in Fig. \[Fermion-diag\]. There are two triangle diagrams for each quark pair $(d$, $D_1)$, $(s$, $D_2)$, and $(t$, $T)$. We will denote by $q$ the SM quark and by $q^\prime$ the exotic one. Once the reduction scheme described above is applied to solve the loop amplitudes, the contribution from the ($q$, $q^\prime$) quark pair can be written as
$$\begin{aligned}
\label{DQ_fer} \Delta Q^{\rm Ferm.}&=& 6\,a\,Q\Bigg\{
\frac{2}{\Delta_{qq^\prime}}\,\left( x_{q^\prime} - x_q \right)
\,\left( 1
-3\,\left(x_{q^\prime}+x_q\right)+2\,\left(x_{q^\prime}-x_q\right)^2\right)
\,{\rm arccosh}\left(\frac{x_{q^\prime} + x_q
-1}{2\,{\sqrt{x_{q^\prime} \,x_q
}}}\right)\nonumber\\&+&4\left(x_{q^\prime} -x_q\right) + \left(
x_{q^\prime}+x_q-2\,\left(x_{q^\prime}-x_q\right)^2 \right)
\,\log \left(\frac{x_{q^\prime} }{x_q }\right) \Bigg\},\end{aligned}$$
$$\begin{aligned}
\label{Dk_fer} \Delta \kappa^{\rm Ferm.}&=&9\,a\,Q\,\left(
x_{q^\prime} - x_q \right) \, \Bigg\{
\frac{2}{\Delta_{q{q^\prime}} }\,\left(x_{q^\prime} + x_q
-\left(x_{q^\prime}-x_q\right)^2 \right) \, {\rm
arccosh}\left(\frac{x_{q^\prime} + x_q-1}{2\,{\sqrt{x_{q^\prime}
\,x_q }}}\right)\nonumber\\ &-& 2 + \left( x_{q^\prime} - x_q
\right) \, \log \left(\frac{x_{q^\prime} }{x_q }\right) \Bigg\},\end{aligned}$$
with $a=g^2/(96\,\pi^2)$, $x_i=m_i^2/m_{Y^0}^2$ and $\Delta_{ij}^2=(x_i+x_j-1)^2-4\,x_j\,x_j$. A factor of 3 has been included to account for the quark color number, and $Q$ stands for the quark charge in units of that of the positron. Eqs. (\[DQ\_fer\]) and (\[Dk\_fer\]) are to be summed over the $(d$, $D_1)$, $(s$, $D_2)$, and $(t$, $T)$ quark pairs.
Both $\Delta Q^{\rm Ferm.}$ and $\Delta \kappa^{\rm Ferm.}$ are antisymmetric under the interchange of $x_q$ and $x_{q'}$, which means that they vanish when the $q$ and $q'$ quarks are degenerate. Since it is expected that the exotic quarks are heavier than the SM ones ($x_{q'}\gg x_{q}$), it would be interesting to have analytical expressions for the scenario in which $x_q\sim 0$ and $x_{q^\prime}$ is arbitrary. After some algebra, Eqs. (\[DQ\_fer\]) and (\[Dk\_fer\]) yield
$$\begin{aligned}
\Delta Q^{\rm Ferm.}&=&12\,a\,Q\,x_{q^\prime}
\left(2+\left(2\,x_{q^\prime}-1\right)
\log\left(\frac{|x_{q^\prime}-1|}{x_{q^\prime}}\right)\right),
\\
\Delta \kappa^{\rm
Ferm.}&=&18\,a\,Q\,x_{q^\prime}\left(1+x_{q^\prime}
\log\left(\frac{|x_{q^\prime}-1|}{x_{q^\prime}}\right)\right).\end{aligned}$$
In the heavy-mass limit, $\Delta \kappa^{\rm Ferm.}\to -9\,a\,Q$ and $\Delta Q^{\rm Ferm.}\to 0$. Of course when $x_{q^\prime}\to
0$, the degenerate fermion case is recovered and both form factors vanish.
Gauge boson contribution
------------------------
![\[Boson-diag\]Feynman diagrams for the gauge boson contributions to the static quantities of the $Y^0$ boson.](Y0-boson.eps){width="3.5in"}
We found it convenient to make the calculation for this contribution in the unitary gauge. Although the triangle diagrams give rise to fourth-order tensor integrals due to the longitudinal part of the gauge boson propagators, our calculation scheme is suited to work out this class of terms straightforwardly. The static electromagnetic properties of the $Y^0$ boson arise from the six Feynman diagrams shown in Fig. \[Boson-diag\], whose amplitudes can be constructed out of the Feynman rules presented in Table \[tab1\]. After solving the loop integrals, the full amplitude can be cast in the form of Eq. (\[elecprop\]), which leads to
$$\begin{aligned}
\label{DQ_bos}\Delta Q^{\rm Bos.}&=& \frac{\,a}{2\,x_Y \,x_W
}\,\left(\Delta_{YW}^2+ 12\,x_X\,x_W\right)
\,\Bigg\{4\,\left(x_Y-x_W\right)+4\,
\left(\left(x_Y+x_W\right)-2\,\left(x_Y -x_W\right)^2\right)
\,\log \left(\frac{x_Y }{x_W }\right) \nonumber\\
&+& \frac{2}{\Delta_{YW}}\,\left( x_Y - x_W \right) \, \left( 1 -
3\left(\,x_W+x_Y\right) +2\,\left(x_Y-x_W\right)^2 \right) \, {\rm
arccosh}\left(\frac{ x_Y + x_W -1}{2\,{\sqrt{x_Y \,x_W
}}}\right)\Bigg\},\end{aligned}$$
and $$\begin{aligned}
\label{Dk_bos} \Delta \kappa^{\rm Bos.}&=& \frac{3\,a}{2\,x_Y
\,x_W }\,\Bigg\{\left( x_Y - x_W \right)
\,\left(1+\left(x_Y-x_W\right)^2 - 2\,\left(x_Y +x_W-6\,x_Y\,x_W
\right) \right) \nonumber\\&-&
\Big(x_Y\,\left(1-x_Y\right)^2\,\left(3+x_Y\right)+
x_Y\,x_W\,\left(x_Y\,\left(8\,x_Y-9\,x_W-13\right)+9\right)\nonumber\\&+&
x_W\,\left(1-x_W\right)^2\,\left(3+x_W\right)+x_Y\,x_W\,\left(x_W\,\left(8\,x_W-9\,x_Y-13\right)+9\right)
\Big) \, \log\left(\frac{x_Y }{x_W }\right) \nonumber\\ &-&
2\,\left( x_Y - x_W \right) \,{\Delta_{YW}} \left( 3
-\left(x_Y-x_W\right)^2 + 2\,\left(x_Y +x_W+6\,x_Y\,x_W \right)
\right) \,{\rm arccosh}\left(\frac{x_Y + x_W-1 }{2\,{\sqrt{x_Y
\,x_W }}}\right) \Bigg\},\end{aligned}$$ with $x_W=m_W/m_{Y^0}$ and $x_{Y}=m_{Y^\pm}/m_{Y^0}$. Due to the mass splitting (\[splitting\]), the bileptons would be nearly degenerate if $m_{Y^\pm}\ge m_W$. Therefore it is worth obtaining analytical expressions for the form factors in this scenario. Eqs. (\[DQ\_bos\]) and (\[Dk\_bos\]) yield the following results for $x_Y=1$:
$$\begin{aligned}
\label{DQ_bos-1}\Delta Q^{\rm Bos.}&=& \frac{a}{2} \,\left( 8 +
x_W\right)\,\Bigg\{ \, 4\,\left(1-x_W\right)+\left( 1 + x_W
\,\left(2\,x_W-5 \right) \right)\,\log(x_W)\nonumber\\
&+&\frac{2}{{\sqrt{\left(x_W-4 \right) \,x_W }}}\,\left( 1 - x_W
\right) \,x_W \, \left(2\,x_W -7 \right) {\rm
arccosh}\left(\frac{\sqrt{x_W}}{2}\right) \Bigg\},\end{aligned}$$
and $$\begin{aligned}
\label{Dk_bos-1} \Delta \kappa^{\rm Bos.}&=&
\frac{3\,a}{4}\Bigg\{2\,\left(1 - x_W \right) \,\left( 8 + x_W
\right) +\left(16 + \left( x_W-3 \right) \,x_W \,\left( 12 + x_W
\right)\right)\,\log(x_W)\nonumber\\ &-&2\,\left(x_W -1 \right)
\,{\sqrt{\left(x_W-4 \right) \,x_W }}\, \left( 12 + x_W
\right){\rm arccosh}\left(\frac{\sqrt{x_W}}{2}\right) \Bigg\}.\end{aligned}$$
From the previous results, it is easy to see that the contributions to the $Y^0$ form factors are antisymmetric under the interchange of the masses of the particles circulating in the loop, which means that they vanish when these particles are degenerate, i.e. $m_q=m_{q'}$ and $m_W=m_Y$.
Numerical evaluation {#num}
====================
We turn now to the numerical analysis of the $Y^0$ form factors. We would like to emphasize that our main aim is to estimate the size and behavior of the form factors in some illustrative scenarios rather than making a careful study of the allowed parameter space of the model, which is beyond the present work.
In addition to the mass of the $Y^0$ boson, there are four other unknown parameters which enter into the $Y^0$ form factors. These are the masses of the three exotic quarks $m_{D_1}$, $m_{D_2}$, and $m_T$, together with the charged bilepton mass $m_{Y^\pm}$. Since the splitting between the bilepton masses is bounded, i.e. $|m^2_{Y^0}-m^2_{Y^\pm}|\leq m^2_{W^+}$, $m_{Y^\pm}$ is bounded once $m_{Y^0}$ is fixed. Although in the minimal 331 model the bilepton masses are bounded from above at 1 TeV as a result of matching the gauge couplings constants at the Fermi scale, which leads to $\sin \theta_W \le 1/4$ [@Ng], in the version with right-handed neutrinos the same condition leads to $\sin \theta_W
\le 3/4$, which yields less stringent constraints on the bilepton masses. The most recent bounds indicate that $m_{Y^0}$ is greater than 100 GeV [@Long; @Bounds]. We will thus analyze the form factors in the range 100 GeV $\le m_{Y^0}\le$ 500 GeV.
As for the exotic quarks, although there are bounds on the masses of the exotic quarks predicted in other SM extensions, to our knowledge there are no such bounds in the specific case of the 331 model with right-handed neutrinos. However, it is reasonable to assume that the exotic quarks are heavier than the top quark. Therefore, for the corresponding masses we will consider values ranging from 200 to 800 GeV. Furthermore, as will be shown below, the maximal value of the fermionic contribution to the static quantities of the $Y^0$ boson is reached in this mass range. Below we will evaluate separately the fermion and boson contribution to the $Y^0$ form factors.
Fermion contribution
--------------------
The general behavior of the fermion contribution to the static quantities of the charged $W$ boson has been discussed to a large extent in the literature [@Burgess; @TTU; @WWg-SM; @WWg-NP]. The main peculiarity of the CP-even electromagnetic form factors of a neutral particle is that the contribution arising from a degenerate fermion pair vanishes since the amplitude is antisymmetrical under the interchange $m_q \to m_{q^\prime}$. Although the latter is also true for an arbitrarily charged gauge boson, their CP-even static quantities do not vanish for degenerate fermions since $Q_q \ne Q_{q^\prime}$. In the following analysis we will consider the scenario in which the exotic quarks are degenerate, with a mass $m_Q$. As already explained, we will consider the range 200 GeV$\leq m_Q \leq $ 800 GeV. In Figs. \[DK-fer-fig1\] and \[DQ-fer-fig1\] we show the $\Delta
\kappa$ and $\Delta Q$ form factors as a function of $m_Q$ for some illustrative values of the neutral bilepton mass $m_{Y^0}$, namely, 300, 350 and 400 GeV. We note that the curves displayed in Figs. \[DK-fer-fig1\] and \[DQ-fer-fig1\] are the full contribution from the three quark families. In the range under consideration for $m_Q$, the form factors are considerable smaller for $m_{Y^0} \le $ 200 GeV. We can clearly observe that there is a dramatic enhancement in the $m_{Y^0}$ threshold $m_{Y^0}=m_q+m_Q$, which stems from the fact that the respective quark pair ($q,\,Q$) can be directly produced from the bilepton provided that $m_{Y^0}\ge m_q+m_Q$. Above the threshold and in the heavy mass limit, both form factors decrease rapidly and vanish when $m_Q$ is much larger than the mass of the SM quarks. It is interesting to point out that the individual contributions to $\Delta \kappa$ from each fermion pair tend to the constant value $-9\,a$ in the heavy fermion limit, whereas $\Delta Q$ vanishes. This is in accordance with the decoupling theorem [@Appelquist]: since $\Delta \kappa$ is associated with a term that arises from dimension-four operators, it is expected to be sensitive to nondecoupling effects of heavy physics, whereas $\Delta Q$ cannot be sensitive to this class of effects as it is associated with a term generated by a nonrenormalizable dimension-six operator [@Inami]. In spite of the nondecoupling nature of the contributions from each quark family, the full $\Delta \kappa$ vanishes in the heavy fermion limit. It turns out that the partial contributions, which are proportional to the quark charge, become constant and their sum vanishes since it is proportional to $Q_{D_1}+Q_{D_2}+Q_T=0$. This is to be contrasted with the behavior of the fermion contribution to the $\Delta \kappa$ form factor of the $W$ boson in the heavy fermion limit. In this case the contribution of each quark family is proportional to $Q_u-Q_d=1$, thus the sum over the three quark families does not vanish.
From Figs. \[DK-fer-fig1\] and \[DQ-fer-fig1\] we can conclude that $\Delta \kappa $ can be of the order of $10\,a$, whereas $\Delta Q$ is about one order of magnitude below. This behavior is similar to that observed for the size of the fermion contribution to the electromagnetic form factors of the $W$ boson in the SM [@WWg-SM] and some of its extensions [@WWg-NP]. Although the maximal value of the form factors is reached around the threshold $m_{Y^0}= m_q+m_Q$, there is no reason to expect that such a scenario is realized in nature. The scenarios shown through Figs. \[DK-fer-fig1\] and \[DQ-fer-fig1\] are very illustrative of the behavior of the quark contribution to the static quantities of the $Y^0$ boson and so we refrain from presenting the most general case in which the exotic quark are nondegenerate.
![\[DK-fer-fig1\]The fermion contribution to the $\Delta \kappa$ form factor as a function of the mass of the exotic quarks, which are assumed to be degenerate, for different values of the neutral bilepton mass: 300 (continuous line), 350 (dashes), and 400 GeV (dashes and points).](DK-fer-fig1){width="2.5in"}
![\[DQ-fer-fig1\]The same as in Fig. \[DK-fer-fig1\] for the $\Delta Q$ form factor.](DQ-fer-fig1){width="2.5in"}
Gauge boson contribution
------------------------
In Figs. \[DK-bos-fig1\] and \[DQ-bos-fig1\] we show the contributions from the gauge bosons to the electromagnetic form factors of the $Y^0$ boson as a function of $m_{Y^0}$ when the bileptons are degenerate and also when $m_{Y^\pm}$ reaches its minimal and maximal allowed values: $m_{Y^\pm}^2=m_{Y^0}^2-m_W^2$ and $m_{Y^\pm}^2=m_{Y^0}^2+m_W^2$. The form factors are restricted to lie in the strip bounded by the extremal lines. Although the form factors seem to increase indefinitely as $m_{Y^0}$ increases, they tend to a constant value for very large $m_{Y^0}$. There is no contradiction with the decoupling limit as one cannot make large the internal mass $m_{Y^\pm}$ while keeping fixed the external mass $m_{Y^0}$ due to the bound (\[splitting\]). Furthermore, the quantities which have physical meaning are the magnetic dipole and electric quadrupole moments \[See Eqs. (\[mu\]) and (\[Q\])\], which do vanish for very large $m_{Y^0}$. From Figs. \[DK-bos-fig1\] and \[DQ-bos-fig1\], it is evident that $\Delta \kappa$ is one order of magnitude larger than $\Delta Q$ for each value of $m_{Y^0}$. The fact that the size of $\Delta \kappa$ is larger than that of $\Delta Q$ has been also observed for the case of the electromagnetic form factors of the charged $W$ boson form within all of the theories studied up to now.
![\[DK-bos-fig1\]The gauge boson contribution to the $\Delta \kappa$ form factor of the $Y^0$ boson as a function of its mass when $m_{Y^\pm}=m_{Y^0}$ (continuous line), $m_{Y^\pm}^2=m_{Y^0}^2-m_W^2$ (dashes) and $m_{Y^\pm}^2=m_{Y^0}^2+m_W^2$ (dashes and points). The last two curves correspond to the case when the $m_{Y^\pm}$ reaches its maximal and minimal allowed values. $\Delta \kappa$ is restricted to lie in the strip bounded by the extremal lines.](DK-bos-fig1.eps){width="2.5in"}
![\[DQ-bos-fig1\]The same as in Fig. \[DK-bos-fig1\] for the $\Delta Q$ form factor.](DQ-bos-fig1.eps){width="2.5in"}
To obtain the total contribution to the $Y^0$ form factors, it is necessary to sum over the fermion and gauge boson contributions, along with the one arising from the scalar sector of the theory. Apart from the specific details of the model, we do not expect that the size of the scalar contribution is different to that observed in the case of the $W$ form factors. In that case, the scalar sector yields a marginal correction. In fact a very large number of Higgs bosons would be required to yield a large correction.
Summary {#con}
=======
A neutral vector boson can have static electromagnetic properties provided that the associated field is no self-conjugate. We have presented the calculation of the static electromagnetic properties of the neutral no self-conjugate boson $Y^0$ which arises in the $SU(3)_c\times SU(3)_L \times U(1)_N$ model with right-handed neutrinos. This model is interesting since it requires that the fermion families be a multiple of the quark color number in order to cancel anomalies, thereby suggesting a solution to the family problem. It has been pointed out that the $Y^0$ boson is a good candidate in high energy experiments since it may be the source of neutrino oscillations as it is responsible of lepton-number violating interactions. The calculation was done in the unitary gauge and the fermion and gauge boson contributions were obtained by a modified version of the Passarino-Veltman reduction scheme. As a crosscheck, the form factors were obtained independently by the Feynman parameter technique and the results, expressed in terms of parametric integrals, were numerically evaluated and compared with the results obtained via the Passarino-Veltman method. A perfect agreement was observed. In this model the $Y^0$ boson only couples to left-handed fermions and so only the CP-even form factors are induced at the one-loop level. The behavior of both contributions was analyzed. In the fermion sector there is the contribution of the three quark pairs $(D_1,\, d)$, $(D_2,\,
s)$, and $(T,\,t)$, with $D_1$, $D_2$, and $T$ three exotic quarks whose charge is identical to that of the respective SM quark. As for the gauge boson contribution, there is the contribution of a singly charged bilepton $Y^\pm$. The symmetry breaking hierarchy yields an upper bound on the splitting between the bilepton masses such that $|m_{Y^0}^2-m_{Y^\pm}^2|\le m_W^2$, which means that the bileptons are nearly degenerate provided that their mass is heavier than $m_W$. From the numerical analysis we can conclude that the size of the $Y^0$ form factors is somewhat similar to that observed for the $W$ boson form factors in the SM and some of its extensions.
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|
Campaign employs star power to combat nursing shortage.
A marketing campaign aimed at encouraging high school students to consider nursing as a career taps the popularity of a television star to help combat the nursing shortage. Army nurse Colleen McMurphy from the television series "China Beach," portrayed by actress Dana Delany, is the centerpiece of a campaign that was initiated by the Texas Hospital Assn. and distributed free to the nation's 17,000 high schools last winter. |
A Dallas-area state representative has introduced legislation aimed at preventing anyone from discriminating against those who want to research intelligent design in Texas. Rep. Bill Zedler of Arlington sponsored House Bill HB2454 because he believes that colleges are keeping important research into the controversial theory from happening.
"It appears there is academic freedom to debate every issue other than this one," he said.
Calling it a "free speech issue," Zedler believes that those who want to study this particular theory do not have equal footing with other scientists.
"Some schools have a guy out there praising Hugo Chavez and nothing happens to him. You have others espousing communism and nothing happens," he explained. "Lo and behold, you talk about anything that might lead to intelligent design, I mean to tell you, [they] are gonna go after you."
Zedler claims that professors are being denied tenure and even losing their jobs because they want to spend university research dollars looking into the theory of intelligent design. When asked if he could cite specific examples, he was unable to, but said we could e-mail him for that information. At the time of posting, we had not received a response to our request for information in that regard.
For his part, Zedler says researchers should be able to "follow the evidence" regardless of where it leads. He believes no one should be discriminated against no matter what theory they put forth and he hopes HB2454 will prevent witch hunts against those who would want to study any theory.
"What this will do is basically put everybody on notice that somebody shouldn't have to be tarred and feathered [for this]," he said.
Zedler doesn't believe more left-leaning scientific research like whether homosexuality is a choice or part of genetic code is being discriminated against, but he claims the bill is necessary for legitimate research into intelligent design. |
Beth and her mom wanted a frog-prince groom’s cake so she could have a great photo opportunity kissing her Frog Prince. And of course it was red velvet – Steel Magnolias-style. My first sculpted cake. Green fondant, gold lustre-dusted gumpaste crown. |
/*
* copyright (c) 2007 Michael Niedermayer <michaelni@gmx.at>
*
* This file is part of FFmpeg.
*
* FFmpeg is free software; you can redistribute it and/or
* modify it under the terms of the GNU Lesser General Public
* License as published by the Free Software Foundation; either
* version 2.1 of the License, or any later version.
*
* FFmpeg is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU
* Lesser General Public License for more details.
*
* You should have received a copy of the GNU Lesser General Public
* License along with FFmpeg; if not, write to the Free Software
* Foundation, Inc., 51 Franklin Street, Fifth Floor, Boston, MA 02110-1301 USA
*/
#ifndef AVUTIL_AES_H
#define AVUTIL_AES_H
#include <stdint.h>
extern const int av_aes_size;
struct AVAES;
/**
* Initialize an AVAES context.
* @param key_bits 128, 192 or 256
* @param decrypt 0 for encryption, 1 for decryption
*/
int av_aes_init(struct AVAES *a, const uint8_t *key, int key_bits, int decrypt);
/**
* Encrypt or decrypt a buffer using a previously initialized context.
* @param count number of 16 byte blocks
* @param dst destination array, can be equal to src
* @param src source array, can be equal to dst
* @param iv initialization vector for CBC mode, if NULL then ECB will be used
* @param decrypt 0 for encryption, 1 for decryption
*/
void av_aes_crypt(struct AVAES *a, uint8_t *dst, const uint8_t *src, int count, uint8_t *iv, int decrypt);
#endif /* AVUTIL_AES_H */
|
/*
* Copyright (C) 2018 - present Instructure, Inc.
*
* This file is part of Canvas.
*
* Canvas is free software: you can redistribute it and/or modify it under
* the terms of the GNU Affero General Public License as published by the Free
* Software Foundation, version 3 of the License.
*
* Canvas is distributed in the hope that it will be useful, but WITHOUT ANY
* WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR
* A PARTICULAR PURPOSE. See the GNU Affero General Public License for more
* details.
*
* You should have received a copy of the GNU Affero General Public License along
* with this program. If not, see <http://www.gnu.org/licenses/>.
*/
import React from 'react'
import ReactDOM from 'react-dom'
import AdvancedTabPanel from 'jsx/gradebook/default_gradebook/components/AdvancedTabPanel'
QUnit.module('GradebookSettingsModal AdvancedTabPanel', suiteHooks => {
let $container
let props
suiteHooks.beforeEach(() => {
$container = document.body.appendChild(document.createElement('div'))
props = {
courseSettings: {
allowFinalGradeOverride: false
},
onCourseSettingsChange: sinon.spy()
}
})
suiteHooks.afterEach(() => {
ReactDOM.unmountComponentAtNode($container)
})
function mountComponent() {
ReactDOM.render(<AdvancedTabPanel {...props} />, $container)
}
function findCheckbox(label) {
const $label = [...$container.querySelectorAll('label')].find(
$el => $el.innerText.trim() === label
)
return $container.querySelector(`#${$label.getAttribute('for')}`)
}
function getAllowFinalGradeOverridesCheckbox() {
return findCheckbox('Allow final grade override')
}
QUnit.module('"Allow final grade override" option', () => {
QUnit.module('when "allow final grade override" is enabled', contextHooks => {
contextHooks.beforeEach(() => {
props.courseSettings.allowFinalGradeOverride = true
mountComponent()
})
test('is checked', () => {
const {checked} = getAllowFinalGradeOverridesCheckbox()
strictEqual(checked, true)
})
test('calls the .onCourseSettingsChange callback when changed', () => {
getAllowFinalGradeOverridesCheckbox().click()
strictEqual(props.onCourseSettingsChange.callCount, 1)
})
test('includes the new setting when calling the .onCourseSettingsChange callback', () => {
getAllowFinalGradeOverridesCheckbox().click()
const [{allowFinalGradeOverride}] = props.onCourseSettingsChange.lastCall.args
strictEqual(allowFinalGradeOverride, false)
})
})
QUnit.module('when "allow final grade override" is disabled', contextHooks => {
contextHooks.beforeEach(() => {
props.courseSettings.allowFinalGradeOverride = false
mountComponent()
})
test('is checked', () => {
const {checked} = getAllowFinalGradeOverridesCheckbox()
strictEqual(checked, false)
})
test('calls the .onCourseSettingsChange callback when changed', () => {
getAllowFinalGradeOverridesCheckbox().click()
strictEqual(props.onCourseSettingsChange.callCount, 1)
})
test('includes the new setting when calling the .onCourseSettingsChange callback', () => {
getAllowFinalGradeOverridesCheckbox().click()
const [{allowFinalGradeOverride}] = props.onCourseSettingsChange.lastCall.args
strictEqual(allowFinalGradeOverride, true)
})
})
})
})
|
1. Introduction {#sec1-ijms-20-03840}
===============
Protein arginine methyltransferases (PRMTs) transfer the methyl group from *S*-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, forming monomethylarginine (mMA) and cofactor *S*-adenosyl-L-homocysteine (SAH) \[[@B1-ijms-20-03840],[@B2-ijms-20-03840],[@B3-ijms-20-03840]\]. Therefore, PRMTs can catalyze protein arginine methylation and influence a wide range of cellular processes, including transcriptional regulation, RNA splicing, cell growth and differentiation \[[@B4-ijms-20-03840],[@B5-ijms-20-03840]\]. According to their different biological characteristics, PRMTs are classified in three categories ([Figure 1](#ijms-20-03840-f001){ref-type="fig"}) \[[@B6-ijms-20-03840]\]. Type І PRMTs (PRMT1, 2, 3, 4, 6 and 8) catalyze mono- and asymmetrical dimethylarginine (ADMA) of arginine residues, whereas, Type II PRMTs (PRMT5 and 9) catalyze mono- and symmetrical dimethylarginine (SDMA) \[[@B7-ijms-20-03840]\]. As the only known Type III PRMT, PRMT7 catalyzes monomethylation of arginine \[[@B8-ijms-20-03840]\].
Previous studies showed that over 90% of the arginine methylation in mammalian cells was produced by PRMT1 catalysis \[[@B9-ijms-20-03840]\]. Furthermore, the disordered expression of PRMT1 is associated with a variety of human diseases including pulmonary fibrosis \[[@B10-ijms-20-03840]\], cardiovascular diseases \[[@B11-ijms-20-03840]\], diabetes, renal diseases \[[@B12-ijms-20-03840]\] and cancer in particular \[[@B13-ijms-20-03840],[@B14-ijms-20-03840],[@B15-ijms-20-03840],[@B16-ijms-20-03840]\]. Overexpression of PRMT1 can promote the growth, survival, metastasis and invasion of tumor cells \[[@B17-ijms-20-03840]\]. Therefore, PRMT1 is considered to be a potential target for the treatment of cancer. Currently, a number of PRMT1 inhibitors have been reported ([Figure 2](#ijms-20-03840-f002){ref-type="fig"}). In 2004, AMI-1 was found through high-throughput screening as the first compound which displayed selectivity to PRMTs over protein lysine methyltransferases (PKMTs) \[[@B18-ijms-20-03840]\]. Later, a number of PRMT1 inhibitors were reported, including RM65 \[[@B19-ijms-20-03840]\], Stilbamidine \[[@B20-ijms-20-03840]\], DB75 \[[@B21-ijms-20-03840]\], Allantodapsone \[[@B20-ijms-20-03840]\] and DCLX069 \[[@B22-ijms-20-03840]\]. However, the weak potency against PRMT1 limited their therapeutic applications. Therefore, there is an urgent need to discover potent PRMT1 inhibitors.
In the current study, a series of 1-substituted 1*H*-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and compound **9a** was discovered to be a potent PRMT1 inhibitor, which contained strong abilities to down-regulate Wnt/β-catenin signaling pathway. Therefore, we suggest that compound **9a** could be an important lead compound for future PRMT-guided drug discovery.
2. Results and Discussion {#sec2-ijms-20-03840}
=========================
2.1. The Molecular Design {#sec2dot1-ijms-20-03840}
-------------------------
The crystal structure of human PRMT1 (hPRMT1) has not yet been solved, so we used our previously published homology model \[[@B23-ijms-20-03840]\] in the current study. As shown in [Figure 3](#ijms-20-03840-f003){ref-type="fig"}A, the active site of PRMT1 is composed of the SAM and substrate arginine binding sites. In theory, if a compound can bind to any sub-site, the methylation will be disturbed. In the current study, we used the arginine binding site as a focus with which to design novel inhibitors. As [Figure 3](#ijms-20-03840-f003){ref-type="fig"}B shows, there are three amino acids with aromatic rings (Tyr47, Tyr156 and Tyr160) that form a hydrophobic pocket, so we designed two aromatic rings to form π-π and hydrophobic interactions with them, which were represented as AR1 and AR2. Two negative charged residues Glu152 and Glu161 were reported to form strong interactions with substrate arginine \[[@B24-ijms-20-03840],[@B25-ijms-20-03840]\], so two positive charged centers were designed, which were represented as PC1 and PC2. In our previous publication \[[@B24-ijms-20-03840]\], a group of compounds with central core of phenyl (AR1) substituted furan (AR2) were discovered as PRMT1 inhibitors. In the current study, we used the tetrazole ring to replace the furan ring as the bioisosteres for designing novel PRMT1 inhibitors. Moreover, in order to investigate the linker length between PC1 and PC2, the different linking groups were incorporated, such as ethyl, propyl, piperazine. According to the pharmacophores and analysis, a series of 1-phenyl substituted tetrazole derivatives ([Figure 3](#ijms-20-03840-f003){ref-type="fig"}C) were designed, in which the benzene and tetrazole ring were according to AR1 and AR2 respectively, and the tertiary amine and secondary amine were according to the PC1 and PC2, respectively.
2.2. Chemistry {#sec2dot2-ijms-20-03840}
--------------
A series of 1,5-substituded tetrazole derivatives **9a**--**f**, **10a**--**e**, **16a**--**e, 18a**--**e** and **20** were synthesized as illustrated in [Scheme 1](#ijms-20-03840-sch001){ref-type="scheme"}, [Scheme 2](#ijms-20-03840-sch002){ref-type="scheme"} and [Scheme 3](#ijms-20-03840-sch003){ref-type="scheme"}. In [Scheme 1](#ijms-20-03840-sch001){ref-type="scheme"}, the commercially available substituted anilines **1a--f** were respectively reacted with ethyl oxalyl monochloride in the presence of triethylamine in anhydrous dichloromethane to generate the compounds **2a**--**f** in good yields (90%--95%). Treatment of **2a**--**f** with triphenylphosphine under refluxing in carbon tetrachloride gave compounds **3a**--**f**, which were reacted directly with sodium azide in acetonitrile to generate 1-substituted phenyl-1*H*-tetrazole-5-carboxylate ethylesters **4a**--**f** in moderate yields over two steps (63%--65%). Then compounds **4a**--**f** reduced by diisobutylaluminium hydride (DIBAL-H) to form 1-substituted phenyl-1*H*-tetrazole-5-aldehydes **5a**--**f** in moderate yields (75%--80%). Meanwhile, the side chains **6a** and **6b** were prepared according the literature protocol \[[@B26-ijms-20-03840]\]. Subsequently, the compounds **5a**--**f** were respectively treated with compound **6a** and **6b** by reductive amination using sodium triacetoxyborohydride (STAB) in dichloroethane to generate compounds **7a**--**f** and **8a**--**e** in moderate yields (75%--85%). Finally, the target compounds **9a**--**f** and **10a**--**e** were obtained by deprotection with saturated hydrochloric acid ethanol solution in good yields (92%--98%).
The syntheses of tetrazole derivatives **16a--e** were depicted in [Scheme 2](#ijms-20-03840-sch002){ref-type="scheme"}. The compounds **4c--d** could be converted into **11c--d** by demethylation using boron tribromide in the yield of 67%. Then the treatment of compounds **11c--d** with methanesulfonyl chloride in the presence of triethylamine by sulfonylation generated **12a**--**b**. Meanwhile, the compounds **11c**--**d** were reacted with 2,2,2-trifluoroethyltrifluoromethanesulfonate in the presence of potassium carbonate by alkylation to give **13a**--**b**. The intermediate **12a**--**b** and **13a**--**b** were directly reduced by DIBAL-Hto form **14a**--**d** in moderate yields over two steps (75%--78%). Subsequently similar with the procedure in [Scheme 1](#ijms-20-03840-sch001){ref-type="scheme"}, compounds **14a**--**d** were respectively reacted with side chains **6a** and **6b** by reductive amination to generated compounds **15a--e**, which were deprotected with saturated hydrochloric acid ethanol solution to afford the target compounds **16a--e** in good yields (92%--95%).
The syntheses of tetrazole derivatives **18a**--**e** and **20** were illustrated in [Scheme 3](#ijms-20-03840-sch003){ref-type="scheme"}. The side chains **6c**--**e** were commercially available, and the preparation of the side chains **6f**--**g** was followed the reported methods \[[@B24-ijms-20-03840],[@B27-ijms-20-03840]\]. Then the compound **5a** was reacted with varied side chains **6c**--**g** by reductive amination to generate the compounds **17a**--**e** in moderate yields (75%--85%). The target compounds **18a**--**e** were obtained by deprotection with saturated hydrochloric acid ethanol solution in good yields (92%--95%). Moreover, the compound **18a** was reacted with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea in the presence of triethylamine and mercury dichloride to give compound **19** in the yield of 71%. Finally, the target compound **20** was afforded by deprotection with saturated hydrochloric acid ethanol solution in the yield of 92%.
2.3. In vitro PRMT1 Inhibition Assays and Selectivity Assays {#sec2dot3-ijms-20-03840}
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A series of 1,5-substituded tetrazole derivatives were synthesized to investigate the structure-activity relationship (SAR) of PRMT1 inhibitors ([Table 1](#ijms-20-03840-t001){ref-type="table"}). Initially, we designed and synthesized a series of molecules (**9a**--**e, 16a**--**d**, Group I) as shown in [Table 1](#ijms-20-03840-t001){ref-type="table"}, which contained substituted phenyl on 1*H*-tetrazol and ethylenediamine side chain. The chemical modification of these compounds is mainly focused on the substituted benzene ring. The initial screening of these compounds was carried out using the radioactive PRMT1 methylation inhibition assay, which measured the amount of methyl groups that transferred from \[^3^H\]-SAM to a biotinylated histone H4 peptide (ac- SGRGKGGKGLGKGGAKRHRKVGGK(Biotin)). In the assay, SAH and AMI-1 were used as the positive controls. It was found that, in Group I, the inhibitory activities of the para-substitution compounds were in general better than those with meta-substitution. Three compounds (**9a**, **9f**, **16c**), which contained 4-OCH(CH~3~)~2~, 4-OCF~3~ and 4-OCH~2~CF~3~ respectively, showed strong inhibitory effects (over 47%) at 10 μM against PRMT1 in the initial screening, and were selected for the IC~50~ determinations, which were 3.5 μM, 23.8 μM and 19.9 μM, respectively. It should be noted that the IC~50~ of compound **9a** is around seven times weaker than SAH but around 20 times stronger than AMI-1 ([Table 1](#ijms-20-03840-t001){ref-type="table"}). In the second step, the Group II compounds were designed and synthesized by extending the ethylenediamine side chain to propylenediamine. However, the inhibitory activities of all the compounds in the Group II (**10a**--**e**, **16e**) were either totally abolished or remarkably reduced in comparison with those of Group I. In the third step, in order to evaluate the influence of other amino side chains, we designed and synthesized a series of compounds (**18a**--**e**, **20**, Group III) based on the structure of compound **9a**. Among these compounds, **18a** and **18e** exhibited 10.0 μM and 29.0 μM IC~50~s respectively against PRMT1, while the other compounds (**18b**--**d**, **20**) showed relatively poor activities and their inhibitory effects were all lower than 39% at a concentration of 10 μM.
To further investigate the selectivity profiles of compounds **9a** (represented in [Figure 4](#ijms-20-03840-f004){ref-type="fig"}), **9f**, **16c**, **18a** and **18e**, the IC~50~s against PRMT5 (the type II PRMT) were measured over 100 μM, as illustrated in [Table 1](#ijms-20-03840-t001){ref-type="table"}. It suggested that in comparison with type II PRMT, these inhibitors showed good selectivity against PRMT1.
2.4. Mechanism of Action (MOA) Study of the Compound **9a** {#sec2dot4-ijms-20-03840}
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The most potent PRMT1 inhibitor in the current study, compound **9a**, was selected for the Mechanism of Action (MOA) study. As illustrated in the [Figure 5](#ijms-20-03840-f005){ref-type="fig"}, various concentrations of SAM or peptide were used to evaluate the potency (IC~50~) of **9a,** and no significant changes were observed according to the concentration changes of either the SAM or peptide. The result of the MOA studies showed that the compound **9a** is a noncompetitive inhibitor for either the cofactor SAM or peptide substrate. Does this result indicate that the compound **9a** inhibit PRMT1 by binding to an allosteric site? Both PRMT1 and PRMT6 are Type I PRMTs, and their structures share the high degree similarity. The co-crystal structure of PRMT6 and its inhibitor, MS023, which also contains ethylenediamine moiety, was solved and clearly showed that ethylenediamine moiety occupied the substrate arginine binding site. Based on the crystal structure, it can be predicated that MS023 should be a competitive inhibitor against the peptide. However, similar to our result, the MOA results showed that the MS023 was noncompetitive with either SAM or peptide substrate \[[@B28-ijms-20-03840]\]. Therefore, we believed that compound **9a** may occupied the substrate arginine binding site, although the MOA results did not show competitive inhibition effects with respect to the peptide. There are potential explanations for the current contradictory results. First, the main binding effects of the substrate were from the outside regions of arginine-binding site. Therefore, compound **9a** did occupy the arginine-binding site, but it did not affect the binding of the whole substrate peptides. Second, the binding of compound **9a** possibly induced major protein conformational changes, which caused the peptides could not enter the binding site to compete with compound **9a** even at the high concentration of the peptides.
2.5. Molecular Modeling Study of the Interactions between Compound **9a** and hPRMT1-SAH Complex {#sec2dot5-ijms-20-03840}
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To gain more detailed information regarding the interactions between the compound **9a** and hPRMT1-SAH complex, it was docked into the protein by using the position of substrate arginine binding site as the reference. There was 100 ns molecular dynamic simulation performed on the complex, and then the stable trajectory was collected for the binding free energy calculations (−9.64 kcal/mol) by using MM-PBSA and Normal Mode as shown in [Table 2](#ijms-20-03840-t002){ref-type="table"}, which indicated a strong binding of compound **9a**. It was noticed that, in the stable MD trajectory, the compound **9a** occupied the substrate arginine binding site ([Figure 6](#ijms-20-03840-f006){ref-type="fig"}A), in which *N*, *N*'-dimethylethylenediamine mimicked the guanidyl group of the arginine substrate and bound closely to the SAH, and the binding pose of compound **9a** was stably maintained during the whole simulation process. The free energy decomposition was performed and the residues whose binding free energy contributions greater than --0.70 kcal/mol were recorded ([Figure 6](#ijms-20-03840-f006){ref-type="fig"}C). It was noticed that the Tyr47, Ile52, Met56, Asp84, Glu108, Glu152, Met154, Tyr156 and Tyr160 formed strong interactions with the compound **9a** ([Figure 6](#ijms-20-03840-f006){ref-type="fig"}B). Among these residues, Tyr47, Ile52, Met56 and Tyr156 formed strong van der Walls interactions, in which Tyr47 and Tyr156 formed π-π interactions with the aromatic ring of compound **9a**, and three negatively charged residues (Asp84, Glu108 and Glu152) contributed large electrostatic interactions because of the positive charges of compound **9a**. The MD simulations also showed that the compound **9a** could form three stable hydrogen bonds with Tyr156, Met154 and Glu152 along the stable trajectory. By using the molecular dynamic simulations, we believed that the binding site of compound **9a** is at the substrate arginine binding position, so that the methylation process could be disturbed. However, the molecular dynamic simulation results need to be further validated by experimental data, such as the key residues mutations in the active site or co-crystallization, which will be considered in our following work.
2.6. The Alteration of **9a** on PRMT1 Patterns at the Cellular Level
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Western blotting was performed to confirm that compound **9a** altered the arginine methylation patterns of PRMT1 in the highly metastatic breast cancer cell line MDA-MB-231, as it has been reported that the expression of PRMT1 is high in the MDA-MB-231 \[[@B29-ijms-20-03840]\]. Before the western blotting experiment was performed, the potential cytotoxic effect of compound **9a** against MDA-MB-231 (breast cancer) cells was examined using WST-8/CCK8 cell viability assays. The results showed the IC~50~ of compound **9a** against MDA-MB-231 for 48 h was much higher than 500 μM. We then extended the time to 72 h, and the IC~50~ was obtained as 541.1 ± 6.5 μM. Therefore, the top concentration of compound **9a** for the western blotting experiment was chosen as 200 μM, and during the experiment, no obvious cell damage was observed. As shown in [Figure 7](#ijms-20-03840-f007){ref-type="fig"}, after the treatment of MDA-MB-231 cells with **9a** for 48 h, the global level of ADMA, which is mainly produced by the type I PRMTs, was significantly decreased in a concentration-dependent manner. It was also noticed that the level of dimethylarginine dimethylaminohydrolases (DDAH), which can metabolize more than 90% of ADMA \[[@B30-ijms-20-03840]\], was significantly decreased in a concentration-dependent manner. The results showed that the decreasing of ADMA was because of the inhibition of PRMT1 rather than being metabolized by DDAH, which indicated that the compound **9a** influenced the PRMT-AMDA pathway. Asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2as) is mediated by PRMT1, and it was observed that the compound **9a** decreased the global level of H4R3me2as in a concentration-dependent manner. The global level of SDMA, which was catalyzed by Type II PRMTs, was not significantly affected. By combining the above information, it could be confirmed that **9a** has significant influences on PRMT pathway at cellular levels.
It was reported that the PRMT1 is required for canonical Wnt signaling \[[@B31-ijms-20-03840]\], and another recent paper reported that the depletion of PRMT1 blocked Wnt-induced micropinocytosis \[[@B32-ijms-20-03840]\], which reminded us to see if the inhibition of PRMT1 by compound **9a** shows influences on the Wnt signaling pathways. The global levels of Wnt3a/β-catenin (Canonical Wnt signaling) and Wnt5a (Non-canonical Wnt signaling) were evaluated, in which the levels of Wnt3a and β-catenin were decreased in concentration-dependent manners, and the level of Wnt5a did not change significantly. The results suggested that the inhibition of PRMT1 by compound **9a** selectively down regulated the canonical Wnt signaling pathway, which was of potential medical interests. To further confirm the relationships between PRMT1 inhibitors and Wnt pathway, more factors or biomarkers need to be evaluated in the future work, such as matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), and methylation of Ras GTPase-activating protein-binding protein 1 (G3BP1) etc.
3. Materials and Methods {#sec3-ijms-20-03840}
========================
3.1. General Information {#sec3dot1-ijms-20-03840}
------------------------
All the required chemicals were purchased from commercial sources and used without further purification. TLC was performed on silica gel 60 pre-coated aluminium plates (0.20 mm thickness) from Macherey-Nagel and visualisation was accomplished with UV light (254 nm). Compounds were purified by flash column chromatography using 80--100 mesh silica gel. ^1^HNMR and ^13^CNMRspectra were obtained from Bruker AVANCE III 400 spectrometers using chloroform-d, DMSO-d6 or deuterium oxide as a solvent. The chemical shifts, given as δ values, were quoted in parts per million (ppm); ^1^HNMR chemical shifts were measured relative to internal tetramethylsilane; multiplicities quoted as singlet (s), doublet (d), triplet (t), quartet (q) or combinations thereof as appropriate. HRMS spectra were obtained on a Thermo Q-Exactive Orbitrap mass spectrometer. Melting points were determined on a WRS-1B apparatus without corrected.
3.2. Chemical Synthesis {#sec3dot2-ijms-20-03840}
-----------------------
### 3.2.1. Synthesis of **9a**--**f** and **10a**--**e** {#sec3dot2dot1-ijms-20-03840}
General procedure for the preparation of compounds **2a**--**f**.
Triethylamine (2.5 eq) was added to the substituted aniline **1a**--**f** (1.0 eq) dissolved in anhydrous dichloromethane (1.5 mL/mmol). The reaction mixture was cooled to 0 °C and ethyl oxalyl monochloride (1.2 eq) was added dropwise to the solution. Subsequently, the reaction was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with dichloromethane, the organic layer was dried over anhydrous Na~2~SO~4~, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **2a**--**f**.
Ethyl *N*-(4-isopropoxyphenyl)oxamate (**2a**)
Yellow solid. Yield: 94%. MP: 128.7--129.9 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.67 (s, 1H, *-NH-*), 7.69--7.55 (m, 2H, *-ArH*), 6.98--6.77 (m, 2H, *-ArH*), 4.57 (Hept, J = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 4.30 (q, *J* = 7.1 Hz, 2H, *-CH2-*), 1.31 (t, *J* = 7.1 Hz, 3H, *-CH3*), 1.26 (s, 3H, *-CH3*), 1.24 (s, 3H, *-CH3*).
Ethyl *N*-(3-isopropoxyphenyl)oxamate (**2b**)
Yellow oil. Yield: 92%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 8.84 (s, 1H, *-NH-*), 7.39 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.26 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.09 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, *-ArH*), 6.74 (ddd, *J* = 8.3, 2.5, 0.9 Hz, 1H, *-ArH*), 4.58 (p, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 4.44 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.46 (t, *J* = 7.2 Hz, 3H, *-CH~3~*), 1.36 (d, *J* = 6.1 Hz, 6H, *-CH(CH~3~)~2~*).
Ethyl *N*-(4-methoxyphenyl)oxamate (**2c**)
Yellow solid. Yield: 94%. MP: 105.7--106.3 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 8.81 (s, 1H, *-NH-*), 7.61--7.56 (m, 2H, *-ArH*), 6.95--6.90 (m, 2H, *-ArH*), 4.44 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 3.83 (s, 3H, *-OCH~3~*), 1.45 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl *N*-(3-methoxyphenyl)oxamate (**2d**)
Yellow solid. Yield: 95%. MP: 88.9--99.3 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 8.87 (s, 1H, *-NH-*), 7.41 (t, *J* = 2.3 Hz, 1H, *-ArH*), 7.30 (d, *J* = 8.1 Hz, 1H, *-ArH*), 7.13 (ddd, *J* = 8.0, 2.0, 0.9 Hz, 1H, *-ArH*), 6.77 (ddd, *J* = 8.3, 2.5, 0.9 Hz, 1H, *-ArH*), 4.44 (q, *J* = 7.2 Hz, 2H, *-CH~2~-*), 3.84 (s, 3H, *-OCH~3~*), 1.46 (t, *J* = 7.2 Hz, 3H, *-OCH~3~*), 1.46 (t, *J* = 7.2 Hz, 3H, *-CH~3~*).
Ethyl *N*-(3-trifluoromethoxyphenyl)oxamate (**2e**)
Yellow oil. Yield: 90%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 8.96 (s, 1H, *-NH-*), 7.70 (d, *J* = 2.5 Hz, 1H, *-ArH*), 7.54 (ddd, *J* = 8.3, 2.1, 0.9 Hz, 1H, *-ArH*), 7.42 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.08 (ddt, *J* = 8.3, 2.3, 1.1 Hz, 1H, *-ArH*), 4.46 (q, *J* = 7.2 Hz, 2H, *-CH2-*), 1.46 (t, *J* = 7.2 Hz, 3H, *-CH3*).
Ethyl *N*-(4-trifluoromethoxyphenyl)oxamate (**2f**)
Yellow solid. Yield: 92%. MP: 131.2--131.9 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 11.01 (s, 1H, *-NH-*), 7.90--7.85 (m, 2H, *-ArH*), 7.42--7.36 (m, 2H, *-ArH*), 4.32 (q, *J* = 7.1 Hz, 2H, *-CH2-*), 1.32 (t, *J* = 7.1 Hz, 3H, *-CH3*).
General procedure for the preparation of compounds **3a**--**f**.
**2a**--**f** (1.0 eq) was dissolved in CCl~4~ (2.0 mL/mmol), and a solution of triphenylphosphine in CCl~4~ (0.8 mL/mmol) was added dropwise to the reaction flask at the room temperature. The reaction was refluxed and stirred for 6 h, and then cooled to the room temperature. The precipitate was filtered off and washed with CCl~4~. The filtrate was concentrated in vacuo without further purification to give **3a**--**f**.
General procedure for the preparation of compounds **4a**--**f**.
To a solution of **3a**--**f** (1.0 eq) in acetonitrile (1 mL/mmol) was added sodium azide (1.5 eq), and the reaction was stirred at the room temperature for 3 h and monitored by TLC. The mixture was quenched with ice water, concentrated and extracted with ethyl acetate. The combined organic layers were washed with water, and dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **4a**--**f**.
Ethyl 1-(4-isopropoxyphenyl)-1H-tetrazole-5-carboxylate (**4a**)
White solid. Yield: 65%. MP: 150.2--151.9 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.44--7.35 (m, 2H, *-ArH*), 7.06--6.99 (m, 2H, *-ArH*), 4.64 (p, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 4.46 (q, *J* = 7.1 Hz, 2H, *-CH2-*), 1.39 (dd, *J* = 7.9, 6.6 Hz, 9H, *-CH~3~*).
Ethyl 1-(3-isopropoxyphenyl)-1H-tetrazole-5-carboxylate (**4b**)
Yellow oil. Yield: 63%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.48 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.35 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.19 (dddd, *J* = 11.7, 8.4, 2.2, 0.9 Hz, 2H, *-ArH*), 4.65 (h, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 4.33 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.30 (s, 3H, *-CH~3~*), 1.28 (s, 3H, *-CH~3~*), 1.20 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl 1-(4-methoxyphenyl)-1H-tetrazole-5-carboxylate (**4c**)
White solid. Yield: 65%. MP: 75.9--76.3 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.46--7.41 (m, 2H, *-ArH*), 7.10--7.05 (m, 2H, *-ArH*), 4.47 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 3.92 (s, 3H, *-OCH~3~*), 1.41 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl 1-(3-methoxyphenyl)-1H-tetrazole-5-carboxylate (**4d**)
White solid. Yield: 64%. MP: 70.1--72.0 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.49 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.16 (ddd, *J* = 8.5, 2.5, 0.9 Hz, 1H, *-ArH*), 7.08 (ddd, *J* = 7.8, 2.0, 0.9 Hz, 1H, *-ArH*), 7.05 (t, *J* = 2.2 Hz, 1H, *-ArH*), 4.48 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 3.89 (s, 3H, *-OCH~3~*), 1.40 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl 1-(3-trifluoromethoxyphenyl)-1H-tetrazole-5-carboxylate (**4e**)
Yellow solid. Yield: 64%. MP: 125.2--126.0 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.66 (dd, *J* = 8.7, 7.7 Hz, 1H, *-ArH*), 7.51 (dd, *J* = 7.9, 2.2 Hz, 2H, *-ArH*), 7.46 (q, *J* = 1.9 Hz, 1H, *-ArH*), 4.49 (q, *J* = 7.1 Hz, 2H, *-CH2-*), 1.41 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl 1-(4-trifluoromethoxyphenyl)-1H-tetrazole-5-carboxylate (**4f**)
Yellow solid. Yield: 65%. MP: 68.2--69.0 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.96--7.84 (m, 2H, *-ArH*), 7.71--7.60 (m, 2H, *-ArH*), 4.32 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.19 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
General procedure for the preparation of compounds **5a**--**f**.
To a solution of **4a**--**f** (1.0 eq) in anhydrous dichloromethane (1.8 mL/mmol) was added diisobutyl aluminium hydride (1.0M in hexanes, 2.0 eq) dropwise at −78 °C and the reaction was stirred for 30 min. The mixture was quenched with methanol, concentrated and extracted with ethyl acetate. The combined organic layers were washed with water, 1 M HCl and dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **5a**--**f.**
1-(4-Isopropoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5a**)
White solid. Yield: 80%. MP: 122.5--123.1 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.05 (s, 1H, *-CHO*), 7.67--7.63 (m, 2H, *-ArH*), 7.17--7.13 (m, 2H, *-ArH*), 4.79--4.72 (m, 1H, *-OCH(CH~3~)~2~*), 1.33 (s, 3H, *-CH~3~*), 1.32 (s, 3H, *-CH~3~*).
1-(3-Isopropoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5b**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.07 (s, 1H, *-CHO*), 7.53 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.38 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.29--7.25 (m, 2H, *-ArH*), 4.69--4.64 (m, 1H, *-OCH(CH~3~)~2~*), 1.31 (d, *J* = 0.8 Hz, 3H, *-CH~3~*), 1.29 (d, *J* = 0.8 Hz, 3H, *-CH~3~*).
1-(4-Methoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5c**)
Colorless oil. Yield: 77%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 10.33 (s, 1H, *-CHO*), 7.51--7.47 (m, 2H, *-ArH*), 7.11--7.07 (m, 2H, *-ArH*), 3.93 (s, 3H, *-OCH~3~*).
1-(3-Methoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5d**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.07 (s, 1H, *-CHO*) 7.59--7.54 (t, 1H, *-ArH*), 7.41 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.31 (dddd, *J* = 7.9, 6.8, 2.0, 0.9 Hz, 2H, *-ArH*), 3.83 (s, 3H, *-OCH~3~*).
1-(3-Trifluoromethoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5e**)
Yellow solid. Yield: 78%. MP: 97.6--98.0 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.11 (s, 1H, *-CHO*), 7.96--7.91 (m, 2H, *-ArH*), 7.75--7.70 (m, 1H, *-ArH*), 7.65 (ddt, *J* = 8.0, 2.3, 1.1 Hz, 1H, *-ArH*).
1-(4-Trifluoromethoxyphenyl)-1H-tetrazole-5-carbaldehyde (**5f**)
Yellow solid. Yield: 80%. MP: 118.7--119.5 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.10 (s, 1H, *-CHO*), 7.94--7.91 (m, 2H, *-ArH*), 7.70 (dtd, *J* = 8.1, 2.2, 1.2 Hz, 2H, *-ArH*).
General procedure for the preparation of compounds **7a**--**f** and **8a**--**e**.
To a solution of **5a**--**f** (1.0 eq) in 1,2-Dichloroethane (8.5 mL/mmol) was added sodium triacetoxyborohydride (2.0 eq) and **6a** or **6b** (1.0 eq) and the reaction was stirred for 12 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **7a--f** or **8a**--**e**.
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**7a**)
Colorless oil. Yield: 85%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.59 (d, *J* = 8.5 Hz, 2H, *-ArH*), 7.05 (d, *J* = 8.9 Hz, 2H, *-ArH*), 4.65 (p, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 3.82 (s, 2H, *-CH~2~-*), 3.31 (s, 2H, *-CH~2~-*), 2.78 (s, 3H, *-CH~3~*), 2.38 (s, 3H, *-CH~3~*), 1.44 (s, 9H, *-C(CH~3~)~3~*), 1.41 (s, 3H, *-CH~3~*), 1.40 (s, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*-(1-(3-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**7b**)
Colorless oil. Yield: 82%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.52 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.35--7.24 (m, 2H, *-ArH*), 7.17 (ddd, *J* = 8.4, 2.5, 0.9 Hz, 1H, *-ArH*), 4.71 (p, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 3.11 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.63 (d, *J* = 6.4 Hz, 3H, *-CH~3~*), 2.48 (t, *J* = 6.6 Hz, 2H, *-CH~2~-*), 2.20 (d, *J* = 6.4 Hz, 3H, *-CH~3~*), 1.31 (dd, *J* = 12.4, 8.1 Hz, 15H, *-CH~3~, -C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-methoxyphenyl)-1H-tetrazol-5-ylmethyl)-*N*'-methyl-ethylenediamine (**7c**)
Colorless oil. Yield: 85%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.66 (dd, *J* = 8.3, 2.8 Hz, 2H, *-ArH*), 7.21--7.11 (m, 2H, *-ArH*), 3.85 (s, 3H, *-CH~3~*), 3.83 (s, 2H, *-CH~2~-*), 3.15 (d, *J* = 6.3 Hz, 2H, *-CH~2~-*), 2.64 (d, *J* = 9.5 Hz, 3H, *-CH~3~*), 2.47 (d, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.18 (d, *J* = 6.8 Hz, 3H, *-CH~3~*), 1.33 (d, *J* = 12.1 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-methoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**7d**)
Colorless oil. Yield: 83%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.55 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.39--7.30 (m, 2H, *-ArH*), 7.20 (ddd, *J* = 8.4, 2.6, 0.9 Hz, 1H, *-ArH*), 3.90 (s, 2H, *-CH~2~-*), 3.84 (s, 3H, *-CH~3~*), 3.13 (d, *J* = 7.2 Hz, 2H, *-CH~2~-*), 2.62 (d, *J* = 6.6 Hz, 3H, *-CH~3~*), 2.48 (d, *J* = 6.6 Hz, 2H, *-CH~2~-*), 2.21 (s, 3H, *-CH~3~*), 1.32 (d, *J* = 10.5 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**7e**)
Colorless oil. Yield: 82%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.93 (s, 1H, *-ArH*), 7.87--7.82 (m, 1H, *-ArH*), 7.79 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.68 (ddt, *J* = 8.0, 2.4, 1.2 Hz, 1H, *-ArH*), 3.94 (s, 2H, *-CH~2~-*), 3.09 (t, *J* = 6.3 Hz, 2H, *-CH~2~-*), 2.59 (d, *J* = 5.4 Hz, 3H, *-CH~3~*), 2.46 (t, *J* = 6.6 Hz, 2H, *-CH~2~-*), 2.19 (s, 3H, *-CH~3~*), 1.31 (d, *J* = 9.5 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**7f**)
Colorless oil. Yield: 84%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.94 (d, *J* = 8.3 Hz, 2H, *-ArH*), 7.69--7.64 (m, 2H, *-ArH*), 3.91 (s, 2H, *-CH~2~-*), 3.13 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.61 (d, *J* = 6.3 Hz, 3H, *-CH~3~*), 2.48 (d, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.18 (d, *J* = 7.0 Hz, 3H, *-CH~3~*), 1.32 (d, *J* = 11.3 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**8a**)
Colorless oil. Yield: 80%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.61 (dd, *J* = 9.1, 2.5 Hz, 2H, *-ArH*), 7.15--7.10 (m, 2H, *-ArH*), 4.76--4.69 (m, 1H, *-OCH(CH~3~)~2~*), 3.81 (s, 2H, *-CH~2~-*), 2.92 (s, 2H, *-CH~2~-*), 2.66 (s, 3H, *-CH~3~*), 2.29 (t, *J* = 7.0 Hz, 2H, *-CH~2~-*), 2.10 (s, 3H, *-CH~3~*), 1.45 (t, *J* = 7.2 Hz, 2H, *-CH~2~-*), 1.34 (d, *J* = 11.2 Hz, 9H, *-C(CH~3~)~3~*), 1.31 (d, *J* = 1.5 Hz, 3H, *-CH~3~*), 1.30 (s, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**8b**)
Colorless oil. Yield: 77%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.51 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.33 (d, *J* = 9.6 Hz, 1H, *-ArH*), 7.28--7.22 (m, 1H, *-ArH*), 7.21--7.14 (m, 1H, *-ArH*), 4.70 (p, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 3.86 (s, 2H, *-CH~2~-*), 2.94 (s, 2H, *-CH~2~-*), 2.67 (d, *J* = 4.2 Hz, 3H, *-CH~3~*), 2.29 (t, *J* = 7.0 Hz, 2H, *-CH~2~-*), 2.11 (s, 3H, *-CH~3~*), 1.46 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.33 (d, *J* = 15.1 Hz, 9H, *-C(CH~3~)~3~*), 1.30 (s, 3H, *-CH~3~*), 1.28 (s, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-methoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**8c**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.67--7.62 (m, 2H, *-ArH*), 7.18--7.14 (m, 2H, *-ArH*), 3.85 (d, *J* = 4.2 Hz, 3H, *-CH~3~*), 3.81 (s, 2H, *-CH~2~-*), 2.94 (s, 2H, *-CH~2~-*), 2.67 (s, 3H, *-CH~3~*), 2.28 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 2.10 (s, 3H, *-CH~3~*), 1.45 (s, 2H, *-CH~2~-*), 1.36 (s, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-N'-(1-(3-methoxyphenyl)-1H-tetrazol-5-yl-methyl)-N'-methyl-1,3-propylenediamine (**8d**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.54 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.39 (t, *J* = 2.3 Hz, 1H, *-ArH*), 7.30 (dddd, *J* = 6.8, 2.8, 1.9, 0.9 Hz, 1H, *-ArH*), 7.23--7.17 (m, 1H, *-ArH*), 3.87 (s, 2H, *-CH~2~-*), 3.83 (s, 3H, *-CH~3~*), 2.93 (s, 2H, *-CH~2~-*), 2.66 (s, 3H, *-CH~3~*), 2.30 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 2.12 (s, 3H, *-CH~3~*), 1.46 (t, *J* = 7.2 Hz, 2H, *-CH~2~-*), 1.35 (s, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**8e**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.98 (s, 1H, *-ArH*), 7.83 (ddd, *J* = 8.0, 4.1, 2.0 Hz, 2H, *-ArH*), 7.68 (dtq, *J* = 7.3, 2.5, 1.2 Hz, 1H, *-ArH*), 3.90 (s, 2H, *-CH~2~-*), 2.87 (s, 2H, *-CH~2~-*), 2.65 (s, 3H, *-CH~3~*), 2.27 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 2.08 (s, 3H, *-CH~3~*), 1.42 (d, *J* = 7.4 Hz, 2H, *-CH~2~-*), 1.35 (s, 9H, *-C(CH~3~)~3~*).
General procedure for the preparation of compounds **9a**--**f** and **10a**--**e**.
Compounds **7a**--**f** or **8a**--**e** (0.51 mmol) was added to saturated hydrochloric acid ethanol solution (10 mL) at room temperature and stirred for 30 min. The reaction solution was filtered and washed with diethylether (20 mL) to give **9a**--**f** or **10a**--**e**.
*N*,*N*'-Dimethyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9a**)
White solid. Yield: 98%. MP: 187.4--189.4 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.49--7.44 (m, 2H, *-ArH*), 7.19--7.13 (m, 2H, *-ArH*), 4.74 (p, *J* = 5.5, 4.9 Hz, 1H, *-OCH(CH~3~)~2~*), 4.35 (s, 2H, *-CH~2~-*), 3.21 (dd, *J* = 14.9, 6.8 Hz, 2H, *-CH~2~-*), 3.15--3.01 (m, 2H, *-CH~2~-*), 2.64 (dd, *J* = 4.9, 2.1 Hz, 3H, *-CH~3~*), 2.48 (d, *J* = 37.8 Hz, 3H, *-CH~3~*), 1.31 (s, 3H, *-CH~3~*), 1.30 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.2, 150.1, 126.7, 124.9, 117.1, 71.9, 51.8, 49.1, 44.2, 41.3, 33.0, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~15~H~25~N~6~O^+^: 305.20844. Found: 305.20831.
*N*,N'-Dimethyl-*N*'-(1-(3-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9b**)
Colorless oil. Yield: 95%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.49 (ddd, *J* = 8.4, 7.4, 0.9 Hz, 1H, *-ArH*), 7.18 (ddd, *J* = 8.5, 2.3, 1.1 Hz, 1H, *-ArH*), 7.09--7.04 (m, 2H, *-ArH*), 4.63 (p, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 4.37 (s, 2H, *-CH~2~-*), 3.22 (td, *J* = 6.2, 1.3 Hz, 2H, *-CH~2~-*), 3.13 (td, *J* = 6.4, 1.3 Hz, 2H, *-CH~2~-*), 2.61 (s, 3H, *-CH~3~*), 2.52 (s, 3H, *-CH~3~*), 1.24 (s, 3H, *-CH~3~*), 1.22 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 158.1, 133.1, 131.3, 119.1, 117.3, 112.8, 72.1, 51.8, 49.2, 44.2, 41.3, 33.0, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~15~H~25~N~6~O^+^: 305.20844. Found: 305.20828.
*N*,*N*'-Dimethyl-*N*'-(1-(4-methoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9c**)
White solid. Yield: 95%. MP: 163.2--163.6 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.45--7.40 (m, 2H, *-ArH*), 7.14--7.10 (m, 2H, *-ArH*), 4.51 (s, 2H, *-CH~2~-*), 3.81 (s, 3H, *-CH~3~*), 3.31 (s, 4H, *-CH~2~-*), 2.67 (s, 3H, *-CH~3~*), 2.64 (d, *J* = 0.7 Hz, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 161.1, 149.8, 126.6, 124.9, 115.3, 55.7, 51.8, 49.1, 44.00, 41.4, 33.0. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~21~N~6~O^+^: 277.17714. Found: 277.17715.
*N*,*N*'-Dimethyl-*N*'-(1-(3-methoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9d**)
White solid. Yield: 98%. MP: 185.6--186.4 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.52--7.47 (m, 1H, *-ArH*), 7.18 (ddd, *J* = 8.5, 2.5, 0.9 Hz, 1H, *-ArH*), 7.10--7.05 (m, 2H, *-ArH*), 4.47 (s, 2H, *-CH~2~-*), 3.77 (s, 3H, *-CH~3~*), 3.29--3.20 (m, 4H, *-CH~2~-*), 2.62 (s, 3H, *-CH~3~*), 2.60 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 160.1, 149.7, 133.0, 131.2, 117.2, 117.1, 110.9, 55.7, 51.9, 49.2, 44.1, 41.4, 33.0. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~21~N~6~O^+^: 277.17714. Found: 277.17703.
*N*,*N*'-Dimethyl-*N*'-(1-(3-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9e**)
White solid. Yield: 97%. MP: 185.6--186.4 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.66 (td, *J* = 8.1, 1.5 Hz, 1H, *-ArH*), 7.58--7.52 (m, 2H, *-ArH*), 7.52--7.48 (m, 1H, *-ArH*), 4.49 (s, 2H, *-CH~2~-*), 3.28 (d, *J* = 4.2 Hz, 2H, *-CH~2~-*), 3.26 (d, *J* = 3.9 Hz, 2H, *-CH~2~-*), 2.63 (s, 3H, *-CH~3~*), 2.62 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 150.7, 149.4, 133.2, 131.8, 123.9, 123.5, 118.1, 51.9, 49.4, 44.5, 41.3, 32.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~18~F~3~N~6~O^+^: 331.14887. Found: 331.14871.
*N*,*N*'-Dimethyl-*N*'-(1-(4-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**9f**)
White solid. Yield: 98%. MP: 194.3--195.2 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.61--7.56 (m, 2H, *-ArH*), 7.51--7.46 (m, 2H, *-ArH*), 4.25 (s, 2H, *-CH~2~-*), 3.15 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 3.02 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.58 (s, 3H, *-CH~3~*), 2.42 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 150.6, 150.3, 130.6, 126.9, 122.5, 51.9, 49.3, 44.3, 41.3, 33.0. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~18~F~3~N~6~O^+^: 331.14887. Found: 331.14871.
*N*,*N*'-Dimethyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**10a**)
Colorless oil. Yield: 94%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.43--7.39 (m, 2H, *-ArH*), 7.14--7.09 (m, 2H, *-ArH*), 4.76 (d, *J* = 1.2 Hz, 2H, *-CH~2~-*), 4.67 (d, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 3.36--3.27 (m, 2H, *-CH~2~-*), 3.05--2.97 (m, 2H, *-CH~2~-*), 2.94--2.89 (m, 3H, *-CH~3~*), 2.61 (s, 3H, *-CH~3~*), 2.14--2.03 (m, 2H, *-CH~2~-*), 1.26 (s, 3H, *-CH~3~*), 1.25 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.4, 148.0, 126.7, 124.5, 117.2, 71.9, 53.5, 48.1, 45.4, 41.1, 32.71, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~16~H~27~N~6~O^+^: 319.22409. Found: 319.22406.
*N*,*N*'-Dimethyl-*N*'-(1-(3-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**10b**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.50 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.20 (ddd, *J* = 8.5, 2.4, 0.9 Hz, 1H, *-ArH*), 7.09--7.03 (m, 2H, *-ArH*), 4.79 (s, 2H, *-CH~2~-*), 4.68--4.60 (m, 1H, *-OCH(CH~3~)~2~*), 3.36--3.28 (m, 2H, *-CH~2~-*), 3.04--2.96 (m, 2H, *-CH~2~-*), 2.91 (s, 3H, *-CH~3~*), 2.61 (s, 3H, *-CH~3~*), 2.15--2.04 (m, 2H, *-CH~2~-*), 1.24 (s, 3H, *-CH~3~*), 1.23 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 158.2, 147.7, 132.7, 131.4, 119.3, 117.3, 112.8, 72.1, 53.6, 48.2, 45.4, 41.1, 32.7, 20.9, 20.8. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~16~H~27~N~6~O^+^: 319.22409. Found: 319.22405.
*N*,*N*'-Dimethyl-*N*'-(1-(4-methoxyphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**10c**)
White solid. Yield: 94%. MP: 188.2--190.1 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.48--7.42 (m, 2H, *-ArH*), 7.19--7.12 (m, 2H, *-ArH*), 4.73 (s, 2H, *-CH~2~-*), 3.84 (s, 3H, *-CH~3~*), 3.32--3.24 (m, 2H, *-CH~2~-*), 3.05--2.98 (m, 2H, *-CH~2~-*), 2.88 (s, 3H, *-CH~3~*), 2.64 (s, 3H, *-CH~3~*), 2.14--2.04 (m, 2H, *-CH~2~-*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 148.1, 126.7, 124.5, 115.4, 55.7, 53.5, 48.1, 45.4, 41.1, 32.7, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~23~N~6~O^+^: 291.19279. Found: 291.19271.
*N*,*N*'-Dimethyl-*N*'-(1-(3-methoxyphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**10d**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.51 (dd, *J* = 8.5, 7.8 Hz, 1H, *-ArH*), 7.20 (ddd, *J* = 8.6, 2.5, 0.9 Hz, 1H, *-ArH*), 7.09 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.06 (ddd, *J* = 7.8, 2.1, 0.9 Hz, 1H, *-ArH*), 4.80 (d, *J* = 1.3 Hz, 2H, *-CH~2~-*), 3.78 (s, 3H, *-CH~3~*), 3.36--3.29 (m, 2H, *-CH~2~-*), 3.05--2.97 (m, 2H, *-CH~2~-*), 2.91 (d, *J* = 1.3 Hz, 3H, *-CH~3~*), 2.61 (s, 3H, *-CH~3~*), 2.17--2.04 (m, 2H, *-CH~2~-*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 160.1, 147.8, 132.7, 131.4, 117.4, 117.2, 110.9, 55.8, 53.6, 48.2, 45.4, 41.1, 32.7, 20.8. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~23~N~6~O^+^: 291.19279. Found: 291.19267.
*N*,*N*'-Dimethyl-*N*'-(1-(3-trifluoromethoxyphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**10e**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.70--7.64 (m, 1H, *-ArH*), 7.58--7.52 (m, 2H, *-ArH*), 7.48 (ddd, *J* = 7.9, 2.0, 1.0 Hz, 1H, *-ArH*), 4.71 (s, 2H, *-CH~2~-*), 3.26--3.20 (m, 2H, *-CH~2~-*), 3.01--2.95 (m, 2H, *-CH~2~-*), 2.83 (s, 3H, *-CH~3~*), 2.60 (s, 3H, *-CH~3~*), 2.10--2.01 (m, 2H, *-CH~2~-*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 148.2, 132.8, 132.0, 124.2, 123.5, 118.1, 53.7, 48.5, 45.5, 41.1, 32.7, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~20~F~3~N~6~O^+^: 345.16452. Found: 345.16431.
### 3.2.2. Synthesis of **16a**--**e** {#sec3dot2dot2-ijms-20-03840}
General procedure for the preparation of compounds **11c**--**d**.
To a solution of compound **4c**--**d** (2.00 g, 8.06 mmol) in dry dichloromethane was added BBr~3~ (16.12 mL, 1 M solution in CH~2~Cl~2~, 16.12 mmol) dropwise under argon at −78 °C and then the reaction mixture was warmed to room temperature and stirred for 12h. The mixture was washed three times with water, the organic layer was dried over Na~2~SO~4~, and the solvent removed under reduced pressure. The solid residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **11c**--**d**.
Ethyl 1-(4-hydroxylphenyl)-1H-tetrazole-5-carboxylate (**11c**)
White solid. Yield: 67%. MP: 136.4--137.0 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.43--7.37 (m, 2H, *-ArH*), 7.06--7.00 (m, 2H, *-ArH*), 4.47 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.41 (t, *J* = 7.2 Hz, 3H, *-CH~3~*).
Ethyl 1-(3-hydroxylphenyl)-1H-tetrazole-5-carboxylate (**11d**)
White solid. Yield: 67%. MP: 160.4--161.3 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.12 (s, 1H, *-OH)*, 7.39 (t, *J* = 8.0 Hz, 1H, *-ArH*), 7.09 (ddd, *J* = 7.9, 2.1, 1.0 Hz, 1H, *-ArH*), 7.06 (t, *J* = 2.1 Hz, 1H, *-ArH*), 7.02 (ddd, *J* = 8.2, 2.4, 1.0 Hz, 1H, *-ArH*), 4.33 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.21 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
General procedure for the preparation of compounds **12a**--**b**.
To a solution of **11c**--**d** (0.60 g, 2.56 mmol) in ethyl acetate was added triethylamine (0.71 mL, 5.12 mmol), methanesulfonyl chloride (0.26 mL, 3.33mmol) at 0 °C and stirred for 10 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na~2~SO~4~, and the solvent removed under reduced pressure without further purification to give **12a**--**b**.
Ethyl 1-(4-methylsulfonylphenyl)-1H-tetrazole-5-carboxylate (**12a**)
White solid, Yield: 95%. MP: 135.7--137.8 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.65--7.61 (m, 2H, *-ArH*), 7.57--7.51 (m, 2H, *-ArH*), 4.49 (q, *J* = 7.2 Hz, 2H, *-CH~2~-*), 3.28 (s, 3H, *-SO~3~CH~3~*), 1.42 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
Ethyl 1-(3-methylsulfonylphenyl)-1H-tetrazole-5-carboxylate (**12b**)
Yellow oil, Yield: 95%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.91--7.87 (m, 1H, *-ArH*), 7.79--7.72 (m, 2H, *-ArH*), 7.66 (dt, *J* = 6.9, 2.3 Hz, 1H, *-ArH*), 4.32 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 3.47 (s, 3H, *-SO~3~CH~3~*), 1.20 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
General procedure for the preparation of compounds **13a**--**b**.
To a solution of **11c**--**d** (0.40 g, 1.71 mmol) in dry DMF was added K~2~CO~3~ (0.28 g, 2.05 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.27 mL, 1.88 mmol) at room temperature and stirred for 3h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na~2~SO~4~, and the solvent removed under reduced pressure without further purification to give **13a**--**b**.
Ethyl 1-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazole-5-carboxylate (**13a**)
White solid, Yield: 94%. MP: 119.2--120.0 °C. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.53--7.48 (m, 2H, *-ArH*), 7.16--7.12 (m, 2H, *-ArH*), 4.47 (qd, *J* = 7.5, 4.4 Hz, 4H, *-CH~2~CF~3~, -CH~2~-*), 1.42 (t, *J* = 7.2 Hz, 3H, *-CH~3~*).
Ethyl 1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazole-5-carboxylate (**13b**)
White solid, Yield: 94%. MP: 77.0--77.6 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.59 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.53 (t, *J* = 2.2 Hz, 1H, *-ArH*), 7.38 (dddd, *J* = 9.3, 8.4, 2.3, 1.0 Hz, 2H, *-ArH*), 4.86 (q, *J* = 8.8 Hz, 2H, *-CH~2~CF~3~*), 4.33 (q, *J* = 7.1 Hz, 2H, *-CH~2~-*), 1.20 (t, *J* = 7.1 Hz, 3H, *-CH~3~*).
General procedure for the preparation of compounds **14a**--**d**.
To a solution of **12a**--**b** or **13a**--**b** (1.0 eq) in anhydrous dichloromethane (1.8 mL/mmol) was added diisobutyl aluminium hydride (1.0 M in hexanes, 2.0 eq) dropwise at −78 °C and the reaction was stirred for 30 min. The mixture was quenched with methanol, concentrated and extracted with ethyl acetate. The combined organic layers were washed with water, 1 M HCl and dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **14a**--**d**.
1-(4-Methylsulfonylphenyl)-1H-tetrazole-5-carbaldehyde (**14a**)
Yellow solid. Yield: 78%. MP: 146.7--147.0 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.10 (s, 1H, *-CHO*), 7.94--7.88 (m, 2H, *-ArH*), 7.68--7.63 (m, 2H, *-ArH*), 3.52 (s, 3H, *-SO~3~CH~3~*).
1-(3-Methylsulfonylphenyl)-1H-tetrazole-5-carbaldehyde (**14b**)
Yellow oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.09 (s, 1H, *-CHO*), 7.87 (t, *J* = 2.1 Hz, 1H, *-ArH*), 7.77--7.72 (m, 2H, *-ArH*), 7.61 (ddd, *J* = 8.0, 2.3, 1.2 Hz, 1H, *-ArH*), 3.49 (s, 3H, *-SO~3~CH~3~*).
1-(4-(2,2,2-Trifluoroethoxy)phenyl)-1H-tetrazole-5-carbaldehyde (**14c**)
Yellow oil. Yield: 76%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.06 (s, 1H, *-CHO*), 7.76--7.72 (m, 2H, *-ArH*), 7.33--7.30 (m, 2H, *-ArH*), 4.92 (q, *J* = 8.9, 7.1 Hz, 2H, *-CH~2~CF~3~*).
1-(3-(2,2,2-Trifluoroethoxy)phenyl)-1H-tetrazole-5-carbaldehyde (**14d**)
White solid. Yield: 75%. MP: 101.5--102.0 °C. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 10.08 (s, 1H, *-CHO*), 7.63 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.49 (t, *J* = 2.3 Hz, 1H, *-ArH*), 7.42 (ddd, *J* = 5.5, 2.0, 0.9 Hz, 1H, *-ArH*), 7.41--7.39 (m, 1H, *-ArH*), 4.87 (q, *J* = 8.8, 1.3 Hz, 2H, *-CH~2~CF~3~*).
General procedure for the preparation of compounds **15a**--**e**.
To a solution of **14a**--**d** (1.0 eq) in 1,2-Dichloroethane (8.5 mL/mmol) was added sodium triacetoxyborohydride (2.0 eq) and **6a** or **6b** (1.0 eq) and the reaction was stirred for 12 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **15a**--**e**.
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**15a**)
Colorless oil. Yield: 77%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.91 (d, *J* = 8.6 Hz, 2H, *-ArH*), 7.65--7.61 (m, 2H, *-ArH*), 3.91 (s, 2H, *-CH~2~-*), 3.50 (s, 3H, *-CH~3~*), 3.13 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.62 (d, *J* = 15.3 Hz, 3H, *-CH~3~*), 2.48 (d, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.19 (d, *J* = 6.5 Hz, 3H, *-CH~3~*), 1.33 (d, *J* = 11.8 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**15b**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.84 (d, *J* = 23.0 Hz, 2H, *-ArH*), 7.77 (t, *J* = 8.1 Hz, 1H, *-ArH*), 7.64 (ddd, *J* = 8.1, 2.4, 1.2 Hz, 1H, *-ArH*), 3.94 (s, 2H, *-CH~2~-*), 3.49 (s, 3H, *-CH~3~*), 3.12 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.62 (d, *J* = 11.0 Hz, 3H, *-CH~3~*), 2.48 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.20 (d, *J* = 4.4 Hz, 3H, *-CH~3~*), 1.32 (d, *J* = 8.5 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**15c**)
Colorless oil. Yield: 82%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.92--7.86 (m, 1H, *-ArH*), 7.77--7.66 (m, 2H, *-ArH*), 7.37--7.33 (m, 1H, *-ArH*), 4.91 (q, *J* = 8.8 Hz, 2H, *-CH~2~-*), 3.85 (s, 2H, *-CH~2~-*), 3.14 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.64 (d, *J* = 13.8 Hz, 3H, *-CH~3~*), 2.48 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.18 (s, 3H, *-CH~3~*), 1.33 (d, *J* = 12.7 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**15d**)
Colorless oil. Yield: 80%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.61 (t, *J* = 8.2 Hz, 1H, *-ArH*), 7.55--7.40 (m, 2H, *-ArH*), 7.34 (dd, *J* = 8.5, 2.5 Hz, 1H, *-ArH*), 4.89 (q, *J* = 8.8 Hz, 2H, *-CH~2~-*), 3.93 (s, 2H, *-CH~2~-*), 3.11 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.61 (d, *J* = 12.7 Hz, 3H, *-CH~3~*), 2.47 (t, *J* = 6.5 Hz, 2H, *-CH~2~-*), 2.19 (s, 3H, *-CH~3~*), 1.32 (d, *J* = 9.0 Hz, 9H, *-C(CH~3~)~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(3-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**15e**)
Colorless oil. Yield: 75%.^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.90 (t, *J* = 2.1 Hz, 1H, *-ArH*), 7.82--7.74 (m, 2H, *-ArH*), 7.66--7.62 (m, 1H, *-ArH*), 3.89 (s, 2H, *-CH~2~-*), 3.48 (s, 3H, *-CH~3~*), 2.93 (s, 2H, *-CH~2~-*), 2.67 (d, *J* = 4.1 Hz, 3H, *-CH~3~*), 2.29 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 2.10 (s, 3H, *-CH~3~*), 1.46 (s, 2H, *-CH~2~-*), 1.35 (s, 9H, *-C(CH~3~)~3~*).
General procedure for the preparation of compounds **16a**--**e**.
Compounds **15a**--**e** (0.51 mmol) was added to saturated hydrochloric acid ethanol solution (10 mL) at room temperature and stirred for 30 min. The reaction solution was filtered and washed with diethylether (20 mL) to give **16a**--**e**.
*N*,N'-Dimethyl-*N*'-(1-(4-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**16a**)
White solid. Yield: 95%. MP: 198.9--199.3 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.65--7.60 (m, 2H, *-ArH*), 7.56--7.52 (m, 2H, *-ArH*), 4.24 (s, 2H, *-CH~2~-*), 3.32 (s, 3H, -*SO~3~CH~3~*), 3.14 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 3.00 (t, *J* = 6.3 Hz, 2H, *-CH~2~-*), 2.58 (s, 3H, *-CH~3~*), 2.41 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 150.2, 150.1, 131.3, 127.1, 124.2, 51.9, 49.4, 44.1, 41.4, 37.1, 33.0. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~21~N~6~O~3~S^+^: 341.13904. Found: 341.13906.
*N*,*N*'-Dimethyl-*N*'-(1-(3-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**16b**)
Colorless oil. Yield: 94%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.68 (td, *J* = 8.1, 0.7 Hz, 1H, *-ArH*), 7.59 (qd, *J* = 2.5, 0.9 Hz, 2H, *-ArH*), 7.57--7.53 (m, 1H, *-ArH*), 4.32 (s, 2H, *-CH~2~-*), 3.30 (s, 3H, -*SO~3~CH~3~*), 3.20--3.15 (m, 2H, *-CH~2~-*), 3.06 (t, *J* = 6.3 Hz, 2H, *-CH~2~-*), 2.59 (s, 3H, *-CH~3~*), 2.47 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 150.6, 148.9, 133.3, 132.0, 125.2, 124.3, 119.5, 51.9, 49.3, 44.4, 41.3, 37.1, 32.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~21~N~6~O~3~S^+^: 341.13904. Found: 341.13892.
*N*,*N*'-Dimethyl-*N*'-(1-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazol-5-yl-methyl)ethylenediamine hydrochloride (**16c**)
White solid. Yield: 95%. MP: 188.7--190.0 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.49--7.44 (m, 2H, *-ArH*), 7.21--7.15 (m, 2H, *-ArH*), 4.59 (q, *J* = 8.4 Hz, 2H, *-CH~2~CF~3~*), 4.25 (s, 2H, *-CH~2~-*), 3.16 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 3.02 (t, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.58 (s, 3H, *-CH~3~*), 2.43 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 158.9, 150.1, 126.8, 126.3, 116.3, 65.6, 65.2, 51.8, 49.1, 44.2, 41.3, 33.0. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~20~F~3~N~6~O^+^: 345.16452. Found: 345.16437.
*N*,*N*'-Dimethyl-*N*'-(1-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-tetrazol-5-ylmethyl)ethylenediamine hydrochloride (**16d**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.54 (ddd, *J* = 8.4, 7.6, 0.7 Hz, 1H, *-ArH*), 7.25 (ddd, *J* = 8.6, 2.4, 1.0 Hz, 1H, *-ArH*), 7.20--7.15 (m, 2H, *-ArH*), 4.57 (q, *J* = 8.4 Hz, 2H, *-CH~2~CF~3~*), 4.40 (s, 2H, *-CH~2~-*), 3.23 (td, *J* = 6.2, 1.4 Hz, 2H, *-CH~2~-*), 3.16 (dd, *J* = 7.2, 5.0 Hz, 2H, *-CH~2~-*), 2.61 (s, 3H, *-CH~3~*), 2.54 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 157.9, 131.5, 118.7, 117.6, 112.1, 65.7, 65.3, 51.9, 49.3, 41.2, 32.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~20~F~3~N~6~O^+^: 345.16452. Found: 345.16437.
*N*,*N*'-Dimethyl-*N*'-(1-(3-methylsulfonylphenyl)-1H-tetrazol-5-yl-methyl)-1,3-propylenediamine hydrochloride (**16e**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.74--7.67 (m, 1H, *-ArH*), 7.60 (dt, *J* = 7.7, 1.4 Hz, 2H, *-ArH*), 7.57--7.52 (m, 1H, *-ArH*), 4.80 (s, 2H, *-CH~2~-*), 3.31 (s, 5H, *-CH~2~-*, -*SO~3~CH~3~*), 3.02--2.96 (m, 2H, *-CH~2~-*), 2.91 (s, 3H, *-CH~3~*), 2.60 (s, 3H, *-CH~3~*), 2.13--2.04 (m, 2H, *-CH~2~-*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 149.0, 148.0, 132.8, 132.2, 125.5, 124.3, 119.5, 53.7, 48.4, 45.4, 41.2, 37.1, 32.7, 20.8. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~23~N~6~O~3~S^+^: 355.15469. Found: 355.15460.
### 3.2.3. Synthesis of **18a**--**e** and **20** {#sec3dot2dot3-ijms-20-03840}
General procedure for the preparation of compounds **17a**--**e**.
To a solution of **5a** (1.0 eq) in 1,2-Dichloroethane (8.5 mL/mmol) was added sodium triacetoxyborohydride (2.0 eq) and **6c**--**g** (1.0 eq) and the reaction was stirred for 12 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous Na~2~SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using EtOAc/petroleum as eluent to give **17a**--**e**.
*N*-tert-Butyloxycarbonyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**17a**)
Colorless oil. Yield: 85%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.57--7.43 (m, 2H, *-ArH*), 7.12--7.03 (m, 2H, *-ArH*), 4.70--4.61 (m, 1H, *-OCH(CH~3~)~2~*), 3.31 (s, 2H, *-CH~2~-*), 2.52 (s, 2H, *-CH~2~-*), 1.61 (s, 2H, *-CH~2~-*), 1.45 (s, 9H, *-C(CH~3~)~3~*), 1.42 (d, *J* = 0.6 Hz, 3H, *-CH~3~*), 1.42--1.39 (m, 3H, *-CH~3~*), 1.27 (s, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-1,3-propylenediamine (**17b**)
Colorless oil. Yield: 80%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.65--7.59 (m, 2H, *-ArH*), 7.15--7.09 (m, 2H, *-ArH*), 4.77--4.69 (m, 1H, *-OCH(CH~3~)~2~*), 3.78 (s, 2H, *-CH~2~-*), 2.77 (q, *J* = 6.6 Hz, 2H, *-CH~2~-*), 2.32 (t, *J* = 7.1 Hz, 2H, *-CH~2~-*), 2.09 (s, 3H, *-CH~3~*), 1.40 (t, *J* = 6.9 Hz, 2H, *-CH~2~-*), 1.36 (s, 9H, *-C(CH~3~)~3~*), 1.32 (s, 3H, *-CH~3~*), 1.31 (d, *J* = 2.3 Hz, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*-methyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-ethylenediamine (**17c**)
Colorless oil. Yield: 85%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.55--7.49 (m, 2H, *-ArH*), 7.07--7.01 (m, 2H, *-ArH*), 4.64 (p, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 4.09 (s, 2H, *-NH~2~*), 3.39 (d, *J* = 16.0 Hz, 2H, *-CH~2~-*), 2.91 (d, *J* = 17.3 Hz, 2H, *-CH~2~-*), 2.86 (s, 3H, *-CH~3~*), 2.14 (s, 2H, *-CH~2~-*), 1.44 (s, 9H, *-C(CH~3~)~3~*), 1.41 (s, 3H, *-CH~3~*), 1.40 (s, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-ethylenediamine (**17d**)
Colorless oil. Yield: 85%. ^1^H NMR (400 MHz, Chloroform-*d*) δ 7.48 (d, *J* = 8.5 Hz, 2H, *-ArH*), 7.11--7.01 (m, 2H, *-ArH*), 4.64 (h, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 4.19 (s, 2H, *-CH~2~-*), 3.33 (d, *J* = 5.9 Hz, 2H, *-CH~2~-*), 2.98 (s, 2H, *-CH~2~-*), 1.45 (s, 9H, *-C(CH~3~)~3~*), 1.42 (d, *J* = 1.3 Hz, 3H, *-CH~3~*), 1.40 (d, *J* = 1.4 Hz, 3H, *-CH~3~*).
*N*-tert-Butyloxycarbonylaminoethyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-piperazine (**17e**)
Colorless oil. Yield: 75%. ^1^H NMR (400 MHz, DMSO-*d*~6~) δ 7.65--7.60 (m, 2H, *-ArH*), 7.17--7.10 (m, 2H, *-ArH*), 6.63 (t, *J* = 5.7 Hz, 1H, *-NH-*), 4.74 (hept, *J* = 6.0 Hz, 1H, *-OCH(CH~3~)~2~*), 3.77 (s, 2H, *-CH~2~-*), 2.98 (q, *J* = 6.4 Hz, 2H, *-CH~2~-*), 2.43--2.15 (m, 10H, *-CH~2~-*), 1.37 (s, 9H, *-C(CH~3~)~3~*), 1.32 (s, 3H, *-CH~3~*), 1.31 (s, 3H, *-CH~3~*).
General procedure for the preparation of compounds **18a**--**e**.
Compounds **17a**--**e** (0.51 mmol) was added to saturated hydrochloric acid ethanol solution (10 mL) at room temperature and stirred for 30 min. The reaction solution was filtered and washed with ethanol (20 mL) to give **18a**--**e**.
*N*-(1-(4-Isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*-methyl-ethylenediamine hydrochloride (**18a**)
White solid. Yield: 95%. MP: 186.5--187.7 °C. 1H NMR (400 MHz, Deuterium Oxide) δ 7.46--7.38 (m, 2H, *-ArH*), 7.13--7.07 (m, 2H, *-ArH*), 4.69--4.65 (m, 1H, *-OCH(CH~3~)~2~*), 4.41 (s, 2H, *-CH~2~-*), 3.14 (td, *J* = 6.3, 1.3 Hz, 2H, *-CH~2~-*), 3.06 (td, *J* = 6.3, 1.3 Hz, 2H, *-CH~2~-*), 2.49 (s, 3H, *-CH~3~*), 1.26 (s, 3H, *-CH~3~*), 1.25 (s,3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 150.5, 126.7, 125.0, 117.1, 71.9, 52.9, 49.0, 41.2, 35.2, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~23~N~6~O^+^: 291.19279. Found: 291.19278.
*N*-(1-(4-Isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*-methyl-1,3-propylenediamine hydrochloride (**18b**)
Colorless oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.42--7.36 (m, 2H, *-ArH*), 7.12--7.07 (m, 2H, *-ArH*), 4.69--4.63 (m, 1H, *-OCH(CH~3~)~2~*), 4.72 (s, 2H, *-CH~2~-*), 3.32--3.24 (m, 2H, *-CH~2~-*), 2.99--2.90 (m, 2H, *-CH~2~-*), 2.86 (s, 3H, *-CH~3~*), 2.04 (tt, *J* = 9.8, 6.6 Hz, 2H, *-CH~2~-*), 1.25 (s, 3H, *-CH~3~*), 1.23 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.4, 147.9, 126.7, 124.5, 117.2, 71.9, 53.7, 48.1, 41.1, 36.2, 22.0, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~15~H~25~N~6~O^+^: 305.20844. Found: 305.20840.
*N*-Methyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-ethylenediamine hydrochloride (**18c**)
White solid. Yield: 92%. MP: 179.7--180.7 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.43--7.36 (m, 2H, *-ArH*), 7.12--7.06 (m, 2H, *-ArH*), 4.67 (d, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 4.49 (s, 2H, *-CH~2~-*), 3.37 (ddd, *J* = 7.3, 6.1, 1.5 Hz, 2H, *-CH~2~-*), 3.29 (ddd, *J* = 7.7, 6.1, 1.6 Hz, 2H, *-CH~2~-*), 2.65 (s, 3H, *-CH~3~*), 1.25 (s, 3H, *-CH~3~*), 1.24 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.2, 149.3, 126.4, 124.7, 117.2, 71.9, 44.5, 43.4, 40.7, 33.1, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~14~H~23~N~6~O^+^: 291.19279. Found: 291.19269.
*N*-(1-(4-Isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-ethylenediaminehydrochloride (**18d**)
White solid. Yield: 93%. MP: 183.1--183.9 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.43--7.38 (m, 2H, *-ArH*), 7.13--7.08 (m, 2H, *-ArH*), 4.69--4.65 (m, 1H, *-OCH(CH~3~)~2~*), 4.52 (s, 2H, *-CH~2~-*), 3.37 (dd, *J* = 7.2, 5.9 Hz, 2H, *-CH~2~-*), 3.26 (ddd, *J* = 7.4, 6.3, 1.1 Hz, 2H, *-CH~2~-*), 1.26 (s, 3H, *-CH~3~*), 1.25 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.2, 149.3, 126.4, 124.7, 117.2, 71.9, 44.6, 40.7, 35.5, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~13~H~21~N~6~O^+^: 277.17714. Found: 291.17709.
*N*-aminoethyl-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-piperazinehydrochloride (**18e**)
Yellow solid. Yield: 92%. MP: 183.2--183.9 °C. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.46--7.40 (m, 2H, *-ArH*), 7.11--7.05 (m, 2H, *-ArH*), 4.00 (s, 2H, *-CH~2~-*), 3.35--3.26 (m, 4H, *-CH~2~-*), 3.19 (s, 4H, *-CH~2~-*), 2.82 (s, 4H, *-CH~2~-*), 1.25 (s, 3H, *-CH~3~*), 1.23 (s, 3H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 158.9, 151.7, 126.7, 116.9, 71.9, 52.5, 51.8, 49.3, 48.3, 33.7, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~17~H~28~N~7~O^+^: 346.23499. Found: 346.23494.
*N*-2,3-bis-(tert-Butoxycarbonyl)guanidino-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine (**19**)
To a solution of **18a** (0.26g, 0.80mmol) in dry DMF was added to stirred for 10 min and then 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.23g, 0.80mmol) was added and stirred for 5 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na~2~SO~4~, and the solvent removed under reduced pressure. The solid residue thus obtained was purified by column chromatography on silica gel using EtOAc/petroleum (1/2, V/V) as eluent to give **19** as yellow oil (0.22g, 82%). ^1^H NMR (400 MHz, Chloroform-*d*) δ 11.45 (s, 1H, *-NH-*), 8.48 (s, 1H, *-NH-*), 7.65--7.59 (m, 2H, *-ArH*), 7.06--6.99 (m, 2H, *-ArH*), 4.63 (p, *J* = 6.1 Hz, 1H, *-OCH(CH~3~)~2~*), 3.79 (s, 2H, *-CH~2~-*), 3.52 (q, *J* = 5.5 Hz, 2H, *-CH~2~-*), 2.78 (t, *J* = 6.0 Hz, 2H, *-CH~2~-*), 2.39 (s, 3H, *-CH~3~*), 1.53 (s, 3H, *-CH~3~*), 1.52 (s, 9H, *-C(CH~3~)~3~*), 1.41 (s, 9H, *-C(CH~3~)~3~*), 1.39 (s, 3H, *-CH~3~*).
*N*-Guanidino-*N*'-(1-(4-isopropoxyphenyl)-1H-tetrazol-5-yl-methyl)-*N*'-methyl-ethylenediamine hydrochloride (**20**)
Compounds 1**9** (0.55 mmol) was added to saturated hydrochloric acid ethanol solution (10 mL) at room temperature and stirred for 30min. The reaction solution was filtered and washed with ethanol (20 mL) to give **20**. Yellow oil. Yield: 92%. ^1^H NMR (400 MHz, Deuterium Oxide) δ 7.40 (dd, *J* = 8.7, 5.3 Hz, 2H, *-ArH*), 7.10 (dd, *J* = 8.7, 4.7 Hz, 2H, *-ArH*), 4.76 (s, 1H, *-NH-*), 4.66 (d, *J* = 5.0 Hz, 2H, *-CH~2~-*), 3.59 (dt, *J* = 25.7, 6.0 Hz, 2H, *-CH~2~-*), 3.42 (dd, *J* = 14.0, 7.2 Hz, 2H, *-CH~2~-*), 2.87 (d, *J* = 34.7 Hz, 3H, *-NH-*, *-NH~2~*), 1.24 (d, *J* = 6.0 Hz, 6H, *-CH~3~*). ^13^C NMR (101 MHz, Deuterium Oxide) δ 159.4, 148.1, 126.7, 124.5, 117.2, 71.9, 54.5, 48.4, 41.6, 36.3, 29.5, 20.9. HRMS (ESI) m/z \[M+H\]^+^ Calcd for C~15~H~25~N~8~O^+^: 333.21458. Found: 333.21451.
3.3. Radioactive Methylation Assay and MOA Study {#sec3dot3-ijms-20-03840}
------------------------------------------------
The enzyme inhibitory activities were measured by the radioisotope assay in ShangHai Chempartner Co. Ltd. according to the standard protocol. The similar procedure was recently performed in the publication \[[@B25-ijms-20-03840]\] The radioactive methylation assay was performed in 1× assay buffer (modified Tris buffer) system containing enzyme (PRMT1/5), peptide and \[^3^H\]-SAM solution and compounds on the assay plate. After 250 nL of compound solutions were added to the assay plate, 15 μL PRMT1/5 enzyme solution or 1× assay buffer for negative control was transfer to per well of prepared compound stock plates and the whole system (the final concentration of PRMT1 or PRMT5 was 0.5 nM or 2 nM in the system) incubated for 15 min at room temperature. Then, 10 μL of peptide and (^3^H)-SAM mixed solution was added to each well to start the reaction (the final concentration of (^3^H)-SAM was 0.25 μM in the system) and the reaction incubated for 60 min at room temperature. Afterwards, the reaction was stopped with addition of 5 μL cold SAM solution to per well. Then, 25 μL of volume per well was transferred to Flashplate from assay plate and incubated for 1 h minimum at room temperature. Finally, the Flashplate was washed with dH~2~O and 0.1% Tween-20 three times and then reading plate in Mi crobeta using program ^3^H-Flashplate. The data was analyzed in GraphPad Prism 5 to obtain IC~50~ values.
The MOA study of compound **9a** was performed against PRMT1 with respect to SAM and peptide substrate independently. In brief, the peptide concentration was kept at 100nM (10× Km) and the IC~50~ values of **9a** were determined at different SAM concentrations (0.5, 1, 2, 6, 20 and 60× Km). And then, the SAM concentration was kept at 250 nm (1× Km) and the IC~50~ values of **9a** monitored at different peptide concentration (0.5, 1, 3, 10, 30 and 100× Km). The method is consistent with the procedure described above.
3.4. Molecular Modeling {#sec3dot4-ijms-20-03840}
-----------------------
Since the crystal structure of human PRMT1 (hPRMT1) has not been solved, the homology model of hPRMT1 in complex with SAH, which was built by referencing the crystal structure of rat PRMT3 (rPRMT3, PDB 1F3L) as the template according to our previous publication \[[@B23-ijms-20-03840]\], was used for the current molecular modeling study. By overlaying the crystal structures of PRMT6-MS023 \[PDB ID 5E8R\] with hPRMT1, the position of MS023 was used as the reference to indicate the binding site, and then compound **9a** was docked by using glide module in Schrödinger Release 2017-4 with default settings \[[@B33-ijms-20-03840]\].
The compound **9a** and hPRMT1-SAH complex was then prepared for molecular dynamic simulations. QM calculations were performed by using the B3LYP 6-31G\* basis set within Gaussian16 \[[@B34-ijms-20-03840]\] to optimize the molecular geometries of compound **9a** and SAH, and the atom-centered point charges were calculated to fit the electrostatic potential using RESP \[[@B35-ijms-20-03840]\]. The system was explicitly solvated in a truncated octahedral TIP3P water box (12 Å from the complex to avoid periodic artefacts from occurring) by using Amber 16 with the amber ff14SB force field \[[@B36-ijms-20-03840]\] and the Generalized Amber Force field (GAFF) \[[@B37-ijms-20-03840]\]. 11 *K^+^* ions were added to neutralize the charges of the system. The whole system was first optimised by energy minimisations and equilibrations according to our standard protocol \[[@B23-ijms-20-03840]\], and then 100 ns free production molecular dynamic simulation was followed in the NPT ensemble (T = 300 K; P = 1 atm). The long-range electrostatic effects were treated by using Periodic boundary conditions (PBC) and particle-mesh-Ewald method (PME), and the temperature was coupled to an external bath using a weak coupling algorithm \[[@B38-ijms-20-03840]\]. The non-bonded interaction cutoff was set as 8 Å and the bond interactions involving H-atoms were constrained by using the SHAKE algorithm. The time step to solve the Newton's equations was chosen as 2 fs and the trajectory files were collected every 100 ps for the subsequent analysis.
MM-PBSA and Normal Mode were performed for the binding free energy calculations, based on 300 snapshots collected from the stable trajectory. The binding free energy contribution of each residues was calculated, and only those greater than −0.7 Kcal/mol were recorded for detailed interactions analysis.
3.5. Cell Culture {#sec3dot5-ijms-20-03840}
-----------------
The MDA-MB-231 cell line used in this study was obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA), and was grown in dulbecco's modified eagle medium (DMEM, Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco). The cells were incubated at 37 °C and 5% CO~2~.
3.6. Cell Viability Assay {#sec3dot6-ijms-20-03840}
-------------------------
The cytotoxicity was determined by the CCK8 assay. Briefly, MDA-MB-231 cells (5 × 10^3^ cells/well) were seeded in 96-well plates in DMEM containing 10% FBS and grew for 24 h. The exponentially growing cells were incubated with various concentrations of compounds for 48h/72h in serum free DMEM at 37 °C (5% CO~2~, 95% humidity). CCK8 reagent (10 μL) was added to each well and incubated for further 2 h, and then the absorbance was analyzed in a multiwell-plate reader (BioTek ELx800) at 450 nm.
3.7. Western Blotting {#sec3dot7-ijms-20-03840}
---------------------
MDA-MB-231 cells were maintained on 6-well plates at the appropriate density. After the attachment, cells were treated with **9a** at indicated concentrations or DMSO control for 48 h. Total cell lysates were separated by SDS-PAGE and transferred onto nitrocellulose membranes. The blots were blocked with 5% nonfat milk for 30 min and the target proteins were probed with appropriate specific antibody overnight at 4 °C, respectively. The blots were washed with TBST for three times and then incubated with anti-rabbit secondary antibody (HRP conjugated) for 1 h. After another three washes, bands were detected in a ChemiScope3400 imaging system using ECL substrate (Millipore, Burlington, MS, USA). Primary antibodies used were as follows: anti-PRMT1 (Cell Signaling Technology no.2449, Danvers, MA, USA), anti-ADMA (Cell Signaling Technology no.13522), anti-SDMA (Cell Signaling Technology no.13222), anti-GAPDH (Cell Signaling Technology no. 5174), anti-H4R3me2a Abcam, ab9231), Wnt3a (Cell Signaling Technology no. 2721s), anti-DDAH (Abcam, ab9231, Cambridge, UK), Wnt5a/b (Cell Signaling Technology no. 2530s), β-catenin (Cell Signaling Technology no. 8480s), MMP9 (Cell Signaling Technology no.1366s). The results were obtained from multiple membranes. No significant differences were observed among loading controls. Therefore, we presented the representative loading control blot image in the figure.
4. Conclusions {#sec4-ijms-20-03840}
==============
In summary, through computer aided drug design, we designed and synthesized 22 1,5-substituded tetrazole derivatives. Among them, five compounds (**9a**, **9f**, **16c**, **18a**, **18e**) showed strong inhibitory effects on PRMT1. Compound **9a** was identified as the most potent PRMT1 inhibitor (IC~50~ = 3.5 μM) in the current study, and it showed strong selectivity to PRMT1 (type I PRMT) with respect to PRMT5 (type II PRMT). The MOA assay showed that compound **9a** did not compete with either SAM or peptides, but according to the crystal structure of human PRMT6 with its inhibitor and combining with the molecular dynamic simulation study, it was believed that compound 9a bound to substrate-arginine binding site. By Western blotting, it was confirmed that compound **9a** inhibited the PRMT1 pathway, and the canonical Wnt/β-catenin signaling pathway was down-regulated. The discovery of compound **9a** is likely to prove to be very important for the understanding of PRMT1 function, and is a potential lead compound for future drug design efforts targeting PRMT1.
The authors thank Ian Paterson and Xinyi Yang for many helpful suggestions and corrections on the current manuscript.
W.H. and H.W. (Hao Wang) conceived and designed the experiments; Y.S., Z.W., H.Y., X.Z., H.W. (Han Wu) and L.M. performed the experiments; W.H., H.W. (Hao Wang) and F.X. analyzed the data; W.H., H.W. (Han Wu) and Y.S. wrote the paper.
This work was supported by National Natural Science Foundation of China (81660588, 81773582), the Key R&D Program of Ningxia (2018BFG02004), and the Program for Leading Talents of Ningxia Province (KJT2018004).
All authors declare no conflict of interest.
PRMT1
Protein arginine methyltransferase 1
SAM
S
-adenosyl-L-methionine
mMA
monomethylarginine
SAH
S
-adenosyl-L-homocysteine
ADMA
Asymmetrical dimethylargine
SDMA
Symmetrical dimethylarginine
DIBAL-H
Diisobutylaluminium hydride
STAB
Sodium triacetoxyborohydride
SAR
Structure-activity relationship
MOA
Mechanism of action
Figures, Schemes and Tables
===========================
{#ijms-20-03840-f001}
{#ijms-20-03840-f002}
{#ijms-20-03840-f003}
{#ijms-20-03840-sch001}
{#ijms-20-03840-sch002}
{#ijms-20-03840-sch003}
{#ijms-20-03840-f004}
{#ijms-20-03840-f005}
{#ijms-20-03840-f006}
{#ijms-20-03840-f007}
ijms-20-03840-t001_Table 1
######
Inhibitory activities of 1,5-substituded tetrazole derivatives against PRMT1 and PRMT5.
-------------------------------------------------------------------------------------------------------------------------------------
Group Compounds R~1~ R~2~ \% Inhibition of PRMT1\ IC~50~ (μM)
(at 10 μM) ^a^
------- ----------------- ----------------------------- ----------------------------- ------------------------- ------------- -------
I 9a 4-OCH(CH~3~)~2~  65 3.5 \>100
9b 3-OCH(CH~3~)~2~  0 \- \-
9c 4-OCH~3~  3 \- \-
9d 3-OCH~3~  7 \- \-
9f 4-OCF~3~  47 23.8 \>100
9e 3-OCF~3~  −17 \- \-
16a 4-OSO~2~CH~3~  23 \- \-
16b 3-OSO~2~CH~3~  13 \- \-
16c 4-OCH~2~CF~3~  52 19.9 \>100
16d 3-OCH~2~CF~3~  3 \- \-
II 10a 4-OCH(CH~3~)~2~  23 \- \-
10b 3-OCH(CH~3~)~2~  0 \- \-
10c 4-OCH~3~  −6 \- \-
10d 3-OCH~3~  −14 \- \-
10e 3-OCF~3~  −12 \- \-
16e 3-OSO~2~CH~3~  −4 \- \-
III 18a 4-OCH(CH~3~)~2~  50 10.0 \>100
18b 4-OCH(CH~3~)~2~  15 \- \-
18c 4-OCH(CH~3~)~2~  10 \- \-
18d 4-OCH(CH~3~)~2~  18 \- \-
18e 4-OCH(CH~3~)~2~  39 29.0 \>100
20 4-OCH(CH~3~)~2~  −7 \- \-
SAH 0.49 0.40
AMI-1 72 \-
-------------------------------------------------------------------------------------------------------------------------------------
^a^ Initial inhibition rate was tested at 10 μM for all compounds, and only those with \>40% inhibition effects were selected for IC~50~ measurements.
ijms-20-03840-t002_Table 2
######
Calculated energy components, binding free energy (kcal/mol) of compound **9a** in hPRMT1.
Simulations ΔE~vdw~ ΔE~ele~ ΔG~pb~ ΔG~np~ ΔG~gas~ ΔG~solv~ ΔG~mmpbsa~ TΔS ΔG~binding~
------------- --------------- ---------------- --------------- -------------- ---------------- --------------- --------------- --------------- -------------
9a −38.58 ± 0.22 −257.49 ± 0.70 268.40 ± 0.49 −4.98 ± 0.01 −296.07 ± 0.70 263.43 ± 0.49 −32.64 ± 0.49 −23.00 ± 3.29 −9.64
[^1]: These authors contributed equally to this work.
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PROS
CONS
Requires long-term strategy, making early mistakes hard to recover from.
VERDICT
Mikado Defenders is a solid tower-defense game with a challenging twist for fans of genre and might just sway those who are yet to fall in love with the action packed strategy of TD titles.
Full Review
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With so many different tower-defense games to choose from on the iPhone, it's hard to believe that a company like TAITO would take the risk of competing with such a large crowd. Thankfully their new title Mikado Defenders is a stand-out from the crowd, with its sumi-e inspired artwork and unique spin on the tower-defense gameplay.
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This is certainly not your average tower-defense game and fans will appreciate the new challenges Mikado Defenders presents. Definitely a must try for any fan of the genre.
Description
Mikado Defenders: an original feudal Japanese defense simulation for the iPhone / iPod touch!
In Mikado Defenders players deploy samurai foot soldiers, archers, and other units, desperately attempting to defend their fortress from an all-out demonic attack. It’s tower defense, with a uniquely Japanese twist!
Set in the Sengoku Era—a time when Japan was torn asunder by civil war—
Build your base up from a humble campsite to an impregnable fortress, complete with barricades and turrets! Investing in your castle is vital if you’re to have any hope fending off the Skull Wheel and other massive demons!
- Guardian Spirits –
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- Class Change System -
Each unit will be promoted to an elite class by increasing its level to certain point!
-Taste of The Traditional Japan Art -
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- Play on your terms: you can suspend games mid-level, and come back to them later, picking up right where you left off!
- Selectable music: enjoy the provided ZUNTATA soundtrack or listen your own tunes! |
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A known winding device of the initially described type, with a corresponding control system, for producing wound rolls whose hardness can be influenced in a predetermined manner, will now be described on the basis of the schematic view shown in FIG. 1.
FIG. 1 illustrates a central contact winding device. In this winding device the web 1 being wound is introduced by means of a contact roller 2 contacting the winding tube 3, or to the film roll 4 that forms on this winding tube, and is wound onto the film roll 4; the contact roller is positioned against the circumference of the film roll 4 that is forming. Positioned in front of the contact roller is a web tension measuring roller 5, which measures the tractive force of the film web running over the contact roller 2. The web tension measuring roller 5 forms a web loop or diverts the web 1, so that the tractive force can be determined from the tension exerted on the web tension measuring roller 5 by the incoming and outgoing portions of the web. Assigned to the web tension measuring roller 5 is a receiver 6 for the measured data, which feeds a signal corresponding to the measured tractive force of the web to a control device, for example, a computer 7. This computer 7 compares the signal obtained from the receiver 6 as an actual value with a desired value stored in the computer 7. If the two signals differ, the speed of the direct-current motor 8 driving the contact roller 2 will be controlled in a positive or negative fashion, specifically in such a way that the actual value fed from the receiver 6 to the computer corresponds to the desired value.
Since the diameter of the film roll 4 increases with the winding time, the motor 9 driving the winding tube 3 and the film roll 4 forming on it must also be regulated according to the increasing diameter of the film roll 4. This is provided for in that a sensor 10 monitors the winding tube 3 or the pins or journals supporting the winding tube 3, and the sensor 10 determines the actual diameter of the film roll 4 by means of the counted revolutions of the winding tube 3. This value provides a measure for changing the torque of the winding motor 9. The torque of the winding motor 9 is controlled accordingly. Thus, the torque of the motor 9 is changed in accordance with the diameter of the film roll that is forming and in accordance with the desired winding characteristics, while the speed of the motor 8 which drives the contact roller 2 is also controlled.
As described, a winding device operating as a central contact winding device is shown in FIG. 1, in which both the contact roller and the winding tube on which the web is wound are driven and both are in continuous contact with each other.
In a different system, the contact roller 2 is moved away from the winding tube 3, or the wound roll 4 that forms on this tube, and is positioned at a distance from the tube. Winding of this kind is referred to as "central gap winding". This mode of operation is always preferred when highly sensitive films must be wound, which run the risk of being damaged by contact pressure from the contact roller.
If the wound rolls are wound by a central gap winding method, the winding motor 8 and the motor 9 driving the contact roller 2 are controlled in the manner described above. A different type of control has not previously been thought possible, inasmuch as the web tension between the winding tube 3, or the film roll 4 forming on the tube, and the displaced contact roller could not be measured, as it was impossible to house measuring devices in the immediate area. If the known winding device described in FIG. 1 is operated as a central gap winding device, the torque of the winding motor is controlled according to the increasing diameter of the wound roll 4 that is in the process of forming in such a way that the desired winding characteristic is obtained. Controlling the torque of the winding motor is only able to provide the desired winding characteristic in a very imprecise fashion, however, so that controlling the torque of the winding motor is no longer adequate for the increased demands with respect to the characteristic of coil hardness in the case of wound rolls with sensitive types of film. |
The fact that second-graders from children could feel this compassion and act upon it, and make enough of an impact that children from 43 other nations also joined in the effort, is quite staggering to me. |
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Special Courage
I was reading an article in Time (very good, I forget the title but it’s in last week’s issue) about the IEDs and the insurgents and the technology and… yeah. Anyway, it astounded me that this American journalist (I can only assume the person writing for an American publication is, in fact, American) was interviewing this terrorist mastermind. This guy (the bad guy) has fashioned IEDs for the insurgents that have killed so many of our men (IEDs are the number one killer of US soldiers in Iraq). He once dreamed of getting his PhD at MIT and now, because its “god’s plan,” he is a terrorist. He is kind of a genius of the other side. He makes explosives out of the most random things..
Anyway, I found myself focusing not on the terrorist, but on the journalist writing the story. I don’t know exactly what I want to do… I’ve always sort of fallen back on teaching, but I’m not so sure now. Is that my passion? Gabe and I are seriously considering homeschooling our kids when we have them so I will have that oppurtunity to rear a child and train a new life… My real passion is writing. I want to write. And the older I get the more compelling my drive to share truth. Whether it be truth about God, about life, about politics, about myself… I hope that it isn’t an uncommon drive. Of course in order to share truth I have to learn it. Which is something I thoroughly enjoy doing. Anyway, journalism is plausible. So how far would I go for a story? I guess it depends on the story.
My friend said that the journalist should just kill the terrorist. But I think that would be a grave mistake. Certainly, that must be his first instinct. I mean, what global citizen wouldn’t want to kill the ones that are terrorizing the world? However, these journalists are lucky to get a meeting with these guys in the first place. They are always outnumbered and their opponents carry big guns – the journalist is probably shot if he is found with a weapon on his person at all. So being all Rambo and killing this guy might provide short term gratification (though not for him because he’ll have a million bullet holes in him) but would do nothing for the cause. If the reporter could instead be respectful (and fear looks a lot like respect) and build some trust, then he could get a bunch of interviews. And at the very least, these articles serve to share with the American people what exactly our troops are facing over there. Who knows… maybe some guy will come to trust the journalist so much that he leaks something…
Anyway, I am in awe of this courage. I hope that, if I do become a journalist, I am that brave.
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Krysann Joye
Hi there! This here is my favorite place and I'm excited to share it. I can't give you a concise blog topic, but this is where I work out my ish. I grew up Christian on the West Coast and got married when I was 18; so you can deconstruct my ideology accordingly. :) I enjoy metaphors and analogies and run-on sentences with enthusiasm. Above all, I want to connect (don't we all) so I hope you find some of that here. |
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abstract: 'The classical ground state magnetic response of the Heisenberg model when rotationally invariant exchange interactions of integer order $q>1$ are added is found to be discontinuous, even though the interactions lack magnetic anisotropy. This holds even in the case of bipartite lattices which are not frustrated, as well as for the frustrated triangular lattice. The total number of discontinuities is associated with even-odd effects as it depends on the parity of $q$ via the relative strength of the bilinear and higher order exchange interactions, and increases with $q$. These results demonstrate that the precise form of the microscopic interactions is important for the ground state magnetization response.'
author:
- 'N. P. Konstantinidis'
bibliography:
- 'qexchange.bib'
title: 'Discontinuous classical ground state magnetic response as an even-odd effect in higher order rotationally invariant exchange interactions'
---
The Heisenberg model plays an extremely important role in the study of magnetism of strongly correlated electron systems [@Auerbach98; @Fazekas99; @Lhuillier01; @Misguich03]. Within its context discontinuities of the ground state magnetization were found, showing that it can be tuned between well-separated values with small changes of an external field. Such discontinuities naturally occur in the presence of magnetic anisotropy, where the field forces the spins to non-continuously change their orientation toward special directions in spin space along which the energy is more efficiently minimized [@Neel36]. Frustrated clusters are of special interest, as competing interactions can lead to discontinuous ground state magnetization response in the absence of anisotropy, with the ground state spin configuration completely changing its symmetry as the discontinuity is traversed [@Coffey92; @NPK05; @Schroder05; @NPK07; @NPK15; @NPK16; @NPK16-1; @NPK17; @NPK17-1]. A non-continuous magnetic response is therefore associated with preferential directions in spin space or non-trivial connectivity of the interacting spins.
Here a new source of discontinuities is identified, rotationally invariant exchange interactions of integer order $q>1$, which require neither magnetic anisotropy nor frustration to generate magnetization jumps. Such discontinuities occur for lattices as simple as the bipartite, as well as for the frustrated triangular lattice that was further considered. These interactions are associated with even-odd effects with respect to the parity of $q$: for positive higher order exchange they generate ground state discontinuities only when $q$ is odd, while for negative there are discontinuities for both even and odd $q$. In the latter case the total number of magnetization gaps also depends on the parity of $q$. For the same type of parity, the total number of discontinuities increases with $q$.
It has been shown that higher order exchange terms are often important for the explanation of experimental data [@Furrer11]. This has been the case with the biquadratic exchange interaction ($q=2$) [@Falk84; @Gaulin86; @Demokritov98; @Millet99; @Orzel01], which can even be quite stronger than the bilinear exchange [@Nakatsuji05; @Tsunetsugu06; @Lauchli06-1]. Its importance can not be understated also from the theoretical point of view [@Anderson63], for example for the chain hosting spins of magnitude $s=1$ [@Thorpe72; @Haldane83; @Haldane83-1; @Affleck87; @Lauchli06], and it has also been considered along with biqubic terms for $s=\frac{3}{2}$ [@Fridman11]. It was also investigated in higher dimensions [@Hayden10; @Kawamura07; @Wenzel13], and for the magnetism of iron-based supeconductors [@Yu15; @Zhuo16]. The classical ground state magnetic response with bilinear and biquadratic exchange has been calculated for short odd-numbered chains [@NPK15-1], while in the case of the icosahedron it has been shown to generate many magnetization discontinuities [@NPK16-1]. A similar Hamiltonian in two dimensional spin space includes the standard bilinear exchange and generalized nematic interactions [@Lee85; @Korshunov85; @Park08; @Poderoso11; @Zukovic16].
Here rotationally invariant exchange interactions with $q$ ranging from 2 to 9 are considered. For spins $s$ the highest order non-trivial exchange interaction term of this type is of order $2s$. This means that for higher $q$ the classical treatment of the problem where the bilinear competes with the $2s$-order exchange interaction provides a very good description of the quantum problem, and that the even-odd effects in $q$ can also be viewed as effects related to $s$ being integer or half-integer. The underlying lattices are of bipartite form, chains and rectangles, and the frustrated triangular lattice.
The Hamiltonian including bilinear and higher order exchange interactions as well as a magnetic field term is $$H = \sum_{<ij>} [ J \vec{s}_i \cdot \vec{s}_j + J' ( \vec{s}_i \cdot \vec{s}_j )^q ] - h \sum_{i=1}^{N} s_i^z
\label{eqn:model}$$ There are $N$ spins $\vec{s}_i$ which are classical unit vectors in three-dimensional spin space. $<ij>$ indicates that interactions are limited to nearest neighbors $i$ and $j$. The first term is the bilinear exchange interaction, scaled with $J$, and the second the higher order exchange interaction of integer order $q>1$, scaled with $J'$. The exchange interactions are taken to be isotropic in spin space. The magnetic field $\vec{h}$ in the Zeeman term points along the $z$ direction without any loss of generality. The interactions are parametrized as $J$=cos$\omega$ and $J'$=sin$\omega$. The bilinear exchange favors antiparallel nearest-neighbors for positive $J$ and parallel for negative $J$. When $J'$ is positive the second term in Hamiltonian (\[eqn:model\]) favors antiparallel nearest-neighbor spins for odd $q$ and perpendicular for even $q$. For negative $J'$ it favors ferromagnetically coupled spins irrespectively of the parity of $q$. The situation is further complicated by the Zeeman term, through which the spins gain maximum magnetic energy when pointing in the direction of the field. The competition of these three terms determines the magnetic properties. In addition, for lattices such as the triangular their frustrated connectivity plays an important role. A ground state magnetization discontinuity is associated with a non-continuous change of the lowest energy spin configuration, which originates in a more efficient energy minimization as the field increases. Here the lowest energy configuration of Hamiltonian (\[eqn:model\]) is numerically calculated as a function of $h$ for $\omega$ $\epsilon$ $[0,2\pi)$ [@Coffey92; @NPK05; @NPK07; @Machens13; @NPK13; @NPK15; @NPK15-1; @NPK16; @NPK16-1; @NPK17; @NPK17-1]. The direction of each spin $\vec{s}_i$ is defined by a polar $\theta_i$ and an azimuthal $\phi_i$ angle. All angles are randomly initialized and each one is moved opposite its gradient direction until the energy minimum is reached. The procedure is repeated for different initial configurations to ensure that the global lowest energy configuration is found.
Firstly bipartite structures are considered, chains and rectangles with periodic boundary conditions, which lack any frustration. Minimization of Hamiltonian (\[eqn:model\]) shows that for lower and higher $\omega$, where the bilinear exchange is positive or weakly negative and the ground state is not ferromagnetic in zero field, the lowest energy configuration is the same for both types of structures for increasing $N$ and different $q$, and consequently also the one for the corresponding infinite lattices. The configuration is planar with a unit cell of two spins with the same polar angle $\theta$, and azimuthal angles that differ by $\pi$. Thus each spin’s nearest-neighbors point in the same direction, while $\theta$ is given from the solution of the equation $$\begin{aligned}
( 2 cos^2\theta -1)^{q-1} = \frac{1}{qJ'} ( \frac{h}{4 cos\theta} - J )
\label{eqn:eqntheta}\end{aligned}$$ (see App. \[appendix:ZF-LEC-Bipartite\] for the case of zero field). The solution of Eq. (\[eqn:eqntheta\]) can be discontinuous at a magnetic field $h_d$. Fig. \[fig:exchangeq=3\] plots the magnetization per spin $\frac{M}{N}=cos\theta$ as a function of $h$ for $q=3$. When $\frac{J'}{J}=0.41667$ (or $\omega=0.12567 \pi$) a discontinuity appears which originates in the higher order exchange interaction, as it is present when $J=0$ ($\omega=\frac{\pi}{2}$), and survives up to $\omega=0.70483\pi$. Fig. \[fig:qexchangewidthlocation\](a) plots the discontinuity field for $J'>0$. The jump occurs for odd but not for even $q$, bringing about an even-odd effect in the parity of higher order exchange interactions. An odd $q$ favors antiparallel nearest-neighbors, while an even $q$ perpendicular. The discontinuity exists for a specific $\omega$ range (see also App. \[appendix:MagnetizationinaField-LEC-Bipartite\]), and is always present for $J=0$ ($\omega=\frac{\pi}{2}$). It requires neither magnetic anisotropy nor frustration in the interactions. A higher $q$ pushes it towards smaller magnetic fields and increases its width per spin $\frac{\Delta M}{N}$ (Fig. \[fig:qexchangewidthlocation\](c)).
For $J>0$ and $J'<0$ another magnetization discontinuity appears, irrespectively of the parity of $q$. The higher order exchange interactions favor parallel spins for any $q$ exactly like the magnetic field, and compete with the antiferromagnetic bilinear exchange. This competition is now the origin of the discontinuity. The lowest energy configuration changes abruptly from the one predicted by Eq. (\[eqn:eqntheta\]) to the ferromagnetic one, with the corresponding discontinuity fields plotted in Fig. \[fig:qexchangewidthlocation\](b) (see also App. \[appendix:MagnetizationinaField-LEC-Bipartite\]). There is another even-odd effect, with the discontinuity triggered by an infinitesimal positive $J$ for even $q$, while a finite $J$ value is needed for odd $q$. On the other hand only a small negative value of $J'$ is required to generate the jump close to the bilinear exchange limit for any $q$. Then only for even $q \geq 6$ and higher $\omega$ the discontinuity breaks up in two, with the one leading to saturation following the pattern of the odd $q$ and lower even $q$ discontinuities. This can also be seen in the plot of the width per spin of the jumps (Fig. \[fig:qexchangewidthlocation\](d)). These results show that the ground state magnetic response gets richer with $q$, demonstrating also the importance of the detailed form of the microscopic interactions and not only their symmetry for the precise determination of the magnetization curve [@Poderoso11].
Hamiltonian (\[eqn:model\]) is frustrated in the case of the triangular lattice. In the absence of higher order exchange interactions and in finite field it has an accidental classical ground state degeneracy that is lifted by thermal [@Kawamura84] and quantum fluctuations [@Chubukov91]. This order by disorder effect is also generated by nonmagnetic impurities [@Maryasin13] and anisotropic terms [@Griset11]. When higher order exchange interactions are included minimization of Hamiltonian (\[eqn:model\]) with periodic boundary conditions shows that they also break the degeneracy and induce order (see App. \[appendix:ZF-LEC-Triangular\] for the case of zero field). The ground state has a triangular unit cell, with spin configurations selected from the finite field ground state degenerate manifold of $\omega=0$ and plotted in Fig. \[fig:qexchangetriangularlowestenergyconfigurations\] (see App. \[appendix:MagnetizationinaField-LEC-Triangular\]). The frustrated connectivity of the triangular lattice generates a ground state magnetization response with more discontinuities than the one of the bipartite lattices. Such discontinuities were first found for a finite version of the triangular lattice, the icosahedron, already for $q=2$ [@NPK16-1]. Again there is an even-odd effect for $J'>0$, with discontinuities occuring only for odd $q$. Figure \[fig:qexchangetriangular\](a) plots the corresponding fields for $q=3$. An infinitesimal positive $J'$ is sufficient to generate two magnetization jumps, which merge for higher $\omega$. The lower field discontinuity changes the configuration from the Y to the fan, while the higher field jump leads to the non-coplanar ”umbrella” configuration. The higher order exchange interaction generates the discontinuities, with both occuring when the bilinear exchange $J=0$ ($\omega=\frac{\pi}{2}$). This time the frustrated connectivity allows the jumps to survive down to infinitesimal $J'$. When $J>0$ and $J'<0$ two discontinuities occur. The lower changes the spin configuration from the ”umbrella” to the V. This magnetization gap also requires an infinitesimal value of (negative) $J'$ to occur. The higher field jump leads the spins directly to the ferromagnetic configuration, similarly to the case of the bipartite lattices. A jump to saturation has been found in the quantum case for the antiferromagnetic Heisenberg model in frustrated lattices and molecules [@Schulenburg02; @Schnack01; @Schmidt05]. It is stressed that infinitesimal deviations from the purely bilinear exchange case generate discontinuous ground state response irrespectively of the sign of $J'$.
Figure \[fig:qexchangetriangular\](b) plots the discontinuity fields when $q=9$. Contrary to the case of the bipartite lattices the discontinuity diagram becomes richer for $J'>0$, with a maximum of five discontinuities for $0.067898 \pi \leq \omega \leq 0.10199 \pi$. An infinitesimal $J'$ generates now a total of three jumps, with the inverted Y configuration appearing for small fields. The jumps are now related not only to a change of the configuration type but also to discontinuous polar angles within the same type of configuration (discontinuities 4 and 5). These results show as in the case of the bipartite lattices that the precise value of $q$ is important for the determination of the ground state magnetic response.
Figure \[fig:qexchangetriangular\](c) shows the discontinuities for $q=2$. An infinitesimal deviation from $\omega=\frac{3\pi}{2}$ generates a jump by changing the configuration from the UUD associated with the $\frac{1}{3}$ magnetization plateau of the triangular lattice to the saturated one. The highest field discontinuities direct all spins to be parallel to the field, as in the bipartite lattices case. An infinitesimal (negative) $J'$ generates the $\frac{1}{3}$ magnetization plateau as indicated by the (red) dashed lines. This plateau is a feature of the antiferromagnetic Heisenberg model in the quantum case [@Schnack01; @Honecker04]. For small negative $J'$ the field drives the system from the Y to the UUD and then to the V configuration, similarly to the effect of finite temperature in the $J'=0$ case [@Kawamura84]. In Fig. \[fig:qexchangetriangular\](d) it is shown that a higher value of $q=8$ again enriches the magnetization response generating more jumps, with the inverted Y configuration entering again for small fields and higher $\omega$. Again the response for $J>0$ and $J'<0$ showcases an even-odd effect with respect to $q$. The discontinuity strengths corresponding to Fig. \[fig:qexchangetriangular\] are plotted in Fig. \[fig:qexchangetriangular2\] (for the rest of the $q$ values see App. \[appendix:MagnetizationinaField-LEC-Triangular\]).
In conclusion, the classical ground state magnetization response has been calculated for bipartite lattices and the triangular lattice, when isotropic exchange interactions of integer order $q>1$ compete with the standard bilinear exchange interaction. These interactions generate magnetization discontinuities even though there is no magnetic anisotropy or necessarily frustration. The total number of discontinuities is associated with even-odd effects in $q$, and also increases with $q$. These results indicate that the precise form of the interactions and not only the symmetry of the Hamiltonian is important for the determination of zero-temperature properties, especially since a general interaction between spins can be expressed as a series expansion in powers of $q$. This is also expected for the thermodynamic properties where all the states are involved, as was shown in the case of nematic interactions [@Poderoso11]. Similar calculations can be performed for frustrated clusters where the addition of biquadratic exchange along with the special connectivity has led to a multitude of discontinuities already for a cluster as small as the icosahedron [@NPK16-1], and more specifically for an even $q$ and bilinear and biquadratic exchange both positive, something not possible for the bipartite and triangular lattices.
![(Color online) Magnetization per spin $\frac{M}{N}$ as a function of the magnetic field over its saturation value $\frac{h}{h_{sat}}$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for $q=3$ and different $\omega$ values for a chain or rectangle. []{data-label="fig:exchangeq=3"}](nematicq=3){width="3.5in" height="2.5in"}
![(Color online) (a) Discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for a chain or rectangle for lower $\omega$ and $q=3$ ((black) solid line), $q=5$ ((red) dotted line), $q=7$ ((green) dashed line), and $q=9$ ((blue) long-dashed line). (b) Similar with (a) for higher $\omega$ and additional lines for $q=2$ ((brown) dot-dashed line), $q=4$ ((violet) dot-long dashed line), $q=6$ ((cyan) double dot-dashed line), and $q=8$ ((magenta) dot-double dashed line). (c) Corresponding magnetization change per spin $\frac{\Delta M}{N}$ for (a). (d) Corresponding $\frac{\Delta M}{N}$ for (b). []{data-label="fig:qexchangewidthlocation"}](qexchangechaindiscontinuities){width="3.5in" height="2.5in"}
![(Color online) Lowest energy configurations of Hamiltonian (\[eqn:model\]) for the triangular lattice. []{data-label="fig:qexchangetriangularlowestenergyconfigurations"}](triangleqexchangeconfigurations){width="3.5in" height="2.5in"}
![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The (red) dashed lines show the fields which are limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular"}](triangleexchangeq=3.eps "fig:"){width="30.00000%" height="1.5in"} ![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The (red) dashed lines show the fields which are limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular"}](triangleexchangeq=9.eps "fig:"){width="30.00000%" height="1.5in"}
![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The (red) dashed lines show the fields which are limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular"}](triangleexchangeq=2.eps "fig:"){width="30.00000%" height="1.5in"} ![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The (red) dashed lines show the fields which are limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular"}](triangleexchangeq=8.eps "fig:"){width="30.00000%" height="1.5in"}
![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular\](a), \[fig:qexchangetriangular\](b), \[fig:qexchangetriangular\](c), and \[fig:qexchangetriangular\](d). []{data-label="fig:qexchangetriangular2"}](triangleexchangeq=3width.eps "fig:"){width="30.00000%" height="1.5in"} ![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular\](a), \[fig:qexchangetriangular\](b), \[fig:qexchangetriangular\](c), and \[fig:qexchangetriangular\](d). []{data-label="fig:qexchangetriangular2"}](triangleexchangeq=9width.eps "fig:"){width="30.00000%" height="1.5in"}
![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular\](a), \[fig:qexchangetriangular\](b), \[fig:qexchangetriangular\](c), and \[fig:qexchangetriangular\](d). []{data-label="fig:qexchangetriangular2"}](triangleexchangeq=2width.eps "fig:"){width="30.00000%" height="1.5in"} ![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=3$, (b) $q=9$, (c) $q=2$, and (d) $q=8$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular\](a), \[fig:qexchangetriangular\](b), \[fig:qexchangetriangular\](c), and \[fig:qexchangetriangular\](d). []{data-label="fig:qexchangetriangular2"}](triangleexchangeq=8width.eps "fig:"){width="30.00000%" height="1.5in"}
Zero Field Lowest Energy Configuration for Bipartite Lattices {#appendix:ZF-LEC-Bipartite}
=============================================================
The lowest energy configuration in the absence of a field is given by the solution of Eq. (\[eqn:eqntheta\]) for $h=0$. The range of $\omega$ for which the lowest energy configuration is antiferromagnetic (AFM) and ferromagnetic (FM) for $2 \leq q \leq 9$ for a bipartite lattice is listed in Table \[table:bipartitezerofield\].
$q$ AFM FM
----- ---------------------------------------------- ------------------------------------------------
2 $ \frac{3}{2} \pi < \omega \leq 0.14758 \pi$ $0.85242 \pi \leq \omega \leq \frac{3}{2} \pi$
3 $1.89758 \pi < \omega \leq 0.70483\pi$ $0.89758 \pi < \omega \leq 1.70483\pi$
4 $\frac{3}{2} \pi < \omega \leq 0.077979 \pi$ $0.92202 \pi < \omega \leq \frac{3}{2} \pi$
5 $1.93717 \pi \leq \omega < 0.68868\pi$ $0.93717 \pi \leq \omega < 1.68868\pi$
6 $\frac{3}{2} \pi < \omega \leq 0.052568 \pi$ $0.94743 \pi < \omega \leq \frac{3}{2} \pi$
7 $1.95483 \pi < \omega < 0.68011 \pi$ $0.95483 \pi < \omega < 1.68011 \pi$
8 $\frac{3}{2} \pi < \omega \leq 0.039583 \pi$ $0.96042 \pi \leq \omega \leq \frac{3}{2} \pi$
9 $1.96478 \pi \leq \omega \leq 0.67471 \pi$ $0.96478 \pi \leq \omega \leq 1.67471 \pi$
: Order of exchange interaction $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for an AFM and a FM lowest energy state in zero magnetic field for a bipartite lattice. For odd $q$ the values on the left-hand sides equal $tan^{-1}(-\frac{1}{q})$. $0.70483\pi$ and $1.70483\pi$ are equal to $tan^{-1}(-\frac{4}{3})$.
\[table:bipartitezerofield\]
Lowest Energy Configuration Magnetization in a Field for Bipartite Lattices {#appendix:MagnetizationinaField-LEC-Bipartite}
===========================================================================
Table \[table:bipartiteoddqdiscontinuities\] lists the $\omega$ range of the two discontinuities for odd $q$ for a bipartite lattice, while Table \[table:bipartiteevenqdiscontinuities\] lists the $\omega$ range of the discontinuities for even $q$. The saturation field $h_{sat}=4(J+qJ')$ except when the zero field ground state is ferromagnetic or a discontinuity leads directly to saturation.
$q$ disc. 1 disc. 2
----- ------------------------------------------ --------------------------------------------
3 $0.12567 \pi < \omega \leq 0.70483 \pi$ $1.70483\pi < \omega < 1.98822 \pi$
5 $0.10361 \pi \leq \omega < 0.68868\pi$ $1.68868\pi \leq \omega < 1.99626 \pi$
7 $0.082519 \pi \leq \omega < 0.68011 \pi$ $1.68011 \pi \leq \omega \leq 1.99818 \pi$
9 $0.067793 \pi < \omega \leq 0.67471 \pi$ $1.67471 \pi < \omega < 1.99893 \pi$
: Odd order of exchange interaction $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for the two magnetization discontinuities for a bipartite lattice. $0.70483\pi$ and $1.70483\pi$ are equal to $tan^{-1}(-\frac{4}{3})$.
\[table:bipartiteoddqdiscontinuities\]
$q$ disc. 1 disc. 2 disc. 3
----- --------------------------------------------- ----------------------------------------- --------------------------------------------
2 $\frac{3}{2} \pi < \omega \leq 1.96827 \pi$ - -
4 $\frac{3}{2} \pi < \omega < 1.99388 \pi$ - -
6 $\frac{3}{2} \pi < \omega < 1.87724 \pi$ $1.87724 \pi \leq \omega < 1.90785 \pi$ $1.87724 \pi \leq \omega \leq 1.99747 \pi$
8 $\frac{3}{2} \pi < \omega \leq 1.87042 \pi$ $1.87042 \pi < \omega < 1.92550 \pi$ $1.87042 \pi < \omega < 1.99863 \pi$
: Even order of exchange interaction $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for the magnetization discontinuities for a bipartite lattice.
\[table:bipartiteevenqdiscontinuities\]
Zero Field Lowest Energy Configuration for the Triangular Lattice {#appendix:ZF-LEC-Triangular}
=================================================================
The range of $\omega$ for which the lowest energy configuration in zero magnetic field has spins at $120^o$ degrees with each other, is FM or of the UUD form for $2 \leq q \leq 9$ for the triangular lattice is listed in Tables \[table:triangularzerofieldeven\] and \[table:triangularzerofieldodd\] (results for $q=2$ have been presented in Ref. [@Kawamura07]).
$q$ $120^o$ FM UUD
----- ----------------------------------------------- ------------------------------------------------ ---------------------------------------------
2 $ 1.93040 \pi \leq \omega \leq \frac{\pi}{4}$ $0.85242 \pi < \omega \leq \frac{3}{2} \pi$ $\frac{3}{2} \pi < \omega < 1.93040 \pi$
4 $1.94400 \pi \leq \omega < 0.35242\pi$ $0.92202\pi < \omega \leq \frac{3}{2} \pi$ $\frac{3}{2} \pi < \omega < 1.94400 \pi$
6 $1.94661 \pi < \omega \leq 0.44100 \pi$ $0.94743 \pi < \omega \leq \frac{3}{2} \pi$ $\frac{3}{2} \pi < \omega \leq 1.94661 \pi$
8 $1.94723 \pi \leq \omega \leq 0.48013 \pi$ $0.96042 \pi \leq \omega \leq \frac{3}{2} \pi$ $\frac{3}{2} \pi < \omega < 1.94723 \pi$
: Ranges of $\omega$ for an $120^0$, a FM and an UUD lowest energy state in zero magnetic field of Hamiltonian (\[eqn:model\]) for even $q$ for the triangular lattice.
\[table:triangularzerofieldeven\]
$q$ $120^o$ FM
----- ----------------------------------------- --------------------------------------------
3 $1.70483 \pi < \omega < 0.078728 \pi$ $0.89758 \pi < \omega \leq 1.70483 \pi$
5 $1.69919 \pi < \omega < 0.085952 \pi$ $0.93717 \pi \leq \omega < 1.68868 \pi$
7 $1.71103 \pi < \omega \leq 0.10312 \pi$ $0.95483 \pi < \omega < 1.68011 \pi$
9 $1.72534 \pi \leq \omega < 0.11086 \pi$ $0.96478 \pi \leq \omega \leq 1.67471 \pi$
: Ranges of $\omega$ for an $120^0$ and a FM lowest energy state in zero magnetic field of Hamiltonian (\[eqn:model\]) for odd $q$ for the triangular lattice. For odd $q$ the values on the left-hand sides of the FM state equal $tan^{-1}(-\frac{1}{q})$. $1.70483\pi$ is equal to $tan^{-1}(-\frac{4}{3})$.
\[table:triangularzerofieldodd\]
Lowest Energy Configuration Magnetization in a Field for the Triangular Lattice {#appendix:MagnetizationinaField-LEC-Triangular}
===============================================================================
Table \[table:triangularoddqdiscontinuities\] lists the $\omega$ range of the discontinuities for odd $q$ for the triangular lattice, while Table \[table:triangularevenqdiscontinuities\] lists the $\omega$ range of the discontinuities for even $q$. Table \[table:triangularevenqplateaus\] lists the ranges of $\omega$ for the limits of the magnetization plateaus for the triangular lattice. The saturation field $h_{sat}=9(J+qJ')$ except when the zero field ground state is ferromagnetic or a discontinuity leads directly to saturation. Figure \[fig:qexchangetriangular1\] shows the discontinuity magnetic fields for $q=4$, 5, 6, and 7, and Fig. \[fig:qexchangetriangular3\] the corresponding magnetization changes per spin. Fig. \[fig:qexchangetriangular4\] shows one of the $q=5$ discontinuties in greater detail.
disc. $q=3$ $q=5$ $q=7$ $q=9$
------- ----------------------------------------- -------------------------------------------- --------------------------------------------- ---------------------------------------------
1 $0 < \omega \leq 0.58941 \pi$ $0 < \omega \leq 0.10255 \pi$ $0 < \omega \leq 0.10838 \pi$ $0 < \omega \leq 0.10199 \pi$
2 $0 < \omega \leq 0.58941 \pi$ $0 < \omega \leq 0.38655 \pi$ $0 < \omega < 0.28976 \pi$ $0 < \omega \leq 0.23687 \pi$
3 $ 0.58941 \pi < \omega < 0.67259 \pi$ $0 < \omega \leq 0.38655 \pi$ $0 < \omega < 0.10257 \pi$ $0 < \omega < 0.10968 \pi$
4 $1.70483 \pi < \omega < 2\pi$ $0.083764 \pi \leq \omega < 0.085952 \pi$ $0.080520 \pi \leq \omega \leq 0.10312 \pi$ $0.067689 \pi \leq \omega \leq 0.10199 \pi$
5 $1.70483 \pi < \omega \leq 1.98909 \pi$ $0.38655 \pi < \omega < 0.64681 \pi$ $0.084496 \pi \leq \omega < 0.10257 \pi$ $0.067898 \pi \leq \omega < 0.10968 \pi$
6 $1.68868 \pi \leq \omega \leq 1.99646 \pi$ $0.10257 \pi \leq \omega < 0.28976 \pi$ $0.10199 \pi < \omega < 0.11086 \pi$
7 $1.69919 \pi < \omega < 2\pi$ $0.28976 \pi \leq \omega < 0.63397 \pi$ $0.10968 \pi \leq \omega \leq 0.23687 \pi$
8 $1.68011 \pi \leq \omega < 1.99838 \pi$ $0.23687 \pi < \omega < 0.62624 \pi$
9 $1.71103 \pi < \omega < 2\pi$ $1.67471 \pi < \omega \leq 1.99904 \pi$
10 $1.72534 \pi \leq \omega < 2\pi$
: Exchange interaction of odd order $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for the magnetization discontinuities for the triangular lattice.
\[table:triangularoddqdiscontinuities\]
disc. $q=2$ $q=4$ $q=6$ $q=8$
------- -------------------------------------------- --------------------------------------------- --------------------------------------------- ------------------------------------------
1 $\frac{3}{2} \pi < \omega < 1.85242 \pi$ $\frac{3}{2} \pi < \omega \leq 1.92160 \pi$ $\frac{3}{2} \pi < \omega \leq 1.92200 \pi$ $\frac{3}{2} \pi < \omega < 1.92202 \pi$
2 $1.85242 \pi \leq \omega < 1.97057 \pi$ $1.92160 \pi < \omega \leq 1.93839 \pi$ $1.92200 \pi < \omega < 1.96903 \pi$ $1.92202 \pi \leq \omega < 1.98410 \pi$
3 $1.93040 \pi \leq \omega \leq 1.97114 \pi$ $1.92160 \pi < \omega \leq 1.99451 \pi$ $1.92200 \pi < \omega \leq 1.99774 \pi$ $1.92202 \pi \leq \omega < 1.99878 \pi$
4 $1.94400 \pi \leq \omega \leq 1.99451 \pi$ $1.94661 \pi < \omega \leq 1.99072 \pi$ $1.94723 \pi \leq \omega < 1.99536 \pi$
5 $1.99072 \pi < \omega < 2\pi$ $1.99536 \pi \leq \omega < 2\pi$
6 $1.99072 \pi < \omega \leq 1.99774 \pi$ $1.99536 \pi \leq \omega < 1.99878 \pi$
: Exchange interaction of even order $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for the magnetization discontinuities for the triangular lattice.
\[table:triangularevenqdiscontinuities\]
$q$ plateau 1 plateau 2
----- ---------------------------------- ----------------------------------
2 $1.85242 \pi \leq \omega < 2\pi$ $1.97114 \pi < \omega < 2\pi$
4 $1.92249 \pi \leq \omega < 2\pi$ $1.99451 \pi < \omega < 2\pi$
6 $1.96776 \pi \leq \omega < 2\pi$ $1.99774 \pi < \omega < 2\pi$
8 $1.98410 \pi \leq \omega < 2\pi$ $1.99878 \pi \leq \omega < 2\pi$
: Exchange interaction of even order $q$ in Hamiltonian (\[eqn:model\]) and corresponding ranges of $\omega$ for the limits of the magnetization plateaus for the triangular lattice.
\[table:triangularevenqplateaus\]
![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The (red) dashed lines show the fields which are the limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular1"}](triangleexchangeq=5.eps "fig:"){width="30.00000%" height="1.5in"} ![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The (red) dashed lines show the fields which are the limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular1"}](triangleexchangeq=7.eps "fig:"){width="30.00000%" height="1.5in"}
![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The (red) dashed lines show the fields which are the limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular1"}](triangleexchangeq=4.eps "fig:"){width="30.00000%" height="1.5in"} ![(Color online) The (black) solid lines show the discontinuity magnetic fields $h_d$ in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The (red) dashed lines show the fields which are the limits of the $\frac{1}{3}$ magnetization plateau. The (green) dot-dashed lines show the saturation field for the highest $\omega$. Each discontinuity is identified by a number. []{data-label="fig:qexchangetriangular1"}](triangleexchangeq=6.eps "fig:"){width="30.00000%" height="1.5in"}
![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular1\](a), \[fig:qexchangetriangular1\](b), \[fig:qexchangetriangular1\](c), and \[fig:qexchangetriangular1\](d). []{data-label="fig:qexchangetriangular3"}](triangleexchangeq=5width.eps "fig:"){width="30.00000%" height="1.5in"} ![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular1\](a), \[fig:qexchangetriangular1\](b), \[fig:qexchangetriangular1\](c), and \[fig:qexchangetriangular1\](d). []{data-label="fig:qexchangetriangular3"}](triangleexchangeq=7width.eps "fig:"){width="30.00000%" height="1.5in"}
![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular1\](a), \[fig:qexchangetriangular1\](b), \[fig:qexchangetriangular1\](c), and \[fig:qexchangetriangular1\](d). []{data-label="fig:qexchangetriangular3"}](triangleexchangeq=4width.eps "fig:"){width="30.00000%" height="1.5in"} ![Magnetization change per spin $\frac{\Delta M}{N}$ for the discontinuities in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for (a) $q=5$, (b) $q=7$, (c) $q=4$, and (d) $q=6$. The numbering of the discontinuities follows Figs \[fig:qexchangetriangular1\](a), \[fig:qexchangetriangular1\](b), \[fig:qexchangetriangular1\](c), and \[fig:qexchangetriangular1\](d). []{data-label="fig:qexchangetriangular3"}](triangleexchangeq=6width.eps "fig:"){width="30.00000%" height="1.5in"}
) in the lowest energy configuration of Hamiltonian (\[eqn:model\]) for the triangular lattice as a function of $\omega$ for $q=5$. (b) Corresponding magnetization change per spin $\frac{\Delta M}{N}$ (Fig. \[fig:qexchangetriangular3\](a)). []{data-label="fig:qexchangetriangular4"}](triangleexchangeq=5-1){width="3.5in" height="2.5in"}
|
package libyaml
type RootK8s struct {
PVClaims []K8sPVClaim `yaml:"volume_claims,omitempty" json:"volume_claims,omitempty"`
}
|
Introduction
============
Cardiovascular disease is one of the major complications of diabetes, resulting in a high percentage of morbidity and mortality and producing significant costs for the healthcare system \[[@B1]\]. Increased fatty acid oxidation and decreased glucose metabolism contribute to the development of diabetic cardiomyopathy and can decrease the ability of the heart to withstand an ischemic insult \[[@B2]\].
Adiponectin is an adipocyte-derived protein with anti-inflammatory, anti-diabetic and anti-atherogenic properties \[[@B3]\]. Adiponectin is also synthesized and secreted by human and murine cardiomyocytes. Local production of adiponectin by cardiomyocytes might have important functions in the regulation of the cardiac function and/or metabolism by autocrine and/or paracrine \[[@B4]\].
There are two types of adiponectin receptors, adiponectin receptor type 1 (adipoR1) and adiponectin receptor type 2 (adipoR2). They serve as receptors for globular and full-length adiponectin, and mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin. Adiponectin receptor type 1 and adiponectin receptor type 2 are not only expressed in skeletal muscle and liver, but also in heart and kidney \[[@B5]\]. Our previous study showed that the expression of myocardial adipoR1 was significantly decreased in type 2 diabetic rats \[[@B6]\]. It is unknown whether the expression of adipoR2 in the heart and the expression of adipoR1 in aorta are also changed in type 2 diabetic rat.
Oxidative stress has been suggested to be involved in the development and progression of diabetes-induced cardiomyopathy \[[@B7]\]. Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase seems to be relevant to the elevated oxidative stress in diabetes \[[@B8]\]. NAD(P)H oxidase consists of membrane-associated subunits (gp91phox and p22phox) and cytosolic subunits (p47phox, p40phox, p67phox and Rac) \[[@B9]\]. Nox4 is one of homologues of gp91phox/Nox2 \[[@B10]\]. Phagocytic NADPH oxidase largely depends on regulation by cytosolic subunits but not Nox4 for which no cytosolic subunits are required. Nox4 isoform is expressed in a wide variety of organs, including the heart \[[@B11]\] and is a major source of oxidative stress in the failing heart \[[@B12]\]. It was reported that the expression of p22phox and Nox4 in the heart of diabetic mice and rats \[[@B13],[@B14]\] and the expression of p47phox in diabetic rat femoral arteries \[[@B15]\] were significantly increased.
Telmisartan, a unique angiotensin II receptor antagonist with selective peroxisome proliferator-activated receptor gamma(PPARgamma)-modulating activity, functioned as a partial agonist of PPARgamma and achieved 25-30% of maximal receptor activation attained with conventional PPARgamma ligands \[[@B16],[@B17]\]. Telmisartan increased plasma adiponectin level in hypertensive patients with type 2 diabetes \[[@B18]\] and also stimulated adiponectin protein expression in murine 3T3-L1 adipocytes \[[@B19]\]. Telmisartan normalizes vascular dysfunction and reduces platelet activation in diabetic rats \[[@B20]\]. Our previous study showed that telmisartan treatment significantly attenuated the decreased expression of myocardial adipoR1 in diabetic rats \[[@B6]\]. It is unknown whether the expression of adipoR2 and NADPH oxidase subunits in the heart and the expression of adipoR1 in aorta are changed by telmisartane treatment in type 2 diabetic rats.
This study was aimed: 1) to explore the expression of adipoR2 in the heart and the expression of adipoR1 in aorta in type 2 diabetic rats induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ); 2) to investigate the effect of telmisartan on the expression of adipoR2 and NADPH oxidase subunits in the heart and the expression of adipoR1 in aorta in type 2 diabetic rats.
Materials and methods
=====================
Induction of diabetes
---------------------
Thirty-six male Wistar rats weighing 140-180g, purchased from Physiological Laboratory of Shanxi Medical University (Taiyuan, Shanxi, China), were used in the study. All rats were housed in a temperature-controlled room (22-24^o^C) and kept on a 12 hour light/dark cycle. All animals received humane care in accordance with the principles of the Chinese Council on Animal Care. After two week's adaptation, all rats were randomly divided into 2 groups: control (C, n = 10) and diabetic (n = 26). Control rats were fed with standard rat chow. Diabetic rats were fed with high-fat chow (ingredients: 10% refined lard, 20% sucrose, 2% cholesterol, 1% sodium cholate and 67% common food), which were provided by Animal Experimental Centre of Shanxi Medical University. Four weeks later, diabetic rats were given the peritoneal injection of a low dose of streptozotocin (30 mg/kg body weight; Sigma, St. Louis, MO, USA) \[[@B21]\], while the control group was given equivalent volume of citric acid buffer. After one week of STZ injection, fasting plasma glucose (FPG) was tested and the rats with FPG ≥7.8 mmol/L and insulin resistance were considered to be diabetic (*n* = 20) \[[@B21]\]. Diabetic rats were again randomly divided into diabetic (D, n = 10) and diabetic treated (DT, n = 10). Telmisartan (5mg/kg/d, Boehringer Ingelheim pharmaceutical company, Germany) \[[@B22]\] was administrated to diabetic treated rats by gavage for 12 weeks. The equivalent volume of normal sodium was administrated to control and diabetic rats by gavage for 12 weeks. Subsequently, blood samples were collected every 2 weeks. Blood was centrifuged at 10,000 g for 45 minutes, plasma was collected and plasma glucose levels were measured. At termination, 1 day before the experiments were finished, all animals were fasted for 12-14 h and then were anesthetized with an intraperitoneal injection of 10% chloral hydrate (0.3mL/100g body weight). The maximum descent-speed of pressure in isovolumetric relaxation period in the left ventricle (-dp/dtmax) and the maximum ascendent-speed of pressure in isovolumic contraction period in the left ventricle (+dp/dtmax) were measured by carotid artery cannula. The rats were sacrificed after blood sample had been withdrawn from abdominal cardinal vein. The blood sample was centrifuged and plasma aliquots were stored at --80°C until assays were done. The heart was immediately taken out of thoracic cavity and the abdominal aorta was immediately taken out of abdominal cavity after the rat was sacrificed. The heart and the abdominal aorta were rinsed with normal sodium and dried by filter-paper and then the heart was weighed. The ratio of heart weight to body weight was calculated. The apex of heart and a part of abdominal aorta were fixed in 10% neutral buffered formalin and processed for histological analysis. The rest part of cardiac ventricle and abdominal aorta were immediately thrown into the liquid nitrogen and then stored in the -70°C refrigerator until analyses were carried out.
Measurement of cardiac function
-------------------------------
Following anesthesia with an intraperitoneal injection of 10% chloral hydrate (0.3ml/100g), the neck skin was cut open and the right common carotid artery was fully exposed. A micromanometer-tipped catheter was inserted into the left ventricle through the right common carotid artery for measurement of left ventricular pressure. Left ventricular end-diastolic pressure (LVEDP) and the maximal rate of rise and decline of ventricular pressure (±dp/dt\[max\]) were obtained by BL-410 Bio-signal analysis system (Chengdu TME Technology Co., Ltd, Sichuan, China).
Plasma analytical procedures
----------------------------
The plasma glucose level was measured by the glucose oxidase method using an autoanalyzer (Beckman Instruments, USA). Plasma cholesterol, triglyceride and free fatty acid were measured colorimetrically by using commercially available kit (SiRuiKe Biotechnology Co., Ltd, Shanghai, China). Plasma adiponectin was measured by using a commercially available ELISA kit (Westang Biotechnology Co., Ltd, Shanghai, China). Plasma insulin was measured by using a commercially available radioimmunoassay kit (China Institute of Atomic Energy, Beijing, China). Insulin sensitivity index (ISI) was calculated as the following formula: $\text{ISI} = \text{In}\left\lbrack \frac{1}{\left( {\text{FPG} \times \text{FINS}} \right)} \right\rbrack$.
Determination of cardiac adiponectin
------------------------------------
Frozen heart tissue was pulverized and homogenized at 4°C in cold buffer (20 mM Tris-HCl, pH 7.5, 50 mM 2-mercaptoethanol, 5 mM EGTA, 2 mM EDTA, 1 mM PMSF, 10 mM NaF, 25 μg/ml leupeptin, 2 μg/ml aprotinin) and then centrifuged at 1500 g for 5 minutes at 4°C. The supernatant was collected and stored at --80°C until analyses were conducted. The protein content of the samples was measured using the Bradford protein assay \[[@B23]\] with the use of bovine serum albumin as a standard. Cardiac adiponectin was measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Westang Biotechnology Co., Ltd, Shanghai, China).
Morphologic study
-----------------
Tissues fixed in 10% buffered formalin were embedded in paraffin, sectioned at 4 μm and stained with hematoxylin and eosin (HE) and Masson's trichrome for light microscopic morphologic study.
Immunohistochemical analysis of adipoR1, adipoR2, CTGF, MCP-1 and NF-κB
-----------------------------------------------------------------------
Ventricular samples and abdominal aorta were immediately fixed in 10% neutral buffered formalin overnight and embedded in paraffin. Paraffin embedded tissue blocks were sectioned at 3 μm and sections were mounted on positively charged slides. The slides were deparaffinized, rehydrated, blocked with 3% hydrogen peroxide \[to block endogenous peroxidase activity, washed with phosphate-buffered saline (PBS)\], and blocked with 5% normal goat serum in PBS for 30 min. The slides were subsequently incubated with primary rabbit polyclonal adiponectin receptor type 1 (1:200) and type 2 (1:400) antibody (Beijing Biosynthesis Biotechnology Co., Ltd, Beijing, China), connective tissue growth factor antibody (1:100, Wuhan Boster Biological Engineering Company Limited, Hubei, China ), MCP-1 antibody (1:100,Beijing Biosynthesis Biotechnology Co., Ltd, Beijing, China) and NF-κB antibody(1:50,Zhongshan Goldenbridge Biotechnology Co., Ltd, Beijing, China)in PBS containing 1% normal goat serum overnight at 4°C. The primary antibody was rinsed off with PBS, and the sections were incubated with biotin labeling goat anti-rabbit secondary antibodies (1:100, Zhongshan Goldenbridge Biotechnology Co., Ltd, Beijing, China) for 30 min. After three washing steps in PBS were completed, the sections were stained using horseradish enzyme labeling strepto-avidin solution (1:100, Zhongshan Goldenbridge Biotechnology Co., Ltd, Beijing, China) for 10 min, washed with PBS, coloured with 3, 3′-diaminobenzidine (DAB), and washed with distilled water. The sections were counterstained using hematoxylin, washed in running water, dehydrated in increasing grades of alcohol, and cleared in xylene before being mounted in resinous mounting medium with coverslips. Some sections incubated with nonspecific rabbit immunoglobulins (IgG) served as negative controls. Quantification was performed with the observer blinded to details. With the use of high power microscope, all slides were observed and photographed. The average of five fields under microscope (×400) in each slice were randomly selected, and the positive stained intensity or the average value of gray scale which had an inverse proportion to the positive stained intensity was quantified by using BI-2000 color image processing system (Chengdu TME Technology Co., Ltd, Sichuan, China).
Semi-quantitative reverse transcription-PCR (RT-PCR) analysis for adipoR, MCP-1 and GLUT4
-----------------------------------------------------------------------------------------
Total RNA extraction was performed using Trizol reagent (Invitrogen, Carlsbad, California, USA) according to the manufacturer's recommendations. Primer sequences were described in Table [1](#T1){ref-type="table"}. The PCR reaction was initiated by 4-minute incubation at 94°C, 32 cycles for denaturation at 94°C for 20 seconds, annealing at 54-56°C for 30 seconds, and extension at 72°C for 30 seconds, terminated after a 10-minute extension at 72°C. Ten microliters of each PCR reaction mixture were electrophoresed in a 1.5% agarose gel and bands were visualized by ethidium bromide staining. The density of the DNA bands of the PCR products was analyzed by using the software (Tianjin DiDe Technology Co., Ltd, Tianjin, China).
######
Primers used in semi-quantitative reverse transcription-PCR
**Gene symbol** **primer (5′→3′)** **Product size (bp)**
----------------- ------------------------------ -----------------------
AdipoR1
Sense 5′-TCTTCCTCATGGCTGTGATG-3′ 190bp
Antisense 5′-TCTAGGCCGTAACGGAATTC-3′
AdipoR2
Sense 5′-ACCCACAACCTTGCTTCATC-3′ 233bp
Antisense 5′-GCTAGCCATGAGCATTAGCC-3′
GLUT4
Sense 5′-GATGCCGTCGGGTTTCCAGCA-3′ 233bp
Antisense 5′-TGAGGGTGCCTTGTGGGATGG-3′
MCP-1
Sense 5′-CTGTCTCAGCCAGATGCAGTT-3′ 147bp
Antisense 5′-GAGCTTGGTGACAAATACTACA-3′
GAPDH
Forward 5′-TGAACGGGAAGCTCACTGG-3′ 307bp
Reverse 5′-TCCACCACCCTGTTGCTGTA-3′
Real-time fluorescence quantitative PCR analysis for p22phox and NOX4
---------------------------------------------------------------------
Extracted RNA and synthesized cDNA were described above. Real-time quantitative polymerase chain reaction was performed with 50 μl reaction volumes containing 25μl 2× FastStart Universal SYBR Green Master Mix (Roche Ltd., Basel, Switzerland), 1μl 0.3 μM of each primer, 5 μl of cDNA template, and 19 μl deionized water. Primer sequences are described in Table [2](#T2){ref-type="table"}. PCR amplifications were done on a real-time fluorescence quantitative PCR detection system (Xi'an Tianlong Science and Technology Co., Ltd,Xi'an, China) using the following parameters: initial denaturation of 95°C for 10 min, followed by 40 cycles for denaturation at 94°C for 30 seconds, annealing at 58°C for 30 seconds, and extension at 72°C for 45 seconds. Relative gene expression levels were quantified using the comparative ΔCt (cycle threshold) method. This method normalized Ct values of the detected gene to the average of that of the housekeeping genes and calculated the relative expression values as fold changes of the control. Ct values were extracted using the software. Data analysis was performed using the 2^-ΔΔCt^ method \[[@B24]\].
######
Primers used in real-time fluorescence quantitative PCR
**Gene symbol** **primer (5′→3′)** **Product size (bp)**
----------------- --------------------------------- -----------------------
NOX4
Forward 5′-TAGCTGCCCACTTGGTGAACG-3′ 245bp
Reverse 5′-TGTAACCATGAGGAACAATACCACC-3′
p22phox
Forward 5′-CTCTATTGTTGCAGGAGTGC-3′ 457bp
Reverse 5′-TCACACGACCTCATCTGTCAC-3′
β-actin
Forward 5′-GTCAGGTCATCACTATCGGCAAT-3′ 147bp
Reverse 5′-AGAGGTCTTTACGGATGTCAACGT-3′
Statistical analysis
--------------------
Data are expressed as mean ± S.E.M. Statistical analysis was performed by one --way ANOVA followed by Tukey's post hoc test. P \<0.05 was considered statistically significant.
Results
=======
Animal characteristics
----------------------
Plasma glucose levels were significantly increased in diabetic rats compared to controls. Telmisartan treatment slightly but significantly reduced the plasma glucose level in diabetic rats. The levels of plasma insulin, total cholesterol, triglycerides and free fatty acid were significantly increased in diabetic rats compared to controls and telmisartan treatment prevented these changes in diabetic rats. Insulin sensitivity index (ISI) were significantly reduced in diabetic rats compared to controls and telmisartan treatment significantly increased the insulin sensitivity index in diabetic rats. The ratio of heart weight to body weight, an index of cardiac hypertrophy, was significantly increased in diabetic rats compared to controls and telmisartan treatment significantly decreased the ratio of heart weight to body weight in diabetic rats (See table one in reference \[[@B6]\], a paper we previously published. The samples we used in this paper were the same as in reference \[[@B6]\]).
Histological changes
--------------------
The results of the myocardium stained by Masson's trichrome and observed through the light microscope were as following: The myocardial cells lined up in order, the spherical or oval cellular nucleus was in the same size and was stained dark and in uniformity, and the cytoplasm was stained red and in uniformity in control rats. The myocardial cells lined up in disorder, the cellular nucleus was in irregular size, breakdown and lost, the myocardial fiber was broken, the boundary between cells was unclear, and collagen fiber was increased in diabetic rats. The pathological changes were obviously improved in diabetic rats treated with telmisartan. The myocardial collagen content was increased in diabetic rats and was decreased in diabetic rats treated with telmisartan (Figure [1](#F1){ref-type="fig"}).
{#F1}
The results of the aorta stained by hematoxylin and eosin (HE) and observed through the light microscope were as following: the intima of aorta was smooth, all level cells lined up in order, endothelial cells were applanate and clung to the smooth and straight internal elastic lamina, and medial elastic lamina lined up in parallel with smooth muscle cell orderly and alternately in control rats. Endothelial cells were broken off and the shallow smooth muscle cells in medial elastic lamina were proliferated and lined up in disorder in diabetic rats. The pathological changes of aorta were obviously improved in diabetic rats treated with telmisartan (Figure [2](#F2){ref-type="fig"}).
{#F2}
Heart function
--------------
Compared to controls, +dp/dtmax and -dp/dtmax were significantly reduced and LVEDP was significantly increased in diabetic rats, indicating that the heart function was significantly decreased in diabetic rats. Telmisartan treatment attenuated these changes in diabetic rats (See table two in reference \[[@B6]\], a paper we previously published. The samples we used in this paper were the same as in reference \[[@B6]\]).
Immunohistochemical assay
-------------------------
The yellow positive staining of adipoR2 was mainly located in myocardial cellular member and cytoplasm. The adipoR2 expression was quantified using the average value of gray scale which had an inverse proportion to the positive stained intensity. The average value of gray scale of adipoR2 was significantly increased in the heart in diabetic rats compared to controls, indicating that the positive stained intensity of adipoR2 was significantly decreased in the heart in diabetic rats compared to controls. Telmisartan treatment significantly decreased the average value of gray scale of adiponectin receptor 2 in the heart in diabetic rats, indicating that telmisartan treatment significantly increased the positive stained intensity of adipoR2 in the heart in diabetic rats (Figure [3](#F3){ref-type="fig"}).
{#F3}
The yellow positive staining of CTGF was mainly located in myocardial cellular cytoplasm. The integrated optical density(IOD)of positive staining of CTGF was significantly increased in the heart in diabetic rats compared to controls. Telmisartan treatment significantly decreased the integrated optical density (IOD) of positive staining of CTGF in the heart in diabetic rats (Figure [4](#F4){ref-type="fig"}).
{#F4}
The yellow positive staining of NF-κB was mainly located in cellular nucleus and the yellow positive staining of MCP-1 was mainly located in cellular cytoplasm in abdominal aorta. The integrated optical density (IOD) of positive staining of NF-κB and MCP-1 was significantly increased in aorta in diabetic rats compared to controls. Telmisartan treatment significantly decreased the integrated optical density (IOD) of positive staining of NF-κB and MCP-1 in aorta in diabetic rats (Figures [5](#F5){ref-type="fig"} and [6](#F6){ref-type="fig"}).
{#F5}
{#F6}
Plasma and myocardial adiponectin levels
----------------------------------------
Plasma and myocardial adiponectin levels were significantly decreased in diabetic rats compared to controls. Telmisartan treatment significantly increased plasma and myocardial adiponectin levels in diabetic rats (See Table two in reference \[[@B6]\], a paper we previously published. The samples we used in this paper were the same as in reference \[[@B6]\]).
Myocardial mRNA expression of adiponectin receptor 2, GLUT4, MCP-1, NOX4 and p22phox
------------------------------------------------------------------------------------
The mRNA expression of myocardial adiponectin receptor 2 and GLUT4 was significantly reduced in diabetic rats compared to controls. Telmisartan treatment significantly increased the mRNA expression of myocardial adiponectin receptor 2 and GLUT4 in diabetic rats (Figures [7](#F7){ref-type="fig"} and [8](#F8){ref-type="fig"}).
{#F7}
{#F8}
The mRNA expression of myocardial MCP-1, NOX4 and p22phox was significantly increased in diabetic rats compared to controls. Telmisartan treatment significantly reduced the mRNA expression of myocardial MCP-1, NOX4 and p22phox in diabetic rats (Figures [9](#F9){ref-type="fig"}, [10](#F10){ref-type="fig"} and [11](#F11){ref-type="fig"}).
{#F9}
{#F10}
{#F11}
The mRNA expression of adiponectin receptor 1 in abdominal aorta
----------------------------------------------------------------
The mRNA expression of adiponectin receptor 1 in abdominal aorta was significantly reduced in diabetic rats compared to controls. Telmisartan treatment significantly increased the mRNA expression of adiponectin receptor 1 in abdominal aorta in diabetic rats (Figure [12](#F12){ref-type="fig"}).
{#F12}
Discussion
==========
This study showed that diabetic rat hearts exhibited increased expression of CTGF and collagen content with concomitant cardiac hypertrophy and fibrosis. Plasma and myocardial adiponectin levels, the mRNA expression of adipoR2 in heart, and the mRNA expression of adipoR1 in aorta were decreased in type 2 diabetic rats. The myocardial mRNA expression of NADPH oxidase subunits, p22phox and Nox4, was increased in type 2 diabetic rats. Telmisartan treatment prevented these changes in diabetic rats.
Effect of telmisartan on the expression of adiponectin receptors in the heart and aorta in type 2 diabetic rats
---------------------------------------------------------------------------------------------------------------
Adiponectin exerts its effect through adiponectin receptor 1 and 2, which are both expressed in the heart in vivo \[[@B5]\] and in the cardiomyocyte in vitro \[[@B4]\]. Adiponectin receptors were also expressed in atherosclerotic lesions, macrophages and vascular endothelial cells \[[@B5],[@B25]\]. Overweight patients with coronary artery disease had decreased surface expression of adiponectin receptors in peripheral monocytes \[[@B26]\]. Although the protein expression of adiponectin receptor 1 in coronary arterioles and aortas was similar between control and diabetic mice, the protein expression of adiponectin receptor 2 was significantly reduced in type 2 diabetic mice \[[@B27]\]. Adenovirus-mediated overexpression of AdipoR1 and 2 in vascular endothelial cells significantly enhanced the antiinflammatory effect of adiponectin \[[@B28]\]. Our study showed that the expression of adipoR2 in the heart and the expression of adipoR1 in aorta were decreased in diabetic rats. The decreased adiponectin receptors may be due to hyperinsulinemia since it has been reported that insulin deficiency increased, but insulin replenishment decreased the expression of adipoR1/2 in animals in vivo \[[@B29]\]. The decreased adiponectin and its receptors may lead to adiponectin resistance, which may limit adiponectin to produce its biological effects, especially its protective effect on diabetic heart and aorta. The decreased adiponectin and its receptors may together play a role in the occurrence and progression of cardiomyopathy and atherosclerosis in type 2 diabetic rats. Adiponectin receptors could be modulated by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR \[[@B25]\]. Our study showed that telmisartan, a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity \[[@B16],[@B17]\], increased the mRNA expression of AdipoR2 in the heart and the mRNA expression of AdipoR1 in the aorta in diabetic rats, indicating that angiotensin II could down-regulate, while PPARgamma agonist could up-regulate the expression of adiponectin receptors. The results of our study are in agreement with the results of studies \[[@B25],[@B30]\] showing that adiponectin receptors were expressed in adult ventricular cardiomyocytes, atherosclerotic lesions and macrophages, and upregulated by activation of peroxisome proliferator-activated receptor gamma.
Adiponectin can improve both glucose metabolism and insulin resistance \[[@B31]\]. Glucose enters the heart via the facilitative glucose transporters GLUT1 and GLUT4 \[[@B32]\]. Glucose transporter expression in the heart is altered in various pathological states. Our study showed that the mRNA expression of GLUT4 was decreased, indicating that glucose metabolism would be reduced in diabetic rat hearts. It was reported that changes in glucose transporter expression contributed to myocardial dysfunction in diabetes \[[@B33]\]. In addition, GLUT4-deficient mice developed striking cardiac hypertrophy \[[@B34]\]. Normalization of glucose homeostasis by transgenic re-expression of GLUT4 in the skeletal muscle resulted in a reversal of the cardiac pathology in mice heterozygous for GLUT4 ablation \[[@B35]\]. Hence, we propose that the decreased cardiac GLUT4 observed in this study may contribute to the deterioration in heart function and to the cardiac hypertrophy seen in diabetic rats. Our study showed that telmisartan treatment reduces cardiac hypertrophy, improved the heart function, and increased myocardial expression of GLUT4 in diabetic rats. The increased adiponectin and its receptors may partly explain the increased GLUT4, which may contribute to the ameliorated heart function in diabetic rats treated with telmisartan.
Effect of telmisartan on the expression of inflammatory cytokines in the heart and aorta in type 2 diabetic rats
----------------------------------------------------------------------------------------------------------------
Heart failure, diabetes, and obesity are recognized as states of chronic inflammation. Inflammatory cytokines may play a role in all three of these conditions \[[@B36],[@B37]\]. Monocyte chemotactic protein-1 (MCP-1) has been shown to be produced and released by the heart and to be increased in failing heart \[[@B38],[@B39]\]. Increased levels of MCP-1 are associated with previously unknown abnormal glucose regulation in patients with acute ST-elevation myocardial infarction \[[@B40]\]. Our study showed that cardiac expression of MCP-1 was increased in diabetic rats. Telmisartan treatment decreased the cardiac expression of MCP-1 in diabetic rats. It was reported that adiponectin suppressed MCP-1 production in lipopolysaccharide-treated 3T3-L1 adipocytes \[[@B41]\]. Oxidative stress increased the level of MCP-1\[[@B42]\]. Therefore, the elevated cardiac MCP-1 may be due to the decreased adiponectin and the increased oxidative stress, and may be involved in the diabetic cardiac deterioration. The increased adiponectin and decreased NADPH oxidase by telmisartan treatment may lead to the decreased inflammation factor MCP-1 in the heart, which may result in the improved heart function in diabetic rats.
This study showed that the expression of MCP-1 and NF-κB was increased in aorta in diabetic rats. Telmisartan treatment significantly reduced the expression of MCP-1 and NF-κB and alleviated the pathological alteration in aorta in diabetic rats, suggesting that telmisartan may lessen the atherosclerotic degree by downregulating the expression of MCP-1 and NF-κB in aorta in diabetic rats. It was reported that adiponectin reduced aortic NF-kappaB expression in ApoE knockout mice and inhibited IκBα phosphorylation and nuclear factor κB protein expression in aorta of type 2 diabetic mice \[[@B27],[@B43]\]. Adenovirus-mediated overexpression of AdipoR significantly enhanced the suppressive effect of adiponectin on NF-kappaB activation in vascular endothelial cells \[[@B28]\]. Therefore, the increased expression of MCP-1 and NF-κB in aorta may be associated with the reduced expression of adiponectin and its receptors.
Effect of telmisartan on the expression of NADPH oxidase in the heart in type 2 diabetic rats
---------------------------------------------------------------------------------------------
Oxidative stress has been suggested to be involved in the development and progression of diabetes-induced cardiomyopathy (7). NADPH oxidase has emerged as the main source of ROS in the cardiovascular tissues \[[@B44]\]. It was reported that the expression of NADPH oxidase subunits, p22phox and Nox4 was significantly increased in the heart of diabetic mice and rats \[[@B13],[@B14],[@B45],[@B46]\], indicating that Nox4 was an important source of ROS in the left ventricle and Nox4-derived ROS contribute to cardiomyopathy at early stages of type 1 diabetes \[[@B45]\]. Consistent with these studies, the present study also showed that the expression of myocardial p22phox and Nox4 was significantly increased in type 2 diabetic rats, suggesting that NADPH oxidase might play a crucial role in the development of diabetic cardiomyopathy. It was reported that telmisartan treatment reduced the protein expression of renal and vascular NADPH oxidase subunits in diabetic mice and cardiac NADPH oxidase activity in diabetic rats \[[@B47],[@B48]\]. Our study showed that telmisartan treatment decreased the myocardial mRNA expression of NADPH oxidase subunits, p22phox and Nox4, which may result in the reduced oxidative stress and the improved heart function, in diabetic rats.
Conclusions
===========
In summary, this study demonstrates that diabetic rat hearts exhibit increased expression of CTGF and collagen content accompanied by cardiac hypertrophy and in creased fibrosis. The plasma and myocardial adiponectin levels and the mRNA expression of myocardial adipoR2 are decreased, which may lead to the decrease in cardiac GLUT 4 and the increase in cardiac MCP-1 in diabetic rats. The cardiac mRNA expression of p22phox and NOX4 is significantly increased, indicating that oxidative stress is increased in the heart in diabetic rats. The decreased mRNA expression of adipoR1 may lead to the increased expression of MCP-1 and NF-κB in aorta in diabetic rats. Telmisartan up-regulates the expression of myocardial adiponectin and its receptor 2 and GLUT4, down-regulates the expression of myocardial p22phox, NOX4, MCP-1, and CTGF, which may contribute to the improvement of heart function in diabetic rats. Telmisartan may also produce the protective role on the vascular by upregulating the expression of adipiR1 and downregulating the expression of MCP-1 and NF-κB in the abdominal aorta in diabetic rats.
Abbreviations
=============
NADPH, Nicotinamide adenine dinucleotide phosphate; STZ, Streptozotocin; adipoR2, Adiponectin receptor 2; adipoR1, Adiponectin receptor 1; GLUT4, Glucose transporter 4; MCP-1, Monocyte chemoattractant protein-1; CTGF, Connective tissue growth factor; NF-κB, Nuclear factor kappa B; PPARgamma, Peroxisome proliferator-activated receptor gamma; FPG, Fasting plasma glucose; LVEDP, Left ventricular end-diastolic pressure; ISI, Insulin sensitivity index; HE, Hematoxylin and eosin; ELISA, Enzyme-linked immunosorbent assay; PBS, Phosphate-buffered saline; DAB, Diaminobenzidine; IOD, Integrated optical density; GAPDH, Glyceraldehyde-3- phosphate dehydrogenase.
Competing interests
===================
All Authors declare that they have no competing interests.
Authors' contributions
======================
ZG designed the study and drafted the manuscript. RZ carried out Masson's trichrome staining, detected the expression of adiponectin receptor 2, MCP-1 and GLUT-4 in the heart, and participated in the statistical analysis. JL contributed to the assay of p22phox, NOX4 and CTGF in the heart, and participated in the statistical analysis. GX carried out HE staining, detected the expression of adiponectin receptor 1, MCP-1 and NF-κB in the aorta, and participated in the statistical analysis. All authors read and approved the final manuscript.
Acknowledgements
================
This work was supported by the grant (No.2007-44 and 2011-48) from Shanxi Scholarship Council of China and the grant from Department of Personnel of Shanxi Province of China in aid for the excellent projects picked out in technological activity.
|
Microphotometric study of glucose-6-phosphate dehydrogenase activity in epididymal spermatozoa during spontaneous lipid peroxidation.
Mammalian spermatozoa are highly sensitive to lipid peroxidation and the glutathione peroxidase/reductase system provides an effective defense against oxidative damage to different degree in different species. Rabbit spermatozoa rely on superoxide dismutase as the primary enzymatic defense against lipid peroxidation and contain only low detectable endogenous glutathione reductase activity while in mouse spermatozoa the glutathione system is the major protective enzyme against cell damage by autoxidation. We describe a cytochemical quantitative assay for glucose-6-phosphate dehydrogenase activity in rabbit and mouse spermatozoa undergoing spontaneous lipid peroxidation during in vitro incubation. Microdensitometric measurements were made by a Vickers M85 a scanning microdensitometer at lambda 585 nm wavelength. Our findings suggest that in mouse spermatozoa, the enhanced glutathione reductase and peroxidase activities induced by the spontaneous lipid peroxidation increases NADPH production from the pentose phosphate shunt, while in rabbit spermatozoa, NADPH production is much lower. |
List of ambassadors of Montenegro
Ambassadors representing Montenegro abroad. Listed in alphabetical order by country.
List of ambassadors
- Željko Perović
- Dragana Radulović
- Vesko Garčević
- Radovan Miljanić
- Ljiljana Tošković
- -
- Irena Radović
- Vladimir Radulović
General Consul Abid Crnovršanin in Frankfurt
- Ivo Armenko
- Antun Sbutega
- Vanja Brailo
- Vojin Vlahović
- Ferhat Dinosha
- Dušan Mrdović
- Ivan Leković
- Slobodan Backović
- Ranko Milović
- Igor Jovović
- Ljubiša Perović
- Ramo Bralić
- Ljubiša Stanković
- Ljubomir Mišurović
- Nebojša Kaluđerović
General Consul Branko Milić in New York City
- Aleksandar Eraković
Non residential
- Željko Radulović in Podgorica
- Nebojša Kaluđerović in Washington, D.C.
- Milorad Šćepanović in New York City
- Milorad Šćepanović in New York City
- Dragana Radulović in Vienna
- Nikola Ciko in Podgorica
- Nebojša Kaluđerović in Washington, D.C.
- Željko Radulović in Podgorica
- Vojin Vlahović in Rome
- Irena Radović in Paris
- Milorad Šćepanović in New York City
- Vojin Vlahović in Rome
- Dragana Radulović in Vienna
- Antun Sbutega
List of Ambassadors to international organizations
- Dragana Radulović, Organization for Security and Co-operation in Europe and other organizations in Vienna
- Ana Vukadinović, Council of Europe in Strasbourg
- Aleksandar Pejović, European Union in Brussels
- Vesko Garčević, NATO in Brussels
- Milorad Šćepanović, UN in New York City
- Ljubiša Stanković, UN in Geneva
- Irena Radović, UNESCO in Paris
See also
Montenegrin diplomatic missions
Foreign relations of Montenegro
References
External links
The Njegoskij Fund Network: Foreign Representations in Montenegro
The Njegoskij Fund Network: Montenegrin Representations Abroad
The Njegoskij Fund Network: Today's Montenegro >> Diplomacy
Embassy of Montenegro in Austria
Embassy of Montenegro in Macedonia
Consulate-General of Montenegro in New York City
The Njegoskij Fund Network: "ambacg-fr.eu", the portal dedicated to the activities of the Embassy of Montenegro in France
Category:Politics of Montenegro
Montenegro
*Main
Ambassadors |
Juror dismissed in Bell corruption case
LOS ANGELES (AP) — A weeping juror was dismissed Thursday for committing misconduct during deliberations in the public corruption trial of six former officials of the suburban city of Bell.
The woman juror admitted she looked up information online and had her daughter search out a definition of what would constitute coercion by other jurors.
An alternate juror was later placed on the panel and Superior Court Judge Kathleen Kennedy ordered that the case must be decided as if the previous deliberations had never occurred.
The defendants are charged with misappropriation of public funds for giving themselves huge salaries and nearly bankrupting the tiny suburb of Los Angeles.
The jury, which has about 100 verdict forms to fill out, had been in its fifth day of deliberations after a three-week trial.
Deliberations were troubled from the outset.
On Monday, the elderly woman identified only as juror No. 3 asked to be dismissed, claiming other jurors were harassing her because of her opinions. The judge asked her to return to deliberations and try to get along with the others.
On Thursday, the jury sent a note to the judge saying they were at an impasse and could not reach verdicts. Then, one juror sent a subsequent note reporting that the woman juror told panelists she had called her personal attorney to seek information on what to do about being coerced by other jurors.
The judge summoned defendants and lawyers to her courtroom and asked juror No. 3 to explain her actions. The woman, who was verging on tears, said she never actually called a lawyer.
"I gave them the attorney's name so they would leave me alone," she said.
But she said she had asked her adult daughter to look up the definition of "coercion" on her computer. She said she told the others that she had the definition but didn't read it to them.
The judge asked why she ignored admonitions not to talk to anyone about the case. She said she needed someone to talk to "about the abuse I was suffering from the other jurors."
She said the daughter told her to be patient and everything would be fine.
She added that she also did research on a website of the California Law Library to find out how long she had to stay "when I had made my decision."
At one point, she buried her face in her hands and began to cry.
"Am I in trouble for this?" she asked.
Most of the attorneys and the prosecutor agreed that the juror had to be replaced.
"I believe it is plain that she was engaged in juror misconduct," said Deputy District Attorney Edward Miller. "How much she tainted other jurors is not clear. I've never seen it so well documented."
The judge told the juror she was being dismissed.
"You're not in trouble," she told her. "There's no reason to be upset. That's why we have alternates."
The juror was sobbing as she was escorted out of the courtroom.
During the trial the prosecution said the defendants convinced themselves they were entitled to nearly six-figure salaries for part-time positions governing the tiny blue-collar city where the median income is $35,000.
The former city manager, Robert Rizzo, and his assistant, Angela Spaccia, who were allegedly behind the looting of the city coffers face trial later in the year.
The officials on trial are former Mayor Oscar Hernandez, former Vice Mayor Teresa Jacobo and former council members George Mirabal, George Cole, Victor Bello and Luis Artiga. All except Artiga served as mayor at some point. |
// Andrés Mejía
#include <algorithm>
#include <iostream>
#include <iterator>
#include <numeric>
#include <sstream>
#include <fstream>
#include <cassert>
#include <climits>
#include <cstdlib>
#include <cstring>
#include <bitset>
#include <string>
#include <cstdio>
#include <vector>
#include <cmath>
#include <queue>
#include <deque>
#include <stack>
#include <list>
#include <map>
#include <set>
using namespace std;
////////////// Prewritten code follows. Look down for solution. ////////////////
#define foreach(x, v) for (typeof (v).begin() x=(v).begin(); x !=(v).end(); ++x)
#define For(i, a, b) for (int i=(a); i<(b); ++i)
#define D(x) cerr << #x " is " << (x) << endl
const double EPS = 1e-9;
int cmp(double x, double y = 0, double tol = EPS) {
return (x <= y + tol) ? (x + tol < y) ? -1 : 0 : 1;
}
////////////////////////// Solution starts below. //////////////////////////////
class Solution {
public:
bool search(const vector<int>& nums, int target) {
if (nums.size() == 0) return false;
int min = find_min(nums, 0, nums.size() - 1);
// Search target in the two sorted arrays: a[0, min-1] and a[min, n-1].
if (0 <= min-1) {
pair<bool, int> x = binary_search(nums, target, 0, min - 1);
if (x.first) return true;
}
if (min <= nums.size() - 1) {
pair<bool, int> x = binary_search(nums, target, min, nums.size() - 1);
if (x.first) return true;
}
return false;
}
private:
// Recursive implementation of binary search.
pair<bool, int> binary_search(const vector<int>& array, int target, int l, int r) {
assert(l <= r);
if (l == r) {
return array[l] == target ? make_pair(true, l) : make_pair(false, -1);
}
int left_length = (r - l + 1) / 2;
assert(left_length >= 1);
int candidate = array[l + left_length - 1];
if (target <= candidate) return binary_search(array, target, l, l + left_length - 1);
return binary_search(array, target, l + left_length, r);
}
// Returns index of the min element in the given rotated sorted array.
// l and r are the indexes where the min element is guaranteed to be
// (so the first call should be find_min(array, 0, array.size()-1)).
int find_min(const vector<int>& array, int l, int r) {
assert(l <= r);
if (l == r) return l;
int left_length = (r - l + 1) / 2;
assert(left_length >= 1);
int a = array[l + left_length - 1]; // last element in left half.
int b = array[r]; // last element in right half.
if (a < b) {
// min is guaranteed to be in the left half, because if it were in the right half that would
// imply b <= a which is a contradiction.
return find_min(array, l, l + left_length - 1);
}
if (b < a) {
// min is guaranteed to be in the right half, because if it were in the left half that would
// imply a <= b which is a contradiction.
return find_min(array, l + left_length, r);
}
assert(a == b);
// Too bad, we don't have enough info to discard half of the array but we can discard one
// element. We need to be careful in cases like "1 1 1 1 2 1" where we want the last 1!
if (array[l] < array[r]) {
return find_min(array, l, r - 1);
}
if (array[l] > array[r]) {
return find_min(array, l + 1, r);
}
assert(array[l] == array[r]);
if (array[r - 1] > array[r]) {
return find_min(array, l + 1, r);
}
return find_min(array, l, r - 1);
}
};
int main(){
Solution s;
cout << s.search({2, 4, 5, 6, 7, 7, 1, 1, 1, 1, 1, 2, 2}, 1) << endl;
return 0;
}
|
Photo: Maya Robinson and Photo by Paramount Pictures
On January 2, a Variety piece, citing Wikipedia, declared that Martin Scorsese’s The Wolf of Wall Street used the F-word 506 times, setting a new record. This report was quickly picked up by news outlets around the world. I love Wikpedia and a good headline, but this authorless claim seemed deserving of fact-checking. And I am a masochist. (See here and here.) So, in the service of making sure the historical record is accurate, I decided to watch the film (two and a half times) and carefully count not only the number of F-words, but, to get a fuller picture of the film’s verbal depravity, every single other bad word and variation used over the course of the film’s three-hour running time. (See a picture of my notes, below.) It was, I thought, a wonderful idea.
Then, my research done and sent to our art department to graph, those fucking fucks over at Slate had to publish a very similar piece last evening. Good job, Slate! But that doesn’t mean that this new area of exploration can’t keep moving forward: I can be the Edison to Slate’s Ben Franklin in advancing the study of counting depraved stockbrokers yelling “fuck.” While they kept their research to the F-word family (and, for the record, while both of us disagreed with Wikipedia, we came up with different numbers: Slate’s 544 to my 569), I also noted every shit, dick, cock, and so on — delivered by all characters, be they main, supporting, or even lost in a crowd. (After Jonah Hill’s Donnie swallows a junior trader’s goldfish, for example, you hear unspecified co-workers yell, “Get the fuck out of here! Fuck off, Mr. Rogers! Fuck you, bow tie! A real fucking idiot!”)
We broke down the data into four graphical treatments — a list of every curse word and how many times it was said, a chart showing just the F-words, a chart showing all of the curse words listed in relation to each other, and then a breakout of which characters are the most profane. Enjoy. (And note: We are aware the comments section, run by an outside vendor, does not allow profanity to be used. This does not make us hypocrites. It makes computers hypocrites.) |
Q:
$\text{Prove that}$ $\frac{\sin(\frac{n+1}2)*\cos(\frac n2)}{\sin\frac 12} \ge\frac n2$
Prove that$$\frac{\sin\left(\frac{n+1}2\right)\times\cos\left(\frac n2\right)}{\sin\left(\frac 12\right)} \ge\frac n2$$
So far I've switched up the problem and gotten it down to all sin functions. I have $$\frac {\sin\left(\frac{2n+1}2\right)+\sin\left(\frac {1}2\right)}{2\sin\left(\frac {1}2\right)}\ge\frac n2$$
So far this is the farthest I've got that seems to make sense. I graph the function each time I do it to make sure that the move I made was a legal move. From the graph I can see that the graph has a maximum at 1.5429
So am I going to have to use induction to prove this statement? or am I going about this all the wrong way?
A:
look: $$
\frac {1}{sin(\frac {1}2)}\ge\frac{\sin(\frac{n+1}2)\cdot\cos(\frac n2)}{\sin(\frac 12)} \ge\frac n2
$$
so:
$$
\frac {1}{\sin(\frac {1}2)}\ge\frac n2 \iff n\le \frac{2}{\sin(\frac {1}2)} \approx 4.2
$$
that can easily be falsified by choosing an $n$ suffieciently large (like $5$ for example)
EDIT
to help you for your "ultimate goal":
$$
\sum_{k=0}^n|\cos(k)|\ge\frac n2 \iff \frac 2n\sum_{k=0}^n|\cos(k)|\ge1
$$
we can prove very easily that this new statement is true for sufficiently large $n$:
$$
\lim_{n\to +\infty}\frac 2n\sum_{k=0}^n|\cos(k)|=2\Big(\frac{1}{\pi} \int_{-\frac{\pi}{2}}^{\frac{\pi}{2}}|\cos(x)|\mbox{ d}x\Big)=\frac{4}{\pi} \ge1 \mbox{(true)}
$$
to get that integral use this fact:
$\{n\ \ \mbox{ mod }\ \ \pi\ \ \ |\ n\in \mathbb{N}\}$ is dense in $]0,\pi[$
then use the definition of riemann sum and successively exploit the fact that $\cos(x)$ is a circular function
to give a complete proof you could use numerical calculations to prove that it works in $0\le n\le N_h$ then this other proof to show that above $N_h$ it also works
|
The effect of birdsfoot trefoil (Lotus corniculatus) and white clover (Trifolium repens) in mixed pasture swards on incoming and established nematode infections in young lambs.
Lotus corniculatus L., a leguminous plant containing condensed tannins, is now being evaluated in Sweden as a component of mixed pastures. This is because of its high nutritive value, palatability, modest requirement for water, calcium and phosphorous and particularly because it has the ability to survive harsh weather conditions that typify northern Scandinavia. This trial was undertaken to assess the possible parasitological benefits of using L. corniculatus when fed as a minor component in a mixed pasture sward to young sheep. This was compared with similar sheep that were fed pasture with a comparable legume content consisting of Trifolium repens L. Separate groups of lambs, maintained in pens and provided with fresh pasture cuts containing either L. corniculatus or T. repens each day, were trickle-dosed with infective larvae of mixed parasite species. For each pasture type, groups of 6 lambs had either established worm burdens only, received incoming infections only, or had the combination of both adult and incoming infections. Worm burdens were monitored by serial faecal egg counts and at the termination of the study, all animals were slaughtered for worm recovery, identification and enumeration. The results showed that there were no differential effects between L. corniculatus and T. repens on the different stages of development for a range of nematode parasite species recovered from these lambs. Several reasons may account for this: such as the low level of condensed tannins in the L. corniculatus variety tested, the minor proportion of this plant in the diet and/or the variety of L. corniculatus used in this trial which do not provide any benefits to controlling parasites of sheep. |
Treatment of intussusception in children operative treatment versus hydrostatic reduction.
Intestinal intussusception is a serious abdominal emergency in infancy and childhood, with a high mortality-rate if not diagnosed and treated early. Since the management of intussusception in children is still controversial, the pro's and con's for barium enema reduction and for surgical treatment are discussed. The results of our own series of 19 patients primarily treated by barium-enema reduction compare favourably with a previous series of 14 patients treated by primary surgery. |
Whether they're athletes, movie stars, or musicians, big names keep pushing the boundaries of bad behavior with sex, drugs, and violence. And our kids have a front-row seat, no less mesmerized than the rest of us. Sure, they're savvy — they know about the difference between image and reality — but they're still kids at heart, desperately seeking role models and ground rules to live by. So what's a teen to think when, often as not, celebs who cross the line are granted Survivor-like immunity, their fame not merely intact but enhanced?
"Every time kids see yesterday's superstar become today's liar, they tend to get more cynical," says Frank Farley, PhD, a psychologist and adolescent specialist at Temple University in Philadelphia. That means parents can't sit on the sidelines. There are valuable lessons to be salvaged from even the tawdriest celeb dramas — teach your children well, and they'll be able to draw on them for a lifetime.
Outrageous Outbursts
Tirades, temper tantrums, hissy fits, giving the finger — hardly a day goes by without some celeb acting up like a spoiled brat. Remember Serena Williams threatening to shove a tennis ball down a line judge's throat at the U.S. Open, or Christian Bale's movie-set meltdown that contained 39 F-bombs? Everyone from Lindsay Lohan to Jude Law has brawled with the paparazzi at some point. Stars sometimes even turn on their fans, like the time singer Avril Lavigne unleashed a torrent of curse words at autograph seekers as well as photographers.
Our kids aren't appalled, but amused — for them it's just another TMZ or YouTube moment. In part, it's because they identify with celebs as cool rebels. "That's why kids troll the Internet and turn these incidents viral," says Farley. "They also do spoofs and parodies of celeb screwups online, since being funny is a sure way to impress their peers."
But beneath the smirks and sniggers, teens need public figures they can emulate. "Kids do take cues from their parents, so it's important to help them decode all that bad behavior," says Celeste Gertsen, PhD, a clinical psychologist and professor at Adelphi University in New York. "Talk to them about how to distinguish professional accomplishment from personal integrity. Ask whether the celeb made a one-time slipup and seems genuinely sorry, or if the mistake is part of a larger pattern that shows a sense of arrogance and entitlement."
Parents can point out that in the case of both Williams and Bale, the outbursts weren't just rude; they were abusive and tantamount to bullying. And while celebs often escape fallout — Williams was smashed with an $82,500 fine but not suspended — your kid won't be so lucky. Tell him that if he pulled the same stunt at Friday night football he'd be booted off varsity for good.
Finally, give your teens a step-by-step plan for staying levelheaded in tense situations. "Remind them to stop and think things through when they feel themselves getting upset so they can control the impulse to act out," advises Gertsen. "It's really all about teaching your kids to have empathy and respect for others. If they realize how someone else is affected by their words and actions, they're much less likely to lose it and get aggressive."
Sports Scandals
Physical talent, drive, and discipline — those qualities abound in star athletes, which is why so many kids identify with them and put them up on pedestals. Problem is, they can't seem to stay there. Whether it's Yankees star Alex Rodriguez finally fessing up to taking performance-enhancing drugs, or Andre Agassi admitting he got high on crystal meth while on the pro tennis circuit, the playing fields these days are littered with scandals of every stripe. "So many stars have failed or fallen off the wagon in some way, and it's really had an impact on kids," says Stanley Teitelbaum, PhD, author of Athletes Who Indulge Their Dark Side: Sex, Drugs, and Cover-Ups (Praeger). "The younger they are, the stronger the sense of disappointment. With older teens, the response is more like 'Whatever' or 'Who cares?' They're not even surprised, just disillusioned and indifferent."
There are many lessons for parents to drive home here. "Start by having a conversation with your child about human frailty and imperfection, and how we all succumb to temptation," suggests Teitelbaum. Even the most cynical teens, he adds, still connect with sports figures on some deeper, subconscious level; when their heroes succeed, kids bask in the glory and feel good about themselves. So it's natural for them to want athletes to be strong and flawless in every way. "I call it the halo effect," says Farley. "It's part of a parent's job to take it off and teach kids that athletes often do destructive things despite their accomplishments."
Then move on to the issue of steroids. Doping is illegal, and it undermines everything that sports is about by giving an unnatural advantage over the competition — whether it affects a game, a championship, the record books, or the Hall of Fame. "Simply put, it's living a lie," says Farley. "So if your teen says what's the big deal or that everybody's doing it, you've got to help him grasp the larger legal and moral repercussions." Make like Socrates and ask lots of questions to help him get the big picture. Is bulking up on steroids any different from cheating? What about fair play and everybody sticking to the rules? Is winning really the only thing that matters? Your end goal is for your kid to come up with the right answers on his own.
Tainted Love
No one can forget the 2009 photo of R&B star Rihanna — her face swollen with bruises, a bloody nose, and split lip, the result of a beating by boyfriend Chris Brown, who was convicted of felony assault and sentenced to 180 days of community service.
On a scale of transgressions this one's a 10, so serious that it can't go unaddressed. "The bottom line here is clear," says Farley. "Abuse is never acceptable, and girls who find themselves victims in any way have to get out, fast."
Experts agree that parents need to recognize the negative, often violent, messages and images being projected to kids, especially young boys. "There's a lot of garbage coming at them that manhood is all about sexual conquest, material wealth, power, and arrogance — what I describe as the bad-ass syndrome," says Kelly H. Johnson, author of A Better Man: True American Heroes Speak to Young Men on Love, Power, Pride, and What It Really Means to Be a Man (Brandylane Publishers). "I have a daughter and five sons. The older boys are in their 20s and the younger ones are in middle school, so I know what I'm talking about. There's definitely less sensitivity these days, while their coarseness is rising."
A lot of that has to do with the movie and music stars kids worship — they're simply not worthy. But parents can provide a counter-balance by strongly voicing their disappointment and disapproval. "Kids have to know the qualities you value and why," says Johnson. "Use precise language — words like dependable, selfless, loyal, which have more depth and content and really get to the heart of a person's character. You want your children to think in those terms, not simply right versus wrong or good versus bad, when they make their own decisions."
Be sure to point out when celebs do something right, as Rihanna finally did. "She scared us all when it seemed she was going to reconcile with Chris Brown," says Johnson. "To her credit, she pulled away and ultimately walked away. I like that it took her months and a false start or two, because it revealed her humanity and showed girls what a tough decision it was to stand up for her dignity and self-worth. She chose the hard right over the easy wrong."
And don't forget to talk about the road to redemption. "For example, if you tell your kids that Brown has a long way to go to regain respect and trust, you're conveying a deeper message as well — that if your kids do something wrong and get caught, they can also make amends, and that you'll be there for them," says Johnson. "That's something they need to hear."
Finally, help your kids find heroes who truly deserve their respect. "There's a wealth of good people out there — fathers and uncles, neighbors and friends, teachers and coaches — who, as opposed to shallow, empty celebrities, have real accomplishments," says Johnson. "Just be sure to take a subtle approach, since teens don't want to feel like they're being lectured. You can't force-feed heroes to your children. They have to find and embrace them on their own."
Originally published in the March 2010 issue of Family Circle magazine. |
Little Bull Creek (Allegheny River tributary)
Little Bull Creek is a tributary of Bull Creek and part of the Allegheny River watershed located in both Allegheny and Butler counties in the U.S. state of Pennsylvania.
Course
Little Bull Creek rises in Butler County. It then flows into Allegheny County, generally along the southeastern side of Pennsylvania Route 28. The stream joins Bull Creek via a culvert underneath Bull Creek Road (a section of Pennsylvania Route 366) at the borough of Tarentum.
See also
List of rivers of Pennsylvania
List of tributaries of the Allegheny River
References
External links
U.S. Geological Survey: PA stream gaging stations
Category:Rivers of Pennsylvania
Category:Tributaries of the Allegheny River
Category:Rivers of Allegheny County, Pennsylvania
Category:Rivers of Butler County, Pennsylvania |
/*
Copyright (c) 2008-2009 NetAllied Systems GmbH
This file is part of COLLADAFramework.
Licensed under the MIT Open Source License,
for details please see LICENSE file or the website
http://www.opensource.org/licenses/mit-license.php
*/
#include "COLLADAFWStableHeaders.h"
#include "COLLADAFWSkinController.h"
namespace COLLADAFW
{
//------------------------------
SkinController::SkinController( const UniqueId& uniqueId )
: Controller( uniqueId, Controller::CONTROLLER_TYPE_SKIN )
{
}
//------------------------------
SkinController::SkinController( const SkinController& pre )
: Controller( pre.getUniqueId(), Controller::CONTROLLER_TYPE_SKIN, pre.getSource () )
, mSkinControllerData(pre.mSkinControllerData)
{
const UniqueIdArray& preJoints = pre.mJoints;
size_t bonesCount = preJoints.getCount();
mJoints.allocMemory(bonesCount);
mJoints.setCount(bonesCount);
for ( size_t i = 0; i < bonesCount; ++i )
{
mJoints[i] = preJoints[i];
}
}
} // namespace COLLADAFW
|
KiWi Versioning: allow passing a list of excluded contexts
Details
Description
There are cases (e.g. reasoning, ldcache) where it is not desirable to create a version of updated triples. The versioning service should be configurable such that users can pass a list of contexts to exclude from versioning. |
Most small businesses have a false sense of cyber-security. That's the key finding of a new survey conducted by security firm Symantec and the National Cyber Security Alliance.
The study, released this week, found that 77 percent of small-business owners or operators say that their company is safe from such threats as hackers, viruses, malware or a cyber-security breach. Eighty-three percent have no formal cyber-security plan and 66 percent are simply not concerned about external or internal cyber threats.
'Fatal to Their Business'
The report said that, even as small- and medium-size businesses (SMBs) increasingly rely on the Net for their business operations, they are not "taking the necessary measures to keep their businesses safe and secure."
Fifty-nine percent of SMBs have no contingency plan for how to deal with losses resulting from a data breach, and 87 percent have no formal written Internet security policy for employees. Sixty-nine percent do not even have an informal one, and, although social media use in SMBs is booming, 70 percent do not have an employee social-media use policy.
Michael Kaiser, NCSA executive director, said in a statement that U.S. SMBs need "to understand they cannot completely remain safe from cyber threats if they do not take the necessary precautions."
Symantec noted that nearly 40 percent of the more than 1 billion cyber attacks the company prevented in the first quarter of this year were targeted at companies with fewer than 500 employees. And, it added, an attack on a "small, poorly protected" company is often "fatal to their business."
Safety Practices
Visa has reported that over 90 percent of the payment data breaches reported to the company were from SMBs. Interestingly, newer companies -- those founded since 2008 -- are nearly 20 percent more likely than older small businesses to have a cyber security plan in place.
Even as they believe their companies are safe, 73 percent of respondents know that a safe and trusted Net is critical to their business success, and 77 percent acknowledge that online security is important for their brand.
Symantec advises several online safety practices that SMBs can establish. One of the first steps, the company said, is to assess where vital data is being kept and how it is being used, so that security can focus on those areas. Strong password policies should be established and enforced, requiring eight characters or more and a combination of letters, numbers and symbols.
A disaster preparedness plan should be mapped out, including backup solutions, and confidential information should be encrypted. A reliable security solution should be employed and kept up to date, business data should regularly be backed up, and employees should be educated about Net safety, company security policies, how to identify possible malware, and what to do if they misplace information.
The survey, conducted by JZ Analytics, surveyed 1,015 small businesses in the U.S. with fewer than 250 employees, and the margin of error is 3.1 percent.
What Is Splunk?
You see servers and devices, apps and logs, traffic and clouds. We see data—everywhere. Splunk® offers the leading platform for Operational Intelligence. It enables the curious to look closely at what others ignore—machine data—and find what others never see: insights that can help make your company more productive, profitable, competitive and secure. What can Splunk do for you? Just ask. |
Q:
how to tell if ms access file was created as 32-bit or 64-bit?
I inherited a 2013 ms access db file but i do not know if the user created it with a 32- or 64-bit version of access. I know how to check my system settings to see what type my OS and MSO are, but how do I tell how a specific third-party file was created?
A:
As far as I know, it doesn't matter. I'm pretty sure that they use the same file format.
A:
There is an interesting article about it.
The General Rule
As a general rule, a database (in accdb file format) developed on Access x32 should run fine on Access x64 and vice versa.
When the General Rule Goes Awry
Although, a database made on Access x32 should run fine on Access x64 (and vice versa), some people report issues. You have 2 options:
Create a new blank database in the target bitness and import everything
Decompile the original database and migrate it to the other bitness and then recompile it
The article also quotes the Microsoft:
“We recommend the 32-bit version of Office for most users, because it’s more compatible with most other applications, especially third-party add-ins.” — Microsoft, see: 64-bit editions of Office 2013
If you run into the above problem, you can choose a preferred bitness (e.g. 32 bit) and for users with 64-bit Access (see the VBA code) display a warning.
|
Q:
How to install PHP composer inside a docker container
I try to work out a way to create a dev environment using docker and laravel.
I have the following dockerfile:
FROM php:7.1.3-fpm
RUN apt-get update && apt-get install -y libmcrypt-dev \
mysql-client libmagickwand-dev --no-install-recommends \
&& pecl install imagick \
&& docker-php-ext-enable imagick \
&& docker-php-ext-install mcrypt pdo_mysql
&& chmod -R o+rw laravel-master/bootstrap laravel-master/storage
Laravel requires composer to call composer dump-autoload when working with database migration. Therefore, I need composer inside the docker container.
I tried:
RUN curl -sS https://getcomposer.org/installer | php -- \
--install-dir=/usr/bin --filename=composer
But when I call
docker-compose up
docker-compose exec app composer dump-autoload
It throws the following error:
rpc error: code = 13 desc = invalid header field value "oci runtime error: exec failed: container_linux.go:247: starting container process caused \"exec: \\\"composer\\\": executable file not found in $PATH\"\n"
I would be more than happy for advice how I can add composer to the PATH within my dockerfile or what else I can do to surpass this error.
Thanks for your support.
Also: this is the gitub repository if you need to see the docker-compose.yml file or anything else.
A:
In Dockerfile :
COPY --from=composer:latest /usr/bin/composer /usr/local/bin/composer
A:
I can install composer adding this line on my test dockerfile:
# Install Composer
RUN curl -sS https://getcomposer.org/installer | php -- --install-dir=/usr/local/bin --filename=composer
Here is the dockerfile:
FROM php:7.1.3-fpm
RUN apt-get update && apt-get install -y libmcrypt-dev \
mysql-client libmagickwand-dev --no-install-recommends \
&& pecl install imagick \
&& docker-php-ext-enable imagick \
&& docker-php-ext-install mcrypt pdo_mysql
# Install Composer
RUN curl -sS https://getcomposer.org/installer | php -- --install-dir=/usr/local/bin --filename=composer
It works for me, to test if the composer are installed i access to my container bash and execute:
composer --version
Composer version 1.6.5 2018-05-04 11:44:59
|
Q:
NetSuite SuiteScript Reference Key not being recognized
I am trying to get a script to set a field in a Purchase Order after processing a Sales Order. The field is 'department' and the reference key is 71. However, I am getting the error: "Invalid department reference key 71 for subsidiary "
The code is simple enough:
obj_New_PO.setFieldValue('department', 71);
I am fairly new to NetSuite scripting so I am not sure on this error. I checked the reference keys for 'department' (under Setup -> Company -> Departments) and 71 does exist.
Any ideas as to why the Purchase Order is not seeing the correct reference key?
Thank you.
A:
Departments are restricted to specific Subsidiaries. You will need to make sure that the Department in question is available in the PO's Subsidiary. Just view the Subsidiaries field on the Department record.
|
Q:
Knockout Mapping: JSON grows when mapping and saving multiple times
When I take a knockout object and serialize it to JSON by doing ko.toJSON, and then unserialize it from JSON using ko.mapping.fromJSON multiple times, the loaded object has this __ko_mapping__ property that recursively grows.
Sample code:
var joe = new Person();
for (var i = 0; i < 10; i++) {
var json = ko.toJSON(joe);
joe = ko.mapping.fromJSON(json);
}
Simple JSFiddle that reproduces it:
http://jsfiddle.net/Gc89Q/1/
How can I load and save multiple times without having the serialized json form grow to be gigantic?
I was considering just setting the __ko_mapping__ property to undefined when loading, but am wondering if there is a better way or something I am missing.
Is this a bug I file an issue for?
A:
Don't overwrite the model. Instead, pass it to fromJSON so the model is updated:
ko.mapping.fromJSON(json, joe);
http://jsfiddle.net/Gc89Q/2/
|
Q:
DRF form render object property (name) instead of Object
The form select option is showing 'survey object' - how can I get it to render the surveyname instead? The lookupfield is using the survey object 'name' property - how can I get the POST form to also use it?
<option value="http://127.0.0.1:8000/data/surveys/mysurvey/">Survey object</option>
<option value="http://127.0.0.1:8000/data/surveys/anothersurvey/">Survey object</option>
A:
"Survery object" is the default representation for your model. So somewhere in your model Survery you have to define its string representation, e.g.
class Survey(models.Model):
name = CharField(max_length=255)
def __str__(self): # or def __unicode__(self) in Python 2
return self.name
In Python 2 Django will call __unicode__() on your model. In Python 3, it will call __str__()
|
At 77, the part of Woody Grant, a beaten-down Midwesterner seemingly slipping into dementia, is getting Dern the best reviews of his career and may earn him an Academy Award nomination. He already won the competitive best actor award at the Cannes Film Festival in May.
Actors of Dern’s vintage are only called on by Hollywood to accept lifetime achievement awards or to play lovable codgers out for one last hurrah in buddy comedies — “Last Vegas,” “Stand Up Guys” and “The Bucket List” are just a few recent examples. But this year, two of their cohorts have meaty, career-crowning roles, and Dern and Robert Redford, earning raves portraying Our Man in the stranded-at-sea saga “All Is Lost,” are touring the awards circuit like it’s 1974.
The recent tide of goodwill has brought the two actors together almost 40 years after they costarred in “The Great Gatsby,” where Redford played Gatsby and Dern played Tom Buchanan, naturally.
Dern is asked to assess his old costar’s performance.
“I thought his courage to take part in the movie on his own when he’s like 76 or 77 or whatever he is like me was fabulous, and I thought he did a good job. And when I saw the movie it was typical Redford because the guy is not going to die. Ever. Even Jeremiah Johnson doesn’t f–king die,” Dern says, referring to Redford’s 1972 film.
Because Dern, in a career that spans 50 years, has perfected the curmudgeon look, he seems like he would be ornery in life, too. But he carries himself like he’s still riding on one of those choppers with Peter Fonda in “The Wild Angels.” He’s dressed in all black and wears a goofy grin on his face that seems to say he can’t believe his dumb luck to still have work at his age.
“I don’t know about me, but I’m sure he will be nominated,” he says, referring to Redford. “The win for me was getting the role.”
Dern cut his teeth in Roger Corman’s Sixties biker movies alongside Fonda, Jack Nicholson and Dennis Hopper, but he never really earned, or chased, the leading-man status of those guys.
Instead, he gravitated toward character parts, happy to step up whenever Hollywood needed an unhinged whack-job. So a career triumph this late in life has an element of redemption, like he’s getting discovered all over again.
“I’ve never been asked to be the lead in a studio movie ever. This was the first time I’ve been in a studio movie in probably 30 years, and that was a treat for me,” he says.
He had just walked through a throng of well-wishers and is stationed at a booth near the back, away from all the premiere hubbub. His most enduring relationship from the New Hollywood years remains Nicholson, who has become one of the film’s most ardent cheerleaders.
“We’ve known each other since 1961. So that’s 53 years,” Dern says. “He was the first person we showed [‘Nebraska’] to and he was very proud of Alexander because he did ‘About Schmidt’” — Nicholson’s 2002 film with Payne — “and he was extremely proud of me and is helping do everything that needs to be done for the movie.”
Will the two of them ever get to work together again?
“We need a story. If he’s excited by it, I’m excited that he’s excited. At one time, they talked about Jack and I doing ‘Water for Elephants’ because in the book there’s two old guys, though in the movie they only kept one old guy,” Dern says. The movie was eventually made with Robert Pattinson of “Twilight,” and the character actor Hal Holbrook in the part of the old guy.
“If I have a regret,” Dern says, “it’s that I never got to work with Redford on another movie, that I never got to work with Jack again.”
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A room full of toiles at the haute couture atelier in the Dior exhibition at Les Arts Décoratifs, open in Paris since July 5. This is just one of three major exhibitions that have been timed to coincide with the house's 70th anniversary. See the rest of the exhibits, plus read WWD's look into the iconic brand's history. Link in bio. #wwdfashion (📷: @dominiquemaitre)
For spring, Pamplemousse's Danica Zheng presented her signature slip dresses attached to a white T-shirt along with floral windbreakers, off-the-shoulder cotton blouses and more. For more highlights from the New York trade shows, go to WWD.com. #wwdfashion
The Green Carpet Fashion Awards closed out Milan Fashion Week yesterday. The fashion industry flocked to the event, showing its efforts to support and spread the message of sustainability. Supermodel Gisele Bündchen said "if each one of us took at least one step is this direction, there is no saying how much could be done." #wwdeye #wwdfashion #mfw (📷: Lodovico Colli di Felizzano)
Etro’s show, titled “The Tree of Life,” was a celebration of the house’s 50th anniversary. “My father founded the company in 1968, which was the year of counterculture and psychedelia. It’s really a show that celebrates that and the paisley design of India and its origin,” said Veronica Etro. #wwdfashion #mfw #ss18 (📷: @delphineachard)
For her first solo album in over 10 years, Fergie tapped Carine Roitfeld, Mert and Marcus, Giovanni Bianco and more to create a fashion-focused video approach for the record, Double Dutchess. "Giovanni really helped me get back in touch with my tomboy side, my hardside," said the singer. #wwdeye #wwdfashion ( : @slovekinpics) |
Client (computing)
A client is a piece of computer hardware or software that accesses a service made available by a server. The server is often (but not always) on another computer system, in which case the client accesses the service by way of a network.
Overview
A client is a computer or a program that, as part of its operation, relies on sending a request to another program or a computer hardware or software that accesses a service made available by a server (which may or may not be located on another computer). For example, web browsers are clients that connect to web servers and retrieve web pages for display. Email clients retrieve email from mail servers. Online chat uses a variety of clients, which vary on the chat protocol being used. Multiplayer video games or online video games may run as a client on each computer. The term "client" may also be applied to computers or devices that run the client software or users that use the client software.
A client is part of a client–server model, which is still used today. Clients and servers may be computer programs run on the same machine and connect via inter-process communication techniques. Combined with Internet sockets, programs may connect to a service operating on a possibly remote system through the Internet protocol suite. Servers wait for potential clients to initiate connections that they may accept.
The term was first applied to devices that were not capable of running their own stand-alone programs, but could interact with remote computers via a network. These computer terminals were clients of the time-sharing mainframe computer.
Types
In one classification, client computers and devices are either thick clients, thin clients, or hybrid clients.
Thick
A Thick client, also known as a rich client or fat client, is a client that performs the bulk of any data processing operations itself, and does not necessarily rely on the server. The personal computer is a common example of a fat client, because of its relatively large set of features and capabilities and its light reliance upon a server. For example, a computer running an Art program (such as Krita or Sketchup) that ultimately shares the result of its work on a network is a thick client. A computer that runs almost entirely as a standalone machine save to send or receive files via a network is by standard called a workstation.
Thin
A thin client is a minimal sort of client. Thin clients use the resources of the host computer. A thin client generally only presents processed data provided by an application server, which performs the bulk of any required data processing. A device using web application (such as Office Web Apps) is a thin client.
Hybrid
A hybrid client is a mixture of the above two client models. Similar to a fat client, it processes locally, but relies on the server for storing persistent data. This approach offers features from both the fat client (multimedia support, high performance) and the thin client (high manageability, flexibility). A device running an online version of the video game Diablo III is an example of hybrid client.
References
Category:Peer-to-peer computing |
Following an online petition to remove actress Amber Heard from Aquaman 2 after a series of leaked audiotapes revealed she admitted to “hitting” ex-husband Johnny Depp, which as of Friday afternoon has collected more than 349,000 signatures, two petitions reportedly were campaigning to take her out as cosmetics brand L’Oréal's global spokesperson as well.
One of the petitions, created by Federica P., slammed 33-year-old Heard as "a liar and an abuser, a shame for women" on change.org and has so far gathered more than 8,600 signatures, approaching its target of 10,000. Meanwhile, the other petition, started by Hillary Deanna on the same platform two weeks ago, which now aims to collect 10,000 signatures, has been supported by more than 7,800 people.
"If roles were reversed, Mr. Depp would have (and has had) many of his, if not all of his roles and sponsorships taken away. Why should this be any different in the case of Ms. Heard, as it [is] now known who the true abuser is?" reads the petition page created by Deanna.
"I’m a domestic abuse survivor and this offends me. Amber Heard doesn’t deserve to be your spokesperson and you shouldn’t want her to. Men can be victims of abuse too. Although it’s not as common. Your support of Ms. Heard is a slap in the face to all women and men who have suffered," added Lisa Stepp in the comment section.
As reported by New York Post on Thursday, Heard admitted in the leaked audiotapes obtained by the Daily Mail that she hit 56-year-old Depp and told him, "You're such a baby. Grow the f--k up, Johnny."
Amid these campaigns to have Heard removed, a petition calling to bring Depp back as Captain Jack Sparrow in the Pirates of the Caribbean franchise -- a role he lost following domestic abuse allegations from his ex-wife -- has collected over 160,000 signatures out of the target of 200,000.
"They have to bring him back to rule the seas again, or we will never watch any Pirates of the Caribbean movie without our Captain," said Riza Siddiqui, who started the petition a year ago. (kes) |
Lanky lock Albert van den Berg could run out in the No 7 jersey for the Springboks against the All Blacks tomorrow.
Following Joe van Niekerk being ruled out of the Test at Loftus Versfeld with a neck injury, Van den Berg might be the shock replacement ahead of the likes of Pierre Spies and Pedrie Wannenburg.
“Albert has played there for Griquas before,” White explained to reporters at a press conference at the team hotel in Pretoria. “We need to decide if we want to play someone who has experience in the position or if we will bring a new guy in.”
“At the moment one of the three of Pierre Spies, Pedrie or Albert will start. It is unfortunate we have this happening but we must deal with it.” Counting against Wannenburg is the fact the he has not trained with the squad. He joined the squad late yesterday, but White indicated that did not mean he would automatically start.
A final decision will be made tonight.
Perhaps the best option would be to move Jacques Cronje to No 7 and bring Wannenburg in at No 8. That would mean two Bulls players would compliment each other in the back row, while they both have extensive experience of linking with scrumhalf Fourie du Preez.
“Joe woke up in the middle of the night complaining of a pain in his neck. We took him for a scan this morning and he is out for the rest of the Tri-Nations,” said White.
The official explanation of Van Niekerk’s injury is: “Van Niekerk has suffered an over-use disc degeneration of his cervical spine disc, presently symptomatic and requiring treatment,” said team doctor Yusuf Hassan. “He will return when satisfactory.” |
The great sparkling wines
characterized by this long cellar ageing,
with wines which really surpass
many of the sensory perceptions imaginable.
Voices of Wine
with David Molina
Trainer in Outlook Wine
GUIDES & COMPETITIONS
Guides are very important,
necessary even.
What’s more important,
the opinion of a wine critic?
or that of a tasting panel?
SPARKLING WINES
I think it’s the most glamorous instant
in the world of wine.
Opening a fine sparkling wine
is not the same as
opening a fine red wine,
both are very good,
but the magic of sparkling wine
has something that captivates everyone
and you don’t know why
but it creates joy and puts a
smile on the face.
STYLES
I think there are two very big,
very differentiated, groups,
one is in the majority,
that of those sparkling wines that
are fresh,
jovial,
light,
easy to drink,
aimed at a consumer who isn’t demanding,
but who just wants easy drinking enjoyment,
and it’s a very big market,
and the other group is those sparkling wines
that require an intellectual stimulation
or for pleasure or hedonism,
more sophisticated, more glamorous,
or more aristocratic, if you
want to put it that way,
because they have subtleties
that require a bit of attention
and delicacy when you drink them.
We’re talking about these wines….
It’s a smaller, but very well
defined, group,
of long aged wines, wines
sleeping, dreaming,
imagining what they are going to give you
later, when you open the bottle.
We‘re talking about sparkling wines
which spend years in the cellar,
and which, even later, once
released on the market,
can continue to provide great pleasure,
that‘s to say, long-aged
sparkling wine doesn’t end
shortly after the disgorgement,
but can live even longer,
but for this you need
good raw material
and a good cook who knows how to cook.
LONG AGEING
The great sparkling wines
characterized by this long cellar ageing,
with wines which really surpass
many of the sensory perceptions imaginable,
and those producers who are
more sensitive, dynamic,
more, let’s say, energetic,
and with the ambition to grow,
to change, to seek quality
to differentiate themselves
from the masses,
they understood that, through doing this,
they could obtain superlative quality factors
that could position them
way above the others.
I think this is a reality,
although there are not many of them doing it,
but many who want to.
FIRST ENCOUNTER
I think it was around 1988, 1990.
I don’t know whether it was a III Lustros.
And I remember it was like
opening a crown jewel.
It was something superlative, exceptional, unique.
it wasn’t an accessible cava,
not in monetary terms,
but in terms of who it’s aimed at.
For me, Gramona is a quality reference.
CHALLENGE
Cava has a challenge and it’s the climate.
It has a very powerful varietal, the Xarel·o.
And it also has the Macabeo and the Parellada,
which don’t have the same
genetic strength as the xarel·lo.
You have to know how to work this very well
in order to obtain this freshness, acidity
and fruit which also allows you to express
the autolytic character over time,
maintaining both for as long
as possible and hand in hand.
QUALITIES OF GRAMONA
I’d say it’s an almost perfect package.
I don’t think perfection exists,
but it’s almost perfect.
it’s experience, it’s knowledge,
It’s technical mastery,
it’s extremely high quality standards.
and perfect know-how.
Other voices of wine
The goal of ageing: educate the wine.
To make it wise
so that it can later show us lots of things..
in a very short time,
so that when you open a bottle
you’ll enjoy it.
And so an aged cava and an aged champagne
have a lot more in common
than a young champagne and a young cava.
|
GLib 2.x has two allocation API:
g_slice_alloc() / g_slice_free()
/ g_malloc() / g_free()
The former is a slab allocator that has the ability, through environment variables/configuration, to fall back to the latter; the latter is a proxy for the system allocator, but had the ability to be expose a stable API that could be replaced by any allocator, through a virtual functions table set before any GLib function was called.
Internally, GLib uses a hodge-podge of calls to g_slice_alloc and g_malloc , depending on the age of the code in question.
With the introduction of constructors to replace initialization functions, the vtable approach for g_malloc() has been deprecated and cannot be used any more—there is no way for any API call to replace the allocator implementation at compile time.
Similarly, with the introduction of the use of -Bsymbolic in our default linker flags, we cannot use LD_PRELOAD and weak symbols to replace malloc() and free() at run time.
Additionally, various programming languages that have bindings for GLib have their own custom allocators, which have been optimized for the language requirements; the intersection between the completely opaque GLib allocation mechanism can lead to memory fragmentation, and difficulties in accounting the memory pressure.
Finally, while system allocators have improved their performance envelope in the time between the introduction of GSlice and now, custom allocators have seen further development, and are routinely used in complex projects that have special requirements for memory allocations. Similarly to the integration with other languages, the memory allocation strategy of GLib makes it completely opaque to the developers of these projects, and prevents tooling from inspecting memory usage, fragmentation, and pressure.
With the push to deprecate and replace g_slice_* with the system allocator currently ongoing in issue #1079, GLib is going to have a single, non-overridable allocator API that wraps the system allocator.
WARNING: This is a strawman. It's meant to be discussed and changed, and it does not represent a final design. Changes should be constructive/iterative.
A new allocator API
The basic approach would be to create a new Allocator API that provided the following entry points:
gpointer g_allocator_alloc ( const GAllocator * allocator , gsize block_size , gsize n_blocks ); gpointer g_allocator_alloc0 ( const GAllocator * allocator , gsize block_size , gsize n_blocks ); gpointer g_allocator_aligned_alloc ( const GAllocator * allocator , gsize block_size , gsize n_blocks , gsize alignment ); void g_allocator_free ( const GAllocator * allocator , gpointer mem_block ); void g_allocator_aligned_free ( const GAllocator * allocator , gpointer mem_block ); void g_allocator_realloc ( const GAllocator * allocator , gpointer mem_block , gsize old_size , gsize new_size );
The GAllocator data structure is a pointer to the allocator vtable, which replicates the API above.
Usage
Allocators are kept in a simple, thread-local stack that can be pushed and popped at will:
void g_allocator_push ( const GAllocator * allocator ); void g_allocator_pop ( void ); const GAllocator * g_allocator_get_current ( void );
Every data structure used by GLib will keep a backpointer of the current allocator at construction time, and will call the appropriate free function when releasing the resources it has; this allows to keep track of the appropriate allocator at run time whenever a new one gets pushed.
GLib provides a default allocator wrapping the system one:
const GAllocator * g_allocator_get_system ( void );
Which is also the default allocator pushed when we enter in the GLib constructor.
Changes in GLib
All allocated types in GLib will need to keep a backpointer to the GAllocator , and must never call g_allocator_get_system() itself.
Changes in external code
Similar changes to GLib should be applied to external code.
Language bindings and applications would be able to set up a new GAllocator instance, and push it at initialization/load.
Prior art
Most of the current design is inspired to the custom allocators crate in Rust. |
Q:
Proving $f(n + 1) > f(n)$ and is f injective?
If I have a function $f:\mathbb N \to \mathbb N$ defined for every $n \in \mathbb N$ by:
$$f(n) = (n+1)!-1$$
How would I prove that $f(n+1) > f(n)$ for every $n\in\mathbb{N}$?
Would it be sufficient to show that $f(n+1) > f(n)$ is true for the lowest element that n can be?
And how would I prove that f is indeed injective?
A:
Since
$$(n+2)!=(n+2)(n+1)!\ge2(n+1)!>(n+1)!,\quad \forall n\ge0$$
then we see that $f(n+1)>f(n)$ and then $f$ is injective since by definition
$$n\ne m\implies f(n)\ne f(m)$$
|
vrijdag 26 juni 2009
Friday we visited the mind.body & spirit festival in Brisbane where everything 'alternative' was on display. The public was 95% women which says something about the new age scene in Australia, the average aussie man watches aussie rules football and drinks beer it seems.Inge dived in a crystal shop and bought a few things to take home.both Inge and I had a neck and back massage at a chinese massage stand, really good as my back muscles were as stiff as a board!
woensdag 24 juni 2009
One of the definite advantages of working from home is you can plan your day as you like and take a day off when it suits you, which is what I did today. I wanted to take Inge to Mount Tamborine to see the shops, galleries, etc. We started off at the Cheese Making Shop/Factory (1st photo) but was a bit dissapointed as everything tasted like cheddar, even their Gouda(!). I spotted a small billboard on the road so the next stop was a dutch cafe called 3 Nations where we had poffertjes (small dutch pancakes) the menu included dutch favourites like pea soup and other delights so worth a visit back again. Inge asked the owner (Boukje, a friesian) where she got her cheese from as we both really miss decent dutch cheese. So some ringing around to do.The next stop was a crystal shop along the main street which was full of quirky shops and galleries. We both really had the feel that we were on holiday even though Mt Tamborine is only 1hrs drive away. The last photo is of a quiant cotswold cottage, called Fig Tree Cottage which you can rent and stay in, maybe an idea for the future.
Yesterday we booked a 2 day stay at Tangalooma Resort on Moreton Island via the internet, at the resort you can hand feed wild dolphins at night. Plenty of other things to do like going out on a boat for some whale watching and taking a closer look at dugongs. We will be going there in mid July so I will keep you all posted.
maandag 22 juni 2009
All the rain and flooding in Queensland has resulted in water travelling down to Lake Eyre (pronounced "air") in South Australia. This is on my wishlist of places to visit and see but the cost of a ticket to go for a few days is as much as a trip to Europe so someother time perhaps.
During the rainy season the rivers from the northeast (in outback Queensland) flow towards the lake through the Channel Country. The amount of water from the monsoon determines whether water will reach the lake and if it does, how deep the lake will get.
However the greater proportion soaked into the desert or evaporated en route to the Lake leaving less than one cubic kilometre in the Lake which covered an area of 800 square kilometres(!!!) or 12% of the Lake
Typically a 1.5 m (5 ft) flood occurs every three years, a 4 m (13 ft) flood every decade, and a fill or near fill four times a century. The flooding at the moment is a once in a decade event.
zondag 21 juni 2009
Today (Sunday) was a rainy day so no day trips away from home, we decided to go and see the Jade Buddha statue which is visiting Brisbane for 4 days before it tours the rest of the country and then around the world. Its 2 3m statue carved out of a solid jade boulder originally found in Canada in 2000 and weighing 18 tons. Thai craftsmen spent years painstakingly carving the statue. It is intended to promote world peace during its travels. Here's the website.....I see it visits the USA but not Europe.
zaterdag 13 juni 2009
Today we took a drive up the Scenic Rim mountains up towards the town of Warwick on the Darling Downs, a 350km round trip. The road up the mountain was great, lots of twists and turns as it made its way through the forest upto the plateau above and the town of Killarney (nothing special) then Warwick. The road is popular with bikers and we even passed some hardy cyclists near the top. The weather was prefect but a chilly 14C on the mountain pass and 22C in the valley. We stopped in Warwick for a bite to eat and a cup of coffee in the high street opposite the town hall and hotel, there are still some nice buildings in the town centre.
dinsdag 9 juni 2009
Australian cities have been ranked among the best in a British survey of the world's most liveable cities.
Melbourne came third behind Vancouver and Vienna, out of 140 major centres.Perth was equal fifth, Sydney ranked ninth, Adelaide was 11th place and Brisbane 16th.
The survey assessed cities based on stability, health care, education, infrastructure and culture.
After being here almost 9 months now both Inge and I vote Brisbane better than Perth. Melbourne is a nice city but the climate in wintertime is like Europe wet and windy. I would say that Vancouver is right to win it and is very nice having been there but what put me off Canada was they almost have no holidays to speak of so cant enjoy themselves because they are too busy working!
The aerial photo I attach is good as it shows you the Brisbane River meandering out to the ocean and Moreton Bay. You can see the Port at the end of the river. That was a real nice boat cruise a few weeks back, must do it again if we get visitors.
The photo of the beach is of the South Bank and the childrens beach area, in what place other than Rio de Janeiro can you laze on a beach right in the middle of the city.
Yes the Australians celebrate the english Queens official birthday on 8 June as a public holiday so we had a long weekend here. It was beautiful sunny weather and 22C so fine for winter so on the way back from flying I took a drive up Mount Tambourine which is a local beatyspot with fantastic views across the Gold Coast Hinterland.The plateau is an irregular shape, about 8 kilometers long and about 5 kilometers across at its widest part. The highest point on Tamborine Mountain is about 600 metres above sea level.
Geologically it is only 20 million years old. Geologists say that it was formed by the ancient shield volcano directly to the south. The landward remains of this immense crater can be clearly seen from the air and from a number of vantage points in the Border Ranges. This is what is so nice gliding here you get to see these fantastic views. Mount Warning, so named by Captain Cook as he sailed up the east coast of Australia in 1770, is just a small volcanic plug near the centre of the crater.
Tamborine Mountain plateau looks down on the surrounding lowlands, across the Nerang and Coomera River valleys to the Gold Coast and Pacific Ocean to the east and over the beautiful Albert River valley and right out to the Great Dividing Range to the west.
vrijdag 5 juni 2009
Today we went to the Greenfest Festival held in Brisbanes Botanical Gardens. The purpose of Greenfest is to create a dynamic gathering of new ideas from all industries, conservation groups, government and other community groups. This gathering provides the opportunity for individuals and networks to adjust towards and invent a greener future faster. Greenfest provides a blend of music, food, fashion, film, art, etc. IT was opened by an aboriginal dance/singing group. Lots to see from the environmental side. We even got to see a Bilby up close - see the photo - a rare marsupial only 400 left in the wild, theres a conservation effort to save them and they are protected from feral cats and foxes by a big fence running around their reserve.The building is the former government Treasury Building. Now its a casino - so stilling taking money from people first in taxes and now by gambling... |
Lipid compositional differences of small, dense low-density lipoprotein particle influence its oxidative susceptibility: possible implication of increased risk of coronary artery disease in subjects with phenotype B.
An increased susceptibility of low-density lipoprotein (LDL) to lipid peroxidative modification may be a key factor in the higher risk of coronary artery disease (CAD) among subjects with phenotype B. Compositional differences in the LDL particle may also be implicated in its atherogenicity and, in particular, may be associated with varying degrees of oxidative susceptibility of LDL, although this remains unclear. We hypothesized that the oxidative susceptibility of small, dense LDL was directly influenced by its lipid composition, which may lead to an increased risk of CAD in subjects with phenotype B. To test this hypothesis, we compared the differences in lipid compositions of LDL particles from subjects with phenotype A and those with phenotype B, and investigated the direct association of lipid composition with susceptibility to lipid peroxidative modification in 102 subjects who underwent a coronary angiographic examination. Subjects with phenotype B (n = 52) had a significantly higher incidence of CAD than subjects with phenotype A (77% v 44%; P <.005). In comparing the oxidative susceptibility of LDL, the lag time was significantly reduced in subjects with phenotype B compared to phenotype A (48.7 +/- 8.6 v 41.5 +/- 5.5 minutes; P <.0001). In addition, the lag time showed a positive correlation with LDL-peak particle diameter (PPD) (r = 0.324, P <.005). Lipid composition per LDL particle was expressed as the ratio of lipid content to apolipoprotein B (apoB) content (wt/wt). Subjects with phenotype B showed a significant depletion in the contents of free-cholesterol (FC), cholesterol ester (CE), and phospholipid (PL) per particle compared to subjects with phenotype A, although there was no significant difference in the triglyceride (TG) content per LDL particle. Except for TG, the lipid content per LDL particle showed a significant positive correlation with lag time in all subjects. Moreover, increased susceptibility of small, dense LDL to lipid peroxidative modification was most strongly associated with a depleted FC content per LDL particle. In conclusion, the greater risk of CAD in subjects with phenotype B may result, in part, from increased susceptibility to lipid peroxidative modification of LDL that is depleted in lipid contents, especially FC content per LDL particle. |
Donald Trump's plan to "make America great again" may include getting you to fork over a whole lot more money for your next iPhone.
After all, that would be the logical progression from the Republican presidential frontrunner's latest bold (crazy?) promise: Getting Apple to start manufacturing its products in the US instead of China.
Porter Gifford/Corbis
"We're going to get Apple to build their damn computers and things in this country instead of in other countries," Trump said in a speech on Monday at Liberty University in Virginia.
Trump's rhetoric is designed to appeal to a base of voters who are struggling to find jobs in the US. Apple, the world's most valuable company with a market capitalization of $534 billion, designs its best-selling iPhone, iPad tablets and Mac computers in the US but relies on partners in China and Chinese factory workers to assemble almost all of them (one model of the Mac is made in the US). But how much would it cost to build those "damn things" in the US? Even a rough calculation of the basic costs shows it's an unfeasible option, leading to an iPhone with a potentially jaw-dropping price tag.
To keep things simple, let's just look at the wages of workers tasked with assembling an iPhone. A worker at Chinese manufacturing giant Foxconn gets paid roughly $400 a month before overtime, according to the New York Times.
Now assume Apple goes the economic route and places a manufacturing plant in Wyoming or Georgia, which happen to have the country's lowest minimum wage at $5.15 an hour. Working eight hours a day, five days a week, a US worker would make $824 a month, or more than double the Chinese worker. If Apple were to employ someone in its home state of California, where the minimum wage is $9 an hour, the monthly pay is $1,400, or more than triple the Foxconn worker.
Now playing: Watch this: Why Donald Trump would make your next iPhone a lot more...
Assume you have a pool of workers skilled enough to handle the task (you don't) and then assume those workers will work for minimum wage (they won't). After awhile, things don't add up.
While there are a number of other factors that go into an iPhone, including the components, shipping, marketing and research and development, doubling the labor costs could significantly hike up the price of an iPhone. The starting price of Apple's marquee iPhone 6S is $650 -- would you be willing to pay for the phone if it was $1,300? Or more?
"Twice as much is conservative," Carolina Milanesi, an analyst at Kantar Worldpanel, said about the price hike of an iPhone if it were manufactured in the US.
Apple
At another point, Trump proposed a 35 percent tax on products built outside of the US. So at a minimum, that would mean your next iPhone could start at $877.50.
Apple declined to comment on Trump's comments and didn't want to get into the potential math of bringing phone manufacturing back to the US.
Trump's comments ignore the fact that Apple did invest $100 million to manufacture the Mac Pro in the US. It also buys some of its components from US companies, including Intel's chip for its Mac computers. The company said earlier this month that it believes it has created 1.9 million jobs in the US through the creation of the app economy around the iPhone and its other products.
Even Apple, with its $200 billion-plus stockpile of cash, couldn't afford to build a phone in the US at a reasonable price. Making a more expensive, "Made in the USA" product isn't an option, especially as consumers start to wise up about how much they're spending on their phones. Every day, decent, low-cost alternative phones are cropping up.
So chalk it up to another wild, impossible-to-deliver-upon claim by Trump. But that's part of his appeal, right? |
Tiger, Arizona
Tiger is a former populated place in Pinal County in the U.S. state of Arizona. The town was settled as Schultz around 1881 in what was then the Arizona Territory, then later reestablished as Tiger after World War I.
History
The area that was to become Tiger was first settled in 1881 after Frank Schultz located gold ore in what was to become the Mammoth Mine. The camp that settled around the mine took the name Schultz, and a post office was established under that name on July 12, 1894.
Since water, needed for refinement of ore, was not present near the mine, a mill was established away on the west bank of the San Pedro River, in a town that came to be known as Mammoth, after the mine and the mill. The ore was hauled to the mill by way of mule teams, until just after the start of the 20th century when an aerial tram was completed between the Mammoth Mine and the Mammoth Mill. As the tram's construction neared completion, and the need for the town waned, the Schultz post office was closed on May 1, 1902.
The mines reopened in 1915 due to World War I's increased demand for the molybdenum and vanadium found in the area. When the war was over, the prices fell, and the mines closed again in 1919. Shortly thereafter, the Mammoth Mine property was purchased by Sam Houghton, who renamed both the mine and the town after his college mascot, the Princeton Tiger. When the price of gold increased in 1933, the town again grew in prosperity, and the new Tiger post office opened on March 1, 1939. It was as Tiger that the town reached its peak in the early 1950s. Soon after, the local mines, as well as the town of Tiger, had run their course, and the post office was discontinued on November 26, 1954.
Remnants
After the San Manuel Copper Company acquired the land, they demolished all remaining structures in order to mine the silica on site for its gold content and as flux material for the San Manuel Smelter. However, the material contained too much lead, and the plan proved fruitless. As such, nothing is left of the town of Tiger today, but the filled-in shaft of the Mammoth mine in the middle of town.
Mining
The Tiger or Mammoth mine is a famous mineral locality, especially for matlockite
and wulfenite. In addition, the mineral yedlinite is a hydrated oxychloride of lead and chromium found only at Tiger, and first noted on preexisting specimens in 1967.
The various mines at Mammoth and Tiger had combined recorded production of around:
400,000 oz gold
1,000,000 oz silver
3.5 million lbs copper
75 million lbs lead
50 million lbs zinc
6 million lbs of moly
2.5 million lbs of vanadium
At 1991 prices, this would be worth about $300 million.
Geography
The site is located approximately west of the town of Mammoth at (32.7078463, -110.6823227), at an elevation of . The Mammoth Mine (later the Tiger Mine) is located at .
Demographics
US Census data places the population of the town at 500 in 1940 after its re-founding as Tiger, and 783 in 1950. It was after this final census that the town is said to have reached its peak population of approximately 1,800 residents, before heading into permanent decline and abandonment.
See also
American Old West
Boomtown
History of Arizona
List of ghost towns in Arizona
References
Further reading
Howell, K.K., 1991, A History of the Mines at Tiger, History of Mining in Arizona v. 2. Full text:
External links
Minerals of Tiger, Arizona, photo gallery
Tiger at Ghosttowns.com
Category:Ghost towns in Arizona
Category:Populated places in Pinal County, Arizona
Category:San Pedro Valley
Category:Mining communities in Arizona |
What is Gluten?
Why it makes some people sick and what food scientists are trying to do about it |
Q:
spring-integration-dsl: Make Feed-Flow Work
I'm trying to code a RSS-feed reader with a configured set of RSS-feeds. I thought that a good approach is to solve that by coding a prototype-@Bean and call it with each RSS-feed found in the configuration.
However, I guess that I'm missing a point here as the application launches, but nothing happens. I mean the beans are created as I'd expect, but there is no logging happening in that handle()-method:
@Component
public class HomeServerRunner implements ApplicationRunner {
private static final Logger logger = LoggerFactory.getLogger(HomeServerRunner.class);
@Autowired
private Configuration configuration;
@Autowired
private FeedConfigurator feedConfigurator;
@Override
public void run(ApplicationArguments args) throws Exception {
List<IntegrationFlow> feedFlows = configuration.getRssFeeds()
.entrySet()
.stream()
.peek(entry -> System.out.println(entry.getKey()))
.map(entry -> feedConfigurator.feedFlow(entry.getKey(), entry.getValue()))
.collect(Collectors.toList());
// this one appears in the log-file and looks good
logger.info("Flows: " + feedFlows);
}
}
@Configuration
public class FeedConfigurator {
private static final Logger logger = LoggerFactory.getLogger(FeedConfigurator.class);
@Bean
@Scope(ConfigurableBeanFactory.SCOPE_PROTOTYPE)
public IntegrationFlow feedFlow(String name, FeedConfiguration configuration) {
return IntegrationFlows
.from(Feed
.inboundAdapter(configuration.getSource(), getElementName(name, "adapter"))
.feedFetcher(new HttpClientFeedFetcher()),
spec -> spec.poller(Pollers.fixedRate(configuration.getInterval())))
.channel(MessageChannels.direct(getElementName(name, "in")))
.enrichHeaders(spec -> spec.header("feedSource", configuration))
.channel(getElementName(name, "handle"))
//
// it would be nice if the following would show something:
//
.handle(m -> logger.debug("Payload: " + m.getPayload()))
.get();
}
private String getElementName(String name, String postfix) {
name = "feedChannel" + StringUtils.capitalize(name);
if (!StringUtils.isEmpty(postfix)) {
name += "." + postfix;
}
return name;
}
}
What's missing here? It seems as if I need to "start" the flows somehow.
A:
Prototype beans need to be "used" somewhere - if you don't have a reference to it anywhere, no instance will be created.
Further, you can't put an IntegrationFlow @Bean in that scope - it generates a bunch of beans internally which won't be in that scope.
See the answer to this question and its follow-up for one technique you can use to create multiple adapters with different properties.
Alternatively, the upcoming 1.2 version of the DSL has a mechanism to register flows dynamically.
|
Q:
Change the url of asp.net page from code behind
I am trying to change change the url of current aspx page to the other url on a click of button. Using Request.Url.AbsoluteUri i can get the url but is it possible to modify?. If yes, what actions will it take i mean will it be a new request or a post back.
Please let me know your views.
Thanks,
Mehul makwana
A:
No, it's not possible to modify the URL of the current page from code behind.
When the code runs, a new request or postback is already in progress, so the current page will not exist any more once the new response is complete.
When the page that is currently being created loads in the browser, it's URL will be used instead of the URL of the current page. This URL has already been decided before the request, so you can't change that either.
What you can do is to use the Response.Redirect method to return a redirection page to the browser with the URL that you want. The browser will then make another request to the server to get the page with that URL.
If you want to change the URL of the page to get without using a redirect, doing it in code behind is too late. You have to change what the button does using client script, so that it requests the new URL directly without doing a postback.
A:
You can use Response.Redirect() or Server.Transfer(), although I'd use the former rather than the latter.
|
Q:
OpenCV Undefined symbols for architecture x86_64: lineDescriptor
I built OpenCV from source along with opencv_contrib as well.
For some reason all my attempts to access the classes in lineDescriptor lead to a linker error.
All of these declarations throw a linker error
BinaryDescriptor bsd = BinaryDescriptor();
Ptr<BinaryDescriptor> bsd1 = BinaryDescriptor::createBinaryDescriptor();
Ptr<LSDDetector> lsd1 = LSDDetector::createLSDDetector();
I fully understand what the error means but I don't know why it is thrown in the first place.
I've looked around and tried different solutions; changing the compiler, verified linker flags and linked my libraries, but the error was still getting thrown.
#include <iostream>
#include "opencv2/opencv.hpp"
#include "opencv2/line_descriptor.hpp"
using namespace cv;
using namespace std;
using namespace line_descriptor;
void detectLines(Mat& original, Mat grey)
{
Ptr<LineSegmentDetector> lsd = createLineSegmentDetector(2);
vector<Vec4f> lines;
lsd->detect(grey, lines);
cout << "Detected " << lines.size() << endl;
lsd->drawSegments(original, lines);
// Linker problems galore
// BinaryDescriptor bsd = BinaryDescriptor();
// Ptr<BinaryDescriptor> bsd1 = BinaryDescriptor::createBinaryDescriptor();
// Ptr<LSDDetector> lsd1 = LSDDetector::createLSDDetector();
}
These are my current linker flags
-lopencv_calib3d -lopencv_core -lopencv_features2d -lopencv_flann -lopencv_highgui -lopencv_imgcodecs -lopencv_imgproc -lopencv_ml -lopencv_objdetect -lopencv_photo -lopencv_shape -lopencv_stitching -lopencv_superres -lopencv_ts -lopencv_video -lopencv_videoio -lopencv_videostab
I personally feel like it has something to do with my flags but I am not sure of the flag that corresponds to the lineDescriptor. Any help will be greatly appreciated!
A:
From the README on opencv_contrib's GitHub:
to run, linker flags to contrib modules will need to be added to use them in your code/IDE. For example to use the aruco module, "-lopencv_aruco" flag will be added.
So you need to simply link the contrib module line_descriptor with the flag
-lopencv_line_descriptor
Here's a thorough answer on SO which goes over linking all libraries at once during the install step.
|
Q:
CRC16 and data communications
Hi I have been trying to calculate a CRC for a device I want to write a software interface for. For simplicity I will say X is the device and Y is the hardware controller. I am looking for a nudge in the right direction I am sure I am on the correct track just a little confused on a few points.
When the device is idle it sends the following strings of data every 2 seconds or so that looks like it is counting up in hex: The 2 bytes between the | | is the CRC I assume. (XX) is the varying byte.
X: 96 10 01 E1 (E4) 01 FF 10 17 | F7 EC | 10 06 E1 96 FE
X: 96 10 01 E1 (E6) 01 FF 10 17 | 7F FA | 10 06 E1 96 FE
X: 96 10 01 E1 (E8) 01 FF 10 17 | C7 9B | 10 06 E1 96 FE
X: 96 10 01 E1 (EA) 01 FF 10 17 | 4F 8D | FE 10 06 E1 96 FE
X: 96 10 01 E1 (EC) 01 FF 10 17 | D7 B6 | FE 10 06 E1 96 FE
X: 96 10 01 E1 (EE) 01 FF 10 17 | 5F A0 | FE 10 06 E1 96 FE
Using reveng with reveng -w 16 -s and the above sets of data I get:
width=16 poly=0x1021 init=0x1e69 refin=true refout=true xorout=0x0000 check=0x3da6 name=(none)
When I intercept the a command from the controller I get:
X: 96 10 01 E1 (EE) 01 FF 10 17 | 5F A0 | FE 10 06 E1 96 FE -- Last line before command
Y: E1 10 01 96 (22) 05 01 C0 A8 35 00 10 17 |0B B8| FE 10 06 96 E1 FE
Where (22) is the the modifier |0B B8| is the CRC. How is the 22 derived from the E4? is it another CRC?
When I sent the same command several times I intercepted the following:
Y: E1100196220501C0A8350010170BB8FE100696E1FE
Y: E11001962A0501C0A835001017C1C7FE100696E1FE
Y: E11001962E0501C0909400101753C8FE100696E1FE
Y: E1100196300501809094001017C3EEFE100696E1FE
Y: E1100196360501C090940010170D48FE100696E1FE
Y: E11001962A0501C09094001017B6F7FE100696E1FE
Y: E11001962A0501C09094001017B6F7FE100696E1FE
Using reveng with reveng -w 16 -s and the above sets of data I get:
width=16 poly=0x1021 init=0xd313 refin=true refout=true xorout=0x0000 check=0x295f name=(none)
The polynomial is the same but init and check vary, sorry for the long post but here is the summary of my questions:
1) Is it common for say the device to use the same polynomial but different init and check to the controller?
2) Is the constant counting strings from the device used to offset the variable byte used to calculate the checksum? If so what is this mechanism called and what methods could be used to derive the relationship between the count and the byte?
3) Am I on the right track or have I got lost along the way?
Thanks for taking the time to read this and would really appreciate a kick in the right direction.
A:
Drop the first byte off of your X and Y sequences, and then you'll get for both:
width=16 poly=0x1021 init=0xffff refin=true refout=true xorout=0xffff check=0x906e name="X-25"
To wit:
% reveng -w 16 -s 100196220501C0A8350010170BB8 1001962A0501C0A835001017C1C7 1001962E0501C0909400101753C8 100196300501809094001017C3EE 100196360501C090940010170D48 1001962A0501C09094001017B6F7
width=16 poly=0x1021 init=0xffff refin=true refout=true xorout=0xffff check=0x906e name="X-25"
% reveng -w 16 -s 1001E1E401FF1017F7EC 1001E1E601FF10177FFA 1001E1E801FF1017C79B 1001E1EA01FF10174F8D 1001E1EC01FF1017D7B6 1001E1EE01FF10175FA0
width=16 poly=0x1021 init=0xffff refin=true refout=true xorout=0xffff check=0x906e name="X-25"
|
So… Bobby Lee is walking down the street with a beer can in his hand…
OK, now for real:
I have to note that Bobby Lee seems like a swell guy and I hope he helps Steemit and all of us!
I am just about to go on a field trip with my pupils so not much time for a regular post. I hope you will like this one. Stay tuned for a travel post soon!
I give up on any prize this might get. I hope it goes to someone with lower rep than mine! Go newbies!
Visit the original post by @fibra59 and consider donating to keep the challenge alive!
https://steemit.com/memechallenge/@fibra59/meme-challenge-needs-your-upvote
Camera: Canon SX170 IS
Big thanks to @fibra59 for the contest. Consider upvoting some or all of his posts! My dear friend @felixxx too - the judge this round You can find a lot more beer posts in my blog as well as other posts on various topics. Thank you for all your sharing, caring and upvoting!
Free STEEM by @klye - site that promotes crypto! Buy BTC with Coinbase. You and I both get 10$ for free if you use this link and buy 100$ worth of BTC.
How to make letters so small? Ask me in chatroom! Let’s hang out!
Post using ChainBB by @cryptoctopus. Click and find out how and why! I posted there before and it does not hurt at all!
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Whoa this cropped up rather quickly, thanks for the warm welcome. It was a nice trek its nice to get out to see what others do/pack that you didn't. The Cullinary solutions are always intresting to see what a man will and won't do without. Someone had a steak on a stick. There was also a Wee one hiking barefooted, that was crazy and left zero room to complain about an 11 mile first day hike, although I'm use to about 5-7. It did however make me consider leaving the shoes at the house and braving the digits to the ground critters. Nighttime might be different though there are quite a few ground dwelling spiders in Fl. |
FORT SMITH (AP) — Prosecutors will ask a federal judge to sentence a former Fort Smith bank official who pleaded guilty to embezzlement to at least three years in prison.
Mary Kay Newman, 45, pleaded guilty in March to embezzlement and misapplication of funds by a bank employee. A customer noticed that her bank statements stopped coming and discovered later that Newman had cashed a certificate of deposit worth $300,000.
The Times Record newspaper reported Sunday the U.S. Attorney’s office filed a memorandum seeking a sentence of 41-51 months for Newman, who is free pending her sentencing Aug. 15 before U.S. District Judge P.K. Holmes III.
Newman had worked at the First National Bank of Fort Smith for more than 20 years. A customer, Ruby Pharis, said Newman had power of attorney to pay medical bills but didn’t have the authority to cash checks, redeem the certificates of deposit or use money for her own benefit, according to a plea bargain.
Prosecutors said Newman defrauded multiple banks and Pharis as part of her scheme.
Pharis had CDs worth nearly $560,000 but in 2011, Newman converted them to six cashier’s checks. She kept $160,000 initially, then another $100,000. After cashing a $300,000 certificate of deposit, she kept $85,000, prosecutors said.
Pharis discovered the plot in December 2011 when she stopped receiving statements from First National. She died a week after Newman pleaded guilty.
Newman acknowledged embezzling more than $300,000 but disputes the government’s claim that the amount was almost $560,000.
A First National auditor says nearly all of the money has been recovered.
Assistant U.S. Attorney Kyra Jenner said in a memorandum to the court that Newman still owes a little more than $18,000 in restitution for lost interest, early withdrawal penalties, attorney’s fees and other expenses incurred by Pharis’ estate.
At the sentencing hearing, a representative of Pharis’ estate will testify Pharis never recovered from Newman’s betrayal, which caused her heartbreak and depression that severely diminished her quality of life, according to Jenner’s notice to the court. |
Surgery for congenital heart defects diagnosed with cross-sectional echocardiography.
Between August 1980 and July 1982, 70 children were operated on for congenital heart defects without the use of cardiac catheterization and/or angiocardiography (7.5% of the total of 929 operations). The diagnosis was established by clinical examination, chest x-ray, electrocardiography, and comprehensive cross-sectional echocardiography. The following lesions were repaired: coarctation of the aorta in infancy (n = 28), total anomalous pulmonary venous drainage (n = 6), aortic valvular/subvalvular lesions (n = 11), mitral and tricuspid valve lesions (n = 4), simple transposition of the great arteries (n = 3), vegetations (n = 3), persistent truncus arteriosus (n = 2), and others (n = 13). Three diagnostic errors occurred, and in four children the initial diagnosis was not complete. No child died as a consequence of an error or incomplete diagnosis, and in only one instance was an inappropriate operation carried out (abdominal coarctation of the aorta). We conclude that operation on selected patients can be safely performed on the basis of noninvasive investigation. |
Q:
Converting string representation of JavaScript array to object
Is there some javascript function that can take a string already formatted as an array, and casts it as an array?
var some_string = "[1,2,3,4]";
var some_array = castAsArray(some_string);
some_array.length // Returns 4.
A:
What you're looking for is JSON.parse(). It'll take any string that represents a valid JavaScript object in JSON (JavaScript Object Notation), and convert it to an object.
var some_string = "[1,2,3,4]";
var some_array = JSON.parse(some_string);
some_array.length // Returns 4.
|
Background {#Sec1}
==========
Rice false smut (RFS) caused by the Clavicipitaceous fungus *Ustilaginoidea virens*, also known as *Villosiclava virens*, has recently become one of the most devastating grain diseases in the majority of rice-planting regions worldwide \[[@CR1]\]. RFS was first reported in Tirunelveli district of Tamil Nadu State of India and previously categorized as a minor disease due to its sporadic occurrence \[[@CR2]\]. However, the disease has expanded rapidly in China due to large-scale planting of high-yield rice cultivars and hybrids, heavy application of nitrogenous fertilizer and global warming in the past two decades, and has been found in about one third of rice cultivation areas in severe years \[[@CR1], [@CR3]\]. RFS outbreaks have also been reported in some American, Italian and Southern Asian rice-growing regions \[[@CR4]\]. The disease incidence rate was estimated to be 15.85 % in 2011 across northern India, and the smut balls formed on up to 100 grains per panicle in some fields with high disease severity \[[@CR5]\].
Aside from huge yield losses (up to 40 % in severe years) caused by RFS, *U. virens* produces abundant amounts of mycotoxins that often contaminate rice products and are poisonous to both human and animals \[[@CR6]--[@CR8]\]. Due to the economic importance of the disease, many studies have been performed on the occurrence, pathogen detection, mycotoxin identification, infection lifecycle and chemical control of the disease \[[@CR4], [@CR9]--[@CR12]\]. However, research on screening of rice germplasm for RFS resistance, molecular mechanisms underlying RFS resistance and the pathogenicity of *U. virens* is scarce \[[@CR13]\]. Breeding for rice cultivars with durable resistance to RFS is considered to be one of the most economical, environmentally safe and effective strategies for disease management. A rapid and effective inoculation method has been developed to evaluate rice resistance to *U. virens* and screen resistant germplasm for breeding \[[@CR14], [@CR15]\]. Although no rice variety has yet been identified to have complete or high level of resistance, cultivars do exhibit significant differences in quantitative resistance to *U. virens* \[[@CR16], [@CR17]\]. Much effort has been taken to identify quantitative trait loci (QTL) associated with rice resistance to *U. virens* \[[@CR17]--[@CR19]\]*.* It was reported that the rice cultivar IR28 has a relatively high resistance to RFS, which was controlled by two major and multiple minor resistance genes \[[@CR17]\]. Eight QTLs controlling RFS resistance were also found in the resistant rice variety Lemont \[[@CR19]\]. However, no QTL for RFS resistance in rice has yet been isolated and resistance mechanisms are largely unknown \[[@CR17]\].
In plants, multiple strategies have evolved to recognize pathogens and thus trigger immune systems to defend against pathogen invasion. Recognition of conserved pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) activates PAMP-triggered immunity (PTI) and prevents further colonization on the hosts by microbial pathogens \[[@CR20]\]. Perception of pathogen effectors by intercellular R proteins in plants activates effector-triggered immunity (ETI), which includes rapid and acute cell death responses in plants and restricts multiplication of pathogens \[[@CR21]\]. Furthermore, systemic acquired resistance (SAR) induced by the signal molecule salicylic acid (SA) may confer long-lasting protection against a wide range of pathogens \[[@CR22]\].
Pathogenesis-related (*PR*) genes are often induced in plant defense signaling through the action of plant hormones including salicylic acid, jasmonic acid or ethylene \[[@CR23]\]. In *Arabidopsis*, expression of *PR1*, *PR2* and *PR5* is induced by SA and used as a signature for SAR \[[@CR24]\]. These induced PR proteins possess antimicrobial activities through their hydrolytic, proteinase-inhibitory and membrane-permeabilizing abilities, or serve as defense signals \[[@CR22], [@CR23]\]. As an example, PR-2 proteins function as β-1,3-glucanases that catalyze the hydrolytic cleavage of 1,3-β-D-glucosidic linkages in β-1,3-glucans present in the fungal cell walls. The disrupted cell walls cause cell lysis and death in fungi \[[@CR25]\]. The PR-3 proteins possess endo-chitinase activities and retard fungal growth by the enzymatic hydrolysis of chitin, the predominant constituent of fungal cell walls. The released chitin fragments often act as endogenous triggers to stimulate plant defenses \[[@CR26]\]. Peroxidases (PR-9) are heme-containing glycoproteins that participate in a number of physiological processes, such as biosynthesis of ethylene, suberization and lignification of plant cells in response to pathogen infection, wounding and abiotic stresses \[[@CR27], [@CR28]\].
Comprehensive transcriptome analyses during the interaction of plants and pathogens are commonly used to provide new insights into molecular mechanisms of plant resistance. Transcriptome comparisons between durable resistant and susceptible rice varieties in response to attack by the blast fungus *Magnaporthe oryzae* revealed that chitin-oligosaccharide sensing factors, wall-associated kinases, MAPK cascades and WRKY transcription factors were involved in rice blast resistance \[[@CR29]\]. In addition, gene expression profiling of rice in response to the infection of rice stripe virus (RSV) and small brown plant-hopper (SBPH) revealed by transcriptome analyses indicated that the jasmonate signaling pathway was important in rice resistance to SBPHs \[[@CR30]\]. Transcriptome analyses were also performed for other host-pathogen interaction through RNA-Seq, including wheat and *Fusarium graminearum* \[[@CR31]\], maize and *Sporisorium reilianum* f. sp. *zeae* \[[@CR32]\], cotton and the wilt fungus *Verticillium dahliae* \[[@CR33]\], soybean and *Xanthomonas axonopodis* pv. *glycines* \[[@CR34]\], banana and *F. oxysporum* f. sp. *cubense* \[[@CR35]\]. Many genes were thereby revealed to be involved in resistance-associated signal transduction and defense mechanism in plants. For example, *PR* genes were found to be significantly up-regulated in rice after blast fungus inoculation \[[@CR36]\] and in the maize resistant variety Mo17 in response to *S. reilianum* f. sp. *zeae* \[[@CR32]\].
Recently, RNA-Seq has been used to reveal stage-specific biological processes related to the compatible rice-*U. virens* interaction and expression profiling in rice varieties at the late stage of *U. virens* infection \[[@CR37], [@CR38]\]. It was reported that the primary site of *U. virens* colonization was at the base of the filaments with the inner spikelets becoming infected by hyphae at 24 h post inoculation (hpi) \[[@CR39]\]. Here, we analyzed and compared gene expression profiles of the RFS resistant variety IR28 and susceptible LYP9 after *U. virens* inoculation at early stages (24 hpi and 48 hpi) using transcriptome data. The results indicate that several major gene families might be involved in rice resistance to *U. virens* infection, including receptor-like kinases, *PR* genes, diterpene phytoalexin biosynthesis genes and WRKY transcription factors. These results provide important information to further understand molecular mechanisms of rice reaction and resistance to false smut.
Results {#Sec2}
=======
Disease symptoms of false smut in rice cultivars IR28 and LYP9 {#Sec3}
--------------------------------------------------------------
To confirm RFS resistance or susceptibility of IR28 and LYP9, disease symptoms were observed on the panicles inoculated with different *U. virens* isolates. Infected grains per inoculated spikelet of the cultivars IR28 and LYP9 were counted (Table [1](#Tab1){ref-type="table"} and Additional file [1](#MOESM1){ref-type="media"}: Figure S1). In general, more false smut balls were produced on LYP9 panicles than those on IR28 panicles for each of three isolates. The average number of false smut balls per panicle formed on LYP9 (26.2 ± 2.40) was significantly more than that on IR28 (5.75 ± 0.74) after P1 inoculation. The number of false smut balls produced on both cultivars inoculated with 37--1 and 39--3 was less than that formed on the panicles after P1 inoculation. These data confirm that the cultivar IR28 is much more resistant to *U. virens* than LYP9. The results also indicate that virulence to both rice cultivars of the isolates 37--1 and 39--3 is much less than that of P1. Therefore, the P1 isolate was chosen for inoculation in further expression profiling analyses.Table 1Virulence assays of three *U. virens* isolates (37--1, 39--3 and P1) to the varieties IR28 and LYP9, showing that IR28 is significantly more resistant to *U. virens* infection than LYP9IsolatesInfected panicle rateFalse smut balls per panicle*P*\_valueIR28LYP9IR28LYP9Mock0 % (*n* = 20)0 % (*n* = 20)0037--120 % (*n* = 20)50 % (*n* = 20)0.45 ± 0.231.05 ± 0.300.0352539--390 % (*n* = 20)95 % (*n* = 20)1.05 ± 0.204.80 ± 0.653.34E-05P1100 % (*n* = 20)100 % (*n* = 15)5.75 ± 0.7426.2 ± 2.401.43E-07*n* stands for the number of panicles
RNA-Seq data and aligning to the reference genomes {#Sec4}
--------------------------------------------------
Changes in gene expression level of rice cultivars IR28 and LYP9 at 24 h and 48 h after P1 inoculation were analyzed using RNA-Seq data. A total of 64.4 million clean reads, each of which was 49 bp in length, were generated from eight cDNA libraries (the susceptible cultivar LYP9 and resistant cultivar IR28 at 24 and 48 hpi and four mock-inoculated controls). About 82 % of the clean reads were successfully aligned to the *Oryza sativa* L. spp. *indica* reference genome (Additional file [2](#MOESM2){ref-type="media"}: Table S1). Saturation analysis showed that newly emerging tags were gradually reduced as the total number of sequence tags increased, and the detectable tags approached saturation when the number of sequencing tags reached \~3 million (Additional file [3](#MOESM3){ref-type="media"}: Figure S2). These results indicate that the gene transcript data were reliable, and suitable for further transcriptome analysis.
Expression profiling analyses in resistant and susceptible cultivars in response to *U. virens* inoculation {#Sec5}
-----------------------------------------------------------------------------------------------------------
To uncover the genes that might be involved in RFS resistance, all differentially expressed genes (DEGs) were identified in IR28 and LYP9 at 24 h and 48 h after P1 inoculation as compared with mock-inoculated samples. Venn diagrams were then drawn to show DEGs that were common to both rice genotypes IR28 and LYP9, or specific to either cultivar in response to P1 inoculation (Fig. [1a](#Fig1){ref-type="fig"}). A total of 1072 DEGs were identified in IR28 at 24 hpi, among which 94 were IR28-specific, 205 were common to IR28 and LYP9, and 773 were DEGs only in IR28 but were expressed (non-DEG) in LYP9. In contrast, 1590 DEGs were identified in LYP9 including 51 LYP9-specific and 1334 were DEGs only in LYP9 but expressed in IR28. Meanwhile, 1190 and 1790 DEGs were identified in IR28 and LYP9 at 48 hpi, respectively. Among them, 389 were identified as DEGs common to IR28 and LYP9, and 786 were categorized as DEGs only in IR28 but expressed in LYP9; 75 were LYP9-specific, and 1326 were found as DEGs only in LYP9 but expressed in IR28. Among common DEGs shared by both cultivars at 24 hpi, more genes were up-regulated in IR28 (138) than in LYP9 (88) while fewer DEGs (67) in IR28 were down-regulated than those (117) in LYP9. Among 389 common DEGs at 48 hpi, more (335) were up-regulated compared with down-regulated ones (54) in IR28, while many more genes (311) were suppressed than transcriptionally induced genes (78) in LYP9 at this infection stage (Fig. [1b](#Fig1){ref-type="fig"}). Interestingly, the majority of common DEGs (438) exhibited opposite expression patterns between the resistant and susceptible varieties after P1 inoculation, suggesting that defense responses are distinctively different between the two varieties in response to *U. virens* infection. We speculate that the IR28-specific DEGs and common DEGs which were up-regulated in IR28 and down-regulated in LYP9 might be involving in RFS resistance (Additional file [4](#MOESM4){ref-type="media"}: Table S2).Fig. 1Venn diagrams of all differentially expressed genes in the resistant variety IR28 and susceptible variety LYP9 in the early stages of *U. virens* infection. **a** The expressed genes (expr) and differentially expressed genes (DEGs) in IR28 (R) and LYP9 (S) at 24 hpi and 48 hpi. A total of 205 DEGs were common in IR28 and LYP9 at 24 hpi while 389 DEGs were common at 48 hpi. **b** Up-regulated and down-regulated genes among common DEGs in IR28 and LYP9 at 24 hpi and 48 hpi. Among common DEGs, more DEGs were up-regulated in IR28 while more DEGs were down-regulated in LYP9
Comparison between transcriptomes of IR28 and LYP9 in response to *U. virens* infection by cluster analysis {#Sec6}
-----------------------------------------------------------------------------------------------------------
A total of 3847 DEGs in IR28 and in LYP9 were classified through cluster analysis. The heat map generated by cluster analysis showed that the majority of DEGs have similar expression patterns between two different time points in the same cultivar. The analysis also showed that these DEGs can be categorized into four major groups: genes down-regulated in both IR28 and LYP9 (group I); genes up-regulated in IR28 while down-regulated in LYP9 (group II); genes up-regulated in both IR28 and LYP9 (group III); and genes up-regulated in LYP9 while suppressed in IR28 (group IV) (Fig. [2](#Fig2){ref-type="fig"}). It was speculated that the genes specifically up-regulated in IR28 may play important roles in RFS resistance.Fig. 2The expression pattern of differentially regulated genes in IR28 and LYP9 during the early stages of *U. virens* infection. A total of 3847 genes were identified to be differentially regulated in IR28 and LYP9 in response to *U. virens* at 24 hpi and 48 hpi. Each column represents the Log~2~ fold change in transcript levels in rice at the indicated times, relative to the levels of mock-inoculated samples. The vertical dimension represents the genes that exhibited changes in transcript level (cutoff: \|log~2~\[fold change\]\| ≥ 1 and FDR ≤ 0.001). The colour scale indicates transcript abundance relative to the mock-inoculated panicles: red, increase in relative transcript abundance; blue, decrease in relative transcript abundance
Gene ontology enrichment analysis {#Sec7}
---------------------------------
To investigate functions or biological processes that the differentially regulated genes might be involved in, gene ontology (GO) enrichment analysis was performed to classify up-regulated DEGs (Additional file [5](#MOESM5){ref-type="media"}: Table S3). Within three major GO categories (cellular components, molecular functions and biological processes), 14 common GO terms, 2 IR28-specific and 31 LYP9-specific GO terms were enriched at 24 hpi, while 12 common GO, 1 IR28-specific and 30 LYP9-specific GO terms were enriched at 48 hpi. The gene names in the GO terms enriched specifically by IR28 were searched for items that might be related to RFS resistance. Among them, the GO term "transferase activity" was the only one that was significantly enriched (*P* ≤ 0.05) in IR28 at both inoculation time points. It is most likely that some genes with transferase activity are involved in RFS resistance (Additional file [6](#MOESM6){ref-type="media"}: Figure S3).
Some protein kinases including receptor-like kinases are likely involved in RFS resistance {#Sec8}
------------------------------------------------------------------------------------------
The 142 DEGs in IR28 that were categorized into the GO term "transferase activity" were subject to Pfam domain searches. The results showed that the majority of these DEGs belonged to two gene families encoding protein kinases and glutathione S transferases (Additional file [7](#MOESM7){ref-type="media"}: Table S4). Comparison of gene expression levels between the resistant and susceptible cultivars showed that expression of glutathione S transferases was not significantly different between IR28 and LYP9. In contrast, the differentially-regulated protein kinases exhibited distinctive expression patterns between the two cultivars (Additional file [6](#MOESM6){ref-type="media"}: Figure S3). Twenty-eight and 35 protein kinase genes were induced in IR28 at 24 hpi and 48 hpi, respectively (Fig. [3](#Fig3){ref-type="fig"}). Notably, 11 protein kinase genes were up-regulated at both inoculation time points. All of the induced protein kinase genes in IR28 at 24 hpi except BGIOSGA00144 were transcriptionally suppressed in LYP9. Meanwhile, the up-regulated kinase genes at 48 hpi in IR28 except BGIOSGA010192 and BGIOSGA017269 were also down-regulated in LYP9 (Fig. [3](#Fig3){ref-type="fig"}). These differentially regulated kinases were classified into four groups, B-lectin receptor-like kinases, leucine-rich repeat (LRR) receptor-like kinases, LysM domain-containing receptor kinases and cytoplasmic kinases (Fig. [3](#Fig3){ref-type="fig"}). In particular, a B-lectin receptor kinase gene (BGIOSGA024885) was dramatically induced at both time points. Another B-lectin receptor kinase gene (BGIOSGA034733) and a protein kinase gene (BGIOSGA010552) were found to be greatly up-regulated with 239- and 306-fold expression in IR28 at 24 hpi and 48 hpi, respectively. Divergent patterns of expression in the resistant and susceptible cultivars strongly suggest that these kinase-encoding genes might be essential for rice resistance to RFS in IR28.Fig. 3The protein kinase genes exhibiting opposite expression patterns between IR28 and LYP9 in response to *U. virens* infection. A total of 28 and 35 protein kinase genes were identified to have opposite expression patterns between the two genotypes at 24 hpi (**a**) and 48 hpi (**b**). Bold fonts indicate the protein kinase genes that have a consistent expression pattern between two inoculation time points. Lectin, LRR, LysM and kinase indicate lectin-receptor like kinases, leucine-rich repeat containing receptor-like kinases and lysin motif-containing receptor-like kinases and cytoplasmic kinases, respectively
Expression profiles of pathogenesis-related genes {#Sec9}
-------------------------------------------------
To identify other important genes that might be involved in biosynthetic or signaling pathways critical for RFS resistance in IR28, pathway enrichment analyses were performed using KEGG (Additional file [8](#MOESM8){ref-type="media"}: Table S5). Only a few defense-associated biosynthetic pathways involving diterpenoid, cutin, suberine or wax were enriched in the transcriptome of the resistant cultivar, while more pathways, such as phenylalanine metabolism and secondary metabolite biosynthesis, were significantly enriched in both rice genotypes after inoculation. Comparisons of expression levels of DEGs in these enriched pathways revealed that many genes were up-regulated in the resistant cultivar, while down-regulated in the susceptible LYP9. Among them, multiple gene families encoding PR proteins were greatly up-regulated after P1 inoculation in IR28 (Fig. [4](#Fig4){ref-type="fig"}).Fig. 4Heat maps showing expression patterns of pathogenesis-related and *PAL* genes that were identified to be differentially regulated in IR28 and LYP9. The technical details and the colour scale are the same as those in Fig. [2](#Fig2){ref-type="fig"}
Five β-1,3-glucanase genes belonging to the *PR2* family exhibited significantly different expression patterns between IR28 and LYP9 after P1 inoculation (Additional file [9](#MOESM9){ref-type="media"}: Table S6). In IR28, these genes were transcriptionally induced at 24 hpi and up-regulated even more dramatically at 48 hpi. In contrast, these genes were generally suppressed or not significantly regulated at both time points in LYP9. Extensive transcriptome analyses in both cultivars also showed that three class I (*PR3*), two class II (*PR4*) and 13 class III chitinase genes (*PR8*) were up-regulated at 24 hpi and 48 hpi in IR28, while these genes were generally down-regulated at the two time points in LYP9 (Fig. [4](#Fig4){ref-type="fig"} and Additional file [9](#MOESM9){ref-type="media"}: Table S6). It is interesting to note that genes BGIOSGA035717 to 21, BGIOSGA033526, BGIOSGA033527, BGIOSGA033529 and BGIOSGA033530 were tandemly arranged in a chitinase gene cluster on chromosome 11. In addition, 16 peroxidase genes (*PR9*), 3 thaumatin-like genes (*PR5*) and 5 proteinase inhibitor genes (*PR6*) were identified as being induced in IR28 while most were inhibited in LYP9 after P1 inoculation. Phenylalanine ammonia-lyases (PALs), sometimes classified as PR proteins, are involved in the synthesis of both phytoalexins and lignin, to inhibit pathogens from penetrating cell walls \[[@CR40]\]. Three *PAL* genes (BGIOSGA014703, BGIOSGA018017 and BGIOSGA005998) involved in the phenylalanine metabolism and phenylpropanoid biosynthesis pathways were also up-regulated only in IR28 (Fig. [4](#Fig4){ref-type="fig"} and Additional file [9](#MOESM9){ref-type="media"}: Table S6). Taken together, our finding that many defense-related genes including *PR* and *PAL* genes showed opposite expression patterns between IR28 and LYP9 after *U. virens* inoculation indicates that these genes play essential roles in RFS resistance in IR28.
Diterpene phytoalexin biosynthesis genes {#Sec10}
----------------------------------------
A total of 15 phytoalexins (PAs) have been characterized in rice, including 14 diterpenoid PAs and one flavonoid PA, sakuranetin \[[@CR41], [@CR42]\]. The diterpenoid PAs in rice have been categorized into four distinct types: phytocassanes A to E, oryzalexins A to F, momilactones A and B, and oryzalexin S \[[@CR43]\]. Many essential genes involved in phytoalexin biosynthesis pathways were previously identified (Fig. [5](#Fig5){ref-type="fig"}). Among them, seven genes were significantly up-regulated in IR28 at 24 hpi and 48 hpi, and enriched specifically in DEGs of the resistant cultivar revealed by KEGG pathway enrichment analyses. These genes included *OsCPS*2 (BGIOSGA008469) which is involved in the phytocassane A-E synthesis, *OsCPS4* (BGIOSGA015502), *CYP99A2* (BGIOSGA015504), *CYP99A3* (BGIOSGA015981), and *OsMAS* (BGIOSGA038038) which are involved in the biosynthesis of momilactone A and B, *CYP76M7* (BGIOSGA008466) that catalyzes the biosynthesis of oyzalexin A-F, and *OsKSL11* (BGIOSGA034012) (Fig. [5](#Fig5){ref-type="fig"} and Additional file [10](#MOESM10){ref-type="media"}: Table S7). Up-regulation of these phytoalexin biosynthesis genes in response to *U. virens* indicates that phytoalexins are important components in rice resistance to RFS.Fig. 5The genes involved in phytoalexin biosynthesis were specifically induced in the resistant variety IR28 in response to *U. virens* infection. Known genes that are responsible for the biosynthesis of different types of phytoalexins were shown. Genes in bold were identified to be up-regulated in IR28
Differential expression of WRKY transcription factors {#Sec11}
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WRKY transcription factors are one of the largest protein superfamilies in plants that can regulate various defense processes and play important roles in controlling the transcription of defense-related genes through binding to W-boxes in their promoters, a key *cis*-element in defense-related transcriptional regulation \[[@CR44], [@CR45]\]. Here, we identified 13 WRKY genes that were differentially expressed in IR28 and LYP9 after P1 inoculation (Fig. [6](#Fig6){ref-type="fig"} and Additional file [11](#MOESM11){ref-type="media"}: Table S8). In IR28, five WRKY transcription factors were found to be significantly up-regulated. Among them, *OsWRKY53*, *OsWRKY69* and *OsWRKY71* genes were induced at both time points in IR28 and significantly inhibited at 48 hpi in LYP9, suggesting that these WRKY proteins might function as key positive regulators in the rice defense against the infection by *U. virens* during initial colonization.Fig. 6Heat map for differentially-regulated WRKY genes between IR28 and LYP9. A total of 13 WRKY genes were identified to be differentially regulated in IR28 and LYP9. The technical details and the colour scale are the same as those in Fig. [2](#Fig2){ref-type="fig"}
The *cis*-acting regulatory element analysis {#Sec12}
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Venn diagrams in Additional file [12](#MOESM12){ref-type="media"}: Figure S4 showed up-regulated and down-regulated DEGs with consistent expression patterns at both time points in IR28 and LYP9 in response to P1 inoculation . In IR28, 454 genes exhibited similar expression patterns between 24 hpi and 48 hpi, including 284 induced and 170 suppressed genes. In susceptible LYP9, 67 genes were up-regulated and 136 genes were down-regulated simultaneously at 24 hpi and 48 hpi. The conserved *cis*-elements in the promoter regions of the DEGs with similar expression patterns may provide clues as to how rice plants respond to pathogen infection. Eleven conserved motifs including five core elements of W-box and several DNA binding sites of Dof and Myb transcription factors were identified when comparing the promoter regions of up-regulated genes with those of down-regulated genes in IR28 (Additional file [13](#MOESM13){ref-type="media"}: Table S9). W-boxes, the binding sites of WRKY transcription factors, were significantly more abundant in the 5'-regulatory regions of up-regulated DEGs in IR28. Strikingly, *cis*-element scanning in the PLACE database revealed that a *cis*-element CTAGCTAG, where the RY repeat motif has been found to be essential for seed-specific expression of some storage proteins, was identified to be significantly more enriched in the promoter regions of up-regulated *PR* genes as compared to other *PR* genes in IR28 (Table [2](#Tab2){ref-type="table"}). The *cis*-element is even more abundant in the promoters of the up-regulated chitinase gene cluster. For comparison, the frequency of the *cis*-element in the 52 up-regulated kinase gene promoters is similar to that in other coding genes in the genome. These data suggest that the RY repeat is a *cis*-regulatory motif that is involved in the regulation of defense-related genes.Table 2RY repeat motifs enriched in the 5'-regulatory regions of 47 *PR* genes, particularly in 9 chitinase genes, which were up-regulated in IR28 and suppressed in LYP9Motif_seqPR genes (47)Chitinase (9)PR genes (660)Protein kinases (52)AnnotationMotif_IDNum^a^RAR^b^*P*\_valueNumRAR*P*\_valueNumRAR*P*\_valueNumRAR*P*\_valueCATGCATG316.33878.89E-131111.74593.85E-071742.53368.03E-2461.10890.8205RY repeat motifS000102CATGCAT555.14831.15E-15167.82136.97E-073372.24644.15E-31141.18450.5290RY repeat motifS000105CATGCAY694.41983.05E-15196.35572.10E-064622.10742.07E-33201.15790.5860RY repeat motifS000100CATGCA923.55642.15E-13255.04687.38E-067001.92706.24E-34280.97831.0000RY repeat motifS000264^a^The number of RY repeat motifs^b^RAR = (motif count in a selected promoter set/number of promoters in the set)/(motif count in total promoters/number of total promoters)*P* values were calculated using Fisher's exact testThe total set of sequence-available *PR* genes (660) and that 52 protein kinase genes that were up-regulated in IR28 were used for comparisons
Validation of DEGs by quantitative RT-PCR analyses {#Sec13}
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To validate the DEGs identified by comparative transcriptome analyses, 14 DEGs that might be essential for RFS resistance were selected, and expression of these genes in response to pathogen inoculation was investigated by quantitative real-time RT-PCR (qRT-PCR). The qRT-PCR results showed that most of the tested genes were generally up-regulated at 24 hpi and 48 hpi in the resistant IR28 and down-regulated in the susceptible LYP9 (Fig. [7a](#Fig7){ref-type="fig"} and Additional file [14](#MOESM14){ref-type="media"}: Figure S5). The correlation between RNA-Seq and qRT-PCR data was further validated by comparing the corresponding expression data from both analyses. The log~2~ ratio values from transcriptome analyses were plotted against those from qRT-PCR. A clear correlation between two methods was found at R^2^ = 0.61 (Fig. [7b](#Fig7){ref-type="fig"}). In general, qRT-PCR data confirm expression patterns of these important RFS resistance-related genes revealed by RNA-Seq analyses.Fig. 7Time-course expression analyses and validation of nine selected DEGs using quantitative real time RT-PCR. **a** Quantitative RT-PCR analyses of nine selected DEGs confirmed that these genes were up-regulated in IR28 and generally suppressed in LYP9 at both 24 and 48 hpi. Log~2~ fold change of transcript levels in the inoculated samples with respect to the transcript levels in mock-inoculated rice panicles was shown. Error bars represent standard errors for three replicates of qRT-PCR assays. **b** The linear correlation between RNA-Seq transcriptome profiles and qRT-PCR data. The log~2~ ratio values from transcriptome data were plotted against those of the qRT-PCR results. A correlation coefficient of 0.61 indicates that there is a good linear correlation between RNA-Seq and qRT-PCR data
Comparison of *U. virens* transcriptome in the resistant and susceptible cultivars during infection {#Sec14}
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To compare expression profiles of *U. virens* during infection of the resistant and susceptible cultivars, clean RNA-Seq reads were mapped to the reference genome of *U. virens* \[[@CR13]\] (Additional file [15](#MOESM15){ref-type="media"}: Table S10). Expression profiles of *U. virens* from the infected resistant cultivar IR28 were analyzed and compared with those from LYP9 described previously \[[@CR13]\]. In IR28, 614 and 542 fungal genes were up-regulated significantly at 24 and 48 hpi compared with that from axenic cultures, respectively. Meanwhile, 425 and 247 genes were identified to be suppressed at 24 and 48 hpi, respectively. Interestingly, predicted host-pathogen interaction database (PHI-base) genes \[[@CR46]\] that are probably involved in host-pathogen interactions were found to be significantly enriched in fungal DEGs from both rice genotypes, indicating their potential roles in pathogenicity of *U. virens*.
As shown in Venn diagrams (Additional file [16](#MOESM16){ref-type="media"}: Figure S6), gene expression profiles of *U. virens* in the resistant cultivar IR28 were much different from those in the susceptible LYP9, although 426 (266 up-regulated and 160 down-regulated) and 433 (285 up-regulated and 148 down-regulated) genes have similar expression patterns during infection of the resistant and susceptible cultivars at 24 and 48 hpi, respectively. GO enrichment analyses revealed that *U. virens* DEGs in two cultivars, especially for down-regulated genes, were enriched in different GO terms (Additional file [17](#MOESM17){ref-type="media"}: Table S11). Interestingly, GO terms in biological processes that are related to fungal multiplication and pathogenicity, such as reproductive process, sexual and asexual reproduction, sporulation and cell adhesion, were significantly enriched in down-regulated genes in the resistant IR28, but not in the susceptible LYP9. These results suggest that biological processes required for successful infection of *U. virens* are greatly suppressed in the resistant cultivar.
Discussion {#Sec15}
==========
RFS is a newly emerging fungal disease that causes severe yield loss and toxin contamination in rice grains \[[@CR13]\]. Screening of rice genetic germplasm for RFS resistance revealed that certain cultivars exhibit relatively stable RFS resistance although no resistance gene has been reported so far. However, little is known about molecular mechanisms underlying durable resistance to RFS in rice. RNA-Seq is a recently developed approach that can be used in transcriptome analyses to reveal genome-wide expression profiling and regulation in plant hosts in response to pathogen infection. The technique has several advantages over other methods. First, RNA-Seq, unlike hybridization-based approaches, can detect gene transcripts despite not having the genome sequence of the target species. Second, RNA-Seq has low background noice \[[@CR47]\]. Third, the technology has a higher sensitivity than DNA microarray and can be used to detect a larger dynamic range of expression levels of gene transcripts \[[@CR48], [@CR49]\].
In this study, RNA-Seq was used to identify genes differentially expressed between the cultivar IR28 with durable RFS resistance and susceptible cultivar LYP9 in response to *U. virens* at early infection stages. Comparative transcriptome analyses suggest that some important protein families including receptor-like kinases, WRKY transcription factors, PR proteins, and phytoalexin biosynthetic enzymes play important roles in RFS resistance. A clear correlation between RNA-Seq and qRT-PCR data confirmed expression patterns of the tested genes in response to *U. virens* infection (Fig. [7](#Fig7){ref-type="fig"} and Additional file [16](#MOESM16){ref-type="media"}: Figure S6). Several transcriptome studies on the interaction of rice and *U. virens* have been reported recently \[[@CR37], [@CR38]\]. Different from other transcriptome analyses, we analyzed and compared transcriptome profiles of the resistant and susceptible rice cultivars at the very early stage of infection (24 hpi and 48 hpi). Although gene expression profiles were partially different among those studies, a large proportion of DEGs revealed here were also reported in other transcriptome analyses. For instance, WRKY transcription factors, such as WRKY53 and WRKY69, were induced in different transcriptome studies. Additionally, some genes that had unique responses to *U. virens* infection revealed by Chao et al. \[[@CR37]\], such as LOC_Os07g07870.1 and LOC_Os08g23790.1, had similar expression patterns in this study. Difference in expression patterns of partial DEGs might be due to different infection stages and different rice genotypes. It has been found that many rice genes had opposite regulation patterns between the early and late stages of *U. virens* infection \[[@CR38]\].
Pathogenesis-related proteins may be crucial for RFS resistance {#Sec16}
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Cluster analyses showed that the majority of DEGs (inoculated vs. non-inoculated) in both genotypes were differentially regulated between the two cultivars in response to *U. virens* inoculation (Fig. [2](#Fig2){ref-type="fig"}). Among the group II genes, 47 *PR* genes were identified including members in the *PR*2-6, *PR*8 and *PR*9 families (Fig. [4](#Fig4){ref-type="fig"}). Some PR proteins, such as β-1,3-glucanases, chitinases and proteinases have direct antifungal activities and hydrolyze molecules on the cell walls of fungal pathogens, including glucans, chitins and proteins directly \[[@CR50], [@CR51]\]. Other PR proteins including thaumatin-like proteins and proteinase inhibitors have enzyme inhibitory activities and exert an effect against fungi by inactivating proteinases secreted by pathogens \[[@CR52]\]. In addition, the peroxidase activity of PR-9 also contributes to fungal disease resistance by cross-linking and strengthening plant cell walls \[[@CR53]\].
Consistent with our findings, *PR* genes in rice have been shown to be induced by diverse biotic stresses including infection by the rice blast fungus *M. oryzae* \[[@CR36]\], the bacterial blight pathogen *Xanthomonas oryzae* pv. *oryzae* \[[@CR54]\], the sheath blight fungus *Rhizoctonia solani* \[[@CR55], [@CR56]\], and the rice dwarf virus (RDV) \[[@CR57]\]. These expression data suggest that *PR* genes have important roles in plant defenses against pathogen infection, which has been experimentally verified. Previous studies demonstrated that over-expression of the *PR* genes encoding β-1,3-glucanases, chitinases and thaumatin-like proteins enhanced resistance to *Fusarium* head blight in wheat \[[@CR58]--[@CR61]\].
Preliminary mapping using 157 recombinant inbred lines derived from an inter-subspecies cross of Daguandao/IR28 identified a QTL conferring RFS resistance in the chromosome 11 in IR28 \[[@CR62]\]. The QTL is physically close to the chitinase gene cluster region, out of which, nine chitinase genes were identified to be highly induced after *U. virens* inoculation (Fig. [4](#Fig4){ref-type="fig"} and Additional file [9](#MOESM9){ref-type="media"}: Table S6). Another study showed that a QTL conferring resistance to *R. solani* was also mapped near to the chitinase gene cluster region \[[@CR63]\], suggesting that the chitinase gene cluster might be involved in broad-spectrum and durable disease resistance. Notably, clean RNA-Seq reads of the susceptible cultivar LYP9 were mapped to these chitinase genes and it was found that no gene in the chitinase cluster was absent from the genome of LYP9. Collectively, these differentially regulated *PR* genes in the resistant and susceptible genotypes might play essential roles in rice resistance against *U. virens.*
Diterpene phytoalexins are important for RFS resistance {#Sec17}
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Diterpene phytoalexins, secondary metabolites with a low molecular mass, have anti-microbial activity and play important roles in plant defense responses \[[@CR64], [@CR65]\]. In this study, seven diterpene phytoalexin biosynthesis genes were identified to be significantly up-regulated in the resistant variety and weakly or not induced in the susceptible variety after inoculation (Fig. [5](#Fig5){ref-type="fig"} and Additional file [10](#MOESM10){ref-type="media"}: Table S7). Among them, *OsCPS4, CYP99A2, CYP99A3* and *OsMAS* are responsible for different steps in the biosynthesis of momilactone A and B (Fig. [5](#Fig5){ref-type="fig"}). Knock-down of *OsCPS4* caused lower accumulation levels of momilactones and oryzalexin S and the *cps4* rice mutant is more susceptible to *M. oryzae* infection than the wild-type \[[@CR66]\]. Simultaneous knock-down of *CYP99A2* and *CYP99A3* specifically suppressed elicitor-inducible production of momilactones \[[@CR67]\]. Additionally, *OsCPS2* and *CYP76M7* are physically located on the same gene cluster involved in biosynthesis of the antifungal phytocassanes \[[@CR68]\]. *OsCPS2* expression in the resistant rice cultivar IL7 was up-regulated at 2 d after *M. oryzae* inoculation, resulting in enhanced phytoalexin production \[[@CR40]\]. *OsKSL11* is another gene where expression was elevated in IR28 after *U. virens* infection. OsKSL11 has been found to react with *syn-*CDP and produce *syn*-stemod-13(17)-ene \[[@CR69]\]. These results suggest that production of phytoalexins, in particular momilactones, is highly induced by *U. virens* infection in rice and can play a key role in RFS resistance.
Conserved *cis*-elements are involved in the regulation of defense responses against *U. virens* infection {#Sec18}
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A recent study reported that the *U. virens* regulated genes shared highly conserved *cis*-elements in the promoters including W-boxes, the DNA binding sites of Myb and Dof proteins, which is highly consistent with our *cis*-element enrichment analyses (Additional file [13](#MOESM13){ref-type="media"}: Table S9) \[[@CR37]\]. WRKY transcription factors are vital components in plant defense against pathogens \[[@CR70]\]. WRKY proteins can regulate phytoalexin production and *PR* gene expression through binding to the *cis*-regulatory element W-box. This study revealed that 13 WRKY transcription factors were differentially regulated in both the resistant and susceptible cultivars after *U. virens* infection. In particular, *OsWRKY53*, *OsWRKY69* and *OsWRKY71* were found to be highly up-regulated in IR28 and suppressed in LYP9 (Additional file [11](#MOESM11){ref-type="media"}: Table S8). It was demonstrated that transgenic rice plants over-expressing *OsWRKY53* and *OsWRKY71* exhibited enhanced resistance to blast disease and *X. oryzae* pv. *oryzae* infection \[[@CR71]--[@CR73]\]. Both Dof and Myb proteins are also important transcription factors that are involved in the regulation of plant defenses and biotic stress resistance \[[@CR74], [@CR75]\]. Taken together, these findings imply that some WRKY, Dof and Myb transcription factors, such as OsWRKY53, OsWRKY69 and OsWRKY71, play important roles in rice transcriptome regulation during *U. virens* infection.
Furthermore, the *cis*-regulatory RY repeat motif was found to be significantly more abundant in the promoter regions of these differentially regulated *PR* genes than other *PR* genes, even though the motif is generally enriched in the *PR* gene promoters. These results suggest that the seed-specific *cis*-element may be also involved in the expression regulation of defense-related genes in response to *U. virens* infection.
Defense-oriented reprogramming of protein kinase genes in rice during early infection of *U. virens* {#Sec19}
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Many protein kinase genes were reported to be transcriptionally regulated in host plants upon pathogen infection \[[@CR76]\]. In agreement with this, we found here that 52 protein kinase genes were highly induced in IR28 after *U. virens* infection. Among these, three categories of receptor-like kinases including lectin-, LRR- and LysM-containing transmembrane kinases were identified which are often involved in the recognition of pathogens by sensing pathogen-associated molecular patterns \[[@CR77]\]. Many LysM receptor-like kinases can mediate plant defense responses against fungal pathogens likely through chitin perception \[[@CR78], [@CR79]\]. BGIOSGA016815, a lectin receptor kinase, was also identified to be induced in response to bacterial, parasite, fungal and viral infection in rice \[[@CR80]\]. Other up-regulated kinase genes encode cytoplasmic kinases that function in the phospho-relay and are essential components in defense signaling. For instance, OsMAPKK4 is phosphorylated by upstream MAPKKK7 (BGIOSGA000957) that was induced by *U. virens* infection in IR28, which prompts signal transduction in response to various biotic and abiotic stresses including pathogen, insect, drought, salinity, flood and cold \[[@CR81]\]. Therefore, we speculate that these differential regulated protein kinases may play crucial roles in RFS resistance signaling.
Conclusion {#Sec20}
==========
In the present study, comparison of expression profiles between the resistant cultivar IR28 and the susceptible LYP9 during early stages of *U. virens* infection uncovered a clear difference in the regulation of defense responses against *U. virens* between the two genotypes. A genome-wide view of expression profiles of the resistant rice cultivar in response to *U. virens* infection promotes understanding of molecular mechanisms underlying RFS resistance. A specific set of protein kinases, PR proteins, WRKY transcription factors, and secondary metabolites including phytoalexins were found to be crucial for RFS resistance. Transgenic rice plants over-expressing some of the identified genes are being developed to confirm their biological functions in RFS resistance. The information revealed by transcriptome analyses will also facilitate the isolation of QTLs associated with resistance to *U. virens* in rice.
Methods {#Sec21}
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Rice materials and fungal inoculation {#Sec22}
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*Oryza sativa* L. spp. *indica* cultivars IR28 (resistant to RFS) and LYP9 (highly susceptible but high-yielding) were grown at the experiment station of Jiangsu Academy of Agricultural Sciences in Nanjing, Jiangsu, China. *U. virens* 37--1 and 39--3 were monospore isolates from samples collected at paddy fields in Jiangsu Province, China, and the P1 isolate originating from Kansas, USA was courtesy of Professor Jinrong Xu, Purdue University. Rice panicles were inoculated with a mixture of conidial and hyphal fragments as described with minor modifications \[[@CR82]\]. Briefly, the *U. virens* isolates were cultured in potato sucrose broth (PSB, fresh potato extract and 2 % sucrose) on an incubator shaker at 120 rpm and 28 °C for a week. The panicles of rice plants at the booting stage were inoculated with conidial suspensions (2 × 10^5^ conidia ml^−1^) at 5 to 7 days before earing. Rice panicles injected with PSB were used as mock controls. The pathogen- or mock-inoculated panicles were harvested at 24 and 48 hpi, immediately frozen in liquid nitrogen, and then kept at −70 °C for RNA isolation. Some inoculated rice plants were grown further for disease symptom observations three weeks after inoculation.
Preparation of cDNA libraries for RNA-Seq {#Sec23}
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Total RNA was isolated using RNApure® total RNA rapid extraction kit according to the manufacturer's instruction (Aidlab Biotechnologies, Beijing). The yield and purity of RNA were evaluated by measurement of absorbance at 260 and 280 nm. RNA integrity was confirmed using Agilent 2100 Bioanalyzer (Agilent Technologies) with a minimum RNA integrated number (RIN) value of 7.0. Total RNA isolated from the samples of three biological replicates at each time point (24 and 48 hpi) was combined for RNA-Seq. Poly(A) + mRNA was enriched from total RNA using oligo(dT) magnetic beads and used for library construction. RNA-Seq libraries were constructed following the standard pipeline at Beijing Genomics Institute (BGI) in Shenzhen, China. Reads of 49 bp length were generated with the Illumina HiSeq™ 2000 sequencing platform at BGI.
Mapping reads to the reference genome and annotated genes {#Sec24}
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Raw reads were downloaded from BGI in FASTQ format. The reference genome of *Oryza sativa* L. ssp. *indica* 93*--*11 and associated gene information were downloaded from Gramene (<http://www.gramene.org/>) and the Rice Genome Annotation Project (<http://rice.plantbiology.msu.edu>). The genome of *U. virens* isolate UV-8b was used as the reference for analyzing *U. virens* transcriptome \[[@CR13]\]. Prior to mapping reads to the reference databases, all reads were filtered to remove adaptor sequences, and eliminate reads in which the percentage of unknown bases (N) was greater than 10 %, or the percentage of the low quality bases (bases with Phred quality score ≤ 5) in a read exceeded 50 %. The resultant clean reads were mapped to rice and *U. virens* genomes using SOAP2 \[[@CR83]\]. No more than two mismatches were allowed in the alignment for each read.
Analysis and screening of differentially expressed genes {#Sec25}
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RPKM (Reads per kb per Million reads) was used to represent the gene expression level of rice and *U. virens* transcripts \[[@CR48]\]. Differentially expressed genes (DEGs) in rice cultivars were identified through comparing gene expression levels between *U. virens-* and mock-inoculated panicles with the criteria of the absolute log~2~ ratio value ≥ 1 and false discovery rate (FDR) ≤ 0.001 \[[@CR84]\]. DEGs of *U. virens* were identified by comparing the gene expression level during infection with that in axenic cultures using the same criteria. The DEGs of rice and *U. virens* were then subjected to GO enrichment analyses using the WEGO (Web Gene Ontology Annotation Plotting) program, respectively \[[@CR85]\]. *P*-values were calculated by comparing the observed frequency of an annotation term with the frequency expected in respective genome using Pearson's chi-squared test. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify significantly enriched metabolic pathways or signal transduction pathways in rice DEGs comparing with the whole genome background. Pathways with Q-values ≤ 0.05 are considered significantly enriched in DEGs as assessed with the PAICE program \[[@CR86]\]. Hierarchical clustering of all DEGs was performed using cluster 3.0 \[[@CR87]\].
Conserved *cis*-elements searches {#Sec26}
---------------------------------
The 1.5 kb sequences upstream of the start codon of selected genes in rice were scanned for putative conserved *cis*-elements identical with or similar to the motifs in PLACE database \[[@CR88]\]. The enriched motifs in the up-regulated genes were determined by comparing frequency in the up-regulated genes with that in down-regulated genes (chi-square test, *P* \< 0.01). Alternatively, Relative Appearance Ratio (RAR) of motifs was calculated using the formula (motif counts in a selected promoter set/number of promoters in the set)/(motif counts in total promoters/number of total promoters) \[[@CR89]\]. *P* values comparing motif frequency in selected gene sets with that in total genes were calculated using Fisher's exact test. The conserved motifs were identified with the criteria of RAR ≥ 3 and *P* value \< 0.01.
Validation of RNA-Seq data by quantitative real-time RT-PCR {#Sec27}
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Some differentially regulated genes identified through RNA-Seq were validated by qRT-PCR. The primer sets used for qRT-PCR were designed based on exon sequences of the selected genes using the online program, oligo analyzer (<http://www.idtdna.com>) and the specificity of PCR primers was evaluated by blasting primer sequences against the NCBI database (Additional file [18](#MOESM18){ref-type="media"}: Table S12). Total RNA (2 μg) was used for cDNA synthesis with MLV reverse transcriptase (Invitrogen). PCR was performed in 20 μl of reaction mix containing 0.4 μl cDNA, 10 μl SYBR Premix Ex Taq™ (Takara, Dalian), 0.4 μl ROX reference dye, and 0.4 μl of each primer (10 μM) using an ABI Prism 7000 System (Applied Biosystems, Foster City, CA). Three replicates for each biological replicate were performed with similar results. Relative gene expression was calculated using the 2^-▵▵Ct^ method \[[@CR90]\].
Additional files {#Sec28}
================
Additional file 1: Figure S1.Disease symptoms observed on LYP9 and IR28 panicles three weeks after *U. virens* P1 inoculation. False smut balls formed on a representative LYP9 panicle (**A**) and on a representative IR28 panicle (**B**) after P1 inoculation. The number of false smut balls formed on LYP9 panicles was significantly more than that on IR28 panicles. (TIFF 21 kb)Additional file 2: Table S1.Statistics of the total RNA-Seq reads and reads mapped to the *Oryza sativa* L. ssp. *indica* reference genome at different inoculation time points in IR28 and LYP9. (XLSX 21 kb)Additional file 3: Figure S2.Saturation analyses of RNA-Seq data. The number of detected genes approached saturation when RNA sequencing reads reached \~3 million for each library. (TIFF 21 kb)Additional file 4: Table S2.The differentially expressed genes that exhibited opposite expression patterns between IR28 and LYP9 at 24 hpi and 48 hpi. (XLSX 21 kb)Additional file 5: Table S3.The enriched GO terms for the genes that were up-regulated in IR28 and LYP9 at 24 hpi and 48 hpi. (XLSX 21 kb)Additional file 6: Figure S3.The expression pattern of DEGs in the enriched GO term "transferase activity" (GO: 0016740) specific to IR28. A total of 142 transferase genes were identified to be differentially regulated in IR28 in response to *U. virens* infection at 24 and 48 hpi. Black dots indicate the transferase genes encoding protein kinases. Each column represents the Log~2~ fold change in gene transcript levels in rice at the indicated times, relative to the levels of mock-inoculated samples. The vertical dimension represents the transferase genes that exhibited changes in transcript level (cutoff: \|log~2~\[fold change\]\| ≥ 1 and FDR ≤ 0.001). The colour scale indicates transcript abundance relative to the mock-inoculated panicles: red, increase in relative transcript abundance; blue, decrease in relative transcript abundance. (TIFF 21 kb)Additional file 7: Table S4.Protein kinase genes in the GO term "transferase activity" (GO: 0016740) that were induced by *U. virens* in IR28 and repressed in LYP9. (XLSX 21 kb)Additional file 8: Table S5.The enriched signaling and biosynthetic pathways of DEGs in IR28 and LYP9 at 24 hpi and 48 hpi revealed by KEGG enrichment analysis. (XLSX 21 kb)Additional file 9: Table S6.Differentially expressed *PR* genes between IR28 and LYP9 at 24 h and 48 h after *U. virens* infection. (XLSX 21 kb)Additional file 10: Table S7.Differential expression of phytoalexin synthesis genes in the susceptible variety LYP9 and the resistant variety IR28 at the early infection stages of *U. virens* (24 hpi and 48 hpi). (XLSX 21 kb)Additional file 11: Table S8.Differentially expressed WRKY genes in IR28 and LYP9 at 24 h and 48 h after *U. virens* infection. (XLSX 22 kb)Additional file 12: Figure S4.Venn diagrams showing the number of genes that exhibited similar expression patterns between 24 hpi and 48 hpi in IR28 (R) and in LYP9 (S). (TIFF 21 kb)Additional file 13: Table S9.The conserved motifs that were more abundant in the 5'-regulatory regions of up-regulated genes compared with down-regulated genes in IR28. (XLSX 21 kb)Additional file 14: Figure S5.Quantitative real-time RT-PCR analyses of six more differentially regulated genes in rice. The results showed that these genes were generally up-regulated in IR28 and suppressed in LYP9 at both 24 and 48 hpi, which is well consistent with transcriptome data. Log~2~ fold change of transcript levels in the inoculated samples with respect to the transcript levels in mock-inoculated rice panicles was shown. Error bars represent standard errors for three replicates of qRT-PCR assays. (TIFF 21 kb)Additional file 15: Table S10.Statistics of RNA-Seq reads mapped to the reference genome of *U. virens* at 24 h and 48 h after inoculation in IR28 and LYP9. (XLSX 21 kb)Additional file 16: Figure S6.Venn diagrams of differentially regulated *U. virens* genes in IR28 (R) and in LYP9 (S) at 24 hpi and 48 hpi. The majority of up-regulated (**A**) and down-regulated genes (**B**) exhibited different expression patterns in IR28 (R) and LYP9 (S) although a large proportion of DEGs shared the similar regulation patterns. (TIFF 21 kb)Additional file 17: Table S11.The enriched GO terms under three different categories for up-regulated and down-regulated *U. virens* genes in IR28 and LYP9. (XLSX 21 kb)Additional file 18: Table S12.The primers designed for quantitative real-time RT-PCR. For each gene, the forward (F) and reverse (R) primer sequences were listed. (XLSX 21 kb)
Yanqing Han and Kang Zhang contributed equally to this work.
**Competing interests**
The authors declare that they have no competing interests.
**Authors' contributions**
YH and KZ contributed equally to this research. WS and YH conceived and designed the experiments. YH, KZ, JY, NZ, AF and YZ conducted the experiments and analyzed data. YL, ZC and TH contributed reagents and materials. YH, TH and WS wrote the manuscript. All authors have read and approved the final manuscript.
We thank Jinrong Xu at Purdue University for providing the *U. virens* isolate P1. The work is supported by the transgenic crop project 2012ZX08009003-003, National Natural Science Foundation of China grant 31471728, the National High Technology Research and Development program of China 2012AA100703, and the 111 project B13006 to W. S.
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public TextItem(string text)
{
Content = text;
}
public ContentItemType Type => ContentItemType.Text;
public object ToJson()
{
return Content;
}
public string GetText()
{
return Content;
}
}
}
|
; Scheme 9 from Empty Space, Function Library
; By Nils M Holm, 2009
; Placed in the Public Domain
;
; (pretty-print object <option> ...) ==> unspecific
; (pp object <option> ...) ==> unspecific
; (pp-file string <option> ...) ==> unspecific
; (pp-loop <option> ...) ==> unspecific
; (pp-string string <option> ...) ==> list
; (pp-string list <option> ...) ==> list
;
; (load-from-library "pretty-print.scm")
;
; Pretty-print Scheme objects, programs, or files. PRETTY-PRINT attempts
; to figure out whether OBJECT is a valid Scheme program. If so, it prints
; it as code and otherwise it prints it as data. The automatic detection
; can be disabled by passing an option to these procedures (see below).
;
; PP is just a less verbose name for PRETTY-PRINT.
;
; PP-FILE pretty-prints all objects in the file STRING.
;
; PP-LOOP pretty-prints all objects read from (current-input-stream).
;
; PP-STRING pretty-prints the form in STRING and returns a list
; containing one pretty-printed line per member (as strings).
; When a LIST is passed to PP-STRING instead of a STRING, it
; will assume it is a list of separate lines and append them with
; #\NEWLINEs in between.
;
; Any of these procedures accept the following <option>s that may be
; passed to it after the object to print:
;
; 'CODE Print OBJECT as if it was a Scheme program.
; 'DATA Print OBJECT as if it was a Scheme object.
; 'SIMPLE Attempt to keep some special forms in a single line,
; if they fit in one (IF, AND, OR, BEGIN, LAMBDA).
; 'MARGIN: n Set the right margin to N. The printer will attempt
; not to write any output beyond that margin. The default
; margin is at column 72.
; 'INDENT: n Indent all lines except for the first one by the given
; number of blanks (for embedding in editors).
; 'OUTPUT-PORT: p
; Send all output to the specified output port instead
; of (current-output-port).
;
; NOTE: This program handles only a subset of R4RS Scheme correctly
; and removes all comments from its input program. Caveat utilitor.
;
; Example: (pp-string '("(let ((a 1) (b 2))"
; "(cons a b))"))
; ==> ("(let ((a 1)"
; " (b 2))"
; " (cons a b))")
(load-from-library "programp.scm")
(load-from-library "for-all.scm")
(load-from-library "read-from-string.scm")
(load-from-library "write-to-string.scm")
(load-from-library "string-unsplit.scm")
; If your Scheme does not support FLUID-LET or DEFINE-MACRO,
; there is an alternative implementation using SYNTAX-RULES in
; lib/fluid-let-sr.scm.
(load-from-library "fluid-let.scm")
(define *Input* #f)
(define *Output* #f)
(define *Convert-unreadable* #f)
(define (read-form)
(if *Input*
(let ((form (if (null? *Input*)
'()
(read-from-string *Input*))))
(cond ((pair? form)
(set! *Input* (cdr form))
(car form))
((null? form)
#f)
(else
(set! *Output* (list #f form *Input*))
(set! *Input* '())
#f)))
(read)))
(define (end-of-input? x)
(if *Input*
(not x)
(eof-object? x)))
(define pretty-print
(let ((read-form read-form)
(end-of-input? end-of-input?))
(lambda (form . options)
(define *Margin* 72)
(define *Offset* 0)
(define *Column* 0)
(define *Output-port* (current-output-port))
(define *Print-as-code* #f)
(define *Print-as-data* #f)
(define *Print-newline* #f)
(define *Really-print* #t)
(define *Max-Column* 0)
(define *Simple* #f)
(define LP "(")
(define RP ")")
(define SP " ")
(define (pr-char c)
(if *Output*
(if (char=? #\newline c)
(begin (set-car! *Output*
(list->string (reverse! (car *Output*))))
(set! *Output* (cons '() *Output*)))
(set-car! *Output* (cons c (car *Output*))))
(write-char c *Output-port*)))
(define (pr-form x)
(if *Output*
(for-each pr-char
(string->list (display-to-string x)))
(display x *Output-port*)))
(define (atom? x)
(and (not (pair? x))
(not (null? x))
(not (vector? x))))
(define (object-length x)
(string-length (write-to-string x)))
(define (exceeds-margin? x . opt-lead)
(let ((lead (if (null? opt-lead)
0
(car opt-lead))))
(>= (+ *Column* lead (string-length (write-to-string x)))
*Margin*)))
(define (spaces n)
(and *Really-print*
(or (zero? n)
(begin (pr-char #\space)
(spaces (- n 1))))))
(define (linefeed)
(if *Really-print*
(pr-char #\newline))
(set! *Max-Column* *Margin*)
(spaces *Offset*)
(set! *Column* *Offset*))
(define (pr s)
(if *Really-print*
(pr-form s))
(set! *Column* (+ *Column* (string-length s)))
(if (> *Column* *Max-Column*)
(set! *Max-Column* *Column*)))
(define (really-simple? x)
(or (not (list? x))
(not (pair? x))
(not (memq (car x) '(lambda cond case do if and or let
let* letrec fluid-let begin)))))
(define (pp-simple-form x)
(if (or (not (list? x))
*Simple*
(for-all really-simple? x))
(let* ((s (write-to-string x))
(k (string-length s)))
(if (and (> (+ *Column* k) *Margin*)
(> *Column* *Offset*))
(linefeed))
(pr s))
(pp-inline-app x)))
(define (pp-datum x)
(cond ((or (null? x)
(symbol? x)
(boolean? x)
(char? x)
(number? x)
(string? x))
(pp-simple-form x))
((vector? x)
(if *Really-print*
(pr-char #\#))
(fluid-let ((*Offset* (+ 1 *Offset*)))
(pp-pair(vector->list x))))
((pair? x)
(pp-pair x))
((procedure? x)
(pp-simple-form (string->symbol "#<procedure>")))
(else
(error "pretty-print: unknown type" x))))
(define (pp-pair x)
(pr LP)
(fluid-let ((*Offset* (+ 1 *Offset*)))
(let pp-members ((x x)
(s #f))
(cond ((pair? x)
(if s
(if (or (pair? (car x))
(vector? (car x)))
(linefeed)
(pr SP)))
(pp-datum (car x))
(pp-members (cdr x) #t))
((not (null? x))
(pr " . ")
(pp-datum x)))))
(pr RP))
(define (pp-quote x q)
(pr q)
(fluid-let ((*Offset* (+ *Offset* (string-length q))))
(if (program? (cadr x))
(pp-form (cadr x))
(pp-datum (cadr x)))))
(define (pp-body x)
(cond ((not (null? x))
(pp-form (car x))
(if (not (null? (cdr x)))
(linefeed))
(pp-body (cdr x)))))
(define (pp-lambda x)
(cond ((or (not *Simple*)
(> (length x) 3)
(exceeds-margin? x))
(pr LP)
(pr "lambda ")
(fluid-let ((*Offset* (+ 2 *Offset*)))
(pp-datum (cadr x))
(linefeed)
(pp-body (cddr x))
(pr RP)))
(else
(pp-simple-form x))))
(define (fits-in-margin? formatter x)
(fluid-let ((*Column* *Column*)
(*Offset* *Offset*)
(*Max-Column* 0)
(*Really-print* #f))
(formatter x)
(< *Max-Column* *Margin*)))
(define (pp-inline-app x)
(pr LP)
(pp-simple-form (car x))
(if (not (null? (cdr x)))
(pr SP))
(fluid-let ((*Offset* (+ 2 (object-length (car x)) *Offset*)))
(pp-body (cdr x)))
(pr RP))
(define (pp-indented-app x)
(pr LP)
(fluid-let ((*Offset* (+ 1 *Offset*)))
(pp-form (car x)))
(let ((indent (if (pair? (car x)) 1 2)))
(fluid-let ((*Offset* (+ indent *Offset*)))
(if (not (null? (cdr x)))
(linefeed))
(pp-body (cdr x)))
(pr RP)))
(define (indented-style-preferred? x)
(and (memq x '(call-with-current-continuation
call/cc
call-with-input-file
call-with-output-file
with-input-from-file
with-output-to-file))
#t))
(define (pp-application x)
(cond ((fits-in-margin? pp-simple-form x)
(pp-simple-form x))
((indented-style-preferred? (car x))
(pp-indented-app x))
((fits-in-margin? pp-inline-app x)
(pp-inline-app x))
(else
(pp-indented-app x))))
(define (pp-cond/case what x)
(letrec
((print-clauses
(lambda (c*)
(cond ((not (null? c*))
(pr LP)
(fluid-let ((*Offset* (+ 1 *Offset*)))
(if (eq? what 'cond)
(pp-form (caar c*))
(pp-datum (caar c*))))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(if (and (eq? 'cond what)
(pair? (cdar c*))
(eq? '=> (cadar c*)))
(fluid-let ((*Offset* (+ 3 *Offset*)))
(pr "=> ")
(pp-body (cddar c*)))
(pp-body (cdar c*))))
(pr RP)
(if (not (null? (cdr c*)))
(linefeed))
(print-clauses (cdr c*)))))))
(pr LP)
(pr (symbol->string what))
(pr SP)
(fluid-let ((*Offset* (+ (if (eq? what 'cond) 6 2)
*Offset*)))
(if (eq? what 'case)
(begin (pp-simple-form (cadr x))
(linefeed)))
(let ((c* (if (eq? what 'cond)
(cdr x)
(cddr x))))
(print-clauses c*)
(pr RP)))))
(define (pp-do x)
(letrec
((print-inits
(lambda (x first)
(cond ((null? x)
#f)
(first
(pp-simple-form (car x))
(print-inits (cdr x) #f))
(else
(linefeed)
(pp-simple-form (car x))
(print-inits (cdr x) #f)))))
(init-part cadr)
(test-part caddr)
(do-body cdddr))
(pr LP)
(pr "do ")
(pr LP)
(fluid-let ((*Offset* (+ 5 *Offset*)))
(print-inits (init-part x) #t))
(fluid-let ((*Offset* (+ 4 *Offset*)))
(linefeed)
(pr LP)
(pp-form (car (test-part x)))
(if (not (null? (cdr (test-part x))))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body (cdr (test-part x)))))
(pr RP))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body (do-body x)))
(pr RP)))
(define (pp-just-indent what x)
(if (and *Simple*
(fits-in-margin? pp-simple-form x))
(pp-simple-form x)
(begin (pr LP)
(pr what)
(if (not (null? (cdr x)))
(pr SP))
(fluid-let ((*Offset* (+ 2 (string-length what) *Offset*)))
(let print ((x (cdr x)))
(cond ((not (null? x))
(pp-form (car x))
(if (not (null? (cdr x)))
(linefeed))
(print (cdr x)))))
(pr RP)))))
(define (pp-let-bindings b* rec)
(pr LP)
(fluid-let ((*Offset* (+ 1 *Offset*)))
(let pp-bindings ((b* b*))
(cond ((not (null? b*))
(pr LP)
(pp-simple-form (caar b*))
(cond ((and rec (pair? (cadar b*)))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-form (cadar b*))))
(else
(pr SP)
(fluid-let ((*Offset* (+ 2
(object-length (caar b*))
*Offset*)))
(pp-form (cadar b*)))))
(pr RP)
(if (not (null? (cdr b*)))
(linefeed))
(pp-bindings (cdr b*))))))
(pr RP))
(define (pp-let x)
(pr LP)
(pr "let ")
(let* ((named? (symbol? (cadr x)))
(bind (if named? (caddr x) (cadr x)))
(body (if named? (cdddr x) (cddr x)))
(name-len (if named?
(+ 1 (object-length (cadr x)))
0)))
(fluid-let ((*Offset* (+ 5 name-len *Offset*)))
(if named?
(begin (pp-simple-form (cadr x))
(pr SP)))
(pp-let-bindings bind #f))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body body))
(pr RP)))
(define (pp-let* x)
(pr LP)
(pr "let* ")
(fluid-let ((*Offset* (+ 6 *Offset*)))
(pp-let-bindings (cadr x) #f))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body (cddr x)))
(pr RP))
(define (pp-letrec x)
(pr LP)
(pr "letrec ")
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-let-bindings (cadr x) #t))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body (cddr x)))
(pr RP))
(define (pp-fluid-let x)
(pr LP)
(pr "fluid-let ")
(fluid-let ((*Offset* (+ 11 *Offset*)))
(pp-let-bindings (cadr x) #f))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-body (cddr x)))
(pr RP))
(define (pp-define-etc what x)
(pr LP)
(pr what)
(pr SP)
(pp-simple-form (cadr x))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(if (or (and (pair? (caddr x))
(eq? 'lambda (caaddr x)))
(pair? (cadr x))
(exceeds-margin? x))
(linefeed)
(pr SP))
(pp-body (cddr x)))
(pr RP))
(define (pp-syntax-rules x)
(letrec
((pp-rules
(lambda (r*)
(cond ((not (null? r*))
(pr LP)
(pp-datum (caar r*))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-form (cadar r*))
(pr RP))
(if (not (null? (cdr r*)))
(linefeed))
(pp-rules (cdr r*)))))))
(pr LP)
(pr "syntax-rules ")
(fluid-let ((*Offset* (+ 14 *Offset*)))
(pp-datum (cadr x)))
(fluid-let ((*Offset* (+ 2 *Offset*)))
(linefeed)
(pp-rules (cddr x))
(pr RP))))
(define (pp-form x)
(if (not (pair? x))
(pp-datum x)
(case (car x)
((quote) (pp-quote x "'"))
((quasiquote) (pp-quote x "`"))
((unquote) (pp-quote x ","))
((unquote-splicing) (pp-quote x ",@"))
((lambda) (pp-lambda x))
((cond) (pp-cond/case 'cond x))
((case) (pp-cond/case 'case x))
((do) (pp-do x))
((if) (pp-just-indent "if" x))
((and) (pp-just-indent "and" x))
((or) (pp-just-indent "or" x))
((let) (pp-let x))
((let*) (pp-let* x))
((letrec) (pp-letrec x))
((fluid-let) (pp-fluid-let x)) ; S9fES ext.
((begin) (pp-just-indent "begin" x))
((define) (pp-define-etc "define" x))
((define-syntax) (pp-define-etc "define-syntax" x))
((syntax-rules) (pp-syntax-rules x))
(else (pp-application x)))))
(set! *Column* 0)
(set! *Offset* 0)
(set! *Margin* 72)
(set! *Print-as-code* #f)
(set! *Print-as-data* #f)
(set! *Print-newline* #f)
(set! *Simple* #f)
(set! *Convert-unreadable* #f)
(let loop ((options options))
(cond ((null? options)
(cond ((and *Print-as-code*
*Print-as-data*)
(error (string-append
"pretty-print: please specify either the"
" CODE or DATA option, but not both")))
(*Print-newline*)
(*Print-as-code*
(pp-form form))
(*Print-as-data*
(pp-datum form))
((program? form)
(pp-form form))
(else
(pp-datum form))))
((eq? 'code (car options))
(set! *Print-as-code* #t)
(loop (cdr options)))
((eq? 'data (car options))
(set! *Print-as-data* #t)
(loop (cdr options)))
((eq? 'linefeed (car options))
(set! *Print-newline* #t)
(loop (cdr options)))
((eq? 'simple (car options))
(set! *Simple* #t)
(loop (cdr options)))
((eq? 'indent: (car options))
(if (null? (cdr options))
(error "pretty-print: missing argument to INDENT:"))
(if (not (number? (cadr options)))
(error "pretty-print: non-numeric argument to INDENT:"))
(set! *Offset* (cadr options))
(loop (cddr options)))
((eq? 'margin: (car options))
(if (null? (cdr options))
(error "pretty-print: missing argument to MARGIN:"))
(if (not (number? (cadr options)))
(error "pretty-print: non-numeric argument to MARGIN:"))
(set! *Margin* (cadr options))
(loop (cddr options)))
((eq? 'output-port: (car options))
(if (null? (cdr options))
(error "pretty-print: missing argument to OUTPUT-PORT:"))
(if (not (output-port? (cadr options)))
(error "pretty-print: expected port in OUTPUT-PORT:"))
(set! *Output-port* (cadr options))
(loop (cddr options)))
(else
(error "pretty-print: unknown option"
(car options)))))
(linefeed))))
(define pp pretty-print)
(define (pp-loop . options)
(let pp* ((x (read-form)))
(cond ((not (end-of-input? x))
(apply pp x options)
(let ((next (read-form)))
(if (not (end-of-input? next))
(pp #f 'linefeed))
(pp* next))))))
(define (pp-file file . options)
(with-input-from-file
file
(lambda ()
(apply pp-loop options))))
(define (pp-string str* . options)
(set! *Input* (if (string? str*)
str*
(string-unsplit #\newline str*)))
(set! *Output* (list '()))
(apply pp-loop options)
(reverse! (cdr *Output*)))
|
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