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11,091,779 | https://en.wikipedia.org/wiki/Selenium-79 | Selenium-79 is a radioisotope of selenium present in spent nuclear fuel and the wastes resulting from reprocessing this fuel. It is one of only seven long-lived fission products. Its fission yield is low (about 0.04%), as it is near the lower end of the mass range for fission products. Its half-life has been variously reported as 650,000 years, 65,000 years, 1.13 million years, 480,000 years, 295,000 years, 377,000 years and most recently with best current precision, 327,000 years.
79Se decays to 79Br by emitting a beta particle with no attendant gamma radiation (i.e., 100% β decay). This complicates its detection and liquid scintillation counting (LSC) is required for measuring it in environmental samples. The low specific activity () and relatively low energy (151 keV) of its beta particles have been said to limit the radioactive hazards of this isotope.
Performance assessment calculations for the Belgian deep geological repository estimated 79Se may be the major contributor to activity release in terms of becquerels (decays per second), "attributable partly to the uncertainties about its migration behaviour in the Boom Clay and partly to its conversion factor in the biosphere." (p. 169). However, "calculations for the Belgian safety assessments use a half-life of 65 000 years" (p. 177), much less than the currently estimated half-life, and "the migration parameters ... have been estimated very cautiously for 79Se." (p. 179)
Neutron absorption cross sections for 79Se have been estimated at 50 barns for thermal neutrons and 60.9 barns for resonance integral.
Selenium-80 and selenium-82 have higher fission yields, about 20 times the yield of 79Se in the case of uranium-235, 6 times in the case of plutonium-239 or uranium-233, and 14 times in the case of plutonium-241.
Mobility of selenium in the environment
Due to redox-disequilibrium, selenium could be very reluctant to abiotic chemical reduction and would be released from the waste (spent fuel or vitrified waste) as selenate (), a soluble Se(VI) species, not sorbed onto clay minerals. Without solubility limit and retardation for aqueous selenium, the dose of 79Se is comparable to that of 129I. Moreover, selenium is an essential micronutrient as it is present in the catalytic centers in the glutathione peroxidase, an enzyme needed by many organisms for the protection of their cell membrane against oxidative stress damages; therefore, radioactive 79Se can be easily bioconcentrated in the food web. In the presence of nitrate () released in deep geological clay formations by bituminized waste issued from the spent fuel dissolution step during their reprocessing, even reduced forms of selenium could be easily oxidised and mobilised.
References
See also
Isotopes of selenium
ANL factsheet
Journal of Analytical Atomic Spectrometry
Fission products
Isotopes of selenium
Radioactive waste | Selenium-79 | [
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11,092,014 | https://en.wikipedia.org/wiki/Named%20data%20networking | Named Data Networking (NDN) (related to content-centric networking (CCN), content-based networking, data-oriented networking or information-centric networking (ICN)) is a proposed Future Internet architecture that seeks to address problems in contemporary internet architectures like IP. NDN has its roots in an earlier project, Content-Centric Networking (CCN), which Van Jacobson first publicly presented in 2006. The NDN project is investigating Jacobson's proposed evolution from today's host-centric network architecture IP to a data-centric network architecture (NDN). The stated goal of this project is that with a conceptually simple shift, far-reaching implications for how people design, develop, deploy, and use networks and applications could be realized.
NDN has three core concepts that distinguish NDN from other network architectures. First, applications name data and data names will directly be used in network packet forwarding; consumer applications would request desired data by its name, so communications in NDN are consumer-driven. Second, NDN communications are secured in a data-centric manner wherein each piece of data (called a Data packet) will be cryptographically signed by its producer and sensitive payload or name components can also be encrypted for the purpose of privacy. In this way, consumers can verify the packet regardless of how the packet is fetched. Third, NDN adopts a stateful forwarding plane where forwarders will keep a state for each data request (called an Interest packet), and erase the state when a corresponding data packet comes back. NDN's stateful forwarding allows intelligent forwarding strategies, and eliminates loops.
Its premise is that the Internet is primarily used as an information distribution network, which is not a good match for IP, and that the future Internet's "thin waist" should be based on named data rather than numerically addressed hosts. The underlying principle is that a communication network should allow a user to focus on the data they need, named content, rather than having to reference a specific, physical location where that data is to be retrieved from, named hosts. The motivation for this is derived from the fact that the vast majority of current Internet usage (a "high 90% level of traffic") consists of data being disseminated from a source to a number of users. Named-data networking comes with potential for a wide range of benefits such as content caching to reduce congestion and improve delivery speed, simpler configuration of network devices, and building security into the network at the data level.
Overview
Today's Internet's hourglass architecture centers on a universal network layer, IP, which implements the minimal functionality necessary for global inter-connectivity. The contemporary Internet architecture revolves around a host-based conversation model, which was created in the 1970s to allow geographically distributed users to use a few big, immobile computers. This thin waist enabled the Internet's explosive growth by allowing both lower and upper layer technologies to innovate independently. However, IP was designed to create a communication network, where packets named only communication endpoints.
Sustained growth in e-commerce, digital media, social networking, and smartphone applications has led to dominant use of the Internet as a distribution network. Distribution networks are more general than communication networks, and solving distribution problems via a point-to-point communication protocol is complex and error-prone.
The Named Data Networking (NDN) project proposed an evolution of the IP architecture that generalizes the role of this thin waist, such that packets can name objects other than communication endpoints. More specifically, NDN changes the semantics of network service from delivering the packet to a given destination address to fetching data identified by a given name. The name in an NDN packet can name anything – an endpoint, a data chunk in a movie or a book, a command to turn on some lights, etc. The hope is that this conceptually simple change allows NDN networks to apply almost all of the Internet's well-tested engineering properties to a broader range of problems beyond end-to-end communications. Examples of NDN applying lessons learned from 30 years of networking engineering are that self-regulation of network traffic (via flow balance between Interest (data request) and data packets), and security primitives (via signatures on all named data) are integrated into the protocol from the start.
History
Early research
The philosophy behind NDN was pioneered by Ted Nelson in 1979, and later by Brent Baccala in 2002. In 1999, the TRIAD project at Stanford proposed avoiding DNS lookups by using the name of an object to route towards a close replica of it. In 2006, the Data-Oriented Network Architecture (DONA) project at UC Berkeley and ICSI proposed a content-centric network architecture, which improved TRIAD by incorporating security (authenticity) and persistence as first-class primitives in the architecture. Van Jacobson gave a Google Talk, A New Way to Look at Networking, in 2006 on the evolution of the network, and argued that NDN was the next step. In 2009, PARC announced their content-centric architecture within the CCNx project, which was led by Jacobson who was a research fellow at PARC at the time. On 21 September 2009, PARC published the specifications for interoperability and released an initial open source implementation (under GPL) of the Content-Centric Networking research project on the Project CCNx site. NDN is one instance of a more general network research direction called information-centric networking (ICN), under which different architecture designs have emerged. The Internet Research Task Force (IRTF) established an ICN research working group in 2012.
Current state
NDN includes sixteen NSF-funded principal investigators at twelve campuses, and growing interest from the academic and industrial research communities. More than 30 institutions form a global testbed. There exists a large body of research and an actively growing code base. contributed to NDN.
The NDN forwarder is currently supported on Ubuntu 18.04 and 20.04, Fedora 20+, CentOS 6+, Gentoo Linux, Raspberry Pi, OpenWRT, FreeBSD 10+, and several other platforms. Common client libraries are actively supported for C++, Java, Javascript, Python, .NET Framework (C#), and Squirrel programming languages. The NDN-LITE is a lightweight NDN library designed for IoT networks and constrained devices. NDN-LITE is being actively developed and so far, NDN-LITE has been adapted to POSIX, RIOT OS, NRF boards. An NDN simulator and emulator are also available and actively developed. Several client applications are being developed in the areas of real-time conferencing, NDN friendly file systems, chat, file sharing, and IoT.
Key architectural principles
End-to-end principle: Enables the development of robust applications in the face of network failures. NDN retains and expands this design principle.
Routing and forwarding plane separation: This has proven necessary for Internet development. It allows the forwarding plane to function while the routing system continues to evolve over time. NDN uses the same principle to allow the deployment of NDN with the best available forwarding technology while new routing system research is ongoing.
Stateful forwarding: NDN routers keep the state of recently forwarded packets, which allows smart forwarding, loop detection, flow balance, ubiquitous caching, etc.
Built-in security: In NDN, data transfer is secured at the network layer by signing and verification of any named data.
Enable user choice and competition: The architecture should facilitate user choice and competition where possible. Although not a relevant factor in the original Internet design, global deployment has demonstrated that “architecture is not neutral". NDN makes a conscious effort to empower end users and enable competition.
Architecture overview
Types of packets
Communication in NDN is driven by receivers i.e., data consumers, through the exchange of two types of packets: Interest and Data. Both types of packets carry a name that identifies a piece of data that can be transmitted in one Data packet.
Packet types
Interest: A consumer puts the name of a desired piece of data into an Interest packet and sends it to the network. Routers use this name to forward the Interest toward the data producer(s).
Data: Once the Interest reaches a node that has the requested data, the node will return a Data packet that contains both the name and the content, together with a signature by the producer's key which binds the two. This Data packet follows in reverse the path taken by the Interest to get back to the requesting consumer.
For the complete specification see NDN Packet Format Specification.
Router architecture
To carry out the Interest and Data packet forwarding functions, each NDN router maintains three data structures, and a forwarding policy:
Pending Interest Table (PIT): stores all the Interests that a router has forwarded but not satisfied yet. Each PIT entry records the data name carried in the Interest, together with its incoming and outgoing interface(s).
Forwarding Information Base (FIB): a routing table which maps name components to interfaces. The FIB itself is populated by a name-prefix based routing protocol, and can have multiple output interfaces for each prefix.
Content Store (CS): a temporary cache of Data packets the router has received. Because an NDN Data packet is meaningful independent of where it comes from or where it is forwarded, it can be cached to satisfy future Interests. Replacement strategy is traditionally least recently used, but the replacement strategy is determined by the router and may differ.
Forwarding Strategies: a series of policies and rules about forwarding interest and data packets. Note that the Forwarding Strategy may decide to drop an Interest in certain situations, e.g., if all upstream links are congested or the Interest is suspected to be part of a DoS attack. These strategies use a series of triggers in the forwarding pipeline and are assigned to name prefixes. For instance, by default /localhost uses the Multicast forwarding strategy to forward interests and data to any local application running on a client NFD. The default forwarding strategy (i.e. "/") is the Best Route forwarding strategy.
When an Interest packet arrives, an NDN router first checks the Content Store for matching data; if it exists in the router returns the Data packet on the interface from which the Interest came. Otherwise the router looks up the name in its PIT, and if a matching entry exists, it simply records the incoming interface of this Interest in the PIT entry. In the absence of a matching PIT entry, the router will forward the Interest toward the data producer(s) based on information in the FIB as well as the router's adaptive Forwarding Strategy. When a router receives Interests for the same name from multiple downstream nodes, it forwards only the first one upstream toward the data producer(s).
When a Data packet arrives, an NDN router finds the matching PIT entry and forwards the data to all down-stream interfaces listed in that PIT entry. It then removes that PIT entry, and caches the Data in the Content Store. Data packets always take the reverse path of Interests, and, in the absence of packet losses, one Interest packet results in one Data packet on each link, providing flow balance. To fetch large content objects that comprise multiple packets, Interests provide a similar role in controlling traffic flow as TCP ACKs in today's Internet: a fine-grained feedback loop controlled by the consumer of the data.
Neither Interest nor Data packets carry any host or interface addresses; routers forward Interest packets toward data producers based on the names carried in the packets, and forward Data packets to consumers based on the PIT state information set up by the Interests at each hop. This Interest/Data packet exchange symmetry induces a hop-by-hop control loop (not to be confused with symmetric routing, or with routing at all!), and eliminates the need for any notion of source or destination nodes in data delivery, unlike in IP's end-to-end packet delivery model.
Names
Design
NDN names are opaque to the network. This allows each application to choose the naming scheme that fits its needs, and naming can thus evolve independently from the network.
Structure
The NDN design assumes hierarchically structured names, e.g., a video produced by UCLA may have the name /ucla/videos/demo.mpg, where ‘/’ delineates name components in text representations, similar to URLs. This hierarchical structure has many potential benefits:
Relationship specification: allows applications to represent the context and relationships of data elements. EX: segment 3 of version 1 of a UCLA demo video might be named /ucla/videos/demo.mpg/1/3
Name aggregation: /ucla could correspond to an autonomous system originating the video
Routing: allows the system to scale and aids in providing the necessary context for the data
Specifying a name
To retrieve dynamically generated data, consumers must be able to deterministically construct the name for a desired piece of data without having previously seen the name or the data through either:
an algorithm allows the producer and consumer to arrive at the same name based on information available to both.
Interest selectors in conjunction with longest prefix matching retrieve the desired data through one or more iterations.
Current research is exploring how applications should choose names that can facilitate both application development and network delivery. The aim of this work is to develop and refine existing principles and guidelines for naming, converting these rules into naming conventions implemented in system libraries to simplify future application development.
Namespaces
Data that may be retrieved globally must have globally unique names, but names used for local communications may require only local routing (or local broadcast) to find matching data. Individual data names can be meaningful in various scopes and contexts, ranging from “the light switch in this room” to “all country names in the world”. Namespace management is not part of the NDN architecture, just as address space management is not part of the IP architecture. However naming is the most important part of NDN application designs. Enabling application developers, and sometimes users, to design their own namespaces for data exchange has several benefits:
increasing the closeness of mapping between an application's data and its use of the network.
reducing the need for secondary notation (record-keeping to map application configuration to network configuration).
expanding the range of abstractions available to the developers.
named based content requests also introduces the concerns on privacy leakage. Thanks to separation of namespace management from NDN architecture, it is possible to provide privacy preserving naming scheme by making minor changes in conventional NDN naming scheme.
Routing
Solutions to IP issues
NDN routes and forwards packets based on names, which eliminates three problems caused by addresses in the IP architecture:
Address space exhaustion: NDN namespace is essentially unbounded. The namespace is only bounded by the max interest packet size of 8kb and the number of possible unique combinations of characters composing names.
NAT traversal: NDN does away with addresses, public or private, so NAT is unnecessary.
Address management: address assignment and management is no longer required in local networks.
In network multicasting: A producer of data does not need to receive multiple interests for the same data since the PIT entries at downstream forwarders will aggregate interests. The producer receives and responds to a single interest and those forwarding nodes in which multiple incoming interest were received will multicast the data replies to the interfaces those interests were received from.
High loss end to end reliability: IP based networks require lost or dropped packets to be retransmitted by the sender. However, in NDN if an interest expires before a data reply reaches the requester the data reply is still cached by forwarders along the return path. The retransmitted interest only needs to reach a forwarder with a cached copy of the data giving NDN based networks higher throughput than IP based networks when packet loss rates are high.
Protocols
NDN can use conventional routing algorithms such as link state and distance vector. Instead of announcing IP prefixes, an NDN router announces name prefixes that cover the data the router is willing to serve. Conventional routing protocols, such as OSPF and BGP, can be adapted to route on name prefixes by treating names as a sequence of opaque components and doing component-wise longest prefix match of a name in an Interest packet against the FIB table. This enables a wide array of inputs to be aggregated in real time and distributed across multiple interface environments simultaneously without compromising content encryption. Key interface analytics are likewise spared by the process. Application transfer and data sharing within the environment are defined by a multi-modal distribution framework, such that the affected cloud relay protocols are unique to the individual runtime identifier.
PIT state
The PIT state at each router supports forwarding across NDN's data plane, recording each pending Interest and the incoming interface(s), and removing the Interest after the matching Data is received or a timeout occurs. This per hop, per packet state differs from IP's stateless data plane. Based on information in the FIB and performance measurements, an adaptive forwarding strategy module in each router makes informed decisions about:
Control flow: since each Interest retrieves at most one Data packet, a router can directly control flow by controlling the number of pending interests it keeps.
Multicast data delivery: the PIT recording the set of interface on which the same data has arrive, naturally supports this feature.
Updating paths to accommodate changes in their view of the network.
Delivery: a router can reason about which Interests to forward to which interfaces, how many unsatisfied Interests to allow in the PIT, as well as the relative priority of different Interests.
Interest
If a router decides that the Interest cannot be satisfied, e.g., the upstream link is down, there is no forwarding entry in the FIB, or extreme congestion occurs, the router can send a NACK to its downstream neighbor(s) that transmitted the Interest. Such a Negative Acknowledgment (NACK) may trigger the receiving router to forward the Interest to other interfaces to explore alternate paths. The PIT state enables routers to identify and discard looping packets, allowing them to freely use multiple paths toward the same data producer. Packets cannot loop in NDN, which means there is no need for time-to-live and other measures implemented in IP and related protocols to address these issues.
Security
Overview
In contrast to TCP/IP security (e.g., TLS) which secures communication by securing IP-to-IP channels, NDN secures the data itself by requiring data producers to cryptographically sign every Data packet. The publisher's signature ensures the integrity and enables authentication of data provenance, allowing a consumer's trust in data to be decoupled from how or where it is obtained. NDN also supports fine-grained trust, allowing consumers to reason about whether a public key owner is an acceptable publisher for a specific piece of data in a specific context. The second primary research thrust is designing and developing usable mechanisms to manage user trust. There has been research into 3 different types of trust models:
hierarchical trust model: where a key namespace authorizes use of keys. A data packet carrying a public key is effectively a certificate, since it is signed by a third party, and this public key is used to sign specific data.
web of trust: to enable secure communication without requiring pre-agreed trust anchors.
lightweight trust for IoT: The NDN trust model primarily based on asymmetric cryptography, which is infeasible for resource constraint devices in IoT paradigm.
Application security
NDN's data-centric security has natural applications to content access control and infrastructure security. Applications can encrypt data and distribute keys as named packets using the same named infrastructure to distribute keys, effectively limiting the data security perimeter to the context of a single application.
To verify a data packet's signature, an application can fetch the appropriate key, identified in the packet's key locator field, just like any other content. But trust management, i.e., how to determine the authenticity of a given key for a particular packet in a given application, is a primary research challenge. Consistent with an experimental approach, NDN trust management research is driven by application development and use: solving specific problems first and then identifying common patterns.
For example, the security needs of NLSR required development of a simple hierarchical trust model, with keys at lower (closer to root) levels, being used to sign keys in higher levels in which keys are published with names that reflect their trust relationship. In this trust model, the namespace matches the hierarchy of trust delegation, i.e., /root/site/operator/ router/process. Publishing keys with a particular name in the hierarchy authorizes them to sign specific data packets and limits their scope. This paradigm can be easily extended to Other applications where real world trust tends to follow a hierarchical pattern, such as in our building management systems (BMS).
Since NDN leaves the trust model under the control of each application, more flexible and expressive trust relations, may also be expressed. One such example is ChronoChat, which motivated experimentation with a web-of-trust model. The security model is that a current chatroom participant can introduce a newcomer to others by signing the newcomer's key. Future applications will implement a cross-certifying model (SDSI) [13, 3], which provides more redundancy of verification, allowing data and key names to be independent, which more easily accommodates a variety of real-world trust relationships.
Routing efficiency and security
Furthermore, NDN treats network routing and control messages like all NDN data, requiring signatures. This provides a solid foundation for securing routing protocols against attack, e.g., spoofing and tampering. NDN's use of multipath forwarding, together with the adaptive forwarding strategy module, mitigates prefix hijacking because routers can detect anomalies caused by hijacks and retrieve data through alternate paths. Owing to multi-source, multicast content-delivery nature of Named Data Networking, the random linear coding can improve over all network efficiency. Since NDN packets reference content rather than devices, it is trickier to maliciously target a particular device, although mitigation mechanisms will be needed against other NDN-specific attacks, e.g., Interest flooding DoS. Furthermore, having a Pending Interest Table, which keeps state regarding past requests, which can make informed forward decisions about how to handle interest has numerous security advantages:
Load Balancing: the number of PIT entries is an indicator of router load; constraining its size limits the effect of a DDoS attack.
Interest timeout: PIT entry timeouts offer relatively cheap attack detection, and the arrival interface information in each PIT entry could support a push-back scheme in which down stream routers are informed of unserved interests, which aides in detecting attacks.
See also
Information-centric networking caching policies
Future Internet Research and Experimentation (EU)
References
External links
DEATH TO TCP/IP cry Cisco, Intel, US gov and boffins galore
FIA-NP: Collaborative Research: Named Data Networking Next Phase (NDN-NP)
Named Data Research Home Page
NSF Awards for NDN 2
FIA: Collaborative Research: Named Data Networking (NDN)
Named Function Networking (NFN)
NDN on Galileo (WebArchive snapshot)
Computer networking
Internet protocols
Network layer protocols | Named data networking | [
"Technology",
"Engineering"
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11,092,492 | https://en.wikipedia.org/wiki/Amalgamation%20property | In the mathematical field of model theory, the amalgamation property is a property of collections of structures that guarantees, under certain conditions, that two structures in the collection can be regarded as substructures of a larger one.
This property plays a crucial role in Fraïssé's theorem, which characterises classes of finite structures that arise as
ages of countable homogeneous structures.
The diagram of the amalgamation property appears in many areas of mathematical logic. Examples include in modal logic as an incestual accessibility relation, and in lambda calculus as a manner of reduction having the Church–Rosser property.
Definition
An amalgam can be formally defined as a 5-tuple (A,f,B,g,C) such that A,B,C are structures having the same signature, and f: A → B, g: A → C are embeddings. Recall that f: A → B is an embedding if f is an injective morphism which induces an isomorphism from A to the substructure f(A) of B.
A class K of structures has the amalgamation property if for every amalgam with A,B,C ∈ K and A ≠ Ø, there exist both a structure D ∈ K and embeddings f': B → D, g': C → D such that
A first-order theory has the amalgamation property if the class of models of has the amalgamation property. The amalgamation property has certain connections to the quantifier elimination.
In general, the amalgamation property can be considered for a category with a specified choice of the class of morphisms (in place of embeddings). This notion is related to the categorical notion of a pullback, in particular, in connection with the strong amalgamation property (see below).
Examples
The class of sets, where the embeddings are injective functions, and if they are assumed to be inclusions then an amalgam is simply the union of the two sets.
The class of free groups where the embeddings are injective homomorphisms, and (assuming they are inclusions) an amalgam is the quotient group , where * is the free product.
The class of finite linear orderings. This is due to the fact that any homogeneous structure from an amalgamation class of finite structure.
A similar but different notion to the amalgamation property is the joint embedding property. To see the difference, first consider the class K (or simply the set) containing three models with linear orders, L1 of size one, L2 of size two, and L3 of size three. This class K has the joint embedding property because all three models can be embedded into L3. However, K does not have the amalgamation property. The counterexample for this starts with L1 containing a single element e and extends in two different ways to L3, one in which e is the smallest and the other in which e is the largest. Now any common model with an embedding from these two extensions must be at least of size five so that there are two elements on either side of e.
Now consider the class of algebraically closed fields. This class has the amalgamation property since any two field extensions of a prime field can be embedded into a common field. However, two arbitrary fields cannot be embedded into a common field when the characteristic of the fields differ.
Strong amalgamation property
A class K of structures has the strong amalgamation property (SAP), also called the disjoint amalgamation property (DAP), if for every amalgam with A,B,C ∈ K there exist both a structure D ∈ K and embeddings f': B → D, g': C → D such that
and
where for any set X and function h on X,
See also
Span (category theory)
Pushout (category theory)
Joint embedding property
Fraïssé's theorem
References
References
Entries on amalgamation property and strong amalgamation property in online database of classes of algebraic structures (Department of Mathematics and Computer Science, Chapman University).
E.W. Kiss, L. Márki, P. Pröhle, W. Tholen, Categorical algebraic properties. A compendium on amalgamation, congruence extension, epimorphisms, residual smallness, and injectivity, Studia Sci. Math. Hungar 18 (1), 79-141, 1983 whole journal issue.
.
Model theory | Amalgamation property | [
"Mathematics"
] | 922 | [
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11,092,582 | https://en.wikipedia.org/wiki/Cold%20saw | A cold saw is a circular saw designed to cut metal which uses a toothed blade to transfer the heat generated by cutting to the chips created by the saw blade, allowing both the blade and material being cut to remain cool. This is in contrast to an abrasive saw, which abrades the metal and generates a great deal of heat absorbed by the material being cut and saw blade.
As metals expand when heated, abrasive cutting causes both the material being cut and blade to expand, resulting in increased effort to produce a cut and potential binding. This produces more heat through friction, resulting in increased blade wear and greater energy consumption.
Cold saws use either a solid high-speed steel (HSS) or tungsten carbide-tipped, resharpenable circular saw blade. They are equipped with an electric motor and often a gear reduction unit to reduce the saw blade's rotational speed while maintaining constant torque. This allows the HSS saw blade to feed at a constant rate with a very high chip load per tooth.
Cold saws are capable of machining most ferrous and non-ferrous alloys. Additional advantages include minimal burr production, fewer sparks, less discoloration and no dust. Saws designed to employ a flood coolant system to keep saw blade teeth cooled and lubricated may reduce sparks and discoloration completely. Saw blade type and number of teeth, cutting speed, and feed rate all must be appropriate to the type and size of material being cut, which must be mechanically clamped to prevent movement during the cutting process.
Blades
Cold saw blades are circular metal cutting saw blades categorized into two types: solid HSS or tungsten carbide-tipped (TCT). Both types of blades are resharpenable and may be used many times before being discarded. Cold saw blades are used to cut metal using a relatively slow rotational speed, usually less than 5000 surface feet per minute (SFM) (25 m/s), and a high chip load per tooth, usually between .001"–.003" (0.025–0.08 mm) per tooth. These blades are driven by a high power motor and high-torque gear reduction unit or an AC vector drive. During the cutting process, the metal is released in a shearing action by the teeth as the blade turns and the feed mechanism moves the blade forward. They are called "cold saw blades" because they transfer all the energy and heat created during the cutting process to the chip. This enables the blade and the work material to remain cold.
Classification
The first type of cold saw blade, solid HSS, may be made from either M2 tool steel or M35 tool steel, alloyed with additional cobalt. Solid HSS saw blades are heat treated and hardened to 64/65 HRC for ferrous cutting applications and 58/60 HRC for non-ferrous cutting applications. This high hardness gives the cutting edges of the teeth a high resistance to heat and wear. However, this increased hardness also makes the blades brittle and not very resistant to shock. In order to produce a high quality HSS cold saw blade, it is necessary to start with very flat and properly tensioned raw material. The blades must be press quenched after hardening to prevent them from being warped. HSS saw blades are typically hollow ground for clearance during the cutting process. The term HSS doesn't necessarily mean what it implies. These blades are usually never run at surface speeds higher than 350 SFM. Solid HSS cold saw blades may be used for cutting many different shapes and types of metal including: tubes, extrusions, structural sections, billets, bars, ingots, castings, forgings etc. These blades may also be coated with special wear resistant coatings such as titanium nitride (TiN) or titanium aluminum nitride (TiAlN), but are more commonly used commercially with a black oxide coating aiding in better coolant distribution over the surface area of the cutting blade.
The second type of cold saw blade, tungsten carbide-tipped (TCT), are made with an alloy steel body and tungsten carbide inserts brazed to the tips of the teeth. These tips are ground on all surfaces to create tangential and radial clearance and provide the proper cutting and clearance angles on the teeth. The alloy body is generally made from a wear-resistant material such as a chrome vanadium steel, heat treated to 38/42 HRC. The tungsten carbide tips are capable of operating at much higher temperatures than solid HSS, therefore, TCT saw blades are usually run at much higher surface speeds. This allows carbide-tipped blades to cut at faster rates and still maintain an acceptable chip load per tooth. These blades are commonly used for cutting non-ferrous alloys, but have gained significant popularity for ferrous metal cutting applications in the last 10 years. The tungsten carbide inserts are extremely hard (98 HRC) and capable of very long wear life. However, they are less resistant to shock than solid HSS cold saw blades. Any vibration during the cutting process may severely damage the teeth. These cold saw blades need to be driven by a backlash free gear box and a constant feed mechanism like a ball-screw feed.
Portable saws
Portable cold saws were primarily designed for sheet metal roofers in the building industry, and can cut up to thick mild steel. Cold saws, as opposed to abrasive saws, are used so that protective coatings are not damaged. They have a heavy duty aluminium catcher which is useful for capturing the swarf, and use cermet tipped blades.
References
Saws
Cutting machines
Metalworking cutting tools | Cold saw | [
"Physics",
"Technology"
] | 1,176 | [
"Physical systems",
"Machines",
"Cutting machines"
] |
11,093,946 | https://en.wikipedia.org/wiki/Ascofuranone | Ascofuranone is an antibiotic produced by various ascomycete fungi including Acremonium sclerotigenum that inhibits the Trypanosoma brucei alternative oxidase and is a lead compound in efforts to produce other drugs targeting this enzyme for the treatment of sleeping sickness. The compound is effective both in vitro cell culture and in infections in mice.
Ascofuranone has also been reported to have anti-tumor activity, and modulate the immune system.
Biosynthesis
The proposed biosynthesis of ascofuranone was reported by Kita et al., as well as by Abe et al. The prenylation of orsellinic acid, followed by terminal cyclization through epoxidation is how ascofuranone can be synthesized. Compound (1), ilicicolinic acid B, was found to be produced from polyketide synthase (PKS) StBA and that AscCABD are responsible for the biosynthesis of ilicicolin A (3). Ilicicolin B (2) was found to be produced by expressing AscC (polyketide synthase) which is then followed by expression of AscA (prenyltransferase). AscD (flavin-dependent halogenase, flavin binding enzyme) is able to catalyze the chlorination of ilicicolinic acid B (2) to yield ilicicolin A (3).
Expodiation of (3) by AscE (P450 monooxygenase) leads to the formation of ilicicolin A epoxide (4). Ilicicolin A epoxide can then be hydroxylated by AscH at C-16 (P450 monooygenase) to yield intermediate (5) which can then be cyclized by AscI (eight-transmembrane protein, TPC) into ascofuranol (6), specifically through 6-endo-tet cyclization. Finally, ascofuranol (6) can be oxidized by AscJ (NAD(P)-dependent alcohol dehydrogenase) leading to the formation of ascofuranone.
References
Antibiotics
Terpeno-phenolic compounds
Aromatic aldehydes
Ketones
Chloroarenes
Tetrahydrofurans
Halogen-containing natural products | Ascofuranone | [
"Chemistry",
"Biology"
] | 505 | [
"Biotechnology products",
"Ketones",
"Functional groups",
"Antibiotics",
"Biocides"
] |
11,094,098 | https://en.wikipedia.org/wiki/Isopropyl%20alcohol%20%28data%20page%29 | This page provides supplementary chemical data on isopropanol.
Material Safety Data Sheet
The handling of this chemical may incur notable safety precautions. It is highly recommend that you seek the Material Safety Datasheet (MSDS) for this chemical from a reliable source such as eChemPortal, and follow its directions.
Structure and properties
Thermodynamic properties
Vapor pressure of Iso-propyl Alcohol
Table data obtained from CRC Handbook of Chemistry and Physics 44th ed.
Distillation data
See also
Tetrachloroethylene (data page)
Spectral data
References
Chemical data pages
Chemical data pages cleanup | Isopropyl alcohol (data page) | [
"Chemistry"
] | 124 | [
"Chemical data pages",
"nan"
] |
11,094,380 | https://en.wikipedia.org/wiki/Enzootic | Enzootic describes the situation where a disease or pathogen is continuously present in at least one species of non-human animal in a particular region. It is the non-human equivalent of endemic.
In epizoology, an infection is said to be "enzootic" in a population when the infection is maintained in the population without the need for external inputs (cf. endemic).
See also
Epizootic
Biodiversity
Pathology
Epidemiology | Enzootic | [
"Biology",
"Environmental_science"
] | 91 | [
"Epidemiology",
"Environmental social science",
"Biodiversity",
"Pathology"
] |
11,094,525 | https://en.wikipedia.org/wiki/Asymmetric%20bacterium | Asymmetric bacteria are bacteria that undergo "non-symmetrical" life cycles. This especially includes those that differentiate temporally, such as prosthecate bacteria.
History
Cell division asymmetries have appeared alongside the evolution of complex developmental processes. While bacteria were historically considered symmetric simple cells, this idea has been overturned by novel technology and observation techniques. However, asymmetric bacteria remain difficult to detect. Asymmetrical growth aids in determining the age of bacteria, because it gives rise to an old pole, or region of inert cell wall material found at the ends of a rod-shaped bacterial cell. Following the "old pole" of the cell wall material allows an observer to create a bacterial lineage.
Types of asymmetry
Bacteria exhibit three different types of asymmetry: conditional asymmetry, reproductive asymmetry, and morphological asymmetry.
Conditional asymmetry is well defined in the case of endospore formation, which is triggered by stressful environmental conditions such as increased heat, pH change, and nutrient depletion. This type of asymmetry is usually seen in Bacilli and Clostridia.
Reproductive asymmetry is classically linked to bacterial budding, where a mother cell concentrates cell wall material to one area and a daughter cell begins to bud from that thickening. Cell growth which gives rise to reproductive asymmetry occurs in three phases: stalk elongation, daughter cell elongation, and septum formation.
Morphological asymmetry is classified by polar elongation. In this type of asymmetrical growth, the daughter cell receives most of the new cell wall material.
Examples
Bacillus subtilis
Caulobacter crescentus
References
Bacteria | Asymmetric bacterium | [
"Biology"
] | 351 | [
"Microorganisms",
"Bacteria stubs",
"Prokaryotes",
"Bacteria"
] |
11,095,055 | https://en.wikipedia.org/wiki/Routing%20Assets%20Database | The Routing Assets Database (RADb), formerly known as the Routing Arbiter Database is a public database in which the operators of Internet networks publish authoritative declarations of routing policy for their Autonomous System (AS) which are, in turn, used by the operators of other Internet networks to configure their inbound routing policy filters. The RADb, operated by the University of Michigan's Merit Network, was the first such database, but others followed in its wake, forming a loose confederation of Internet routing registries, containing sometimes-overlapping, and sometimes-conflicting, routing policy data, expressed in Routing Policy Specification Language (RPSL) syntax.
History
The RADb was developed in the early 1990s as part of the National Science Foundation (NSF)-funded Routing Arbiter Project. The Routing Policy Specification Language was subsequently retroactively formalized in RFC 2280, in January, 1998.
Usage
Historically, most larger Internet service providers, and all within the European RIPE NCC region require customers to be registered in an Internet Routing Registry prior to propagating BGP announcements of their routes. This has not been a rigorously-enforced operational standard, however, and has declined since a peak in the early 2000s.
Security
The Internet Routing Registry system is an artifact of the 1990s era of the Internet, as the Internet's economy and governance were in transition from an academic mode to a commercial mode, and predate the era of ubiquitous cryptography. The RADb initially relied upon a trust model, in which write access to the database was not strictly controlled. A write-permissions access model was subsequently added, in which individuals or roles representing each Autonomous System had authority to write records related to that AS, including which IP address blocks it would originate routing advertisements for, and which other Autonomous Systems were allowed to advertise transit routing paths to it. The first generation of security allowed network operators to specify a MAIL-FROM attribute, requiring that updates be sent from a specific email address. Next, (B)CRYPT-PW / MD5-PW password hash authentication was added, and finally a PGP-KEY attribute was added, allowing users to cryptographically sign submitted edits. Subsequent work by the Regional Internet Registries created additional IRRs which strictly tied permission to advertise IP blocks to RIR allocation data. But since DNSSEC already existed and had been applied to the in-addr zone, no end-to-end cryptographic integrity mechanism was ever added to RPSL.
See also
Autonomous system (Internet)
Border Gateway Protocol
Internet Assigned Numbers Authority
Regional Internet registry
Routing
References
Internet Routing Registry (IRR) homepage
IRR FAQs
Routing Registry template
http://www.irrd.net/
IRR Toolset
External links
Internet architecture
Internet governance
Internet Standards
Internet databases | Routing Assets Database | [
"Technology"
] | 577 | [
"Internet architecture",
"IT infrastructure"
] |
11,095,324 | https://en.wikipedia.org/wiki/Integro-differential%20equation | In mathematics, an integro-differential equation is an equation that involves both integrals and derivatives of a function.
General first order linear equations
The general first-order, linear (only with respect to the term involving derivative) integro-differential equation is of the form
As is typical with differential equations, obtaining a closed-form solution can often be difficult. In the relatively few cases where a solution can be found, it is often by some kind of integral transform, where the problem is first transformed into an algebraic setting. In such situations, the solution of the problem may be derived by applying the inverse transform to the solution of this algebraic equation.
Example
Consider the following second-order problem,
where
is the Heaviside step function. The Laplace transform is defined by,
Upon taking term-by-term Laplace transforms, and utilising the rules for derivatives and integrals, the integro-differential equation is converted into the following algebraic equation,
Thus,
.
Inverting the Laplace transform using contour integral methods then gives
.
Alternatively, one can complete the square and use a table of Laplace transforms ("exponentially decaying sine wave") or recall from memory to proceed:
.
Applications
Integro-differential equations model many situations from science and engineering, such as in circuit analysis. By Kirchhoff's second law, the net voltage drop across a closed loop equals the voltage impressed . (It is essentially an application of energy conservation.) An RLC circuit therefore obeys
where is the current as a function of time, is the resistance, the inductance, and the capacitance.
The activity of interacting inhibitory and excitatory neurons can be described by a system of integro-differential equations, see for example the Wilson-Cowan model.
The Whitham equation is used to model nonlinear dispersive waves in fluid dynamics.
Epidemiology
Integro-differential equations have found applications in epidemiology, the mathematical modeling of epidemics, particularly when the models contain age-structure or describe spatial epidemics. The Kermack-McKendrick theory of infectious disease transmission is one particular example where age-structure in the population is incorporated into the modeling framework.
See also
Delay differential equation
Differential equation
Integral equation
Integrodifference equation
References
Further reading
Vangipuram Lakshmikantham, M. Rama Mohana Rao, “Theory of Integro-Differential Equations”, CRC Press, 1995
External links
Interactive Mathematics
Numerical solution of the example using Chebfun
Differential equations | Integro-differential equation | [
"Mathematics"
] | 523 | [
"Mathematical objects",
"Differential equations",
"Equations"
] |
11,095,705 | https://en.wikipedia.org/wiki/AEROS%20%28satellite%29 | AEROS satellites were to study the aeronomy i. e. the science of the upper atmosphere and ionosphere, in particular the F region under the strong influence of solar extreme ultraviolet radiation. To this end the spectrum of this radiation was recorded aboard by one instrument (of type Hinteregger) on the one hand and a set of 4 other instruments measuring the most important neutral uand iononized parameters at the satellite's position on the other.
AEROS was built by Ball Aerospace for a co-operative project between NASA and the Bundesministerium für Foschung und Technologie (BMwF), Federal Republic of Germany.
Named for the Greek god of the air at the suggestion of the BMwF .
AEROS A and B carried identical instrumentation only the instrument measuring short scale variations of the electron density didn't work on A. A third Aeros C was planned for Earth Resources studies in a 3-axis spin-stabilized configuration, to be launched by a Shuttle in 1986.(Needs research)
Specifications
Source: Yenne
Launch vehicles: Scout
Launch location: Western Space and Missile Center at Vandenberg AFB
Launch dates: 16 December 1972 (AEROS), 16 July 1974 (AEROS B)
Re-entry dates: 22 August 1973 (AEROS), 2 September 1975 (AEROS B)
Total weight: 280 pounds and 436 pounds for AEROS C
Diameter: 36 inches
Height: 28 inches
Shape: Cylindrical
Power: Solar cells/nickel-cadmium batteries
Power requirements: 4.7-34.3 watts
References
External links
Goddard Space Flight Center
AEROS B Satellite
Weather satellites of the United States
NASA satellites
Science and technology in West Germany
Satellites of Germany
Spacecraft launched in 1972
Spacecraft launched in 1974
Spacecraft which reentered in 1973
Spacecraft which reentered in 1975 | AEROS (satellite) | [
"Astronomy"
] | 367 | [
"Astronomy stubs",
"Spacecraft stubs"
] |
11,095,814 | https://en.wikipedia.org/wiki/Prosthecate%20bacteria | Prosthecate bacteria are a non-phylogenetically related group of Gram-negative bacteria that possess appendages, termed prosthecae. These cellular appendages, also known as stalks, are neither pili nor flagella, as they are extensions of the cellular membrane and contain cytosol. One notable group of prosthecates is the genus Caulobacter.
Function of prostheca
Prosthecates are generally chemoorganotrophic aerobes that can grow in nutrient-poor habitats, being able to survive at nutrient levels on the order of parts-per-million for which reason they are often found in aquatic habitats. These bacteria will attach to surfaces with their prosthecae, allowing a greater surface area with which to take up nutrients (and release waste products). Some prosthecates will grow in nutrient-poor soils as aerobic heterotrophs.
See also
Oligotrophic
External links
Poindexter, Jeanne S. Dimorphic Prosthecate Bacteria: The Genera Caulobacter, Asticcacaulis, Hyphomicrobium, Pedomicrobium, Hyphomonas and Thiodendron.
References
Bacteria | Prosthecate bacteria | [
"Biology"
] | 259 | [
"Microorganisms",
"Prokaryotes",
"Bacteria"
] |
14,751,689 | https://en.wikipedia.org/wiki/Ocean%20Observatories%20Initiative | The Ocean Observatories Initiative (OOI) is a National Science Foundation (NSF) Major Research Facility composed of a network of science-driven ocean observing platforms and sensors (ocean observatories) in the Atlantic and Pacific Oceans. This networked infrastructure measures physical, chemical, geological, and biological variables from the seafloor to the sea surface and overlying atmosphere, providing an integrated data collection system on coastal, regional and global scales. OOI's goal is to deliver data and data products for a 25-year-plus time period, enabling a better understanding of ocean environments and critical ocean issues.
History
As early as 1987, the ocean sciences community began discussions about the science, design concepts, and engineering of ocean research observatories, leading to the formation of the International Ocean Network (ION) in 1993. The ION national committee was formed in 1995 and later expanded into the Dynamics of Earth and Ocean Systems (DEOS) committee, tasked with providing a focus for exploratory planning for an ocean observatory network.
In 2003 the Pew Oceans Commission recommended changes designed to improve society's use and stewardship of, and impact on, the coastal and global ocean.
Momentum for research-oriented ocean observing built with two National Research Council (NRC) studies in 2000 and 2003 ("Illuminating the Hidden Planet: The Future of Seafloor Observatory Science" and "Enabling Ocean Research in the 21st Century" ), and a series of community workshops. In 2000, the National Science Board (NSB) approved the OOI as a potential Major Research Equipment and Facilities Construction project for inclusion in a future National Science Foundation budget, which allowed for focused planning efforts.
In 2004, the NSF Division of Ocean Sciences (NSF OCE) established the OOI Project Office under the Ocean Research Interactive Observatory Network (ORION) to coordinate further OOI planning between two independent but complementary groups, Joint Oceanographic Institutions (JOI) and Consortium for Ocean Research and Education (CORE). The Program Office subsequently transitioned solely to JOI, which then merged with CORE to form the Consortium for Ocean Leadership in 2007. In 2005, the OOI Project Office asked for the ocean research community's help in developing the OOI network design by soliciting Request for Assistance (RFA) proposals that resulted in 48 proposals, representing the thoughts and ideas of more than 550 investigators and direct participants, and the involvement of over 130 separate educational and research institutions. Using the responses from the RFA process and associated review results, the OOI ORION Project Office and the external Science & Technical Advisory Committee developed an initial Conceptual Network Design (CND) for the OOI, which then served as the focus at an OOI Design and Implementation Workshop in March 2006.
In August 2006, NSF convened a Conceptual Design Review (CDR) to assess the Project's technical feasibility and budget, the Project's Management Plan, including schedules and milestones, and education and outreach plans. The CDR Panel affirmed that the OOI, as proposed, would transform oceanographic research in the coming decades, and that the CND provided a good starting point for developing the OOI network.
Further refinement of the design based on engineering best-practices and financial reviews caused the initial CND to be revisited. The OOI Project Office working with the OOI advisory committees, consisting of unconflicted members of the community, and in consultation with NSF, then generated a revised CND.
In 2007, the National Science and Technology Council's Joint Subcommittee on Ocean Science and Technology developed an Ocean Research Priorities Strategy (ORPS), which provides a research investment framework to advance understanding of ocean processes and interactions that facilitate responsible use of the ocean environment. The ORPS identified three cross-cutting elements, one of which is ocean observing for research and management.
In late 2007, the OOI project completed its Preliminary Design Review and in 2008 completed its Final Network Design Review resulting in the Final Network Design. In May 2009, the National Science Board authorized the Director of NSF to award funds for the construction and initial operation of the OOI. In September 2009, NSF and the Consortium for Ocean Leadership signed a Cooperative Agreement that initiated the construction phase of the OOI.
Locations of OOI's global arrays were selected by a team of roughly 300 scientists to target regions that were under-sampled and subject to extreme conditions (e.g., high winds and sea states) that were challenging for continuous or even frequent ship-based measurements. The originally planned global study sites include instrumented moorings and gliders in four locations: Argentine Basin, Irminger Sea, Southern Ocean, and Station Papa.
The first year of funding under the Cooperative Agreement supported a range of construction efforts performed by the Marine Implementing Organizations (Woods Hole Oceanographic Institution, University of Washington, and Oregon State University), including production, engineering, and prototyping of key coastal and open-ocean components (moorings, buoys, sensors), award of the primary seafloor cable contract, completion of a shore station for power and data, and software development for sensor interfaces to the network. Subsequent years of funding supported the design, build, and deployment of coastal, deep-ocean, and seafloor systems.
The OOI was commissioned and accepted by the NSF in 2016 and data from more than 900 sensors at the seven sites became freely available for download in and near-real time online. The annual budget is approximately $44 million.
In 2018, in keeping with some of the recommendations laid out in Sea Change: 2015-2025 Decadal Survey of Ocean Sciences, the Argentine Basin Array was descoped and the Southern Ocean Array was reduced in scope to the surface mooring only, which was later removed in 2020. All OOI data collected at the Argentine Basin and Southern Ocean sites continue to be served on the OOI website.
In October 2018, the Program Management office of the OOI shifted from the Consortium for Ocean Leadership to the Woods Hole Oceanographic Institution.
Organizational structure
The OOI Program is managed and coordinated by the OOI Project Office at the Woods Hole Oceanographic Institution (WHOI), with four organizations responsible for operations and maintenance of specific components of the OOI system.
Woods Hole Oceanographic Institution is responsible for the Coastal & Global Scale Nodes, which includes the Coastal Pioneer Array and two Global Arrays, including their associated moorings, autonomous vehicles, and sensors.
Oregon State University is responsible for the Coastal Endurance Array moorings, autonomous vehicles, and sensors.
University of Washington is responsible for the Regional Cabled Array, including its cabled seafloor systems, moorings, and sensors.
Oregon State University is responsible for the OOI data center.
Themes
The sites and platforms of the OOI components target the following key scientific processes:
Ocean-atmosphere exchange
Quantifying the air-sea exchange of energy and mass, especially during high winds (greater than 20 meters-per-second), is critical to providing estimates of energy and gas exchange between the surface and deep ocean and improving the predictive capability of storm forecasting and climate change models.
Climate variability, ocean circulation and ecosystems
Climate variability affects ocean circulation, weather patterns, the ocean's biochemical environment and marine ecosystems. Understanding how these processes change in current and future conditions is a key motivation for collecting multidisciplinary observations.
Turbulent mixing and biophysical interactions
Turbulent mixing plays a critical role in the transfer of materials within the ocean and in the exchange of energy and gases between the ocean and atmosphere. Horizontal and vertical mixing within the ocean can have a profound effect on a wide variety of biological processes.
Coastal ocean dynamics and ecosystems
The coastal ocean is host to a variety of dynamic and heterogeneous processes, including human influences, which often strongly interact. Better understanding of these complex and intertwined relationships and their impacts will aid mastery and management of coastal resources in a changing climate.
Plate-scale, ocean geodynamics
Active tectonic plate boundaries influence the ocean from physical, chemical and biological perspectives to varying degrees. Lithospheric movements and interactions at plate boundaries at or beneath the seafloor are responsible for short-term events such as earthquakes, tsunamis and volcanic eruptions. These regions are also host to the densest hydrothermal and biological activity in the ocean basins.
Fluid-rock interactions and the subseafloor biosphere
The oceanic crust contains the largest aquifer on Earth and supports a vast deep biosphere. Thermal circulation and reactivity of seawater-derived fluids can modify the composition of oceanic plates, lead to the formation of hydrothermal vents that support unique micro- and macro-biological communities and concentrate methane to form massive methane gas and methane hydrate reservoirs.
Components
The OOI is composed of two coastal arrays (Coastal Pioneer Array and Coastal Endurance Array), two global arrays (Global Irminger Sea Array and Global Station Papa Array), the Regional Cabled Array (RCA), and Cyberinfrastructure. Data continue to be served from the discontinued arrays in the Argentine Basin and Southern Ocean.
Coastal and Global Arrays
Coastal arrays provide sustained, adaptable access to complex coastal systems. Coastal arrays extend from the continental shelf to the continental slope, allowing scientists to examine coastal processes including upwelling, hypoxia, shelf break fronts, and the role of filaments and eddies in cross-shelf exchange. Technologies that gather data in the coastal region include moored buoys with fixed sensors, moored vertical profilers, seafloor cables, gliders and autonomous underwater vehicles.
The coastal observatory includes a long-term Endurance Array in the Eastern Pacific and a re-locatable Pioneer Array in the Western Atlantic. Woods Hole Oceanographic Institution installed and operates the Pioneer Array. Oregon State University installed and operates the Endurance Array.
There are two global arrays currently in operation (Global Irminger Sea Array and Global Station Papa Array). The Argentine Basin and the Southern Ocean Arrays were removed, but their data remain available through OOI's data portal.
Coastal Pioneer Array
The Coastal Pioneer Array is a network of platforms and sensors that operate on the continental shelf and slope south of New England. A moored array was centered at the shelf break in the Mid-Atlantic Bight south of Cape Cod, Massachusetts. In 2024, the Coastal Pioneer Array was relocated to the southern Mid-Atlantic Bight, between Cape Hatteras and Norfolk Canyon off the coast of North Carolina.
Coastal Pioneer Array data enable scientists to examine how exchange processes structure physical, chemical and biological properties over the continental shelf and slope. Continuous rapid sampling at intervals of hours to days over multiple spatial scales (meters to hundreds of kilometers) provides insight into oceanographic processes that occur through more than one seasonal or annual cycle.
Scientific motivation
The Mid-Atlantic Bight shelf-break front is a persistent oceanographic feature associated with the changing bathymetry of the continental shelf and slope. The frontal region is influenced by Gulf Stream rings, meanders and filaments.
The frontal region is associated with along- and cross-shelf transport of heat, freshwater, nutrients, and carbon. These fluxes control water mass and ecosystem characteristics in multiple regions. Many of the processes along the shelf-break front evolve rapidly and occur over short spatial scales.
Design
The Pioneer Array provides a three-dimensional view of key biophysical interactions at the shelf break using its flexible, multiplatform array that combines moored and mobile components with high spatial and temporal resolution. The array includes seven sites of moorings that span along 9 km and across 47 km of continental shelf. The mooring sites are located 9.2 km to 17.5 km apart from each other. Three of the seven sites contain paired moorings. In its initial location south of Cape Cod, the Pioneer is embedded within an established regional observing system. The Pioneer Array is planned to move from place to place over approximately five-year intervals to characterize processes in different coastal ocean environments.
Two autonomous underwater vehicles (AUVs) sample the frontal region in the vicinity of the moored array and five coastal gliders resolve mesoscale features on the outer shelf and the slope sea between the shelf break front and the Gulf Stream. Two profiling gliders have acted as moorings by sampling at a single point. Gliders monitor a total area of 185 km by 130 km. Nominal AUV missions sample in the along-shelf and cross-shelf directions in two 14 km by 47 km rectangles.
Coastal Endurance Array
The Coastal Endurance Array, located on the continental shelf and slope off Oregon and Washington, provides a long-term network of moorings, benthic nodes, cabled and uncabled sensors and gliders. It is part of a larger network of observatories on the Pacific Coast which also includes the OOI Regional Cabled Array, the OOI Global Station Papa Array and NOAA Pacific Marine Environmental Laboratory (PMEL) Surface Buoy, and Ocean Networks Canada observatories.
Scientific Motivation
The array focuses on observing inter-annual (e.g. El Niño-Southern Oscillation) and decadal (e.g. Pacific Decadal Oscillation) patterns. Instruments examine wind-driven upwelling and downwelling dynamics as well as the influence of the Columbia River on the coastal ecosystem.
Design
The array consists of two lines of moorings, one off Newport, Oregon (the Oregon Line) and the other off Grays Harbor, Washington (the Washington Line). The site for the Oregon Line was selected because it is close to the historic Newport Hydrographic Line, along which regular oceanographic sampling has occurred since 1961. The site of the Washington Line was selected as a companion line to the north. Both areas are influenced by the nearby Columbia River plume, the largest source of freshwater to the US west coast.
Glider observations span 500 km from northern Washington (~48°N) to Coos Bay, Oregon (~43°N). Gliders sample from 20 m isobaths between the mooring lines along one north–south transect at 126°W and five east–west transects out to 126°W or to 128°W for transects intersecting with the arrays. Some Endurance Array Oregon Line infrastructure connects to the RSN cabled network to provide enhanced power and communications for observing water column and seafloor processes.
Global Arrays
Locations of the global arrays were selected by a team of scientists (~300 people) based on regions that are under-sampled and subject to extreme conditions (e.g., high winds and sea states) that are challenging for continuous or even frequent ship-based measurements. The planned global study sites included instrumented moorings and gliders in four locations: Argentine Basin; Irminger Sea; Southern Ocean; and Station Papa. The Global Argentine Basin Array and the Global Southern Ocean Array were decommissioned in 2018 and 2020, respectively. The global arrays are developed and operated by Woods Hole and Scripps.
Observations from these high latitude areas are critical to understanding ocean circulation and climate change processes. The global arrays include moorings composed of fixed and moving sensors that measure air-sea fluxes of heat, moisture, and momentum—as well as physical, biological, and chemical properties of the water column. Each array also includes gliders to sample within the array's footprint.
Global Irminger Sea Array
Scientific Motivation
The Global Irminger Sea Array is located in the North Atlantic off the southern tip of Greenland. High winds and waves drive strong atmosphere-ocean interactions, including energy and gas exchanges that contribute to CO2 sequestration and the region's high biological productivity and fisheries. This area is also a site of North Atlantic Deep Water formation, important to the large-scale thermohaline circulation of ocean water.
Design
The Irminger Sea Array includes a set of four moorings. With a distance between moorings approximately ten times that of the water depth, the array is able to collect data on the mesoscale variability. One mooring site consists of a paired Global Surface and subsurface Global Hybrid Profiler mooring. The other two sites consist of subsurface Global Flanking Moorings. The water above the subsurface Global Hybrid Profiler Mooring is sampled by vertically profiling gliders. The water in and around the array is sampled by open-ocean gliders collecting data on spatial variability. Data from the gliders is transmitted wirelessly though an acoustic modem to the moorings and to a satellite for transmission to OOI's servers. Wireless reprogramming of the gliders and certain parts of the array is also possible to collect data on sudden events or environmental changes.
Global Station Papa Array
Scientific Motivation
The Global Station Papa Array is located in the Gulf of Alaska North of the Coastal Endurance and Regional Cabled Arrays. The array is part of a larger network of observatories in the Northeast Pacific.
The three moorings of the array are co-located with the Ocean Station Papa surface buoy, which is maintained by the NOAA PMEL. This region is known for its productive fishery and low eddy variability, but it suffers from extreme vulnerability to ocean acidification. Continuous measurements of physical, biological, and chemical properties will help monitor mesoscale and large-scale patterns such as the Pacific Decadal Oscillation.
Design
The Global Station Papa Array is a set of three moorings. With a distance between moorings approximately ten times that of the water depth, the array is able to collect data on the mesoscale variability. Unlike the design of the Global Irminger Sea Array, the Global Station Papa array does not have an OOI Surface Mooring. Instead the subsurface Global Hybrid Profiler Mooring is co-located with the NOAA PMEL Surface Mooring at one corner of the triangle. Similar to the Global Irminger Sea Array, the other two corners are occupied by subsurface Global Flanking Moorings. The moorings are supplemented by open-ocean gliders that collect data on spatial variability in and around the array and vertically profiling gliders that sample the waters above the subsurface moorings. Data from the gliders is transmitted wirelessly though an acoustic modem from the moorings to a satellite for transmission to OOI's servers. Shore-based control of the gliders and certain parts of the array is used to collect data on sudden events or environmental changes.
Regional Cabled Array (RCA)
The Regional Cabled Array (RCA) consists of cabled arrays of ocean observing sensors in the Northeast Pacific Ocean. The RCA crosses the Juan de Fuca plate, making the RCA the first U.S. ocean observatory to span a tectonic plate. Its observations allow for the in-depth study of volcanic activity, methane seeps, hydrothermal vents, and submarine earthquakes, as well as biological, chemical, and physical processes in the overlying water column.
The platforms and sensors are connected by approximately 900 kilometers (560 miles) of electro-optical cable. The design provides high power (10 kV, 8 kW) and bandwidth (10 GbE) to sensor arrays on the seafloor and throughout the water column using moorings with instrumented wire-following profilers, 200 m instrumented platforms and winched profilers. The cables provide two-way real-time communication between the seafloor and water column instrumentation and the shore station in Pacific City, Oregon. The RCA was installed and operated by the University of Washington.
Seven large seafloor substations (Primary Nodes) provide power and bandwidth to six sites that include those on the Oregon shelf and Offshore sites of the Endurance Array. Two additional sites span the continental margin to the base of the slope. The slope base site is located about 125 km west of Newport, Oregon and sits at a depth of 2900 m. It hosts both seafloor and instrumented profiling moorings and allows investigation of the variability and interactions of deep ocean waters, the California Current, and upwelling. It provides the foundation for making connections of transport up the slope and understanding the connection of deep to shallow processes acting at the Oregon Offshore Site.
Other sites in the RCA focus on Southern Hydrate Ridge, an area of massive sub-seafloor gas-hydrate deposits and fluxes of methane from the seafloor into the ocean, and Axial Seamount, the most magmatically robust volcano on the Juan de Fuca Ridge spreading center that erupted in April 2011.
The RCA complements the NEPTUNE cabled observatory that Ocean Networks Canada operates on the northern Juan de Fuca plate. Together these observatories enable long-term, plate-scale seafloor and ocean investigations in the Northeast Pacific.
Cabled Continental Margin Array
Scientific Motivation
The Continental Margin portion of the RCA, located west of Newport, Oregon, focuses on observations of biogeochemical and physical oceanographic processes, coastal ecosystems, methane seeps/hydrate deposits, and seismic events along the Cascadia subduction zone west of Newport, Oregon.
Geophysical observations at the Slope Base site detect seismic and tsunami events associated with earthquakes along the Cascadia subduction zone and far field. This site also contains seafloor infrastructure and moorings with instrumented profilers designed to observe the deeper portions of the California Current, biogeochemical processes in the overlying water column including ocean acidification and thin layers, and topographic forcing of ocean waters induced by steep, rough topography.
Southern Hydrate Ridge is located in a region of buried deposits of methane hydrates and, more rarely, hydrates exposed on the seafloor. Methane-rich fluids and bubble plumes emitted from these seeps support dense benthic microbial communities and may provide a carbon source for the upper water column, supporting methane-oxidizing bacteria and larger organisms. As a potent greenhouse gas, it is also important to quantify methane released into the atmosphere. Destabilization of methane hydrates may also lead to slope failures, representing significant geohazards. New overview and quantification sonars funded by Germany through the Bremen University, for the first time, image all methane plumes emanating from Southern Hydrate Ridge.
Design
The Continental Margin Array includes infrastructure located on the continental slope and continental slope base that connects to the Endurance Array Oregon Line at the Offshore and Shelf sites. The Oregon slope base site is located by the Cascadia subduction zone, just off the continental slope. The Southern Hydrate Ridge site is located on the continental slope. Fiber-optic cables provide power and two-way communication to Junction Boxes, which house sensors and geophysical instruments such as seismometers and hydrophones. The three Junction Boxes at the Southern Hydrate Ridge include sensors that image and measure the methane hydrate plumes to help understand the movement and chemistry of these fluids. Junction Boxes paired with Cabled Deep and Shallow Profiler Moorings at the slope base site take observations throughout the water column from seafloor to ocean surface. Seafloor infrastructure includes a broadband seismometer and low frequency hydrophone to monitor local and far-field seismic events. All infrastructure is connected to the cable for power and real-time data flow coupled with live communications that permit event-response capabilities. Broadband hydrophones on the moorings from Axial to the Oregon Shelf site delineate mammal vocalizations, and sounds made by human activities.
Cabled Axial Seamount Array
Scientific Motivation
The Axial Seamount portion of the RCA is located more than 500 km offshore and includes sites located within the caldera of Axial Seamount and at its base. The Axial Seamount is an active submarine volcano and on the Juan de Fuca Ridge spreading center.
The Axial Caldera site is located on the summit of the seamount 1500 m below the sea surface. The observatory at the Axial Seamount is the most advanced underwater volcanic observatory in the world. Instrumentation at the Cabled Axial Seamount Array facilitate study of seismic activity, volcanic eruptions, hydrothermal vents, formation and alteration of oceanic crust, and how the temperature and chemical changes associated with volcanic activity affect microbial and macrofaunal communities.
Infrastructure within the caldera has also been augmented by instruments with funding from NSF, the Office of Naval Research and NASA. These instruments span broad science investigations into crustal deformation at the volcano with follow-on studies focused on Cascadia Subduction Zone earthquakes. New instruments funded by NASA will also provide insights into the search for life on other planets.
The Axial Base site is an open-ocean environment where the North Pacific Current/California Current interacts with the subpolar gyre, making this site an important place where heat, salt, gasses, and biota are transported. Data collection aims to find connections between ocean dynamics, ecosystems, and climate at a range of scales, from basin to regional level.
Design
The Axial Caldera site has five medium-power junction boxes that contain data-collecting instruments. Seismometers and hydrophones collect geophysical data. Pressure-tilt devices detect changes in seafloor height and angle associated with the inflation and deflation of the magma chambers. Several types of instruments including cameras, sensors, and a 3D thermistor array are used to study the hydrothermal vents.
At the Axial Base site, junction boxes are paired with a Cabled Deep Profiler Mooring and a Cabled Shallow Profiler Mooring. The Cabled Deep Profiler Mooring contains a Wire-Following Profiler that samples the water column from 150 m below the surface to near bottom (up to 2600 m, depending on water depth). The Cabled Shallow Profiler Mooring samples shallow waters (200 m to just below the surface) with an instrumented science pod. Seafloor infrastructure, such as a broadband seismometer and low-frequency hydrophone, allows the RCA to monitor local and far-field seismic events.
Fiber-optic cables provide power and two-way real-time communication to the instruments from the shore. Live communication allows event response capabilities.
Cyberinfrastructure
The OOI Cyberinfrastructure (CI) manages and integrates data from more than 800 instruments deployed across the five ongoing ocean arrays, linking the marine infrastructure to the global community of users.
Raw data from the arrays are transmitted to operations centers located in Pacific City (Regional Cabled Array), Oregon State University (uncabled instruments on the Pacific Coast), or Woods Hole Oceanographic Institution (uncabled instruments on the Atlantic coast). The data are then uploaded to the OOI CI.
The OOI CI has been in operation since 2013. As of May 2020, it has collected and curated 36 terabytes of data and has served over 189 million requests to users from more than 100 countries. All raw and processed datasets are made available online to users and a full archive of all raw datasets is stored in multiple locations. OOI data quality control procedures were designed with the goal of meeting the IOOS Quality Assurance of Real Time Ocean Data (QARTOD) standards.
The OOI Data Explorer is the primary tool to access datasets. Previous data from the OOI Data Portal is in the process of being transferred to the Data Explorer portal. Access to data and subsets of data is also available through the Raw Data Archive, the Analytical Data Archive, the OOI Environmental Research Division Data Access Program (ERDDAP) server, and the OOI Machine to Machine (M2M) API Interface.
References
External links
Ocean Observatories Initiative Website
Oregon State University – OOI Endurance Array
University of Washington – OOI Regional Component
Ocean Observatories Facility Board
Oceanography
Physical oceanography
Cyberinfrastructure | Ocean Observatories Initiative | [
"Physics",
"Technology",
"Environmental_science"
] | 5,637 | [
"Information and communications technology",
"Hydrology",
"Applied and interdisciplinary physics",
"IT infrastructure",
"Cyberinfrastructure",
"Oceanography",
"Physical oceanography"
] |
14,752,143 | https://en.wikipedia.org/wiki/Tekla%20Structures | Tekla Structures is a building information modeling software able to model structures that incorporate different kinds of building materials, including steel, concrete, timber and glass. Tekla allows structural drafters and engineers to design a building structure and its components using 3D modeling, generate 2D drawings and access building information. Tekla Structures was formerly known as Xsteel (X as in X Window System, the foundation of the Unix GUI).
Features
Tekla Structures is used in the construction industry for steel and concrete detailing, precast and cast in-situ. The software enables users to create and manage 3D structural models in concrete or steel, and guides them through the process from concept to fabrication. The process of shop drawing creation is automated. It is available in different configurations and localized environments.
Tekla Structures is known to support large models with multiple simultaneous users, but is regarded as relatively expensive, complex to learn and fully utilize. It competes in the BIM market with AutoCAD, Autodesk Revit, DProfiler and Digital Project, Lucas Bridge, PERICad and others. Tekla Structures is Industry Foundation Classes (IFC) compliant.
Modeling scopes within Tekla Structures includes Structural Steel, Cast-in-Place (CIP), Concrete, Reinforcing Bar, Miscellaneous Steel and Light Gauge Drywall Framing. The transition of Xsteel to Tekla Structures in 2004 added significant more functionality and interoperability. It is often used in conjunction with Autodesk Revit, where structural framing is designed in Tekla and exported to Revit using the DWG/DXF formats.
Applications
Engineers have used Tekla Structures to model stadiums, offshore structures, pipe rack structures, plants, factories, residential buildings, bridges and skyscrapers. Tekla Structures was used in the construction design for various projects around the world, including:
Grandstand Replacement, Daytona International Speedway (USA)
Frontstretch Grandstands, Daytona International Speedway (USA)
Denver International Airport Expansion (USA)
San Jose Earthquakes Stadium (USA)
BB&T Ballpark (Charlotte, USA)
Spillway Replacement, Manitoba Hydro (USA)
National Stadium Roof, Singapore Sports Hub (Singapore)
Red Bear Student Center, University of Saskatchewan (Canada)
Troja Bridge (Prague)
Tesco Supermarket (Sheringham, UK)
Baylor University Stadium (Australia)
Canopée des Halles, Forum des Halles (Paris, France)
Sutter Medical Center (California, USA)
Expansion, Chennai International Airport (India)
Dongdaemun Design Plaza (Seoul)
Capital Gate (Abu Dhabi)
Midfield Terminal Complex, Abu Dhabi Airport (Abu Dhabi)
King Abdullah Financial District (Saudi Arabia)
King Abdulaziz Center for World Culture (Saudi Arabia)
National Museum of Qatar (Qatar)
Hilton Garden Inn (UAE)
Puuvilla Shopping Centre (Finland)
College Football Hall of Fame (Atlanta, GA)
Optus Stadium (Perth, Australia)
Tekla Structures was used extensively for the steel design of Capital Gate at Abu Dhabi, UAE. Files exported from Tekla facilitated faster steel fabrication. One of the architects, Jeff Schofield, stated that "it was the right time in history and we had the right technology to make this happen".
The Manitoba Hydro Spillway Replacement was designed using Tekla Structures to "successfully model and co-ordinate its design", a project that won the TEKLA 2012 North American BIM Award for "Best Concrete Project". It was the "first hydroelectric project that has seen steel, concrete, and rebar fully detailed using Tekla Structures".
Stable version release - history dates
Tekla Structures 16.0 - March 2010
Tekla Structures 17.0 - February 2011
Tekla Structures 18.0 - March 2012
Tekla Structures 19.0 - March 2013
Tekla Structures 20.0 - February 2014
Tekla Structures 21.0 - March 2015
Tekla Structures 2016 - March 2016
Tekla Structures 2017 - March 2017
Tekla Structures 2018 - March 2018
Tekla Structures 2019 - March 2019
Tekla Structures 2020 - March 2020
Tekla Structures 2021 - March 2021
Tekla Structures 2022 - March 2022
Tekla Structures 2023 - March 2023
Tekla Structures 2024 - March 2024
See also
Comparison of CAD editors for CAE
References
Computer-aided design software
Building information modeling | Tekla Structures | [
"Engineering"
] | 870 | [
"Construction",
"Building information modeling",
"Building engineering",
"Construction software"
] |
14,752,773 | https://en.wikipedia.org/wiki/Boveri%E2%80%93Sutton%20chromosome%20theory | The Boveri–Sutton chromosome theory (also known as the chromosome theory of inheritance or the Sutton–Boveri theory) is a fundamental unifying theory of genetics which identifies chromosomes as the carriers of genetic material. It correctly explains the mechanism underlying the laws of Mendelian inheritance by identifying chromosomes with the paired factors (particles) required by Mendel's laws. It also states that chromosomes are linear structures with genes located at specific sites called loci along them.
It states simply that chromosomes, which are seen in all dividing cells and pass from one generation to the next, are the basis for all genetic inheritance.
Over a period of time random mutation
creates changes in the DNA sequence of a gene. Genes are located on chromosomes.
Background
The chromosome theory of inheritance is credited to papers by Walter Sutton in 1902 and 1903, as well as to independent work by Theodor Boveri during roughly the same period. Boveri was studying sea urchins, in which he found that all the chromosomes had to be present for proper embryonic development to take place. Sutton's work with grasshoppers showed that chromosomes occur in matched pairs of maternal and paternal chromosomes which separate during meiosis and "may constitute the physical basis of the Mendelian law of heredity".
This groundbreaking work led E.B. Wilson in his classic text to name the chromosome theory of inheritance the "Sutton-Boveri Theory". Wilson was close to both men since the young Sutton was his student and the prominent Boveri was his friend (in fact, Wilson dedicated the aforementioned book to Boveri). Although the naming precedence is now often reversed to "Boveri-Sutton", there are some who argue that Boveri did not actually articulate the theory until 1904.
Verification
The proposal that chromosomes carried the factors of Mendelian inheritance was initially controversial, but in 1905 it gained
strong support when Nettie Stevens showed that the "accessory chromosome" of mealworms' sperm cells was decisive in the sex identity of the progeny, a discovery supported by her mentor E.B. Wilson. Later, Eleanor Carothers documented definitive evidence of independent assortment of chromosomes in a species of grasshopper. Debate continued, however, until 1915 when Thomas Hunt Morgan's work on inheritance and genetic linkage in the fruit fly Drosophila melanogaster provided incontrovertible evidence for the proposal. The unifying theory stated that inheritance patterns may be generally explained by assuming that genes are located in specific sites on chromosomes.
References
External links
Each Organism's Traits Are Inherited from a Parent through Transmission of DNA SciTable by Nature Education.
Biology theories
Cell biology
History of genetics | Boveri–Sutton chromosome theory | [
"Biology"
] | 544 | [
"Cell biology",
"Biology theories"
] |
14,753,571 | https://en.wikipedia.org/wiki/3C%2020 | 3C 20 is a radio galaxy located in the constellation Cassiopeia. It is one of largest known galaxies with a diameter of . The galaxy features a prominent double hotspot in its eastern lobe. An unusually low fraction of the flux lies within the radio core, which is suggested to be caused by a combination of factors, including jet orientation, synchrotron self-absorption and aging, as well as interactions with surrounding gas and dust.
References
Notes
Radio galaxies
Cassiopeia (constellation)
020
+51.02
2817481 | 3C 20 | [
"Astronomy"
] | 114 | [
"Cassiopeia (constellation)",
"Galaxy stubs",
"Astronomy stubs",
"Constellations"
] |
14,753,714 | https://en.wikipedia.org/wiki/Chapter%20book | A chapter book is a story book intended for intermediate readers, generally age 7–10. Unlike picture books for beginning readers, a chapter book tells the story primarily through prose rather than pictures. Unlike books for advanced readers, chapter books contain plentiful illustrations. The name refers to the fact that the stories are usually divided into short chapters, which provide readers with opportunities to stop and resume reading if their attention spans are not long enough to finish the book in one sitting. Chapter books are usually works of fiction of moderate length and complexity.
Examples
Flat Stanley (1964) by Jeff Brown
Busybody Nora (1976) by Johanna Hurwitz
References
Books by type
Children's literature
Components of intellectual works | Chapter book | [
"Technology"
] | 141 | [
"Components of intellectual works",
"Components"
] |
14,753,789 | https://en.wikipedia.org/wiki/APBB1 | Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.
Function
The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants have been described for this gene but some of their full length sequence is not known.
Interactions
APBB1 has been shown to interact with APLP2, TFCP2, LRP1 and Amyloid precursor protein.
References
External links
Further reading
Proteins | APBB1 | [
"Chemistry"
] | 228 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,753,839 | https://en.wikipedia.org/wiki/GTF2I | General transcription factor II-I is a protein that in humans is encoded by the GTF2I gene.
Function
This gene encodes a multifunctional phosphoprotein, TFII-I, with roles in transcription and signal transduction. Haploinsuffiency (deletion of one copy) of the GTF2I gene is noted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23. It is duplicated in the 7q11.23 duplication syndrome. The exon(s) encoding 5' UTR has not been fully defined, but this gene is known to contain at least 34 exons, and its alternative splicing generates 4 transcript variants in humans. A single gain-of-function point mutation in GTF2I is also found in certain Thymomas. Single nucleotide polymorphism (SNP) in GTF2I is correlated to autoimmune disorders.
Interactions
GTF2I has been shown to interact with:
Bruton's tyrosine kinase,
HDAC3,
Histone deacetylase 2,
MAPK3,
Myc,
PRKG1,
Serum response factor and
USF1 (human gene).
References
Further reading
External links
Transcription factors | GTF2I | [
"Chemistry",
"Biology"
] | 281 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,753,852 | https://en.wikipedia.org/wiki/PlatBox%20Project | PlatBox Project, formally known as Boxed Economy Project, is a multi-agent based computer simulation software development project founded by Iba Laboratory at Keio University, Japan. The main work of PlatBox Project is to develop PlatBox Simulator and Component Builder, which are claimed to be the first multi-agent computer simulation software that do not require end-users to have any computer programming skill in order to create and execute multi-agent computer simulation models. Currently, the project is organized by Takashi Iba, assistant professor from Keio University, and Nozomu Aoyama. PlatBox Simulator and Component Builder are currently offered only in Japanese; however, the English version is expected to be out anytime soon.
PlatBox Simulator
PlatBox Simulator is a multi-agent based simulation platform developed by PlatBox Project.
ComponentBuilder
ComponentBuilder is a multi-agent based simulation modeling tool developed by PlatBox Project.
See also
Agent-based model
Repast (modeling toolkit)
Articles
Resolving the Existing Problems by Boxed Economy Simulation Platform. T. Iba, Y. Chubachi, Y. Matsuzawa, K. Asaka, K. Kaiho, Agent-based Approaches in Economic and Social Complex Systems, A. Namatame, et al. (eds.), IOS Press, 2002, pp. 59–68.
Boxed Economy Foundation Model: Toward Simulation Platform for Agent-Based Economic Simulations. T. Iba, Y. Takabe, Y. Chubachi, J. Tanaka, K. Kamihashi, R. Tsuya, S. Kitano, M. Hirokane, Y. Matsuzawa, New Frontiers in Artificial Intelligence, Takao Terano, Toyoaki Nishida, Akira Namatame, Syusaku Tsumoto, Yukio Ohsawa, Takashi Washio (Eds.), Springer-Verlag, 2001, pp. 227–236
Iterated Prisoners' Dilemma on Alliance Networks. T. Furukawazono, Y. Takada, T. Iba, International Workshop and Conference on Network Science 2007, New York, May, 2007
Understanding Social Complex Systems with PlatBox Simulator. T. Iba, The 5th International Conference on Computational Intelligence in Economics and Finance (CIEF2006), Taiwan, Oct., 2006 (pp. 64–67)
Building a Simulation Model of the Currency Basket Peg System. M. Kunitomo, T. Iba, H. Takayasu, The 5th International Conference on Computational Intelligence in Economics and Finance (CIEF2006), Taiwan, Oct.,2006 (pp. 129–132)
Building a Simulation Model of Foreign Exchange Market: Reproduction of Yen Dollar Market. A. Usami, R. Tsuya, T. Iba, H. Takayasu, The 5th International Conference on Computational Intelligence in Economics and Finance (CIEF2006), Taiwan, Oct., 2006 (pp. 133–136)
Consumer Network and Market Dynamics. S. Itoh, Y. Murakami, T. Iba, The 5th International Conference on Computational Intelligence in Economics and Finance (CIEF2006), Taiwan, Oct., 2006 (pp. 22–25)
Analysis of Factors which Contribute to Inter-Enterprise Competition. T. Shimizu, Y. Takada, T. Iba, The 5th International Conference on Computational Intelligence in Economics and Finance (CIEF2006), Taiwan, Oct., 2006 (pp. 68–71)
A Collaborative Tool for Modeling and Simulating Social Complex Systems. T. Iba, N. Aoyama, Y. Takada, Y. Murakami, The First International Conference on Knowledge, Information and Creativity Support Systems (KICSS2006), Thailand, Aug., 2006 (pp. 239–244)
Social Interaction Models: Toward A Platform for Infection Transmission Science. Takashi Iba, International Symposium on Trends in Transmission Models for Infectious Diseases 2005 - Modeling Biology Focusing on Social Risk Assessment-, Tokyo, Japan, 2005
Development Tools of Simulation Models with MDA. Nozomu Aoyama, Rintaro Takeda, Takashi Iba, Hajime Ohiwa, International Workshop on Massively Multi-Agent Systems, Kyoto, Japan, Dec. 2004
A Framework and Tools for Modeling and Simulating Societies as Evolutionary Complex Systems. Takashi Iba, 2nd International Conference of the European Social Simulation Association, Spain, Sep, 2004
Analysis on the Factor of Price Volatility in Deregulated Electric Power Market. Ryunosuke Tsuya, Naoto Sato, Takashi Iba, Yyoshiyasu Takefuji, 2nd International Conference of the European Social Simulation Association, Spain, Sep, 2004
From Conceptual Models to Simulation Models: Model Driven Development of Agent-Based Simulations. Takashi Iba, Yoshiaki Matsuzawa, Nozomu Aoyama, 9th Workshop on Economics and Heterogeneous Interacting Agents, Kyoto, Japan, May 2004.
Boxed Economy Foundation Model. T. Iba, Y. Chubachi, Y. Takabe, K. Kaiho, and Y. Takefuji, The AAAI-02 Workshop on Multi-Agent Modeling and Simulation of Economic Systems, pp. 78–83, Canada, July 2002.
Boxed Economy Simulation Platform for Agent-Based Economic and Social Modeling. T. Iba, Y. Takefuji, Computational Analysis of Social and Organizational Systems 2002, Pittsburgh, USA, June 2002.
Boxed Economy Simulation Platform and Foundation Model. T. Iba, Y. Takabe, Y. Chubachi, Y. Takefuji, Workshop of Emergent Complexity of Artificial Markets, 4th International Conference on Computational Intelligence and Multimedia Applications, pp. 34–38, Kanagawa, October 2001.
Boxed Economy Foundation Model: Toward Simulation Platform for Agent-Based Economic Simulations. T. Iba, Y. Takabe, Y. Chubachi, J. Tanaka, K. Kamihashi, R. Tsuya, S. Kitano, M. Hirokane, Y. Matsuzawa, JSAI 2001 International Workshop on Agent-based Approaches in Economic and Social Complex Systems, Matsue, May 2001, pp. 186–193
Exploratory Model Building: Toward Agent-Based Economics. T. Iba, M. Hirokane, H. Kawakami, H. Takenaka, Y. Takefuji, International Session, The 4th Annual Meeting of the Japan Association for Evolutionary Economics, Tokyo, March 2000.
Boxed Economy Model : Fundamental Concepts and Perspectives. T. Iba, M. Hirokane, Y. Takabe, H. Takenaka, Y. Takefuji, First International Workshop on Computational Intelligence in Economics and Finance, Atlantic City, U.S., March 2000.
External links
PlatBox Project
Software projects | PlatBox Project | [
"Technology",
"Engineering"
] | 1,411 | [
"Software projects",
"Information technology projects"
] |
14,753,859 | https://en.wikipedia.org/wiki/ING1 | Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.
Function
This gene encodes a tumor suppressor protein that can induce cell growth arrest and apoptosis. The encoded protein is a nuclear protein that physically interacts with the tumor suppressor protein TP53 and is a component of the p53 signaling pathway. Reduced expression and rearrangement of this gene have been detected in various cancers. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported.
One of the isoforms of ING1 (p33(ING1) is involved in the modulation of DNA repair. It appears that p33(ING1) cooperates with p53 in nucleotide excision repair. Also, proliferating cell nuclear antigen (PCNA) interacts with p33(ING1b) in the elimination of UV-damaged cells through the induction of programmed cell death (apoptosis).
Location on Chromosome 13
ING1 is located near the following genes on Chromosome 13
CARKD Carbohydrate Kinase Domain-Containing Protein (Unknown Function)
COL4A2: A2 Subunit of type IV collagen
RAB20: Potential regulator of Connexin 43 trafficking.
CARS2: Mitochondrial Cystienyl-tRNA Synthetase 2
Interactions
ING1 has been shown to interact with:
CREB binding protein,
DMAP1,
HDAC1,
P53,
PCNA,
SAP30,
SIN3A,
SMARCA4, and
SMARCC1.
References
Further reading
External links
Transcription factors | ING1 | [
"Chemistry",
"Biology"
] | 321 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,753,869 | https://en.wikipedia.org/wiki/MAX%20%28gene%29 | MAX (also known as myc-associated factor X) is a gene that in humans encodes the MAX transcription factor.
Function
The protein product of MAX contains the basic helix-loop-helix and leucine zipper motifs. It is therefore included in the bHLHZ family of transcription factors. It is able to form homodimers with other MAX proteins and heterodimers with other transcription factors, including Mad, Mxl1 and Myc. The homodimers and heterodimers compete for a common DNA target site (the E-box) in a gene promoter zone. Rearrangement of dimers (e.g., Mad:Max, Max:Myc) provides a system of transcriptional regulation with greater diversity of gene targets. Max must dimerise in order to be biologically active.
Transcriptionally active hetero- and homodimers involving Max can promote cell proliferation as well as apoptosis.
Interactions
The protein product of Max has been shown to interact with:
Myc,
MNT,
MSH2,
MXD1,
MXI1,
MYCL1,
N-Myc,
SPAG9,
TEAD1, and
Transformation/transcription domain-associated protein.
Clinical relevance
This gene has been shown mutated in cases of hereditary pheochromocytoma. More recently the Max gene becomes mutated and becomes inactivated in small cell lung cancer (SCLC). This is mutually exclusive with alterations at Myc and BRG1, the latter coding for an ATPase of the SWI/SNF complex. It was demonstrated that the BRG1 product regulates the expression of Max through direct recruitment to the Max promoter region, and that depletion of BRG1 strongly hinders cell growth, specifically in Max-deficient cells, suggesting that the two together cause synthetic lethality. Furthermore, Max required BRG1 to activate neuroendocrine transcriptional programs and to up-regulate Myc targets, such as glycolytic-related genes.
References
Further reading
External links
Transcription factors | MAX (gene) | [
"Chemistry",
"Biology"
] | 422 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,753,919 | https://en.wikipedia.org/wiki/PAX8 | Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.
Function
This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth. The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the Müllerian system, and the thymus. Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells. PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr).
PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis. They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development.
PAX8 has been shown to interact with NK2 homeobox 1.
Clinical significance
The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development. These mutations can affect different functions of the protein including DNA binding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
Cancer
PAX8 mutations are associated with various forms of cancer.
Mechanisms
PAX8 is considered a "master regulator transcription factor". As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific. Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells. Over 90% of thyroid tumors arise from follicular thyroid cells. A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma. The mechanism for this transformation is not well understood, but there are several proposed possibilities.
Inhibition of normal PPARy function by chimeric PAX8/PPARy protein through a dominant negative effect
Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y
Deregulation of PAX8 function
Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways
The PAX 8 gene has some association with follicular thyroid tumors. It has been observed that PAX8/PPAR y-positive tumors rarely express RAS mutations in combination. This suggests that follicular carcinomas develop in two distinct pathways either with PAX8/PPAR y or RAS.
Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The mechanism of switching on the genes is unknown. Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis. Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis. This could be a possible avenue for therapeutic targets in renal cancer.
Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes). PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion.
Associated cancer types
Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas.
PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas., and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).
Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas. For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors. Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas. Expression of PAX8 is also induced during the development of cervical cancer.
Tumors expressing the PAX8/PPARy are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion.
See also
Pax genes
References
Further reading
External links
Transcription factors | PAX8 | [
"Chemistry",
"Biology"
] | 1,191 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,753,970 | https://en.wikipedia.org/wiki/Multiplicative%20partition | In number theory, a multiplicative partition or unordered factorization of an integer is a way of writing as a product of integers greater than 1, treating two products as equivalent if they differ only in the ordering of the factors. The number is itself considered one of these products. Multiplicative partitions closely parallel the study of multipartite partitions, which are additive partitions of finite sequences of positive integers, with the addition made pointwise. Although the study of multiplicative partitions has been ongoing since at least 1923, the name "multiplicative partition" appears to have been introduced by . The Latin name "factorisatio numerorum" had been used previously. MathWorld uses the term unordered factorization.
Examples
The number 20 has four multiplicative partitions: 2 × 2 × 5, 2 × 10, 4 × 5, and 20.
3 × 3 × 3 × 3, 3 × 3 × 9, 3 × 27, 9 × 9, and 81 are the five multiplicative partitions of 81 = 34. Because it is the fourth power of a prime, 81 has the same number (five) of multiplicative partitions as 4 does of additive partitions.
The number 30 has five multiplicative partitions: 2 × 3 × 5 = 2 × 15 = 6 × 5 = 3 × 10 = 30.
In general, the number of multiplicative partitions of a squarefree number with prime factors is the th Bell number, .
Application
describe an application of multiplicative partitions in classifying integers with a given number of divisors. For example, the integers with exactly 12 divisors take the forms , , , and , where , , and are distinct prime numbers; these forms correspond to the multiplicative partitions , , , and respectively. More generally, for each multiplicative partition
of the integer , there corresponds a class of integers having exactly divisors, of the form
where each is a distinct prime. This correspondence follows from the multiplicative property of the divisor function.
Bounds on the number of partitions
credits with the problem of counting the number of multiplicative partitions of ; this problem has since been studied by others under the Latin name of factorisatio numerorum. If the number of multiplicative partitions of is , McMahon and Oppenheim observed that its Dirichlet series generating function has the product representation
The sequence of numbers begins
Oppenheim also claimed an upper bound on , of the form
but as showed, this bound is erroneous and the true bound is
Both of these bounds are not far from linear in : they are of the form .
However, the typical value of is much smaller: the average value of , averaged over an interval , is
a bound that is of the form .
Additional results
observe, and prove, that most numbers cannot arise as the number of multiplicative partitions of some : the number of values less than which arise in this way is . Additionally, Luca et al. show that most values of are not multiples of : the number of values such that divides is .
See also
Partition (number theory)
Divisor
References
Further reading
External links
Number theory
Integer sequences | Multiplicative partition | [
"Mathematics"
] | 663 | [
"Sequences and series",
"Discrete mathematics",
"Integer sequences",
"Mathematical structures",
"Recreational mathematics",
"Mathematical objects",
"Combinatorics",
"Numbers",
"Number theory"
] |
14,753,989 | https://en.wikipedia.org/wiki/Sky-Watcher | Sky-Watcher is a commercial distribution company established in 1999 by the Synta Technology Corporation of Taiwan (Synta Taiwan). It markets telescopes and astronomy equipment, such as mounts and eyepieces, aimed at the amateur astronomy market. The products are manufactured at Synta Taiwan's Suzhou Synta Optical Technology Co., Ltd. in Suzhou (Jiangsu), China. The brand is distributed in Canada, Europe and in the late 2000s, it was extended to the United States market.
Company history
In 1999, the Sky-Watcher brand was established to sell Synta Taiwan's optics, with head offices in Richmond, British Columbia, Canada. They began producing Dobsonian telescopes in 2000, followed by Maksutov–Cassegrains in 2001, and Apochromat ED-APO refracting telescopes in 2004.
Sky-Watcher sells telescopes from 2.4" (62mm) up to 16" (406mm) aperture with manual, motor-driven, or GoTo mounts. Since 2008, Sky-Watcher has manufactured Dobsonians with collapsible tubes, a product line they call Flex Tube-Dobsonians.
Products
Sky-Watcher products include telescopes, spotting scopes, mounts, and other accessories.
References
External links
Official Sky-Watcher International website
Official Canadian website
Sky-Watcher U.S.A Telescopes and Optics
Telescope manufacturers
Companies based in Suzhou
Chinese companies established in 1999
Chinese brands
Taiwanese brands | Sky-Watcher | [
"Astronomy"
] | 300 | [
"Telescope manufacturers",
"People associated with astronomy"
] |
14,754,020 | https://en.wikipedia.org/wiki/DDR1 | Discoidin domain receptor family, member 1, also known as DDR1 or CD167a (cluster of differentiation 167a), is a human gene.
Function
Receptor tyrosine kinases (RTKs) play a key role in the communication of cells with their microenvironment. These molecules are involved in the regulation of cell growth, differentiation and metabolism. The protein encoded by this gene is a RTK that is widely expressed in normal and transformed epithelial cells and is activated by various types of collagen. This protein belongs to a subfamily of tyrosine kinase receptors with a homology region to the Dictyostelium discoideum protein discoidin I in their extracellular domain. Its autophosphorylation is achieved by all collagens so far tested (type I to type VI). A closely related family member is the DDR2 protein. In situ studies and Northern-blot analysis showed that expression of this encoded protein is restricted to epithelial cells, particularly in the kidney, lung, gastrointestinal tract, and brain. In addition, this protein is significantly over-expressed in several human tumors from breast, ovarian, esophageal, and pediatric brain. This gene is located on chromosome 6p21.3 in proximity to several HLA class I genes. Alternative splicing of this gene results in multiple transcript variants.
References
Further reading
Clusters of differentiation
Tyrosine kinase receptors | DDR1 | [
"Chemistry"
] | 303 | [
"Tyrosine kinase receptors",
"Signal transduction"
] |
14,754,029 | https://en.wikipedia.org/wiki/CUTL1 | Cux1 (CUTL1, CDP, CDP/Cux) is a homeodomain protein that in humans is encoded by the CUX1 gene.
Function
The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It regulates gene expression, morphogenesis, and differentiation and it also plays a role in cell cycle progression, particularly at S-phase. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined, and the p200 isoform of Cux1 is processed proteolytically to smaller active isoforms, such as p110. Cux1 DNA binding is stimulated by activation of the PAR2/F2RL1 cell-surface G-protein-coupled receptor in fibroblasts and breast-cancer epithelial cells to regulate Matrix metalloproteinase 10, Interleukin1-alpha, and Cyclo-oxygenase 2 (COX2) genes.
Role in tumor growth
Genetic data from over 7,600 cancer patients shows that over 1% has the deactivated CUX1 which links to progression of tumor growth. Researchers from the Wellcome Trust Sanger Institute reported that the mutation of CUX1 reduces the inhibitory effects of a biological inhibitor, PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), resulted in higher activity of the growth promoting enzyme, phosphoinositide 3-kinase (PI3K) which leads to tumor progression. Although CUX1 is mutated at a lower rate compared to other known gene mutations that cause cancer, this deactivated gene is found across many cancer types in this study to be the underlying cause of the disease.
CASP
The CUX1 gene Alternatively Spliced Product was first reported in 1997. The CUX1 gene has up to 33 exons. CASP mRNA includes exons 1 through 14 and 25 through 33. The human CASP protein is predicted to contain 678 amino acids, of which 400 are shared with CUTL1. CASP protein is approximately 80 kD. It lacks the DNA binding region of CUTL1, but instead contains a trans-membrane domain that allows it to insert into lipid bilayers. It has been localized to the Golgi apparatus.
CASP has been reported to be part of a complex with Golgin 84 that tethers COPI vesicles and is important for retrograde transport in the Golgi and between the Golgi and endoplasmic reticulum. The targeting of vesicles involves tethers and SNAREs.
Interactions
Cux1 (CUTL1, CDP, CDP/Cux) has been shown to interact with:
CREB binding protein,
Retinoblastoma protein, and
SATB1
These physical interactions are reported in BioPlex 2.0
MAGEA10
EXT2
RAB30
HLA-DQA1
STX6
WDR83
SLC39A4
LAMP1
POTEB
SLC39A12
Notes
References
Further reading
External links
Transcription factors | CUTL1 | [
"Chemistry",
"Biology"
] | 656 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,039 | https://en.wikipedia.org/wiki/KCNA5 | Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.
Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. KCNA5 encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization, thereby contributing to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Mutations in this gene have been related to both atrial fibrillation and sudden cardiac death. KCNA5 are also key players in pulmonary vascular function, where they play a role in setting the resting membrane potential and its involvement during hypoxic pulmonary vasoconstriction.
Interactions
KCNA5 has been shown to interact with DLG4, PDZ domain-containing proteins such as SAP97, and Actinin, alpha 2.
See also
Voltage-gated potassium channel
References
Further reading
External links
Ion channels | KCNA5 | [
"Chemistry"
] | 283 | [
"Neurochemistry",
"Ion channels"
] |
14,754,054 | https://en.wikipedia.org/wiki/PITX2 | Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth, and abdominal organs. This protein acts as a transcriptional regulator involved in the basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.
Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells. There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.
Studies have shown that in chick embryos, Pitx2 is a direct regulator of cVg1, a growth factor homologous to mammalian GDF1. cVg1 is a Transforming growth factor beta signal that is expressed posteriorly before the formation of the embryo germ layers. The Pitx2 regulation of cVg1 is essential both during normal embryonic development and during establishment of polarity in twins created by experimental division of a single, original embryo. Pitx2 is shown to be essential for upregulation of cVg1 through the binding of enhancers, and is necessary for the proper expression of cVg1 in the posterior marginal zone. Expression of cVg1 in the PMZ is in turn necessary for the proper development of the primitive streak. Experimental knockouts of the PITX2 gene are associated with the subsequent upregulation of related Pitx1, which is able to partially compensate for the loss of Pitx2. Pitx2's ability to regulate the polarity of the embryo may be responsible for the ability of developing chicks to establish proper polarity in embryos created by cuts performed as late as the blastoderm stage.
Pitx2 plays a role in limb myogenesis. Pitx2 can determine the development and activation of the MyoD gene (the gene responsible for skeletal myogenesis). Studies have shown that expression of Pitx2 happens before MyoD is expressed in muscles. Further studies show that Pitx2 is directly recruited to act on the MyoD core enhancer and thus, directing the expression of the MyoD gene. Pitx 2 is in a parallel pathway with Myf5 and Myf6, as both paths effect expression of MyoD. However, in the absence of the parallel pathway, Pitx2 can continue activating MyoD genes. The expression of Pitx2 saves MyoD gene expression and keeps expressing this gene for limb myogenesis. Yet, the Pitx 2 pathway is PAX3 dependent and requires this gene to enact limb myogenesis. Studies support this finding as in the absence of PAX3, there is Pitx2 expression deficit and thus, MyoD does not express itself in limb myogenesis. The Pitx2 gene is thus shown to be downstream of Pax3 and serve as an intermediate between Pax3 and MyoD. In conclusion, Pitx2 plays an integral role in limb myogenesis.
Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.
Pitx2 expression has been shown to be important for normal anterior pituitary gland development. Studies using mice embryos established Pitx2 expression is required in a dosage dependent manner. Mice with a homozygous null mutation of the Pitx2 gene showed that it is not required for initial pituitary formation but is needed for further development. Littermates of normal homozygotes, Pitx2+/+, versus homozygous null, Pitx2-/-, at embryonic day 10.5 provided a comparison of differing pouch sizes and cell types. Mice with the homozygous null gene had a smaller pouch and mesenchymal cell growth and differentiation arrested. While embryos with a hypomorphic mutation, Pitx2neo/+, of the gene were considered morphologically normal. Along with normal pituitary expansion, Pitx2 is needed for normal expression of cell transcription genes of hormones produced in the anterior pituitary. Of which are luteinizing hormone (LH), follicle stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), growth hormone (GH), and thyroid stimulating hormone (TSH). A study conducted using Pitx2neo/neo mice at postnatal day 1, found the transcripts of hormone genes for LH beta (LHb) and FSH beta (FSHb), and GnRH receptor (GnRHR) were nearly absent or nearly abolished, respectively. While transcription genes for GH and TSH producing cells, and growth hormone releasing hormone receptor (GHRHR) of Pitx2neo homozygous mice were moderately reduced. Further analysis of the transcription factors, Gata2, Egr1 and SF1, involved in LHb and FSHb differentiation found a reduction or absence of them in Pitx2neo/neo mice. The transcription factors, Prop1 and Pit1, which control development of GH and TSH producing cells, were also studied in Pitx2neo homozygous mice but only Pit1 expression was reduced. A reduction or absence of the transcription factors of the gonadotropin cells of the anterior pituitary leads to a loss of full pituitary cell function.
Clinical significance
Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.
Pitx2 is overexpressed in many cancers. For example, thyroid, ovarian, and colon cancer all have higher levels of Pitx2 compared to noncancerous tissues. Scientists speculate that cancer cells improperly turn on Pitx2, leading to uncontrolled cell proliferation. This is consistent with the role of Pitx2 in regulating the growth-regulating genes cyclin D2, cyclin D1, and C-Myc.
In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1. Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1. Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents. In experiments where Pitx2 expression was decreased, renal cancer cells had decreased cell proliferation and greater susceptibility to doxorubicin treatment, which is consistent with other results.
In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells. In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC. Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression. Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.
In Congenital Heart Disease, heterozygous mutations in Pitx2 have been involved in the development of Tetralogy of Fallot, ventricular septal defects, atrial septal defects, transposition of great arteries, and endocardial cushion defect (ECD). The mutations of the Pitx2 gene are created through alternative splicing. The isoform of Pitx2 important for cardiogenesis is Pitx2c. The lack of expression of this particular isoform correlates with these congenital defects. Pitx2 mutations significantly reduce transcriptional activity of Pitx2 and synergistic activation between Pitx2 and NKX2(also important for development of the heart). The large phenotypic spectrum due to the mutation of Pitx2 may be attributed to a variety of factors including: different genetic backgrounds, epigenetic modifiers and delayed/complete penetrance. The mutation of Pitx2 is not defined as the cause of these congenital heart defects, but currently perceived as a risk factor for their development.
Studies have also shown that Pitx2 displays an oncogenic role that is correlated with patients that have lung adenocarcinoma (LUAD). Pitx2 was overexpressed in LUAD when compared with neighboring normal tissues and is reported to increase clinical stages of the carcinoma and decrease survival. Patients with LUAD that presented with higher levels of Pitx2 had a lower overall survival rate compared to those with lower levels of Pitx2. The Pitx2 gene plays a role in lung adenocarcinoma that is dependent on activating the Wnt/β-catenin signaling pathway. When analyzing experimental findings from this Wnt/β-catenin signaling pathway, a TCGA dataset showed that Pitx2 had a positive correlation with WNT3A. These results propose that Pixt2 is directly bound to the WNT3A promoter region which will enhance WNT3A's transcription. This transcriptional regulation of WNT3A has been reported to encourage migration and the infiltration process of LUAD which can worsen a LUAD patients’ prognosis. Experimental knockdown of Pixt2 repressed tumor growth of LUAD; this supports the claim that Pixt2 is associated with the tumorigenesis of cancers, specifically in lung adenocarcinoma. These results suggest that Pitx2 may have a potential to serve as a biomarker for patients that present with LUAD.
References
Further reading
External links
Transcription factors | PITX2 | [
"Chemistry",
"Biology"
] | 2,361 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,119 | https://en.wikipedia.org/wiki/Bestrophin%201 | Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene (RPD ID - 5T5N/4RDQ).
The bestrophin family of proteins comprises four evolutionary related genes (BEST1, BEST2, BEST3, and BEST4) that code for integral membrane proteins. This family was first identified in humans by linking a BEST1 mutation with Best vitelliform macular dystrophy (BVMD). Mutations in the BEST1 gene have been identified as the primary cause for at least five different degenerative retinal diseases.
The bestrophins are an ancient family of structurally conserved proteins that have been identified in nearly every organism studied from bacteria to humans. In humans, they function as calcium-activated anion channels, each of which has a unique tissue distribution throughout the body. Specifically, the BEST1 gene on chromosome 11q13 encodes the Bestrophin-1 protein in humans whose expression is highest in the retina.
Structure
Gene
The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the four bestrophin genes has a unique 3-prime end of variable length.
BEST1 has been shown by two independent studies to be regulated by Microphthalmia-associated transcription factor.
Protein
Bestrophin-1 is an integral membrane protein found primarily in the retinal pigment epithelium (RPE) of the eye. Within the RPE layer, it is mainly located on the basolateral plasma membrane. Protein crystallization structures indicate this protein's primary ion channel function as well as its calcium regulatory capabilities. Bestrophin-1 consists of 585 amino acids and both N- and the C-termini are located within the cell.
The structure of Best1 consists of five identical subunits that each span the membrane four times and form a continuous, funnel-shaped pore via the second transmembrane domain containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The pore is lined with various nonpolar, hydrophobic amino acids. Both the structure and the composition of the pore help to ensure that only small anions are able to move completely through the channel. The channel acts as two funnels working together in tandem. It begins with a semi-selective, narrow entryway for anions, and then opens to a larger, positively charged area which then leads to a narrower pathway that further limits the size of anions passing through the pore. A calcium clasp acts as a belting mechanism around the larger, middle section of the channel. Calcium ions control the opening and closing of the channel due to conformational changes caused by calcium binding at the C-terminus directly following the last transmembrane domain.
Tissue and subcellular distribution
The location of expression of the BEST1 gene is essential for protein functioning and mislocalization is often connected to a variety of retinal degenerative diseases. The BEST1 gene expresses the Best1 protein primarily in the cytosol of the retinal pigment epithelium. The protein is typically contained in vesicles near the cellular membrane. There is also research to support that the Best1 protein is localized and produced in the endoplasmic reticulum (intracellular organelle involved in protein and lipid synthesis). Best1 is typically expressed with other proteins also synthesized in the endoplasmic reticulum, such as calreticulin, calnexin and Stim-1. Calcium ion involvement in the countertransport of chloride ions also supports the idea that Best1 is involved in forming calcium stores within the cell.
Function
Best1 primarily functions as an intracellular calcium-activated chloride channel on the cellular membrane that is not voltage-dependent. More recently Best1 has been shown to act as a volume-regulating anion channel.
Diseases
Best vitelliform macular dystrophy (BVMD)
Best's vitelliform macular dystrophy (BVMD) is one of the most common Best1-associated diseases. BVMD typically becomes noticeable in children and is represented by the buildup of lipofuscin (lipid residuals) lesions in the eye. Diagnosis normally follows an abnormal electrooculogram in which decreased activation of calcium channels in the basolateral membrane of the retinal pigment epithelium becomes apparent. A mutation in the BEST1 gene leads to a loss of channel function and eventually retinal degeneration. Although BVMD is an autosomal dominant form of macular dystrophy, expressivity varies within and between affected families although the overwhelming majority of affected families come from northern European descent. Typically, people with this condition experience five progressively worsening stages, though timing and severity varies greatly. BVMD is often caused by the single missense mutations; however, amino acid deletions have also been identified. A loss of function of the Best1 chloride channel could likely explain some of the most common issues associated with BVMD: an inability to regulate intracellular ion concentrations and regulate overall cell volume. To date, over 100 disease-causing mutations have been related to BVMD as well as a number of other degenerative retinal diseases.
Adult-onset vitelliform macular dystrophy (AVMD)
Adult-onset vitelliform macular dystrophy (AVMD) consists of lesions similar to BVMD on the retina. However, the cause is not as definitive as BVMD. The inability to diagnosis AVMD via genetic testing makes differentiating between AVMD and pattern dystrophy difficult. It is also unknown whether there is truly a clinical difference between AVMD caused by BEST1 mutations and AVMD caused by PRPH2 mutations. AVMD usually involves less vision loss than BVMD and cases do not usually run in families.
Autosomal recessive bestrophinopathy (ARB)
Autosomal recessive bestrophinopathy (ARB) was first identified in 2008. People with ARB demonstrate a decrease in vision during the first ten years of life. Parents and family members typically show no abnormalities as the disease is autosomal recessive, indicating that both alleles of the BEST1 gene must be mutated. Vitelliform lesions are often present and some cases involve cystoid macular edema. In addition, other complications have been observed. Vision decreases slowly over time, although rates of decline vary. Mutations causing ARB range from missense mutations to single base mutations in non-coding regions.
Autosomal dominant vitreoretinochoroidopathy
Autosomal dominant vitreoretinochoroidopathy was first identified in 1982 and presents itself in both eyes with decreases in peripheral vision due to excessive fluid and changes in eye retinal pigmentation. Early onset cataracts are also likely.
Retinitis pigmentosa (RP)
Retinitis pigmentosa was first described in relation to the BEST1 gene in 2009 and was found to be associated with four different missense mutations in the BEST1 gene in people. All affected individuals experience a diminished response to light within their retina and may have changes in pigmentation, pale optic discs, fluid accumulation and decreased visual acuity.
All of the diseases above do not have any known treatments or cures. However, as of 2017, researchers are currently working on discovering treatments with stem cell transplants of the retinal pigment epithelium.
References
Further reading
External links
GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview
Ion channels | Bestrophin 1 | [
"Chemistry"
] | 1,607 | [
"Neurochemistry",
"Ion channels"
] |
14,754,174 | https://en.wikipedia.org/wiki/AXL%20receptor%20tyrosine%20kinase | Tyrosine-protein kinase receptor UFO is a protein that in human is encoded by the AXL gene. The gene was initially designated as UFO, in allusion to the unidentified function of this protein. However, in the years since its discovery, research into AXL's expression profile and mechanism has made it an increasingly attractive target, especially for cancer therapeutics. In recent years, AXL has emerged as a key facilitator of immune escape and drug-resistance by cancer cells, leading to aggressive and metastatic cancers.
AXL is a cell surface receptor tyrosine kinase, part of the TAM family of kinases including TYRO3 and MERTK.
Gene and protein structure
The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.
The protein encoded by this gene is a member of the receptor tyrosine kinase subfamily. Although it is similar to other receptor tyrosine kinases, the Axl protein represents a unique structure of the extracellular region that juxtaposes IgL and FNIII repeats.
The AXL protein is characterized by an extracellular structure consisting of two fibronectin type 3-like repeats and two immunoglobulin-like repeats along with its intracellular tyrosine kinase domain.
AXL is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.
Function
The AXL receptor transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependant protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation, migration, differentiation and survival. Activation of Axl leads to autophosphorylation of its intracellular domain. Proteolytic cleavage of the AXL extracellular domain by the metalloproteinases ADAM10 and ADAM17 can downregulate this signalling activity.
Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-κB, and JAK/STAT.
This receptor can also mediate cell aggregation by homophilic binding.
AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature. In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including dendritic cells, macrophages, and NK cells.
Axl is an inhibitor of the innate immune response. The function of activated AXL in normal tissues includes the efficient clearance of apoptotic material and the dampening of TLR-dependent inflammatory responses and natural killer cell activity.
AXL is a putative driver of diverse cellular processes that are critical for the development, growth, and spread of tumours, including proliferation, invasiveness and migration, epithelial-to-mesenchymal transition, stemness, angiogenesis, and immune modulation. AXL has been implicated as a cancer driver and correlated with poor survival in numerous aggressive tumors including triple-negative breast cancer (TNBC), acute myeloid leukemia (AML), non-small-cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer, among others.
Clinical significance
Axl was first isolated in 1988 and identified as an oncogene in a screen for transforming genes in patients with a chronic myelogenous leukemia- that progressed to 'blast crisis'. Since then, increased AXL expression has been associated with numerous cancers including lung cancer, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and melanoma among others, and shown to have a strong correlation with poor survival outcomes.
AXL has been shown to be a key driver of drug-resistance to targeted therapies, immuno therapies and chemotherapy in various animal models. Based on current knowledge of AXL's role in therapy resistance, future studies will help to determine whether AXL has a translational application as a biomarker for predicting therapeutic response to established drugs.
Recently, AXL has been implicated in chronic fibrotic diseases in several organs, including the liver.
AXL also play an important role in Zika virus and SARS-CoV-2 infection, allowing for entry of the virus into host cells.
This phenomenon is known to rely on phosphatidylserine incorporated in the viral envelope during egress, which then binds to AXL via the adapter GAS6. AXL mediates internalization into the endosome from which these viruses escape and initiate replication.
As a drug target
Studies have shown that AXL knockdown leads to downregulation of transcription factors required for EMT, including Slug, Twist, and Zeb1, and to increased expression of E-cadherin.
Clinical studies
Cancer
Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target multiple kinase receptors in addition to AXL. The most advanced AXL selective inhibitor is bemcentinib (BGB324 or R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. Bemcentinib is being pursued as monotherapy and as combination therapy with existing and emerging targeted therapies, immunotherapies and chemotherapy.
A monoclonal antibody targeting AXL (YW327.6S2) and an AXL decoy receptor (GL2I.T) are currently in preclinical development. Additionally, an oral AXL inhibitor (TP-0903) is expected to enter Phase 1 clinical trial in November 2016 (in advanced solid tumours: NCT02729298).
Astellas Pharma is currently testing gilteritinib (ASP2215), a dual FLT3-AXL tyrosine kinase inhibitor in acute myeloid leukemia (AML). In 2017, gilteritinib gained FDA orphan drug status for AML.
These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.
Interactions
AXL receptor tyrosine kinase has been shown to interact with TENC1. Also, it interacts with CBL, GRB2, LCK, NCK2, PIK3R1, PIK3R2, PIK3R3, PLCG1, SOCS1, and TNS2.
References
Further reading
External links
Tyrosine kinase receptors | AXL receptor tyrosine kinase | [
"Chemistry"
] | 1,381 | [
"Tyrosine kinase receptors",
"Signal transduction"
] |
14,754,213 | https://en.wikipedia.org/wiki/HSPA9 | Mitochondrial 70kDa heat shock protein (mtHsp70), also known as mortalin, is a protein that in humans is encoded by the HSPA9 gene.
Function
The product encoded by this gene belongs to the heat shock protein 70 family which contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate proteins. This gene encodes a heat-shock cognate protein. This protein plays a role in the control of cell proliferation. It may also act as a chaperone.
Interactions
HSPA9 has been shown to interact with FGF1 and P53.
Clinical relevance and genetic deficiency
In 2015, a group around Andrea Superti-Furga showed that biallelic variants in the HSPA9 gene may result in a combination of congenital malformations called the EVEN-PLUS syndrome. These genetic variants have been shown to interfere with normal HSPA9 function
References
Further reading
External links
PDBe-KB provides an overview of all the structure information available in the PDB for Human Stress-70 protein, mitochondrial
Heat shock proteins
Molecular chaperones
Mitochondrial proteins | HSPA9 | [
"Chemistry"
] | 230 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,754,222 | https://en.wikipedia.org/wiki/Ribosomal%20protein%20SA | 40S ribosomal protein SA is a ribosomal protein that in humans is encoded by the RPSA gene. It also acts as a cell surface receptor, in particular for laminin, and is involved in several pathogenic processes.
Function
Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Many of the effects of laminin are mediated through interactions with cell surface receptors. These receptors include members of the integrin family, as well as non-integrin laminin-binding proteins. The RPSA gene encodes a multifunctional protein, which is both a ribosomal protein and a high-affinity, non-integrin laminin receptor. This protein has been variously called Ribosomal protein SA; RPSA; LamR; LamR1; 37 kDa Laminin Receptor Precursor; 37LRP; 67 kDa Laminin Receptor; 67LR; 37/67 kDa Laminin Receptor; LRP/LR; LBP/p40; and p40 ribosome-associated protein. Ribosomal protein SA and RPSA are the approved name and symbol. The amino acid sequence of RPSA is highly conserved through evolution, suggesting a key biological function. It has been observed that the level of RPSA transcript is higher in colon carcinoma tissue and lung cancer cell lines than their normal counterparts. Also, there is a correlation between the upregulation of this polypeptide in cancer cells and their invasive and metastatic phenotype. Multiple copies of the RPSA gene exist; however, most of them are pseudogenes thought to have arisen from retropositional events. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.
Structure and stability
The complementary DNA (cDNA) of the RPSA gene is formed by the assembly of seven exons, six of which correspond to the coding sequence. The amino acid sequence of RPSA, deduced from the sequence of its cDNA, includes 295 residues. RPSA can be sub-divided in two main domains: an N-domain (residues 1–209), which corresponds to exons 2-5 of the gene, and a C-domain (residues 210–295), which corresponds to exons 6–7. The N-domain of RPSA is homologous to the ribosomal protein S2 (RPS2) of prokaryotes. It contains a palindromic sequence 173LMWWML178 which is conserved in all metazoans. Its C-domain is highly conserved in vertebrates. The amino acid sequence of RPSA is 98% identical in all mammals. RPSA is a ribosomal protein which has acquired the function of laminin receptor during evolution. The structure of the N-domain of RPSA is similar to those of prokaryotic RPS2. The C-domain is intrinsically disordered in solution. The N-domain is monomeric in solution and unfolds according to a three state equilibrium. The folding intermediate is predominant at 37 °C.
Interactions
Several interactions of RPSA that had originally been discovered by methods of cellular biology, have subsequently been confirmed by using recombinant derivatives and in vitro experiments. The latter have shown that the folded N-domain and disordered C-domain of RPSA have both common and specific functions.
RPSA binds to proteins that are involved in the translation of the genetic code. (i) Yeast two-hybrid screens have shown that RPSA binds to Ribosomal protein S21 of the 40S small ribosomal subunit. (ii) Serial deletions of RPSA have shown that the segment of residues 236–262, included in the C-domain, is involved in the interaction between RPSA and the 40S subunit of ribosome. (iii) Studies that were based on nuclear magnetic resonance spectroscopy (NMR), have shown that the anticodon binding domain of Lysyl-tRNA synthetase binds directly to the C-domain of RPSA.
RPSA was initially identified as a laminin binding protein. Both recombinant N-domain and C-domain of RPSA bind laminin in vitro, and they bind with similar dissociation constants (300 nM).
Both RPSA and laminin belong to the heparin/heparan sulfate interactome. Heparin binds in vitro to the N-domain of RPSA but not to its C-domain. Moreover, the C-domain of RPSA and heparin compete for binding to laminin, which shows that the highly acidic C-domain of RPSA mimicks heparin (and potentially heparan sulfates) for the binding to laminin.
RPSA is a potential cellular receptor for several pathogenic Flaviviruses, including the dengue virus (DENV), and Alphaviruses, including the Sindbis virus (SINV). The N-domain of RPSA includes a binding site for SINV in vitro. The N-domain also includes weak binding sites for recombinant domain 3 (ED3, residues 296–400) from the envelope proteins of two Flaviviruses, West-Nile virus and serotype 2 of DENV. The C-domain includes weak binding sites for domain 3 of the yellow fever virus (YFV) and of serotypes 1 and 2 of DENV. In contrast, domain 3 from the Japanese encephalitis virus does not appear to bind RPSA in vitro.
RPSA is also a receptor for small molecules. (i) RPSA binds aflatoxin B1 both in vivo and in vitro. (ii) RPSA is a receptor for epigallocatechin-gallate (EGCG), which is a major constituent of green tea and has many health related effects. EGCG binds only to the N-domain of RPSA in vitro, with a dissociation constant of 100 nM, but not to its C-domain.
References
Further reading
Ribosomal proteins
Transmembrane receptors | Ribosomal protein SA | [
"Chemistry"
] | 1,336 | [
"Transmembrane receptors",
"Signal transduction"
] |
14,754,377 | https://en.wikipedia.org/wiki/CHI3L1 | Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene. The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and hepatic stellate cells. The biological function of YKL-40 is unclear. It is not known to have a specific receptor. Its pattern of expression is associated with pathogenic processes related to inflammation, extracellular tissue remodeling, fibrosis and solid carcinomas and asthma.
Function
Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling. YKL-40 lacks chitinase activity due to mutations within the active site (conserved sequence: DXXDXDXE; YKL-40 sequence: DGLDLAWL).
Regulation and mechanism
YKL-40 has been linked to activation of the AKT pro-survival (anti-apoptotic) signaling pathway. YKL-40 promotes angiogenesis through VEGF-dependent and independent pathways.
YKL-40 is a migration factor for primary astrocytes and its expression is controlled by NFI-X3, STAT3, and AP-1.
CHI3l1 is induced by a variety of cancers and in the presence of semaphorin 7A (protein) can inhibit multiple anti-tumor immune system responses. Activating an antiviral immune pathway known as the RIG-like helicase (RLH) has the ability to counter CHI3l1 induction. Cancer cells can offset RLH by stimulating NLRX1. Poly(I:C), an RNA-like molecule, can stimulate RLH activation. RLH activation can also inhibit the expression of receptor IL-13Rα2 and pulmonary metastasis. It stores NK cell accumulation and activation. It augments the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner.
Cancer
It is assumed that YKL-40 plays a role in cancer cell proliferation, survival, invasiveness and in the regulation of cell-matrix interactions. It is suggested that YKL-40 is a marker associated with a poorer clinical outcome in genetically defined subgroups of different tumors. YKL-40 was recently introduced into (restricted) clinical practice. A few techniques are available for its detection.
YKL-40 is a Th2 promoting cytokine that is present at high levels in the tumor microenvironment and in the serum of cancer patients. Elevated levels of YKL-40 correlate strongly with stage and outcome of various types of cancer, which establish YKL-40 as a biomarker of disease severity. Targeting YKL-40 with neutralizing antibodies is effective as a treatment in animal models of glioblastoma multiforme.
YKL-40 also enhances tumor survival in response to gamma-irradiation.
Alzheimer's disease and neurodegeneration
As Alzheimer's disease progresses, soluble amyloid beta aggregates in the brain can induce the activation of microglia, which triggers synthesis of pro-inflammatory mediators. This leads to increased Chi3l1 expression in astrocytes. There is evidence that YKL-40 levels are elevated in Alzheimer's patients compared to cognitively normal individuals. Elevated levels of YKL-40 mRNA were found in Alzheimer's-inflicted brains in comparison with normal controls. Additionally, YKL-40 is correlated other dementia biomarkers, such as tau proteins and amyloid beta. YKL-40 is being examined as a novel Alzheimer's biomarker quantified in the cerebrospinal fluid or blood.
In Huntington's disease YKL-40 has an increasing trend in cerebrospinal fluid in the later disease stages and correlates highly with symptom severity.
References
External links
Further reading
Glycoproteins | CHI3L1 | [
"Chemistry"
] | 1,043 | [
"Glycoproteins",
"Glycobiology"
] |
14,754,383 | https://en.wikipedia.org/wiki/NGC%20383 | NGC 383 is a double radio galaxy with a quasar-like appearance located in the constellation Pisces. It was discovered by German-British astronomer William Herschel on 12 September 1784. It is listed as Arp 331 in Halton Arp's Atlas of Peculiar Galaxies.
Recent discoveries by the National Radio Astronomy Observatory in 2006 reveal that NGC 383 is being bisected by high energy relativistic jets traveling at relatively high fractions of the speed of light. The relativistic electrons in the jets are detected as synchrotron radiation in the x-ray and radio wavelengths. The focus of this intense energy is the galactic center of NGC 383. The relativistic electron jets detected as synchrotron radiation extend for several thousand parsecs and then appear to dissipate at the ends in the form of streamers or filaments.
There are four other nearby galaxies NGC 379, NGC 380, NGC 385, and NGC 384 which are suspected of being closely associated with NGC 383, as well as several other galaxies at relatively close distance.
Two supernovae have been observed in NGC 383:
SN 2015ar (type Ia, mag. 18.8) was discovered by E. Conseil and G. Arlic on 11 November 2015.
SN 2017hle (type Ia, mag. 18) was discovered by Xingming Observatory Sky Survey (XOSS) on 18 October 2017.
See also
Relativistic beaming
Relativistic jets
References
External links
3C31 = B0104+321 (Alan Bridle / 18 June 2008)
www.jb.man.ac.uk/atlas/
Wikisky image of NGC 383
Radio galaxies
0383
00689
31
Pisces (constellation)
17840912
Lenticular galaxies
Discoveries by William Herschel
+05-03-053
331 | NGC 383 | [
"Astronomy"
] | 394 | [
"Pisces (constellation)",
"Constellations"
] |
14,754,384 | https://en.wikipedia.org/wiki/CTAG1B | Cancer/testis antigen 1 also known as LAGE2 or LAGE2B is a protein that in humans is encoded by the CTAG1B gene. It is most often referenced by its alias NY-ESO-1.
Cancer/Testis Antigen 1B is a protein belonging to the family of Cancer Testis Antigens (CTA) that are expressed in a variety of malignant tumours at the mRNA and protein levels, but also restricted to testicular germ cells in normal adult tissues. A clone of CTAG gene was originally identified by immunological methods in oesophageal carcinoma using patient serum. The aberrant re-expression of CTAs is induced by molecular mechanisms including DNA demethylation, histone post-translational modification, and microRNA-mediated regulation. The effect of DNA demethylation is evident by the capability of demethylating agents, such as 5-aza-2-deoxycytidine, to induce CTAs re-expression in tumour cells but not in normal epithelial cells.
Gene
CTAG1B is located on the long arm of chromosome X (Xq28), containing three exons that are approximately 8 Kb in length. CTAG1B is found to have a neighbouring gene of identical sequence: CTAG1A.
Protein
The gene encodes a 180-amino acid polypeptide, expressed from 18 weeks during embryonic development until birth in human fetal testis. It is also strongly expressed in spermatogonia and in primary spermatocytes of adult testis, but not in post-meiotic cells or testicular somatic cells. Structurally, CTAG1B features a glycine-rich N-terminal region, as well as a hydrophobic C-terminal region with a Pcc-1 domain. The protein has been shown to be homologous to two other CTAs located in the same region: LAGE-1 and ESO3. The exact function of CTAG1B remains to be unknown. Studies have suggested its role in cell cycle progression and growth, although not being elusive, through the analysis of CTAG1B's structure and expression pattern. The coexpression of CTAG1B with melanoma antigen gene C1 (MAGE-C1), another CTA, further supports its involvement in cell cycle regulation and apoptosis, due to the role of MAGE proteins in these processes. Moreover, its restricted expression pattern in male germ cells suggests its role in germ cell self-renewal or differentiation, supported by the nuclear localization of CTAG1B in mesenchymal stem cells in contrast to its cytoplasmic expression in cancer cells.
Humoral Immune Response
It is also believed that cancer-testis antigens are immunogenic proteins, since many members of the family have been shown to induce spontaneous cellular and humoral immune responses in patients with advanced stage tumours. The first reported simultaneous humoral and cellular response against CTAG1B was from a metastatic melanoma patient. 3 HLA-A2 restricted epitopes in CTAG1B were identified as the recognition sites for CD8+ cytotoxic T lymphocytes. Integrated humoral immune responses against CTAG1B have been detected in patients with: Multiple myeloma, breast cancer, non small-cell lung carcinoma, and ovarian cancer. As such, CTAG1B is believed to be a promising candidate for cancer immunotherapy due to its exclusive expression in normal tissues and re expression in tumour cells, as well as its high immunogenicity. These features also suggest a limited off-target toxicity of CTAG1B-based cancer therapies. The immunisation with CTAG1B could be a successful approach to induce antigen specific immune responses in cancer patients. Up until May 2018, there have been 12 clinical trials registered using a CTAG1B cancer vaccine, 23 using modified T cells, and 13 using combinatorial immunotherapy.
Examining the expression of a number of CTA genes in 23 samples of sporadic medullary thyroid carcinoma has revealed that CTAG1B expression significantly correlates with tumour recurrence. A humoral response against this CTA was detected in 54.5% of CTAG1B-expressing patients, and in 1 of 6 patients with an CTAG1B-negative tumour. Anti-CTAG1B antibodies were present in 35.7%, demonstrating that medullary thyroid carcinoma is associated with humoral immune response to CTAG1B. Another study has shown that CTAG1B binding to CALR on macrophages and dendritic cells provides a link between CTAG1B, the innate immune system, and possibly the adaptive immune response against CTAG1B.
References
Further reading
External links
Proteins | CTAG1B | [
"Chemistry"
] | 1,015 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,754,403 | https://en.wikipedia.org/wiki/Neutrophil%20cytosolic%20factor%204 | Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.
Function
The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed.
Clinical significance
GWAS studies showed that Crohn's disease patient with certain SNPs in NCF4 are more susceptible to get Crohn's disease. Crohn's patient with rs4821544 variants showed a decreased reactive oxygen species after stimulation with GM-CSF which is a proinflammtory cytokine.
Interactions
Neutrophil cytosolic factor 4 has been shown to interact with Ku70, Neutrophil cytosolic factor 1 and Moesin.
References
Further reading
Proteins | Neutrophil cytosolic factor 4 | [
"Chemistry"
] | 365 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,754,423 | https://en.wikipedia.org/wiki/PAX5 | Paired box protein Pax-5 is a protein that in humans is encoded by the PAX5 gene.
Function
The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly conserved DNA-binding domain, known as the paired box. The PAX proteins are important regulators in early development, and alterations in the expression of their genes are thought to contribute to neoplastic transformation. The PAX5 gene encodes the B-cell lineage specific activator protein (BSAP) that is expressed at early, but not late stages of B-cell differentiation. Its expression has also been detected in developing CNS and testis, therefore, PAX5 gene product may not only play an important role in B-cell differentiation, but also in neural development and spermatogenesis.
Clinical significance
The PAX5 gene is located in chromosome 9p13 region, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype, and in derived large-cell lymphomas. This translocation brings the potent E-mu enhancer of the IgH gene locus into close proximity of the PAX5 promoters, suggesting that the deregulation of PAX5 gene transcription contributes to the pathogenesis of these lymphomas.
Up to 97% of the Reed–Sternberg cells of Hodgkin's lymphoma express Pax-5.
Interactions
PAX5 has been shown to interact with TLE4 and Death associated protein 6.
See also
Pax genes
References
Further reading
External links
Transcription factors | PAX5 | [
"Chemistry",
"Biology"
] | 363 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,437 | https://en.wikipedia.org/wiki/RE1-silencing%20transcription%20factor | RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the REST gene, and acts as a transcriptional repressor. REST is expressly involved in the repression of neural genes in non-neuronal cells. Many genetic disorders have been tied to alterations in the REST expression pattern, including colon and small-cell lung carcinomas found with truncated versions of REST. In addition to these cancers, defects in REST have also been attributed a role in Huntington Disease, neuroblastomas, and the effects of epileptic seizures and ischemia.
Function
This gene encodes a transcriptional repressor which represses neuronal genes in non-neuronal tissues. It is a member of the Kruppel-type zinc finger transcription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element (NRSE, also known as RE1). The protein is also found in undifferentiated neuronal progenitor cells, and it is thought that this repressor may act as a master negative regulator of neurogenesis. Alternatively spliced transcript variants have been described; however, their full length nature has not been determined. REST is found to be down-regulated in elderly people with Alzheimer's disease.
REST contains 8 Cys2His2 zinc fingers and mediates gene repression by recruiting several chromatin-modifying enzymes.
REST is also responsible for ischaemia induced neuronal cell death, in mouse models of brain ischaemia. Ischaemia, which results from reduced blood perfusion of tissues, decreasing nutrient and oxygen supply, induces REST transcription and nuclear accumulation, leading to the epigenetic repression of neuronal genes leading to cell death. The mechanism beyond REST induction in ischaemia, might be tightly linked to its oxygen-dependent nuclear translocation and repression of target genes in hypoxia (low oxygen) where REST fulfils the functions of a master regulator of gene repression in hypoxia.
Interactions
RE1-silencing transcription factor has been shown to interact with RCOR1.
References
Further reading
External links
Transcription factors | RE1-silencing transcription factor | [
"Chemistry",
"Biology"
] | 468 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,562 | https://en.wikipedia.org/wiki/3C%2035 | 3C 35 is a giant radio galaxy with an active galactic nucleus (AGN). It is classified as a Fanaroff & Riley type II radio galaxy. It is located in the constellation Cassiopeia.
It is listed as a quasar by the SIMBAD astronomical database.
References
External links
www.jb.man.ac.uk/atlas/ (J. P. Leahy)
Wikisky image of 3C 35 (near PGC 4310)
Quasars
Radio galaxies
Cassiopeia (constellation)
035
49.04
4310 | 3C 35 | [
"Astronomy"
] | 119 | [
"Cassiopeia (constellation)",
"Galaxy stubs",
"Astronomy stubs",
"Constellations"
] |
14,754,630 | https://en.wikipedia.org/wiki/Homeobox%20protein%20Nkx-2.5 | Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene.
Function
Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development (Shiojima et al., 1995). It has been demonstrated that a Drosophila homeobox-containing gene called 'tinman' is expressed in the developing dorsal vessel and in the equivalent of the vertebrate heart. Mutations in tinman result in loss of heart formation in the embryo, suggesting that tinman is essential for Drosophila heart formation. Furthermore, abundant expression of Csx, the presumptive mouse homolog of tinman, is observed only in the heart from the time of cardiac differentiation. CSX, the human homolog of murine Csx, has a homeodomain sequence identical to that of Csx and is expressed only in the heart, again suggesting that CSX plays an important role in human heart formation.
In humans, proper NKX2-5 expression is essential for the development of atrial, ventricular, and conotruncal septation, atrioventricular (AV) valve formation, and maintenance of AV conduction. Mutations in expression are associated with congenital heart disease (CHD) and related ailments. Patients with NKX2-5 mutations commonly present AV conduction block and atrial septal defects (ASD). Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. The NKX2-5 transcription factor may help myocytes endure cytotoxic stress, however further exploration in this field is required.
NK-2 homeobox genes are a family of genes that encode for numerous transcription factors that go on to aid in the development of many structures including the thyroid, colon, and heart. Of the NK-2 genes, NKX2-5 transcription factor is mostly involved in cardiac development and defects with this gene can lead to congenital heart defects including, but not limited to atrial septal defects. NKX2-5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development. In NKX2-5 gene knock out mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes. In the case of loss of function of NKX2-5, test subjects developed increased heart rate and decreased variability in heart rate. This discovery indicates that NKX2-5 is necessary for proper cardiac formatting as well as proper cardiac function after formatting. NKX2-5 has also been shown to bind to the promoter of FGF-16 and regulate its expression. This finding suggests that NKX2-5 is implicated in cardiac injury via cytotoxic effects.
Interactions
During embryogenesis, NKX2-5 is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. In early cardiogenesis, cardiac precursor cells from the cardiac crescent congregate along the ventral midline of the developing embryo and form the linear heart tube. In Nkx2-5 knock out mice, cardiac development halts at the linear heart tube stage and looping morphogenesis disrupted.
NKX2-5 has been shown to interact with GATA4 and TBX5.
NKX2-5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans. NKX2-5 is dependent upon the JAK-STAT pathway and works along with MEF2, HAND1, and HAND2 transcription factors to direct heart looping during early heart development. NKX2-5 in vertebrates is equivalent to the ‘tinman’ gene in Drosophila and directly activates the MEF2 gene to control cardiomyocyte differentiation. NKX2-5 operates in a positive feedback loop with GATA transcription factors to regulate cardiomyocyte formation. NKX2-5 influences HAND1 and HAND2 transcription factors that control the essential asymmetrical development of the heart's ventricles. The gene has been shown to play a role in the heart's conduction system, postnatally. NKX2-5 is also involved in the intrinsic mechanisms that decide ventricle and atrial cellular fate. During ventricular chamber formation, NKX2-5 and NKX2-7 are required to maintain cardiomyocyte cellular identity. Repression of either gene results in the differentiating cardiomyocytes to move towards atrial chamber identity. The NKX2-5 mutation has also been associated with preeclampsia; though research is still being conducting in this area.
References
Further reading
External links
Transcription factors | Homeobox protein Nkx-2.5 | [
"Chemistry",
"Biology"
] | 1,050 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,697 | https://en.wikipedia.org/wiki/Involucrin | Involucrin is a protein component of human skin and in humans is encoded by the IVL gene. In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin.
Gene
This gene is mapped to 1q21, among calpactin I light chain, trichohyalin, profillaggrin, loricrin, and calcyclin.
Function
Involucrin is a highly reactive, soluble, transglutaminase substrate protein present in keratinocytes of epidermis and other stratified squamous epithelia. It first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane functioning as a glutamyl donor during assembly of the cornified envelope.
Involucrin is synthesised in the stratum spinosum and cross linked in the stratum granulosum by the transglutaminase enzyme that makes it highly stable. Thus it provides structural support to the cell, thereby allowing the cell to resist invasion by micro-organisms.
Apigenin, a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent, has been found to regulate normal human keratinocyte differentiation by suppressing involucrin, and this is associated with reduced cell proliferation without apoptosis.
Clinical significance
As one of the precursor proteins of the cornified cell envelope, involucrin is markedly increased in inflammatory skin diseases such as psoriasis
Lamellar ichthyosis involves a decrease in expression of involucrin. This decrease could contribute to the altered desquamation process seen in the disease, since the clinical improvement associated with retinoid treatment is accompanied by increased expression of involucrin.
Structure
Involucrin consists of a conserved N-terminal region of about 75 amino acid residues followed by two extremely variable length segments that contain glutamine-rich tandem repeats. The glutamine residues in the tandem repeats are the substrate for the transglutaminase in the cross-linking reaction. The total size of the protein varies from 285 residues (in dog) to 835 residues (in orangutan).
References
Further reading
Protein domains | Involucrin | [
"Biology"
] | 499 | [
"Protein domains",
"Protein classification"
] |
14,754,768 | https://en.wikipedia.org/wiki/IKZF1 | DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.
Ikaros - transcription factor
Ikaros is a transcription factor that is encoded by the IKZF genes of the Ikaros family zinc finger group. Zinc finger is a small structural motif of protein that allows protein binding to DNA or RNA molecule that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold.
Ikaros displays crucial functions in the hematopoietic system and is a known regulator of immune cells development, mainly in early B cells, CD4+ T cells. Its dysfunction has been linked to the development of chronic lymphocytic leukemia. In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia and that it also has a part in the differentiation and function of individual T helper cells.
Ikaros also has a role during the later stages of B cell development during VDJ recombination in switch class of the antibody isotypes and expression of the B cell receptor.
In Ikaros knockout mice, T cells but not B cells are generated late in mouse development due to late compensatory expression of the related gene Aiolos (IKZF3). Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation. SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL) as well as type 1 diabetes. The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa.
Further evidence shows that Ikaros regulates the development of medullary thymic epithelial cells (mTECs). Conditional deletion of Ikzf1 in thymic epithelial cells by Foxn1-Cre in mice, results in the dysregulation of various mTEC subsets, including the loss of Aire+ mTECs. The loss of Aire (Autoimmune regulator) expressing mTECs also causes global loss of tissue restricted antigens (TRAs) and Aire-dependent mimetic cell populations, with the loss of TRAs eventually leading to breakdown of immune tolerance.
Genes of the Ikaros Zinc Finger Family group
The Ikaros Zinc Finger (IkZF) family of transcription factors are known regulators of hematopoietic cell development and many immune cells including that of CD4+ T cells.
The IkZF family consists of five members: Ikaros (encoded by the gene Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5). These factors contain N-terminal zinc finger (ZF) domains, which are responsible for mediating direct interactions with DNA, and C-terminal ZFs, which facilitate homo- and heterodimerization between IkZF family members.
IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes.
Ikaros deficiency
The mutation in the IKZF1 gene can cause dysfunction of the Ikaros transcription factor. The dysfunction affects expression in B cells that can lead to deregulation of the BCR signaling during B cell development and is associated with B cell transformation. The deregulation then can result in low proliferation rate and increased apoptosis of the B cells. The deregulation may be related with lymphoproliferative disorders and different forms of leukemia.
Interactions
IKZF1 has been shown to interact with:
CTBP1,
HDAC1,
HDAC7A,
Histone deacetylase 5,
IKZF2,
IKZF3,
IKZF4,
SIN3A,
Cereblon
SIN3B.
GATA2
References
Further reading
External links
Transcription factors | IKZF1 | [
"Chemistry",
"Biology"
] | 920 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,828 | https://en.wikipedia.org/wiki/DFFA | DNA fragmentation factor subunit alpha (DFFA), also known as Inhibitor of caspase-activated DNase (ICAD), is a protein that in humans is encoded by the DFFA gene.
Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
The C-terminal domain of DFFA (DFF-C) consists of four alpha-helices, which are folded in a helix-packing arrangement, with alpha-2 and alpha-3 packing against a long C-terminal helix (alpha-4). The main function of this domain is the inhibition of DFFB by binding to its C-terminal catalytic domain through ionic interactions, thereby inhibiting the fragmentation of DNA in the apoptotic process. In addition to blocking the DNase activity of DFFB, the C-terminal region of DFFA is also important for the DFFB-specific folding chaperone activity, as demonstrated by the ability of DFFA to refold DFFB.
Interactions
DFFA has been shown to interact with DFFB.
References
Further reading
Protein domains | DFFA | [
"Biology"
] | 399 | [
"Protein domains",
"Protein classification"
] |
14,754,845 | https://en.wikipedia.org/wiki/ID3%20%28gene%29 | DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.
Function
Members of the ID family of helix-loop-helix (HLH) proteins lack a basic DNA-binding domain and inhibit transcription through formation of nonfunctional dimers that are incapable of binding to DNA.[supplied by OMIM]
Interactions
ID3 (gene) has been shown to interact with TCF3.
Repressors of ID3
BTG2 binds to the promoter of Id3 and represses its activity. By this mechanism, the upregulation of Id3 in the hippocampus caused by BTG2 ablation prevents terminal differentiation of hippocampal neurons.
See also
Inhibitor of DNA-binding protein
References
Further reading
External links
Transcription factors | ID3 (gene) | [
"Chemistry",
"Biology"
] | 163 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,869 | https://en.wikipedia.org/wiki/Msh%20homeobox%202 | Homeobox protein MSX-2 is a protein that in humans is encoded by the MSX2 gene.
Function
This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2.
Msx2 is a homeobox gene localized on human chromosome 5 that encodes a transcription repressor and activator (MSX-2) responsible for craniofacial and limb-bud development. Cells will express msx2 when exposed to signaling molecules BMP-2 and BMP-4 in situ. It is well documented that expression of cell-cell adhesion molecules such as E-cadherins will promote structural integrity and an epithelial arrangement of cells, while expression of N-cadherin and vimentin promote mesenchymal arrangement and cell migration. Msx2 downregulates E-cadherins and upregulates N-cadherin and vimentin which indicates its role in inducing epithelial mesenchymal transition (EMT). Germline knockout mice have been created for this gene (Msx2 +/-) in order to examine functional loss. Clinical studies on craniosynostosis, or the premature fusion of cranial structures, have shown the condition to be genetically linked to mutation in the msx2 homeobox gene.
Interactions
Msh homeobox 2 has been shown to interact with DLX5, DLX2 and MSX1.
References
Further reading
External links
GeneReviews/NCBI/UW/NIH entry on Enlarged Parietal Foramina/Cranium Bifidum
Transcription factors
Human proteins | Msh homeobox 2 | [
"Chemistry",
"Biology"
] | 430 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,754,901 | https://en.wikipedia.org/wiki/3C%2061.1 | 3C 61.1 is a Seyfert galaxy located in the constellation Cepheus.
References
External links
Simbad
www.jb.man.ac.uk/atlas/
Cepheus (constellation)
Seyfert galaxies
061.1
2832137
8C 0210+860 | 3C 61.1 | [
"Astronomy"
] | 63 | [
"Galaxy stubs",
"Astronomy stubs",
"Constellations",
"Cepheus (constellation)"
] |
14,754,963 | https://en.wikipedia.org/wiki/AIFM1 | Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene on the X chromosome. This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.
Structure
AIFM1 is expressed as a 613-residue precursor protein that containing a mitochondrial targeting sequence (MTS) at its N-terminal and two nuclear leading sequences (NLS). Once imported into the mitochondria, the first 54 residues of the N-terminal are cleaved to produce the mature protein, which inserts into the inner mitochondrial membrane. The mature protein incorporates the FAD cofactor and folds into three structural domains: the FAD-binding domain, the NAD-binding domain, and the C-terminal. While the C-terminal is responsible for the proapoptotic activity of AIFM1, the FAD-binding and NAD-binding domains share the classical Rossmann topology with other flavoproteins and the NAD(P)H dependent reductase activity.
Three alternative transcripts encoding different isoforms have been identified for this gene. Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains. A pseudogene that is thought to be related to this gene has been identified on chromosome 10.
Function
This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells that is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the cleavage of this protein at residue 102 by calpains and/or cathepsins into a soluble and proapoptogenic form that translocates to the nucleus, where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. AIFM1 also contributes reductase activity in redox metabolism.
Clinical significance
Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome). At a cellular level, AIFM1 mutations result in deficiencies in oxidative phosphorylation, leading to severe mitochondrial encephalomyopathy. Clinical manifestations of this mutation are characterized by muscular atrophy, neuropathy, ataxia, psychomotor regression, hearing loss and seizures.
Interactions
AIFM1 has been shown to interact with HSPA1A.
Evolution
Phylogenetic analysis indicates that the divergence of the AIFM1 and other human AIFs (AIFM2a and AIFM3) sequences occurred before the divergence of eukaryotes. This conclusion is supported by domain architecture of these proteins. Both eukaryotic and eubacterial AIFM1 proteins contain additional domain AIF_C.
References
Further reading
External links
AIFM1 on the Atlas of Genetics and Oncology
Proteins | AIFM1 | [
"Chemistry"
] | 631 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,754,966 | https://en.wikipedia.org/wiki/Sodium%20lauroyl%20sarcosinate | Sodium lauroyl sarcosinate (INCI), also known as sarcosyl, is an anionic surfactant derived from sarcosine used as a foaming and cleansing agent in shampoo, shaving foam, toothpaste, and foam wash products.
This surfactant is amphiphilic due to the hydrophobic 12-carbon chain (lauroyl) and the hydrophilic carboxylate. Since the nitrogen atom is in an amide linkage, the nitrogen is not pH active and is neutrally charged in all aqueous solutions regardless of pH. The carboxylate has a pKa of about 3.6 and is therefore negatively charged in solutions of pH greater than about 5.5.
pH-sensitive vesicles can be prepared using this surfactant with another cationic or water-insoluble amphiphiles such as 1-decanol.
Addition of an mixture of equal parts of sodium lauroyl sarcosinate and the non-ionic surfactant sorbitan monolaurate (S20) to a buffered water:ethanol solution led to the formation of micelle-like aggregates, even though neither surfactant formed micelles when present alone. Such aggregates can help carry other small molecules, such as drugs, through the skin.
In culture
Sodium lauroyl sarcosinate was sold as a special ingredient called "Gardol" in Colgate "Dental Cream", as toothpaste was then called, during the 1950s
through the mid-1960s in the US
and the mid-1970s in France.
Its current use as a preventive dentifrice is in Arm & Hammer Baking Soda Toothpaste, a Church & Dwight product, where it is used as a surfactant.
References
External links
"Occupational Allergic Contact Dermatitis From Sodium Lauroyl Sarcosinate in Liquid Soap," Zemtsov, Alexander MD, MSC; Fett, Deborah MD, Dermatitis, June 2005, Volume 16, Issue 2, p. 97
Cosmetics chemicals
Household chemicals
Organic sodium salts
Anionic surfactants | Sodium lauroyl sarcosinate | [
"Chemistry"
] | 437 | [
"Organic sodium salts",
"Salts"
] |
14,754,990 | https://en.wikipedia.org/wiki/HIST2H3C | Histone H3.2 is a protein that in humans is encoded by the HIST2H3C gene.
Function
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a member of the histone H3 family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in a histone cluster on chromosome 1. This gene is one of four histone genes in the cluster that are duplicated; this record represents the telomeric copy.
Interactions
HIST2H3C has been shown to interact with NCOA6.
References
Further reading
External links | HIST2H3C | [
"Chemistry"
] | 246 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,064 | https://en.wikipedia.org/wiki/DAZ1 | Deleted in azoospermia 1, also known as DAZ1, is a protein which in humans is encoded by the DAZ1 gene.
Function
This gene is a member of the DAZ gene family and is a candidate for the human Y-chromosomal azoospermia factor (AZF). Its expression is restricted to pre-meiotic germ cells, particularly in spermatogonia. It encodes an RNA-binding protein that is important for spermatogenesis. Four copies of this gene are found on chromosome Y within palindromic duplications; one pair of genes is part of the P2 palindrome and the second pair is part of the P1 palindrome. Each gene contains a 2.4 kb repeat including a 72-bp exon, called the DAZ repeat; the number of DAZ repeats is variable and there are several variations in the sequence of the DAZ repeat. Each copy of the gene also contains a 10.8 kb region that may be amplified; this region includes five exons that encode an RNA recognition motif (RRM) domain. This gene contains three copies of the 10.8 kb repeat. However, no transcripts containing three copies of the RRM domain have been described; thus the RefSeq for this gene contains only two RRM domains.
Interactions
DAZ1 has been shown to interact with DAZAP2, DAZL and DAZ associated protein 1.
References
Further reading | DAZ1 | [
"Chemistry"
] | 305 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,080 | https://en.wikipedia.org/wiki/3C%2066B | 3C 66B is an elliptical Fanaroff and Riley class 1 radio galaxy located in the constellation Andromeda. With an estimated redshift of 0.021258, the galaxy is about 300 million light-years away.
The orbital motion of 3C 66B showed supposed evidence for a supermassive black hole binary (SMBHB) with a period of 1.05 ± 0.03 years, but this claim was later proven wrong (at 95% certainty).
Messier 87 (M87), about 55 million light-years away, is the largest giant elliptical galaxy near the Earth, and also contains an active galactic nucleus. The smooth jet of 3C 66B rivals that of M87.
3C 66B is an outlying member of Abell 347 which is part of the Perseus–Pisces Supercluster.
References
External links
www.jb.man.ac.uk/atlas/ (J. P. Leahy)
3C66B = B0220+427 (Alan Bridle / 31 May 2006)
Wikisky image of PGC 9067
Radio galaxies
Seyfert galaxies
066B
Andromeda (constellation)
009067
01841
J02231141+4259313
Elliptical galaxies
Perseus-Pisces Supercluster | 3C 66B | [
"Astronomy"
] | 284 | [
"Andromeda (constellation)",
"Constellations"
] |
14,755,100 | https://en.wikipedia.org/wiki/DVL1 | Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.
Function
DVL1, the human homolog of the Drosophila dishevelled gene (dsh), encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification. DVL1 is a candidate gene for processes involved in cell transformations involved in neuroblastoma. The Schwartz–Jampel syndrome and Charcot–Marie–Tooth disease type 2A have been mapped to the same region as DVL1. The phenotypes of these diseases may be consistent with defects which might be expected from aberrant expression of a DVL gene during development. Three transcript variants encoding three different isoforms have been found for this gene.
Interactions
DVL1 has been shown to interact with:
AXIN1,
DVL3,
EPS8, and
Mothers against decapentaplegic homolog 3.
See also
Dishevelled
References
Further reading
External links
DVL1 on the Atlas of Genetics and Oncology | DVL1 | [
"Chemistry"
] | 250 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,113 | https://en.wikipedia.org/wiki/GTF2H4 | General transcription factor IIH subunit 4 is a protein that in humans is encoded by the GTF2H4 gene.
Interactions
GTF2H4 has been shown to interact with:
GTF2F1,
MED21,
POLR2A,
TATA binding protein,
Transcription Factor II B, and
XPB.
See also
Transcription Factor II H
References
Further reading
External links
Transcription factors | GTF2H4 | [
"Chemistry",
"Biology"
] | 79 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,755,138 | https://en.wikipedia.org/wiki/NME2 | Nucleoside diphosphate kinase B is an enzyme that in humans is encoded by the NME2 gene.
Function
Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of 'A' (encoded by NME1) and 'B' (encoded by this gene) isoforms. Multiple alternatively spliced transcript variants encoding the same isoform have been found for this gene. Co-transcription of this gene and the neighboring upstream gene (NME1) generates naturally occurring transcripts (NME1-NME2) which encode a fusion protein consisting of sequence sharing identity with each individual gene product.
Interactions
NME2 has been shown to interact with NME3 and HERC5.
References
Further reading | NME2 | [
"Chemistry"
] | 151 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,169 | https://en.wikipedia.org/wiki/PTPN2 | Tyrosine-protein phosphatase non-receptor type 2 is an enzyme that in humans is encoded by the PTPN2 gene.
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
Epidermal growth factor receptor and the adaptor protein Shc were reported to be substrates of this PTP, which suggested the roles in growth factor mediated cell signaling. Three alternatively spliced variants of this gene, which encode isoforms differing at their extreme C-termini, have been described.
The different C-termini are thought to determine the substrate specificity, as well as the cellular localization of the isoforms. Two highly related but distinctly processed pseudogenes that localize to distinct chromosomes have been reported.
References
Further reading | PTPN2 | [
"Chemistry"
] | 220 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,183 | https://en.wikipedia.org/wiki/Small%20nuclear%20ribonucleoprotein%20polypeptide%20N | Small nuclear ribonucleoprotein-associated protein N is a protein that in humans is encoded by the SNRPN gene.
The protein encoded by this gene is one polypeptide of a small nuclear ribonucleoprotein complex and belongs to the snRNP SMB/SMN family. The protein plays a role in pre-mRNA processing, possibly tissue-specific alternative splicing events. Although individual snRNPs are believed to recognize specific nucleic acid sequences through RNA-RNA base pairing, the specific role of this family member is unknown. The protein arises from a bicistronic transcript that also encodes a protein identified as the SNRPN upstream reading frame (SNURF). Multiple transcription initiation sites have been identified and extensive alternative splicing occurs in the 5' untranslated region. Additional splice variants have been described but sequences for the complete transcripts have not been determined. The 5' UTR of this gene has been identified as an imprinting center. Alternative splicing or deletion caused by a translocation event in this paternally-expressed region is responsible for Prader-Willi syndrome due to parental imprint switch failure.
SNRPN-methylation is used to detect uniparental disomy of chromosome 15. After fluorescent-in-situ-hybridization has confirmed the presence of either SNRPN or UBE3A (a neighboring gene that is also imprinted), the methylation test (of SNRPN) can reveal whether the patient has uniparental disomy. SNRPN is maternally methylated (silenced). UBE3A appears to be paternally methylated (silenced).
References
Further reading | Small nuclear ribonucleoprotein polypeptide N | [
"Chemistry"
] | 366 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,222 | https://en.wikipedia.org/wiki/DNA%20polymerase%20lambda | DNA polymerase lambda, also known as Pol λ, is an enzyme found in all eukaryotes. In humans, it is encoded by the POLL gene.
Function
Pol λ is a member of the X family of DNA polymerases. It is thought to resynthesize missing nucleotides during non-homologous end joining (NHEJ), a pathway of DNA double-strand break (DSB) repair. NHEJ is the main pathway in higher eukaryotes for repair of DNA DSBs. Chromosomal DSBs are the most severe type of DNA damage. During NHEJ, duplexes generated by the alignment of broken DNA ends usually contain small gaps that need to be filled in by a DNA polymerase. DNA polymerase lambda can perform this function.
The crystal structure of pol λ shows that, unlike the DNA polymerases that catalyze DNA replication, pol λ makes extensive contacts with the 5' phosphate of the downstream DNA strand. This allows the polymerase to stabilize the two ends of a double-strand break and explains how pol λ is uniquely suited for a role in non-homologous end joining.
In addition to NHEJ, pol λ can also participate in base excision repair (BER), where it provides backup activity in the absence of Pol β. BER is the major pathway for repair of small base damages resulting from alkylation, oxidation, depurination/depyrimidination, and deamination of DNA.
Besides its catalytic polymerase domain, pol λ has an 8 kDa domain and a BRCT domain. The 8 kDa domain has lyase activity that can remove a 5' deoxyribosephosphate group from the end of a strand break. The BRCT domain is a phosphopeptide binding domain that is common among DNA repair proteins and is likely involved in coordinating protein-protein interactions. Pol λ is structurally and functionally related to pol μ, another member of the X family that also participates in non-homologous end joining. Like pol μ, pol λ participates in V(D)J recombination, the process by which B-cell and T-cell receptor diversity is generated in the vertebrate immune system. Whereas pol μ is important for heavy-chain rearrangements, pol λ seems to be more important for light-chain rearrangements. The yeast Saccharomyces cerevisiae has a single homolog of both pol λ and pol μ called Pol4.
Translesion synthesis is a damage tolerance mechanism in which specialized DNA polymerases substitute for replicative polymerases in copying across DNA damages during replication. DNA polymerase lambda appears to be involved in translesion synthesis of abasic sites and 8-oxodG damages.
Interactions
Pol λ has been shown to interact with PCNA.
References
DNA repair
DNA-binding proteins | DNA polymerase lambda | [
"Biology"
] | 597 | [
"Molecular genetics",
"DNA repair",
"Cellular processes"
] |
14,755,313 | https://en.wikipedia.org/wiki/FOXO4 | Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.
Structure and function
FOXO4 is a member of the forkhead family of transcription factors in O subclass, which is characterized by a winged helix domain used for DNA binding. There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation. Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis. Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.
Clinical significance
Associations with longevity
FOXO transcription factors have been shown to be the downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans. FOXO's activation of these pathways produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.
FOXO4 can bind with p53 protein to induce cellular senescence. A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.
Cancer
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation. FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1. In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size. Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia. The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.
In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ. When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin. These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).
In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4. As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.
Interactions
PIN1, Mdm2 – FOXO4 has been shown to interact with PIN1 and Mdm2.
CIC – chromosomal translocation resulting in a fusion CIC-FOXO4 protein is observed in some tumors.
See also
FOX proteins
References
Further reading
External links
Forkhead transcription factors
Aging-related proteins | FOXO4 | [
"Biology"
] | 852 | [
"Senescence",
"Aging-related proteins"
] |
14,755,358 | https://en.wikipedia.org/wiki/Secreted%20frizzled-related%20protein%201 | Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Function
Secreted frizzled-related protein 1 (SFRP1) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. SFRP1 and SFRP5 may be involved in determining the polarity of photoreceptor cells in the retina. SFRP1 is expressed in several human tissues, with the highest levels in the heart.
The Secreted frizzled-related protein (SFRP) family consists of five secreted glycoproteins in humans (SFRP1, SFRP2, SFRP3, SFRP4, SFRP5) that act as extracellular signaling ligands. Each SFRP is ~300 amino acids in length and contains a cysteine-rich domain (CRD) that shares 30–50% sequence homology with the CRD of Frizzled (Fz) receptors. SFRPs are able to bind Wnt proteins and Fz receptors in the extracellular compartment. The interaction between SFRPs and Wnt proteins prevents the latter from binding the Fz receptors. SFRPs are also able to downregulate Wnt signaling by the formation of an inhibitory complex with the Frizzled receptors. The Wnt pathway plays a key role in embryonic development, cell differentiation and cell proliferation. It has been shown that the deregulation of this critical developmental pathway occurs in several human tumor entities.
SFRP1 is a 35 kDa prototypical member of the SFRP family. It acts as a biphasic modulator of Wnt signaling, counteracting Wnt-induced effects at high concentrations and promoting them at lower concentrations. It is located in a chromosomal region (8p12-p11.1) that is frequently deleted in breast cancer and is thought to harbour a tumor suppressor gene.
Tumor suppression
There are 3 types of tumor suppressor genes:
Genes that affect cell growth
Genes that limit the cell cycle and induce apoptosis
Genes that repair damaged DNA
SFRP1 appears to fall in the first category of genes, those that affect cell growth.
The role of SFRP1 as a tumor suppressor has been proposed in many cancers, based on its loss in patient tumors. Its frequent inactivation by methylation-induced silencing is consistent with it behaving as a tumor suppressor. Also, the SFRP1 gene is located in a region on chromosome 8 that is frequently lost in many cancer types. Expression levels of several targets of the Wnt signaling pathways are increased in tumor tissue compared with normal, and the expression of SFRP1 is lost in patient tumor samples. The role for the Wnt/β-catenin signaling in cancer has been well defined: β-catenin drives transcription of genes that contribute to the tumor phenotype by regulating processes such as proliferation, survival and invasion.
Gumz et al. showed that SFRP1 expression in UMRC3 cells (clear cell renal cell carcinoma cell line) resulted in a growth-inhibited phenotype. SFRP1 expression not only reduced the expression of Wnt target genes, but also markedly inhibited tumor cell growth in culture, soft agar and xenografts in athymic nude mice. Growth in culture and anchorage-independent growth were inhibited in SFRP1-expressing UMRC3 cells. The growth-inhibitory effects of SFRP1 were due primarily to decreased cell proliferation rather than an increase in apoptosis. This was consistent with the effect of SFRP1 on cellular proliferation as seen in prostate cancer, where retroviral-mediated expression of SFRP1 resulted in inhibited cellular proliferation but had no effect on apoptosis. Also, restoration of SFRP1 expression attenuated the malignant phenotype of cRCC; moreover, other studies showed reexpression of SFRP1 resulted in decreased colony formation in colon and lung cancer models.
Wnt-dependent signaling
The Wnt signaling pathways are initiated by the binding of the Wnt ligand to the Fz receptor. There are three different molecular pathways downstream of the Wnt/Fz interaction. The majority of research has focused on the Wnt/β-catenin pathway (also known as the "canonical" Wnt pathway), which manages cell fate determination by regulating gene expression. The Wnt/Ca2+ and Wnt/polarity pathways are known as the "non-canonical pathways". The decision of which pathway is activated most likely depends on which Wnt ligand and Fz receptor are present, as well as the cellular context. Nineteen Wnt ligands and ten different members of the Fz seven-transmembrane receptor family have been described in the human genome. As a result, a large variety of responses could be initiated from the Wnt/Fz interactions.
The Wnt/β-catenin pathway starts with the binding of Wnt to a receptor complex encompassing a Fz receptor and LRP co-receptor. After Wnt binds, an intracellular protein named Dishevelled (Dvl) is activated via phosphorylation. β-catenin degradation complexes in the cytoplasm are composed of adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β) and Axin. APC promotes the degradation of β-catenin by increasing the affinity of the degradation complex to β-catenin. Axin is a scaffolding protein which holds the degradation complex together. The activated Dvl associates with Axin and prevents GSK3β and casein kinase 1α (CK1α) from phosphorylating critical substrates, such as β-catenin. Phosphorylation of β-catenin marks the protein for ubiquitylation and rapid degradation by proteasomes. Thus, the binding of Wnt to the receptor results in a non-phosphorylated form of β-catenin which localizes to the nucleus and, after displacing the Groucho corepressor protein, forms a complex with Tcf/Lef transcription factors and co-activators (such as CREB binding protein) and induces the expression of downstream target genes.
β-catenin is actively stabilized in over 50% of breast cancers and its nuclear localization correlates with poor patient prognosis. Several target genes of the Wnt signaling pathway, such as cyclin D1, are activated in a significant proportion of breast tumours. It has been shown that SFRP1 transcription can be driven by B-catenin in normal intestinal epithelial cells. Neoplastic epithelial cells were treated with lithium chloride, which inhibits GSK3B and thus stabilizes B-catenin. Lithium chloride is widely used to mimic Wnt signaling. Rather than suppressing SFRP1 expression, B-catenin/TCF activity was associated with the induction of SFRP1. This is consistent with a negative feedback response restricting the exposure of a normal cell to a prolonged Wnt growth factor signal.
Hedgehog signaling in the intestinal epithelium represses the canonical Wnt signaling to restrict expression of Wnt target genes to stem or progenitor cells. It was thought that the Hedgehog signaling pathway does this via the induction of the secreted-type Wnt inhibitor. Katoh et al. searched for the GLI-binding site within the promoter region of Wnt inhibitor genes. GLI are transcription factors that activate the transcription of Hedgehog target genes. The GLI-binding site was identified within the 5’-flanking promoter region of the human SFRP1 gene. The GLI-binding site was conserved among promoter regions of mammalian SFRP1 orthologs. These facts indicate that the SFRP1 gene was identified as the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. SFRP1 was found to be expressed in mesenchymal cells. Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effect of canonical Wnt signaling. Thus, SFRP1 is most likely the Hedgehog target to confine canonical Wnt signaling within stem or progenitor cells. Epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent Wnt signal inhibition.
Genome instability
Regions of the short arm of chromosome 8 are frequently deleted in a range of solid tumors, indicating that tumor suppressor genes reside at these loci. Caldwell et al. have shown frequent interstitial deletions in a series of prostate cancers, squamous cell head and neck cancers and colorectal carcinomas. There was also an association between 8p11.2 deletion and local invasion.
The first coding exon contains the whole of the frizzled-related cysteine rich domain (CRD), while the third exon (COOH-terminal domain) contains the netrin-related domain. Netrin is a regulator of apoptosis; the SFRP1 netrin-related motif is also found in a range of other proteins that is thought to mediate protein-protein interactions. The middle exon most likely represents a spacer between the first and third exon. There are 2 introns present within the coding sequence of SFRP1.
Protein-truncating mutations in tumor DNA
Three out of 10 advanced colorectal tumors had mutations leading to premature termination of the SFRP1 translation product. The mutations were two single-base deletions (26delG and 67delG) and a single-base change (G450A), which generates an in-frame stop codon. These three mutations were found within the first exon, which was shown previously to be sufficient for Wnt antagonist activity by itself [26, 32]. Of the 10 tumors analyzed, no truncating mutations were found in the second or third exons of SFRP1.
An additional 51 tumors were analyzed via direct sequence analysis, yielding 49 clearly interpretable results. Only the first exon was sequenced for stop codon mutations, but none were found. This indicates that point mutation is not a frequent method of inactivation of the SFRP1 gene in colorectal cancer.
Common exon 1 polymorphism
The primary translation product of SFRP1 contains an atypical signaling sequence, where a chain of 15 hydrophilic amino acids precede the hydrophobic domain. Looking at 7 tumors without the truncating mutation, the retained SFRP1 allele contained an in-frame three-base insertion after nucleotide 37. This is thought to lead to an extra alanine in the protein after codon 13. However, no significant association was found between the development of colorectal cancer and the presence of the 3-bp insertion.
Alternatively spliced 3’ end
An unspliced form of SFRP1 is the dominant form in the lung and liver, leading to an extended protein. This extended sequence contains a hydrophobic region that may act as a transmembrane anchor, modifying the localization of the protein. This may then influence the function of SFRP1 in different tissues because an untethered protein may be more effective in antagonizing Wnt signaling to tumor cells than would a membrane-bound form.
Epigenetics
Downregulated expression in several kinds of malignancy
NSCLC (48% of investigated cell lines)
SCLC (38% of investigated cell lines)
Bladder cancers (38%)
Breast cancers (46%)
Malignant mesotheliomas (48%)
Colorectal cancers (76%)
Mechanism of down regulation
DNA methylation involves the addition of a methyl group to the carbon-5 position of the cytosine ring in the CpG dinucleotide and converting it to methylcytosine. This process is catalyzed by DNA methyltransferase. In numerous cancers, the CpG islands of selected genes are aberrantly methylated (hypermethylated) which results in transcriptional repression. This may be an alternate mechanism of gene inactivation.
Multiple genes have been discovered to be frequently methylated in cancers and leukemias. More specifically, the deregulation of the Wnt signaling pathway has been implicated in a wide array of cancers that is mainly seen as a result of loss-of-function mutations of APC and axin or as a gain-of-function mutation of CTNNB1 (B-catenin). The GC content of the SFRP1 promoter in humans is 56.3%.
It has been found that the overexpression of B-catenin may lead to enhanced proliferation in myeloma plasma cells; thus, soluble Wnt inhibitors are potential tumor suppressor genes and, if inactivated, may contribute to myeloma pathogenesis. This led Chim et al. to investigate the role of aberrant gene methylation of a panel of soluble Wnt antagonists, including SFRP1. Complete methylation led to silencing of respective genes (no transcripts), whereas absence of gene methylation was associated with constitutive gene expression. Methylation of soluble Wnt antagonists would be important in the pathogenesis of multiple myeloma if Wnt signaling was regulated by an autocrine loop by Wnt and Fz. If an autocrine loops exists, then both the ligand (Wz) and receptor (Fzd) should be simultaneously expressed in myeloma cells and growth of tumour cells should be inhibited upon addition of SFRP1. Chim et al. demonstrated simultaneous expression of Wz and Fzd in myeloma plasma cells. Moreover, treatment with recombinant SFRP1 inhibited the growth of myeloma cells in a dose-dependent manner. These findings implicate soluble Wnt inhibitors as tumor suppressors that could be inactivated by methylation.
Veeck and colleagues found all of their eight breast cancer cell lines had complete methylation in the SFRP1 promoter region, while no methylation was detectable in non-malignant cell lines. After treatment with 5-Aza-2’-deoxycytidine (DAC), an inhibitor of DNA methyltransferase, SFRP1 expression was restored in all four treated breast cancer cell lines, supporting the hypothesis of methylation-mediated SFRP1 gene silencing in breast cancer.
Furthermore, the transcriptional silencing mechanism underlying DNA methylation which is brought about through the hypermethylation of CpG-rich islands present in the promoter region of genes, can cooperate with histone deacetylation to change chromatin structure to a repressed form. Lo and colleagues looked at the effects of DAC and trichostatin A (TSA, selectively inhibits the mammalian histone deacetylase family of enzymes) on cancer cells. In 4 breast cancer cell lines, SFRP1 expression was significantly restored after treatment with DAC alone. TSA, only in combination with DAC, had a slightly enhanced effect on SFRP1 expression in these cell lines. A different breast cancer cell line (SKBR3, showed loss of SFRP1 expression without significant methylation of the SFRP1 promoter. Lo et al. hypothesized that this may be due to silencing via histone deacetylation. After SKBR3 cells were treated with TSA, SFRP1 expression was restored in a dose- and time-dependent manner. Yet another breast cancer cell line (T47D) required both DAC and TSA to upregulate SFRP1 expression. This indicates that T47D cells are tightly regulated by two layers of epigenetic control (DNA methylation and histion deacetylation) and relieving inhibition by both mechanisms is necessary for reactivation of SFRP1. This study shows that both the epigenetic mechanisms, DNA methylation and histone deacetylation, are involved in silencing of SFRP1.
Hormones
Uterine leiomyomas are the most common tumors found in the female genital tract. Leiomyomas have been reported to grow under the influence of ovarian steroids (estrogen and progesterone). Aberrations of wnt signaling, as well as SFRPs, can contribute to the neoplastic process. This led Fukuhara et al. to investigate whether SFRP1 is associated with the pathogenesis of uterine leiomyomas by analyzing mRNA and protein expression of SFRP1 in leiomyomas and matched normal myometrium. The following outlines their findings:
Expression in normal myometrium and leiomyoma
Twenty-three out of 25 patients showed high expression of SFRP1 mRNA in leiomyoma than the matched normal myometrium. During the menstrual cycle, the level of SFRP1 mRNA in leiomyoma was highest in the follicular phase. Gonadotropin releasing hormone analogue (GnRHa) decreases estrogen secretion from the ovary. Patients treated with (GnRHa) presurgically showed the lowest expression of SFRP1 in both myometrial and leiomyoma tissues. These findings suggest that SFRP1 could be under the control of estrogen. Gene expression of estrogen receptors in leiomyomas is stronger than that in the myometrium. This suggests that leiomyoma possess increased sensitivity to E2 (estradiol, a form of estrogen) and the estrogen-dependent expression of SFRP1 in leiomyoma could be associated with the growth and pathogenesis of leiomyoma.
Expression after estrogen or progesterone treatment
Smooth muscle cells cultured from the myometrium showed no significant induction of SFRP1 mRNA in response to treatment with E2 and/or progesterone. Conversely, cells cultured from leiomyomas showed significant dose-dependent induction of SFRP1 mRNA in response to treatment with E2; however, progesterone had no effect on SFRP1 even when coapplied with E2.
Effect of proliferation, serum deprivation and hypoxia on expression
Both hypoxic conditions and serum deprivation induced increased expression of SFRP1 in leiomyoma cells. However, the smooth muscle cells cultured from the myometrium showed no significant correlation between SFRP1 expression and oxygen concentration. This suggests that SFRP1 may protect the cells from the damage caused by these stresses.
Angiogenesis
The formation of new blood capillaries is an important component of pathological tissue repair in response to ischemia. The angiogenic process is complex and involves endothelial cell (EC) movement and proliferation.
SFRP1 has been shown to have a role in new vascularization after an ischemic event and as a potent angiogenic factor. In vitro SFRP1 modulated the EC angiogenic response (migration, differentiation) and in vivo SFRP1 stimulated neovascularization in plug or tumor models. The directed movements of EC during de novo vessel formation are coordinated through cellular adhesion mechanisms, cytoskeletal reorganization and by association with elevated expression of angiogenic factors such as, the key factor, vascular endothelial growth factor. The regulation of the EC cytoskeleton is critical to EC spreading and motility. SFRP1 was found to have a major role in mediating EC spreading by regulating reorganization of the actin network and focal contact formations.
In vivo data supports a critical role for SFRP1 in ischemia-induced angiogenesis in adults. Using adenovirus-expressing SFRP1, impaired the canonical Wnt/Fzd pathway in the early phase of ischemia and as a result reduced vascular cell proliferation and delayed vessel formation. When SFRP1 was induced specifically in ECs along the kinetics of ischemia repair, a biphasic response was seen: a delay in capillary formation until day 15 and then an increase in vascular formation at day 25. This indicates that SFRP1 can fine tune the outcome of Wnt/Fzd signaling at different steps in the course of neovessel formation.
Clinical relevance
Loss of SFRP1 protein expression is associated with poor overall survival (OS) in patients with early breast cancer (pT1 tumours); this indicates that SFRP1 may be a putative tumor suppressor gene. SFRP1 methylation has been shown to be an independent risk factor for OS. Veeck and colleagues demonstrate, via Kaplan-Meier analysis, that clear SFRP1 promoter methylation is associated with unfavourable prognosis. Furthermore, a correlation between SFRP1 methylation and OS in breast cancer is dependent on a gene dose effect. In order for the OS to be affected, a sufficient amount of tumour cells may be required to lose SFRP1 expression due to promoter methylation.
As a drug target
Heparin and heparan sulfate (HS) are mammalian glycosaminoglycans with the highest negative charge density of known biological macromolecules. They bind by ionic interactions with a variety of proteins. Heparin is widely used as an injectable anticoagulant. SFRP1 are heparin-binding proteins, with the heparin-binding domain within the C-terminal region of the SFRP1 protein. In vitro studies show that SFRP1 is stabilized by heparin, suggesting that heparin or endogenous heparan-sulfate proteoglycan (HSPG) has the potential to promote SFRP1/Wnt binding by serving as a scaffold to facilitate interaction between SFRP1 and Wnt proteins. Lowering HSPG levels in tissue have been shown to impair Wnt signaling in vivo, supporting the idea that HSPG plays an important role in Wnt signaling regulation. Furthermore, SFRP1 is tyrosine-sulfated at two N-terminal tyrosines; this modification is, however, inhibited by heparin. Tyrosine sulfation could partially destabilize the SFRP1 protein, which is supported by previous studies showing that SFRP1 is susceptible to degradation in the absence of heparin. The finding that heparin can inhibit intracellular post-translational modification of SFRP1 was surprising. This indicates that heparin may inhibit the process of tyrosine sulfation, for example, by tyrosyl-protein sulfotransferases enzymes or sulfate donor pathways. Since heparin is highly negatively charged and cannot permeate the membrane, it must activate a signal transduction pathway to carry out its effect. It is well known that fibroblast growth factors (FGFs) bind heparin with relatively high affinity. HSPGs have also been shown to be involved in FGF cell signaling. Zhong et al. revealed a specificity of FGFs and FGF receptors on SFRP1 accumulation, demonstrating that FGF and their receptors are involved in post-translational modification of SFRP1. As stated above, SFRP1 has been shown to attenuate the malignant phenotype and decrease the growth of tumors. Thus, Heparin is a potential drug that could be used to stabilize and accumulate SFRP1 in cancer cells.
As a biomarker
Aberrant promoter hypermethylation of SFRP1 occurs frequently during the pathogenesis of human cancers and has been found to be one of the primary mechanisms in SFRP1 down-regulation. Methylation-specific PCR (MSP) is able to detect this epigenetic change and could be used for cancer detection. Detection and quantification of promoter CpG methylation in body fluid is both feasible and noninvasive. Combined MSP analyses of multiple genes in voided urine could provide a reliable way to improve cancer diagnosis.
Urakami et al. were able to detect cancers cells using conventional MSP analysis of Wnt-antagonist genes (including SFRP1) in voided urine of patients with bladder tumor. Their results showed a high percentage of identical methylation with tumor-tissue DNA. Conversely, no aberrant methylation was detected in >90% of urine DNA from normal controls. This demonstrates that methylation detection of SFRP1 is both feasible and reliable and that the urine methylation score (M score) of Wnt antagonist genes could be used as an excellent noninvasive diagnostic biomarker for bladder tumor. Furthermore, the M score of Wnt-antagonist genes may reflect the presence of bladder tumor that progresses to invasive disease that would signal for future aggressive treatment. An optimal hypermethylation panel of Wnt-antagonist genes could contribute significantly to early detection of bladder tumor and predict bladder tumor aggressiveness. In fact, the methylation of SFRP1 genes in fecal DNA isolated from stool samples has been used to screen for colorectal cancer.
Immunotherapy
Immunotherapy is a treatment used to produce immunity to a disease or enhance the resistance of the immune system to an active disease process, such as cancer
Wnt and Fz genes are frequently overexpressed in head and neck squamous cell carcinoma (HNSCC). Treatment of a HNSCC cell line (SNU 1076) with anti-Wnt1 antibodies reduced the activity of the Wnt/Fz dependent transcription factor LEF/TCF and diminished the expression of cyclin D1 and B-catenin proteins. Similar to anti-Wnt antibodies, treatment with recombinant SFRP1 inhibited growth of SNU 1076 cells as well. This suggests that Wnt and Fz receptors may be attractive targets for immunotherapy and drug therapy of HNSCC.
Epigenetic Therapy
Epigenetic Therapy is the use of drugs or other epigenome-influencing techniques to treat medical conditions.
It is recently regarded as promising therapy to NSCLC.
As can be seen in the above, SFRP1 was downregulated epigenetically in NSCLC and was recently proposed as one of epigenetic therapy target.
Interactions
Secreted frizzled-related protein 1 has been shown to interact with FZD6.
References
Further reading
Tumor suppressor genes
Gene expression | Secreted frizzled-related protein 1 | [
"Chemistry",
"Biology"
] | 5,585 | [
"Gene expression",
"Molecular genetics",
"Cellular processes",
"Molecular biology",
"Biochemistry"
] |
14,755,368 | https://en.wikipedia.org/wiki/PMEL%20%28gene%29 | Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene. Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.
Structure and function
PMEL is a 100 kDa, 661 amino acids long type I transmembrane glycoprotein that is expressed primarily in melanosomes, which are the melanin-producing organelles in melanocytes of pigment cells of the skin and eye, and in most malignant melanomas.
This protein is involved in melanosome maturation, including melanogenesis, melanosome biogenesis, and melanin polymerization (Eisenberg) . The transmembrane form of PMEL is modified in the secretory pathway by elaboration of N-linked oligosaccharides and addition and modification of O-linked oligosaccharides. It is then targeted to precursors of the pigment organelle, the melanosome, where it is proteolytically processed to several small fragments. Some of these fragments form non-pathological amyloid that assemble into sheets and form the striated pattern that underlies melanosomal ultrastructure. PMEL cleavage is mediated by several proteases including a proprotein convertase of the furin family, a "sheddase" that might include members of the a disintegrin and metalloproteinase (ADAM) family, and additional proteases in melanosomes or their precursors. After the amyloidogenic region is cleaved, the small remaining integral membrane fragment is digested by γ-secretase.
The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF).
Function in cancer and cancer treatment
The gp100 protein is a melanoma antigen i.e. a tumor-associated antigen.
Short fragments of it have been used to develop the gp100 cancer vaccine which is or contains gp100:209-217(210M).
Hydrophilic recombinant gp100 protein (HR-gp100) has been topically applied on human intact skin in vitro, and used as a vaccine in a mouse model. It was demonstrated that HR-gp100 permeates into human skin, and is processed and presented by human dendritic cells. In the mouse model, an HR-gp100-based vaccine triggered antigen-specific T cell responses, as shown by proliferation assays, ELISA and intracellular staining for IFN-γ.
The gp100 protein contains differentiation antigens., and has been widely studied to be used as a target for melanoma immunotherapy. Different sequences of the GP100 peptide could be used for immunization against tumors. According to a case study, modifications of GP100, such as GP100-209 and GP100-208, have shown a greater number of antigen-specific CTL's (cytotoxic T lymphocytes), which can target and kill cancer cells (Eisenberg).
References
Further reading
External links
Oncology | PMEL (gene) | [
"Chemistry"
] | 687 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,755,377 | https://en.wikipedia.org/wiki/Structure%20specific%20recognition%20protein%201 | FACT complex subunit SSRP1 also known as structure specific recognition protein 1 is a protein that in humans is encoded by the SSRP1 gene.
Function
The protein encoded by this gene is a subunit of a heterodimer that, along with SUPT16H, forms chromatin transcriptional elongation factor FACT. FACT interacts specifically with histones H2A/H2B to effect nucleosome disassembly and transcription elongation. FACT and cisplatin-damaged DNA may be crucial to the anticancer mechanism of cisplatin. This encoded protein contains a high mobility group box which most likely constitutes the structure recognition element for cisplatin-modified DNA. This protein also functions as a co-activator of the transcriptional activator p63.
Interactions
Structure specific recognition protein 1 has been shown to interact with NEK9.
SSRP1 further interacts with transcriptional activator p63. SSRP1 enhances the activity of full-length p63, but it has no effect on the N-terminus-deleted p63 (DeltaN-p63) variant.
References
Further reading
External links
Transcription factors | Structure specific recognition protein 1 | [
"Chemistry",
"Biology"
] | 247 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,755,479 | https://en.wikipedia.org/wiki/CHRNB2 | Neuronal acetylcholine receptor subunit beta-2 is a protein that in humans is encoded by the CHRNB2 gene.
Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy.
It has been discovered that suppression, rather than stimulation, of B2-containing nAChR currents yields an antidepressant effect. This is believed to explain the significantly increased prevalence of cigarette smoking in depressed individuals and the profound rise in depressive symptoms during abstinence.
Interactive pathway map
See also
Nicotinic acetylcholine receptor
References
Further reading
External links
Ion channels
Nicotinic acetylcholine receptors | CHRNB2 | [
"Chemistry"
] | 216 | [
"Neurochemistry",
"Ion channels"
] |
14,755,527 | https://en.wikipedia.org/wiki/ERG%20%28gene%29 | ERG (ETS-related gene) is an oncogene. ERG is a member of the ETS (erythroblast transformation-specific) family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.
Function
Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA. Transcriptional regulator ERG is required for platelet adhesion to the subendothelium and regulates hematopoiesis. It has a DNA binding domain and a PNT (pointed) domain. ERG is expressed at higher levels in early myelocytes than in mature lymphocytes (types of white blood cells). Therefore, ERG may act as a regulator of differentiation of early hematopoietic cells.
The Mld2 mutation, generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. Homozygous Mld2 is embryonic lethal at day 13.5. Adult mice heterozygous for the Mld2 mutation have hematopoietic stem cell defects. This means that when the ERG gene was not actively transcribed and the ERG protein produced, a mouse's hematopoietic cells were unable to function properly. Since ERG is important to the ability of the hematopoietic cells to function and self-renew, there may be applications in using blood stem cells for tissue repair, transplantation and other therapeutic applications.
Cancer
This gene can be classified as a proto-oncogene. During chromosomal translocations that occur in cell division, ERG can accidentally get stuck onto a different chromosome than where it belongs. This is analogous to another translocation, the Philadelphia chromosome. This results in fusion gene products, which can have bad consequences for cells. Examples of these fusion gene products would be TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing’s sarcoma, and FUS-ERG in acute myeloid leukemia. DNA binding protein ERG fuses with RNA binding proteins EWS and TLS/FUS in Ewing's sarcoma and acute myeloid leukemias respectively and function as transcriptional activators. ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis. Morpholino splice-switching oligonucleotides have been used to induce exon 4 skipping in prostate cancer cell lines, mouse models and tissue explants, leading to anti-cancer effects, including reduction of proliferation and induction of apoptosis.
TMPRSS2 gene fusion
ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in human prostate cancer, especially in hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. The fusion gene is critical to the progression of cancer because it inhibits the androgen receptor expression and it binds and inhibits androgen receptors already present in the cell. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue. In 90% of prostate cancers overexpressing ERG, they also possess a fusion TMPRSS2-ERG protein, suggesting that this fusion is the predominant subtype in prostate cancer.
EWS gene fusion
Ewing's sarcoma is associated with chromosomal translocations, which typically results in fusion genes with transcriptional regulators. This means that the protein transcribes for with the gene could be produced in excess or under- produced resulting in unnatural activity in cells. Typically this is the first step in a cell's progression to malignancy. In about 10% of Ewing's Sarcoma cases have an EWS1-ERG fusion.
Fusion with TLS/FUS
In acute myeloid leukemia, the t(16;21) translocation in myeloid leukemia fuses TLS/FUS to ERG which disrupts the natural TLS/FUS RNA binding domain, and instead inserting the ERG DNA binding domain.
Location
ERG is located on chromosome 21. The ERG protein is expressed at a similar level throughout the body.
Interactions
ERG has been shown to interact with:
C-jun
ETS2
EWSR1
FUS
TMPRSS2
USP9X
References
Further reading
External links
Transcription factors
Oncogenes | ERG (gene) | [
"Chemistry",
"Biology"
] | 1,009 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,755,566 | https://en.wikipedia.org/wiki/Glypican%203 | Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).
Structure and function
The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa. Six glypicans (GPC1-6) have been identified in mammals. Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. GPC3 has been found to regulate Wnt/β-catenin and Yap signaling pathways. GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling. The core protein of GPC3 may serve as a co-receptor or a receiver for Wnt. A cysteine-rich domain at the N-lobe of GPC3 has been identified as a hydrophobic groove that interacts with Wnt3a. Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation. Wnt also recognizes a heparan sulfate structure on GPC3, which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to heparan sulfate. GPC3 also modulates Yap signaling. It interacts with FAT1, a potential upstream cell surface receptor of YAP1 in human cells. GPC3 is also found to bind Alpha-fetoprotein in liver cancer.
Disease linkage
Deletion mutations in this gene are associated with Simpson–Golabi–Behmel syndrome.
Diagnostic utility
Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not. Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma. The YP7 murine antibody has been humanized and named as 'hYP7'. GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors. However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.
Therapeutic potential
To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33, YP7, HN3 and HS20 have been made and widely tested. The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 murine monoclonal antibody that recognizes the C-lobe of GPC3 by hybridoma technology. The antibody has been humanized (named hYP7) via antibody engineering for clinical applications. The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3 targeting the N-lobe of GPC3 and the human monoclonal antibody HS20 targeting the heparan sulfate chains on GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3, the antibody-drug conjugates based on hYP7 and the T-cell engaging bispecific antibodies derived from YP7 and GC33, have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33, hYP7 and HN3 are being reported at various stages for treating liver cancer. In mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells can eliminate GPC3-positive cancer cells, by inducing perforin- and granzyme-mediated cell death and reducing Wnt signaling in tumor cells. CAR (hYP7) T cells are being evaluated at a clinical trial at the NIH.
See also
Glypican
References
Further reading
External links
GeneReviews/NIH/NCBI/UW entry on Simpson-Golabi-Behmel Syndrome
Immunologic tests | Glypican 3 | [
"Biology"
] | 1,145 | [
"Immunologic tests"
] |
14,755,599 | https://en.wikipedia.org/wiki/MST1R | Macrophage-stimulating protein receptor is a protein that in humans is encoded by the MST1R gene. MST1R is also known as RON (Recepteur d'Origine Nantais) kinase, named after the French city in which it was discovered. It is related to the c-MET receptor tyrosine kinase.
Interactions
MST1R has been shown to interact with Grb2.
References
Further reading
Tyrosine kinase receptors | MST1R | [
"Chemistry"
] | 96 | [
"Tyrosine kinase receptors",
"Signal transduction"
] |
14,755,668 | https://en.wikipedia.org/wiki/B-cell%20linker | B-cell linker (BLNK) protein is expressed in B cells and macrophages and plays a large role in B cell receptor signaling. Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity. Its function is to temporally and spatially coordinate and regulate downstream signaling effectors in B cell receptor (BCR) signaling, which is important in B cell development. Binding of these downstream effectors is dependent on BLNK phosphorylation. BLNK is encoded by the BLNK gene and is also known as SLP-65, BASH, and BCA.
Structure and localization
BLNK consists of a N-terminal leucine zipper motif followed by an acidic region, a proline-rich region, and a C-terminal SH2 domain. The leucine zipper motif allows BLNK to localize to the plasma membrane, presumably by coiled-coil interactions with a membrane protein. This leucine zipper motif distinguishes BLNK from lymphoctye cytosolic protein 2, also known as LCP-2 or SLP-76, which plays a similar role in T cell receptor signaling. Although LCP-2 has an N-terminal heptad-like organization of leucine and isoleucine residues like BLNK, it has not been experimentally shown to have the leucine zipper motif. Recruitment of BLNK to the plasma membrane is also achieved by binding of the SH2 domain of BLNK to a non-ITAM phospho-tyrosine on the cytoplasmic domain of CD79A, which is a part of Igα and the B cell receptor complex.
Function
BLNK's function and importance in B cell development were first illustrated in BLNK deficient DT40 cells, a chicken B cell line. DT40 cells had interrupted B cell development: there was no calcium mobilization response in the B cell, impaired activation of the mitogen-activated protein (MAP) kinases p38, JNK, and somewhat inhibited ERK activation upon (BCR) activation as compared to wild type DT40 cells. In knockout mice, BLNK deficiency results in a partial block in B cell development, and in humans BLNK deficiency results in a much more profound block in B cell development.
Linker or adaptor proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. BLNK is essential for normal B-cell development as part of the B cell receptor signaling pathway. [supplied by OMIM]
Evidence also suggests that BLNK may have tumor suppressive activity through its interaction with Bruton's tyrosine kinase (Btk) and regulation of the pre-B cell checkpoint.
Phosphorylation and interactions
The acidic region of BLNK contains several inducibly phosphorylated tyrosine residues, at least five of which are found in humans. Evidence suggests that BLNK is phosphorylated by the tyrosine-protein kinase Syk after B cell receptor activation. Phosphorylation of these residues provides docking sites necessary for downstream protein-protein interactions between BLNK and the SH2 domain-containing proteins Grb2, PLCG2, Btk, the Vav protein family, and Nck. BLNK has also been shown to interact with SH3KBP1 and MAP4K1. A more recent mass spectrometry study of BLNK in DT40 cells found that at least 41 unique serine, threonine, and tyrosine residues are phosphorylated on BLNK.
References
Further reading
External links
Proteins | B-cell linker | [
"Chemistry"
] | 771 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,755,739 | https://en.wikipedia.org/wiki/EPH%20receptor%20A4 | EPH receptor A4 (ephrin type-A receptor 4) is a protein that in humans is encoded by the EPHA4 gene.
This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands.
In 2012, a publication in Nature Medicine revealed a connection between EPHA4 and the neurodegenerative disease Amyotrophic lateral sclerosis (ALS), where a defective gene allows ALS patients to live considerably longer than patients with an intact gene. This opens up for development of treatment for this currently untreatable disease.
References
Further reading
Tyrosine kinase receptors | EPH receptor A4 | [
"Chemistry"
] | 226 | [
"Tyrosine kinase receptors",
"Signal transduction"
] |
14,755,756 | https://en.wikipedia.org/wiki/Histidine-rich%20glycoprotein | Histidine-rich glycoprotein (HRG) is a glycoprotein that in humans is encoded by the HRG gene. The HRG protein is produced in the liver, and it could also be synthesized by monocytes, macrophages, and megakaryocytes. It possesses a multi-domain structure, which makes it capable of binding to numerous ligands and modulating various biological processes including immunity, vascularization and coagulation.
Structure
Gene
The HRG gene lies on location of 3q27 on the chromosome 3, spans approximately 11kb, and consist of 7 exons. Two common isoforms of the HRG gene have been found in humans. These isoforms exist due to a polymorphism occurring in exon 5.
Protein
HRG is a glycoprotein of 70-75kDa present at a relatively high concentration in the plasma of vertebrates. The primary structure of human HRG is predicted to be a 507 amino acid multidomain polypeptide consisting of two cystatin-like regions at the N-terminus, a histidine-rich region (HRR) flanked by proline-rich regions (PRR), and a C-terminal domain. HRG has an unusually high concentration of histidine and proline residues, each constituting approximately 13% of total amino acids, concentrated within the HRR and PRR. The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG). Human HRG is also composed of approximately 14% carbohydrate attached to six predicted N-linked glycosylation sites.
Function
This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. It is known that HRG binds heme, dyes, and divalent metal ions and it is thought to have multiple roles in the human blood, including roles in immunity, angiogenesis and coagulation.
It can inhibit rosette formation and interacts with heparin, thrombospondin, and plasminogen. Two of the protein's effects, the inhibition of fibrinolysis and the reduced inhibition of coagulation, indicate a potential prothrombotic effect. HRG is also reported to be involved in clearance of apoptotic phagocytes, immune complexes, cell adhesion, migration and angiogenesis, due to its ability to bind various ligands such as phospholipids, fibrinogen, plasminogen, heparin, heparansulfate, tropomysin, and heme, as well as the divalent metal ions zinc, copper, mercury, cadmium and nickel. Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.
Clinical significance
The implications of HRG in cancer have been described as "multi-faceted". For example, the protein appears to have both pro- and anti-angiogenic effects. In biomarker studies, the protein has been found to have potential prognostic and diagnostic value for cancer. Furthermore, the absence of the protein is associated with thrombophilia. HRG has also been shown to inhibit the M2-like phenotype of tumor-associated macrophages.
In addition, HRG has been discovered to play a role in infection. Some studies have found HRG has the antibacterial activity against Streptococcus pyogenes and a direct interaction between a S. pyogenes virulence factor (sHIP) and the human HRG has been identified.
Interactions
This protein is known to interact with:
Thrombospondin
Haem
Zn2+
Heparin
Plasminogen
IgG
References
Further reading
Glycoproteins
Genes on human chromosome 3 | Histidine-rich glycoprotein | [
"Chemistry"
] | 829 | [
"Glycoproteins",
"Glycobiology"
] |
14,755,888 | https://en.wikipedia.org/wiki/Reticulon%204%20receptor | Reticulon 4 receptor (RTN4R) also known as Nogo-66 Receptor (NgR) or Nogo receptor 1 is a protein which in humans is encoded by the RTN4R gene. This gene encodes the receptor for reticulon 4, oligodendrocytemyelin glycoprotein and myelin-associated glycoprotein. This receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system.
Function
The Nogo-66 Receptor (NgR) is a high affinity binding receptor for a region of Nogo, a myelin associated protein that inhibits axon outgrowth. NgR was identified by Strittmatter and colleagues using an expression cloning strategy.
NgR is implicated in neuronal plasticity and regeneration. Its relative importance in mediating myelin inhibition in vitro and in vivo is currently under intense investigation, since this protein might be a good drug target for treatment of various neurological conditions such as spinal cord injury and stroke.
Nogo pathway: rho kinase
While the entire pathway is not fully understood, the relationship between NgR and neuronal outgrowth has been fleshed out. NgR is a membrane protein that, when bound to neurite outgrowth inhibitor (Nogo), inhibits cell growth through the activation of rho kinase (ROCK).
NgR activation of p75
It was known that NgR, Nogo, and another membrane receptor called p75 were involved in inhibiting neurite outgrowth. Through a variety of experimental procedures Wang et al. were able to identify the biochemical relationship between NgR and p75. First, it was observed that when p75 was knocked out in mice, outgrowth inhibition was no longer seen. Completing binding assays and co-immunoprecipitations revealed that p75 and NgR were not bound to each other through the cellular membrane. Mutating either p75 or NgR, however, resulted in truncated protein that would help reveal the binding interactions. When the extracellular domains of the receptors were removed no outgrowth inhibition was seen. This would suggest that the receptors interact extracellularly. Furthermore, it was reaffirmed that Nogo and myelin-associated gylcoprotein (MAG) bind NgR and not p75. The receptor p75 lacks a binding domain for either of these proteins.
Activation of rho protein
The work of Kaplan and Miller shows that there is an interaction between the p75/NgR receptors and Rho GDP dissociation inhibitor (Rho-GDI). Kaplan and Miller show that when Nogo is bound to NgR, Rho-GDI is associated with p75. When Rho-GDI is drawn to p75 it is no longer bound to Rho-GDP. This allows for GTP to be exchanged for GDP activating the Rho protein. Rho-GTP, a Rho GTPase, then activates ROCK which phosphorylates other proteins which inhibit neurite outgrowth. When Nogo is not bound to NgR, p75 is not activated and Rho-GDI remains bound to Rho-GDP. The Rho protein remains bound with GDP and remains inactive. ROCK therefore does not become activated and cannot change transcription patterns to inhibit neuronal outgrowth.
Therapeutic Inhibition
It is reasonable that inhibition of the above mechanism could aid the recovery of those suffering from spinal cord injuries. One such therapy is currently in clinical trials. The drug, called Cethrin, is produced by a group called Alseres. Cethrin is a ROCK inhibitor and therefore acts in the above pathway to prevent the activation of ROCK so neurite outgrowth can occur. Cethrin is applied as a paste to the site of injury during decompression surgery.
Regulation of Visual Cortex Plasticity
The Nogo-66 receptor (NgR) limits experience-driven visual cortex plasticity. In mutant mice, non-functional NgR resulted in enhancement of visual cortex plasticity after the critical period into adulthood, such that adult plasticity in the mutant mice resembled normal visual plasticity in juvenile mice brains. This function of NgR is of particular interest to the study of visual disorders that may result from imbalanced input during the critical period, such as amblyopia.
See also
Reticulon 4
References
Further reading
Receptors | Reticulon 4 receptor | [
"Chemistry"
] | 914 | [
"Receptors",
"Signal transduction"
] |
14,755,955 | https://en.wikipedia.org/wiki/EPH%20receptor%20B1 | Ephrin type-B receptor 1 is a protein that in humans is encoded by the EPHB1 gene.
Function
Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene is a receptor for ephrin-B family members.
Interactions
EPH receptor B1 has been shown to interact with:
ACP1
GRB7 and
NCK1
Ephrin-B2
References
Further reading | EPH receptor B1 | [
"Chemistry"
] | 238 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,756,009 | https://en.wikipedia.org/wiki/Anti-Hebbian%20learning | In neuroethology and the study of learning, anti-Hebbian learning describes a particular class of learning rule by which synaptic plasticity can be controlled. These rules are based on a reversal of Hebb's postulate, and therefore can be simplistically understood as dictating reduction of the strength of synaptic connectivity between neurons following a scenario in which a neuron directly contributes to production of an action potential in another neuron.
Evidence from neuroethology
Neuroethological study has provided strong evidence for the existence of a system which adheres to an anti-Hebbian learning rule. Research on the mormyrid electric fish has demonstrated that the electrosensory lateral-line lobe (ELL) receives sensory input from knollenorgans (electroreceptive sensory organs) which utilize a self-generated electrical discharge (called an EOD; electric organ discharge) to extract information from the environment about objects in close proximity to the fish.
In addition to information from sensory receptors, the ELL receives a signal from the area of the brain responsible for initiating the electrical discharges, known as the EOD command nucleus. This efference copy diverges, transmitted through two separate pathways, before the signals converge along with electrosensory input on Purkinje-like Medium Ganglion cells in the ELL. These cells receive information through extensive apical dendritic projections from parallel fibers that signal the transmission of an order to release an EOD. These cells also receive information from neurons conveying electrosensory information.
Important to anti-Hebbian learning, the synapses between the parallel fibers and the apical dendrites of Medium Ganglion cells show a specific pattern of synaptic plasticity. Should activation of the dendrites by parallel fibers occur in a short time period preceding the initiation of a dendritic broad spike (an action potential which travels through the dendrites), the strength of the connection between the neurons at these synapses will be reduced. Activation by the parallel fibers in all other circumstances – including activation significantly preceding as well as any activation following the broad spike – will result in the strengthening of the synapse.
Significance
Since the neurons of the ELL receive both a corollary discharge (another term for an efference copy) of the motor output commands sent to the EOD, and afferent input from the electrosensory receptors, the animal is able to eliminate predictable inputs produced by its own motor output. The system is able to filter the expected input from the EOD, while signals which are unexpected, arriving at odd intervals with regard to the motor command are effectively strengthened by the learning rule. This allows the extraction of information about objects which cause an alteration in the flow of the electric field around the fish, highlighting changes while discarding uninformative sensory inputs.
The adaptation of these synapses, though, will only increase the strength of a synaptic connection until the resulting excitation aids in activation of a broad-spike wave. As a result, if changes in external environment are consistent, the connections between the neurons previously described will reach a level at which excitation, similar to the initial state, is once again held at a threshold, so that slight changes in the incoming sensory information will result in contribution to broad-spike initiation. In this manner, the organism is able to learn to ignore redundant sensory information in the environment. The eventual desensitization to these consistencies is essential to prevent excessive noise from masking important sensory information. Numerous potential causes which could result in a consistent alteration in the reception of EOD signals include: growth, changes in water conductance (salinity), low water levels (where the shallow bottom of the body of water would interfere with electrical currents), and possibly injuries.
Predicted application
Synaptic plasticity operating under the control of an anti-Hebbian learning rule is thought to occur in the cerebellum. Understanding the operation of neural learning could provide valuable insights for the treatment of cerebellar-related disorders. The knowledge could also serve a significant function in the computer-based collection of data, repeatedly adjusting to redundant inputs while emphasizing the appearance of alterations.
Example
The following algorithm was proposed by (Péter Földiák, 1990). In this algorithm, there are input neurons and output neurons . Each input neuron is connected to an output neuron by a weight . Also, the output neurons are connected to each other by weights in a symmetric weight matrix . The neural activation of the output neurons is defined as a fixed point of the following stable state equation:where is the logistic activation function, and is the activation threshold of the -th output neuron.
This can be more succinctly written in matrix notation as .
The algorithm is as follows:
Take a set of input vectors.
Initialize .
For each input vector ,
Solve for the output vector that satisfies . This can be done by integrating along the vector field .
Anti-Hebbian update . If or , then is set to 0.
Hebbian update:
Threshold update: .
Here, , , , and are hyperparameters. can be interpreted as the target probability for each output neuron to be activated. If a certain input pattern is very common, the anti-Hebbian term forces its output to be very sparse. In this way, the anti-Hebbian term automatically generates efficient sparse codes, analogous to an emergent Huffman code.
See also
Hebbian theory
Active sensory systems
Synaptic plasticity
Learning rule
References
Bell, C.C. (1981), "An Efference Copy Which is Modified by Reafferent Input." Science. 214, 450–452.
Roberts, P.D & Bell, C.C. (2002) "Active control of spike-timing dependent synaptic plasticity in an electrosensory system." Journal of Physiology. 96, 445–449.
Zupanc, G.K.H. 2004. Behavioral Neurobiology: An Integrative Approach. Oxford University Press: Oxford, UK.
Ethology
Neuroscience
Neurophysiology
Neuroethology
Neuroplasticity | Anti-Hebbian learning | [
"Biology"
] | 1,280 | [
"Neuroscience",
"Behavior",
"Neuroethology",
"Behavioural sciences",
"Ethology"
] |
14,756,059 | https://en.wikipedia.org/wiki/Environmental%20toxicology | Environmental toxicology is a multidisciplinary field of science concerned with the study of the harmful effects of various chemical, biological and physical agents on living organisms. Ecotoxicology is a subdiscipline of environmental toxicology concerned with studying the harmful effects of toxicants at the population and ecosystem levels.
Rachel Carson is considered the mother of environmental toxicology, as she made it a distinct field within toxicology in 1962 with the publication of her book Silent Spring, which covered the effects of uncontrolled pesticide use. Carson's book was based extensively on a series of reports by Lucille Farrier Stickel on the ecological effects of the pesticide DDT.
Organisms can be exposed to various kinds of toxicants at any life cycle stage, some of which are more sensitive than others. Toxicity can also vary with the organism's placement within its food web. Bioaccumulation occurs when an organism stores toxicants in fatty tissues, which may eventually establish a trophic cascade and the biomagnification of specific toxicants. Biodegradation releases carbon dioxide and water as by-products into the environment. This process is typically limited in areas affected by environmental toxicants.
Harmful effects of such chemical and biological agents as toxicants from pollutants, insecticides, pesticides, and fertilizers can affect an organism and its community by reducing its species diversity and abundance. Such changes in population dynamics affect the ecosystem by reducing its productivity and stability.
Although legislation implemented since the early 1970s had intended to minimize harmful effects of environmental toxicants upon all species, McCarty (2013) has warned that "longstanding limitations in the implementation of the simple conceptual model that is the basis of current aquatic toxicity testing protocols" may lead to an impending environmental toxicology "dark age".
Governing policies on environmental toxicity
U.S. policies
To protect the environment, the National Environmental Policy Act (NEPA) was written. The main point that NEPA brings to light is that it "assures that all branches of government give proper consideration to the environment prior to undertaking any major federal actions that significantly affect the environment." This law was passed in 1970 and also founded the Council on Environmental Quality (CEQ). The importance of CEQ was that it helped further push policy areas.
CEQ created environmental programs including the Federal Water Pollution Control Act, Toxic Substance Control Act, Resources Conservation and Recovery Act (RCRA and the Safe). CEQ was essential in creating the foundation for most of the "current environmental legislation except for Superfund and asbestos control legislation."
Some initial impacts of NEPA pertain to the interpretation within Courts. Not only did Courts interpret NEPA to expand over direct environmental impacts from any projects, specifically federal, but also indirect actions from federal projects.
Toxic Substance Control Act
TSCA, also known as the Toxic Substance Control Act, is a federal law that regulates industrial chemicals that have the potential to be harmful to humans and the environment. TSCA specifically targets "the manufacture, importation, storage, use, disposal, and degradation of chemicals in commercial use." The EPA allows the following to be done: "1. Pre-manufacture testing of chemicals to determine health or environmental risk 2. Review of chemicals for significant risk prior to the start of commercial production 3. Restriction or prohibition on the production or disposal of certain chemicals 4. Import and export control of chemicals prior to their entering or leaving the USA."
The Clean Air Act
The Clean Air Act was aided by the signing of the 1990 amendments. These amendments protected reducing acid, the ozone layer, improving air quality and toxic pollutants. The Clean Air Act was actually revised and with, support from President George H.W Bush, it was signed in. The biggest major threats that this act targets are: urban air pollution, toxic air emissions, stratospheric ozone, acid rain etc. Apart from targeting these specific areas, it also established a national operating that "permits program to make the law more workable, and strengthened enforcement to help ensure better compliance with the Act."
Regulations and enforcement actions on polychlorinated biphenyls
As mentioned above, though the United States did ban the use of polychlorinated biphenyls (PCBs), there is the possibility that they are present in products made before the PCB ban in 1979. The Environmental Protection Agency (EPA) released its ban on PCBs on April 19, 1979. According to the EPA, "Although PCBs are no longer being produced in this country, we will now bring under control the vast majority of PCBs still in use," said EPA Administrator Douglas M. Castle. "This will help prevent further contamination of our air, water and food supplies from a toxic and very persistent man-made chemical."
PCBs has been tested on laboratory animals and have caused cancer and birth defects. PCB is suspected of having certain effects on liver and skin of humans. They are also suspected of causing cancer as well. EPA "estimates that 150 million pounds of PCBs are dispersed throughout the environment, including air and water supplies; an additional 290 million pounds are located in landfills in this country." Again, even though they have been banned, there is still a large amount of PCBs are circulating within the environment and are possibly causing effects on the skin and liver of humans.
There were some cases in which people or companies that disposed of PCBs incorrectly. Up until now, there have been four cases in which EPA had to take legal actions against people/companies for their methods of disposal. The two cases involving the companies, were fined $28,600 for improper disposal. It is unknown what fined was charged against the three people for "illegally dumping PCBs along 210 miles of roadway in North Carolina."
Though PCBs were banned, there are some exceptions where they are being used. The area in which it has been completely prohibited is "the manufacture, processing, distribution in commerce, and "non-enclosed" (open to the environment) uses of PCBs unless specifically authorized or exempted by EPA. "Totally enclosed" uses (contained, and therefore exposure to PCBs is unlikely) will be allowed to continue for the life of the equipment." In terms of electrical equipment containing PCBs is allowed under specific controlled conditions. Out of the 750 million pounds of PCBs, electrical equipment represents 578 million pounds. Any new manufacture of PCB is prohibited.
Sources of environmental toxicity
There are many sources of environmental toxicity that can lead to the presence of toxicants in our food, water and air. These sources include organic and inorganic pollutants, pesticides and biological agents, all of which can have harmful effects on living organisms. There can be so called point sources of pollution, for instance the drains from a specific factory, but also non-point sources (diffuse sources) like the rubber from car tires that contain numerous chemicals and heavy metals that are spread in the environment.
PCBs
PCBs are organic pollutants that are still present in our environment today, despite being banned in many countries, including the United States and Canada. Due to the persistent nature of PCBs in aquatic ecosystems, many aquatic species contain high levels of this chemical. For example, wild salmon (Salmo salar) in the Baltic Sea have been shown to have significantly higher PCB levels than farmed salmon as the wild fish live in a heavily contaminated environment.
PCBs pertains to a group of human-produced "organic chemicals known as Chlorinated hydrocarbons" The chemical and physical properties of a PCS determine the quantity and location chlorine and unlike other chemicals, they have no form of identification. The range of toxicity is not consistent and because PCBs have certain properties ( chemical stability, non-flammability) they have been used in a colossal amount of commercial and industrial practices. Some of those include, "Electrical, heat transfer and hydraulic equipment, plasticizers in paints, plastics and rubber products and pigments, dyes and carbonless copy paper" to name a few.
Heavy metals
Metals like cadmium, mercury, and lead have minimal roles in living organisms if any, so the accumulation of these, even if a little, can lead to health issues.
For example, because humans consume fish, it is important to monitor fishes for such trace metals. It has been known for a long time that these trace metals get passed up the food web because of their lack of biodegradability or capability to break down. Such build-up can lead to liver damage and cardiovascular diseases in people. It is also important to monitor fishes not just for public health, but also to assess the health of coastal ecosystems.
For instance, it has been shown that fish (i.e. rainbow trout) exposed to higher cadmium levels and grow at a slower rate than fish exposed to lower levels or none. Moreover, cadmium can potentially alter the productivity and mating behaviours of these fish.
Heavy metals can also alter the genetic makeup in aquatic organisms. In Canada, a study examined genetic diversity in wild yellow perch along various heavy metal concentration gradients in lakes polluted by mining operations. Researchers wanted to determine what effect metal contamination had on evolutionary responses among populations of yellow perch. Along the gradient, genetic diversity over all loci was negatively correlated with liver cadmium contamination. Additionally, there was a negative correlation observed between copper contamination and genetic diversity. Some aquatic species have evolved heavy metal tolerances. In response to high heavy metal concentrations a Dipteran species, Chironomus riparius, of the midge family, Chironomidae, has evolved to become tolerant to cadmium toxicity in aquatic environments. Altered life histories, increased cadmium excretion, and sustained growth under cadmium exposure is evidence that shows that C. riparius exhibits genetically based heavy metal tolerance.
Additionally, a case study in China looked at the concentrations of Cu (copper), Cr (chromium), Cd (cadmium), and Pb (lead) in the edible parts of the fishes Pelteobagrus fluvidraco, the banded catfish, and Cyprinus carpio, the common carp living in Taihu Lake. These metals were actively being released from sources such as industrial waste stemming from agriculture and mining and then going into coastal ecosystems and becoming stored in the local fish, especially their organs. This was especially alarming because too much copper consumption can lead to diarrhea and nausea in humans and liver damage in fish. Additionally, too much lead can lead to defects in learning, behavior, metabolism, and growth in some vertebrates, including humans. Much of these heavy metals were found in the two fish species' liver, kidney, and gills, however, their concentrations were fortunately found to be below the threshold amount for human consumption made by the Chinese Food Health Criterion. Overall, the study showed that the remediation efforts here did in fact reduce the amount of heavy metals built up in the fish.
Generally speaking, the specific rate of build-up of metals in fish depends on the metal, the fish species, the aquatic environment, the time of year, and fishes' organs. For example, metals are more commonly known to be found the most in carnivorous species with omnivorous species following behind. In this case, perhaps due to the properties of the water differing at different parts of the year, there were more heavy metals spotted in the two fish species in the summer compared to the winter. Overall, it is relatively understood that the amount of metals in the liver and kidney of a fish represents the amount that has been actively stored in their bodies whereas the amount of metals in the gills represents the amount that has been accumulated from the surrounding water. This is why the gills are thought to be better bioindicators of metal pollution.
Radiation
Radiation is given off by matter as either rays or waves of pure energy or high-speed particles. Rays or waves of energy, also known as electromagnetic radiation, include sunlight, X-rays, radar, and radio waves. Particle radiation includes alpha and beta particles and neutrons. When humans and animals are exposed to high radiation levels, they can develop cancer, congenital disabilities, or skin burns. Plants also face problems when exposed to large levels of radiation. After the Chernobyl disaster in 1986, the nuclear radiation damaged the surrounding plants' reproductive tissues, and it took approximately three years for these plans to regain their reproductive abilities. The study of radiation and its effects on the environment is known as radioecology.
Metals toxicity
The most known or common types of heavy metals include zinc, arsenic, copper, lead, nickel, chromium, aluminum, and cadmium. All of these types cause certain risks on human and environment health.
Though certain amount of these metals can actually have an important role in, for example, maintaining certain biochemical and physiological, "functions in living organisms when in very low concentrations, however they become noxious when they exceed certain threshold concentrations." Heavy metal are a huge part of environmental pollutions and their toxicity "is a problem of increasing significance for ecological, evolutionary, nutritional and environmental reasons."
Aluminum
Aluminum is the most common natural metal in the Earth's crust and is naturally cycled throughout the environment via processes like the weathering of rocks and volcano eruptions. Those natural processes release more aluminum into the freshwater environments than do humans, but anthropogenic impact has been causing values to rise above the recommended amount by the U.S. EPA and World Health Organization. Aluminum is used commonly in industrially-made items like paints, paper, household appliances, packaging, processing of food and water, and for health care items like antiperspirants and vaccine production. Run-off from those industrial uses then bring the metal flowing into the environment.
Generally, too much exposure to aluminum affects motor and cognitive skills. In mammals, the metal has been shown to affect gene expression, DNA repair, and DNA binding. One study showed how the effects of aluminum include neurodegeneration and nerve cell death in mice. Another study has shown it to be related to human diseases associated with the nervous system such as Alzheimer's and Parkinson's disease and autism.
Exposure to contaminants can change the tissues of marine life like fish too. For example, its accumulation has been shown to cause neurodegeneration in cerebral regions of the brains such as those of O. mossambicus, otherwise known as Mozambique tilapia. Aluminum also decreases locomotive abilities of fishes since aluminum is thought to negatively impact with their oxygen supply. Finally, the metal causes slow responses to arousal and other environmental stimuli, overall abnormal behavior, and changes with the neurotransmitters in their bodies such as adrenaline and dopamine.
Arsenic
Arsenic, one of the most important heavy metals, causes ecological problems and health issues in humans. It is "semimetallic property, is prominently toxic and carcinogenic, and is extensively available in the form of oxides or sulfides or as a salt of iron, sodium, calcium, copper, etc." It is also one of the most abundant elements on earth and its specific inorganic forms are very dangerous to living creatures (animals, plants, and humans) and the environment.
In humans, arsenic can cause cancer in the bladder, skin, lungs and liver. One of the major sources of arsenic exposure in humans is contaminated water, which is a problem in more than 30 countries in the world.
Humans tend to encounter arsenic by "natural means, industrial source, or from unintended sources." Water can become contaminated by arsenical pesticides or natural arsenical chemicals. There are some cases in which arsenic has been used in suicide attempts and can result in acute poisoning. Arsenic "is a protoplastic poison since it affects primarily the sulphydryl group of cells causing malfunctioning of cell respiration, cell enzymes and mitosis."
Lead
Another extremely toxic metal, lead can and has been known to cause "extensive environmental contamination and health problems in many parts of the world." The physical appearance of lead is bright and silver colored metal. Some sources of lead pollution in the environment include Metal plating and fishing operations, soil waste, factory chimneys, smelting of ores, wastes from batter industries, fertilizers and pesticides and many more. Unlike, other metals such as copper, lead only plays a physiological aspect and no biological functions. In the US, "more than 100 to 200,000 tons of lead per year is being released from vehicle exhausts" and some can be brought in by plants, flow in water or fixation into the soil.
Humans come in contact with lead through mining, fossil fuel burning. In burning, lead and its compounds are exposed into air, soil, and water. Lead can have different effects on the body and effects the central nervous system. Someone who has come in contact with lead can have either acute or chronic lead poisoning. Those who experience acute poisoning have symptoms such as appetite, headache, hypertension, abdominal pain, renal dysfunction, fatigue, sleeplessness, arthritis, hallucinations and vertigo." Chronic exposure on the other hand, can cause more severe symptoms such as, "mental retardation, birth defects, psychosis, autism, allergies, dyslexia, weight loss, hyperactivity, paralysis, muscular weakness, brain damage, kidney damage and may even cause death."
Mercury
Mercury, a shiny silver-white, can transform into a colorless and odorless gas when heated up. Mercury highly affects the marine environment and there have been many studies conducted on the effects on the water environment. The biggest sources of mercury pollution include "agriculture, municipal wastewater discharges, mining, incineration, and discharges of industrial wastewater" all relatively connected to water.
Mercury exists in three different forms and all three possess different levels of bioavailability and toxicity. The three forms include organic compounds, metallic elements and inorganic salts. As stated above, they are present in water resources such as oceans, rivers and lakes. Studies have shown that mercury turns into methylmercury (MeHg) and seeps into the environment. Plankton then get the metal into their system, and they are then eaten by other marine organisms. This cycle continues up the food web. This process is called biomagnification and "causes significant disturbance to aquatic lives."
Mercury hurts marine life but can also be very hurtful towards humans' nervous system. Higher levels of mercury exposure can change many brain functions. It can "lead to shyness, tremors, memory problems, irritability, and changes in vision or hearing." Furthermore, breathing in mercury can lead to dysfunction in sensory and mental capabilities in humans as well such as with the use of one's motor skills, cognition, and sight.
Because of these worrying side effects, there was a study done in the Pacific coast of Columbia to assess the levels of mercury in the environment and in the people living there from gold-mining. The researchers found that the median total mercury concentration in hair measured from people living in two communities, Quibdo and Paimado, was 1.26g/g and 0.67 g/g respectively. Residents in other areas of Columbia have been found to have similar levels. These levels are greater than the recommended threshold values held by the U.S. Environmental Protection Agency (EPA). In addition, they measured the concentration of mercury found in fish living nearby in the Atrato River. Even though the concentration was determined to have a low risk factor for human health and consumption, the concentration (0.5 g/g) was above the World Health Organization's (WHO) recommended threshold.
They also determined that approximately 44% of the total sites around the river had a moderate level of pollution, further emphasizing that more intervention programs should be conducted to curb the seepage of mercury into the environment. This was a major concern especially since the Choco region is a biodiversity hotspot for all manner of organisms, not just humans. In the end, the highest levels of total airborne mercury were found to be in the gold shops downtown, further emphasizing the cost of gold-mining in such native communities and the need for better programs directed towards preventing its spread.
Cadmium
According to, ATSDR ranking, cadmium is the 7th most toxic heavy metal. Cadmium is interesting in that once it is exposed to humans (at work) or animals in their environment, it will accumulate inside the body throughout the life of the human/animal. Though cadmium was used as replacement for tin in WWI and pigment in paint industries back in the day, currently it is seen mostly in rechargeable batteries, tobacco smoke and some alloys production.
As stated by the Agency for Toxic Substance and Disease Registry, in " the US, more than 500,000 workers get exposed to toxic cadmium each year." It is also stated that the highest exposure to cadmium can be seen in China and Japan.
The effects of cadmium on the kidney and bones is huge. It can cause bone mineralization which "is the process of laying down minerals on a matrix of the bone". This can happen through renal dysfunction or bone damage.
Chromium
The 7th most abundant element, chromium, can occur naturally when one burns oil and coal and is released into the environment through sewage and fertilizers. Chromium usage can be seen in, "industries such as metallurgy, electroplating, production of paints and pigments, tanning, wood preservation, chemical production and pulp and paper production." Chromium toxicity affects the "biological processes in various plants such as maize, wheat, barley, cauliflower, citrullus and in vegetables. Chromium toxicity causes chlorosis and necrosis in plants."
Pesticides
Pesticides are a major source of environmental toxicity. These chemically synthesized agents have been known to persist in the environment long after their administration. The poor biodegradability of pesticides can result in bioaccumulation of chemicals in various organisms along with biomagnification within a food web. Pesticides can be categorized according to the pests they target. Insecticides are used to eliminate agricultural pests that attack various fruits and crops. Herbicides target herbal pests such as weeds and other unwanted plants that reduce crop production.
Pesticides in general have been shown to negatively impact the reproductive and endocrine systems of various reptiles and amphibians, so much that it is cautiously thought to be one of the main factors behind the decline in their populations all over the world. These pesticides impair their immune, nervous, behavioral systems including causing lower fertility rates, abnormal hormone levels, and lower fitness of offspring. Amphibians are thought to be especially in low decline because the release of agricultural pesticides is simultaneous with the secretion of pheromones during their season of reproduction. For instance, it has been demonstrated that greater quantities of pesticides correlates with greater number of defects in toads.
For example, the chloroacetanilide class of herbicides is used worldwide in the control of weeds and grasses for agriculture. They are mainly used for crops such as corn, rice, soybean, sunflower, cotton, among others and are able to stay in the environment for long periods of time. Thus they can be found in soil, groundwater, and surface water due to soil erosion, leaching, and surface runoff. The amount of time they stay in the environment depends on the soil type and climate conditions like temperature and moisture. Chloroacetanilide herbicides include acetochlor, alachlor, among others. They are all listed as B2, L2, and C classes of carcinogens by the U.S. EPA.
Another herbicide called atrazine is still commonly used throughout the world even with the European Union banning its usage in 2005. Shockingly, its use was still prevalent in the U.S. in 2016 and in Australia for some time. Because it can dissolve in water, many concerns have been raised about its potential to contaminate soil and water along the surface and ground. Various studies have been conducted to determine the impact of atrazine on wildlife.
For example, studies have shown it to cause stunted growth and suppress or damage the immune and reproductive systems of aquatic life. It also is linked to cancer not only in fish, but also in mammals like humans. Additionally, atrazine is known to induce aromatase which causes the bodies of fish and amphibians to produce estrogen even when they are not supposed to. The herbicide also causes changes in gene expression which can be passed down from parent to offspring and get in the way of thyroid homeostasis. For example, a study done on male African clawed frogs show that exposure to atrazine led to smaller testicular size and lower testosterone levels. Another study done with the Northern leopard frog and Blanchard's cricket frog found that atrazine lowered their success with metamorphosis, the process of turning into an adult frog from the initial stage of a tadpole. This makes sense since metamorphosis is controlled by hormones from the thyroid gland which atrazine is known to negatively impact.
Furthermore, a study was done to study the effects of atrazine on freshwater crayfish Cherax destructor from the Czech Republic, a keystone species. They found that the hepatopancreas, the body part that serves as both the liver and pancreas in these crustaceans, became damaged after being exposed. A build-up of lactate and ammonia also resulted, leading to liver failure, tissue hypoxia, lactic acidosis, muscle fatigue, and pain. There was also damage and even deterioration of the gills however they were able to heal after 2 weeks. Damage to gills was also found in the bivalve Diplodon expansus.
DDT
Dichlorodiphenyltrichloroethane (DDT) is an organochlorine insecticide that has been banned due to its adverse effects on both humans and wildlife. DDT's insecticidal properties were first discovered in 1939. Following this discovery, DDT was widely used by farmers in order to kill agricultural pests such as the potato beetle, codling moth and corn earworm. In 1962, the harmful effects of the widespread and uncontrolled use of DDT were detailed by Rachel Carson in her book The Silent Spring. Such large quantities of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) that were released into the environment were toxic to both animals and humans.
DDT is not easily biodegradable and thus the chemical accumulates in soil and sediment runoff. Water systems become polluted and marine life such as fish and shellfish accumulate DDT in their tissues. Furthermore, this effect is amplified when animals who consume the fish also consume the chemical, demonstrating biomagnification within the food web. The process of biomagnification has detrimental effects on various bird species because DDT and DDE accumulate in their tissues inducing egg-shell thinning. Rapid declines in bird populations have been seen in Europe and North America as a result.
Humans who consume animals or plants that are contaminated with DDT experience adverse health effects. Various studies have shown that DDT has damaging effects on the liver, nervous system and reproductive system of humans.
By 1972, the United States Environmental Protection Agency (EPA) banned the use of DDT in the United States. Despite the regulation of this pesticide in North America, it is still used in certain areas of the world. Traces of this chemical have been found in noticeable amounts in a tributary of the Yangtze River in China, suggesting the pesticide is still in use in this region.
Though DDT was banned in 1972, some of the pesticide (as well as other chemical) lingered in the environment. This lingering of toxic material led to the near extinction of peregrine falcon. There was high levels of DDT were found in many areas such as "eggs, fat and tissues of the bird." The government . worked with conservation groups in helping them breed out of the contaminated area. Finally, in 1999 the birds were taken off the U.S endangered species list.
Sulfuryl fluoride
Sulfuryl fluoride is an insecticide that is broken down into fluoride and sulfate when released into the environment. Fluoride has been known to negatively affect aquatic wildlife. Elevated levels of fluoride have been proven to impair the feeding efficiency and growth of the common carp (Cyprinus carpio). Exposure to fluoride alters ion balance, total protein and lipid levels within these fish, which changes their body composition and disrupts various biochemical processes.
PFAS chemicals
Per and poly fluoroalkyl substances, known as PFAS, are a group of approximately 15 000 chemicals. The common structure of these chemicals involves a functional group and a long carbon tail that is fully or partially fluorinated. The first PFAS chemical, polytetrafluoroethylene (PTFE), was accidentally synthesized in 1938 by DuPont researcher Roy J. Plunkett while making refrigerants. The chemical was found to have unique and useful properties such as resistance to water, oil, and extreme temperatures. In 1945 DuPont patented this chemical, along with other PFAS chemicals like PFOA with the now household name, Teflon. American multinational conglomerate 3M began mass producing Teflon in 1947. Then in the 1960's, the US navy and 3M created a new type of fire-fighting foam using PFAS chemicals, "aqueous film-forming foam" or AFFF, which was then shipped around the world and used at airports, military sites, and fire-fighting training centers. The chemicals are now used in many household products including nail polish, makeup, shampoos, soaps, toothpastes, menstrual products, clothes, contact lenses and toilet paper. The chemicals are also used in fracking, artificial grass, lubricants (mechanical, industrial and bicycle), food packaging, magazines, pesticides, refrigerants, and even surgically implanted medical devices.
These chemicals have been given the nickname "forever chemicals" due to their extreme stability and resistance to natural degradation in the environment. They also bioaccumulate in humans and animals, with many of the PFAS chemicals having half-lives of several years. The also "biomagnify", so animals higher in the food chain tend to have higher concentration of the chemicals in their blood. PFAS has been found in almost all human blood samples tested, one study found 97% of Americans has PFAS in their blood.
PFAS chemicals have been linked to high cholesterol, altered kidney and thyroid function, ulcerative colitis, immunosuppression, decreased effectiveness of vaccines, low birth weight, reproductive issues, and cancers such as kidney, testicular and liver cancer. However, we are still uncovering the full health effects of these chemicals.
PFAS chemicals are now ubiquitous in the environment, recent research found PFAS chemicals in all rain water studied. DuPont and 3M had both done internal studies on the potential harmful effects of these chemicals, and had known for decades of their potential to cause cancers and low birth weight. Yet this research was not made public and the companies continued to make large profits off the harmful chemicals. In 2000 3M announced they will voluntarily halt production of PFOA and PFOS — technically known as "long-chain" chemicals — and will stop putting them in products by 2002. They replaced these chemicals with new "short-chain" PFAS formulations, but scientists have found these replacements to be possibly just as hazardous.
Lawsuits around the world have now sprung up against companies and governments who knew of the harm these chemicals could do and continued to use them. Regulation talks on these chemicals is now happening world-wide. Remediation of these "forever chemicals" has been attempted in hot spots around the world, by placing the contaminated soil in landfill or heating at extremely high temperature. However, these are both very expensive, and new, cheaper remediation tools are desperately required.
Organophosphate chemicals
Organophosphate pesticides (OPs) are ester derivatives of phosphorus. These substances are found in pesticides, herbicides, and insecticides and were generally thought to be safe because they degrade quickly in the natural environment assuming there is sunlight, air, and soil. However, studies have shown these pesticides to negatively affect photosynthesis and growth in plants. These substances also get into the soil via runoff and cause decreases in soil fertility as well. Moreover, they have also been known to cause erratic swimming, respiratory stress, changes in behavior, and delayed metamorphosis in aquatic organisms.
In a specific case study, organophosphate pesticides like chlorpyrifos, diazinon, fenitrothion, and quinalphos used in agriculture in the northwestern part of Bangladesh were found to have high or acute ecological risks on the surface water and soil for aquatic insects and crustaceans. More specifically, it showed higher ecological risks for Daphnia compared to other marine organisms. The discovery of such high concentrations of pesticides could be due to the local farmers using more pesticides than the recommended amount. This could be due to agriculture being the country's biggest economical activity. With the country's rising population numbers, necessity for more food will only increase, thereby putting more pressure on farmers.
Cyanobacteria and cyanotoxins
Cyanobacteria, or blue-green algae, are photosynthetic bacteria. They grow in many types of water. Their rapid growth ("bloom") is related to high water temperature as well as eutrophication (resulting from enrichment with minerals and nutrients often due to runoff from the land that induces excessive growth of these algae). Many genera of cyanobacteria produce several toxins. Cyanotoxins can be dermatotoxic, neurotoxic, and hepatotoxic, though death related to their exposure is rare. Cyanotoxins and their non-toxic components can cause allergic reactions, but this is poorly understood. Despite their known toxicities, developing a specific biomarker of exposure has been difficult because of the complex mechanism of action these toxins possess.
Cyanotoxins in drinking water
The occurrence of this toxin in drinking water depends on a couple of factors. One, is the drinking water's level in raw source water and secondly, it depends on the effectiveness of removing these toxins from water when drinking water is actually being produced. Due to being no data on the absence/presence of these toxins in drinking water, it is very hard to actually monitor the amounts that are present in finished water. This is a result of the U.S not having state or federal programs in place that actually monitor the presence of this toxins in drinking water treatment plants.
Effects on humans
Though data on the effects of these two toxins are limited, from what is available it suggests the toxins attack the liver and kidney. There was an hepatoenteritis-like outbreak in Palm Island, Australia (1979), due to the consumption of water that contained, "C. raciborskii, a cyanobacteria that can produce cylindrospermopsin." Most cases (typically involving children) have required they be taken to a hospital. The results of hospitilation include: Vomiting, kidney damage (due to lose of water, protein and electrolytes) fever, bloody diarrhea, and headaches.
Societies
American College of Toxicology (ACT)
Society of Environmental Toxicology and Chemistry (SETAC)
Society of Toxicology (SOT)
Journals
Environmental Health Perspectives
Environmental Toxicology
Environmental Toxicology & Pharmacology
Journal of Environmental Science and Health
Journal of Toxicology and Environmental Health
Toxicological & Environmental Chemistry
See also
Ecotoxicology
Environmental chemistry
Environmental science
Manganese
Paraquat
Toluene
Toxicology
Unacceptable Levels (2013 documentary film)
References
Notes
Further reading
External links
Brief history of environmental toxicology | Environmental toxicology | [
"Environmental_science"
] | 7,444 | [
"Toxicology",
"Environmental toxicology"
] |
14,756,417 | https://en.wikipedia.org/wiki/Programmed%20cell%20death%20protein%201 | Programmed cell death protein 1 (PD-1), (CD279 cluster of differentiation 279). PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).
PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.
PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.
Discovery
In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1. In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.
Structure
PD-1 is a type I membrane protein of 288 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T-cell receptor TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3 ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
Ligands
PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
Function
Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. IFN-γ is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.
Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy. Triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.
In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.
Overexpression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion (e.g. in chronic infection or cancer).
Clinical significance
Cancer
PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.
Combination therapy using both anti-PD1 along with anti-CTLA4 therapeutics have emerged as important tumor treatments within the field of checkpoint inhibition.
A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant. Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivate CD8+ T cells ability to lyse cancer cells.
In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment. A combination of PD1 and CTLA4 induced up to a ten-fold higher number of CD8+ T cells that are actively infiltrating the tumor tissue. The authors hypothesized that the higher levels of CD8+ T cell infiltration was due to anti-CTLA-4 inhibited the conversion of CD4 T cells to T regulator cells and further reduced T regulatory suppression with anti-PD-1. This combination promoted a more robust inflammatory response to the tumor that reduced the size of the cancer. Most recently, the FDA has approved a combination therapy with both anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) in October 2015.
The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown. PD-L1 expression on the surface on cancer cells plays a significant role. PD-L1 positive tumors were twice as likely to respond to combination treatment. However patients with PD-L1 negative tumors also have limited response to anti-PD1, demonstrating that PD-L1 expression is not an absolute determinant of the effectiveness of therapy.
Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.
The 2018 Nobel Prize for Medicine was awarded to James P Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".
Anti-PD-1 therapeutics
A number of cancer immunotherapy agents that target the PD-1 receptor have been developed.
One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients. Colon and pancreatic cancer did not have a response. Nivolumab (Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.
Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects. It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015, Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.
Toripalimab is a humanized IgG4 monoclonal antibody against PD-1 which was approved in China in 2018 and in the United States in 2023.
Drugs in early stage development targeting PD-1 receptors (checkpoint inhibitors) include pidilizumab (CT-011, Cure Tech) and BMS-936559 (Bristol Myers Squibb). Both atezolizumab (MPDL3280A, Roche) and avelumab (Merck KGaA, Darmstadt, Germany and Pfizer) target the similar PD-L1 receptor.
Animal studies
HIV
Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitate HIV eradication. T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection. Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus. Immune blockade of PD-1 resulted in restoration of T cell inflammatory phenotype necessary to combat the progression of disease.
Alzheimer's disease
Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice. Immune blockade of PD-1 evoked an IFN-γ dependent immune response that recruited monocyte-derived macrophages to the brain that were then capable of clearing the amyloid-β plaques from the tissue. Repeated administrations with anti-PD-1 were found to be necessary to maintain the therapeutic effects of the treatment. Amyloid fibrils are immunosuppressive and this finding has been separately confirmed by examining the effects of the fibrils in neuroinflammatory diseases. PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.
References
Further reading
External links
What I Talk about When I Talk about the Discovery of PD-1 (Yasumasa Ishida)
PD-1_Project PD-1 project - Honjo Lab
PD-1プロジェクト(in Japanese) - Honjo Lab
Clusters of differentiation
Immune system | Programmed cell death protein 1 | [
"Biology"
] | 2,702 | [
"Immune system",
"Organ systems"
] |
14,756,523 | https://en.wikipedia.org/wiki/KLF5 | Krueppel-like factor 5 is a protein that in humans is encoded by the KLF5 gene.
Function
This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. Since the protein localizes to the nucleus and binds the epidermal growth factor response element, it is thought to be a transcription factor.
Interactions
KLF5 has been shown to interact with Protein SET.
Clinical significance
KLF5 expression has been linked to higher survival rates for lung cancer patients.
See also
Kruppel-like factors
References
Further reading
External links
Transcription factors | KLF5 | [
"Chemistry",
"Biology"
] | 120 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,756,541 | https://en.wikipedia.org/wiki/CHRNE | Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.
Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome.
Role in health and disease
Congenital myasthenic syndrome (CMS) is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). The majority of mutations causing CMS are found in the AChR subunits genes.
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult AChR subunits. Mutations of the AChR often result in endplate deficiency. The most common AChR gene mutation that underlies CMS is the mutation of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an arginine (Arg) into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.
See also
Nicotinic acetylcholine receptor
References
Further reading
External links
Ion channels
Nicotinic acetylcholine receptors | CHRNE | [
"Chemistry"
] | 447 | [
"Neurochemistry",
"Ion channels"
] |
14,756,569 | https://en.wikipedia.org/wiki/P%20protein | P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (OCA2) gene. The P protein is believed to be an integral membrane protein involved in small molecule transport, specifically of tyrosine—a precursor of melanin. Certain mutations in OCA2 result in type 2 oculocutaneous albinism. OCA2 encodes the human homologue of the mouse p (pink-eyed dilution) gene.
The human OCA2 gene is located on the long arm (q) of chromosome 15, specifically from base pair 28,000,020 to base pair 28,344,457 on chromosome 15.
Function
OCA2 provides instructions for making the protein called P protein which is located in melanocytes which are specialized cells that produce melanin, and in the cells of the retinal pigment epithelium. Melanin is responsible for giving color to the skin, hair, and eyes. Moreover, melanin is found in the light-sensitive tissue of the retina of the eye which plays a role in normal vision.
The exact function of protein P is unknown, but it has been found that it is essential for the normal coloring of skin, eyes, and hair; and likely involved in melanin production. This gene seems to be the main determinant of eye color depending on the amount of melanin production in the iris stroma (large amounts giving rise to brown eyes; little to no melanin giving rise to blue eyes).
This gene is mutated in Astyanax mexicanus, a Mexican fish which is characterized by a chronic albinism in cave-dwelling individuals. It exists as a deletion in fish from the Pachón and Molino caves, which produces albinism.
Clinical significance
Mutations in the OCA2 gene cause a disruption in the normal production of melanin; therefore, causing vision problems and reductions in hair, skin, and eye color. Oculocutaneous albinism caused by mutations in the OCA2 gene is called oculocutaneous albinism type 2. The prevalence of OCA type 2 is estimated at 1/38,000-1/40,000 in most populations throughout the world, with a higher prevalence in the African population of 1/3,900–1/1,500. Other diseases associated with the deletion of the OCA2 gene are Angelman syndrome (light-colored hair and fair skin) and Prader–Willi syndrome (unusually light-colored hair and fair skin). With both these syndromes, the deletion often occurs in individuals with either syndrome.
A mutation in the HERC2 gene adjacent to OCA2, affecting OCA2's expression in the human iris, is found common to nearly all people with blue eyes. It has been hypothesized that all blue-eyed humans share a single common ancestor with whom the mutation originated.
The His615Arg allele of OCA2 is involved in the light skin tone and the derived allele is restricted to East Asia with high frequencies, with highest frequencies in Eastern East Asia (49-63%), midrange frequencies in Southeast Asia, and the lowest frequencies in Western China and some Eastern European populations.
References
Further reading
External links
GeneReviews/NCBI/NIH/UW entry on Oculocutaneous Albinism Type 2
Genes on human chromosome 15
Eye color
Proteins | P protein | [
"Chemistry"
] | 748 | [
"Biomolecules by chemical classification",
"Proteins",
"Molecular biology"
] |
14,756,577 | https://en.wikipedia.org/wiki/PDZK1 | Na(+)/H(+) exchange regulatory cofactor NHE-RF3 is a protein that in humans is encoded by the PDZK1 gene.
Interactions
PDZK1 has been shown to interact with:
AKAP10,
CLCN3,
Cystic fibrosis transmembrane conductance regulator
FARP2,
PDZK1IP1,
SLC22A12,
SLC22A4,
SLC34A3,
SLK, and
Sodium-hydrogen antiporter 3 regulator 1.
Related gene problems
TAR syndrome
1q21.1 deletion syndrome
1q21.1 duplication syndrome
References
Further reading | PDZK1 | [
"Chemistry"
] | 138 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,756,596 | https://en.wikipedia.org/wiki/SOX10 | Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.
Function
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and determination of cell fate. The encoded protein acts as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development.
In melanocytic cells, there is evidence that SOX10 gene expression may be regulated by MITF.
Mutations
Mutations in this gene are associated with Waardenburg–Shah syndrome and uveal melanoma.
Immunostain
SOX10 is used as an immunohistochemistry marker, being positive in:
Neuroectodermal neoplasms of neural crest origin, especially:
Melanoma, although desmoplastic melanomas may be only focally positive.
Nevus
Interactions
The interaction between SOX10 and PAX3 is studied best in human patients with Waardenburg syndrome, an autosomal dominant disorder that is divided into four different types based upon mutations in additional genes. SOX10 and PAX3 interactions are thought to be regulators of other genes involved in the symptoms of Waardenburg syndrome, particularly MITF, which influences the development of melanocytes as well as neural crest formation. MITF expression can be transactivated by both SOX10 and PAX3 to have an additive effect. The two genes have binding sites near one another on the upstream enhancer of the c-RET gene. SOX10 is also thought to target dopachrome tautomerase through a synergistic interaction with MITF, which then results in other melanocyte alteration.
SOX10 can influence the generation of Myelin Protein Zero (MPZ) transcription through its interactions with proteins such as OLIG1 and EGR2, which is important for the functionality of neurons. Other cofactors have been identified, such as SP1, OCT6, NMI, FOXD3 and SOX2.
The interaction between SOX10 and NMI seems to be coexpressed in glial cells, gliomas, and the spinal cord and has been shown to modulate the transcriptional activity of SOX10.
See also
SOX genes
List of histologic stains that aid in diagnosis of cutaneous conditions
References
Further reading
External links
Transcription factors | SOX10 | [
"Chemistry",
"Biology"
] | 505 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,756,599 | https://en.wikipedia.org/wiki/SULT1A3 | Sulfotransferase 1A3/1A4 is an enzyme that in humans is encoded by the SULT1A3 gene.
Sulfotransferase enzymes catalyze the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. These cytosolic enzymes are different in their tissue distributions and substrate specificities. The gene structure (number and length of exons) is similar among family members. This gene encodes a phenol sulfotransferase with thermolabile enzyme activity. Four sulfotransferase genes are located on the p arm of chromosome 16; this gene and SULT1A4 arose from a segmental duplication. This gene is the most centromeric of the four sulfotransferase genes. Exons of this gene overlap with exons of a gene that encodes a protein containing GIY-YIG domains (GIYD1). Three alternatively spliced variants that encode the same protein have been described.
References
Further reading
External links | SULT1A3 | [
"Chemistry"
] | 223 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,756,639 | https://en.wikipedia.org/wiki/ST2%20cardiac%20biomarker | The ST2 cardiac biomarker (also known as soluble interleukin 1 receptor-like 1) is a protein biomarker of cardiac stress encoded by the IL1RL1 gene. ST2 signals the presence and severity of adverse cardiac remodeling and tissue fibrosis, which occurs in response to myocardial infarction, acute coronary syndrome, or worsening heart failure.
ST2 provides prognostic information that is independent of other cardiac biomarkers such as BNP, NT-proBNP, highly sensitive troponin, GDF-15, and galectin-3. One study indicated that discrimination is independent of age, body mass index, history of heart failure, anemia and impaired kidney function or sex.
Protein
ST2 is a member of the interleukin 1 receptor family. The ST2 protein has two isoforms and is directly implicated in the progression of cardiac disease: a soluble form (referred to as soluble ST2 or sST2) and a membrane-bound receptor form (referred to as the ST2 receptor or ST2L). When the myocardium is stretched, the ST2 gene is upregulated, increasing the concentration of circulating soluble ST2. The ligand for ST2 is the cytokine interleukin-33 (IL-33). Binding of IL-33 to the ST2 receptor, in response to cardiac disease or injury, such as an ischemic event, elicits a cardioprotective effect resulting in preserved cardiac function. This cardioprotective IL-33 signal is counterbalanced by the level of soluble ST2, which binds IL-33 and makes it unavailable to the ST2 receptor for cardioprotective signaling. As a result, the heart is subjected to greater stress in the presence of high levels of soluble ST2.
Correlation with mortality
Published and peer-reviewed findings indicate that ST2 is a predictor of mortality at presentation. Studies have shown patients with ST2 levels above a clinical threshold consistently have a much higher risk of mortality while, equally important, patients with ST2 levels below threshold have a very low risk of mortality. Although it has been shown that ST2 concentrations correlate with heart failure severity there is no level that perfectly separates patients with and without heart failure for disease diagnosis. However, as a prognostic marker it has been clearly shown that patients are at a higher risk of adverse outcomes when ST2 levels are above a cutoff value of 35 ng/mL.
Patients with ACS
ST2 is a strong predictor of cardiovascular death and risk of developing new heart failure in ST Elevation Myocardial Infarction (STEMI) & NSTE-ACS patients. In patients presenting with Acute Coronary Syndrome (ACS), those in the highest quartile (above 35 ng/ml) have more than 3 times higher risk of cardiovascular death and new heart failure at 30 days, than those in the lower quartiles. At one year, there is a relative risk of 2.3 for adverse outcomes.
ST2 is an active participant in the cardiac remodeling pathway and could identify which patients will respond to Eplerenone, or other therapies that reverse myocardial fibrosis.
Clinical utility
ST2 has considerable prognostic value and is used as an aid for risk stratification in identifying patients who are at high risk of mortality and rehospitalization in patients diagnosed with heart failure.
ST2 is independent of natriuretic peptides, such as natriuretic peptide BNP and NT-proBNP, and therefore provide unique and complementary prognostic information.
ST2 is also not adversely influenced by age, impaired renal function or elevated body mass index (BMI), common confounding situations for natriuretic peptide measurements.
Repeated measurements of ST2 may aid in clinical decision-making.
The ST2 test
ST2 is measured by an immunoassay, commercially marketed as the Presage ST2 Assay by Critical Diagnostics of San Diego, California. The assay has Food and Drug Administration approval and a CE Mark.
References
Biomarkers | ST2 cardiac biomarker | [
"Biology"
] | 867 | [
"Biomarkers"
] |
14,756,669 | https://en.wikipedia.org/wiki/DNA%20replication%20factor%20CDT1 | CDT1 (Chromatin licensing and DNA replication factor 1) is a protein that in humans is encoded by the CDT1 gene. It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.
Role in pre-replication complexes
The protein encoded by this gene is a key licensing factor in the assembly of pre-replication complexes (pre-RC), which occurs during the G1 phase of the cell cycle. In the assembly of pre-RCs, origin recognition complexes (ORC1-6) recognize and bind to DNA replication origins. CDT1, along with the protein CDC6, are then recruited to the forming pre-RC, followed by minichromosome maintenance complexes (MCM2-7).
The activity of CDT1 during the cell cycle is tightly regulated during the S phase by the protein geminin, which inhibits it, and by SCFSKP2, which ubiquinates the protein to tag it for proteasomal degradation. This regulation is important in preventing relicensing, thus ensuring that DNA is only replicated once per cell cycle.
Orthologs
CDT1 belongs to a family of replication proteins conserved from yeast to humans. Examples of orthologs in other species include:
S. pombe – CDT1 (CDC10-dependent transcript 1)
Drosophila melanogaster – 'double parked' or Dup
Xenopus laevis - CDT1
Interactions
DNA replication factor CDT1 has been shown to interact with SKP2. Cdt1 is recruited by the origin recognition complex in origin licensing. Null-mutations for CDT1 are lethal in yeast; the spores undergo mitosis without DNA replication. The overexpression of CDT1 causes rereplication in H. sapiens, which activates the Chk1 pathway, preventing entry into mitosis.
References
Further reading
External links
Proteins
DNA replication | DNA replication factor CDT1 | [
"Chemistry",
"Biology"
] | 401 | [
"Genetics techniques",
"Biomolecules by chemical classification",
"DNA replication",
"Molecular genetics",
"Molecular biology",
"Proteins"
] |
14,756,741 | https://en.wikipedia.org/wiki/Cav1.4 | {{DISPLAYTITLE:Cav1.4}}
Cav1.4 also known as the calcium channel, voltage-dependent, L type, alpha 1F subunit (CACNA1F), is a human gene.
This gene encodes a member of the alpha-1 subunit family; a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants of the gene described here have been observed but have not been thoroughly characterized. Mutations in this gene have been shown to cause incomplete X-linked congenital stationary night blindness type 2 (CSNB2).
See also
Calcium channel
References
Further reading
External links
GeneReviews/NCBI/NIH/UW entry on X-Linked Congenital Stationary Night Blindness
Ion channels | Cav1.4 | [
"Chemistry"
] | 260 | [
"Neurochemistry",
"Ion channels"
] |
14,756,761 | https://en.wikipedia.org/wiki/Indian%20hedgehog%20%28protein%29 | Indian hedgehog homolog (Drosophila), also known as IHH, is a protein which in humans is encoded by the IHH gene. This cell signaling protein is in the hedgehog signaling pathway. The several mammalian variants of the Drosophila hedgehog gene (which was the first named) have been named after the various species of hedgehog; the Indian hedgehog is honored by this one. The gene is not specific to Indian hedgehogs.
Function
The Indian hedgehog protein is one of three proteins in the mammalian hedgehog family, the others being desert hedgehog (DHH) and sonic hedgehog (SHH). It is involved in chondrocyte differentiation, proliferation and maturation especially during endochondral ossification. It regulates its effects by feedback control of parathyroid hormone-related peptide (PTHrP).
Indian Hedge Hog, (Ihh) is one of three signaling molecules from the Hedgehog (Hh) gene family. Genes of the Hh family, Sonic Hedgehog (Shh), Desert Hedgehog (Dhh) and Ihh regulate several fetal developmental processes. The Ihh homolog is involved in the formation of chondrocytes during the development of limbs. The protein is released by small, non-proliferating, mature chondrocytes during endochondral ossification. Recently, Ihh mutations are shown to cause brachydactyly type A1 (BDA1), the first Mendelian autosomal dominant disorder in humans to be recorded. There are seven known mutations to Ihh that cause BDA1. Of particular interest, are mutations involving the E95 residue, which is thought to be involved with proper signaling mechanisms between Ihh and its receptors. In a mouse model, mice with mutations to the E95 residue were found to have abnormalities to their digits.
Ihh may also be involved in endometrial cell differentiation and implantation. Studies have shown progesterone to upregulate Ihh expression in the murine endometrium, suggesting a role in implantation. Ihh is suspected to be involved in the downstream regulation of other signaling molecules that are known to play a role in murine implantation. Mouse models involving Ihh null mice demonstrated failure of attachment and decidualization.
References
Further reading
Proteins
Morphogens | Indian hedgehog (protein) | [
"Chemistry",
"Biology"
] | 490 | [
"Biomolecules by chemical classification",
"Molecular biology",
"Proteins",
"Morphogens",
"Induced stem cells"
] |
14,756,767 | https://en.wikipedia.org/wiki/KCNA2 | Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.
Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1.
Interactions
KCNA2 has been shown to interact with KCNA4, DLG4, PTPRA, KCNAB2, RHOA and Cortactin.
Clinical
Mutations in this gene have been associated with hereditary spastic paraplegia.
See also
Voltage-gated potassium channel
Pandinotoxin
References
Further reading
External links
Ion channels | KCNA2 | [
"Chemistry"
] | 311 | [
"Neurochemistry",
"Ion channels"
] |
14,756,828 | https://en.wikipedia.org/wiki/60S%20acidic%20ribosomal%20protein%20P0 | 60S acidic ribosomal protein P0 is a protein that in humans is encoded by the RPLP0 gene.
Ribosomes catalyze protein synthesis and consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein, which is the functional equivalent of the E. coli L10 ribosomal protein, belongs to the L10P family of ribosomal proteins. It is a neutral phosphoprotein with a C-terminal end that is nearly identical to the C-terminal ends of the acidic ribosomal phosphoproteins P1 and P2. The P0 protein can interact with P1 and P2 to form a pentameric complex consisting of P1 and P2 dimers, and a P0 monomer. The protein is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.
References
Further reading
Ribosomal proteins | 60S acidic ribosomal protein P0 | [
"Chemistry"
] | 251 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,756,913 | https://en.wikipedia.org/wiki/TFDP1 | Transcription factor Dp-1 is a protein that in humans is encoded by the TFDP1 gene.
Function
The E2F transcription factor family (see MIM 189971) regulates the expression of various cellular promoters, particularly those involved in the cell cycle. E2F factors bind to DNA as homodimers or heterodimers in association with dimerization partner DP1. TFDP1 may be the first example of a family of related transcription factors; see TFDP2 (MIM 602160).[supplied by OMIM]
Interactions
TFDP1 has been shown to interact with:
E2F1,
E2F5, and
P53.
References
Further reading | TFDP1 | [
"Chemistry"
] | 147 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,756,976 | https://en.wikipedia.org/wiki/Linear%20acetylenic%20carbon | Linear acetylenic carbon (LAC), also known as carbyne or a Linear Carbon Chain (LCC), is an allotrope of carbon that has the chemical structure as a repeat unit, with alternating single and triple bonds. It would thus be the ultimate member of the polyyne family.
This polymeric carbyne is of considerable interest to nanotechnology as its Young's modulus is – forty times that of diamond; this extraordinary number is, however, based on a novel definition of cross-sectional area that does not correspond to the space occupied by the structure. Carbyne has also been identified in interstellar space; however, its existence in condensed phases has been contested recently, as such chains would crosslink exothermically (and perhaps explosively) if they approached each other.
History and controversy
The first claims of detection of this allotrope were made in 1960 and repeated in 1978. A 1982 re-examination of samples from several previous reports determined that the signals originally attributed to carbyne were in fact due to silicate impurities in the samples. Absence of carbyne crystalline rendered the direct observation of a pure carbyne-assembled solid still a major challenge, because carbyne crystals with well-defined structures and sufficient sizes are not available to date. This is indeed the major obstacle to general acceptance of carbyne as a true carbon allotrope. The mysterious carbyne still attracted scientists with its possible extraordinary properties.
During the past thirty five years an increasing body of experimental and theoretical work has been published in the scientific literature dealing with the preparation of carbyne and the study of its structure, properties and potential applications.
In 1968 a silver-white new mineral was discovered in graphitic gneisses of the Ries Crater (Nordlingen, Bavaria, Germany). This material was found to consist entirely of carbon and its hexagonal cell dimensions matched those reported earlier for carbyne by Russian scientists. It was concluded that this novel form of natural carbon, chaoite, was generated from graphite by the combined action of high temperature and high pressure, presumably caused by the impact of meteorite. Soon afterwards this “white” carbon was synthesized by sublimation of pyrolytic graphite in vacuum.
In 1984, a group at Exxon reported the detection of clusters with even numbers of carbons, between 30 and 180, in carbon evaporation experiments, and attributed them to polyyne carbon. However, these clusters later were identified as fullerenes.
In 1991, carbyne was allegedly detected among various other allotropes of carbon in samples of amorphous carbon black vaporized and quenched by shock waves produced by shaped explosive charges.
In 1995, the preparation of carbyne chains with over 300 carbons was reported. They were claimed to be reasonably stable, even against moisture and oxygen, as long as the terminal alkynes on the chain are capped with inert groups (such as tert-butyl or trifluoromethyl) rather than hydrogen atoms. The study claimed that the data specifically indicated a carbyne-like structures rather than fullerene-like ones. However, according to H. Kroto, the properties and synthetic methods used in those studies are consistent with generation of fullerenes.
Another 1995 report claimed detection of carbyne chains of indeterminate length in a layer of carbonized material, about thick, resulting from the reaction of solid polytetrafluoroethylene (PTFE, Teflon) immersed in alkali metal amalgam at ambient temperature (with no hydrogen-bearing species present). The assumed reaction was
,
where M is either lithium, sodium, or potassium. The authors conjectured that nanocrystals of the metal fluoride between the chains prevented their polymerization.
In 1999, it was reported that copper(I) acetylide (), after partial oxidation by exposure to air or copper(II) ions followed by decomposition with hydrochloric acid, leaves a "carbonaceous" residue with the spectral signature of chains with n=2–6. The proposed mechanism involves oxidative polymerization of the acetylide anions into carbyne-type anions or cumulene-type anions . Also, thermal decomposition of copper acetylide in vacuum yielded a fluffy deposit of fine carbon powder on the walls of the flask, which, on the basis of spectral data, was claimed to be carbyne rather than graphite. Finally, the oxidation of copper acetylide in ammoniacal solution (Glaser's reaction) produces a carbonaceous residue that was claimed to consist of "polyacetylide" anions capped with residual copper(I) ions,
.
On the basis of the residual amount of copper, the mean number of units n was estimated to be around 230.
In 2004, an analysis of a synthesized linear carbon allotrope found it to have a cumulene electronic structure—sequential double bonds along an sp-hybridized carbon chain—rather than the alternating triple–single pattern of linear carbyne.
In 2016, the synthesis of linear chains of up to 6,000 sp-hybridized carbon atoms was reported. The chains were grown inside double-walled carbon nanotubes, and are highly stable protected by their hosts.
Polyynes
While the existence of "carbyne" chains in pure neutral carbon material is still disputed, short chains are well established as substructures of larger molecules (polyynes). As of 2010, the longest such chain in a stable molecule had 22 acetylenic units (44 atoms), stabilized by rather bulky end groups.
Structure
The carbon atoms in this form are each linear in geometry with sp orbital hybridisation. The estimated length of the bonds is (triple) and (single).
Other possible configurations for a chain of carbon atoms include polycumulene (polyethylene-diylidene) chains with double bonds only (). This chain is expected to have slightly higher energy, with a Peierls gap of . For short molecules, however, the polycumulene structure seems favored. When n is even, two ground configurations, very close in energy, may coexist: one linear, and one cyclic (rhombic).
The limits of flexibility of the carbyne chain are illustrated by a synthetic polyyne with a backbone of 8 acetylenic units, whose chain was found to be bent by or more (about at each carbon) in the solid state, to accommodate the bulky end groups of adjacent molecules.
The highly symmetric carbyne chain is expected to have only one Raman-active mode with Σg symmetry, due to stretching of bonds in each single-double pair, with frequency typically between 1800 and , and affected by their environments.
Properties
Carbyne chains have been claimed to be the strongest material known per density. Calculations indicate that carbyne's specific tensile strength (strength divided by density) of beats graphene (), carbon nanotubes (), and diamond (). Its specific modulus (Young's Modulus divided by density) of around is also double that of graphene, which is around .
Stretching carbyne 10% alters its electronic band gap from . Outfitted with molecular handles at chain's ends, it can also be twisted to alter its band gap. With a end-to-end twist, carbyne turns into a magnetic semiconductor.
In 2017, the band gaps of confined linear carbon chains (LCC) inside double-walled carbon nanotubes with lengths ranging from 36 up to 6000 carbon atoms were determined for the first time ranging from , following a linear relation with Raman frequency. This lower bound is the smallest band gap of linear carbon chains observed so far. In 2020, the strength (Young's modulus) of linear carbon chains (LCC) was experimentally calculated to be about which is much higher than that of other carbon materials like graphene and carbon nanotubes. The comparison with experimental data obtained for short chains in gas phase or in solution demonstrates the effect of the DWCNT encapsulation, leading to an essential downshift of the band gap.
The LCCs inside double-walled carbon nanotubes lead to an increase of the photoluminescence (PL) signal of the inner tubes up to a factor of 6 for tubes with (8,3) chirality. This behavior can be attributed to a local charge transfer from the inner tubes to the carbon chains, counterbalancing quenching mechanisms induced by the outer tubes.
Carbyne chains can take on side molecules that may make the chains suitable for energy and hydrogen storage.
With a differential Raman scattering cross section of 10−22 cm2 sr−1 per atom, carbyne chains confined inside carbon nanotubes are the strongest Raman scatterer ever reported, exceeding any other know material by two orders of magnitude.
References
Further reading
Nanotechnology
Allotropes of carbon
Alkynes
Polyynes | Linear acetylenic carbon | [
"Chemistry",
"Materials_science",
"Engineering"
] | 1,866 | [
"Alkynes",
"Allotropes of carbon",
"Allotropes",
"Materials science",
"Organic compounds",
"Nanotechnology"
] |
14,757,004 | https://en.wikipedia.org/wiki/TNFSF12 | Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.
Function
TWEAK was discovered in 1997. The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. Leukocytes are the main source of TWEAK including human resting and activated monocytes, dendritic cells and natural killer cells. TWEAK can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis.
Clinical significance
Excessive activation of the TWEAK pathway in chronic injury has been described to promote pathological tissue changes including chronic inflammation, fibrosis and angiogenesis. In chronic liver disease, for example, TWEAK expression is enhanced and causes hepatic stellate cells, which are key regulators of liver fibrosis, to proliferate.
References
Further reading | TNFSF12 | [
"Chemistry"
] | 271 | [
"Biochemistry stubs",
"Protein stubs"
] |
14,757,100 | https://en.wikipedia.org/wiki/CLIC1 | Chloride intracellular channel protein 1 is a protein that in humans is encoded by the CLIC1 gene.
Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity.
Interactions
CLIC1 has been shown to interact with TRAPPC2.
See also
Chloride channel
References
Further reading
External links
Ion channels | CLIC1 | [
"Chemistry"
] | 121 | [
"Neurochemistry",
"Ion channels"
] |
14,757,426 | https://en.wikipedia.org/wiki/NFAT5 | Nuclear factor of activated T-cells 5, also known as NFAT5 and sometimes TonEBP, is a human gene that encodes a transcription factor that regulates the expression of genes involved in the osmotic stress.
The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.
Osmotic stress
Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is hypertonic, cells lose water and consequently, shrink. To counteract this, cells increase their sodium uptake in order to lose less water. However, an increase in intracellular ionic concentration is harmful to the cell. Cells can alternatively synthesize enzymes and transporters that increase intracellular concentration of organic osmolytes, which are less toxic than excess ions but which also aid in water retention. Under conditions of hyperosmolarity, NFAT5 is synthesized and accumulates in the nucleus. NFAT5 stimulates the transcription of genes for aldose reductase (AR), the sodium chloride-betaine cotransporter (SLC6A12) the sodium/myo-inositol cotransporter (SLC5A3), the taurine transporter (SLC6A6) and neuropathy target esterase which are involved in the production and uptake of organic osmolytes. Additionally, NFAT5 induces heat shock proteins, Hsp70, and osmotic stress proteins. NFAT5 is also implicated in cytokine production.
It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla. Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.
Structure
The NFAT family consists of five different forms: NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5 (this protein). The proteins in this family are expressed in nearly every tissue in the body and are known transcriptional regulators in cytokine and immune cell expression. Among the different forms of NFAT, NFAT5 is an important component of the hyperosmolar stress response system.
cDNA of NFAT5 was first isolated from a human brain cDNA library. Subsequent analysis revealed that NFAT5 is a member of the Rel family, which also consists of NF-κB and NFATc proteins. The largest Rel protein, it consists of nearly 1,500 amino acid residues. Like the other Rel proteins, NFAT5 contains the Rel homology domain, a conserved DNA-binding domain. Outside of the Rel homology domain, no similarities exist between NFAT5 and NF-κB or NFATc. Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import. Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation. Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation.
Mechanism of Activation
Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane. Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6. This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression.
It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals. However, the downstream transcription of the NFAT5 gene by p38 MAPK is currently not yet characterized. It is hypothesized that p38 MAPK phosphorylation activates c-Fos and interferon regulatory factors (IRFs), which bind to AP-1-binding sites and ISRES (Interferon Stimulated Response Element) respectively. Binding to these sites consequently activates the transcription of target genes.
Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.
Additional Roles
NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.
NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest.
Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known.
References
Further reading
External links
Transcription factors
Human proteins | NFAT5 | [
"Chemistry",
"Biology"
] | 1,321 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,757,547 | https://en.wikipedia.org/wiki/GABRB2 | The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its dominant GABAA receptor subtype is composed of α1, β2, and γ2 subunits with the stoichiometry of 2:2:1, which accounts for 43% of all GABAA receptors.
Alternative splicing of the GABRB2 gene leads at least to four isoforms, viz. β2-long (β2L) and β2-short (β2S, β2S1, and β2S2). Alternatively spliced variants displayed similar but non-identical electrophysiological properties. GABRB2 is subjected to positive selection and known to be both an alternative splicing and a recombination hotspot; it is regulated via epigenetic regulation including imprinting and gene and promoter methylation
GABRB2 has been associated with a number of neuropsychiatric disorders, and found to display altered expression in cancer.
Structure
GABRB2 encodes the GABAA receptor beta-2 subunit. It is highly expressed in the brain with dominance in the gray matter. In humans, it is located on chromosome 5q34, with 11 exons and 10 introns spanning more than 260 kb, and a promoter region ranging from 1000 bp upstream to 689 bp downstream of exon 1. Alternative splicing of the gene product yields at least four isoforms, viz. β2-long (β2L), β2-short (β2S) and two additional short isoforms β2S1 and β2S2. These isoforms, composed of 512, 474, 313, and 372 amino acids respectively, display dissimilar electrophysiological properties. In mice, the corresponding Gabrb2 gene on chromosome 11A5 comprises 12 exons and 11 introns, and the two isoforms β2L and β2S from alternative splicing consisted of 512 and 474 amino acids respectively.
The β-2 subunit is a component of the ligand-gated chloride GABAA receptors which belongs to the Cys-loop superfamily. Like all subunits of this family, it consists of an extracellular N-terminal domain containing a Cys-loop of 13 amino acids, four membrane-spanning domains (TM1-4) with a large intracellular loop between TM3 and TM4, and an extracellular C-terminal domain. Five subunits from varied families (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) combine to form the heteropentameric GABAA receptor. TM2 from each subunit participates in the formation of the ion pore of the receptor, and α2β2γ2 is the major subtype in the brain that accounts for 43% of all GABAA receptors.
Regulation
Phosphorylation is an important mechanism for the modulation of GABAA receptor function. GABRB2 includes a consensus sequence for a calmodulin-dependent protein kinase II within exon 10 which is only expressed by β2L. As a result, upon repetitive stimulation, the β2L isoform-containing GABAA receptors are more vulnerable to run-down than those containing the short isoforms. Accordingly, ATP depletion reduces the inhibitory transmission of the GABAergic system due to GABAA receptors rundown through β2. Since this rundown occasioned by the presence of β2L would lead to improved maintenance of survival-favoring activities such as hunting and food gathering in the face of energy deprivation, it could be selected as an evolutionary advantage over the shorter isoforms.
Multiple lines of evidence confirmed the epigenetic regulation of GABRB2 gene expression via methylation and imprinting. GABRB2 mRNA expression level varied with germline genotypes, and with the gender of the parent in accord with the process of imprinting.
Function
GABRB2 is highly expressed in the brain where it plays its major role. In the immature brain, GABAA receptors participate in excitatory transmission, which is important to synaptogenesis, neurogenesis, and the formation of the glutamatergic system. In the mature brain, GABAA receptors fulfill their conventional inhibitory role, with the β2 subunits participating in some of the fastest inhibitory transmissions that prevent hyperexcitability, regulate the stress response of the hypothalamic-pituitary-adrenal axis, as well as pain signals mediated by the thalamus. Moreover, GABRB2 is associated with cognitive function, energy regulation, time perception, and the maintenance of efferent synaptic terminals in the mature ear.
Clinical significance
GABRB2 is associated with a spectrum of neuropsychiatric disorders, and displays of differential gene expression between tumor and non tumor tissues.
Psychiatric disorders
Schizophrenia
Single nucleotide polymorphisms (SNPs) in GABRB2 were first associated with schizophrenia (SCZ) in Han Chinese, and confirmed subsequently for German, Portuguese, and Japanese SCZ patients. Furthermore, their significant associations have been extended to cognitive function, psychosis, and neuroleptic-induced tardive dyskinesia in schizophrenics. Recurrent copy number variations (CNVs) in GABRB2 were likewise associated with schizophrenia. GABRB2 expression was decreased in genotype and age-dependent manners, with reduced β2L/β2S ratios in schizophrenics serving as a key determinant of the response of receptor function to the energy status. The regulation of its expression by methylation and imprinting, as well as its N-glycosylation of the β2-subunit, were altered in SCZ. That GABRB2 is both a recombination hotspot and subject to positive selection could be an important factor in the widespread occurrence of SCZ. Gabrb2-knockout mice displayed schizophrenia-like behavior including prepulse inhibition deficit and antisocial behavior that were ameliorated by the antipsychotic risperidone, strongly supporting the proposal based on postmortem SCZ brains that GABRB2 represents the key genetic factor in SCZ etiology.
Other psychiatric disorders
GABRB2 was significantly associated with bipolar disorder, with a genotype-dependent decrease in GABRB2 mRNA levels weaker than that observed in SCZ. In major depressive disorder, the expressions of GABAA subunit genes were altered, and the expression of GABRB2 was significantly decreased in the anterior cingulate cortex, in the postmortem brains of patients.
The expression of GABRB2 was significantly increased in the internet gaming disorder group, and GABRB2 was the downstream target for two circulating microRNA, viz. hsa-miR-26b-5p and hsa-miR-652-3p, which were significantly downregulated in these subjects.
The GABAergic system was suggested to be a factor in the physiopathology of premenstrual dysphoric disorder (PMDD). GABA levels were altered in the brain of PMDD patients. Two highly recurrent copy number variations in GABRB2 were associated with PMDD in Chinese and German patients, providing thereby a possible explanation of part of the complex psychological symptoms of PMDD.
Drug dependence
SNPs in GABRB2 were significantly associated with alcohol dependence and consumption in Southwestern Native Americans, Finnish, Scottish, and Sidney populations. Chronic alcohol administration induced an increase in the expression of Gabrb2 in a rat model. and sleep time was decreased in Gabrb2 knockout mice.
SNPs in GABRB2 were significantly associated with heroin addiction in African American subjects. Haplotypes in GABRB2 yielded a significant association with heroin dependence in the Chinese population.
Neurological disorders
Epilepsy
Numerous de novo mutations in GABRB2 were associated with infantile and early childhood epileptic encephalopathy (IECEE). As well, SNPs in GABRB2 were significantly associated with epilepsy in the North Indian population. Moreover, Gabrb2 knockout mice displayed audiogenic epilepsy, which further confirmed the contribution of GABRB2 to the etiology of epilepsy.
Autism spectrum disorder
The density of GABAA receptors showed a significant reduction in autistic brains. and SNPs in GABRB2 were significantly associated with autism. De novo pathogenic mutations in the GABRB2 gene contribute to the physiopathology of Rett syndrome. β2 subunit mRNA expression level was subjected to significant upregulation in a mouse model of Rett syndrome
Neurodegenerative disorders
Deficits in the GABergic system and decreased levels of GABA were reported in Alzheimer's disease (AD). An SNP near GABRB2 was associated with AD. Two SNPs in GABRB2 were significantly associated with frontotemporal dementia (FTD) risk, and GABRB2 was downregulated in a cellular system of FTD and a mouse model of tauopathy.
Cancer
Genomic classifiers including GABRB2 could differentiate correctly between malignant and benign nodules. and GABRB2 alone or in combination with other genes correctly distinguished between malignant and benign tumors. GABRB2 was upregulated and hypomethylated in papillary thyroid carcinoma. The downregulation of GABRB2 enhanced the apoptotic cell death and decreased proliferation, migration, and invasiveness of thyroid cancer cells.
GABRB2 was upregulated in adrenocortical carcinoma and salivary gland cancer, but downregulated in patients with colorectal cancer, brain tumors, kidney renal clear cell carcinoma and lung cancer
Therapeutic implications
The β2 subunit-containing GABAA receptors are more sensitive to GABA. Tyrosine and proline residues in the Cys-loop of this subunit were important elements in the binding and response to GABA, and the subunit also mediated the receptor binding of alcohol and anesthetics, anticonvulsive activity of loreclezole, hypothermic response to etomidate, as well as the sedative effects of both etomidate and loreclezole. It was identified as a target for the endocannabinoid 2-arachidonylglycerol, and Gabrb2 expression was upregulated by the antiepileptic drug qingyangshenylycosides and downregulated by the opioid oxycodone The wide-ranging involvement of the GABRB2 and its gene products in neuropsychiatric pharmacology are in accord with their central roles in inhibitory signaling in the brain.
See also
GABAA receptor
Notes
References
External links
Ion channels | GABRB2 | [
"Chemistry"
] | 2,346 | [
"Neurochemistry",
"Ion channels"
] |
14,757,553 | https://en.wikipedia.org/wiki/GATA6 | Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the GATA6 gene. The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence.
Clinical significance
Mutations in the gene have been linked with pancreatic agenesis and congenital heart defects.
Lung Endodermal Epithelial Development
GATA-6, a zinc finger transcription factor, is important in the endodermal differentiation of organ tissues. It is also indicated in proper lung development by controlling the late differentiation stages of alveolar epithelium and aquaporin-5 promoter activation. Furthermore, GATA-6 has been linked to the production of LIF, a cytokine that encourages proliferation of endodermal embryonic stem cells and blocks early epiblast differentiation. If left unregulated in the developing embryo, this cytokine production and chemical signal contributes to the phenotypes discussed further below.
Upon the disruption of GATA-6 in an embryo, the distal lung epithelial development is stunted in transgenic mice models The progenitor cells, or stem cells, for alveolar epithelial tissues develop and are specified appropriately, however further differentiation does not occur. Also the distal-proximal bronchiole development is affected, resulting in a reduced quantity of airway exchange sites.
This branching deficit, which will cause bilateral pulmonary hypoplasia after birth, has been locally associated with areas lacking differentiated alveolar epithelium, implicating this phenotype as inherent to endodermal function, and thus may be indirectly linked to improper GATA-6 expression. That is, a deficit of bronchiole branching may not be a result of direct transcriptional error in GATA-6, but rather a side effect of such an error.
See also
GATA transcription factor
References
Further reading
External links
Transcription factors | GATA6 | [
"Chemistry",
"Biology"
] | 417 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,757,643 | https://en.wikipedia.org/wiki/Stream%20restoration | Stream restoration or river restoration, also sometimes referred to as river reclamation, is work conducted to improve the environmental health of a river or stream, in support of biodiversity, recreation, flood management and/or landscape development.
Stream restoration approaches can be divided into two broad categories: form-based restoration, which relies on physical interventions in a stream to improve its conditions; and process-based restoration, which advocates the restoration of hydrological and geomorphological processes (such as sediment transport or connectivity between the channel and the floodplain) to ensure a stream's resilience and ecological health. Form-based restoration techniques include deflectors; cross-vanes; weirs, step-pools and other grade-control structures; engineered log jams; bank stabilization methods and other channel-reconfiguration efforts. These induce immediate change in a stream, but sometimes fail to achieve the desired effects if degradation originates at a wider scale. Process-based restoration includes restoring lateral or longitudinal connectivity of water and sediment fluxes and limiting interventions within a corridor defined based on the stream's hydrology and geomorphology. The beneficial effects of process-based restoration projects may sometimes take time to be felt since changes in the stream will occur at a pace that depends on the stream dynamics.
Despite the significant number of stream-restoration projects worldwide, the effectiveness of stream restoration remains poorly quantified, partly due to insufficient monitoring. However, in response to growing environmental awareness, stream-restoration requirements are increasingly adopted in legislation in different parts of the world.
Definition, objectives and popularity
Stream restoration or river restoration, sometimes called river reclamation in the United Kingdom, is a set of activities that aim to improve the environmental health of a river or stream. These activities aim to restore rivers and streams to their original states or to a reference state, in support of biodiversity, recreation, flood management, landscape development, or a combination of these phenomena. Stream restoration is generally associated with environmental restoration and ecological restoration. In that sense, stream restoration differs from:
river engineering, a term which typically refers to physical alterations of a water body, for purposes that include navigation, flood control or water supply diversion and are not necessarily related to ecological restoration;
waterway restoration, a term used in the United Kingdom describing alterations to a canal or river to improve navigability and related recreational amenities.
Improved stream health may be indicated by expanded habitat for diverse species (e.g. fish, aquatic insects, other wildlife) and reduced stream bank erosion, although bank erosion is increasingly generally recognized as contributing to the ecological health of streams. Enhancements may also include improved water quality (i.e., reduction of pollutant levels and increase of dissolved oxygen levels) and achieving a self-sustaining, resilient stream system that does not require periodic human intervention, such as dredging or construction of flood or erosion control structures. Stream restoration projects can also yield increased property values in adjacent areas.
In the past decades, stream restoration has emerged as a significant discipline in the field of water-resources management, due to the degradation of many aquatic and riparian ecosystems related to human activities. In the U.S. alone, it was estimated in the early 2000s that more than one billion U.S. dollars were spent each year to restore rivers and that close to 40,000 restoration projects had been conducted in the continental part of the country.
Restoration approaches and techniques
Stream restoration activities may range from the simple improvement or removal of a structure that inhibits natural stream functions (e.g. repairing or replacing a culvert, or removing barriers to fish passage such as weirs), to the stabilization of stream banks, or other interventions such as riparian zone restoration or the installation of stormwater-management facilities like constructed wetlands. The use of recycled water to augment stream flows that have been depleted as a result of human activities can also be considered a form of stream restoration. When present, navigation locks have a potential to be operated as vertical slot fishways to restore fish passage to some extent for a wide range of fish, including poor swimmers.
Stream-restoration projects normally begin with an assessment of a focal stream system, including climatic data, geology, watershed hydrology, stream hydraulics, sediment transport patterns, channel geometry, historical channel mobility, and flood records. Numerous systems exist to classify streams according to their geomorphology. This preliminary assessment helps to understand the stream dynamics and determining the cause of the observed degradation to be addressed; it can also be used to determine the target state for the intended restoration work, especially since the "natural" or undisturbed state is sometimes no longer achievable due to various constraints.
Two broad approaches to stream restoration have been defined in the past decades: form-based restoration and process-based restoration. Whereas the former focuses on the restoration of structural features and/or patterns considered to be characteristic of the target stream system, the latter is based on the restoration of hydrological and geomorphological processes (such as sediment transport or connectivity between the channel and the floodplain) to ensure a stream's resilience and ecological health.
Form-based restoration
Form-based stream restoration promotes the modification of a stream channel to improve stream conditions. Targeted outcomes can include improved water quality, enhanced fish habitat and abundance, as well as increased bank and channel stability. This approach is widely used worldwide, and is supported by various government agencies, including the United States Environmental Protection Agency (U.S. EPA).
Form-based restoration projects can be carried out at various scales, including the reach scale. They can include measures such as the installation of in-stream structures, bank stabilization and more significant channel reconfiguration efforts. Reconfiguration work may focus on channel shape (in terms of sinuosity and meander characteristics), cross-section or channel profile (slope along the channel bed). These alterations affect the dissipation of energy through a channel, which impacts flow velocity and turbulence, water-surface elevations, sediment transport, and scour, among other characteristics.
Installation of in-stream structures
Deflectors
Deflectors are generally wooden or rock structures installed at a bank toe and extending towards the center of a stream, in order to concentrate stream flow away from its banks. They can limit bank erosion and generate varying flow conditions in terms of depth and velocity, which can positively impact fish habitat.
Cross-vanes and related structures
Cross-vanes are U-shaped structures made of boulders or logs, built across the channel to concentrate stream flow in the center of the channel and thereby reduce bank erosion. They do not impact channel capacity and provides other benefits such as improved habitat for aquatic species. Similar structures used to dissipate stream energy include the W-weirs and J-Hook vanes.
Weirs, step pools and grade-control structures
These structures, which can be built with rocks or wood (logs or woody debris), gradually lower the elevation of the stream and dissipate flow energy, thereby reducing flow velocity. They can help limit bed degradation. They generate water accumulation upstream from them and fast flowing conditions downstream from them, which can improve fish habitat. However, they can limit fish passage if they are too high.
Engineered log jams
An emerging stream restoration technique is the installation of engineered log jams. Because of channelization and removal of beaver dams and woody debris, many streams lack the hydraulic complexity that is necessary to maintain bank stabilization and healthy aquatic habitats. Reintroduction of large woody debris into streams is a method that is being experimented in streams such as Lagunitas Creek in Marin County, California and Thornton Creek, in Seattle, Washington. Log jams add diversity to the water flow by creating riffles, pools, and temperature variations. Large wood pieces, both living and dead, play an important role in the long-term stability of engineered log jams. However, individual pieces of wood in log jams are rarely stable over long periods and are naturally transported downstream, where they can get trapped in further log jams, other stream features or human infrastructures, which can generate nuisances for human use.
Bank stabilization
Bank stabilization is a common objective for stream-restoration projects, although bank erosion is generally viewed as favorable for the sustainability and diversity of aquatic and riparian habitats. This technique may be employed where a stream reach is highly confined, or where infrastructure is threatened.
Bank stabilization is achieved through the installation of riprap, gabions or through the use of revegetation and/or bioengineering methods, which relies on the use of live plants to build bank stabilizing structures. As new plants sprout from the live branches, the roots anchor the soil and prevent erosion. This makes bioengineering structures more natural and more adaptable to evolving conditions than "hard" engineering structures. Bioengineering structures include fascines, brush mattresses, brush layer, and vegetated geogrids.
Other channel-reconfiguration techniques
Channel reconfiguration involves the physical modification of the stream. Depending on the scale of a project, a channel's cross-section can be modified, and meanders can be constructed through earthworks to achieve the target stream morphology. In the U.S., such work is frequently based on the Natural Channel Design (NCD), a method developed in the 1990s. This method involves a classification of the stream to be restored based on parameters such as channel pattern and geometry, topography, slope, and bed material. This classification is followed by a design phase based on the NCD method, which includes 8 phases and 40 steps. The method relies on the construction of the desired morphology, and its stabilization with natural materials such as boulders and vegetation to limit erosion and channel mobility.
Criticisms to form-based restoration
Despite its popularity, form-based restoration has been criticized by the scientific community. Common criticisms are that the scale at which form-based restoration is often much smaller than the spatial and temporal scales of the processes that cause the observed problems and that the target state is frequently influenced by the social conception of what a stream should look like and does not necessarily take into account the stream's geomorphological context (e.g., meandering rivers tend to be viewed as more "natural" and more beautiful, whereas local conditions sometimes favour other patterns such as braided rivers). Numerous criticisms have also been directed at the NCD method by fluvial geomorphologists, who claim that the method is a "cookbook" approach sometimes used by practitioners that do not have sufficient knowledge of fluvial geomorphology, resulting in project failures. Another criticism is the importance given to channel stability in the NCD method (and with some other form-based restoration methods), which can limit the streams' alluvial dynamic and adaptability to evolving conditions. The NCD method has been criticized for its improper application in the Washington, D.C. area to small-order, interior-forested, upper-headwater streams and wetlands, leading to loss of natural forest ecosystems.
Process-based restoration
Contrary to form-based restoration, which consists of improving a stream's conditions by modifying its structure, process-based restoration focuses on restoring the hydrological and geomorphological processes (or functions) that contribute to the stream's alluvial and ecological dynamics. This type of stream restoration has gained in popularity since the mid-1990s, as a more ecosystem-centered approach. Process-based restoration includes restoring lateral connectivity (between the stream and its floodplain), longitudinal connectivity (along the stream) and water and/or sediment fluxes, which might be impacted by hydro-power dams, grade control structures, erosion control structures and flood protection structures. Valley Floor Resetting epitomises process-based restoration by infilling the river channel and allowing the stream to carve its anastomosed channel anew, matching 'Stage Zero' on the Stream Evolution Model. In general, process-based restoration aims to maximize the resilience of the system and minimize maintenance requirements. In some instances, form-based restoration methods might be coupled with process-based restoration to restore key structures and achieve quicker results while waiting for restored processes to ensure adequate conditions in the long term.
Improving connectivity
The connectivity of streams to their adjacent floodplain along their entire length plays an important role in the equilibrium of the river system. Streams are shaped by the water and sediment fluxes from their watershed, and any alteration of these fluxes (either in quantity, intensity or timing) will result in changes in equilibrium planform and cross-sectional geometry, as well as modifications of the aquatic and riparian ecosystem. Removal or modification of levees can allow a better connection between streams and their floodplain. Similarly, removing dams and grade control structures can restore water and sediment fluxes and result in more diversified habitats, although impacts on fish communities can be difficult to assess.
In streams where existing infrastructures cannot be removed or modified, it is also possible to optimize sediment and water management in order to maximize connectivity and achieve flow patterns that ensure minimum ecosystem requirements. This can include releases from dams, but also delaying and/or treating water from agricultural and urban sources.
Implementing a minimum stream corridor width
Another method of ensuring the ecological health of streams while limiting impacts on human infrastructures is to delineate a corridor within which the stream is expected to migrate over time. This method is based on the concept of minimum intervention within this corridor, whose limits should be determined based on the stream's hydrology and geomorphology. Although this concept is often restricted to the lateral mobility of streams (related to bank erosion), some systems also integrate the space necessary for floods of various return periods. This concept has been developed and adapted in various countries around the world, resulting in the notion of "stream corridor" or "river corridor" in the U.S., "room for the river" in the Netherlands, "" ("freedom space") in France (where the concept of "erodible corridor" is also used) and Québec (Canada), "" ("space reserved for water(courses)") in Switzerland, "" in Italy, "fluvial territory" in Spain and "making space for water" in the United Kingdom. A cost-benefit analysis has shown that this approach could be beneficial in the long term due to lower stream stabilization and maintenance costs, lower damages resulting from erosion and flooding, and ecological services rendered by the restored streams. However, this approach cannot be implemented alone if watershed-scale stressors contribute to stream degradation.
Additional practices
In addition to the aforementioned restoration approaches and methods, additional measures can be implemented if stream degradation factors occur at the watershed scale. First, high-quality areas should also be protected. Additional measures include revegetation/reforestation efforts (ideally with native species); the adoption of agricultural best management practices that minimize erosion and runoff; adequate treatment of sewage water and industrial discharge across the watershed; and improved stormwater management to delay/minimize the transport of water to the stream and minimize pollutant migration. Alternative stormwater management facilities include the following options:
Bioretention systems and rain gardens
Constructed wetlands
Infiltration basins
Retention basins
Effectiveness of stream restoration projects
In the 2000s, a study of stream restoration efforts in the U.S. led to the creation of the National River Restoration Science Synthesis (NRRSS) database, which included information on over 35,000 stream restoration projects carried out in the U.S. Synthesizing efforts are also carried out in other parts of the world, such as Europe. However, despite the large number of stream restoration projects carried out each year worldwide, the effectiveness of stream restoration projects remains poorly quantified. This situation appears to result from limited data on the restored streams' biophysical and geochemical contexts, to insufficient post-monitoring work and to the varying metrics used to evaluate project effectiveness. Depending on the objectives of the restoration project, the goals (restoration of fish populations, of alluvial dynamics, etc.) may take considerable time to be fully achieved. Therefore, whereas monitoring efforts should be proportional to the scale of the situation to be addressed, long-term is often necessary in order to fully evaluate a project's effectiveness.
In general, project effectiveness has been found to be dependent on selection of an appropriate restoration method considering the nature, cause and scale of the degradation problem. As such, reach-scale projects generally fail at restoring conditions whose root cause lies at the watershed scale, such as water quality issues. Furthermore, project failures have sometimes been attributed to design based on insufficient scientific bases; in some cases, restoration techniques may have been selected mainly for aesthetic reasons. Additional factors that can influence the effectiveness of river restoration projects include the selection of sites to be restored (for example, sites located near undisturbed reaches could be recolonized more effectively) and the amount of tree cutting and other destructive work necessary to carry out the restoration work (which can have long-lasting detrimental effects on the quality of the habitat). Although often viewed as a challenge, public involvement is generally considered to be a positive factor for the long-term success of stream restoration projects.
Introduction in legislation
Stream restoration is gradually being introduced in the legislative framework of various states. Examples include the European water framework's commitment to restoring surface water bodies, the adoption of the concept of freedom space in the French legislation, the inclusion in the Swiss legislation of the notion of space reserved for watercourses and of the requirement to restore streams to a state close to their natural state, and the inclusion of river corridors in land use planning in the American states of Vermont and Washington. Although this evolution is generally viewed positively by the scientific community, a concern expressed by some is that it could lead to less flexibility and less room for innovation in a field that is still in development.
Informational resources
The River Restoration Centre, based at Cranfield University, is responsible for the National River Restoration Inventory, which is used to document best practice in river watercourse and floodplain restoration, enhancement and management efforts in the United Kingdom. Other established sources for information on stream restoration include the NRRSS in the U.S. and the European Centre for River Restoration (ECRR), which holds details of projects across Europe. ECRR and the LIFE+ RESTORE project have developed a wiki-based inventory of river restoration case studies.
See also
Daylighting (streams)
Environmental restoration
Land rehabilitation
Retrofit (environmental management)
Restoration ecology
Riparian zone restoration
Subterranean river
References
Notes
Federal Interagency Stream Restoration Working Group (United States)(2001). Stream Corridor Restoration: Principles, Processes, and Practices. GPO Item No. 0120-A; SuDocs No. A 57.6/2:EN 3/PT.653. .
Water streams
Ecological restoration
Environmental engineering
Environmental terminology
Freshwater ecology
Hydraulic engineering
Hydrology
Habitat
Riparian zone
Rivers
Water and the environment | Stream restoration | [
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14,757,671 | https://en.wikipedia.org/wiki/HOXB6 | Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.
Function
This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development, including that of lung and skin, and has been localized to both the nucleus and cytoplasm. Altered expression of this gene or a change in the subcellular localization of its protein is associated with some cases of acute myeloid leukemia and colorectal cancer.
During development
HOXB6 gene is only expressed in erythroid progenitor cells, which are the precursor to red blood cells used for transport of oxygen and carbon dioxide throughout the body. During development, the formation of the HOX gene factor happens in the first stages of fetal development, namely soon after the establishment of the mesoderm, which is the “middle layer” of the future embryo. However, HOXB6 is only expressed once the undifferentiated stem cells of the embryo distinguish themselves into the erythpoietic phase. The research has shown that HOXB6 is not expressed in hematopoietic stem cells located in the red bone marrow, which are the precursor cells to all types of blood cells, or primordial germ cells (PGCs), the precursor to cells passed on in each generation. Since it is a transcriptional factor, HOXB6 regulates erythropoiesis (red blood cell formation) using mRNA as the basis for certain protein productions. The specific gene factor for erythrogenesis has relatively been unobserved in the scientific community, and no known diseases have been associated with a defect HOXB6 gene. However, it has been shown in correlation with major skeletal deformations.
HOXB6 is a structural protein that has been shown to influence the growth and differentiation of the different blood lineages. This gene has also been shown to encourage the growth of granulocytes and monocytes, but at the cost of other blood cells. HOXB6 has the ability to cause the indefinite proliferation of murine marrow cells, as well as expand hematopoietic stem cells. When expressed abnormally, HOXB6 displays many characteristics of a potent oncoprotein. An oncoprotein can cause the transformation of a normal cell into a tumor cell. Overexpression of HOXB6, along with the addition of MEIS1 protein, has been implicated in the development of acute myeloid leukemia (AML). Acute myeloid leukemia is a cancer of the blood cells, specifically the leukocytes. The chromosomal irregularity most frequently seen in HOXB6 AML is a reappearing interstitial deletion of chromosome 2. Fundamental HOXB6 expression stops myeloid differentiation and debilitates erythropoiesis, megakaryopoiesis, and lymphopoiesis.
See also
Leukemia
Myeloid tissue
References
Further reading
External links
Transcription factors | HOXB6 | [
"Chemistry",
"Biology"
] | 667 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,757,750 | https://en.wikipedia.org/wiki/IFI16 | Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the IFI16 gene.
Function
This gene encodes a member of the HIN-200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. The protein localizes to the nucleoplasm and nucleoli, and interacts with p53. It modulates p53 function, and inhibits cell growth in the Ras/Raf signaling pathway. IFI16 has been shown to play a role in the sensing of intracellular DNA - a hallmark of virally infected cells - and has also been linked to the death of HIV-infected helper CD4 T cells by pyroptosis, a highly inflammatory form of programmed cell death. Recently, it has been shown how IFI16, once extracellularly released, can induce inflammation upon TLR4 binding, acting as a DAMP.
References
Further reading
External links
Transcription factors | IFI16 | [
"Chemistry",
"Biology"
] | 254 | [
"Induced stem cells",
"Gene expression",
"Transcription factors",
"Signal transduction"
] |
14,757,941 | https://en.wikipedia.org/wiki/3C%2079 | 3C 79 is a Seyfert Galaxy and a radio galaxy located in the constellation Aries. It is hosted by an elliptical galaxy described as elongated with a complex morphology.
According to radio mapping made by Very Large Array, 3C 79 has an asymmetric appearance. It has two radio lobes. The western lobe is found closely positioned to the radio core with diffused emission in south direction, while the eastern lobe is more aligned to the axis of the radio source.
The extended emission-line region (EELR) is almost certainly photoionized by the hidden quasar. This emission-line region has an X-shaped morphology with two of its structures having ordered rotation.
References
External links
www.jb.man.ac.uk/atlas/ (J. P. Leahy)
Wikisky image of PGC 1524618
079
Radio galaxies
3C 79
Aries (constellation)
Seyfert galaxies | 3C 79 | [
"Astronomy"
] | 192 | [
"Galaxy stubs",
"Astronomy stubs",
"Constellations",
"Aries (constellation)"
] |
8,920,000 | https://en.wikipedia.org/wiki/TopoFusion | TopoFusion GPS Mapping software designed to plan and analyze trails using topographic maps and GPS tracks.
History
The software was created in 2002 by two brothers who were outdoor bikepacking enthusiasts and felt software could help them plan better trails. They developed the first version of the software in 2002 and one included it as part of his doctorate dissertation on GPS Driven Trail Simulation and Network Production. In 2004 the developers and one other jointly presented the paper Digital Trail Libraries which illustrated some of the graph theory algorithms used by the software. the software remains supported with refined functionality and improved support for additional maps and GPS Devices.
Features
The software was designed to plan and analyze trails. When used for planning proposed routes may be planned and checked against different maps, and the result(s) downloaded to a GPS tracking device. Topofusion is particularly noted for eased of switch and combining maps and for capability of simultaneously managing multiple trails. After a trail has been executed the resultant GPS log can be uploaded to TopoFusion and the actual route analyzed with the addition of any photographic images recorded on route.
The product is marketed as a fully featured 'professional version and a more basic version with reduced functionality at lower cost. A fully featured trial version which is not time limited is available which restricts usability by watermarking map display tiles by overlaying the word 'DEMO'. The software is available directly Microsoft Windows only, however TopoFusion has claimed users have reported success using VMWare Fusion and Parallels emulation on Mac OS.
Applications
TopoFusion has been found useful by those engaged in the sport of geocaching.
The software has been used in assisting analysis of GPS routes. A survey reported in 2004 of GPS tracking of motorists visiting the Acadia National Park in Maine, United States was assisted by use of Topofusion to review the scenes visited. It has also been used in studies of agriculture transportation logistics.
TopoFusion can also assist in determining where photographs have been taken on a trail and can geocoded photo the image or tag it onto a map. For this to be successful the digital camera's time must be synchronized with the GPS unit time, and both the GPS track and digital images made available to Topofusion. The time when the image was taken can then be matched to the time on the GPS log and this enables the image to be enhanced with geocode fields when Real-time geotagging was not available when the image was taken. TopoFusion can also optionally annotate maps with images.
References
External links
Official website
Photo software
Wireless locating
Global Positioning System
Plotting software | TopoFusion | [
"Technology",
"Engineering"
] | 523 | [
"Global Positioning System",
"Wireless locating",
"Aircraft instruments",
"Aerospace engineering"
] |
8,920,050 | https://en.wikipedia.org/wiki/Melde%27s%20experiment | Melde's experiment is a scientific experiment carried out in 1859 by the German physicist Franz Melde on the standing waves produced in a tense cable originally set oscillating by a tuning fork, later improved with connection to an electric vibrator. This experiment, "a lecture-room standby", attempted to demonstrate that mechanical waves undergo interference phenomena. In the experiment, mechanical waves traveled in opposite directions form immobile points, called nodes. These waves were called standing waves by Melde since the position of the nodes and loops (points where the cord vibrated) stayed static.
Standing waves were first discovered by Franz Melde, who coined the term "standing wave" around 1860. Melde generated parametric oscillations in a string by employing a tuning fork to periodically vary the tension at twice the resonance frequency of the string.
History
Wave phenomena in nature have been investigated for centuries, some being some of the most controverted themes in the history of science, and so the case is with the wave nature of light. In the 17th century, Sir Isaac Newton described light through a corpuscular theory. The English physicist Thomas Young later contrasted Newton's theories in the 18th century and established the scientific basis upon which rest the wave theories. At the end of the 19th century, at the peak of the Second Industrial Revolution, the creation of electricity as the technology of the era offered a new contribution to the wave theories. This advance allowed Franz Melde to recognize the phenomena of wave interference and the creation of standing waves. Later, the Scottish physicist James Clerk Maxwell in his study of the wave nature of light succeeded in expressing waves and the electromagnetic spectrum in a mathematical formula.
Principle
A string undergoing transverse vibration illustrates many features common to all vibrating acoustic systems, whether these are the vibrations of a guitar string or the standing wave nodes in a studio monitoring room. In this experiment the change in frequency produced when the tension is increased in the string – similar to the change in pitch when a guitar string is tuned – will be measured. From this the mass per unit length of the string / wire can be derived. This is called as the principle of the Melde's Experiment
Finding the mass per unit length of a piece of string is also possible by using a simpler method – a ruler and some scales – and this will be used to check the results and offer a comparison.
See also
Sonar
Wind instruments
Sonometer
References
Wave mechanics | Melde's experiment | [
"Physics"
] | 489 | [
"Waves",
"Wave mechanics",
"Physical phenomena",
"Classical mechanics"
] |
8,920,077 | https://en.wikipedia.org/wiki/Linutop | The Linutop is a small, light, environmentally friendly nettop computer containing a metal case and no moving parts, that runs the Linutop OS (a customized version of Linux based on the Xubuntu and Ubuntu/XFCE distribution). It is sold by Linutop SAS of Paris, France.
Linutop Kiosk software and Linutop Tv server offer a full Digital signage solution.
A variety of QT applications oriented towards secure web browsing and digital signage are available in the Operating system. Linutop is multimedia-capable and offers line-out/mic-in for sound. The device can be configured easily into a LTSP thin client. Linutop is suited for use in internet cafés, public libraries and schools.
History
Linutop 1
The first device was based on the ThinCan reference design from Estonian company Artec Group.
Linutop 2
On February 20, 2008, the company unveiled the Linutop 2 based on the FIC ION A603 mini PC (like Works Everywhere Appliance). Linutop 2 had a stronger Geode processor and more memory, allowing it to run OpenOffice.org. It has 512 MB RAM and 1 GB flash memory storage.
Hardware
Specifications
Linutop XS
The Linutop XS is the smallest computer offered by Linutop. Due to its small size, and the absence of fan making it very silent, it is often hidden behind the dynamic display screens by professionals. The compact Linutop XS comes in a small aluminum case with dimensions 9 cm × 6 cm × 2 cm (3.5 in × 2.3 in × 0.8 in) for a weight of 92 grams (3 oz) and a power consumption of 3 watts. On board, there is a processor running at 900 MHz, a RAM of 1 GB and an 8 GB flash memory.
Connectors: HDMI, mini-jack audio, RJ-45 Ethernet, four USB 2.0, 5-volt micro USB power.
The Linutop XS is a professional packaging of the Raspberry Pi 2 and incorporates a 1080p HD video Hardware accelerator. With this compact configuration, designed for the fields of education, transport, trade and health for
the dissemination of information.
Linutop 6
Linutop 6 is the most powerful Linutop.
The Linutop 6 microcomputer is in the form of a small fanless metal case with dimensions 9.5 cm × 9.1 cm × 3.6 cm (3.7 in × 3.6 in × 1.4 in) for a weight of 350 grams (12 oz) and an energy consumption of 14 watts. On board, there is an Intel ATOM x5-Z8350 processor, a 2 GB RAM and a 16 GB flash memory.
Connectors: HDMI, RJ-45 Ethernet, four USB 2.0, 5-volt power supply.
With this configuration, the Linutop 6 computer targets a varied use where compactness and power are required.
Linutop OS
Linutop Kiosk
Linutop Kiosk is a software in Linutop OS that allows you to easily configure:
A secure Internet access point.
A dynamic display, multi-format (photos, HD videos, MP3, web pages, music, PDF ...)
Linutop OS 14.04 for PC
Linutop OS 14.04 is based on Xubuntu / XFCE
It contains features designed for business use cases:
Firefox 44, Libre Office 4, et VLC 2, Terminal server client, pdf viewer, GNU Paint, Mirage, Archive Manager, VNC, Gedit, Samba
Internet kiosk : Full screen, toolbar management, white/blacklist management.
Display kiosk : user can define a playlist loop of URLs, photos, video and PDF
Configuration panel allows the user to "lock" the configuration, to backup or restore on bootable USB Key.
size 850 MB for USB key, hard drive or flash memory
minimum PC requirements : PIII 800 MHz, 512 MB RAM
Linutop OS XS for Raspberry Pi
Linutop OS XS is based on Raspbian / XFCE
It contains features designed for business use cases:
Epiphany web browser, Libre Office 3, et VLC 2 (with hardware acceleration), Terminal server client, pdf viewer, GNU Paint, Mirage, Archive Manager, VNC, Gedit, Samba
Internet kiosk : Full screen, toolbar management, white/blacklist management.
Display kiosk : user can define a playlist loop of URLs, photos, video and PDF
Configuration panel allows the user to "lock" the configuration, to configure the graphics.
size 2900 MB for microSD flash memory
Raspberry Pi compatibility : Zero, Zero W, A, A+, B, B+, 2, 3
a demo version of Linutop OS is available for free
Also available in NOOBS format.
Linutop TV
Linutop tv has been designed to manage a network of connected digital signage screens and allows centralized management via an HTTP interface. Each screens needs a player (PC, Raspberry Pi, or Linutop Mini PC), running Linutop Kiosk software, connected to the server in order to update display content automatically.
Linutop tv is a server solution available in two versions:
SaaS (or "cloud") server: accessible via Internet.
Private (local) server: works on the local network. This solution is often used in corporations intranet. It offers maximum security.
References
Linutop XS introduction
External links
Linutop Wiki
Linutop Video
FIC ION A603 mini PC
Linutop 2 Mini PC review - TrustedReviews
Linutops fanless linux pc review - Slashgear
Tiny Linutop 3 computer - Technabob
Linutop 5 fanless mini linux desktop - Ubergizmo
Sources
Official website
Linutop Blog
See also
fit-PC
EeePC
Zonbu
Koolu
Raspberry Pi
Ubuntu (operating system)
Digital Signage
Interactive kiosk
Computers and the environment
Linux-based devices
Mini PC
Computer companies of France | Linutop | [
"Technology"
] | 1,299 | [
"Computers and the environment",
"Computers",
"Computing and society"
] |
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