Premise:
I-Mycophenolate mofetil [MMF, i-prodrug ye-mycophenolic acid (MPA)] ivame ukusetshenziswa ngamanani aphindwe kabili ne-cyclosporine kunakwe-tacrolimus ngoba kukholakala ukuthi ukuvela kwe-MPA kuphansi phakathi nokwelashwa kwe-cyclosporine. Lolu cwaningo luhlose ukuqhathanisa amahora angu-12, izinga eliqinile lesikhathi-isikhathi le-MPA kanye nama-metabolite ayo e-phenol- ne-acyl-glucuronide (MPAG no-AcMPAG, ngokulandelana) ezigulini ezisimeme zokuthutha izinso ezigcinwe nge-cyclosporine (n = 12) noma i-tacrolimus (n = 12). Ngesikhathi sesigaba sokumunca eqenjini le-cyclosporine, amanani anqunyiwe okulinganiselwa kwenani eliphelele kanye ne-MPA ekhululekile aphakeme kakhulu kodwa indawo ephelele ngaphansi kwesikhathi-isikhathi (AUC0-12) ayizange ihluke kakhulu. Ngaphezu kwalokho, ukuvela ku-AcMPAG kwakuphakeme eqenjini le-cyclosporine (P < 0.05). Iziguli eziyishumi kweziyishumi nambili eqenjini le-cyclosporine zazisemthethweni wokwelashwa nge-ketoconazole; kodwa-ke, ukuvela ku-MPA noma i-MPAG akuzange kwehluke uma i-MMF inikwa ngomlomo kumagundane e-Sprague-Dawley anoma angena i-ketoconazole.

Hypothesis:
Ngokuphetha, i-MPA ilawula ukuhleleka kwe-cyclosporine nemiphumela yayo ngendlela ehlukile kune-tacrolimus; kodwa-ke, iziguli ezisebenzisa i-MPA kungenzeka zingadingi izidakamizwa eziphindwe kabili ze-MMF ukuze zithole ukuvezwa okufanayo.


Premise:
I-CMV iwumkhiqizo ovamile wesifo kubamukeli bezitho eziqinile ezitshalelwe, futhi labo abathola ukutshalelwa kwamaphaphu babonakala bethinteka kaningi futhi kakhulu. Ngenxa yokuthi isikhathi sokuvikela kwe-ganciclovir kungase sibe nomthelela ekuveleni kwesifo se-CMV kubamukeli bezitho eziqinile ezitshalelwe, sihlole ukusebenza kohlelo lokuvikela lwamaviki ayisithupha kubamukeli bokutshalelwa kwamaphaphu. Sahlola nokwazi kokwenyuka okuphindwe kane kwesikali se-antibody ye-CMV ukuhlinzeka ngokuthuthuka kwesifo se-CMV. Abamukeli abangamashumi amabili nanye abalandelanayo bokutshalelwa kwamaphaphu babhalisiwe: abangu-15 babe ne-antibody ye-CMV eyimpendulo enhle ngesikhathi sokutshalelwa, futhi abayisithupha bengenayo i-antibody ye-CMV eyimpendulo enhle futhi bathole ukutshalelwa kwamaphaphu kubadali abane-CMV eqinile. Isilinganiso +/- isilinganiso esimiselwe sokulandelela kwakuyizinsuku ezingu-430 +/- 157 (kubandakanya izinsuku ezingu-178-730, ubulungiswa bezinsuku ezingu-449). Uhlelo lwe-ganciclovir lwamaviki ayisithupha aluvimbelanga ukutheleleka kwe-CMV (okwenzeka kwiziguli ezingu-17/21, 81%) namkwa isifo se-CMV (esabonakala kwiziguli ezingu-8/21, 38%). Ukwenyuka okuphindwe kane kwesikali se-antibody ye-CMV kwaqala kuphela ngaphambi kokuqala kwesifo se-CMV ezenzakalweni ezingu-3/13 (23%).

Hypothesis:
Siphetha ngokuthi uhlelo lwamaviki ayisithupha lokulashwa ngeganciclovir aluvimbeli ukutheleleka nge-CMV noma isifo kubantu abalashwe ngokutshala amaphaphu futhi nokwenyuka kwezinga lamagciwane elwa ne-CMV etholakala egazini ngokulandelana kuvame ukunganduleli ukuthuthuka kwesifo se-CMV.


Premise:
Impendulo yokuvuvuka emva kokuqalisa ukwelashwa nge-antibhayothikhi kanye namapharamitha omonakalo wama-neuronal aqhathaniswa ngesikhathi sokwelashwa ngomthambo we-quinupristin/dalfopristin (100 mg/kg njengokufakwa kwesikhashana noma okuqhubekayo) kanye ne-ceftriaxone (10 mg/kg/h) esilingweni sokulingisa i-meningitis ye-Streptococcus pneumoniae kumagundane. Ngokusebenzisa zombili izindlela zokufakwa, i-quinupristin/dalfopristin beyibulala amagciwane ngokungaphansi kune-ceftriaxone. Kodwa-ke, ukuqoqeka kwezakhi zodonga lwamaseli ezibangela ukuvuvuka (lipoteichoic acid (LTA) kanye ne-teichoic acid (TA)) kanye nomsebenzi we-tumour necrosis factor (TNF) kuketshezi lomgogodla (CSF) bekuphansi kakhulu emaqenjini amabili e-quinupristin/dalfopristin kunasezimvini ezilashelwe nge-ceftriaxone. Amazinga asembindini e-LTA/TA (amaphesenti angama-25/75) ayenjena: (i) amahora angu-14 emva kokutheleleka: 133 (72/155) ng/mL ngokufakwa okuqhubekayo kwe-quinupristin/dalfopristin kanye nama-193 (91/308) ng/mL ngokufakwa okusingesikhashana, uma kuqhathaniswa nama-455 (274/2042) ng/mL e-ceftriaxone (P = 0.002 kanye no-0.02 ngokulandelana); (ii) amahora angu-17 emva kokutheleleka: 116 (60/368) ng/mL ngokufakwa okuqhubekayo kwe-quinupristin/dalfopristin kanye nama-117 (41/247) ng/mL ngokufakwa okusingesikhashana, uma kuqhathaniswa nama-694 (156/2173) ng/mL e-ceftriaxone (P = 0.04 kanye no-0.03 ngokulandelana). Amahora angu-14 emva kokutheleleka imisebenzi yombindini we-TNF (amaphesenti angama-25/75) yayingu-0.2 (0.1/1.9) U/mL ngokufakwa okuqhubekayo kwe-quinupristin/dalfopristin kanye no-0.1 (0.01/3.5) U/mL ngokufakwa okusingesikhashana, uma kuqhathaniswa nama-30 (4.6/180) U/mL e-ceftriaxone (P = 0.02 ukuqhathanisa ngakunye); amahora angu-17 emva kokutheleleka umsebenzi we-TNF ubungu-2.8 (0.2/11) U/mL (ukufakwa okuqhubekayo kwe-quinupristin/dalfopristin) kanye no-0.1 (0.04/6.1) U/mL (ukufakwa okusingesikhashana), uma kuqhathaniswa nama-48.6 (18/169) U/mL e-ceftriaxone (P = 0.002 kanye no-0.001). Ukuqoqeka kwe-neuron-specific enolase (NSE) amahora angu-24 emva kokutheleleka bekuphansi kakhulu ezilwaneni ezilashelwe nge-quinupristin/dalfopristin: 4.6 (3.3/5.7) microg/L (ukufakwa okuqhubekayo) kanye no-3.6 (2.9/4.7) microg/L (ukufakwa okusingesikhashana) kunakulawo alashelwe nge-ceftriaxone (17.7 (8.8/78.2) microg/L) (P = 0.03 kanye no-0.009 ngokulandelana).

Hypothesis:
Ekuphetheni, ukwelashwa ngama-antibiotics nge-quinupristin/dalfopristin endaweni engaphakathi komgogodla womunefomu kwanciphisa ukuvuvukala ngemva kokuqala ukwelashwa ngama-antibiotics.


Premise:
Ukusebenza kwe-STAT3 okuzimele ngokufosforileshini ye-tyrosine kwama-tyrosine kinases ashintshiwe noma andisiwe (pYSTAT3) kubalulekile ekuqaleni komdlavuza, ukuqhubeka, ukuhlasela, kanye nokunyakaza kwamaseli e-carcinoma. Sitshengise ukuthi i-AF1q ihlobene nokusebenza kwe-STAT3 emaselin omdlavuza webele. Kuma-model e-xenograft, ukukhuliswa kwe-AF1q kuvuse i-STAT3 futhi kukhuthaze ukukhula komdlavuza kanye nokusakazeka ezimpukwini ze-NSG ezingenayo i-immunodeficient. Isimo sokukhipha i-cytokine samaseli e-MDA-MB-231LN omdlavuza webele esine-AF1q eshintshiwe sibonise ushintsho ekubonakalisweni kwe-platelet-derived growth factor subunit B (PDGF-B). I-PDGF-B ekhuthazwe yi-AF1q ikhuthaze ukunyakaza, ukuhambelana, kanye nokuhlasela kwamaseli e-MDA-MB-231LN, futhi i-AF1q yenze ukwanda kwe-platelet-derived growth factor receptor (PDGFR) ekuxhumaneni. Ngaphezu kwalokho, ekuxhumaneni kwe-PDGFR eyenziwe yi-AF1q kukhulise ukusebenza kwe-STAT3 ngokusebenzisa ukuvuswa kwe-Src kinase, okungavinjelwa ngomvimbi we-Src kinase i-PP1. Phezu kwalokho, i-AF1q yenze ukuthi kukhule ukusebenza kwe-tyrosine kinase ngokusebenzisa ukuxhumana kwe-PDGFR, okungavinjelwa nge-imatinib.

Hypothesis:
Okokugcina, sikhombisile ukuthi ukwanda kwe-AF1q kunikeza imiphumela eqhubekayo ne-oncogenic ye-pYSTAT3 kumaselula e-invasive carcinoma ngokuqalisa i-Src kinase ngokuqalisa umbhidlango we-PDGF-B/PDGFR.


Premise:
I-Estrogen receptor-α (ER-α), ehlanganiswe ne-ESR1, itholakala ngokuhlolwa kwe-immunohistochemistry cishe ku-70% yamacansi omkhoma avundla ubisi futhi isebenza njengesibonakalisi esiqinile. Ukuguquka kwe-ESR1 okuvuselayo endaweni ye-ligand-binding kubikwe kufinyelela ku-35-40% yamakhensa e-ER-positive metastatic futhi ahambisana nokumelana nokwelashwa kwe-endocrine kanye nokwanda kwesifo. Okwamanje, akucacile ukuthi ukuguquka kwe-ESR1 kuguqula yini ukubonakala kwe-ER okwenziwa nge-immunohistochemical ekusetshenzisweni kwansuku zonke. Kulolu cwaningo, ukuguquka kwe-ESR1 emkhomeni wobisi kutholakale ngokusebenzisa i-Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), i-hybridization capture-based next-generation sequencing assay evunywe yi-Food and Drug Administration. Amakhensa angama-586 obisi avela ezigulini ezinesimo esithuthukile noma esihambayo sihlaziyiwe ngokusebenzisa i-MSK-IMPACT ngesikhathi socwaningo. Ukuguquka kwe-ESR1 somatic kutholakale kumasampula angama-67 amakhensa obisi avela kuziguli ezingu-66. Ukuhlaziywa kwe-immunohistochemical kwe-ER, i-progesterone receptor, kanye ne-human epidermal growth factor receptor 2 kwenziwa emkhomeni wokuqala kanye nemkhoma ethintekile yalezi ziguli ngesikhathi sokuhlolelwa. Ukuguquka okungama-20 okwahlukene kwe-ESR1 kutholakale ekuthinteni indawo ye-ligand-binding, konke kumasampula amakhensa obisi avela kuziguli ezike zelashwa nokwelashwa kwe-endocrine. Ukuguquka okuhlangene kakhulu kube yi-D538G (n = 22), i-Y537S (n = 7), kanye ne-E380Q (n = 7). Wonke amasampula amakhensa obisi anokuguquka kwe-ESR1 abe ne-ER-positive ngokuhlolwa kwe-immunohistochemistry. Ukubuyekezwa kwe-ER immunohistochemistry kumkhoma wokuqala ongalashelwe kanye nomkhoma oselashiwe ovela ezigulini ezingu-34 akutholanga ukuguquka okubonakala esimeni se-ER-positive immunohistochemical (iphesenti lesilinganiso samaseli ahlasela umkhoma anokukhuthazwa kwe-nuclear: umkhoma wokuqala ongalashelwa 90%, umkhoma oselashiwe 95%).

Hypothesis:
Siphetha ngokuthi ukuguquka kwe-ESR1 akubuthakathisi ngendlela ebonakalayo ukubonakala kwe-ER okuphawulekile ngokusebenzisa i-immunohistochemistry.


Premise:
Umdlavuza wesofegi (EC) uyisifo esihlasela kakhulu, esinezinhlobo ezimbili ezinkulu zama-histology: i-adenocarcinoma (EAC) ne-squamous cell carcinoma (ESCC). Lezi zinhlobo ezimbili ze-EC zihluka kakhulu mayelana nako konke okuphathelene nazo. Ukuphuhla kwe-ESCC kuhlobene kakhulu nokubhema kanye nokuphuza utshwala, kanti ukuba nesisindo esikhulu kanye nesifo se-gastroesophageal reflux (GERD) kuyizinto ezinkulu ezilethela ubungozi hhayi nje kuphela kwe-EAC, kodwa naku-Barrett's esophagus (BE), okuyinto yokuguqulwa kwamangqamuzana asohlotsheni lwamathumbu olwandulela i-EAC. Ukuba nesisindo esikhulu kubangela ukuqoqana kwamathonsi amafutha (LD) ezindaweni ezingafanele emzimbeni, okungezizo izindawo zamafutha. I-LD iyizingxenyekazi zamangqamuzana ezibandakanyeka ekunikezeleni ukudla emangqamuzaneni, ekuxhumaneni kwamagqamuzana, ekwandiseni amanqqamuzana kanye nasekukhiqizeni izakhi ezilethela ukuvuvukala. Ngakho-ke, inhloso yalolu cwaningo kwakuwukuphenya ukubakhona kanye neqhaza le-LD kumdlavuza wesofegi. Lolu cwaningo lukhombisa ukwenyuka kwenzinga le-LD ekuthuthukeni kwe-EAC, emasampulini esofegi kusukela kubantu abangenazo izinkinga zesisindo kuya kwabanezisindo ezikhulu, kanye nakubantu abanesifo se-BE, kanye neziguli ze-EAC, kanti akukho zinguquko ezibonakalayo ezibonakalayo emasampulini e-ESCC, uma kuqhathaniswa namasampula angenamdlavuza. Ukwengeza, ukuze kulinganiswe ukuhlangabezana nezinto eziyingozi ze-BE ne-EAC, isigaba samangqamuzana esofegi angenayo umdlavuza safakwa ku-oleic acid (OA) kanye nesikhutha esiwumphumela wamasidi kanye/noma i-deoxycholic acid (DCA), okwaveza ukwenyuka okubalulekile ngobuningi be-LD kanye nokubonakalisa kwe-COX-2 ne-CXCL-8, kanye nokukhiqizwa kwe-IL-8. Ngaphezu kwalokho, ukubonakalisa kwe-COX-2 kanye nenani le-LD kwakhombisa uxhumano oluhle olubalulekile futhi kwabonakala ndawonye e-EAC, kodwa hhayi e-ESCC, okwenza sicabange ukuthi i-LD ingaba yindawo yokukhiqizwa kwe-eicosanoid e-EAC.

Hypothesis:
Okokugcina, lolu cwaningo lukhombisa ukuthi ukukhuluphala, kanye nokuvuvuka okuhambisana ne-BE kanye ne-EAC kuholela ekuncipha kancane kwe-LD, okungaba nomsebenzi wokuhlela ukukhiqizwa kanye/noma ukusebenza kwezakhi zokuvuvuka, ngaleyo ndlela kube nomthelela ekuqaleni nasekuqhubekeni kwe-BE kanye ne-EAC.


Premise:
Ukuqhubeka komdlavuza wesitho sangasese kuya esikhathini lapho ushintshela ekulimeleni ezindaweni ezahlukahlukene zomzimba kanye nasekubeni amandla okuphila asheshe ahambe kuyisinyathelo esisemqoka kakhulu. Sike sakuveza phambilini ukuthi ukushukuma kweprotheyini kinase C (PKC) okulandelwa i-Twist1 kanye nesivuseleli sehomoni yesilisa (AR) kubamba iqhaza elibalulekile ekumeleni ukudluliswa kwamahomoni yesilisa, kodwa umshini wezingxenye ophathekayo usasele ungakaziwa ngokugcwele. Lolu cwaningo luhlose ukucacisa umshini wezingxenye ofanelekile, lugxile kunzikandaweni yokubhala ye-NF-κB. Sihlolisise umsebenzi we-NF-κB ngemva kokulwa ne-PKC, kanye nokubonakalisa kwe-Twist1 ne-AR ngemva kokulwa ne-NF-κB emasosheni omdlavuza wesitho sangasese somuntu. Siphinde sahlola isimo se-PKC/NF-κB ngemva kokulwa nomyalezo we-AR emasosheni amelana nokwelashwa ngamahomoni. Ngenxa yalokho, ukulwa nemiyalezo ye-PKC kusetshenziswa ukucindezela nokuvinjelwa kwezingxenye ezincane ze-PKC, kunciphise umsebenzi we-RelA, kanti ukuvimba i-NF-κB kucindezele ukusetshenziswa kwe-Twist1 ne-AR. Ngokuphambene nalokho, ukuvimba umyalezo we-AR ngokukhipha ihomoni yesilisa kanye nesibulali samahomoni esisha enzalutamide kubangele ukushukuma kwe-PKC nokuqinisa kwamandla kwe-RelA, okuholele ekukhuleni kwe-Twist1/AR ezingeni lomhlahlandlela. Ngaphezu kwalokho, ukuvimbela umyalezo we-NF-κB kuvimbele ukuphakama okubangwa enzalutamide kwe-Twist1 ne-AR. Okokugcina, i-NF-κB iqiniswe emasosheni amelana namahomoni kanye namelana nenzalutamide.

Hypothesis:
Okokuphetha, i-NF-κB signaling yayibhekene nokwanda kwe-Twist1 nge-PKC ngenxa yokuthuthukiswa kwe-AR, okuholela ekusebenzeni okungafanele kwe-AR.


Premise:
Amaseli omdlavuza athanda i-glycolysis ukuze athole amandla, ngisho noma kukhona umoya owanele ukwenza lokhu kungadingeki. Lokhu kubizwa ngephuzu le-Warburg, futhi kukhuthaza ukuvela komdlavuza kanye nokwanda kwawo emzimbeni. Kulolu cwaningo, sikhombise ukuthi i-EZH2, i-protein eyandisa umdlavuza enezindima eziningi ekwandeni komdlavuza, ukuhlasela kanye nokusabalala, ikhuthaza ukuvela komdlavuza weglioblastoma kanye nokwanda kwawo ngokusebenzisa iphuzu le-Warburg. Siqaphele ukuthi i-HIF1α iyinto ehlosiwe yi-EZH2 nokuthi ukusebenza kwayo kudingeka ukuze i-EZH2 ikwazi ukushintsha indlela umzimba osebenzisa ngayo izakhi, nokuthi i-HIF1α iyasebenza uma i-EZH2 ikhiqizwa ngokweqile. I-EZH2 inciphisa ukukhiqizwa kwe-EAF2, okubese kwandisa amazinga e-HIF1α.

Hypothesis:
Siphetha kulemi miphumela ukuthi i-EZH2 ivimba ukubumbeka kwamatumo kanye nokudlondlobala kwesifo ngokwengxenye ngokuqalisa i-glycolysis ngokusebenzisa umgudu we-EAF2-HIF1α.


Premise:
I-Intramitochondrial Sr2+, efana ne-Ca2+, ivimba i-oxidative phosphorylation ku-intact rat-liver mitochondria. Kokubili i-Ca2+ ne-Sr2+ zivimba umsebenzi we-hydrolytic we-ATPase kumahlulana e-submitochondrial. Ukuvimba okuhhafu-maksimum komsebenzi we-ATPase kwafinyelelwa elinganisweni le-2.5 mM Ca2+ noma 5.0 mM Sr2+ uma ilinganiselwa le-Mg2+ kulendawo kwakuyi-1.0 mM. Ukuvinjelwa komsebenzi we-ATPase yi-cations zombili kwakuncishiswe kakhulu ukwanda kwe-Mg2+ concentration endaweni yokusebenza. Ngaphezu kwalokho, idatha ye-kinetical kanye nokuboniswa kwe-concentration ye-MgATP, i-substrate ye-ATPase, ebukhoneni bamalinganiselwa ahlukene e-Ca2+ noma e-Sr2+ akhombisa kakhulu ukuthi lama-cations avimba i-ATP hydrolysis ngokuncintisana ne-Mg2+ ekwakhiweni kwe-MgATP.

Hypothesis:
Ngokusekelwe esivumelwaneni esihle phakathi kwalezi ziphumo kanye nama-submitochondrial particles kanye nemiphumela yokuhlanganiswa kwe-oxidative phosphorylation ne-carboxyatractyloside noma i-oligomycin kuma-mitochondria agcwaliswe nge-Sr2+ kungaphetha ngokuthi i-intramitochondrial Ca2+ noma i-Sr2+ ivimba i-oxidative phosphorylation kuma-mitochondria aphelele ngokunciphisa ukutholakala kwama-adenine nucleotides kokubili ku-ADP/ATP carrier kanye ne-ATP synthase.


Premise:
I-calcium ye-mitochondria ingumshukumisi obalulekile we-metabolism yamaseli. I-CCDC90A yabikwa njengomhleli we-mitochondrial calcium uniporter (MCU) complex, isitshetsho esikhethayo esilawula ukuthatha i-calcium kwe-mitochondria, ngakho-ke yaqanjwa kabusha i-MCUR1. Lapha sibonisa ukuthi ukucindezelwa kwe-CCDC90A kumafibroblast abantu kukhiqiza inkinga eqondile yokuhlanganiswa kwe-cytochrome c oxidase (COX), okuholela ekuncipisweni kwe-mitochondrial membrane potential kanye nokukhinyabezeka komkhawulo wokuthatha i-calcium ye-mitochondria. Amafibroblast eziguli ezinezinkinga zokuhlanganiswa kwe-COX ngenxa yemithente kuma-TACO1 noma i-COX10 nawo akhombisa ukunciphisa kwe-mitochondrial membrane potential kanye nokukhinyabezeka komkhawulo wokuthatha i-calcium, kokubili okwasindiswa ngokufakwa kwe-cDNA ezejwayelekile ezihambisanayo. Ukususwa kwe-fmp32, i-homolog ye-CCDC90A ku-Saccharomyces cerevisiae, isidalwa esingenayo i-MCU, nako kukhiqiza ukungasebenzi kahle kwe-COX, okubonisa ukuthi umsebenzi we-CCDC90A ulondolozekile ekuthuthukeni kwempilo.

Hypothesis:
Siphethela ngokuthi i-CCDC90A idlala indima ekuhlanganiseni i-COX futhi ayilawuli ngqo i-MCU.


Premise:
Ama-mitochondria akhiqiza inani elikhulu le-ATP emasosheni amaningi, kufaka phakathi amaseli obuchopho. Ukulawula le mishini eyinkimbinkimbi ukuze ivumelane nezidingo zamandla eseli kuyinqubo eyinkimbinkimbi esingakakaqondi ngokuphelele. Kulesi simo, i-3',5'-cyclic AMP (cAMP) iphakanyiswe ukuthi idlala indima ebalulekile ekuxhumaneni kwezinhlelo zokukhipha imiyalezo nokudla kanye nokulawulwa kokukhiqizwa kwe-ATP yi-mitochondria. Emasosheni, izimpawu ze-cAMP zingathinta ama-mitochondria ohlangothini lwe-cytosolic kodwa kamuva nje, uphawu lwe-cAMP olukhiqizwe ngaphakathi kwe-matrix yama-mitochondria yi-soluble adenylyl cyclase (sAC) kuphakanyiswe ukuthi ilawula ukuphefumula kanjalo nokukhiqizwa kwe-ATP. Nokho, kulwazi oluncane mayelana nalezi zinqubo ema-mitochondria obuchopho, futhi izinto ezisebenza kophawu lwe-cAMP olukhiqizwe ngaphakathi kwe-matrix azicacile ngokuphelele njengoba kokubili i-protein kinase A (PKA) kanye ne-exchange protein activated by cAMP 1 (EPAC1) kuphakanyiswe ukuthi kubandakanyekile. Lapha, sibuyekeza ulwazi lwamanje futhi sihlobisana ne-mitochondria yobuchopho. Ngaphezu kwalokho, ngokuya ngezikalo zokuphefumula, i-membrane potential, nokukhiqizwa kwe-ATP kuma-mitochondria ahlukanisiwe ekhaleni lobuchopho begundane, sitshengisa ukuthi izivimbeli ze-sAC, i-PKA, noma i-EPAC zithinta ukusebenza kwe-mitochondria ngezindlela ezahlukene.

Hypothesis:
Ekugcineni, siphakamisa ukuthi ama-mitochondria obuchopho alawula ukusebenza kwawo ngezinkomba ze-cAMP ezidluliselwa nge-sAC nokuthi kokubili i-PKA ne-EPAC kungahle kubandakanyeke emva kwe-cAMP.


Premise:
I-ADP ayisiyo kuphela okuyingxenye ebalulekile ekukhiqizeni i-ATP, kodwa futhi ingumvimbi onamandla wesikhala sokudlula kwamangqamuzana e-mitochondrial (mPTP). Kulolu cwaningo, sihlola ukuthi ingcindezi ye-oxidative ithinta kanjani amandla e-ADP njengomvimbi we-mPTP futhi nokuthi ukuncishiswa kwayo kokubakhona kwama-reactive oxygen species (ROS) kungaba nendima. Sinqume ngokulinganisa imiphumela ye-ADP ekukwazini kuka-mitochondrial ukukhulisa i-calcium (CRC) kuze kufike ekungenisweni kwe-mPTP kumamitochondria ahlukene enhliziyweni. Sisebenzise izinhlelo ezimbili zeminyaka yobudala yengcindezi ye-oxidative (amagundane amadala nanasifo sikashukela) nezinhlelo ezimbili ezintsha zengcindezi ye-oxidative (i-ischemia reperfusion (IR) ne-tert-butyl hydroperoxide (t-BH)). Kumamitochondria okulawula, i-CRC yayingu 344 ± 32 nmol/mg yeprotheni. I-ADP engu-500 μmol/L yenyusa i-CRC yafika ku-774 ± 65 nmol/mg yeprotheni. Lo miphumela ye-ADP ibonakala ihlangene nesilinganiso sayo ngoba engu-50 μmol/L ibe nomthelela omncane kakhulu. Futhi, i-oligomycin, evimba ukuguqulwa kwe-ADP ibe yi-ATP nge-F0F1ATPase, yenyusa kakhulu umthelela we-ADP engu-50 μmol/L. Ingcindezi ye-oxidative eyiminyaka eminingi ayizange ibe nomthelela ku-CRC noma emiphumeleni ye-ADP engu-500 μmol/L. Ngemva kokuvela kwe-IR noma i-t-BH, i-CRC yehliswa kakhulu yafika ku-1 ± 0.2 no-32 ± 4 nmol/mg weprotheni, ngokulandelana. Ngokumangalisa, i-ADP yenyusa i-CRC yafika ku-447 ± 105 kanye no-514 ± 103 nmol/mg yeprotheni kwi-IR nakwi-t-BH, ngokulandelana. Ngakho-ke, yanyusa i-CRC ngesilinganiso esifanayo njengasekuphathweni. Kumamitochondria okulawula, i-ADP yehlisa kokubili i-substrate kanye nokunyuka kwe-calcium okubangelwe yi-ROS. Kodwa-ke, kumamitochondria e-t-BH, umthelela we-ADP kwi-ROS wawuncane kakhulu.

Hypothesis:
Siphetha ngokuthi i-ADP ibuyisela ngamandla amakhono e-CRC emithonjeni ecindezeleke kakhulu.


Premise:
Abacwaningi bangaphambili baye babonisa ukuthi 3,4-methylenedioxymethamphetamine (MDMA) edalayo i-hyperthermia, emisipha yamathambo yezilwane, iya ncike kwi-uncoupling protein 3 (UCP3). Ngokulinda uphenyo lwethu ukuthi in vivo phosphorylation ye-UCP1 yandiswa ngaphansi kwezimo zokujwayela amakhaza, saqala ukuphenya ukuthi (a) ingabe i-UCP3 yayiphosphorylated in vivo kanye (b) ukuthi ingabe in vivo phosphorylation ye-UCP3 kwakuphumela ekuvuzeni okukhulu kwe-proton ngemuva kokunika i-MDMA ezilwaneni. Idatha yethu ibonisa ukuthi ukwelashwa nge-MDMA (kodwa hhayi ukwelashwa nge-PBS) kwezilwane kuphumela kokubili in vivo serine kanye ne-tyrosine phosphorylation ye-UCP3 emitochondria yemisipha yamathambo, ehlukaniswe phambi kwe-phosphatase inhibitors ukugcina in vivo phosphorylation. Ngaphezu kwalokho, ukuvuza kwe-proton kuphela kwenyuka emitochondria yemisipha yamathambo ehlukanisiwe kusuka ezilwaneni ezelashwe nge-MDMA (ebakhona ye-phosphatase inhibitors) kanye nokuvuza kwe-proton okukhulile kungenxa ye-UCP3 ephosphorylated. Ubuningi be-UCP3 emitochondria yemisipha yamathambo abuphazamiseki ngokuphathwa kwe-MDMA. Ukugcinwa kwe-UCP3 phosphorylation nokwanda kokuvuza kwe-proton kuyalahleka lapho imitochondria yemisipha yamathambo ihlukaniswa ngaphandle kwe-phosphatase inhibitors.

Hypothesis:
Siphetha ngokuthi ukwelashwa kwe-UCP3 kwezilwane kwandisa ukukhipha kwama-proton emithambo yamathambo emikhakhayi yesikhumba ngokuvusa i-MDMA ngokushintsha okuzibophayo kwe-MDMA ngaphakathi emzimbeni ngokufaka ifosfeti (phosphorylation).


Premise:
I-CsrA (umlawuli wokulondoloza i-carbon A) iwumhleli wogqoko lwe-RNA obaktheria osakazeke kabanzi olawula ukuqala kokutolika nezinga le-mRNA emibhalweni ethize. Kumabaktheria angu-γ-proteobacteria, umsebenzi we-CsrA uphikiswa ngokuncintisana yi-RNA encane eyodwa noma ngaphezulu (ama-sRNA) equkethe izindawo eziningi zokubophela i-CsrA, kodwa i-CsrA emabakteriya angaphandle kwe-γ-proteobacteria iphikiswa uphroteni obizwa nge-FliW. Lapha sibonisa ukuthi i-FliW yase-Bacillus subtilis ayibopheli ezinsaleni ezifanayo ze-CsrA ezidingekayo ekubopheni i-RNA. Esikhundleni salokho, izinguquko ze-CsrA ezingazweli ukuphikiswa kwe-FliW (crw) zishintsha izinsalela ze-CsrA ebusweni be-allosteric obungamele umsebenzi ongazange wachazwa ngaphambilini. Ezinye izinguquko ze-crw zisusa ukubophana kwe-CsrA-FliW, kodwa ezinye azikususi, okusho ukuthi ukuhlangana kwe-FliW ne-RNA akufanele kucatshangwe ngokumelana.

Hypothesis:
Siphetha ngokuthi i-FliW ivimba ihomoni ye-parathyroid ngendlela engenamncintisano, eyehlukile kakhulu kuleyo eyaziwayo yezivimbi ze-sRNA.


Premise:
Umphathi jikelele wokuhumusheka kwe-Spx we-Bacillus subtilis ulawulwa emazingeni amaningi enqubo yokuveza ijini. Ugcinwa emazingeni aphansi ngesikhathi sokukhula okungahlukunyezwanga yi-ATP-dependent protease ClpXP. Ngaphansi kokwengama kwe-disulfide, amazinga e-Spx ayenyuka ngenxa yokwehla kwe-ClpXP-catalyzed proteolysis. Izifundo zakamuva zika-Larsson nabasebenzi bakhe (Mol. Microbiol. 66:669-684, 2007) zabonisa ukuthi umkhiqizo wejini i-yjbH udingeka ekulawuleni i-proteolytic ye-Spx. Esifundweni samanje, ukuhlaziywa kwe-yeast two-hybrid kanye nokuxhumanisa kwe-protein-protein kubonise ukuthi i-Spx ixhumana ne-YjbH. In vitro i-YjbH yaboniswa ukuthi ithuthukisa i-proteolysis ye-Spx ezingxubeni zemisebenzisi equkethe i-ClpXP protease kodwa hhayi i-ClpCP protease. Isimo se-YjbH esinqunyulwe eningini eliphambili esinokususa kwehlukanisa 1 ukuya 24 (YjbH(Delta1-24)) asibonisanga umsebenzi wokuthuthukisa i-proteolysis. I-YjbH ikhethekile kwe-Spx njengoba ingalisheshisanga i-proteolysis ye-substrate ye-ClpXP i-green fluorescent protein (GFP)-SsrA, isimumethe se-GFP esinophawu lwe-C-terminal SsrA olubonakala yi-ClpXP. Kusetshenziswa i-inductively coupled plasma atomic emission spectroscopy kanye ne-4-(2-pyridylazo) resorcinol release experiments, i-YjbH yatholakala iqukethe ama-atom e-zinc. Ukuhlaziywa kwe-zinc ye-YjbH(Delta1-24) kwaveza ukuthi isifunda esi-N-terminal esicebile nge-histidine asibalulekile ekuhlanganisweni kwe-atom elilodwa lokungenani le-Zn. I-atom le-Zn elihlanganiselwe esifundeni se-N-terminal lakhululwa ngokushesha ephrothinini ngokusebenzisa i-oxidant enamandla.

Hypothesis:
Siphetha ngokuthi i-YjbH iyisibambiso samadimande esithuthukisa ukubulawa kwe-proteini i-Spx okwenzeka nge-ClpXP.


Premise:
Ukukhiqizwa kwe-exoprotease ku-Bacillus subtilis kulawulwa ngokuqinisekile yisistimu elawula izingxenye ezimbili, i-DegS-DegU, futhi, ngaphezu kwalokho, ngezinye izinto ezincane. Umkhiqizo wegene elingu-degR ungena eqenjini lesibili futhi unikeza umthelela omuhle ngendlela eyencike ku-DegS-DegU. Sithole ukuthi ukubhalwa kwe-degR kwavinjelwa ukuphazamiseka kokuthi i-mecA noma i-mecB kodwa kwakhululwa ngokuphazamiseka okuqhubekayo kwe-comK. Ukuphazamiseka kwe-comK yodwa, nokho, akuzange kushintsha ukubhalwa kwe-degR. Siphinde sathola ukuthi ukuguqulwa kwe-mecA kudinga indawo ezungeze isikhundla esingu-52 esiphathelene nendawo yokuqala yokubhalwa kwe-degR ukuze kube nomthelela wayo. Sesikhombisile ngaphambilini ukuthi ukubhalwa kwe-degR kuholwa yisici esihlukahlukene se-sigma, i-sigmaD. Lapho ukuzibonakalisa kwe-degR kuholwa yisiqalisi se-sigmaA esakhiwe ngobuchwepheshe, ukuphazamiseka kwe-mecA/B akuzange kuholele kunoma yikuphi ukwehla okubalulekile ekuzibonakalisa kwe-degR, okukhombisa ukuthi umthelela ongemuhle wokuguqulwa kwe-mec usebenza ngokubhalwa okuholwa yi-sigmaD. Sekukhombisiwe ukuthi i-MecA ne-MecB zilawula ngokuphikisana ne-ComK, futhi ukuguqulwa kwe-mecA/B okungekho kuholela ekuzibonakalisa kwe-comK okuphezulu.

Hypothesis:
Kulemi miphumela siphetha ngokuthi i-ComK ilawula ngendlela engemihle ukuvokalwa kwe-degR ngokuvimbela umshini we-sigmaD osiqhuba ukubhalwa kwe-degR, kungenzeka ngobudlelwano nendawo elawulayo.


Premise:
Ukuvezwa kwesikhanyiso okuncike ekuphakathi kwebaningi kwe-Vibrio fischeri kulawulwa yi-autoinducer N-3-oxohexanoyl-L-homoserine lactone (autoinducer 1 [AI-1]), okuthi ngokusebenzisa i-LuxR kuqale ukubhalwa kwe-lux operon (luxICDABEG, ekhoda i-autoinducer synthase esuselwayo [LuxI] kanye nama-enzyme esikhanyiso). Kamuva sathola indawo entsha ye-V. fischeri, i-ainS, edingeka ekwakhiweni kwe-autoinducer yesibili, i-N-octanoyl-L-homoserine lactone (AI-2), engakwazi ngokusebenzisa i-LuxR ukuqalisa ukubhalwa kwe-lux operon uma kungekho i-AI-1. Ukuze kuchaziwe iqhaza lokulawula le-AI-2, kwakhiwa umutanti we-luxI ainS owawunakekelwa kabili; ngokuphambene nesizinda sabazali kanye nomutanti we-luxI, umutanti we-luxI ainS awuzange uveze ukushuba kwesikhanyiso futhi awuzange ukhiqize i-autoinducer yesikhanyiso etholakalayo, okukhombisa ukuthi i-V. fischeri ayenzi ama-autoinducer esikhanyiso ngaphandle kwalawa okwakhiwa kwawo okuqondiswa yi-luxI ne-ainS. Umutanti owonakele kuphela ku-ainS ukhombise ukushuba kwesikhanyiso okusheshayo uma kuqhathaniswa nesizinda sabazali, okukhombisa ukuthi i-AI-2 isebenza ku-V. fischeri ukuhlehlisa ukushuba kwesikhanyiso. Ngokuvumelana nalokho okubonisiwe, ukwengezwa kwangaphandle kwe-AI-2 kunqande ukusheshisa ngendlela encike esikhalini ku-V. fischeri kanye ne-Escherichia coli ethwele amagene e-lux. I-AI-2 ayizange ilamule i-luxR negative autoregulation, yodwa noma ikhona i-AI-1, futhi yanqanda ukushuba kwesikhanyiso ku-E. coli ngaphandle kokuthi ngabe i-luxR ilawulwa yi-promoter yayo yendabuko noma eyomuntu wangaphandle. Ukunyuka kwezinga le-AI-1 kunqobe umthelela onqandayo we-AI-2, futhi ukukhuthazwa okulinganayo kwesikhanyiso kudinge i-AI-2 engaphezulu ngokuphindwe ka-25 kuya ku-45 uma kuqhathaniswa ne-AI-1.

Hypothesis:
Siphetha ngokuthi i-AI-1 ivimba ukubhalwa kwe-lux operon.


Premise:
I-Mycobacterium smegmatis, imbewu yokhula ngokushesha engenalo isifo se-mycobacterium, isetshenziswa njengomfuziselo ukufunda ngofuzo lwe-mycobacterial. I-Acetamidase ye-M. smegmatis iyona enzyme ekhiqizeka kakhulu ye-Mycobacteria, esebenzisa izinhlobo eziningana ze-amide njengomthombo obalulekile wekhabhoni kanye ne-nitrogen. I-operon ye-acetamidase inendlela elawulwa ngokuphindaphindiwe, okuquka amaprotheni amathathu okulawula, abakhiqizi abane, namaelementi amathathu e-operator. Esifundweni sethu esidlule, sikhombise ukuthi ukuphinda-phindeka kwe-AmiA kuhola ekulawulweni okungemuhle kwe-acetamidase ngokuvimba umkhiqizi i-P2. Kulolu cwaningo, sithole i-protein entsha elawula ngendlela enhle, i-AmiC exhumana ne-AmiA ngokuhlangana kwe-protein ne-protein. Ukuhlaziywa kwe-Gel mobility shift kukhombise ukuthi i-protein ye-AmiC ivimba i-AmiA ekubophezeleni kwayo kumkhiqizi i-P2. Ukuxhumana kwe-AmiC namaelementi e-cis-acting kukhombise amandla ayo okubophezela ezindaweni eziningi zokulawula ze-operon njenge-P3, i-OP3, nomkhiqizi/operator ye-P1. Ngokunjalo, ukwengeza isikhuthazi i-acetamide ku-AmiC kuphazamisa izinhlangano, okwenza i-AmiC ibonakale njenge-protein yokuzwa kwamaamides. Ukufana komfanekiso nemifanekiso yokuxhumana emakhemikhalini kusikisela ukuthi i-AmiC iyilungu lama-Periplasmic binding proteins, abophezela ngokukhethekile kubazikhuthazi kodwa hhayi kuma-suppressor. Ukwanda kwe-AmiC kuthola ukwehla kokulawulwa kwe-negative regulator, i-amiA, kanye nokwenyuka okuqhubekayo kwe-acetamidase.

Hypothesis:
Ngokususela kulezi zimo ezitholakele, siphetha ngokuthi i-AmiC ilawula ngendlela eyiyo i-operon ye-acetamidase.


Premise:
Kuphakanyiswe ukuthi isivimbeli samatissue se-metalloproteinases-1 (TIMP-1) sibandakanyeka ekuxazululeni kwembobo yesibindi ngokuzenzakalelayo. Inhloso yalolu cwaningo kwakuwukuphenya ukuthi ngabe i-TIMP-1 iyashintsha yini ukuxazululwa kwembobo yesibindi ngokuzenzakalelayo ngokuhambisana nokuvimbelwa kwe-matrix metalloproteinases (MMP) kanye nokuvuselelwa kwamaseli ama-hepatic stellate (HSC). Izibindi zezilwane ezinjengamagundane ezinguqulo ze-TIMP-1 ezihlosiwe esibindini (TIMP-Tg) kanye namahayibridi okulawula (Cont) zaqoqwa ezinsukwini ezingu-0, 3, 7, kanye nama-28 ngemuva kokusinda okuzenzakalelayo emanyaleni yesibindi edalwe yi-CCl(4). Izinga lokuxazululwa kwembobo, ukuvela kwe-MMP, amaseli aphozithivu e-alpha-smooth-muscle actin (alpha-SMA), kanye ne-procollagen-(I) messenger RNA (mRNA) esibindini zahlolwa ngezinkathi ezifanele kuwo womabili amaqembu. Saphinda sahlola umthelela we-TIMP-1 ekufeni kwamaseli e-HSC. Amagundane e-TIMP-Tg akhombisa ukwehla okubalulekile ekuxazululweni kwembobo yesibindi ezenzakalelayo uma kuqhathaniswa namagundane e-Cont. Iqophelo le-hydroxyproline, inani lamaseli aphozithivu e-alpha-SMA, kanye ne-procollagen-(I) mRNA kwehla ngokushesha ngesikhathi kumagundane e-Cont, kanti lezi zimpawu zashintsha kancane kumagundane e-TIMP-Tg. Izinga lefomu elivelele le-metalloproteinases-2 (MMP-2) kumagundane e-TIMP-Tg lalincane kunalelo emagundaneni e-Cont. I-TIMP-1 yehlisa kakhulu amaseli angezona izicubu zesibindi afayo emodeli yokuxazululwa kwembobo yesibindi, futhi ivimbela ukufa kwamaseli e-HSC okuhambisana nokucindezela umsebenzi we-caspase-3 ngaphakathi kwetissue.

Hypothesis:
Okokugcina, i-fibrosis yanciphisa kakhulu ukuguquka kwesiqu se-TIMP-1 esibizini ngokuhlanganisa ukuncishiswa kwemisebenzi ye-MMP kanye nokucindezela i-apoptosis ku-HSC.


Premise:
I-liver fibrosis, okuyinqubo ye-pathophysiologic yesibindi ngenxa yokulimala okuphilayo okuqhubekayo njengempendulo yokulimala kwesibindi okuyisifo esikhona isikhathi eside, ekugcineni izothuthukela ibe yi-cirrhosis. I-Puerarin, i-isoflavone glucoside ebioactive etholakala emthini wesintu waseShayina obizwa nge-pueraria, ibikwe ukuthi inezici eziningi ezilwa nokuvuvukala kanye nezilwa ne-fibrosis. Kodwa-ke, izindlela ezijulile azikacwaningwa kahle. Lolu cwaningo luhlose ukuphenya imiphumela ye-puerarin ekusebenzeni kwesibindi kanye nenqubo ye-fibrosis kumagundane abangelwe i-CCl4. Amagundane e-C57BL/6J ajovwe ngaphakathi kwesikhwama sesisu nge-10% ye-CCl4 kwi-olive oil (2mL/kg) ngaphandle noma ne-puerarin ehlangene nayo (100 no-200mg/kg ngaphakathi kwesikhwama sesisu kanye ngosuku) amaviki amane alandelanayo. Njengoba kukhombisiwe i-ameliorative serum hepatic enzymes kanye nokuncishiswa kwezinto ezingajwayelekile kwe-histopathologic, idatha eqoqiwe ikhombise ukuthi i-puerarin ingavikela ekuhlukumezekeni kwesibindi okuyisifo esibangelwe yi-CCl4. Ngaphezu kwalokho, ukuthuthuka kwe-fibrosis okubangelwe yi-CCl4, njengoba kufakazelwa ukukhula kokuvezwa kwe-alpha smooth muscle actin (α-SMA), i-collagen-1, i-transforming growth factor (TGF)-尾 kanye ne-connective tissue growth factor (CTGF) esibindini, kuncishiswe yi-puerarin. Izindlela ezingahlobana nalezi zithonya zokucindezela zaqondakala ngokuvimbela indlela yokudlulisa umyalezo ye-NF-κB, ukukhiqizwa kwe-reactive oxygen species (ROS) kanye nokuphazamiseka komsebenzi wama-mitochondria ku-vivo. Ngaphezu kwalokho, lokhu kuvikelwa okubaliwe ngenhla kwaholwa yikwehla kokulawulwa kwe-PARP-1 ngenxa ye-puerarin ngoba i-puerarin ingaphucula ukuvezwa kwe-PARP-1 esibindini esicekelwe phansi yi-CCl4 kanye ne-PJ34, uhlobo oluthile lwe-PARP-1 inhibitor, ilingise ukuvikeleka kwe-puerarin.

Hypothesis:
Njengesiphetho, i-puerarin ibambe indima yokuvikela ekuvuvukaleni kwesibindi okubangelwa yi-CCl4 kungenzeka ngokuvimba i-PARP-1 kanye nokulandelayo ukunciphisa i-NF-κB, ukukhiqizwa kwe-ROS kanye nokungasebenzi kahle kwama-mitochondria.


Premise:
I-Polyenylphosphatidylcholine (PPC), okuyi-phospholipid extract eningi kumasoya, ivimbela ukuthuthuka kwesirhosha sesibindi kumamodeli ezilwane. Indlela yokusebenza kwayo ayaziwa. Ngokususela ohlotyeni lokuthi i-PPC ingasebenza ngokunciphisa ukwanda kwamaseli e-hepatic stellate, safunda umthelela we-PPC nezingxenye zayo ezinkulu, i-dilinoleoylphosphatidylcholine (DLPC) ne-palmitoyl-linoleoylphosphatidylcholine (PLPC), ekwandeni kwamaseli e-stellate okukhuthazwa yi-PDGF nasekudlulisweni kwesignali engaphakathi kweseli. Amaseli e-hepatic stellate ajwayelekile emagundaneni ekulimeni kwamaselula, alandelwa ukungasondleki, futhi agcinwa ne-10ng/ml ye-PDGF ngaphandle noma ngokukhona kwama-phospholipid. Ukwanda kwamaseli kwakalwa nge-3H-thymidine incorporation. Ukusebenza kwe-P44MAPK kwakalwa nge-kinase assay, kanti i-AP-1 binding yakalwa nge-electrophoretic mobility shift assay. I-PPC (200 ng/ml) yavinjelwa ngokuphumelele ukwanda okukhuthazwa yi-PDGF (p < 0.05; ANOVA, n = 3) futhi yaphikisana nokusebenza kwe-P44MAPK okukhuthazwa yi-PDGF kanye ne-AP-1 binding. Lo mphumela wawulingiswa yi-DLPC kodwa hhayi yi-PLPC. Akukho nakuyiphi phakathi kwe-DLPC noma i-PLPC eyavimba ukusebenza kwamaresepta e-PDGF.

Hypothesis:
Siphetha ngokuthi i-PPC inomthelela ongakaze wabonwa ngaphambilini ekwandeni kwamaseli e-stellate okukhuthazwa yi-mitogen okungase kube yimiphumela ye-DLPC.


Premise:
Iseli esisebenzayo somdlandla webhilibhili (HSC) sibalulekile ekubambekeni kwesibindi njengomthombo omkhulu wecollagen I kanye ne-III kanye nezivimbelanqamulajuqu zemetalloproteinase-1 (TIMP-1). Ngesikhathi sokuzilungisa okungahleliwe kokubambeka kwesibindi, kunokunciphisa kokuvakashiswa kwe-TIMP, ukwanda komsebenzi wecollagenase, kanye nokwanda kokubulawa kwamaseli e-HSC, okukhombisa iqhaza elingaba khona le-TIMP-1 ekuphileni kwe-HSC. Kulo mbiko, sisebenzisa amasampula okulima amaseli kanye namaphethini empilweni ukubonisa ukuthi i-TIMP-1 ngokuqondile ivimba ukubulawa kwamaseli e-HSC. I-TIMP-1 ibonise imphumela eyiqiniso, ebalulekile, nokuya ngezinga lokuvikela ukubulawa kwamaseli e-HSC eqaliswe emasampuleni okulima amaseli futhi yakhuthazwa ukuba ibulale amaseli ngokuncipha kweserum, ukuhlangabezana ne-cycloheximide, kanye nokukhuthazwa kokukukhula kwemizwa. I-TIMP-1 eguqulwe engasebenzi (i-T2G mutant) lapho zonke ezinye izindawo zigcinwe khona ayizange ivimbe ukubulawa kwamaseli, okukhombisa ukuthi ukuvimba ukubulawa kwamaseli kwakuhlelwe ngokuvimba i-MMP. Izivimbelanqamulajuqu ze-MMP ezenziwe ngabantu nazo zavimba ukubulawa kwamaseli e-HSC. Izifundo zesifo sesibindi esibambekile zabonisa ukuthi ukuvakashiswa okuqhubekayo kwe-TIMP-1 mRNA okuqinisekiswe nge-PCR kuhlobene nokuqhubeka kwe-HSC esebenzayo equndwe ukuhlobana kwe-alpha smooth muscle actin, kanti ekubambekeni, ukulahleka kwe-HSC esebenzayo kuhlobene nokuncishiswa kwe-TIMP-1 mRNA.

Hypothesis:
Sinquma ukuthi i-TIMP-1 ivimba i-apoptosis yamasosha omzimba angu-CD14dim avusiwe ngokuvimba i-MMP.


Premise:
Ukwakhiwa kwamaseli estellate esibindini (ama-HSCs) kudlala indima ebalulekile ekuthuthukiseni i-fibrosis yesibindi. I-C1q/tumor necrosis factor-related protein 3 (CTRP3), ilungu lama-CTRPs, ibandakanyeka kwi-fibrosis. Kodwa-ke, kulwazi oluncane mayelana nendima ye-CTRP3 kwi-fibrosis yesibindi. Lolu cwaningo luhlose ukuthola indima yalo kwi-fibrosis yesibindi kanye nokuhlola indlela okungenzeka ukuthi kusebenze ngayo. Imiphumela yethu ikhombise ukuthi i-CTRP3 ibivezwe kancane emathuphini e-fibrosis yesibindi kanye nama-HSCs avuselelwe. Ukwandiswa kwe-CTRP3 kuvinjelwe ukwanda nokuhamba kwamaseli e-HSCs, kanye nokucindezela ukuvela kwama-extracellular matrix (ECM) kumaseli e-HSC-T6 akhuthazwa yi-transforming growth factor-尾1 (TGF-尾1). Ngaphezu kwalokho, ukwandiswa kwe-CTRP3 kuvimbele kakhulu izinga lokuvela kwe-phosphorylation ye-Smad3 kumaseli e-HSC-T6 akhuthazwa yi-TGF-尾1.

Hypothesis:
Ekuphetheni, ucwaningo lwamanje lukhombise ukuthi i-CTRP3 inqanda ukwanda kanye nokuhamba kwamaseli e-HSC-T6 akhuthazwe yi-TGF-尾 1 futhi yanciphisa i-liver fibrosis, okungenani ingxenye, ngokuvimba indlela yokusakaza ye-Smad.


Premise:
Isidingo sokuphucuzwa kokucacisa ekwelashweni okusendaweni yezifo ezivuvukele emathunjini (IBD) sisiholele ekusebenziseni amasomu anegciwane elinegesi eliwuphawu olubi ukulungisa amahlandla avuvukelwe emathunjini. Inhloso yalolu cwaningo kwakuwukucacisa imbangela yalokho esikubonile ngaphambilini ukuthi la masomu aqoqeka, ikakhulukazi, embozweni eyivuvukele yamagundane akhishwe kucolitis yokuhlola, ngemuva kokuphathwa kwegolo. Ukuhlaziya kwamaphroteni (tandem mass spectrometry, kuqinisekiswe ngeWestern blot) kwezibonelo zombozo evuvukele, ekhishwe ku-pH 3, 5 no-7, kwaveza ukwanda kokuvela kwetransferrin (TF) ku-pH 3. Ukuhlolwa kwehistoloji kubonise ukuthi i-TF yayisengxenyeni egolo lomboza evuvukele. Amasomu anegciwane elinegesi eliwuphawu olubi (kodwa hhayi aphakathi nendawo) ananela kokuyi-TF kokubili okuthengwayo nokwemboza ku-pH ephansi, kodwa hhayi ku-pH ephakathi nendawo. Ngaphezu kwalokho, ukuhlala ngaphambili kwamasomu anegciwane elinegesi eliwuphawu olubi ne-TF kwanciphisa kakhulu ukunamathela kwawo embedeni evuvukele yegolo lekati.

Hypothesis:
Kungashiwo ukuthi, ku-pH ephansi, efanayo naleyo esetshenziswa ekoloni elungelweni olunobubomvu (ulcerative colitis), i-TF ihlanganyela ukuze inamathele ezakudliweni kwamandla ezicucu emanzini (liposomes) ezinegciwane elibi eliphuma esikudeni esibomvile.


Premise:
I-Curcumin (i-diferulolylmethane) ikhombisa imiphumela enamandla okulwa nokuvuvukala emasosheni amathumbu (IEC) kanye namasosha okulwa nezifo emzimbeni kulabo abazohloliwe futhi ibukeka iphephisa ezilokazaneni ezifakwe izinto zamakhemikhali zomgogodla, ngokomcansi wokusebenza okucatshangwayo ngokuvimba i-NF-kappaB. Yize kukhombisiwe ukuthi kuyasebenza ekunciphiseni izinga lokubuyisa enkingeni yokuvuvukala kwomathumbu ezigulini, ukusebenza kwe-curcumin kwisifo sika-Crohn (CD) noma kuma-model okulwa nezifo angu-Th-1/Th-17 e-CD akukaze kuhlolwe. Ngakho-ke, saphenyisisa imiphumela ye-curcumin yokudla (0.1-1%) ekuthuthukisweni kokuvuvukala kwomathumbu, ukuvuseleleka kokulwa nezifo, kanye nokusebenza kwe-NF-kappaB emzimbeni kumantshontsho angenagciwane e-IL-10(-/-) noma e-IL-10(-/-);NF-kappaB(EGFP) ahlanganiswe nemicroflora ehlanzekile ekhethekile. I-morphology yamathumbu angaphambili nangasemuva ikhombise umthelela omncane wokuvikela we-curcumin kuphela ku-0.1%. Ukuvakashwa kwe-IFN-gamma yomathumbu kanye ne-IL-12/23p40 mRNA kulandele indlela efanayo (mayelana noku-50% ukuvimba ku-0.1%). Ukukhishwa kwe-IL-12/23p40 kanye ne-IFN-gamma ngomthombo wokukhiqiza amathumbu kanye namasosha ezindawo ezivuvukele zamadlebe kwakuphakeme emantshontshweni e-IL-10(-/-) futhi akuncishiswanga yi-curcumin yokudla. Ngokumangalisayo, ukuvuseleleka kwe-NF-kappaB emantshontshweni e-IL-10(-/-) (i-phospho-NF-kappaBp65) noma kwi-IL-10(-/-);NF-kappaB(EGFP) emantshontshweni (isitho sonke noma ukuthwebula kwezithombe ze-confocal) akuzange kuvinjwe yi-curcumin. Ngaphezu kwalokho, siyakhombisa ukuthi i-IL-10 kanye ne-curcumin zisebenza ngokuhlanganyela ukunciphisa ukusebenza kwe-NF-kappaB ku-IEC kanye nokukhiqizwa kwe-IL-12/23p40 amasosha omphimbo kanye namasosha okuhambisa ulwazi.

Hypothesis:
Siphetha ngokuthi indlela eyinhloko yokusebenza kwe-curcumin ekuvimbeleni i-colitis eyenziwa ngamakhemikhali kungokuvimba i-NF-kappaB.


Premise:
Ukukhuluphala kuyisici sobungozi bokuthuthuka kwesifo esikhathazayo semithombe. I-Pea iyingqayizivele nokuqukethwe kwayo okuphakeme kokudla okusingethe amafayibha, ama-polyphenolics, kanye nama-glycoproteins, konke okwaziwa ngokuba nomphumela omuhle empilweni. Sihlose ukuphenya umthelela wokuhlanganyela kwe-green pea (GP) ekuthintekeni kwamagundane adliwa ukudla okunokunono okuphakeme (HFD) kwe-colitis ebangelwe yi-dextran sulfate sodium (DSS). Amagundane esifazane anezinsuku eziyisithupha ubudala we-C57BL/6J adliwa i-45% HFD noma i-HFD ehlanganyele ngo-10% GP. Ngemuva kwezonto eziyisikhombisa zokungezelela ukudla, i-colitis iveleliswe ngokungeza 2.5% DSS emanzini okuphuza izinsuku eziyisikhombisa kulandelwa isikhathi sokubuyisa ezinye izinsuku eziyisikhombisa. Ukwengeza i-GP kusizile esikhaleni sesikali somthelela wesifo kumagundane adla i-HFD ngesikhathi sokubuyisa, futhi kwehlisa ukungena kwama-neutrophil, umbono we-mRNA we-monocyte chemoattractant protein-1 (MCP-1) nezimpawu zokukhathazeka i-interleukin (IL)-6, i-cyclooxygenase-2 (COX-2), i-IL-17, i-interferon-γ (IFN-γ), kanye ne-inducible nitric oxide synthase (iNOS) emagundaneni adla i-HFD. Ngaphezu kwalokho, ukwengeza i-GP kwandise okuqukethwe kwemucin 2 nokukhuluma kwe-mRNA kwezimpawu zokuhlukaniswa kweseli le-goblet kufaka phakathi i-Trefoil factor 3 (Tff3), i-Kr眉ppel-like factor 4 (Klf4), kanye ne-SAM pointed domain ETS factor 1 (Spdef1) emagundaneni adla i-HFD. Ngaphezu kwalokho, i-GP yanciphisa i-endoplasmic reticulum (ER) stress njengoba kukhombiswe ukwehliswa kokukhuluma kweprotheni ye-Activating transcription factor-6 (ATF-6) namagene ayo aqondiswe i-chaperone protein glucose-regulated protein 78 (Grp78), i-CCAAT-enhancer-binding protein homologous protein (CHOP), i-ER degradation-enhancing α-mannosidase-like 1 protein (Edem1), kanye ne-X-box binding protein 1 (Xbp1) emagundaneni adla i-HFD.

Hypothesis:
Ekugcineni, ukunikezwa kwe-GP kwanciphisa ubunzima be-colitis eyenziwe yi-DSS kumagundane afunzwe yi-HFD, okwakuhambisana nokucindezela ukuvuvukala, ukuncipha kwe-mucin, kanye nokucindezela i-ER stress kukholo.


Premise:
I-Bilirubin icatshangwa ukuthi inomthelela wokuvikela ukuvuvukala ngokuvimba ukuhamba kwamaseli amhlophe egazi elixhumene nesakhiwo seselula sokujiyisa amathambo (VCAM-1) nangokucindezela ukuvela kwe-inducible nitric oxide synthase (iNOS). Njengoba i-VCAM-1 ne-iNOS zingabalamuli abalulekile bokulimala kwamatissue emodeli yemouse ye-dextran sodium sulfate (DSS) yesifo sokuqumba sesibumbu, sihlolile ukuthi i-bilirubin ivikela yini ukulimala kwekholo ezimpondweni eziphathwa nge-DSS. Izimpondwa zesilisa ze-C57BL/6 zanikwa i-2.5% ye-DSS emanzini okuphuza izinsuku eziyi-7, ngesikhathi ezithola imijovo yesikhathi esisodwa ye-bilirubin (30 mg/kg) noma i-potassium phosphate vehicle. Umsebenzi wesifo waqashelwa, izibalo zegazi lasemithanjeni nokuhlolwa kwamazinga amanitrate egazini kwanqunywa, namasu esitho somphimbo ahlaziywa ngokulimala kwe-histological, ukuhlasela kwamaseli amhlophe, nokuzibonakalisa kwe-iNOS. Umthelela we-bilirubin ekukhiqizweni kwe-IL-5 ngamaseli e-HSB-2 kanye nokuhamba kwamaseli e-Jurkat transendothelial nawo wanqunywa. Izimpungushe eziphathwe nge-DSS ezithole i-bilirubin ngesikhathi esisodwa zilahlekelwe yisisindo somzimba esingaphansi, zinamazinga amanitrate aphansi egazini, futhi zibonakalisa ukusinda kwesifo okunciphile kunesilwane esihlanzwe nge-vehicle. Ngokuhambisana, izinhlolovo ze-histopathological zembule ukuthi izimpungushe ezinye i-bilirubin ziveze ukulimala okuncane kwekholo, okuhlanganisa ukuncishiswa kwamaeosinophils, amalymphocytes, namasosha, kanye nokuncipha kokuzibonakalisa kwe-iNOS. Ukunikwa kwe-bilirubin kuye kwahlotshaniswa nokuncipha kokuhlasela kwamaeosinophil namasosha amathumbu amancane, nokukhula okuhambisanayo kwe-eosinophilia yegazi lasemithanjeni. I-Bilirubin ivimbe ukuhamba kwe-Jurkat kodwa ayizange ishintshe ukukhiqizwa kwe-IL-5.

Hypothesis:
Ngokuphethayo, i-bilirubin ivimbela i-colitis eyenziwa yi-DSS ngokuvimba ukuhamba kwamasosha omzimba (ama-leukocyte) ukuwela endleleni yegazi (i-vascular endothelium) nangokucindezelela isiqubulo se-iNOS.


Premise:
Izinga lokuvela kwezifo ezinokuqubuka kwemilalazi linyuke eminyakeni yakamuva. Ngaphakathi kwekholo, imindeni yama-mucin (MUC) nama-trefoil factor (TFF) isiza ekuvikeleni kwemilalazi. Ukusetshenziswa kwamagciwane amahle (probiotic) kunomthelela esigabeni se-MUC semathumbu. Ngaphezu kwalokho, izingxenye zokudla zingaba nomthelela ezinhlayiyeni zemilalazi noma zibe nemiphumela eqondile esivikela se-MUC. Inhloso yethu kwakuwukuthola ukuthi ngabe ukudla kanye/noma i-Lactobacillus rhamnosus GG (LGG) kungaxazulula yini ukuqubuka kwesigujana esibangwa yidextran sodium sulfate (DSS) ngokushintsha ukuvezwa kwama-gene e-MUC ne-TFF. Amagundane e-C57BL/6 adliswa ukudla okunamaphroteni e-casein, esoy, noma ewhey ngo-20% (wt:wt) kanye noma ngaphandle kwe-LGG isikhathi esiyizinsuku eziyi-12. Ezinsukwini eziyisikhombisa ngemuva kokuqala ukudla kwe-LGG, amagundane anikwa i-DSS engu-2% emanzini okuphuza izinsuku ezine. Amaqembu amabili engeziwe e-casein enakanye noma kungekho i-LGG anikwa amanzi empompi, kwaba yizigaba eziyisishiyagalombili sezephelele. Usuku olulodwa ngemuva kokunikwa i-DSS, amagundane abulawa kwase kuqoqwa amathishu ekholo nekhekham neziqulatho zekhekhamu kwase kuhlolwa nge-qRT-PCR. Amaphroteni ewhey akhuphule kakhulu izinga le-LGG ekhekhamu uma kuqhathaniswa nokudla okunye. Emaqenjini endla ye-casein, ukuvezwa kwe-MUC1 ne-TFF-3 ekholoni kwanyuswa kakhulu yi-DSS ngaphandle kokuncika kwi-LGG. Uma kuqhathaniswa namaqembu aphathwe nge-DSS, amaphroteni esoy anciphise i-MUC-1 ne-TFF-3 ekholoni. Ngokufanayo, amaphroteni esoy anciphise umthelela we-DSS ezilinganisweni zokuqubuka, ukuvezwa kwe-gene yeTNFα, kanye nokufinyezwa kwekholo. Bekungenamthelela ophelele we-LGG kulezi zilinganiso.

Hypothesis:
Ekupheleni, iprotheni yesoya inciphise ukuvela kwegeni le-TNFα okubangelwa ukuphehla ngokwamandla kwe-MUC, i-TFF, kanye ne-DSS ngaphandle kwe-LGG.


Premise:
I-Hypoxia inducible factor 1α (HIF1α) iwumgcini omkhulu okhokhelela ekuhlelelaneni kwemethabholizimi, inqubo yefiziyoloji ebalulekile ukugcina ukuphila kwamaseli ezisekelo ngaphansi kwe-hypoxia. Nokho, akuqondisiseki kahle ukuthi i-HIF1α idlulisela kanjani ekungeneni enyukliyasi kumaseli ezisekelo ngaphansi kwe-hypoxia. Lapha, siphenye indima ye-protein adaptor yemota ebizwa nge-Bicaudal D homolog 1 (BICD1) ekuthuthweni kwe-HIF1α okwenziwa yi-dynein ukuya enyukliyasi kanye nomthelela wokulawulwa kwe-BICD1 ekuzijwayezeni kwe-hypoxia kanyenomthombo wokwelapha kumaseli ezisekelo asuka kwi-human umbilical cord blood (UCB-MSCs). Emiphumeleni yethu, ukucishwa kwe-BICD1 kodwa hhayi i-BICD2 kwashabalalisa ukudluliselwa kwe-HIF1α enyukliyasi kanye nomsebenzi wayo. Ukungezeleka kwe-BICD1 kwaqhubeka kwathuthukisa ukudluliselwa kwe-HIF1α enyukliyasi okubangelwa yi-hypoxia. I-hypoxia yavuselela ukuboshelwa okuqondile kwe-HIF1α kwe-BICD1 kanye ne-chain ethile ye-dynein (i-Dynein IC), okwashabalaliswa ukucishwa kwe-BICD1. Ukuvikelwa kwe-Akt kwanciphisa ukubosheleka kwe-BICD1 kwe-HIF1α kanye nokudluliselwa kwe-HIF1α enyukliyasi. Ngokuphambene, ukusebenza kwe-Akt noma ukucishwa kwe-GSK3尾 kwaqhubeka kwathuthukisa ukudluliselwa kwe-HIF1α enyukliyasi okubangelwa yi-hypoxia. Phezu kwalokho, ukucishwa kwe-BICD1 kwashabalalisa ukuhlelwa kabusha kwe-glycolytic okubangelwa yi-hypoxia futhi kwandisa ukuqoqeka kwe-mitochondrial ROS kanye ne-apoptosis kuma-UCB-MSCs ngaphansi kwe-hypoxia. Kwimodeli yokwelapha isilonda sesikhumba sikagundane, ukuphila kwamaseli atshaliwe kanye namandla okwelapha isilonda sesikhumba e-UCB-MSCs ezilungiselelwe nge-hypoxia kuncishiswe ukucishwa kwe-BICD1 futhi kwaqhubeka kwakhuliswa ukucishwa kwe-GSK3尾.

Hypothesis:
Okokugcina, sivezile ukuthi ukuhanjiswa kwe-FGF okubangelwe ukuthi i-HIF1 α ingene emhlahlandeleni kubalulekile ekulungiseleleni okuphathelene nokusweleka komoya, okuyinto enquma amandla okuzidalulula kabusha kwe-UCB-MSCs.


Premise:
I-Von Hippel-Lindau protein (pVHL) ivame isebenza ekudaleni i-ubiquitin-mediated degradation ye-hypoxia-inducible factor-1alpha (HIF-1alpha) ngaphansi kwezimo ze-normoxic kodwa hhayi ngaphansi kwezimo ze-hypoxic, futhi ikhuthaza ukuhlukaniswa kwamanyuroni kwamaseli angaphambili emzimbeni. Nokho, indima ye-pVHL ekuhlukanisweni kwamaseli angaphambili emzimbeni ngaphansi kwanoma yisiphi isimo ayikahlolisiswa ngokugcwele. Lapha, sibonisa ukuthi ngaphansi kwesimo se-anoxic ukuqhamuka kwe-pVHL kanye nezimpawu zamanyuroni kwamaseli angaphambili emzimbeni kuvinjelwa, kanti i-HIF-1alpha iyakhuthazwa. Ngaphezu kwalokho, amaseli angaphambili emzimbeni akhombisa i-pVHL ngemuva kokudluliswa kwegene akhombisa ukuhlukana okucacile kwamanyuroni kanye nokungakhuthazwa kwe-HIF-1alpha ngaphansi kwesimo se-normoxic kodwa hhayi ngaphansi kwesimo se-anoxic.

Hypothesis:
Ngakho-ke, siphetha ngokuthi i-pVHL ivimba ukuhlukaniswa kwama-neural ngaphansi kwesimo se-anoxic.


Premise:
Inhlangano eyenza amafektha ahoxekayo (HIF) iwumlawuli osemqoka wokusabela kweseli kumazinga aphansi e-oxygen okugqugquzela ukunikezwa kwe-oxygen nokuhlela kabusha indlela yokusebenza kweseli uma kungekho i-oxygen eyanele. Nokho, izinga nesikhathi sokuvela kwe-HIF-1α ekuhoxeni kufanele kulinganiswe ngokucophelela emasosheni ukuze kugwenywe imiphumela engafuneki ehambisana nomsebenzi omningi. Ukuvela kwe-HIF-1α mRNA kucindezelwa ekuhoxeni isikhathi eside, okukhombisa ukuthi ukulawulwa kokubhalwa kwe-HIF1A gene kulawulwa kanzima yizindlela zokubuyisela emuva eziphefumulo. Kukhona okuncane okwaziwa ngokuxazululwa kwesabelo se-HIF-1α protein kanye nokucindezela kwe-HIF-1α mRNA ekuhoxeni isikhathi eside. Lapha, sikhombisa ukuthi i-Repressor Element 1-Silencing Transcription factor (REST) ibophekela ku-HIF-1α promoter ngendlela eyencike ekuhoxeni. Ukwehliswa kwe-REST kusetshenziswa i-RNAi kwandisa ukuvela kwe-HIF-1α mRNA, protein kanye nomsebenzi wokubhala. Ngaphezu kwalokho, ukwehliswa kwe-REST kwandisa ukusetshenziswa kwe-glucose kanye nokukhiqizwa kwe-lactate ngendlela eyencike ku-HIF-1α (kodwa hhayi ku-HIF-2α). Okokugcina, i-REST ithuthukisa ukuxazululwa kokuvela kwe-HIF-1α protein ekuhoxeni isikhathi eside.

Hypothesis:
Okokuphetha, siphakamisa umqondo wokuthi i-hypoxia inqanda umsebenzi we-transcription ye-HIF-1α ngesikhathi eside se-REST, ngalokho ifaka isandla ekuxazululeni umsebenzi we-HIF-1α.


Premise:
Ukubonakala kwe-core autophagy kinase, i-Unc51-like kinase 1 (ULK1), kulawulwa ngezinga lokuqamba nokutolika ukudla kwethuba elide elikhuthaza i-autophagy. Kodwa-ke, ukuthi i-ULK1 ilawulwa kanjani ngesikhathi sophoxo akuqondakali kahle. Ngaphambilini, sibonise ukuthi ukuvela kwe-ULK1 kukhuthazwa ingcindezi yophoxo. Lapha, sibika i-microRNA entsha elungisa i-ULK1, i-miR-93; ukuqanjwa kwayo kuhlobene ngendlela engathandeki nokutolika kwe-ULK1 ngaphansi kwesimo sokweswela umoya. I-miR-93 ihloshe i-ULK1 futhi inciphisa amazinga ayo eprotheni ngaphansi kwesimo sokweswela umoya. I-miR-93 ivimba futhi i-autophagy ekhuthazwa ukweswela umoya ngokuvimbela i-LC3-I ukuya kwi-transition ye-LC3-II kanye nokubhidlizwa kwe-P62; lezi zinqubo ziguqulwa ukweqiswa komvimbi wendabuko we-miR-93. Ukuphinde kuqanjwe i-ULK1 ngaphandle kwezinto zokusabela ze-miR-93 kubuyisela i-autophagy ekhuthazwa ukweswela umoya evinjwe yi-miR-93. Okokugcina, sithole imiphumela ye-miR-93 ekuphileni kwamaseli nasekufeni kwamaseli ezinhlobeni zamaseli angezona ezomdlavuza namaseli omdlavuza. Sithole ukuthi i-miR-93 igcina ukuphila kwe-MEFs (amafibroblasts omlingatshana wegundane) futhi ivimba ukufa kwawo ngaphansi kweswela umoya.

Hypothesis:
Ngakho-ke, sifika esiphethweni sokuthi i-miR-93 inendima eyidlalayo ekuqaleni kwe-autophagy ebangelwa yi-hypoxia ngokukulawula i-ULK1.


Premise:
Izimo ze-hypoxic ziphakanyiswa ukuthi ziyathinta isimo sokwehlukana kwamabunzi esitolo (SC), kufaka phakathi namabunzi esitolo embryonic (ESC). I-Hypoxia inducible factor (HIF) ingomunye wamamolecule amakhulu angaphakathi kweseli onokuziphendulela ekuphenduleni kweseli kwi-hypoxia. I-Hypoxia istabiliza i-HIF ngokuvimba umsebenzi we-HIF prolyl-hydroxylases (PHD), eyaziwayo ngenhloso ye-HIF-alpha subunits yokubhidlizwa kwe-proteosomal. Ukuze sibhekane nomthelela wokustabiliza kwe-HIF ekugcineni i-stemness signature ye-mouse ESC (mESC), sihlole umthelela wokuvimba kwama-PHD ne-hypoxia (1% O2 no-5% O2) ekwehlukaneni okuzenzakalelayo kwe-ESC okuqalwe ukuhlaziywa kwe-leukemia inhibitory factor isikhathi esingamahora angu-24 nama-48. Isivimbi esisaziwa kakhulu se-panhydroxylase i-dimethyloxaloylglycine (DMOG) nesivimbi se-PHD i-JNJ-42041935 (JNJ) esiphakanyiswe se-specificity esingcono se-PHDs kusetshenzisiwe. Lezi zivimbi zombili namazinga womabili e-hypoxia enyuse kakhulu amazinga e-protein e-HIF-1alpha ne-HIF-2alpha kanye nomsebenzi we-transcriptional we-HIF kwi-mESC ehlukana ngokuzenzakalela. Lokhu kwakuhambelana nokwehla okubalulekile kokwanda kwamaseli okuvezwe ukuvimba okuphelele kokuhlanganiswa kwe-DNA kanye nokuboshwa kwengxenye kwi-S phase emva kwamahora angu-48. Ngaphezu kwalokho, ukustabiliza kwe-HIF kuqinise ukwehla kokuvakaliswa kwezinye izimpawu zokukhiqiza (OCT-4, NANOG, ZFP-42, TNAP) kwi-mESC ehlukana ngokuzenzakalela. Kodwa, ngesikhathi esifanayo, kwakukhona ukwehla okubalulekile ekuvakaleni kwezinye zama-gene akhethwe njengezimpawu zokwehlukana kwamaseli (isibonelo: SOX1, BRACH T, ELF5).

Hypothesis:
Ngokuphetha, ukusimama kwesikhashana kwe-hypoxia kusetshenziswa izinqando ze-PHD i-JNJ ne-DMOG kanye ne-HIF akuzange kuvimbele ukulahleka okuzenzekelayo kwezimpawu ze-pluripotency ku-mESC.


Premise:
I-BTK inhibitor ibrutinib ibonise umthelela wokwelashwa ovelele kwi-mantle cell lymphoma (MCL). Kodwa-ke, cishe ingxenye eyodwa kwezintathu yeziguli ayiphenduli kumuthi ekuqaleni. Ukuze sithole izindlela eziyisisekelo zokumelana ne-ibrutinib eqalayo kwi-MCL, sihlaziye izinguquko ze-transcriptome emazingeni amaseli ahlukahlukene anesimiso se-ibrutinib kanye nalawo amelana nayo ngesikhathi sokwelashwa nge-ibrutinib. Sithole ukuthi isignesha yegene ye-MYC yayicindezelwe yi-ibrutinib ezinhlosweni ezizwelayo kodwa hhayi emazingeni amaseli amelanayo. Sikhombisile ukuthi igene ye-MYC ayilungile ngokwesakhiwo futhi iphrotheni ye-MYC yayikhiqizwe ngokweqile kumaseli e-MCL. Ngaphezu kwalokho, ukucekelwa phansi kwe-MYC nge-RNA interference kuvinjelwe ukukhula kwamaseli ezinhlosweni ezizwelayo ze-ibrutinib kanye nalawo amelana nayo. Sihlolile amathuba okuvimbela i-MYC ngokusebenzisa ukuvinjelwa kwe-HSP90. Iphrotheni ye-chaperon ikhiqizwe ngokweqile kuwo womabili amazinga amaseli kanye namaseli e-MCL asuselwa ezigulini. Sikhombisile ukuthi i-MYC iyikhasimende yangempela ye-HSP90 ekuhlanganisweni kwe-MCL ngokusebenzisa kokubili i-immunoprecipitation kanye ne-chemical precipitation. Ngaphezu kwalokho, ukuvimbelwa kwe-HSP90 ngokusebenzisa i-PU-H71 kukhuthaze i-apoptosis futhi kubangele ukumiswa kwesayikili yamaseli. I-PU-H71 ibuye ikhombise ukuvinjelwa okunamandla futhi okuhlobene ngqo nohlelo lwe-MYC transcriptional uma kuqhathaniswa nezinye izindlela ze-oncogenic. Esimweni se-xenograft esitholakala esigulini se-MCL, i-HSP90 inhibitor ivinjelela ukukhula kwesimila futhi yelulela ukuphila. Okokugcina, sikhombisile ukuthi i-PU-H71 ikhuthaze i-apoptosis futhi yehlise iphrotheni ye-MYC kumaseli e-MCL atholakala ezigulini ezazingamelana ne-ibrutinib ngokwemithetho yokwelashwa.

Hypothesis:
Nesiphetho, umsebenzi we-MYC ungaphansi kokwenqaba kwangaphakathi kwe-ibrutinib ku-MCL.


Premise:
I-Activation-induced cytidine deaminase (AID) iyadingeka ekuguquleni amaseli okushisa angaphezu kwesisindo kanye nokuhlanganiswa kabusha kwesigaba se-immunoglobulin (Ig) emaseliheni e-B asesikhungweni esivuthayo (GC). Ngezinye izikhathi, i-AID ingahlosela amagene angewona awe-Ig ngaleyo ndlela iqhubele phambili isifo somdlavuza wamaselikha e-B we-GC. Kamuva nje sibonise ukuthi i-kinase edlala indima enkulu ye-BCR-ABL1 iqala ukubonakalisa i-AID ngendlela engafanele ku-pre-B acute lymphoblastic leukemia (ALL) kanye ne-lymphoid chronic myelogenous leukemia esesikhungweni sokuqhuma. Ukucacisa ukubaluleka kwezinto eziphilayo zokubonakalisa i-AID ngendlela engafanele, sifunde ukulahleka komsebenzi we-AID ohlelweni olulingisayo lwe-BCR-ABL1 ALL emanyane. Amagundane ahlonjisiwe ngesitho somgogodla esihlaselwe nge-BCR-ABL1 AID(-/-) ayephila isikhathi eside uma eqhathaniswa namagundane ahlonjiswe namaseli esifo somdlavuza egcinwe kumaseli e-AID(+/+) esithweni somgogodla. Ngokuhambelana nendima ebangela ye-AID ekungathembeki kwezofuzo, i-AID(-/-) leukemia yayinezinga eliphansi lokwengezeka kanye nokusulwa nokudlulisa nokwengeza kwezinga eliphansi lokushintsha kwamagene angewona awe-Ig, kufaka i-Pax5 kanye ne-Rhoh uma kuqhathaniswa ne-AID(+/+) leukemias. Amaseli e-AID(-/-) ne-AID(+/+) ALL abonisa ukuhlukana kwephetheni ye-gene expression, futhi amaseli e-AID(-/-) ALL ahlulekile ukwehlisa inani lamagene afiphela isifo kufaka ne-Rhoh, i-Cdkn1a (p21), kanye ne-Blnk (SLP65).

Hypothesis:
Siqeda ngokuthi i-ALL isheshisa ukuguquka kwama-clone kwi-BCR-ABL1 AID ngokuqinisa ukungastabili kwamajini nokushintsha okungafanele somatic hypermutation, kanye ngokuqondisa okungemuhle kwamajini alwa nezifo.


Premise:
Izinguquko ezivuselelayo ze-c-Kit zitholakala kaningi ezigulini ze-acute myeloid leukemia (AML) ezinegciwane le-t(8;21) chromosomal translocation eyenza i-fusion protein ye-AML1-ETO. Lapha sibonisa ukuthi i-mutant esebenzayo ye-c-Kit isebenzisana ne-AML1-ETO ukwenza i-AML ezinhlolweni zokulungiswa komgogodla wamathambo empondweni. Amaseli e-leukemic akhombisa i-AML1-ETO nge-c-Kit(D814V) ayedluliselwa ngokulandelana. Izivivinyo zokudlulisela zibonise ukuthi amaseli e-leukemic i-lineage(-)c-Kit(+)Sca-1(+) (KSL), kodwa hhayi amaseli e-leukemic lineage(+), angamele kakhulu amaseli e-leukemia stem (LSCs). Ukuqhathaniswa kwama-profile wokubonakala kwamajini phakathi kwe-KSL leukemic namaseli avamile kuveze ukuthi i-CD200R1 yayivezwe kakhulu kumaseli e-KSL leukemic uma kuqhathaniswa namaseli e-KSL avamile. Ukunyuswa kwe-CD200R1 kuqinisekiwe kumaseli e-leukemic lineage(-), kodwa hhayi kumaseli e-leukemic lineage(+). Ukuvezwa kwe-CD200R1 kumaseli e-leukemic lineage(-) akuhambisani nokuvamisa kwe-LSCs, okukhombisa ukuthi i-CD200R1 akuyona inkomba esebenzisekayo ye-LSCs kulezi zinhlelo. Okukhuthazayo, i-CD200R1 yanyuswa kumaseli e-KSL adluliselwa nge-AML1-ETO, kodwa hhayi kwezinye izinguquko ezenza i-leukemia, kufaka i-c-Kit(D814V), i-AML1(D171N), kanye ne-AML1(S291fsX300). Ngokuhambisana, ukunyuswa kwe-CD200R1 kumaseli e-leukemic lineage(-) kubonwe kuphela ku-BM yezimpuku eziphethwe yi-leukemia ene-AML1-ETO positive.

Hypothesis:
Ekugcineni, i-AML1-ETO yenyusa i-CD200R1 emasosheni angenayo (lineage(-)), okwakuyimpawu ye-AML1-ETO eyayikhombisa i-leukemia kumagundane.


Premise:
Ukuze sifunde indima yohlobo lwe-oncogene ye-NRAS (NRAS(G12V)) esimweni sokuba ne-acute myeloid leukemia (AML), sisebenzise uhlelo lwe-Vav promoter-tetracycline transactivator (Vav-tTA) oluhambisana nezinga le-TRE-NRAS(G12V) transgene ezimpukwini ze-Mll-AF9 knock-in ezithuthukisa i-AML. Ukucindezela okuhleliwe kokuvela kwe-NRAS(G12V) kwanciphisa kakhulu isibalo samasosha amhlophe egazini (WBC) ezimpukwini ezinalesi sifo futhi kwabangela ukufa kwamaseli e-AML afakiwe okuhambelana nokwehliswa kwesibonakaliso se-Ras/Erk. Emva kokuphela okukhulu kwamaseli e-AML, isifo se-myeloproliferative (MPD) esifana ne-AML savela kabusha esabonakaliswa amaseli angazange aveze i-NRAS(G12V). Uma kuqhathaniswa ne-AML yokuqala, i-AML efana ne-MPD yabonisa ukwehliswa okubalulekile kobuhlasimulisi, ukwehliswa kwe-myelosuppression, nendlela yokukhiqiza ehlukile.

Hypothesis:
Siphetha ngokuthi, ku-AML ebangelwe i-transgene ye-Mll-AF9, ukuvakashwa kwe-NRAS(G12V) kunikela ekulondolozeni i-leukemia ebucayi ngokucindezela i-apoptosis kanye nokunciphisa ukuhlukaniswa kwamacells e-leukemia.


Premise:
Ukuphindaphinda kwangaphakathi okuhlelekile (ITD) engxenyeni ye-juxtamembrane ye-Fms-efana ne-tyrosine kinase 3 (FLT3), uhlobo lwesithathu lwe-receptor tyrosine kinase (RTK), kungukungahambi kahle kwemolekhuli okuvame kakhulu okuhambisana ne-acute myeloid leukemia (AML). Ukuvela kakhulu kwalolu guquko olwenziwayo kukwenza kube yinto ephambili ekwelashweni okusekelwe kwimolekhuli. Izivimbeli ze-indolinone tyrosine kinase zinomsebenzi owaziwa ngokumelene ne-KIT, olunye ilungu lomndeni wesithathu we-RTK. Ngenxa yokufana okugcinekile phakathi kwamalungu alomndeni, saqagela ukuthi umsebenzi wezinye izivimbeli ze-KIT uzokwanda kuze kube yi-FLT3. Sisebenzise imizila eyahlukene yamaseli e-leukemia (BaF3, MV 4-11, RS 4;11) ukuhlola umsebenzi wezakhi ze-indolinone ngokumelene nomsebenzi we-FLT3 kinase kokubili, uhlobo lwendalo (WT) kanye ne-ITD isoforms. Kokubili i-SU5416 ne-SU5614 bekunamandla okuvimba i-autophosphorylation ye-ITD ne-WT FLT3 (i-SU5416 izinga elivimba u-50% [IC(50)], 100 nM; kanye ne-SU5614 IC(50) 10 nM). Ukusebenza kwe-FLT3 okuncikile ekuvuselelweni kwezakhi zezimpawu ezehlukanisiwe ze-mitogen-activated protein kinase (MAPK) kanye ne-signal transducer and activator of transcription 5 (STAT5) kwavinjelwa futhi ngokwelashwa kwamazinga afanayo. Ukuvinjelwa kwe-FLT3 nge-SU5416 kanye ne-SU5614 kwaholela ekunciphiseni ukukhula (IC(50), 250 nM kanye ne-100 nM, ngokulandelana) kanye nokuqalisa i-apoptosis yemizila yamaseli e-leukemia ane-FLT3 ITD. Ukwelashwa kwalama seli ngesici sokukhula esihlukile (i-granulocyte-macrophage colony-stimulating factor [GM-CSF]) kubuyisele izimpawu ze-MAPK nokukhula kwamaseli, okukhombisa ukuqonda kwemiphumela evimbelayo eboniwe.

Hypothesis:
Siphetha ngokuthi i-SU5416 ne-SU5614 ziyizinqamlajuqu ezinamandla ze-FLT3.


Question:
Literature on Cardiac amyloidosis.  Please let me know where I can get literature on Cardiac amyloidosis.  My uncle died yesterday from this disorder.  Since this is such a rare disorder, and to honor his memory, I would like to distribute literature at his funeral service.  I am a retired NIH employee, so I am familiar with the campus in case you have literature at NIH that I can come and pick up.  Thank you
Answer:
Cardiac amyloidosis is a disorder caused by deposits of an abnormal protein (amyloid) in the heart tissue. These deposits make it hard for the heart to work properly.


Question:
Literature on Cardiac amyloidosis.  Please let me know where I can get literature on Cardiac amyloidosis.  My uncle died yesterday from this disorder.  Since this is such a rare disorder, and to honor his memory, I would like to distribute literature at his funeral service.  I am a retired NIH employee, so I am familiar with the campus in case you have literature at NIH that I can come and pick up.  Thank you
Answer:
The term "amyloidosis" refers not to a single disease but to a collection of diseases in which a protein-based infiltrate deposits in tissues as beta-pleated sheets. The subtype of the disease is determined by which protein is depositing; although dozens of subtypes have been described, most are incredibly rare or of trivial importance. This analysis will focus on the main systemic forms of amyloidosis, both of which frequently involve the heart.


Question:
Migraine seems to be a spectrum of conditions rather than only one easily diagnosed affliction.  Many innovative migraine treatments are now in use, but it seems that each treatment only addresses a narrow set of conditions; for example, my daughter has tried many different treatment options (QEEG, HEG, TMS, topamax, ...) without success.  Has any research been done to characterize which treatment types are effective against which migraine types?
Answer:
There is no absolute cure for migraine since its pathophysiology has yet to be fully understood. There are two ways to approach the treatment of migraine headache with drugs: prevent the attacks, or relieve the symptoms during the attacks. Prevention involves the use of medications and behavioral changes. Drugs originally developed for epilepsy, depression, or high blood pressure to prevent future attacks have been shown to be extremely effective in treating migraine. Botulinum toxin A has been shown to be effective in prevention of chronic migraine. Behaviorally, stress management strategies, such as exercise, relaxation techniques, biofeedback mechanisms, and other therapies designed to limit daily discomfort, may reduce the number and severity of migraine attacks. Making a log of personal triggers of migraine can also provide useful information for trigger-avoiding lifestyle changes, including dietary considerations, eating regularly scheduled meals with adequate hydration, stopping certain medications, and establishing a consistent sleep schedule. Hormone therapy may help some women whose migraines seem to be linked to their menstrual cycle. A weight loss program is recommended for obese individuals with migraine. Relief of symptoms, or acute treatments, during attacks consists of sumatriptan, ergotamine drugs, and analgesics such as ibuprofen and aspirin. The sooner these treatments are administered, the more effective they are.


Question:
When and how do you know when you have congenital night blindness?
Answer:
X-linked congenital stationary night blindness is a disorder of the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing in low light (night blindness). They also have other vision problems, including loss of sharpness (reduced acuity), severe nearsightedness (high myopia), involuntary movements of the eyes (nystagmus), and eyes that do not look in the same direction (strabismus). Color vision is typically not affected by this disorder. The vision problems associated with this condition are congenital, which means they are present from birth. They tend to remain stable (stationary) over time. Researchers have identified two major types of X-linked congenital stationary night blindness: the complete form and the incomplete form. The types have very similar signs and symptoms. However, everyone with the complete form has night blindness, while not all people with the incomplete form have night blindness. The types are distinguished by their genetic cause and by the results of a test called an electroretinogram, which measures the function of the retina.


Question:
Gene changes or chromosomal changes of MSUD? What is the technical and simple language of MSUD? Are there any treatments for MSUD?
Answer:
Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease. These three genes provide instructions for making proteins that work together as a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.


Question:
I was born with Diabetes Insipidus and have many problems since the cell was removed when I was 22 and ALL
Answer:
Diabetes insipidus is an uncommon condition in which the kidneys are unable to prevent the excretion of water.


Question:
I may have a couple anal fissures and looking to speak with someone to get some information and support.
Answer:
An anal fissure is a small split or tear in the thin moist tissue (mucosa) lining the lower rectum (anus).


Question:
Are there any researches indicating how early an individual may experience any signs or symptoms of Rheumatoid Arthritis?
Answer:
Swelling and Pain in the Joints Different types of arthritis have different symptoms. In general, people with most forms of arthritis have pain and stiffness in their joints. Rheumatoid arthritis is characterized by inflammation of the joint lining. This inflammation causes warmth, redness, swelling, and pain around the joints. A person also feels sick, tired, and sometimes feverish. Rheumatoid arthritis generally occurs in a symmetrical pattern. If one knee or hand is affected, the other one is also likely to be affected.Diagnostic Tests Rheumatoid arthritis can be difficult to diagnose in its early stages for several reasons. There is no single test for the disease. In addition, symptoms differ from person to person and can be more severe in some people than in others. Common tests for rheumatoid arthritis include:- The rheumatoid factor test. Rheumatoid factor is an antibody that is present eventually in the blood of most people with rheumatoid arthritis. However, not all people with rheumatoid arthritis test positive for rheumatoid factor, especially early in the disease. Also, some people who do test positive never develop the disease.- The citrulline antibody test. This blood test detects antibodies to cyclic citrullinated peptide (anti-CCP). This test is positive in most people with rheumatoid arthritis and can even be positive years before rheumatoid arthritis symptoms develop. When used with the rheumatoid factor test, the citrulline antibody test results are very useful in confirming a rheumatoid arthritis diagnosis.- Other common tests for rheumatoid arthritis include the erythrocyte sedimentation rate, which indicates the presence of inflammation in the body, a test for white blood cell count, and a blood test for anemia.Diagnosis Can Take Time Symptoms of rheumatoid arthritis can be similar to those of other types of arthritis and joint conditions, and it may take some time to rule out other conditions. The full range of symptoms develops over time, and only a few symptoms may be present in the early stages. Learn more about how rheumatoid arthritis is diagnosed.


Question:
Are there any researches indicating how early an individual may experience any signs or symptoms of Rheumatoid Arthritis?
Answer:
Rheumatoid arthritis is characterized by inflammation of the joint lining. This inflammation causes warmth, redness, swelling, and pain around the joints. The pain of rheumatoid arthritis varies greatly from person to person, for reasons that doctors do not yet understand completely. Factors that contribute to the pain include swelling within the joint, the amount of heat or redness present, or damage that has occurred within the joint.


Question:
article defining 'conversion disorder' In your article defining 'conversion disorder', [http://www.nlm.nih.gov/medlineplus/ency/article/000954.htm] , the quote "Conversion disorder is a mental health condition in which a person has blindness paralysis, or other nervous system (neurologic) symptoms that cannot be explained be medical evaluation" , seemed to imply that the physical symptoms were valid as proving to be valid, but however the doctor could not 'figure' out why,.....but when I went to another source, another article quotes the disorder as a "physical disability that is not caused by any physical impairment" -so I am defining this as symptoms that are visibly correct as analyzed visually but when under examination for deadened nerves or broken bones, no evidence is found? >that is the definition I am getting from the other source about this disorder. For example, someone claims blindness, as my instructor explained, and when the person claiming blindness is placed near a ledge , does not walk off the ledge.....since I am assuming also that optical tests of the retina, or pupil proved nothing substantial?
Answer:
Diagnostic testing does not find any physical cause for the symptoms. The doctor will do a physical exam and may order diagnostic tests. These are to make sure there are no physical causes for the symptom.


Question:
I have been battling Anal fissure for close to two years now and it has refused to heal all these while. Please what do you suggest i do?  Thanks
Answer:
Most fissures heal on their own and do not need treatment. To prevent or treat anal fissures in infants, be sure to change diapers often and clean the area gently.CHILDREN AND ADULTSWorrying about pain during a bowel movement may cause a person to avoid them. But not having bowel movements will only cause the stools to become even harder, which can make anal fissure worse.Prevent hard stools and constipation by:- Making dietary changes -- eating more fiber or bulk, such as fruits, vegetables, and grains- Drinking more fluids- Using stool softenersApplying the following ointments or creams to the area may soothe the skin:- Numbing cream, if pain interferes with normal bowel movements- Petroleum jelly- Zinc oxide, 1% hydrocortisone cream, Preparation H, and other productsA sitz bath is a warm water bath used for healing or cleansing. You should sit in the bath two to three times a day. The water should cover only your hips and buttocks.If the anal fissures do not go away with home care methods, treatment may involve:- Botox injections into the muscle in the anus (anal sphincter)- Minor surgery to relax the anal muscle- Prescription creams such as nitrates or calcium channel blockers, applied over the fissure to help relax the muscles


Question:
My daughter has menkes syndrome and would like to know how to go about. Thx
Answer:
These resources address the diagnosis or management of Menkes syndrome: - Gene Review: Gene Review: ATP7A-Related Copper Transport Disorders - Genetic Testing Registry: Menkes kinky-hair syndrome - MedlinePlus Encyclopedia: Copper in diet - MedlinePlus Encyclopedia: Menkes syndrome These resources from MedlinePlus offer information about the diagnosis and management of various health conditions: - Diagnostic Tests - Drug Therapy - Surgery and Rehabilitation - Genetic Counseling - Palliative Care


Question:
NO HEALTH CARE ON MY SON SUFFERING FROM GENDER DYSPHORIA WHAT CAN WE DO TO HELP HIM HE WORKED OUT OF HIGH SCHOOL NO PROBLEMS NOW NOT WORKING AND SHUTTING HIMSELF IN HIS ROOM 24/7 THERES NOTHING ABOUT THIS CONDITION IN OUR AREA WE LIVE IN [LOCATION]. NO HELP IN AREA WHAT CAN WE DO HE HAS HAD BAD THOUGHTS ALREADY PLEASE HELP US WITH SOME SORT OF INFO THANK YUO [NAME] [LOCATION] [CONTACT]
Answer:
Individual and family therapy is recommended for children to create a supportive environment at home and in school. Individual and, if appropriate, couples therapy is recommended for adults. Sex reassignment through surgery and hormonal therapy is an option. But identity problems may continue after this treatment.


Question:
My mother recently died from Bowel Ischemia and Septic Shock.  My question is this, she was in the ER for 12 hours before she was even seen by the general surgeon and then he wasn't convinced that it was this condition yet.  He said that he'd check on her in the morning once she was finally put into an ICU room (this was at 11 p.m.).  I last spoke to her at midnight that evening and that was the last time that she was conscious.  By the time she got to the ICU just 2-3 hours later, she was unresponsive and put on life support.  Surgery was eventually performed later that afternoon and 90% of her small intestine had to be removed.  She died early the next evening.  My question to you is did they wait too long to do anything for her?  Could she have been saved if surgery had been done sooner?  I'm possibly thinking of bringing on a lawsuit.....Please advise with any answers to my questions that you can give.  Thank you!
Answer:
Septic shock has a high death rate. The death rate depends on the patient's age and overall health, the cause of the infection, how many organs have failed, and how quickly and aggressively medical therapy is started.


Question:
my husband was diagnosed with Rocky Mountain Spotted fever about 6 1/2 years ago.  Then about 1 1/2 years ago he was diagnosed with Lyme Disease.  With him having had both what damage if any to his body could possibly happen.  He has had alot of medical problems since.  Now has been diagnosed with type II diabetes.
Answer:
If diagnosed in the early stages, Lyme disease can be cured with antibiotics. Without treatment, complications involving the joints, heart, and nervous system can occur. But these symptoms are still treatable and curable. In rare cases, a person keeps having symptoms that interfere with daily life after they have been treated with antibiotics. This is also known as post-Lyme disease syndrome. The cause of this syndrome is unknown. Symptoms that occur after antibiotics are stopped may not be signs of active infection and may not respond to antibiotic treatment.


Question:
My father is having cardiomyopathy through genes. He is 83 now. He was absoulutely normal till now. recently he is getting breathlessness. and he was admitted to the hospital twice. The doctors are telling that multi dieases are attacking his heart. I just want to know exactly what is happening and what precautions that he should take in future. What are the chances of survival? Please help.
Answer:
The outlook depends on many different things, including:   - Cause and type of cardiomyopathy   - How well the condition responds to treatment   - The severity of the heart problem    Heart failure is usually a long-term (chronic) illness. It may get worse over time. Some people develop severe heart failure. In this case, medicines, surgery, and other treatments may no longer help. Patients with certain types of cardiomyopathy are at risk for dangerous heart rhythm problems.


Question:
Hi, My name is [NAME] from india i have suffering from typhoid please give me solution  i have one question i had got treatment from one year but i am not well now give me solution?
Answer:
Fluids and electrolytes may be given by IV (into a vein) or you may be asked to drink water with electrolyte packets.  Antibiotics are given to kill the bacteria. There are increasing rates of antibiotic resistance throughout the world, so your health care provider will check current recommendations before choosing an antibiotic.


Question:
atypical pnuemonia.  what is the possibility of atypical pneumonia occurring again less than a month after treatment?
Answer:
Most patients with pneumonia due to mycoplasma or chlamydophila get better with the right antibiotics. Legionella pneumonia can be severe. It can lead to problems, especially in patients with kidney failure, diabetes, COPD, or a weak immune system. It can also lead to death.


Question:
Can u please send stuff on fibromyalgia as well
Answer:
Fibromyalgia is a common syndrome in which a person has long-term pain, spread throughout the body. The pain is most often linked to fatigue, sleep problems, headaches, depression, and anxiety. People with fibromalgia may also have tenderness in the joints, muscles, tendons, and other soft tissues.


Question:
Can u please send stuff on fibromyalgia as well
Answer:
SummaryFibromyalgia is a disorder that causes muscle pain and fatigue. People with fibromyalgia have "tender points" on the body. Tender points are specific places on the neck, shoulders, back, hips, arms, and legs. These points hurt when pressure is put on them. People with fibromyalgia may also have other symptoms, such as- Trouble sleeping- Morning stiffness- Headaches- Painful menstrual periods- Tingling or numbness in hands and feet- Problems with thinking and memory (sometimes called "fibro fog")No one knows what causes fibromyalgia. Anyone can get it, but it is most common in middle-aged women. People with rheumatoid arthritis and other autoimmune diseases are particularly likely to develop fibromyalgia. There is no cure for fibromyalgia, but medicine can help you manage your symptoms. Getting enough sleep, exercising, and eating well may also help.NIH: National Institute of Arthritis and Musculoskeletal and Skin Diseases


Question:
It was really helpful after reading about type 1 diabetes but would like some more suggestions from you .my friend is 35 year old and its been 1 year of his diabetes n his sugar level is around 100 or 120 OR SO.. each time he tests his sugar level. is there ANY COMPLICATIONS? HE ALSO GO FOR EXERCISES AND BLOOD TEST EVERY 2 OR 3 MONTHS N TAKES A PROPER DIET LIKE GREEN JUICE,OLIVE OIL AND ALL. WAITING FOR YOUR FEED BACK. THANK YOU.
Answer:
After many years, diabetes can lead to serious health problems:  - You could have eye problems, including trouble seeing (especially at night) and sensitivity to light. You could become blind.  - Your feet and skin could develop sores and infections. If you have these sores for too long, your foot or leg may need to be amputated. Infection can also cause pain and itching.  - Diabetes may make it harder to control your blood pressure and cholesterol. This can lead to heart attack, stroke, and other problems. It can become harder for blood to flow to the legs and feet.  - Nerves in the body can become damaged, causing pain, itching, tingling, and numbness.  - Because of nerve damage, you could have problems digesting the food you eat. You could feel weakness or have trouble going to the bathroom. Nerve damage can also make it harder for men to have an erection.  - High blood sugar and other problems can lead to kidney damage. The kidneys may not work as well as they used to. They may even stop working, so that you would need dialysis or a kidney transplant.


Question:
I just read an article submitted by you that stated your research shows that you've identified the mechanism that causes burning mouth syndrome. Also because of these findings you can find a treatment. I've had this for 15 yrs and am just holding on. When will a good treatment be available??  I belong to a group of over 500 bmsers. We're suffering terribly and were from all over the world. What would the treatment be?
Answer:
If the underlying cause of burning mouth syndrome is determined, treatment is aimed at the triggering factor(s). If no cause can be found, treatment can be challenging. The following are potential therapies for burning mouth syndrome; we strongly recommend that you work with your health care provider in determining which therapy is right for you.A lozenge-type form of the anticonvulsant medication clonazepam (Klonopin) Oral thrush medications Medications that block nerve pan Certain antidepressants B vitamins Cognitive behavioral therapy Special oral rinses or mouth washes Saliva replacement products Capsaicin In addition to these medications, the following measures may be helpful in reducing symptoms of burning mouth syndrome: Sip water frequently Suck on ice chips Chew sugarless gum Avoid irritating substances like tobacco, hot or spicy foods, alcoholic beverages, mouthwashes that contain alcohol, and products high in acid, like citrus fruits and juices, as well as cinnamon or mint.


Question:
I'm looking for books about hypotension/low blood pressure. Can you suggest any that I might be able to purchase?
Answer:
Summary You've probably heard that high blood pressure is a problem. Sometimes blood pressure that is too low can also cause problems. Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps out blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is the diastolic pressure. Your blood pressure reading uses these two numbers. Usually they're written one above or before the other, such as 120/80. If your blood pressure reading is 90/60 or lower, you have low blood pressure. Some people have low blood pressure all the time. They have no symptoms and their low readings are normal for them. In other people, blood pressure drops below normal because of a medical condition or certain medicines. Some people may have symptoms of low blood pressure when standing up too quickly. Low blood pressure is a problem only if it causes dizziness, fainting or in extreme cases, shock. NIH: National Heart, Lung, and Blood Institute


Question:
My Daughter have Distal renal tubular acidosis. we are from Mexico, and we ae woundering if can send to us more infomation. maybe you can reccommend to us a association???? i don?t know
Answer:
Distal renal tubular acidosis is a disease that occurs when the kidneys do not properly remove acids from the blood into the urine. As a result, too much acid remains in the blood (called acidosis).


Question:
I would like to learn more about my condition. Please send me any literature you feel I could use. thanks, [NAME]
Answer:
Klinefelter syndrome is a genetic condition that occurs in males when they have an extra X chromosome.


Question:
I would like to learn more about my condition. Please send me any literature you feel I could use. thanks, [NAME]
Answer:
Klinefelter syndrome is a chromosomal condition that affects male physical and cognitive development. Its signs and symptoms vary among affected individuals. Affected individuals typically have small testes that do not produce as much testosterone as usual. Testosterone is the hormone that directs male sexual development before birth and during puberty. A shortage of testosterone can lead to delayed or incomplete puberty, breast enlargement (gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility). Some affected individuals also have genital differences including undescended testes (cryptorchidism), the opening of the urethra on the underside of the penis (hypospadias), or an unusually small penis (micropenis). Older children and adults with Klinefelter syndrome tend to be taller than their peers. Compared with unaffected men, adults with Klinefelter syndrome have an increased risk of developing breast cancer and a chronic inflammatory disease called systemic lupus erythematosus. Their chance of developing these disorders is similar to that of women in the general population. Children with Klinefelter syndrome may have learning disabilities and delayed speech and language development. They tend to be quiet, sensitive, and unassertive, but personality characteristics vary among affected individuals.


Question:
How do I get rid of these little devils? Me and My mom have tried so many things to get rid of these bugs and they just don't go away were the family that takes 2 showers and now about 3 showers a day we never understood how they could have infected us but I was just wondering is washing our clothes the best bet to get rid of these things, because apparently it hasn't worked for us. So is there any suggestions?
Answer:
To get rid of lice, take the following important steps:   - Bathe regularly to get rid of lice and their eggs.   - Change your clothes often.   - Wash clothes in hot water (at least 130°F/54°C) and machine dry using the hot cycle.   - Items that can't be washed, such as stuffed toys, mattresses, or furniture, can be thoroughly vacuumed to get rid of lice and eggs that have fallen off the body.   Your provider may prescribe a skin cream or a wash that contains permethrin, malathione, or benzyl alcohol. If your case is severe, the provider may prescribe medicine that you take by mouth.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
Talipes equinovarus is a congenital (present from birth) condition where the foot turns inward and downward. The cause of this condition is not known, although it may be passed down through families in some cases. This condition occurs in about 1 out of every 1,000 births. Treatment may involve moving the foot into the correct position and using a cast to keep it there. This process is done in small increments over a period of time. In severe cases, surgery may be needed.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
Clubfoot is the most common congenital disorder of the legs. It can range from mild and flexible to severe and rigid.  The cause is not known, but the condition may be passed down through families in some cases. Risk factors include a family history of the disorder and being male. The condition occurs in about 1 out of every 1,000 live births.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
Tay-Sachs disease is a rare inherited disorder that causes progressive destruction of nerve cells in the brain and spinal cord. Tay-Sachs is caused by the absence of a vital enzyme called hexosaminidase-A (Hex-A). Without Hex-A, a fatty substance, or lipid, called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells. Tay-Sachs disease is inherited in an autosomal recessive pattern.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
Tay-Sachs disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.  The most common form of Tay-Sachs disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Tay-Sachs disease experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with this severe infantile form of Tay-Sachs disease usually live only into early childhood.  Other forms of Tay-Sachs disease are very rare. Signs and symptoms can appear in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form. Characteristic features include muscle weakness, loss of muscle coordination (ataxia) and other problems with movement, speech problems, and mental illness. These signs and symptoms vary widely among people with late-onset forms of Tay-Sachs disease.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
There is no known way to prevent this disorder. Genetic testing can detect if you are a carrier of the gene for this disorder. If you or your partner are from an at-risk population, it is recommended that you undergo testing before starting a family. Testing the amniotic fluid can diagnose Tay-Sachs disease in the womb.


Question:
I have a list of questions about Tay sachs disease and clubfoot   1. what is TSD/Clubfoot, and how does it effect a baby  2. what causes both? can it be prevented, treated, or cured  3. How common is TSD? how common is Clubfoot  4. How can your "agency" help a women/couple who are concerned about this congenital condition, and is there a cost?  If you can answer these few questions I would be thankful, please get back as soon as you can.
Answer:
There is no treatment for Tay-Sachs disease itself, only ways to make the person more comfortable.


Question:
Are ear lobe creases always heart disease and 100% heart attack pending? What are other causes? I'm 56 have pierced ears but haven't wore earrings in years. In the last 7 years I rarely eat meat and when I do it's chicken or fish maybe beef every 5 years or so and its maybe a hamburger lean. If you do have arteriosclerosis is there anyway to reverse it?
Answer:
A substance called plaque can build up in the walls of your coronary arteries. This plaque is made up of cholesterol and other cells. A heart attack may occur when:   - A tear in the plaque occurs. This triggers blood platelets and other substances to form a blood clot at the site that blocks most or all of the oxygen-carrying blood from flowing to a part of the heart muscle. This is the most common cause of heart attack.   - A slow buildup of plaque may narrow one of the coronary arteries so that it is almost blocked.   In either case, there is not enough blood flow to the heart muscle and heart muscle dies. The cause of heart attack is not always known.   Heart attack may occur:   - When you are resting or asleep   - After a sudden increase in physical activity   - When you are active outside in cold weather   - After sudden, severe emotional or physical stress, including an illness   Many risk factors may lead to the development of plaque buildup and a heart attack.


Question:
Are ear lobe creases always heart disease and 100% heart attack pending? What are other causes? I'm 56 have pierced ears but haven't wore earrings in years. In the last 7 years I rarely eat meat and when I do it's chicken or fish maybe beef every 5 years or so and its maybe a hamburger lean. If you do have arteriosclerosis is there anyway to reverse it?
Answer:
Coronary Heart Disease A heart attack happens if the flow of oxygen-rich blood to a section of heart muscle suddenly becomes blocked and the heart can't get oxygen. Most heart attacks occur as a result of coronary heart disease (CHD). CHD is a condition in which a waxy substance called plaque builds up inside of the coronary arteries. These arteries supply oxygen-rich blood to your heart. When plaque builds up in the arteries, the condition is called atherosclerosis. The buildup of plaque occurs over many years. Eventually, an area of plaque can rupture (break open) inside of an artery. This causes a blood clot to form on the plaque's surface. If the clot becomes large enough, it can mostly or completely block blood flow through a coronary artery. If the blockage isn't treated quickly, the portion of heart muscle fed by the artery begins to die. Healthy heart tissue is replaced with scar tissue. This heart damage may not be obvious, or it may cause severe or long-lasting problems. Coronary Artery Spasm A less common cause of heart attack is a severe spasm (tightening) of a coronary artery. The spasm cuts off blood flow through the artery. Spasms can occur in coronary arteries that aren't affected by atherosclerosis. What causes a coronary artery to spasm isn't always clear. A spasm may be related to: Taking certain drugs, such as cocaine Emotional stress or pain Exposure to extreme cold Cigarette smoking The animation below shows how plaque buildup or a coronary artery spasm can lead to a heart attack. Click the "start" button to play the animation. Written and spoken explanations are provided with each frame. Use the buttons in the lower right corner to pause, restart, or replay the animation, or use the scroll bar below the buttons to move through the frames. The animation shows how blocked blood flow in a coronary artery can lead to a heart attack.


Question:
my son born with alopicia totalis and swealling around the eyes , we have done for him Whole Exome Sequencing , they  identified a heterozygous likely pathogenic variant in the SOX18 gene, which supports the clinical diagnosis of hypotrichosis-lymphedema-telangiectasia syndrome , i would like to know if i can trat this or any thing that we can do to help the symptos ,pleae help
Answer:
Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare condition that, as the name suggests, is associated with sparse hair (hypotrichosis), lymphedema, and telangiectasia, particularly on the palms of the hands. Symptoms usually begin at birth or in early childhood and become worse over time. HLTS is thought to be caused by changes (mutations) in the SOX18 gene. It can follow both an autosomal dominant or an autosomal recessive pattern of inheritance, depending on the affected family. There is currently no cure for the condition. Treatment is based on the signs and symptoms present in each person.