Effect of a Pacific sea surface temperature anomaly on the circulation over North America

During the fall and winter of 1976-1977, sea surface temperature (SST) in the north Pacific was characterized by abnormally cold temperatures in the central and western portions of the north Pacific with a warm pool located off the west coast of the U.S. It was suggested that the north Pacific SST anomalies were one of the multiple causes of the abnormally cold temperatures in eastern North America during the 1976-1977 winter. An attempt was made to test this hypothesis by conducting a numerical experiment with the GLAS general circulation model

Transformation kinetics of alloys under non-isothermal conditions

The overall solid-to-solid phase transformation kinetics under non-isothermal conditions has been modeled by means of a differential equation method. The method requires provisions for expressions of the fraction of the transformed phase in equilibrium condition and the relaxation time for transition as functions of temperature. The thermal history is an input to the model. We have used the method to calculate the time/temperature variation of the volume fraction of the favored phase in the alpha-to-beta transition in a zirconium alloy under heating and cooling, in agreement with experimental results. We also present a formulation that accounts for both additive and non-additive phase transformation processes. Moreover, a method based on the concept of path integral, which considers all the possible paths in thermal histories to reach the final state, is suggested.Comment: 16 pages, 7 figures. To appear in Modelling Simul. Mater. Sci. En

A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA

The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. Recent seasonal H3 vaccines do not protect against swine-origin H3N2 variant (H3N2v) strains that recently have caused severe human infections. Here, we report a human VH1-69 gene-encoded monoclonal antibody (mAb) designated H3v-47 that exhibits potent cross-reactive neutralization activity against human and swine H3N2 viruses that circulated since 1989. The crystal structure and electron microscopy reconstruction of H3v-47 Fab with the H3N2v hemagglutinin (HA) identify a unique epitope spanning the vestigial esterase and receptor-binding subdomains that is distinct from that of any known neutralizing antibody for influenza A H3 viruses. MAb H3v-47 functions largely by blocking viral egress from infected cells. Interestingly, H3v-47 also engages Fcγ receptor and mediates antibody dependent cellular cytotoxicity (ADCC). This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines

Silencing of the Rotavirus NSP4 Protein Decreases the Incidence of Biliary Atresia in Murine Model

Biliary atresia is a common disease in neonates which causes obstructive jaundice and progressive hepatic fibrosis. Our previous studies indicate that rotavirus infection is an initiator in the pathogenesis of experimental biliary atresia (BA) through the induction of increased nuclear factor-kappaB and abnormal activation of the osteopontin inflammation pathway. In the setting of rotavirus infection, rotavirus nonstructural protein 4 (NSP4) serves as an important immunogen, viral protein 7 (VP7) is necessary in rotavirus maturity and viral protein 4 (VP4) is a virulence determiner. The purpose of the current study is to clarify the roles of NSP4, VP7 and VP4 in the pathogenesis of experimental BA. Primary cultured extrahepatic biliary epithelia were infected with Rotavirus (mmu18006). Small interfering RNA targeting NSP4, VP7 or VP4 was transfected before rotavirus infection both in vitro and in vivo. We analyzed the incidence of BA, morphological change, morphogenesis of viral particles and viral mRNA and protein expression. The in vitro experiments showed NSP4 silencing decreased the levels of VP7 and VP4, reduced viral particles and decreased cytopathic effect. NSP4-positive cells had strongly positive expression of integrin subunit α2. Silencing of VP7 or VP4 partially decreased epithelial injury. Animal experiments indicated after NSP4 silencing, mouse pups had lower incidence of BA than after VP7 or VP4 silencing. However, 33.3% of VP4-silenced pups (N = 6) suffered BA and 50% of pups (N = 6) suffered biliary injury after VP7 silencing. Hepatic injury was decreased after NSP4 or VP4 silencing. Neither VP4 nor VP7 were detected in the biliary ducts after NSP4. All together, NSP4 silencing down-regulates VP7 and VP4, resulting in decreased incidence of BA

Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis

Background: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. Results: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. Conclusions: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy

Biliary atresia

Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life

Asymmetric Dual Chiral Catalysis using Iridium Phosphoramidites and Diarylprolinol Silyl Ethers: Insights into Stereodivergence

Recent examples of asymmetric dual chiral catalysis (ADCC), where two chiral catalysts are employed under one-pot reaction conditions, have demonstrated how all stereoisomers of a product could be effectively accomplished through changes in the catalyst chirality. Insufficient mechanistic details on the action of two chiral catalysts and molecular insights into the origin of stereodivergence prompted us to undertake a comprehensive density functional theory (B3LYP-D3) investigation on an α-allylation reaction of an aldehyde by using an allyl alcohol, resulting in two new chiral centers in the product. The structural and energetic features of the stereocontrolling transition states helped us delineate how all four product stereoisomers could be accessed by using suitable combinations of chiral iridium phosphoramide and diarylprolinol silyl ether in this ADCC reaction. The covalent activation of the pronucleophile (aldehyde) by the organocatalyst furnishes a chiral enamine, whereas the action of the transition-metal catalyst (chiral Ir phosphoramidite, <b>P</b>) on racemic allyl alcohol gives the Ir-π-allyl phosphoramidite complex [IrCl­(<b>P</b>)₂(π-allyl)], which serves as the electrophilic partner. The enantioselectivity is directly controlled by the sense of axial chirality of the Ir-bound phosphoramidite ligand, which affects whether an <i>R</i> or <i>S</i> stereocenter would be generated at the β-carbon of the product. The “recognition/interaction” between the two chiral catalysts in the diastereocontrolling C–C bond formation transition states through a series of weak noncovalent interactions (C–H···π, C–H···O, C–H···Cl, C–H···F, and lone pair···π) is identified as playing a pivotal role in influencing the favorable mode of addition of the <i>si</i> or <i>re</i> face of the chiral enamine to Ir-π-allyl phosphoramidite (<i>si-si</i>/<i>re-re</i>) and hence controls the chirality at the α-carbon atom of the developing product

Sweet's syndrome leading to acquired cutis laxa in a child (Marshall's syndrome): A rare case report

Sweet's syndrome is very rare in children, fewer than 80 cases are reported in literature. The lesions usually resolve either spontaneously or after treatment without scarring. Marshall's syndrome is characterised by acute inflammatory skin lesions with subsequent development of localised elastolysis without any internal organ involvement. It is an extremely rare condition in children. There are very few cases reported as Sweet's syndrome leading to acquired cutis laxa - Marshall's syndrome. Sweet's syndrome shows excellent response to systemic steroids, whereas there is no satisfactory treatment for Cutis laxa

Origin of Stereodivergence in Cooperative Asymmetric Catalysis with Simultaneous Involvement of Two Chiral Catalysts

Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match-mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites <b>P</b>_{<i>R</i>/<i>S</i>}–Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of <b>P</b>_{<i>R</i>/<i>S</i>}–Ir−π-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C–C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona–enamine plays an anchoring role. The quinolone ring is noted as participating in a π-stacking interaction with the phenyl ring of the Ir−π-allyl moiety in the case of <b>P</b>_<i>R</i> with the (8<i>R</i>,9<i>R</i>)-cinchona catalyst combination, whereas a series of C–H···π interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when <b>P</b>_<i>R</i> is used with (8<i>S</i>,9<i>S</i>)-cinchona