The rockefeller university

BackgroundCognitive decline and accompanying neurological changes associated with non-CNS cancer diagnosis and treatment have been increasingly identified in a subset of patients. Initially believed to be because of neurotoxic effects of chemotherapy exposure, observation of cognitive decline in patients not treated with chemotherapy, cancer-diagnosed individuals prior to treatment, and patients receiving alternative treatment modalities (surgery, endocrine therapy, and radiation) has led to the investigation of additional potential etiologies and moderating factors. Stressful experiences have long been posited as a contributor to these cognitive changes. Through reciprocal connectivity with peripheral systems, the brain maintains a dynamic circuitry to adapt to stress (allostasis). However, overuse of this system leads to dysregulation and contributes to pathophysiology (allostatic load). At this time, little research has been conducted to systematically examine the role of allostatic load in cancer-related cognitive dysfunction. Methods and ResultsHere, we integrate theories of stress biology, neuropsychology, and coping and propose a model through which individuals with a high level of allostatic load at diagnosis may be particularly vulnerable to the neurocognitive effects of cancer. ConclusionsOpportunities for future research to test and extend proposed mechanisms are discussed in addition to points of prevention and intervention based on individual variation in stress reactivity and coping skills. Copyright (c) 2014 John Wiley & Sons, Ltd.

Gene expression is highly regulated at the step of transcription initiation, and transcription activators play a critical role in this process. RbpA, an actinobacterial transcription activator that is essential in Mycobacterium tuberculosis (Mtb), binds selectively to group 1 and certain group 2 sigma-factors. To delineate the molecular mechanism of RbpA, we show that the Mtb RbpA sigma-interacting domain (SID) and basic linker are sufficient for transcription activation. We also present the crystal structure of the Mtb RbpA-SID in complex with domain 2 of the housekeeping sigma-factor, sigma(A). The structure explains the basis of sigma-selectivity by RbpA, showing that RbpA interacts with conserved regions of sigma(A) as well as the nonconserved region (NCR), which is present only in housekeeping sigma-factors. Thus, the structure is the first, to our knowledge, to show a protein interacting with the NCR of a sigma-factor. We confirm the basis of selectivity and the observed interactions using mutagenesis and functional studies. In addition, the structure allows for a model of the RbpA-SID in the context of a transcription initiation complex. Unexpectedly, the structural modeling suggests that RbpA contacts the promoter DNA, and we present in vivo and in vitro studies supporting this finding. Our combined data lead to a better understanding of the mechanism of RbpA function as a transcription activator.

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V-H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V-H-gene-restricted ontogenies.

The first measurement of the cross section ratio sigma(t (t) over barb (b) over bar)/sigma(t (t) over bar jj) is presented using a data sample corresponding to an integrated luminosity of 19.6 fb(-1) collected in pp collisions at root s = 8 TeV with the CMS detector at the LHC. Events with two leptons (e or mu) and four reconstructed jets, including two identified as b quark jets, in the final state are selected. The ratio is determined for a minimum jet transverse momentum p(T) of both 20 and 40 GeV/c. The measured ratio is 0.022 +/- 0.003 (stat) +/- 0.005 (syst) for p(T) > 20GeV/c. The absolute cross sections sigma(t (t) over barb (b) over bar) and sigma(t (t) over bar jj) are also measured. The measured ratio for p(T) > 40 GeV/c is compatible with a theoretical quantum chromodynamics calculation at next-to-leading order. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

Taylor's law (TL), a widely verified quantitative pattern in ecology and other sciences, describes the variance in a species' population density (or other nonnegative quantity) as a power-law function of the mean density (or other nonnegative quantity): Approximately, variance = a(mean)(b), a > 0. Multiple mechanisms have been proposed to explain and interpret TL. Here, we show analytically that observations randomly sampled in blocks from any skewed frequency distribution with four finite moments give rise to TL. We do not claim this is the only way TL arises. We give approximate formulae for the TL parameters and their uncertainty. In computer simulations and an empirical example using basal area densities of red oak trees from Black Rock Forest, our formulae agree with the estimates obtained by least-squares regression. Our results show that the correlated sampling variation of the mean and variance of skewed distributions is statistically sufficient to explain TL under random sampling, without the intervention of any biological or behavioral mechanisms. This finding connects TL with the underlying distribution of population density (or other nonnegative quantity) and provides a baseline against which more complex mechanisms of TL can be compared.

During the past decade, advanced techniques in structural biology have provided atomic level information on the platelet integrin IIb3 activation mechanism that results in it adopting a high-affinity ligand-binding conformation(s). This review focuses on advances in imaging intact IIb3 in a lipid bilayer in the absence of detergent and new structural insights into the changes in the ligand-binding pocket with receptor activation and ligand binding. It concludes with descriptions of novel therapeutic IIb3 antagonists being developed based on an advanced knowledge of the receptor's structure.

Chronic hepatitis B virus (HBV) infection is prevalent, deadly, and seldom cured due to the persistence of viral episomal DNA (cccDNA) in infected cells. Newly developed genome engineering tools may offer the ability to directly cleave viral DNA, thereby promoting viral clearance. Here, we show that the CRISPR/Cas9 system can specifically target and cleave conserved regions in the HBV genome, resulting in robust suppression of viral gene expression and replication. Upon sustained expression of Cas9 and appropriately chosen guide RNAs, we demonstrate cleavage of cccDNA by Cas9 and a dramatic reduction in both cccDNA and other parameters of viral gene expression and replication. Thus, we show that directly targeting viral episomal DNA is a novel therapeutic approach to control the virus and possibly cure patients.

Central memory T (T-CM) cells in lymph nodes (LNs) and resident memory T (T-RM) cells in peripheral tissues have distinct roles in protective immunity(1-5). Both are generated after primary infections, but their clonal origins have been unclear. To address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HIS) of the gene encoding the T cell receptor (TCR) beta-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells(6). For every abundant T-RM cell clone generated in the skin, an abundant T-CM cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin T-RM and LN T-CM cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires. Although they bore the same TCR, T-RM cells mediated rapid contact hypersensitivity(7) responses, whereas T-CM cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin T-RM cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin T-RM and LN T-CM cells in similar numbers from the same naive T cells.

During 1 year, experimentally naive C57BL/6NCrl weanlings born to timed-pregnant dams from a single vendor demonstrated markedly increased mortality associated with runting, abnormal gait, and decreased activity. Gram-positive, aerobic, a-hemolytic, coccoid bacteria were isolated from the meninges (n = 16), blood (n = 1), and kidneys (n = 1) of clinically affected weanlings (n = 15); from the uterus (n = 1), meninges (n = 1), and oral cavity (n = 2) of 3 dams; and from the meninges and oral cavity of a clinically affected 86-d-old mouse in the same colony. Multifocal, necrosuppurative meningoencephalitis and ventriculitis with intralesional gram-positive coccoid bacteria were present in all but 2 affected animals. The bacterium also was isolated from the oral cavity of an asymptomatic timed-pregnant dam (1 of 23) from the same vendor and from 8 mice at the vendor's facility. All isolates (n = 25) were identified by using 2 semiautomated rapid-identification systems, one of which consistently identified the causative bacterium as Aerococcus viridans 2 (n = 12) or 3 (n = 13), with probabilities of 55.7% to 98.3%. The bacterium did not grow in 6.5% NaCl at 10 degrees C, thus suggesting a Streptococcus species. Partial 16S rRNA sequencing of 4 isolates suggested S. hyointestinalis (probability, 93.4%) and S. gallinaceus (99.5%). Full 16S rRNA sequences for 3 isolates identified the bacterium as a novel Streptococcus species most closely related to S. acidominimus strain LGM (96.5%) and Streptococcus species strain Smarlab 3301444 (96.3%) and for which we propose the name S. azizii.

We have previously found that children heterozygous for IL4 variable-number tandem repeat (VNTR) (rs8179190) or IL4-33 (rs2070874) variants were at risk for severe malaria (SM), whereas homozygous children were protected suggesting a complex genetic control. Hence, to dissect this complex genetic control of IL4 VNTR and IL4-33, we performed further investigation by conditional logistic regression analysis and found a strong interaction between both markers (p<10(-6)). The best-fit model revealed three genotype combinations associated with different levels of SM risk. The highest risk (odds ratio (OR)=4.8, 95 % confidence interval (CI)= 2.0-11.5) was observed for subjects carrying at least one copy of both IL4-33 allele T and IL4 VNTR allele 1, who exhibited higher interleukin (IL)-4 plasma levels (p=0.007). Children homozygous for IL4 VNTR allele 2 had a lower SM risk as well as lower IL-4 plasma levels. Our findings indicate that the genetic interaction between these two IL-4 variants is a key factor of SM susceptibility, probably because of its direct role in IL-4 regulation.