The rockefeller university

Background: The relationship between the pathogenic amyloid beta-peptide species A beta 1-42 and tau pathology has been well studied and suggests that A beta 1-42 can accelerate tau pathology in vitro and in vivo. The manners if any in which A beta 1-40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between A beta 1-42 and A beta 1-40. Results: In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to A beta 1-42 induced cleavage, phosphorylation and aggregation of wild-type//full length tau while exposure to A beta 1-40 didn't. Functional studies with A beta 1-40 were carried out in tau-GFP transgenic flies and showed that A beta 1-42, as previously reported, disrupted cytoskeletal structure while A beta 1-40 had no effect at same dose. To further explore how A beta 1-40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either A beta 1-42 or A beta 1-40. We found that treatment with A beta 1-42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, A beta 1-40 injection didn't alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser(262) was shown to be significantly decreased after direct inject of A beta 1-40 into the entorhinal cortex of P301S mice. Conclusions: These results demonstrate that A beta 1-40 plays different role in tau pathogenesis compared to A beta 1-42. A beta 1-40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser(262), which has been shown to be neurotoxic.

Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light-chain-enhancer of B cells (NF-kappa B) pathway. Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-kappa B pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders.

Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian-human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants.

A search for heavy, right-handed neutrinos, N-l (l = e, mu), and right-handed W-R bosons, which arise in the left-right symmetric extensions of the standard model, has been performed by the CMS experiment. The search was based on a sample of two lepton plus two jet events collected in proton-proton collisions at a center-of-mass energy of 8 TeV corresponding to an integrated luminosity of 19.7 fb(-1). For models with strict left-right symmetry, and assuming only one N-l flavor contributes significantly to the WR decay width, the region in the two-dimensional (M-WR, M-Nl) mass plane excluded at a 95% confidence level extends to approximately M-WR = 3.0 TeV and covers a large range of neutrino masses below the W-R boson mass, depending on the value of M-WR. This search significantly extends the (M-WR, M-Nl) exclusion region beyond previous results.

Hair follicle stem cells (HFSCs) and their transit amplifying cell (TAC) progeny sense BMPs at defined stages of the hair cycle to control their proliferation and differentiation. Here, we exploit the distinct spatial and temporal localizations of these cells to selectively ablate BMP signaling in each compartment and examine its functional role. We find that BMP signaling is required for HFSC quiescence and to promote TAC differentiation along different lineages as the hair cycle progresses. We also combine in vivo genome-wide chromatin immunoprecipitation and deep-sequencing, transcriptional profiling, and loss-of-function genetics to define BMP-regulated genes. We show that some pSMAD1/5 targets, like Gata3, function specifically in TAC lineage-progression. Others, like Id1 and Id3, function in both HFSCs and TACs, but in distinct ways. Our study therefore illustrates the complex differential roles that a key signaling pathway can play in regulation of closely related stem/progenitor cells within the context of their overall niche.

Background: Topical corticosteroids are the most common first-line treatment for psoriasis. Tachyphylaxis, a decreased response to treatment with repetitive application of the drug, is a controversial phenomenon associated with topical corticosteroid treatment. Objective: We sought to prove or disprove tachyphylaxis to occluded halobetasol 0.05% versus vehicle. Methods: Patients with plaque psoriasis were recruited to this study. The study involved 3 phases (1, 2A, and 2B) with each phase being separated by a treatment vacation period. In phases 1 and 2A, 2 plaques were randomized to either halobetasol 0.05% or vehicle ointment application. In phase 2B, halobetasol 0.05% was applied to both. Target Lesion Severity Scale was used for clinical assessment. Results: Twenty patients were enrolled. No difference in time to clearance (P = .88) or time to recurrence (P = .92) of the treated plaques was found between phases 1 and 2A. Percentage of improvement was higher in phase 2A compared with phase 1 (89.4%, P < .05 vs 71%, P < .05), as a result of reduction of vehicle effect. In phase 2B, a greater improvement was found for previously corticosteroid-treated plaques. Limitations: Limitations are small sample size and 1 corticosteroid tested. Conclusion: No evidence of tachyphylaxis to the topical corticosteroid halobetasol 0.05% ointment treatment in patients with plaque psoriasis was found.

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, in the bloodstream of its mammalian host to evade the host immune response. VSGs are expressed exclusively from subtelomeric loci, and we have previously shown that telomere proteins TbTIF2 and TbRAP1 play important roles in VSG switching and VSG silencing regulation, respectively. We now discover that the telomere duplex DNA-binding factor, TbTRF, also plays a critical role in VSG switching regulation, as a transient depletion of TbTRF leads to significantly more VSG switching events. We solved the NMR structure of the DNA-binding Myb domain of TbTRF, which folds into a canonical helix-loop-helix structure that is conserved to the Myb domains of mammalian TRF proteins. TheTbTRFMyb domain tolerates well the bulky J base in T. brucei telomere DNA, and the DNA-binding affinity of TbTRF is not affected by the presence of J both in vitro and in vivo. In addition, we find that point mutations in TbTRF Myb that significantly reduced its in vivo telomere DNA-binding affinity also led to significantly increased VSG switching frequencies, indicating that the telomere DNA-binding activ-ity is critical for TbTRF's role in VSG switching regulation.

Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is 4 in adult males, 6 in adult females and 3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.

Despite its global relevance, our understanding of how influenza A virus transmission impacts the overall population dynamics of this RNA virus remains incomplete. To define this dynamic, we inserted neutral barcodes into the influenza A virus genome to generate a population of viruses that can be individually tracked during transmission events. We find that physiological bottlenecks differ dramatically based on the infection route and level of adaptation required for efficient replication. Strong genetic pressures are responsible for bottlenecks during adaptation across different host species, whereas transmission between susceptible hosts results in bottlenecks that are not genetically driven and occur at the level of the recipient. Additionally, the infection route significantly influences the bottleneck stringency, with aerosol transmission imposing greater selection than direct contact. These transmission constraints have implications in understanding the global migration of virus populations and provide a clearer perspective on the emergence of pandemic strains.

A triply bridged fused diporphyrin appended with six thioglucose units is reported. This new, chemically, and photochemically stable amphiphilic compound is taken up by breast cancer cells and causes cell death upon light exposure. Photophysical studies reveal absorption bands in the near IR region, and photosensitized formation of singlet oxygen in high quantum yields. (C) 2014 Elsevier Ltd. All rights reserved.