The rockefeller university

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

Increasing evidence suggests that tRNA levels are dynamically and specifically regulated in response to internal and external cues to modulate the cellular translational program. However, the molecular players and the mechanisms regulating the gene-specific expression of tRNAs are still unknown. Using an inducible auxin-degron system to rapidly deplete RPB1 (the largest subunit of RNA Pol II) in living cells, we identified Pol II as a direct gene-specific regulator of tRNA transcription. Our data suggest that Pol II transcription robustly interferes with Pol III function at specific tRNA genes. This activity was further found to be essential for MAF1-mediated repression of a large set of tRNA genes during serum starvation, indicating that repression of tRNA genes by Pol II is dynamically regulated. Hence, Pol II plays a direct and central role in the gene-specific regulation of tRNA expression.

Aims: Explore potential of 31 tear biomarkers involved in screening for diabetic peripheral neuropathy (DPN). Assess the utility of aesthesiometry for measuring corneal damage in DPN and determine optimal cutoff point for detecting DPN. Methods: Screening test pilot study recruited 90 participants from a tertiary hospital in Lima, Peru. Participants were grouped by diabetes and neuropathy status. Tears collected on Schirmer strips, and proteins measured by both ELISA and multiplex-bead assay. Corneal sensitivity was measured by aesthesiometry, and DPN by vibration perception threshold testing. Results: There were 89 participants included in the analysis. The mean age was 55.7 +/- 1.46, and 58.4% were female. MMP-9 and TGF-alpha concentrations were higher in participants with DPN versus diabetes alone, though not significant. Aesthesiometry was decreased in individuals with DPN when compared to participants with diabetes alone (p < 0.01) and normal controls (p < 0.01). Optimal cutoff point for aesthesiometry was found to be 5.8 cm, with 79% sensitivity and 75% specificity. Conclusions: Tears are an insufficient standalone tool for detecting DPN based on the biomarkers analyzed. Aesthesiometry is a simple, inexpensive, and accurate method to assess corneal damage associated with moderate-severe DPN, and its integration into screening practices has potential to improve detection of DPN in poor-resource settings. (C) 2020 Elsevier B.V. All rights reserved.

Background A recently published Position Statement (PS) by thePreimplantation Genetics Diagnosis International Society (PGDIS)regarding utilization of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) contained inaccuracies and misrepresentations. Because opinions issued by thePGDIShave since 2016 determined worldwide IVF practice, corrections appear of importance. Methods TheInternational Do No Harm Group in IVF (IDNHG-IVF)is a spontaneously coalesced body of international investigators, concerned with increasing utilization of add-ons to IVF. It is responsible for the presented consensus statement, which as a final document was reached after review of the pertinent literature and again revised after the recent publication of the STAR trial and related commentaries. Results In contrast to the PGDIA-PS, we recommend restrictions to the increasing, and by IVF centers now often even mandated, utilization of PGT-A in IVF cycles. While PGT-A has been proposed as a tool for achieving enhanced singleton livebirth outcomes through embryo selection, continued false-positive rates and increasing evidence for embryonic self-correction downstream from the testing stage, has ledIDNHG-IVFto conclude that currently available data are insufficient to impose overreaching recommendations for PGT-A utilization. Discussion Here presented consensus offers an alternative to the 2019PGDISposition statement regarding utilization of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF). Mindful of what appears to offer best outcomes for patients, and in full consideration of patient autonomy, here presented opinion is based on best available evidence, with the goal of improving safety and efficacy of IVF and minimizing wastage of embryos with potential for healthy births. Conclusions As thePGDISnever suggested restrictions on clinical utilization of PGT-A in IVF, here presented rebuttal represents an act of self-regulation by parts of the IVF community in attempts to control increasing utilization of different unproven recent add-ons to IVF.

Introduction: Atopic dermatitis (AD) is a heterogeneous disease. Recent advancements in understanding AD pathogenesis resulted in the exponential expansion of its therapeutic pipeline, particularly following the success and FDA-approval of dupilumab. Different phenotypes of AD by age and ethnicity have also recently been described and clinical studies of emerging treatments will further clarify the role of each cytokine pathway in AD. Areas covered: We review the impressive repertoire of biologics for treatment of moderate-to-severe AD, including those targeting Th2, Th22, Th17/IL-23 and IgE. We highlight the scientific rationale behind each approach and provide a discussion of the most recent clinical efficacy and safety data. Expert opinion: AD is a complex disease and recent research has identified numerous endotypes, reinforcing the rationale for developing targeted therapeutics to antagonize these factors. Dupilumab has revolutionized AD treatment and its mechanistic studies also offer crucial insight into AD pathogenesis. Nevertheless, this biologic does not work for everyone, highlighting the need for a more precise approach to address the unique immune fingerprints of each AD subset. Ultimately targeted therapeutics will complement our understanding of the AD molecular map and help push AD management into an era of personalized medicine.

Background: The hidradenitis suppurativa clinical response (HiSCR) is the gold standard primary outcome measure for hidradenitis suppurativa clinical trials; however, it does not assess the presence of draining tunnels, a common finding in advanced disease. It is unclear what the effect of the presence or absence of draining tunnels has on the efficacy of adalimumab therapy in moderate and advanced disease. Objectives: We evaluated the efficacy of adalimumab versus placebo using the International Hidradenitis Suppurativa Severity Scoring System (IHS4). Additionally, we assessed the effect of draining tunnels on therapeutic response as measured by both the HiSCR and change in nodule counts. Methods: Reanalysis was conducted with the IHS4 and PIONEER 1 and 2 individual patient data. Both binary outcomes (achieving HiSCR and achieving change in IHS4 severity category) and continuous outcomes (nodule counts and IHS4 score) were calculated with R. Regression modeling was undertaken to assess the effect of draining tunnels and other variables. P<.05 was considered statistically significant. Results: The significance of adalimumab therapy depended on the outcome measure used. Placebo response rates were highest when binary outcome measures were used. Draining tunnels, smoking, antibiotics, and body mass index influenced HiSCR response in PIONEER 2. Significant differences in disease severity were observed between PIONEER 1 and 2 data sets. Conclusions: Elevated placebo response rates in PIONEER 1 and 2 are partially attributable to the use of binary outcome measures. Draining tunnels influence clinical response as measured by HiSCR and nodule counts in PIONEER 2. Further investigation into the effect of body mass index on clinical response is required.

Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess residual plaques despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied 50 subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls. Skin biopsies from all subjects were characterized using three methods: mRNA expression, histology, and FACS of hematopoietic skin cells. Although all three methods provided evidence of drug effect, gene expression analysis revealed the persistence of key psoriasis pathways in treated plaques, including granulocyte adhesion and diapedesis, T helper type17 activation pathway, and interferon signaling with no novel pathways emerging. Focal decreases in parakeratosis and keratinocyte proliferation and differential reduction in IL-17 producing CD103e T cells, but no change in CD103thorn tissue-resident memory T cells were observed. Of note, antitumor necrosis factor increased the interferon signaling pathway already present. Interestingly mast cells were the dominant source of IL-22 in all psoriasis subjects. These data suggest that while subtle differences can be observed in drug-treated plaques, underlying biologic mechanisms are similar to those present in untreated psoriatic lesions.

Genetic polymorphisms of the L-type voltage-gated calcium channel (VGCC) are associated with psychiatric disorders including major depressive disorder. Alterations of S100A10 (p11) level are also implicated in the etiology of major depressive disorder. However, the existence of an endogenous regulator in the brain regulating p11, L-type VGCC, and depressive behavior has not been known. Here we report that Ahnak, whose function in the brain has been obscure, stabilizes p11 and Anxa2 proteins in the hippocampus and prefrontal cortex in the rodent brain. Protein levels of Ahnak, p11, and Anxa2 are highly and positively correlated in the brain. Together these data suggest the existence of an Ahnak/p11/Anxa2 protein complex. Ahnak is expressed in p11-positive as well as p11-negative neurons. Ahnak, through its N-terminal region, scaffolds the L-type pore-forming alpha 1 subunit and, through its C-terminal region, scaffolds the beta subunit of VGCC and the p11/Anxa2 complex. Cell surface expression of the alpha 1 subunits and L-type calcium current are significantly reduced in primary cultures of Ahnak knockout (KO) neurons compared to wild-type controls. A decrease in the L-type calcium influx is observed in both glutamatergic neurons and parvalbumin (PV) GABAergic interneurons of Ahnak KO mice. Constitutive Ahnak KO mice or forebrain glutamatergic neuron-selective Ahnak KO mice display a depression-like behavioral phenotype similar to that of constitutive p11 KO mice. In contrast, PV interneuron-selective Ahnak KO mice display an antidepressant-like behavioral phenotype. Our results demonstrate L-type VGCC as an effector of the Ahnak/p11/Anxa2 complex, revealing a novel molecular connection involved in the control of depressive behavior.

A multi-person interview on the unrolling corona pandemic with Samuel Alizon, Akiko Iwasaki, Gerard Krause and Rino Rappuoli.

Understanding the mechanisms governing ecological stability-why a property such as primary productivity is stable in some communities and variable in others-has long been a focus of ecology. Compensatory dynamics, in which anti-synchronous fluctuations between populations buffer against fluctuations at the community level, are a key theoretical mechanism of stability. Classically, compensatory dynamics have been quantified using a variance ratio approach that compares the ratio between community variance and aggregate population variance, such that a lower ratio indicates compensation and a higher ratio indicates synchrony among species fluctuations. However, population dynamics may be influenced by different drivers that operate on different timescales, and evidence from aquatic systems indicates that communities can be compensatory on some timescales and synchronous on others. The variance ratio and related metrics cannot reflect this timescale specificity, yet have remained popular, especially in terrestrial systems. Here, we develop a timescale-specific variance ratio approach that formally decomposes the classical variance ratio according to the timescales of distinct contributions. The approach is implemented in a new R package, called tsvr, that accompanies this paper. We apply our approach to a long-term, multisite grassland community dataset. Our approach demonstrates that the degree of compensation vs. synchrony in community dynamics can vary by timescale. Across sites, population variability was typically greater over longer compared to shorter timescales. At some sites, minimal timescale specificity in compensatory dynamics translated this pattern of population variability into a similar pattern of greater community variability on longer compared to shorter timescales. But at other sites, differentially stronger compensatory dynamics at longer compared to shorter timescales produced lower-than-expected community variability on longer timescales. Within every site, there were plots that exhibited shifts in the strength of compensation between timescales. Our results highlight that compensatory vs. synchronous dynamics are intrinsically timescale-dependent concepts, and our timescale-specific variance ratio provides a metric to quantify timescale specificity and relate it back to the classic variance ratio.