The rockefeller university

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.

Streptococcus pneumoniae (pneumococcus) is a leading cause of infections worldwide. Disease is preceded by asymptomatic colonization of the upper respiratory tract. Classical culture-based methods (CCBM) suggest that colonization in the elderly is <5%. Recently, use of qPCR has challenged these observations. We estimated pneumococcal carriage prevalence and serotypes among Portuguese elderly using qPCR and compared results with those obtained by CCBM. Nasopharyngeal and oropharyngeal paired samples (599 each) of individuals over 60 years living in nursing (n=299) or family (n=300) homes were screened for the presence of pneumococci by qPCR targeting lytA and piaB. Positive samples were molecular serotyped. Use of qPCR improved detection of pneumococci in oropharyngeal samples compared to CCBM: from 0.7% to 10.4% (p<0.001) in the nursing home collection, and from 0.3% to 5.0% (p<0.001) in the family home collection. No significant differences were observed between both methods in nasopharyngeal samples (5.4% vs. 5.4% in the nursing homes; and 4.3% vs. 4.7% in the family homes). Twenty-one serotypes/serogroups were detected by qPCR compared to 14 by CCBM. In conclusion, use of qPCR suggests that pneumococcal carriage in Portuguese elderly is approximately 10%, and unveiled a large pool of serotypes. These results are important to understand progression to disease and impact of pneumococcal vaccines in the elderly.

The original version of our manuscript, entitled, " The IL1RN mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation" unfortunately contained mistakes in Fig. 1a and d legends. The text should read as follows:

Extreme climatic events (ECEs) are becoming more frequent and more intense due to climate change. Furthermore, there is reason to believe ECEs may modify "tail associations" between distinct population vital rates, or between values of an environmental variable measured in different locations. "Tail associations" between two variables are associations that occur between values in the left or right tails of the distributions of the variables. Two positively associated variables can be principally "left-tail associated" (i.e., more correlated when they take low values than when they take high values) or "right-tail associated" (more correlated when they take high than low values), even with the same overall correlation coefficient in both cases. We tested, in the context of non-spatial stage-structured matrix models, whether tail associations between stage-specific vital rates may influence extinction risk. We also tested whether the nature of spatial tail associations of environmental variables can influence metapopulation extinction risk. For instance, if low values of an environmental variable reduce the growth rates of local populations, one may expect that left-tail associations increase metapopulation extinction risks because then environmental "catastrophes" are spatially synchronized, presumably reducing the potential for rescue effects. For the non-spatial, stage-structured models we considered, left-tail associations between vital rates did accentuate extinction risk compared to right-tail associations, but the effect was small. In contrast, we showed that density dependence interacts with tail associations to influence metapopulation extinction risk substantially: For population models showing undercompensatory density dependence, left-tail associations in environmental variables often strongly accentuated and right-tail associations mitigated extinction risk, whereas the reverse was usually true for models showing overcompensatory density dependence. Tail associations and their asymmetries are taken into account in assessing risks in finance and other fields, but to our knowledge, our study is one of the first to consider how tail associations influence population extinction risk. Our modeling results provide an initial demonstration of a new mechanism influencing extinction risks and, in our view, should help motivate more comprehensive study of the mechanism and its importance for real populations in future work.

Chronic mucocutaneous candidiasis (CMC) characterized by persistent and recurrent Candida infection of the skin, nails, and the mucosa membranes has been proposed as the major infectious phenotype in patients with gain-of-function mutation of signal transducer and activator of transcription 1 (STAT1) 1. However, viral infections caused mostly by herpesviruses, and a broad range of autoimmune disorders may also be part of the clinical phenotype. We report here on a 31 years old female patient suffering from severe mucosal aphthous mucositis and ulcers and recurrent herpes simplex for decades. We found a previously unknown heterozygous sequence variant inSTAT1(c.1219C>G; L407V) affecting the DNA-binding domain of the protein in the patient and her 4 years old daughter. We found this mutation gain-of-function (GOF) by using immunoblot and luciferase assays. We detected low proportion of IL-17A-producing CD4+ T cell lymphocytes by using intracellular staining and flow cytometry. Candida-induced secretion of IL-17A and IL-22 by mononuclear cells from the patient was markedly decreased compared to controls. These data suggest that the novel mutant allele may result in impaired differentiation of CD4+ T cells to CD4+/IL-17+ cells. The clinical phenotype of the disease in this patient was unique as it was dominated primarily by severe aphthous stomatitis and ulcerative esophagitis and only partly by typical CMC resulting in diagnostic delay. We suggest that patients with severe recurrent aphthous stomatitis and esophagitis should be evaluated forSTAT1GOF mutation. Based on the broad clinical spectrum of the disease, we also suggest that CMC and CMC disease may not be an appropriate term to define clinicallySTAT1GOF mutation.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.