The rockefeller university

Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection toward multiple malignancies, including a greater than 500-fold incidence of head and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiotherapy to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 patients with FA-HNSCC including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, radiotherapy, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation. Although there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.

Chronic kidney disease (CKD) is a common cause of morbidity and mortality in domestic cats, but the cause is still largely elusive. While some viruses have been associated with this disease, none have been definitively implicated as causative. Recently, Rodent chaphamaparvovirus 1 was recognized as the cause of murine inclusion body nephropathy, a disease reported for over 40 years in laboratory mice. A novel virus belonging to the same genus, Carnivore chaphamaparvovirus 2, was recently identified in the feces of cats with diarrhea. The goal of this study was to investigate the possible role of chaphamaparvoviruses including members of Rodent chaphamaparvovirus 1 and Carnivore chaphamaparvovirus 2 in the development of feline CKD. The presence of these viruses was retrospectively investigated in formalin-fixed paraffin-embedded feline kidney samples using polymerase chain reaction, in situ hybridization, and immunohistochemistry. Cats were divided into 3 groups: normal (N = 24), CKD (N = 26), and immunocompromised (N = 25). None of the kidney tissues from any of the 75 cats revealed the presence of chaphamaparvovirus DNA, RNA, or antigen. We conclude that viruses belonging to the chaphamaparvovirus genus are unlikely to contribute to the occurrence of feline CKD.

Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene. APS-1 patients suffer from various autoimmune diseases, due to the defective thymic deletion of autoreactive T cells, and the development of a large range of autoantibodies (auto-Abs) against various tissue antigens, and some cytokines. The mechanisms underlying CMC remained elusive for many years, until the description in 2010 of high serum titers of neutralizing auto-Abs against IL-17A, IL-17F, and/or IL-22, which are present in almost all APS-1 patients. Excessively high mucosal concentrations of IFN-gamma were recently proposed as an alternative mechanism for CMC in APS-1.

Social living facilitates individual access to rewards, cognitive resources, and objects that would not be otherwise accessible. There are, however, some drawbacks to social living, particularly when competing for scarce resources. Furthermore, variability in our ability to make social decisions can be associated with neuropsychiatric disorders. The neuronal mechanisms underlying social decision-making are beginning to be understood. The momentum to study this phenomenon has been partially carried over by the study of economic decision-making. Yet, because of the similarities between these different types of decision-making, it is unclear what is a social decision. Here, we propose a definition of social decision-making as choices taken in a context where one or more conspecifics are involved in the decision or the consequences of it. Social decisions can be conceptualized as complex economic decisions since they are based on the subjective preferences between different goods. During social decisions, individuals choose based on their internal value estimate of the different alternatives. These are complex decisions given that conspecifics beliefs or actions could modify the subject's internal valuations at every choice. Here, we first review recent developments in our collective understanding of the neuronal mechanisms and circuits of social decision-making in primates. We then review literature characterizing populations with neuropsychiatric disorders showing deficits in social decision-making and the underlying neuronal circuitries associated with these deficits.

The molecular basis of platelet-fibrin interactions remains poorly understood despite the predominance of fibrin in thrombi. We have studied the interaction of platelets with polymerizing fibrin by adding thrombin to washed platelets in the presence of the peptide RGDW, which inhibits the initial platelet aggregation mediated by fibrinogen binding to aIIbb3 but leaves intact a delayed increase in light transmission (delayed wave; DW) as platelets interact with the polymerizing fibrin. The DW was absent in platelets from a patient with Glanzmann thrombasthenia, indicating a requirement for aIIbb3. The DW required aIIbb3 activation and it was inhibited by the aIIbb3 antagonists eptifibatide and the monoclonal antibody (mAb) 7E3, but only at much higher concentrations than needed to inhibit platelet aggregation initiated by a thrombin receptor activating peptide (T6). Surface plasmon resonance and scanning electron microscopy studies both supported fibrin having greater avidity for aIIb b3 than fibrinogen rather than greater affinity, consistent with fibrin's multivalency. mAb 10E5, a potent inhibitor of T6-induced platelet aggregation, did not inhibit the DW, suggesting that fibrin differs from fibrinogen in its mechanism of binding. Inhibition of factor XIII-mediated fibrin cross-linking by .95% reduced the DW by only 32%. Clot retraction showed a pattern of inhibition similar to that of the DW. We conclude that activated aIIbb3 is the primary mediator of platelet-fibrin interactions leading to clot retraction, and that the interaction is avidity driven, does not require fibrin cross-linking, and is mediated by a mechanism that differs subtly from that of the interaction of aIIbb3 with fibrinogen.

Neurons in nucleus gigantocellularis (NGC) have been shown by many lines of evidence to be important for regulating generalized CNS arousal. Our previous study on mouse pups suggested that the development of NGC neurons' capability to fire action potential (AP) trains may both lead to the development of behavioral arousal and may itself depend on an increase in delayed rectifier currents. Here with whole-cell patch clamp we studied delayed rectifier currents in two stages. First, primary cultured neurons isolated from E12.5 embryonic hindbrain (HB), a dissection which contains all of NGC, were used to take advantage of studying neurons in vitro over using neurons in situ or in brain slices. HB neurons were tested with Guangxitoxin-1E and Resveratrol, two inhibitors of Kv2 channels which mediate the main bulk of delayed rectifier currents. Both inhibitors depressed delayed rectifier currents, but differentially: Resveratrol, but not Guangxitoxin-1E, reduced or abolished action potentials in AP trains. Since Resveratrol affects the Kv2.2 subtype, the development of the delayed rectifier mediated through Kv2.2 channels may lead to the development of HB neurons' capability to generate AP trains. Stage Two in this work found that electrophysiological properties of the primary HB neurons recorded are essentially the same as those of NGC neurons. Thus, from the two stages combined, we propose that currents mediated through Kv2.2 are crucial for generating AP trains which, in turn, lead to the development of mouse pup behavioral arousal.

During the germinal center (GC) reaction, B cells undergo profound transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Mapping chromatin accessibility during the humoral immune response, we show that OCT2 was the dominant transcription factor linked to differential accessibility of GC regulatory elements. Silent chromatin regions destined to become GC-specific super-enhancers (SEs) contained pre-positioned OCT2-binding sites in naive B cells (NBs). These preloaded SE 'seeds' featured spatial clustering of regulatory elements enriched in OCT2 DNA-binding motifs that became heavily loaded with OCT2 and its GC-specific coactivator OCin GC B cells (GCBs). SEs with high abundance of pre-positioned OCT2 binding preferentially formed long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions were dependent on recruitment of OCAB. Pre-positioning key regulators at SEs may represent a broadly used strategy for facilitating rapid cell fate transitions. Elemento, Melnick and colleagues examine the chromatin and transcriptional changes that occur during differentiation of human primary B cells into antibody-secreting cells. In naive B cells, the transcription factor OCT2 is preloaded at high-affinity super-enhancer sites present in repressed 'silent' chromatin; upon activation, OCis recruited to these regions, where it facilitates arrays of OCT2 binding to lower-affinity octamer motifs, leading to active formation of germinal center B cell-specific super-enhancers.

Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk. Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI). Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry. Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient. Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

Synchrony among population fluctuations of multiple coexisting species has a major impact on community stability, i.e. on the relative temporal constancy of aggregate properties such as total community biomass. However, synchrony and its impacts are usually measured using covariance methods, which do not account for whether species abundances may be more correlated when species are relatively common than when they are scarce, or vice versa. Recent work showed that species commonly exhibit such 'asymmetric tail associations'. We here consider the influence of asymmetric tail associations on community stability. We develop a 'skewness ratio' which quantifies how much species relationships and tail associations modify stability. The skewness ratio complements the classic variance ratio and related metrics. Using multi-decadal grassland datasets, we show that accounting for tail associations gives new viewpoints on synchrony and stability; e.g. species associations can alter community stability differentially for community crashes or explosions to high values, a fact not previously detectable. Species associations can mitigate explosions of community abundance to high values, increasing one aspect of stability, while simultaneously exacerbating crashes to low values, decreasing another aspect of stability; or vice versa. Our work initiates a new, more flexible paradigm for exploring species relationships and community stability. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.