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The blood-testis barrier (BTB) separates the seminiferous epithelium into the apical and basal compartments. The BTB has to operate timely and accurately to ensure the correct migration of germ cells, meanwhile maintaining the immunological barrier. Testin was first characterized from primary Sertoli cells, it is a secretory protein and a sensitive biomarker to monitor junctions between Sertoli and germ cells. Till now, the functions of testin on BTB dynamics and the involving mechanisms are unknown. Herein, testin acts as a regulatory protein on BTB integrity. In vitro testin knockdown by RNAi caused significant damage to the Sertoli cell barrier with no apparent changes in the protein levels of several major tight junction (TJ), adhesion junction, and gap junction proteins. Also, testin RNAi caused the diffusion of two TJ structural proteins, occludin and ZO-1, diffusing away from the Sertoli cell surface into the cytoplasm. Association and colocalization between ZO-1 and occludin were decreased after testin RNAi, examined by Co-IP and coimmunofluorescent staining, respectively. Furthermore, testin RNAi induced a dramatic disruption on the arrangement of actin filament bundles and a reduced F-actin/G-actin ratio. The actin regulatory protein ARP3 appeared at the Sertoli cell interface after testin RNAi without its protein level change, whereas overexpressing testin in Sertoli cells showed no effect on TJ barrier integrity. The above findings suggest that besides as a monitor for Sertoli-germ cell junction integrity, testin is also an essential molecule to maintain Sertoli-Sertoli junctions.

Spatially localized oscillations in periodically forced systems are intriguing phenomena. They may occur in spatially homogeneous media (oscillons), but quite often emerge in heterogeneous media, such as the auditory system, where localized oscillations are believed to play an important role in frequency discrimination of incoming sound waves. In this paper, we use an amplitude-equation approach to study the spatial profile of the oscillations and the factors that affect it. More specifically, we use a variant of the forced complex Ginzburg-Landau (FCGL) equation to describe an oscillatory system below the Hopf bifurcation with space-dependent Hopf frequency, subject to both parametric and additive forcing. We show that spatial heterogeneity, combined with bistability of system states, results in spatial asymmetry of the localized oscillations. We further identify parameters that control that asymmetry, and characterize the spatial profile of the oscillations in terms of maximum amplitude, location, width and asymmetry. Our results bear qualitative similarities to empirical observation trends that have found in the auditory system. (C) 2020 Elsevier B.V. All rights reserved.

The activation of behaviour in a daily rhythm governed by the light cycle is a universal phenomenon among humans, laboratory mammals and other vertebrates. For mice, the active period is during the dark. We have quantified the increase in activity when the lights shut off (Light to Dark, L to D) using a generalized CNS arousal assay with 20 ms resolution, rather than traditional running wheels. Data analysis yielded the rare demonstration of an equation which precisely tracks this behavioural transition and, surprisingly, its reverse during D to L. This behavioural dynamic survives in constant darkness (experiment 2) and is hormone-sensitive (experiment 3). Finally (experiment 4), mice on a light schedule analogous to one which proved troublesome for U.S. Navy sailors, had dysregulated activity bursts which did not conform to the transitions between D and L. These experiments show the lawfulness of a behavioural phase transition and the consequence of deviating from that dynamic pattern. And, in a new way, they bring mathematics to the realm of behavioural neuroscience.

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes:IFNAR1,IFNAR2,IFNGR2, andIL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF)STAT1mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-alpha R1, IFN-alpha R2, and IFN-gamma R2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-alpha- and IFN-gamma-stimulated monocytes from DS patients but lower than those in patients with GOFSTAT1mutations. Following stimulation with IFN-alpha or -gamma, but not with IL-6 or IL-21, pSTAT1 and IFN-gamma activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients withSTAT1GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-alpha- and IFN-gamma-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOFSTAT1mutations. Unlike patients with GOFSTAT1mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8(+)T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

Rationale Agonists of the kappa opioid receptor (KOR) have been shown to block the rewarding effects of drugs of abuse, but with negative side effects. The antipruritic drug nalfurafine, approved in Japan in 2009, is a potent, selective KOR agonist that does not cause significant side effects in humans. Nalfurafine has not been extensively tested for its effect on drug reward and reinforcement in preclinical models. Objectives The goal of this study was to compare the effects of nalfurafine and a reference KOR agonist for a variety of KOR-mediated endpoints in male C57BL6 mice. Specifically, we aimed to evaluate the "therapeutic window"-doses of agonists lower than those eliciting negative side effects, while still effective for desired therapeutic effects. Methods In this study, several low doses of nalfurafine and U50,488 were tested for serum prolactin release, rotarod-mediated sedation, and place-conditioning in male C57BL6 mice. These agonists were also tested for effects on intravenous cocaine self-administration, both on an FR1 schedule and on a progressive ratio schedule for 0.5 mg/kg/infusion cocaine. Results Serum prolactin levels increased following doses of both nalfurafine (3 mu g/kg and 10 mu g/kg) and U50,488 (3 mg/kg). These doses did not cause sedation in the rotarod assay or aversion in a place-conditioning assay, but blocked conditioned place preference for cocaine. Immediate pretreatment of mice with 10 mu g/kg nalfurafine and 3 mg/kg U50,488, however, potentiated cocaine self-administration. Further 10 mu g/kg nalfurafine was also observed to potentiate cocaine-seeking behavior as demonstrated by increased progressive ratio break point. Conclusions Both nalfurafine and U50,488 showed a separation of negative side effects and the modulation of cocaine reward, suggesting this effect of KOR agonists at low doses may be characteristic of the KOR system in general. At higher doses, nalfurafine had similar effects to traditional KOR agonists like U50,488, indicating that its relative potency, rather than differences in KOR signaling, may be responsible for its unique effects in humans.

Why do some young and previously healthy individuals develop severe COVID-19? In this Comment, Casanova and colleagues suggest that monogenic inborn errors of immunity may be responsible based on lessons from other viral infections. Severe COVID-19 is rare in previously healthy individuals who are less than 50 years of age, affecting probably no more than 1 in 1,000 such infected individuals. We suggest that these patients may become critically ill because of monogenic inborn errors that disrupt protective immunity to SARS-CoV-2.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFN gamma) immunity, including interleukin IL-12 receptor-beta 1 (IL-12R beta 1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFN gamma receptor 1 (IFN gamma R1) deficiency, IFN gamma receptor 2 (IFN gamma R2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

Autologous stem cell transplantation (ASCT) remains the standard of care for transplantation-eligible patients with multiple myeloma (MM). Bortezomib with lenalidomide and dexamethasone (VRD) is the most common triplet regimen for newly diagnosed MM in the United States. Carfilzomib with lenalidomide and dexamethasone (KRD) has shown promising efficacy and may supplant VRD. We compared stem cell yields and autograft minimal residual disease (MRD)-negativity after VRD and KRD induction. Deeper responses (ie, very good partial response or better) were more common with KRD. Precollection bone marrow (BM) cellularity, interval from the end of induction therapy to start of stem cell collection, and method of stem cell mobilization were similar for the 2 cohorts. Days to complete collection was greater with KRD (2.2 days, versus 1.81 days with VRD), which more often required >= 3 days of apheresis. Precollection viable CD34(+) cell content was greater with VRD, as was collection yield (11.11 x 10(6), versus 9.19 x 10(6) with KRD). Collection failure (defined as <2 x 10(6) CD34(+) cells/kg) was more frequent with KRD (5.4% versus .7% with VRD). The difference in stem cell yield between VRD and KRD is associated with the degree of lenalidomide exposure. Age >= 70 years predicted poorer collection for both cohorts. Stem cell autograft purity/MRD-negativity was higher with KRD (81.4%, versus 57.1% with VRD). For both cohorts, MRD-negativity was attained in a larger fraction of autografts than in precollection BM. For patients proceeding to ASCT, the time to neutrophil/platelet engraftment was comparable in the 2 study arms. In summary, our data demonstrate that KRD induces deeper clinical responses and greater autograft purity than VRD without compromising stem cell yield or post-transplantation engraftment kinetics. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.