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In this issue of Blood, Aluri et al report 6 unrelated male patients who carried gain-of-function (GOF) variants of the X-linked gene TLR8.(1) The patients had invasive bacterial and fungal infections associated with splenomegaly and lymphadenopathy. They had an excess of double-negative T cells, abnormal B-cell maturation, and neutropenia, and some patients had bone marrow failure.

Evolutionarily young genes are usually preferentially expressed in the testis across species. Although it is known that older genes are generally more broadly expressed than younger genes, the properties that shaped this pattern are unknown. Older genes may gain expression across other tissues uniformly, or faster in certain tissues than others. Using Drosophila gene expression data, we confirmed previous findings that younger genes are disproportionately testis biased and older genes are disproportionately ovary biased. We found that the relationship between gene age and expression is stronger in the ovary than any other tissue and weakest in testis. We performed ATAC-seq on Drosophila testis and found that although genes of all ages are more likely to have open promoter chromatin in testis than in ovary, promoter chromatin alone does not explain the ovary bias of older genes. Instead, we found that upstream transcription factor (TF) expression is highly predictive of gene expression in ovary but not in testis. In the ovary, TF expression is more predictive of gene expression than open promoter chromatin, whereas testis gene expression is similarly influenced by both TF expression and open promoter chromatin. We propose that the testis is uniquely able to express younger genes controlled by relatively few TFs, whereas older genes with more TF partners are broadly expressed with peak expression most likely in the ovary. The testis allows widespread baseline expression that is relatively unresponsive to regulatory changes, whereas the ovary transcriptome is more responsive to trans-regulation and has a higher ceiling for gene expression.

Background. Limited information is available on pneumococcal colonization among adults. We studied pneumococcal carriage dynamics in healthy adults using high-sensitivity approaches. Methods. Eighty-seven adults (25-50 years old) were followed for 6 months in Portugal. Nasopharyngeal, oropharyngeal, and saliva samples were obtained monthly; pneumococcal carriers were also sampled weekly. Carriage was investigated by quantitative polymerase chain reaction (targeting lytA and piaB) and culture. Positive samples were serotyped. Results. Approximately 20% of the adults were intermittent carriers; 10% were persistent carriers (>4 months). Pneumococcal acquisition and clearance rates were 16.5 (95% confidence interval [Cl], 11.2-24.2) and 95.9 (95% CI, 62.3-145.0) cases/1000 person-weeks, respectively. Living with children increased pneumococcal acquisition (hazard ratio, 9.7 [95% Cl, 2.6-20.5]; P < .001). Median duration of carriage was 7 weeks and did not depend on regular contact with children. Conclusions. The pneumococcal carrier state in healthy adults is more dynamic than generally assumed: Acquisition is frequent and duration of carriage is often long. 'Ibis suggests that some adults may act as reservoirs of pneumococci and hence, depending on the social structure of a community, the magnitude of herd effects potentially attainable through children vaccination may vary. These findings are important when designing strategies to prevent pneumococcal disease in adults.

Objective: The goal of this study was to determine if a 6-week, peer-led intervention improves health literacy and numeracy among people living with HIV (PLWH). Methods: We used a randomized controlled trial with repeated measurements, which included six, 90 minute, group-based training sessions. We recruited PLWH participants (n = 359) from safety-net practices in the New York City Metropolitan area and Rochester, NY. Participants were randomly assigned (1:1) to an intervention group (n = 180) or a control group (n = 179). Outcome measures were collected at baseline, eight weeks post-baseline, and at six months using the Brief Estimate of Health Knowledge and Action-HIV (BEHKA-HIV), the Electronic Health Literacy Scale (eHEALS), the Rapid Estimate of Adult Literacy (REALM), and the Newest Vital Sign (NVS). Results: The intervention group had statistically significant improvements in eHealth literacy and BEHKAHIV compared to the control group. There were no statistically significant changes in general health literacy or numeracy in either group. The intervention had the greatest impact on participants with the lowest levels of eHealth literacy at baseline. Conclusion: The intervention had a positive impact on participants & rsquo; HIV health literacy and eHealth literacy. Practice implications: Our findings have implications for broadening the function of peer-workers in the health care continuum. (c) 2020 Elsevier B.V. All rights reserved.

Backtracking, the reverse motion of the transcriptase enzyme on the nucleic acid template, is a universal regulatory feature of transcription in cellular organisms but its role in viruses is not established. Here we present evidence that backtracking extends into the viral realm, where backtracking by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) may aid viral transcription and replication. Structures of SARS-CoV-2 RdRp bound to the essential nsp13 helicase and RNA suggested the helicase facilitates backtracking. We use cryo-electron microscopy, RNA-protein cross-linking, and unbiased molecular dynamics simulations to characterize SARS-CoV-2 RdRp backtracking. The results establish that the single-stranded 3 ' segment of the product RNA generated by backtracking extrudes through the RdRp nucleoside triphosphate (NTP) entry tunnel, that a mismatched nucleotide at the product RNA 3 ' end frays and enters the NTP entry tunnel to initiate backtracking, and that nsp13 stimulates RdRp backtracking. Backtracking may aid proofreading, a crucial process for SARS-CoV-2 resistance against antivirals.

Intravesical immunotherapy using Bacille Calmette-Guerin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8(+) T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8(+) T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fc. receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naive and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-19(1,2). A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-19(3). Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

cerebellum is thought to have a variety of functions because it developed with the evolution of the cerebrum and connects with different areas in the frontoparietal cortices. Like neurons in the cerebral cortex, those in the cerebellum also exhibit strong activity during planning in addition to the execution of movements. However, their specific roles remain elusive. In this article, we review recent findings focusing on preparatory activities found in the primate deep cerebellar nuclei during tasks requiring deliberate motor control and temporal prediction. Neurons in the cerebellum are active during anti-saccade preparation and their inactivation impairs proactive inhibitory control for saccades. Experiments using a self-timing task show that there are mechanisms for tracking elapsed time and regulating trial-by-trial variation in timing, and that the cerebellum is involved in the latter. When predicting the timing of periodic events, the cerebellum provides more accurate temporal information than the striatum. During a recently developed synchronized eye movement task, cerebellar nuclear neurons exhibited periodic preparatory activity for predictive synchronization. In all cases, the cerebellum generated preparatory activity lasting for several hundred milliseconds. These signals may regulate neuronal activity in the cerebral cortex that adjusts movement timing and predicts the timing of rhythmic events. This article is part of a Special Issue entitled: In Memoriam: Masao Ito?A Visionary Neuroscientist with a Passion for the Cerebellum. ? 2020 IBRO. Published by Elsevier Ltd. All rights reserved.