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Successful cancer immunotherapy entails activation of innate immune receptors to promote dendritic cell (DC) maturation, antigen presentation, up-regulation of costimulatory molecules, and cytokine secretion, leading to activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 compounds for innate immune activators using TNF production by THP-1 cells as a readout. We identified and optimized a potent human and mouse Toll-like receptor (TLR)1/TLR2 agonist, Diprovocim, which exhibited an EC50 of 110 pM in human THP-1 cells and 1.3 nM in primary mouse peritoneal macrophages. In mice, Diprovocim-adjuvanted ovalbumin immunization promoted antigen-specific humoral and CTL responses and synergized with anti–PD-L1 treatment to inhibit tumor growth, generating long-term antitumor memory, curing or prolonging survival of mice engrafted with the murine melanoma B16-OVA. Diprovocim induced greater frequencies of tumor-infiltrating leukocytes than alum, of which CD8 T cells were necessary for the antitumor effect of immunization plus anti–PD-L1 treatment.

Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)- dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.

Ankle fractures are common musculoskeletal injuries that may result in tibiotalar joint dislocations. Ankle fracture-dislocations occur via similar mechanisms as ankle fractures, although the persistence or magnitude of the deforming force is sufficient to disrupt any remaining bony or soft-tissue stability. Ankle fracture-dislocations likely represent distinct clinical entities, as the pathology, management, and patient outcomes following these injuries differ from those seen in more common ankle fractures without dislocation. Ankle fracture-dislocations have higher rates of concomitant injury including open fractures, chondral lesions, and intra-articular loose bodies. Long-term outcomes in ankle fracture-dislocations are worse than ankle fractures without dislocation. Higher rates of posttraumatic osteoarthritis and chronic pain have also been reported. In this review, we discuss the current literature regarding the history, management, and outcomes of ankle-fracture dislocations and highlight the need for future study.

The posterior malleolar fragment is frequently involved in rotational ankle fractures, but diagnosis and definitive management remains controversial. Ankle fractures with a posterior malleolar component that are not identified and treated in a timely manner may contribute significantly to future comorbidities, including continued pain, instability, and the development of arthritis. This article highlights the anatomic features of posterior malleolar ankle fractures, the classification schemes used, and discusses the various nonsurgical and surgical methods currently used. Level of Evidence: Level V, expert opinion.

Ankle fractures are common musculoskeletal injuries that may result in tibiotalar joint dislocations. Ankle fracture-dislocations occur via similar mechanisms as ankle fractures, although the persistence or magnitude of the deforming force is sufficient to disrupt any remaining bony or soft-tissue stability. Ankle fracture-dislocations likely represent distinct clinical entities, as the pathology, management, and patient outcomes following these injuries differ from those seen in more common ankle fractures without dislocation. Ankle fracture-dislocations have higher rates of concomitant injury including open fractures, chondral lesions, and intra-articular loose bodies. Long-term outcomes in ankle fracture-dislocations are worse than ankle fractures without dislocation. Higher rates of posttraumatic osteoarthritis and chronic pain have also been reported. In this review, we discuss the current literature regarding the history, management, and outcomes of ankle-fracture dislocations and highlight the need for future study.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2 , which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B , a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. Histones modified in common lymphomas Despite being a focus of research activity for many years, the mutations driving the two most common non-Hodgkin lymphomas — follicular lymphoma and diffuse large B-cell lymphoma — have remained cryptic. Whole genome sequencing, combined with transcriptome analysis and further resequencing of candidate genes in additional tumours, now show that histone methyltransferases and acetylases are frequently affected by mutations in these tumours. This study suggests a previously unappreciated importance of chromatin biology in lymphomagenesis.

Bacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans -translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans -translation by these molecules. These results show that trans -translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways. Antibiotic-resistant bacterial pathogens pose a substantial threat to human health. Here, aided by structural analyses, the authors describe the molecular mechanism behind the activity of a series of compounds that inhibit trans-translation and are effective in eradicating N. gonorrhoeae infection in mice.

The COVID-19 pandemic has disproportionately affected health care workers. We sought to estimate SARS-CoV-2 seroprevalence among hospital health care workers in Quebec, Canada, after the first wave of the pandemic and to explore factors associated with SARS-CoV-2 seropositivity. Between July 6 and Sept. 24, 2020, we enrolled health care workers from 10 hospitals, including 8 from a region with a high incidence of COVID-19 (the Montréal area) and 2 from low-incidence regions of Quebec. Eligible health care workers were physicians, nurses, orderlies and cleaning staff working in 4 types of care units (emergency department, intensive care unit, COVID-19 inpatient unit and non-COVID-19 inpatient unit). Participants completed a questionnaire and underwent SARS-CoV-2 serology testing. We identified factors independently associated with higher seroprevalence. Among 2056 enrolled health care workers, 241 (11.7%) had positive SARS-CoV-2 serology. Of these, 171 (71.0%) had been previously diagnosed with COVID-19. Seroprevalence varied among hospitals, from 2.4% to 3.7% in low-incidence regions to 17.9% to 32.0% in hospitals with outbreaks involving 5 or more health care workers. Higher seroprevalence was associated with working in a hospital where outbreaks occurred (adjusted prevalence ratio 4.16, 95% confidence interval [CI] 2.63–6.57), being a nurse or nursing assistant (adjusted prevalence ratio 1.34, 95% CI 1.03–1.74) or an orderly (adjusted prevalence ratio 1.49, 95% CI 1.12–1.97), and Black or Hispanic ethnicity (adjusted prevalence ratio 1.41, 95% CI 1.13–1.76). Lower seroprevalence was associated with working in the intensive care unit (adjusted prevalence ratio 0.47, 95% CI 0.30–0.71) or the emergency department (adjusted prevalence ratio 0.61, 95% CI 0.39–0.98). Health care workers in Quebec hospitals were at high risk of SARS-CoV-2 infection, particularly in outbreak settings. More work is needed to better understand SARS-CoV-2 transmission dynamics in health care settings.

The primary means of disseminating sport and exercise science research is currently through journal articles. However, not all studies, especially those with null findings, make it to formal publication. This publication bias towards positive findings may contribute to questionable research practices. Preregistration is a solution to prevent the publication of distorted evidence resulting from this system. This process asks authors to register their hypotheses and methods before data collection on a publicly available repository or by submitting a Registered Report. In the Registered Report format, authors submit a stage 1 manuscript to a participating journal that includes an introduction, methods, and any pilot data indicating the exploratory or confirmatory nature of the study. After a stage 1 peer review, the manuscript can then be offered in-principle acceptance, rejected, or sent back for revisions to improve the quality of the study. If accepted, the project is guaranteed publication, assuming the authors follow the data collection and analysis protocol. After data collection, authors re-submit a stage 2 manuscript that includes the results and discussion, and the study is evaluated on clarity and conformity with the planned analysis. In its final form, Registered Reports appear almost identical to a typical publication, but give readers confidence that the hypotheses and main analyses are less susceptible to bias from questionable research practices. From this perspective, we argue that inclusion of Registered Reports by researchers and journals will improve the transparency, replicability, and trust in sport and exercise science research. The preprint version of this work is available on SportR χ iv: https://osf.io/preprints/sportrxiv/fxe7a/ .