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Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines., Mares et al. develop Proteolysis-Targeting Chimeras (PROTACs) that degrade its target RIPK2 in vivo at low doses for a prolonged period of time. This study suggests that PROTAC has a therapeutic potential that is superior to traditional RIPK2 small-molecule inhibitors.

Objective Spinal arteriovenous malformations (SAVMs) are a very rare and complex spinal cord pathology that require high clinical acumen to diagnose and treat. Management includes both nonoperative and operative paradigms. A review of the literature yields a paucity of data regarding the surgical outcomes of SAVMs, with the majority of data limited to single-center outcomes and/or small sample sizes. The purpose of this study was to use a multi-institutional international database to study the natural history of SAVMs. Methods We used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to select patients that underwent laminectomy for surgical excision of a SAVM between 2008 and 2017. Results The data from 196 patients were studied (65.8% male, 34.2% female). A majority of cases were in the thoracic region (53.6%), followed by thoracolumbar (31.6%) and cervical (14.8%) regions. The mean age was 57.4 years and 52.5% patients were graded ASA class 3–5 before the operation. The mean operation time was 215 minutes, with a significantly lower operative time for thoracic arteriovenous malformations (195.6 minutes) when compared with cervical (266.6 minutes) and thoracolumbar (223.7 minutes). The mean length of hospital stay was 6.4 days. Patients had a 6.6% readmission rate and a 4.6% reoperation rate within 30 days. Conclusions This study presents the largest analysis of patients undergoing surgery for SAVMs and 30-day postoperative outcomes. Operative time differed based on SAVM location. The three most frequent complications (deep vein thrombosis, wound infection, and UTI) occurred at rates of 3.6% or less.

Food-based diet indices provide a practical, rapid, and inexpensive way of evaluating dietary intake. Rather than nutrients, diet indices assess the intake of whole foods and dietary patterns, and compare these with nutrition guidelines. An athlete-specific diet index would offer an efficient and practical way to assess the quality of athletes’ diets, guide nutrition interventions, and focus sport nutrition support. This study describes the development and validation of an Athlete Diet Index (ADI). Item development was informed by a review of existing diet indices, relevant literature, and in-depth focus groups with 20 sports nutritionists (median of 11 years’ professional experience) from four elite athlete sporting institutes. Focus group data were analyzed (NVivo 11 Pro; QSR International Pty. Ltd., 2017, Melbourne, Australia), and key themes were identified to guide the development of athlete-relevant items. A modified Delphi survey in a subgroup of sports nutritionists (n = 9) supported item content validation. Pilot testing with athletes (n = 15) subsequently informed face validity. The final ADI (n = 68 items) was categorized into three sections. Section A (n = 45 items) evaluated usual intake, special diets or intolerances, dietary habits, and culinary skills. Section B (n = 15 items) assessed training load, nutrition supporting training, and sports supplement use. Section C (n = 8 items) captured the demographic details, sporting type, and caliber. All of the athletes reported the ADI as easy (40%) or very easy (60% of participants) to use and rated the tool as relevant (37%) or very relevant (63% of participants) to athletes. Further evaluation of the ADI, including the development of a scoring matrix and validation compared with established dietary methodology, is warranted.

Background Primary melanocytic neoplasms of the central nervous system (CNS) are rare and account for 1% of all melanomas. This study used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the epidemiology of primary CNS melanoma and further characterize their treatment. Methods Data from the National Cancer Institute SEER program, collected from 1973–2015, were retrospectively analyzed. A total of 86 records of malignant melanoma cases with CNS as the primary site were identified, and 54 patients were studied based on the inclusion criteria. Demographic, tumor, and treatment regimen effectiveness were studied. Results A total of 54 patients were included in this study. Tumors were distributed evenly in size and localized primarily to the cerebral meninges and spinal cord. A total of 13% of patients underwent biopsy, 40.7% gross total resection (GTR), 7.4% subtotal resection (STR), 46.3% radiation therapy (RT), and 27.3% chemotherapy (CT) in a variety of treatment combinations. GTR alone and STR + RT resulted in increased disease-specific survival compared to biopsy alone, but no survival benefit was found with biopsy with RT and/or CT as well as STR alone. Conclusions To our knowledge, this is the largest single database study completed for primary malignant melanoma of the CNS. The study identified the need for tumor resection for the proper treatment of these lesions, particularly GTR. GTR could be paired with adjuvant RT or RT + CT providing survival benefit as well. In cases when GTR is unable to be completed, STR + RT provides significant improvement in survival compared to biopsy alone.

Between 2013 and 2016, police in one Brazilian city killed 3,287 people—66.5 percent of whom were black. It might not seem surprising, then, that this place is also one of the only in the world that has a prison just for police. But this prison is exceptional, a “model” place, as those who run it say. It isn’t “dungeon-like” or a “warehouse of black lives,” as scholars describe prisons in this country and elsewhere. Among an apiary, a tilapia pond, and groves of citrus trees, few police are here because they killed on the job. Using ethnography from in and outside this prison, we examine narratives of socialization, redemption, and mundane and exceptional killing to illustrate what operates beneath the public veneer of the punishment of police. This lays bare key assumptions about the function of policing and the possibility of reform amid capitalism, in a vital moment of global political rupture. To speak of impunity for police violence, or of iterative gains in reform, is to dramatically misunderstand the work of policing.

Since the discovery of the first microRNA (miRNA) in Caenorhabditis elegans about 25 years ago, small RNAs have emerged as key players in the broad regulation of gene expression in most developmental processes in both plants and animals. miRNAs are small (20–24 nt) noncoding RNA molecules involved in posttranscriptional regulation of gene expression.miRNAs regulate gene expression by cleavage of the target transcript and/or through translational repression. The former appears to be a more prevalent mechanism in plants whereas the later appears to be predominant in animals. The level of miRNA-target sequence complementarity typically dictates whether mRNA repression or transcript cleavage occurs. This article will focus on our current understanding of the roles of miRNAs in plant development with a key focus on developmentally importantmiRNAs of the model plant, Arabidopsis thaliana, their modes of action, and the networks to which they belong. This article will also briefly discuss conservation of microRNAs across other plant species and directions for future research on miRNA.

Learning disabilities are currently conceptualised as involving underlying weaknesses in cognitive processing, which has prompted growing interest in cognitive interventions that may alleviate lear...

McCabe is right on one thing and wrong on another. She is right to draw our attention to the different aspects that a verb might have—and not only because attention to aspect helps us understand wh...