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Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence,

Introduction: Platelet function testing using serial VerifyNow P2Y12 platelet reactivity units (PRUs) is established for guiding clopidogrel antiplatelet therapy in cerebral aneurysm stenting procedures. However, for ticagrelor, the impact of serial PRU testing and the identification of safe PRU ranges remains unexplored., Methods: Flow diversion stenting ( n = 232) and stent-assisted coiling procedures ( n = 83) performed 05/2017-12/2021 were reviewed. Out of these, 31 flow diversion and 18 stent-coiling procedures were performed on 44 patients using ticagrelor. Baseline demographics, ticagrelor PRUs, and clinical outcomes were assessed., Results: Collectively, 257 ticagrelor P2Y12 PRUs were obtained. PRUs were <100 in 192/257 (74.7%) tests. Only 11/257 (4.3%) PRUs were >200. The overall median ticagrelor PRU was 38 (IQR 11-101). Among the 49 procedures, median PRUs before the procedure (25, IQR 10-67), on the day of the procedure (68, IQR 44-117), and on the day after the procedure (37, IQR 21-79) did not show the significant differences between the groups. A total of seven thromboembolic complications occurred. Median PRUs surrounding the thromboembolic complications (median 182, IQR 148-235) were significantly higher than preprocedural ( p < .001), day of surgery ( p < .01), and postprocedural PRUs ( p < .01). All seven procedures harbored demographic, anatomic, or procedural features increasing the risk for thromboembolic complications., Discussion: The majority of periprocedural ticagrelor PRUs were <100. PRUs at the time point of thromboembolic complications were >120. Despite procedure-complicating features in each thromboembolic case, it raises the question whether safe ticagrelor PRU levels might be lower than those commonly applied for clopidogrel., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The M1 middle cerebral artery (MCA) commonly bifurcates into M2 superior and M2 inferior segments. However, MCA anatomy is highly variable rendering classification for mechanical thrombectomy trials difficult. This study explored safety and effectiveness of M2 MCA stroke thrombectomy stratified by M2 MCA anatomy., Methods: Cases of large vessel occlusion strokes treated by mechanical thrombectomy between February 2016 and August 2022 were reviewed (N = 784). M1 (n = 431) and M2 (n = 118) MCA occlusions were assessed. Among M2 MCA occlusions, only prototypical MCA bifurcation anatomy cases were included (n = 99). Dominance was assessed based on angiography. Procedural and outcome data were compared between M1, M2 superior, and M2 inferior MCA occlusions., Results: Baseline demographics and periprocedural criteria of M2 superior (n = 56) and M2 inferior (n = 43) occlusion mechanical thrombectomies were comparable. The occluded branch was dominant in 41/43 (95.3%) M2 inferior cases, but in only 37/56 (66.1%) M2 superior cases (P < 0.001). The 90-day favorable functional outcome (modified Rankin Scale score 0-2) and mortality (modified Rankin Scale score 6) rates were 60.0% and 8.9% in M2 superior, 42.9% and 32.6% in M2 inferior, and 44.1% and 26.0% in M1 (n = 431) cases. Compared with M2 superior cases, in M2 inferior cases, favorable outcome rates were lower (P = 0.094) and mortality rates were higher (P = 0.003) and resembled M1 rates (P = 0.750 and P = 0.355, respectively)., Conclusions: In the setting of prototypical MCA bifurcation anatomy, thrombectomy of dominant M2 inferior occlusions had outcome rates similar to M1 occlusions. In contrast, M2 superior occlusions had significantly lower mortality rates and a trend toward better favorable functional outcome rates., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.

SNAPSHOT USA is a multicontributor, long-term camera trap survey designed to survey mammals across the United States. Participants are recruited through community networks and directly through a website application (https://www.snapshot-usa.org/). The growing Snapshot dataset is useful, for example, for tracking wildlife population responses to land use, land cover, and climate changes across spatial and temporal scales. Here we present the SNAPSHOT USA 2021 dataset, the third national camera trap survey across the US. Data were collected across 109 camera trap arrays and included 1711 camera sites. The total effort equaled 71,519 camera trap nights and resulted in 172,507 sequences of animal observations. Sampling effort varied among camera trap arrays, with a minimum of 126 camera trap nights, a maximum of 3355 nights, a median 546 nights, and a mean 656 ± 431 nights. This third dataset comprises 51 camera trap arrays that were surveyed during 2019, 2020, and 2021, along with 71 camera trap arrays that were surveyed in 2020 and 2021. All raw data and accompanying metadata are stored on Wildlife Insights (https://www.wildlifeinsights.org/), and are publicly available upon acceptance of the data papers. SNAPSHOT USA aims to sample multiple ecoregions in the United States with adequate representation of each ecoregion according to its relative size. Currently, the relative density of camera trap arrays varies by an order of magnitude for the various ecoregions (0.22-5.9 arrays per 100,000 km 2 ), emphasizing the need to increase sampling effort by further recruiting and retaining contributors. There are no copyright restrictions on these data. We request that authors cite this paper when using these data, or a subset of these data, for publication. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the US Government., (© 2024 The Ecological Society of America.)

A cancer diagnosis in young adulthood disrupts the achievement of developmental milestones, and young adults struggle to make sense of their cancer experience due to a lack of opportunities to both openly talk about cancer and engage in reflective activities. However, entertainment narratives - or stories - may be an alternative to prompt these activities, as narratives can elicit self-expansion that may help fulfill intrinsic needs. One way to think about these narratives is as memorable messages. These messages stick with a person for a long period of time, have an anticipatory socialization effect, and may prompt the sense-making process through narrative communication. Little is known, though, about the use of entertainment narratives among young adults with cancer. We interviewed 25 young adults with cancer about entertainment narratives that were memorable during their cancer experience and how those narratives affected them. From these in-depth, semi-structured interviews, we found that entertainment narratives were generally helpful if they provided distraction from cancer, were relatable, and/or prompted participants to explore their emotions. We found that entertainment narratives were generally harmful if they worsened participants' emotional state, either by exacerbating fears of death and/or depicting cancer unrealistically. Our findings suggest that entertainment narratives are memorable messages, and that helpful messages increased feelings of competence and validation, which could promote psychological adaptation to the disease. Harmful messages increased fear and invalidated participants' difficult experiences, which could lead to greater illness centrality and internalized stigma. Implications for future research are discussed.

Background: Tenecteplase (TNK) is a genetically modified variant of alteplase (TPA) and has been established as a non-inferior alternative to TPA in acute ischemic stroke (AIS). Whether TNK exerts distinct benefits in large vessel occlusion (LVO) AIS is still being investigated., Objective: To describe our first-year experience after a healthcare system-wide transition from TPA to TNK as the primary thrombolytic., Methods: Patients with AIS who received intravenous thrombolytics between January 2020 and August 2022 were retrospectively reviewed. All patients with LVO considered for mechanical thrombectomy (MT) were included in this analysis. Spontaneous recanalization (SR) after TNK/TPA was a composite variable of reperfusion >50% of the target vessel territory on cerebral angiography or rapid, significant neurological recovery averting MT. Propensity score matching (PSM) was performed to compare SR rates between TNK and TPA., Results: A total of 148 patients were identified; 51/148 (34.5%) received TNK and 97/148 (65.5%) TPA. The middle cerebral arteries M1 (60.8%) and M2 (29.7%) were the most frequent occlusion sites. Baseline demographics were comparable between TNK and TPA groups. Spontaneous recanalization was significantly more frequently observed in the TNK than in the TPA groups (unmatched: 23.5% vs 10.3%, P=0.032). PSM substantiated the observed SR rates (20% vs 10%). Symptomatic intracranial hemorrhage, 90-day mortality, and functional outcomes were similar., Conclusions: The preliminary experience from a real-world setting demonstrates the effectiveness and safety of TNK before MT. The higher spontaneous recanalization rates with TNK are striking. Additional studies are required to investigate whether TNK is superior to TPA in LVO AIS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Human-driven environmental changes shape ecological communities from local to global scales. Within cities, landscape-scale patterns and processes and species characteristics generally drive local-scale wildlife diversity. However, cities differ in their structure, species pools, geographies and histories, calling into question the extent to which these drivers of wildlife diversity are predictive at continental scales. In partnership with the Urban Wildlife Information Network, we used occurrence data from 725 sites located across 20 North American cities and a multi-city, multi-species occupancy modelling approach to evaluate the effects of ecoregional characteristics and mammal species traits on the urbanization-diversity relationship. Among 37 native terrestrial mammal species, regional environmental characteristics and species traits influenced within-city effects of urbanization on species occupancy and community composition. Species occupancy and diversity were most negatively related to urbanization in the warmer, less vegetated cities. Additionally, larger-bodied species were most negatively impacted by urbanization across North America. Our results suggest that shifting climate conditions could worsen the effects of urbanization on native wildlife communities, such that conservation strategies should seek to mitigate the combined effects of a warming and urbanizing world., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10 -4 ), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10 -8 ) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment., (© 2022. The Author(s).)

Background and Purpose: IV thrombolysis with alteplase before mechanical thrombectomy for emergent large-vessel-occlusion stroke is associated with access-site bleeding complications. However, the incidence of femoral access-site complications with tenecteplase before mechanical thrombectomy requires exploration. Here, femoral access-site complications with tenecteplase versus alteplase before mechanical thrombectomy for large-vessel-occlusion stroke were compared., Materials and Methods: All patients receiving IV thrombolytics before mechanical thrombectomy for large-vessel-occlusion stroke who presented from January 2020 to August 2022 were reviewed. In May 2021, our health care system switched from alteplase to tenecteplase as the primary thrombolytic for all patients with stroke, facilitating the comparison of alteplase-versus-tenecteplase femoral access-site complication rates. Major (requiring surgery) and minor (managed conservatively) access-site complications were assessed., Results: One hundred thirty-nine patients underwent transfemoral mechanical thrombectomy for large-vessel-occlusion stroke, of whom 46/139 (33.1%) received tenecteplase and 93/139 (66.9%) received alteplase. In all cases ( n = 139), an 8F sheath was inserted without sonographic guidance, and vascular closure was obtained with an Angio-Seal. Baseline demographics, concomitant antithrombotic medications, and periprocedural coagulation lab findings were similar between groups. The incidence of conservatively managed groin hematomas (2.2% versus 4.3%), delayed access-site oozing requiring manual compression (6.5% versus 2.2%), and arterial occlusion requiring surgery (2.2% versus 1.1%) was similar between the tenecteplase and alteplase groups, respectively ( P = not significant). No dissection, arteriovenous fistula, or retroperitoneal hematoma was observed., Conclusions: Tenecteplase compared with alteplase before mechanical thrombectomy for large-vessel-occlusion stroke is not associated with an alteration in femoral access-site complication rates., (© 2023 by American Journal of Neuroradiology.)

Background: While online portals may be helpful to engage patients in shared decision-making at the time of cancer screening, because of known disparities in patient portal use, sole reliance on portals to support cancer screening decision-making could exacerbate well-known disparities in this health care area. Innovative approaches are needed to engage patients in health care decision-making and to support equitable shared decision-making., Objective: We assessed the acceptability of text messages to engage sociodemographically diverse individuals in colorectal cancer (CRC) screening decisions and support shared decision-making in practice., Methods: We developed a brief text message program offering educational information consisting of components of shared decision-making regarding CRC screening (eg, for whom screening is recommended, screening test options, and pros/cons of options). The program and postprogram survey were offered to members of an online panel. The outcome of interest was program acceptability measured by observed program engagement, participant-reported acceptability, and willingness to use similar programs (behavioral intent). We evaluated acceptability among historically marginalized categories of people defined by income, literacy, and race., Results: Of the 289 participants, 115 reported having a low income, 146 were Black/African American, and 102 had less than extreme confidence in their health literacy. With one exception, we found equal or greater acceptability, regardless of measure, within each of the marginalized categories of people compared to their counterparts. The exception was that participants reporting an income below US $50,000 were less likely to engage with sufficient content of the program to learn that there was a choice among different CRC screening tests (difference -10.4%, 95% CI -20.1 to -0.8). Of note, Black/African American participants reported being more likely to sign up to receive text messages from their doctor's office compared to white participants (difference 18.7%, 95% CI 7.0-30.3)., Conclusions: Study findings demonstrate general acceptance of text messages to inform and support CRC screening shared decision-making., (©Soohyun Hwang, Allison J Lazard, Meredith K Reffner Collins, Alison T Brenner, Hillary M Heiling, Allison M Deal, Seth D Crockett, Daniel S Reuland, Jennifer Elston Lafata. Originally published in JMIR Cancer (https://cancer.jmir.org), 05.05.2023.)

COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses., (© 2023. The Author(s).)

Introduction: Tobacco marketing includes text and visual content, which conveys important meaning to consumers and influences use. Little is known about the marketing tactics used by a popular brand of cigarillos on social media to promote their products, including their visual design., Methods: A content analysis was conducted to analyze text and visuals for all posts on Swisher Sweets' official Instagram account from Jan 23, 2013 to Feb 28, 2020. We assessed product depictions (e.g. warnings, smoking cues), presence of FDA-prohibited or potentially misleading claims (e.g. lower risk, organic), marketing tactics (e.g. celebrities, selling propositions), flavors, and demographic representation., Results: We coded 1402 posts. Smoking cues (e.g. images of people smoking, product imagery) were in 764 posts (54.5%), and a warning appeared in 690 (49.2%) posts, but obscured in 29.4% of those instances (n = 203). No posts included FDA-prohibited claims, but some potentially misleading language was identified, including the use of words or visual depictions of smooth (n = 254, 18.1%) and quality/well-made (n = 239, 17%). Marketing tactics such as scarcity (n = 159, 11.3%), event promotion (n = 586, 41.8%), and alcohol depictions (n = 171, 12.2%) were common, and flavor names appeared in 598 posts (42.7%). People depicted were often young adults (n = 709, 50.6%), Black/African American (n = 549, 39.2%), and in groups (n = 473, 33.7%)., Conclusions: Both text and visuals are used to market Swisher Sweets on their Instagram account. Using social images of young adults, especially Black individuals, signals the intended use of the product. These images of visual-based social media may influence appeal, glamorization, and normalization of cigarillo smoking among vulnerable populations., Implications: Tobacco marketing, including from popular cigarillo brands like Swisher Sweets, is widely used to influence consumer perceptions and behavior. Social media marketing includes text and visual, both of which increase product appeal and encourage use. Visual-based social media from the industry itself have been understudied, particularly for cigarillos. This study characterizes the ways in which Swisher Sweets uses text and visuals to market their products through their Instagram account, including smoking cues, potentially misleading language, use of celebrity endorsers, and promotion and sponsorship of events., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pre-existing SARS-CoV-2-specific T cells, but not antibodies, have been detected in some unexposed individuals. This may account for some of the diversity in clinical outcomes ranging from asymptomatic infection to severe COVID-19. Although age is a risk factor for COVID-19, how age affects SARS-CoV-2-specific T cell responses remains unknown. We found that pre-existing T cell responses to specific SARS-CoV-2 proteins, Spike (S) and Nucleoprotein (N), were significantly lower in elderly donors (>70 years old) than in young donors. However, substantial pre-existing T cell responses to the viral membrane (M) protein were detected in both young and elderly donors. In contrast, young and elderly donors exhibited comparable T cell responses to S, N, and M proteins after infection with SARS-CoV-2. These data suggest that although SARS-CoV-2 infection can induce T cell responses specific to various viral antigens regardless of age, diversity of target antigen repertoire for long-lived memory T cells specific for SARS-CoV-2 may decline with age; however, memory T cell responses can be maintained by T cells reactive to specific viral proteins such as M. A better understanding of the role of pre-existing SARS-CoV-2-specific T cells that are less susceptible to age-related loss may contribute to development of more effective vaccines for elderly people., (© 2021 The Authors. Published by Elsevier Inc.)

The edible long-horned grasshopper Ruspolia differens Serville (Orthoptera:Tettigoniidae) is a highly nutritious food source consumed in over 20 African countries. Its occurrence is highly seasonal, and wild harvesting is carried out using locally designed and inefficient light traps, thus limiting sustainable utilization as an important food source. To ensure year-round production and availability of R. differens , we evaluated the effects of low-cost and affordable diets based on agricultural by-products on their growth performance, survival, fecundity, and longevity. A total of four diets with varying ratios of agricultural by-products were evaluated: Diet 1 [33.3% maize bran (MB) + 33.3% wheat bran (WB) + 33.3% Moringa oleifera leaf powder (MOLP)], Diet 2 [25% MB + 25% WB + 25% MOLP + 25% shrimp powder (SP)], Diet 3 [20% MB + 20% WB + 20% MOLP + 20% SP + 20% soya bean meal], and Diet 4 ("control"-routinely used diet). The grasshoppers were subjected to the diets from the 1st nymphal instar (24-h-old stages) through adult stages until death. Diet 3 had the highest crude protein content (28%) and digestibility (74.7%). R. differens fed Diet 3 had the shortest development time (57 days) [ p < 0.001], highest survival (87%) [ p < 0.001], and maximum longevity (89 days) [ p = 0.015] and fecundity (247 eggs/female) [ p = 0.549] across the various diets. Female survival rate (59%) on Diet 3 was significantly higher compared to the males (41%). The adult female weight gain was significantly higher compared to males fed on different diets. Percentage hatchability of eggs was not significantly different when females were fed Diet 3 and Diet 2. There was a significantly positive correlation between longevity and fecundity of R. differens reared on Diet 2 and 3. These diets could be further optimized and fine-tuned for improved cost-effective mass production of R. differens continent-wide to reduce dependence on erratic and poor seasonal harvest during swarms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Margaret, Collins, Subramanian, Egonyu, Nakimbugwe, Ssepuuya, Faith, Ekesi and Tanga.)

Microbial infections are a threat to women's reproductive health. Although reproductive cycles and pregnancy are controlled by sex hormones, the impact of hormones on host-pathogen interactions and immune function in the female reproductive tract are understudied. Furthermore, the changing endocrine environment throughout pregnancy may influence how and when women are susceptible to ascending infection. Because most intrauterine microbial infections originate in the lower reproductive tract, it is vital that future studies determine how different hormonal conditions influence the lower reproductive tract's susceptibility to infection to understand temporal components of infection susceptibilities across pregnancy. These studies should also extend to nonpregnant women, as it is critical to establish how hormonal fluctuations across the menstrual cycle and hormonal contraceptives may influence disease susceptibility. This review summarizes current knowledge of how estrogen and progesterone impact vaginal and cervical mucosal immunity, barrier function, and interactions with microbial communities., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1-24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network., (© 2021. The Author(s).)

Constitutive activation of the canonical NF-κB signaling pathway is a major factor in Kaposi's sarcoma-associated herpes virus pathogenesis where it is essential for the survival of primary effusion lymphoma. Central to this process is persistent upregulation of the inhibitor of κB kinase (IKK) complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKKγ, has been well characterized, it remains unclear how the kinase subunits are rendered active mechanistically. Using a combination of cell-based assays, biophysical techniques, and structural biology, we demonstrate here that vFLIP alone is sufficient to activate the IKK kinase complex. Furthermore, we identify weakly stabilized, high molecular weight vFLIP-IKKγ assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP-induced NF-κB activation pivots on the formation of structurally specific vFLIP-IKKγ multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-κB activation is in contrast to those utilized by endogenous cytokines and cellular FLIP homologues., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate. Ongoing research is focused on the entry of SCFAs into systemic circulation from the gut lumen, their migration to cerebral circulation and across the blood brain barrier, and their potential to exert acute and chronic effects on brain structure and function. This review aims to discuss our current mechanistic understanding of the direct and indirect influence that SCFAs have on brain function, behaviour and physiology, which will inform future microbiota-targeted interventions for brain disorders., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Basaloid follicular hamartoma (BFH) is a rare, benign follicular neoplasm which typically presents as brown to skin-colored papules on the face, scalp, and trunk. Histologically, BFH consists of cords and strands of basaloid cells forming cystic structures with scant stroma and should be distinguished from infundibulocystic basal cell carcinoma to avoid overly aggressive treatment. Although BFH has been found to be associated with distinct syndromes, including alopecia, myasthenia gravis, and cystic fibrosis, there is often clinical, histopathologic, and genetic overlap with nevoid basal cell carcinoma syndrome (NBCCS). In this article, we describe a case of a 13-year-old patient with NBCCS who presented with multiple BFHs and propose that it its inclusion into the diagnostic criteria for NBCCS be considered., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Dual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors., Methods: Assessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices., Results: Both geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy., Conclusions: The latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

HIV-1-negative factor (Nef) protein antagonizes serine incorporator 5 (SERINC5) by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identify cyclin K (CycK) and cyclin-dependent kinase 13 (CDK13) as a Nef-associated kinase complex. CycK/CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counteractivity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we generate chimeric proteins between CD8 and SERINC5 to study their response to Nef. Nef not only downregulates but, importantly, also binds to this chimera in an S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Germ-free rodents, raised in the absence of a measurable gut microbiome, have been a key model to study the microbiome-gut-brain axis. Germ-free mice exhibit marked behavioural and neurochemical differences to their conventionally raised counterparts. It is as yet unclear how these neurochemical differences lead to the behavioural differences. Here, we test the electrophysiological properties of hippocampal plasticity in adult germ-free mice and compare them to conventionally raised counterparts. Whilst basal synaptic efficacy and pre-synaptic short-term plasticity appear normal, we find a striking alteration of hippocampal long-term potentiation specifically in male germ-free slices. However, the spike output of these neurons remains normal along with altered input-output coupling, potentially indicating homeostatic compensatory mechanisms, or an altered excitation/inhibition balance. To our knowledge this is the first time the electrophysiological properties of the hippocampus have been assessed in a microbiome deficient animal. Our data indicate that the absence of a microbiome alters integration of dendritic signalling in the CA1 region in mice., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Importance: Rap artists are among the most recognizable celebrities in the US, serving as role models to an increasingly diverse audience of listeners. Through their lyrics, these artists have the potential to shape mental health discourse and reduce stigma., Objective: To investigate the prevalence and nature of mental health themes in popular rap music amid a period of documented increases in mental health distress and suicide risk among young people in the US and young Black/African American male individuals in particular., Design and Setting: Lyric sheets from the 25 most popular rap songs in the US in 1998, 2003, 2008, 2013, and 2018, totaling  125 songs, were analyzed by 2 trained coders from March 1 to April 15, 2019, for references to anxiety, depression, suicide, metaphors suggesting mental health struggles, and stressors associated with mental health risk., Main Outcomes and Measures: Mental health references were identified and categorized based on Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) and Mayo Clinic definitions. Stressors included issues with authorities, environmental conditions, work, and love life. Descriptive language and trend analyses were used to examine changes over time in the proportion of songs with mental health references. Stressors were analyzed for their co-occurrence with mental health references., Results: Most of the 125 analyzed songs featured lead artists from North America (123 [98%]). Most lead artists were Black/African American male individuals (97 [78%]), and artists' mean (SD) age was 28.2 (4.5) years. Across the sample, 35 songs (28%) referenced anxiety; 28 (22%) referenced depression; 8 (6%) referenced suicide; and 26 (21%) used a mental health metaphor. Significant increases were found from 1998 to 2018 in the proportion of songs referencing suicide (0% to 12%), depression (16% to 32%), and mental health metaphors (8% to 44%). Stressors related to environmental conditions (adjusted odds ratio, 8.1; 95% CI, 2.1-32.0) and love life (adjusted odds ratio, 4.8; 95% CI, 1.3-18.1) were most likely to co-occur with lyrics referencing mental health., Conclusions and Relevance: References to mental health struggles have increased significantly in popular rap music from 1998 to 2018. Future research is needed to examine the potential positive and negative effects these increasingly prevalent messages may have in shaping mental health discourse and behavioral intentions for US youth.

Cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, is a target of thalidomide and thalidomide-derived immunomodulatory drugs (IMiDs). The binding of these IMiDs to CRBN alters the substrate specificity of the ligase, thereby mediating multiple effects that are exploited in cancer therapy. However, to date, it is not clear which other possible targets might be involved in the efficacy of IMiDs. One especially prominent effect of a number of thalidomide analogs is their ability to inhibit angiogenesis, which is typically enhanced in fluorinated analogs. So far, the involvement of CRBN in antiangiogenic effects is under debate. Here, starting from a systematic set of thalidomide analogs and employing a quantitative in vitro CRBN-binding assay, we study the correlation of fluorination, CRBN binding and antiangiogenic effects. We clearly identify fluorination to correlate both with CRBN binding affinity and with antiangiogenic effects, but do not find a correlation between the latter two phenomena, indicating that the main target for the antiangiogenic effects of thalidomide analogs still remains to be identified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

Within the last decade, bromodomain and extraterminal (BET) domain inhibitors were introduced as the first in a wave of new agents known as bromodomain inhibitors. These original examples exhibited anti-inflammatory and anticancer properties, and some have progressed to human clinical trials. BET proteins and their conserved N-terminal bromodomains, BD1 and BD2, have been implicated in the regulation of transcription. The early-generation BET inhibitors showed equal affinity for BD1 and BD2, and therefore the differential roles of BD1 and BD2 remain poorly understood. A recent study published in Science by Gilan et al. outlines the transcriptional and phenotypic effects of inhibiting BD1 and BD2 individually, specifically in the context of cancer and immunoinflammatory pathologies. These findings suggest that BD1 and BD2 have separate and distinct roles in transcriptional regulation, and that BD1- and BD2-selective agents may exhibit higher clinical efficacies in solid tumors, such as prostate cancer, with fewer off-target side effects seen with early generation compounds., Competing Interests: None., (AJCEU Copyright © 2020.)

Chronic beryllium disease (CBD) is a metal hypersensitivity/autoimmune disease in which damage-associated molecular patterns (DAMPs) promote a break in T cell tolerance and expansion of Be2+/self-peptide-reactive CD4+ T cells. In this study, we investigated the mechanism of cell death induced by beryllium particles in alveolar macrophages (AMs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independent of caspase, receptor-interacting protein kinases 1 and 3, or ROS activity. Before cell death, Be-exposed AMs secreted TNF-α that boosted intracellular stores of IL-1α followed by caspase-8-dependent fragmentation of DNA. IL-1α and nucleosomal DNA were subsequently released from AMs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMs released only IL-1α. In mice exposed to Be, TNF-α promoted release of DAMPs and was required for the mobilization of immunogenic DCs, the expansion of Be-reactive CD4+ T cells, and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNF-α on AMs led to a break in peripheral tolerance. This potentially novel mechanism may underlie the known relationship between fine particle inhalation, TNF-α, and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.

Background: Mohs micrographic surgeons should be adept in identifying and managing perineural invasion (PNI), lymphovascular invasion (LVI), and single-cell spread (SCS), features denoting high-risk behavior of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and microcystic adnexal carcinoma (MAC)., Objective: The purpose of this article is to review the literature and guidelines regarding the diagnosis of PNI, LVI, and SCS in BCC, cSCC, and MAC and examine the role of advanced diagnostic studies, adjuvant therapy, and reconstructive techniques of these high-risk tumors., Materials and Methods: We performed a literature search including the following terms: PNI, LVI, SCS, BCC, cSCC, keratinocyte carcinoma, MAC, sentinel lymph node biopsy, radiation, chemotherapy, and staging. Relevant studies, case reports, and review articles were included, as well as National Comprehensive Cancer Network guidelines., Results: Pancytokeratin immunohistochemistry may aid in the diagnosis of high-risk features of BCC and cSCC. Reconstruction of the Mohs defect should be carefully considered to allow for thorough inspection. Radiation therapy should be considered as an adjuvant treatment option for high-risk cSCC and BCC. Close surveillance for recurrence is warranted., Conclusion: The Mohs surgeon should be competent in identification of high-risk tumors and to understand how best to manage, further treat, and follow these tumors.

Vesicular stomatitis virus Indiana strain glycoprotein (VSVind.G) mediates broad tissue tropism and efficient cellular uptake. Lentiviral vectors (LVs) are particularly promising, as they can efficiently transduce non-dividing cells and facilitate stable genomic transgene integration; therefore, LVs have an enormous untapped potential for gene therapy applications, but the development of humoral and cell-mediated anti-vector responses may restrict their efficacy. We hypothesized that G proteins from different members of the vesiculovirus genus might allow the generation of a panel of serotypically distinct LV pseudotypes with potential for repeated in vivo administration. We found that mice hyperimmunized with VSVind.G were not transduced to any significant degree following intravenous injection of LVs with VSVind.G envelopes, consistent with the thesis that multiple LV administrations would likely be blunted by an adaptive immune response. Excitingly, bioluminescence imaging studies demonstrated that the VSVind-neutralizing response could be evaded by LV pseudotyped with Piry and, to a lesser extent, Cocal virus glycoproteins. Heterologous dosing regimens using viral vectors and oncolytic viruses with Piry and Cocal envelopes could represent a novel strategy to achieve repeated vector-based interventions, unfettered by pre-existing anti-envelope antibodies., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate human papillomavirus (HPV) vaccination rates among men in the USA and to compare vaccination rates among men who had served in the military to those reporting no previous military service., Methods: We performed a cross-sectional analysis using Behavioral Risk Factor Surveillance System (BRFSS) data from the 2013 to 2015 to analyze HPV vaccination rates for vaccine eligible adult men. The BRFSS is a multistage, cross-sectional telephone survey conducted nationally by state health departments. Univariable and logistic regression analyses were performed to examine the relationship between military service and HPV vaccination status was assessed as well as the number of HPV vaccination doses received., Results: A total of 5,274 participants were analyzed representing a weighted estimate of 1.5 million HPV vaccine eligible men in the USA. The vaccination rate among veterans was 25.3% (95% confidence interval (CI), 18.8-33.3%) compared to 15.9% (95% CI, 14.3-17.6%) for civilians (p < 0.01). Veterans were more likely to report having received at least one dose of the HPV vaccine compared to civilian men (adjusted odds ratios [aOR] = 2.7, 95% CI, 1.7%-4.1%, p < 0.001)., Conclusions: Veteran men are more likely to have received HPV vaccination than similarly aged civilian men. However, for both civilians and veterans, the HPV vaccination coverage remains low when compared to their female counterparts., (© Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2019.)

TMEM16F is a Ca 2+ -gated ion channel that is required for Ca 2+ -activated phosphatidylserine exposure on the surface of many eukaryotic cells. TMEM16F is widely expressed and has roles in platelet activation during blood clotting, bone formation and T cell activation. By combining microscopy and patch clamp recording we demonstrate that activation of TMEM16F by Ca 2+ ionophores in Jurkat T cells triggers large-scale surface membrane expansion in parallel with phospholipid scrambling. With continued ionophore application,TMEM16F-expressing cells then undergo extensive shedding of ectosomes. The T cell co-receptor PD-1 is selectively incorporated into ectosomes. This selectivity depends on its transmembrane sequence. Surprisingly, cells lacking TMEM16F not only fail to expand surface membrane in response to elevated cytoplasmic Ca 2+ , but instead undergo rapid massive endocytosis with PD-1 internalisation. These results establish a new role for TMEM16F as a regulator of Ca 2+ activated membrane trafficking.

Vesicular stomatitis virus Indiana strain G protein (VSVind.G) is the most commonly used envelope glycoprotein to pseudotype lentiviral vectors (LV) for experimental and clinical applications. Recently, G proteins derived from other vesiculoviruses (VesG), for example, Cocal virus, have been proposed as alternative LV envelopes with possible advantages over VSVind.G. Well-characterized antibodies that recognize VesG will be useful for vesiculovirus research, development of G protein-containing advanced therapy medicinal products (ATMPs), and deployment of VSVind-based vaccine vectors. Here, we show that one commercially available monoclonal antibody, 8G5F11, binds to and neutralizes G proteins from three strains of VSV, as well as Cocal and Maraba viruses, whereas the other commercially available monoclonal anti-VSVind.G antibody, IE9F9, binds to and neutralizes only VSVind.G. Using a combination of G protein chimeras and site-directed mutations, we mapped the binding epitopes of IE9F9 and 8G5F11 on VSVind.G. IE9F9 binds close to the receptor binding site and competes with soluble low-density lipoprotein receptor (LDLR) for binding to VSVind.G, explaining its mechanism of neutralization. In contrast, 8G5F11 binds close to a region known to undergo conformational changes when the G protein moves to its postfusion structure, and we propose that 8G5F11 cross-neutralizes VesGs by inhibiting this. IMPORTANCE VSVind.G is currently regarded as the gold-standard envelope glycoprotein to pseudotype lentiviral vectors. However, recently other G proteins derived from vesiculoviruses have been proposed as alternative envelopes. Here, we investigated two commercially available anti-VSVind.G monoclonal antibodies for their ability to cross-react with other vesiculovirus G proteins, identified the epitopes they recognize, and explored their neutralization activity. We have identified 8G5F11, for the first time, as a cross-neutralizing antibody against several vesiculovirus G proteins. Furthermore, we elucidated the two different neutralization mechanisms employed by these two monoclonal antibodies. Understanding how cross-neutralizing antibodies interact with other G proteins may be of interest in the context of host-pathogen interaction and coevolution, as well as providing the opportunity to modify the G proteins and improve G protein-containing medicinal products and vaccine vectors., (© Crown copyright 2018.)

Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4 + T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4 + Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80 hi DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80 hi DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80 hi DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Retroviral and lentiviral vectors often use the envelope G protein from the vesicular stomatitis virus Indiana strain (VSVind.G). However, lentivector producer cell lines that stably express VSVind.G have not been reported, presumably because of its cytotoxicity, preventing simple scale-up of vector production. Interestingly, we showed that VSVind.G and other vesiculovirus G from the VSV New Jersey strain (VSVnj), Cocal virus (COCV), and Piry virus (PIRYV) could be constitutively expressed and supported lentivector production for up to 10 weeks. All G-enveloped particles were robust, allowing concentration and freeze-thawing. COCV.G and PIRYV.G were resistant to complement inactivation, and, using chimeras between VSVind.G and COCV.G, the determinant for complement inactivation of VSVind.G was mapped to amino acid residues 136-370. Clonal packaging cell lines using COCV.G could be generated; however, during attempts to establish LV producer cells, vector superinfection was observed following the introduction of a lentivector genome. This could be prevented by culturing the cells with the antiviral drug nevirapine. As an alternative countermeasure, we demonstrated that functional lentivectors could be reconstituted by admixing supernatant from stable cells producing unenveloped virus with supernatant containing envelopes harvested from cells stably expressing VSVind.G, COCV.G, or PIRYV.G.

Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Key to the survival and proliferation of PEL is the canonical NF-κB pathway, which becomes constitutively activated following overexpression of the viral oncoprotein KSHV vFLIP (ks-vFLIP). This arises from its capacity to form a complex with the modulatory subunit of the IκB kinase (IKK) kinase, IKKγ (or NEMO), resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis, both of which are important drivers of tumorigenesis. Using a combination of cell-based and biophysical assays together with structural techniques, we showed that the observed resistance to cell death is largely independent of autophagy or major death receptor signaling pathways and demonstrated that direct targeting of the ks-vFLIP-IKKγ interaction both in cells and in vitro can be achieved using IKKγ-mimetic peptides. Our results further reveal that these peptides not only induce cell killing but also potently sensitize PEL to the proapoptotic agents tumor necrosis factor alpha and etoposide and are the first to confirm ks-vFLIP as a tractable target for the treatment of PEL and related disorders. IMPORTANCE KSHV vFLIP (ks-vFLIP) has been shown to have a crucial role in cellular transformation, in which it is vital for the survival and proliferation of primary effusion lymphoma (PEL), an aggressive malignancy associated with infection that is resistant to the majority of chemotherapeutic drugs. It operates via subversion of the canonical NF-κB pathway, which requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKγ. While this interaction has been directly linked to protection against apoptosis, it is unclear whether the suppression of other cell death pathways implicated in ks-vFLIP pathogenesis is an additional contributor. We demonstrate that the interaction between ks-vFLIP and IKKγ is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKγ complex can be disrupted using peptides leading to direct killing and the sensitization of PEL cells to proapoptotic agents. Our studies thus provide a framework for future therapeutic interventions., (Copyright © 2017 Briggs et al.)

Nodular cutaneous amyloidosis (NCA), the least common form of primary cutaneous amyloidosis, is characterized clinically by waxy, purpuric plaques and nodules and histologically by amyloid deposits in the dermis and subcutaneous tissue. We present a patient who developed multiple, non-contiguous NCA lesions over a three year period without evidence of systemic disease. We reviewed the literature and found few other cases of this unusual presentation.