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Graduate students are increasingly expected to publish peer-reviewed scholarship during the course of their studies, yet predictable mentoring and education on academic publishing is not available to all graduate students. Although academic librarians are well positioned to offer such instruction, their efforts are not always informed by comprehensive investigations of what, and how, graduate students need to learn. This study used focus groups with graduate students and faculty mentors to explore strengths and gaps in current mentoring and learning practices, while also discovering and uncovering suggestions and opportunities for further development in education about scholarly publishing. Thematic analysis of the data revealed that current training and mentorship meet some, but not all, of students' needs and preferences. Future library instruction should employ a blended and compassionate approach to teaching about this complex topic, and this study offers a way forward as librarians-as-partners in scholarly communication.

Abstract Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Abstract EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell–cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.

Abstract Background Emerging adults (EAs) who are not 4-year college students nor graduates are at elevated risk for lifetime alcohol use disorder, comorbid drug use, and mental health symptoms, compared to college graduates. There is a need for tailored brief alcohol intervention (BAI) approaches to reduce alcohol risk and to facilitate healthy development in this high-risk population. Most BAIs include a single session focused on discussing risks associated with drinking and correcting normative beliefs about drinking rates. EAs may benefit from additional elements that enhance general wellness. The substance-free activity session (SFAS) aims to clarify life goals and values and increase goal-directed activities that provide alternatives to alcohol use, and the relaxation training (RT) session teaches relaxation and stress reduction skills. Methods The present study is a randomized 3-group (BAI + SFAS vs. RT + SFAS vs. education control) trial with 525 EAs (175 per group; estimated 50% women and 50% African American) who report recent risky drinking and who are not students or graduates of 4-year colleges. Participants will have the option of completing the intervention sessions in person or via a secure video teleconference. Levels of drinking and alcohol-related problems will be evaluated at baseline and 1, 3, 6, and 12 months post-intervention. The primary hypothesis is that both BAI + SFAS and RT + SFAS participants will report significantly greater reductions in alcohol use and problems relative to education control participants, with no differences in outcomes between the two active treatment conditions. Discussion The results of this study will inform alcohol prevention efforts for high-risk community dwelling emerging adults. Trial registration ClinicalTrials.gov Identifier: NCT04776278.

Background: Livestock farming has increased in complexity considerably due to the growing demand for animal products combined with a decreasing number of farmers and ranchers. To meet this challenge, Precision Livestock Farming (PLF) aims to develop fully automated tools to continuously monitor animals, such as cattle, to detect issues earlier and improve productivity. The objective of this scoping review is to provide an overview of precision livestock farming technologies used for cattle monitoring. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines were followed in this review. Peer-reviewed journal and conference papers from 2005 to 2023 were included, with a focus on technological systems used for cattle monitoring or disease detection. Extracted data included publication year, geographical region, type of technology used, type of monitoring, goal of the intervention, and the level of validation. The relationships between the technology, type of monitoring, and goal of intervention were also explored. Results: 413 papers were found to meet the eligibility criteria. The countries with the most papers were China (n = 55), Japan (n = 52), the United States (n = 38), Australia (n = 25), and India (n = 20). The most common types of technology were found to be inertial sensors (37 %) and images or videos (35 %). Simple classification methods were used in 48 % of papers and machine learning in 29 %. The two most common goals stated in PLF papers were determining animal behavior (30 %) and animal health (12 %). Conclusion: Overall, the results provide a snapshot of the types and uses of technologies in PLF for cattle management and suggest emerging technologies and applications of these tools to improve cattle health and welfare.

The objective of this study was to conduct a systematic review of published literature on ammonia (NH3) and enteric methane (CH4) emissions from beef and dairy cattle operations to obtain statistically representative emission factors based on dietary intakes of nutrients or energy, and to identify major causes of emission variations. NH3 emissions from lagoon or other manure storage facilities were not included in this review. The NH3 and CH4 emission rates, expressed as a percentage losses of dietary nutrients or energy, demonstrated much less variation compared with emission rates expressed in g/animal/day. Air temperature and dietary crude protein (CP) content were identified as two major factors that can affect NH3 emission rates in addition to farm type. Feed digestibility and energy intake were identified as two major factors that can affect CH4 emission rates expressed as a percentage losses of dietary energy. Generally, increasing productivity and feed efficiency represented the greatest opportunity for mitigating NH3 or CH4 emissions per unit of livestock product. Expressing CH4 loss on a digestible energy basis rather than a gross energy intake basis can better represent the large variation among diets and the effects of varying dietary emission mitigation strategies.

Prescribed rangeland burning in April is a long-standing practice in the Flint Hills region of eastern Kansas to maintain the tallgrass prairie ecosystem. The smoke plumes originating from these fires increases ambient PM2.5 concentrations and potentially contributes to ozone (O3) exceedances in downwind communities. Source apportionment research using Unmix modeling has been utilized to estimate contributions of Kansas rangeland burning to ambient PM2.5 concentrations. The objective of this study was to investigate the potential correlations between O3 and various sources of PM2.5 that are derived from receptor modeling, and then to specifically estimate contributions of Kansas rangeland burning to ambient O3 concentrations through regression analysis. Various daily meteorological data were used as predictor variables. Multiple regression models were developed for the eight-hour daily maximum O3 as well as the daily contributions of the five PM2.5 source categories that were derived from receptor modeling. Cross correlation was analyzed among residuals of the meteorological regression models for O3 and the daily contributions of the five PM2.5 source categories in order to identify the potential hidden correlation between O3 and PM2.5. The model including effects of meteorological variables and episodic contributions from fire and industrial emissions can explain up to 78% of O3 variability. For non-rainy days in April, the daily average contribution from prescribed rangeland burning to O3 was 1.8 ppb. On 3% of the days in April, prescribed rangeland burning contributed over 12.7 ppb to O3; and on 7% of the days in April, burning contributed more than 7.2 ppb to O3. When the intensive burning activities occur in days with high O3 background due to high solar radiation or O3 carryover from the previous day, the contributions from these episodic fire emissions could result in O3 exceedances of the National Ambient Air Quality Standards (NAAQS). The regression models developed in this study demonstrated that the most valuable predictors for O3 in the Flint Hills region include the O3 level on the previous day, total solar radiation, difference between daily maximum and minimum air temperature, and levels of episodic fire and industrial emissions. The long term goal is to establish an online O3 forecasting tool that can assist regulators and land managers in smoke management during the burning season so that the intensive burning activities can be planned to avoid forecasted high O3 days and thus prevent O3 exceedance.

IntroductionNon-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity.MethodsWe used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival.ResultsWe identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55–58) versus 72 months (95% CI 71–73) (hazard ratio (HR) 1.14, 95% CI 1.12–1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62–69) versus NHW 69 months (95% CI 97–71) (HR 1.02, 95% CI 0.98–1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p

Abstract Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.

Abstract Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome. Dysregulated necroptosis has been implicated in numerous inflammatory pathologies. As such, new small molecule necroptosis inhibitors are of great interest, particularly ones that operate downstream of MLKL activation, where the pathway is less well defined. To better understand the mechanisms involved in necroptosis downstream of MLKL activation, and potentially uncover new targets for inhibition, we screened known kinase inhibitors against an activated mouse MLKL mutant, leading us to identify the lymphocyte-specific protein tyrosine kinase (Lck) inhibitor AMG-47a as an inhibitor of necroptosis. We show that AMG-47a interacts with both RIPK1 and RIPK3, that its ability to protect from cell death is dependent on the strength of the necroptotic stimulus, and that it blocks necroptosis most effectively in human cells. Moreover, in human cell lines, we demonstrate that AMG-47a can protect against cell death caused by forced dimerisation of MLKL truncation mutants in the absence of any upstream signalling, validating that it targets a process downstream of MLKL activation. Surprisingly, however, we also found that the cell death driven by activated MLKL in this model was completely dependent on the presence of RIPK1, and to a lesser extent RIPK3, although it was not affected by known inhibitors of these kinases. Together, these results suggest an additional role for RIPK1, or the necrosome, in mediating human necroptosis after MLKL is phosphorylated by RIPK3 and provide further insight into reported differences in the progression of necroptosis between mouse and human cells.

Abstract Background Oncology rapidly shifted to telemedicine in response to the COVID‐19 pandemic. Telemedicine can increase access to healthcare, but recent research has shown disparities exist with telemedicine use during the pandemic. This study evaluated health disparities associated with telemedicine uptake during the COVID‐19 pandemic among cancer patients in a tertiary care academic medical center. Methods This retrospective cohort study evaluated telemedicine use among adult cancer patients who received outpatient medical oncology care within a tertiary care academic healthcare system between January and September 2020. We used multivariable mixed‐effects logistic regression models to determine how telemedicine use varied by patient race/ethnicity, primary language, insurance status, and income level. We assessed geospatial links between zip‐code level COVID‐19 infection rates and telemedicine use. Results Among 29,421 patient encounters over the study period, 8,541 (29%) were delivered via telemedicine. Several groups of patients were less likely to use telemedicine, including Hispanic (adjusted odds ratio [aOR] 0.86, p = 0.03), Asian (aOR 0.79, p = 0.002), Spanish‐speaking (aOR 0.71, p = 0.0006), low‐income (aOR 0.67, p

Abstract Purpose Cancer patients frequently utilize the emergency department (ED) for a variety of diagnoses both related to and unrelated to their cancer, yet ED outcomes for cancer patients are not well documented. This study sought to define risks and identify predictors for inpatient admission and hospital mortality among cancer patients presenting to the ED. Patients and Methods We utilized the National Emergency Department Sample to identify patients with and without a diagnosis of cancer presenting to the ED between January 2016 and December 2018. We used multivariable mixed‐effects logistic regression models to assess the influence of cancer on outcomes of hospital admission after the ED visit and hospital mortality for the whole patient cohort and individual presenting diagnoses. Results There were 340 million weighted ED visits, of which 8.3 million (2.3%) were associated with a cancer diagnosis. Compared to non‐cancer patients, patients with cancer had an increased risk of inpatient admission (64.7% vs. 14.8%; p

The pseudokinase MLKL is activated by the upstream kinase RIPK3 in the necroptotic pathway but the structural basis of MLKL activation is not well understood yet. Here, the authors present the crystal structures of the human RIPK3:MLKL complex and human RIPK3 kinase alone, which reveal structural differences between human and murine RIPK3 and they discuss mechanistic implications.

Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth.

Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.

Objective:. To determine if artificial neural networks (ANN) could predict the risk of intra-abdominal abscess (IAA) development post-appendectomy. Background:. IAA formation occurs in 13.6% to 14.6% of appendicitis cases with “complicated” appendicitis as the most common cause of IAA. There remains inconsistency in describing the severity of appendicitis with variation in treatment with respect to perforated appendicitis. Methods:. Two “reproducible” ANN with different architectures were developed on demographic, clinical, and surgical information from a retrospective surgical dataset of 1574 patients less than 19 years old classified as either negative (n = 1,328) or positive (n = 246) for IAA post-appendectomy for appendicitis. Of 34 independent variables initially, 12 variables with the highest influence on the outcome selected for the final dataset for ANN model training and testing. Results:. A total of 1574 patients were used for training and test sets (80%/20% split). Model 1 achieved accuracy of 89.84%, sensitivity of 70%, and specificity of 93.61% on the test set. Model 2 achieved accuracy of 84.13%, sensitivity of 81.63%, and specificity of 84.6%. Conclusions:. ANN applied to selected variables can accurately predict patients who will have IAA post-appendectomy. Our reproducible and explainable ANNs potentially represent a state-of-the-art method for optimizing post-appendectomy care.

Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

The GntR superfamily is one of the largest families of transcription factors in prokaryotes. Here the authors combine biophysical analysis and structural biology to dissect the mechanism by which NanR — a GntR-family regulator — binds to its promoter to repress the transcription of genes necessary for sialic acid metabolism.

Abstract Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness. To test our hypothesis, we modeled: (a) the impact of risk compensation on rates of HIV adaptation via strain replacement in response to a partially effective vaccine; and (b) the combined impact of risk compensation and viral adaptation on vaccine-mediated epidemic control. We used an agent-based epidemic model that was calibrated to HIV-1 trends in South Africa, and includes demographics, sexual network structure and behavior, and within-host disease dynamics. Our model predicts that risk compensation can increase the rate of HIV viral adaptation in response to a vaccine. In combination, risk compensation and viral adaptation can, under certain scenarios, reverse initial declines in prevalence due to vaccination, and result in HIV prevalence at 15 years equal to or greater than prevalence without a vaccine.

The viral Protein Kinase-1 (PK-1) phosphorylates the regulatory protein p6.9, which facilitates baculoviral genome release. Here, the authors combine X-ray crystallography with biophysical and biochemical analyses as well as molecular dynamics simulations to characterize Cydia pomenella granulovirus PK-1, which forms a dimer with a parallel side-to-side arrangement of the kinase domains and furthermore, they provide insights into its catalytic mechanism and evolutionary relationships with other kinases.

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis.

The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).

Abstract Background We assessed breast cancer mortality in older versus younger women according to race/ethnicity, neighborhood socioeconomic status (nSES), and health insurance status. Methods The study included female breast cancer cases 18 years of age and older, diagnosed between 2005 and 2015 in the California Cancer Registry. Multivariable Cox proportional hazards modeling was used to generate hazard ratios (HR) of breast cancer specific deaths and 95% confidence intervals (CI) for older (60+ years) versus younger (

Abstract Sand size can affect the ability to incorporate topdressing into the turf canopy and thatch on golf course putting greens; unincorporated sand interferes with mowing and play. This 3-year field trial was initiated to determine the effects of sand size on sand incorporation, surface wetness, and anthracnose (caused by Colletotrichum cereale Manns sensu lato Crouch, Clarke, and Hillman) of annual bluegrass [Poa annua L. f. reptans (Hausskn) T. Koyama] maintained as a putting green. The experimental design was a randomized complete block with four replications; treatments included a non-topdressed control and three topdressing sands (medium-coarse, medium, or medium-fine) applied every 2 weeks at 0.15 L·m−2 during the summer. Topdressing with medium-coarse sand was more difficult to incorporate than the medium and medium-fine sands, resulting in a greater quantity of sand collected with mower clippings. Analyzing the particle distribution of sand removed by mowing confirmed that coarser sand particles were more likely to be removed in mower clippings. Surface wetness measured as volumetric water content (VWC) at the 0- to 38-mm depth zone was greater in non-topdressed plots than topdressed plots on 35% of observations. Few differences in VWC were found among sand size treatments. Turf responses to topdressing were not immediate; however, as sand accumulated in the turf canopy, topdressed plots typically had lower anthracnose severity than non-topdressed turf after the first year. Additionally, topdressing with medium and medium-fine sands produced similar or occasionally lower disease severity than topdressing with medium-coarse sand. The lack of negative effects of medium and medium-fine sands combined with better incorporation after topdressing and less disruption to the putting surface should allow golf course superintendents to apply topdressing at frequencies and/or quantities needed during the summer to maintain high-quality turf and playing conditions.

Background: HIV-1 set point viral load (SPVL) is a highly variable trait that influences disease progression and transmission risk. Men who are exclusively insertive (EI) during anal intercourse require more sexual contacts to become infected than exclusively receptive (ER) men. Thus, we hypothesize that EIs are more likely to acquire their viruses from highly infectious partners (i.e., with high SPVLs) and to have higher SPVLs than infected ERs. Methods: We used a one-generation Bernoulli model, a dynamic network model, and data from the Multicenter AIDS Cohort Study (MACS) to examine whether and under what circumstances MSM differ in SPVL by sexual role. Results: Both models predicted higher SPVLs in EIs than role versatile (RV) or ER men, but only in scenarios where longer-term relationships predominated. ER and RV men displayed similar SPVLs. EI men remained far less likely than ER men to become infected, however. When the MACS data were limited by some estimates of lower sex partner counts (a proxy for longer relationships), EI men had higher SPVLs; these differences were clinically relevant (>0.3 log10 copies/mL) and statistically significant (p

Pulmonary infection due to Mycobacterium abscessus occurs in patients with cystic fibrosis, but rarely in immunocompetent children without underlying lung pathology. Treatment is complicated by frequent resistance to many antibiotics. We present a case report of a 4-month-old female infant with 2 months of cough, difficulty feeding, and failure to thrive, with extensive culture-confirmed M. abscessus pulmonary infection without identified immunodeficiency or underlying lung pathology following multidisciplinary evaluation. We describe our complete evaluation including immunodeficiency evaluation incorporating whole-exome sequencing, describe our antibiotic selection and treatment duration given complicated susceptibility pattern of the M. abscessus isolate, and review literature for nontuberculous mycobacterial pulmonary disease in immunocompetent children. A complete multidisciplinary evaluation for underlying lung disease and primary and acquired immunodeficiency should be undertaken in pediatric patients with M. abscessus pneumonia. Confirming macrolide susceptibility through erm(41) gene evaluation is clinically important for isolates with complicated susceptibility pattern.

CXCL12 activates CXCR4 and is involved in embryogenesis, hematopoiesis, and angiogenesis. It has pathological roles in HIV-1, WHIM disease, cancer, and autoimmune diseases. An antagonist, AMD3100, is used for the release of CD34+ hematopoietic stem cells from the bone marrow for autologous transplantation for lymphoma or multiple myeloma patients. Adverse effects are tolerated due to its short-term treatment, but AMD3100 is cardiotoxic in clinical studies for HIV-1. In an effort to determine whether Saccharomyces cerevisiae expressing a functional human CXCR4 could be used as a platform for identifying a ligand from a library of less ∼1,000 compounds, a high-throughput screening was developed. We report that 2-carboxyphenyl phosphate (fosfosal) up-regulates CXCR4 activation only in the presence of CXCL12. This is the first identification of a compound that increases CXCR4 activity by any mechanism. We mapped the fosfosal binding site on CXCL12, described its mechanism of action, and studied its chemical components, salicylate and phosphate, to conclude that they synergize to achieve the functional effect.

The Polycomb Repressive-Deubiquitinase (PR-DUB) complex is responsible for the removal of the ubiquitin epigenetic modification from Histone 2A. Here the authors describe the structure of the Drosophila PR-DUB complex, providing new insight into its regulation and how cancer-associated mutations disrupt PR-DUB activity.

RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.

Cytokines are key molecules in controlling haematopoiesis that signal via the JAK/STAT pathway. Here the authors present the structures of SOCS1 bound to its JAK1 target as well as in complex with elonginB and elonginC, providing a molecular explanation for the potent JAK- inhibitory activity of SOCS1.

Pseudokinases lack kinase activity, yet they impact cellular physiology through the regulation of bona fide signaling kinases. Here the authors describe the structure of the SgK223 pseudokinase and its adjacent domains, and identify regulatory interfaces required for self-assembly and downstream signaling.

Chlamydiae replicate in host cells within specialised vacuoles (inclusions), which are eventually ruptured to liberate the bacteria, leading to cell lysis. Here, Kerret al. use a laser ablation technique and videomicroscopy to show that inclusion rupture triggers a necrotic pathway in the host cell.

Summary: Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction. : Petrie et al. identify proteins encoded by some poxviruses with homology to the pseudokinase domain of the terminal necroptosis effector, MLKL. Via species-specific mechanisms, viral MLKL proteins block necroptotic death in human and mouse cells by sequestering RIPK3 to prevent phosphorylation and activation of MLKL. Keywords: poxvirus, innate immunity, pseudokinase, necroptosis, programmed necrosis, MLKL, RIPK3

The impacts of continued degradation of watersheds on coastal coral reefs world-wide is alarming, and action addressing anthropogenic stressors and subsequent rehabilitation of watersheds and adjacent reefs is an urgent priority. The aim of this study is to develop and improve the use of antioxidant enzymes as bioindicators of stress in coral species. In order to fully develop such tools, it is necessary to first understand baseline cycling of these enzymes within coral tissues. Due to inherent links between reproduction and oxidative stress, these aims may be facilitated by sampling coral tissues over reproductively-linked lunar cycles to determine variations from baseline. By developing a greater understanding of biochemical markers of stress in corals, specifically antioxidant defense enzymes catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and superoxide dismutase (SOD) in Hawaiian Pocillopora damicornis, we have provided molecular tools that identify thresholds of stress on coral reefs. Our results suggest that the coral reproductive state is a significant factor affecting the activity of antioxidant enzymes. Specifically, CAT and GR display maximum activity during peak reproductive state. Whereas significant maximal Se-independent GPx and SOD activity was measured during off-peak reproductive cycles. Such insight into the cyclical variation of the activity of these enzymes should be applied towards differentiating the influence of natural biological activity cycling in diagnostic tests identifying the effects of different physical environmental factors and chemical pollutants on coral health. Through the development and application of these molecular biomarkers of stress, we look to improve our ability to identify problems at the sub-lethal level, when action can be taken to mitigate a/biotic impacts.

We report a cluster of 6 pediatric residents of Houston, Texas, USA, who presented with Plasmodium vivax infection within an eight-week period. All had immigrated to the United States from Afghanistan within the previous year. The clustering raises the possibilities of local mosquito vectored infection and/or synchronous relapses. Molecular typing and local mosquito testing are crucial in delineating the source of similar clusters in nonendemic regions. Single-dose hypnozoite eradication treatment may be considered in emigrating children to malaria nonendemic countries.

ABSTRACT Human respiratory syncytial virus (HRSV) is a negative-stranded RNA virus that causes a globally prevalent respiratory infection, which can cause life-threatening illness, particularly in the young, elderly, and immunocompromised. HRSV multiplication depends on replication and transcription of the HRSV genes by the virus-encoded RNA-dependent RNA polymerase (RdRp). For replication, this complex comprises the phosphoprotein (P) and the large protein (L), whereas for transcription, the M2-1 protein is also required. M2-1 is recruited to the RdRp by interaction with P and also interacts with RNA at overlapping binding sites on the M2-1 surface, such that binding of these partners is mutually exclusive. The molecular basis for the transcriptional requirement of M2-1 is unclear, as is the consequence of competition between P and RNA for M2-1 binding, which is likely a critical step in the transcription mechanism. Here, we report the crystal structure at 2.4 Å of M2-1 bound to the P interaction domain, which comprises P residues 90 to 110. The P90–110 peptide is alpha helical, and its position on the surface of M2-1 defines the orientation of the three transcriptase components within the complex. The M2-1/P interface includes ionic, hydrophobic, and hydrogen bond interactions, and the critical contribution of these contacts to complex formation was assessed using a minigenome assay. The affinity of M2-1 for RNA and P ligands was quantified using fluorescence anisotropy, which showed high-affinity RNAs could outcompete P. This has important implications for the mechanism of transcription, particularly the events surrounding transcription termination and synthesis of poly(A) sequences. IMPORTANCE Human respiratory syncytial virus (HRSV) is a leading cause of respiratory illness, particularly in the young, elderly, and immunocompromised, and has also been linked to the development of asthma. HRSV replication depends on P and L, whereas transcription also requires M2-1. M2-1 interacts with P and RNA at overlapping binding sites; while these interactions are necessary for transcriptional activity, the mechanism of M2-1 action is unclear. To better understand HRSV transcription, we solved the crystal structure of M2-1 in complex with the minimal P interaction domain, revealing molecular details of the M2-1/P interface and defining the orientation of M2-1 within the tripartite complex. The M2-1/P interaction is relatively weak, suggesting high-affinity RNAs may displace M2-1 from the complex, providing the basis for a new model describing the role of M2-1 in transcription. Recently, the small molecules quercetin and cyclopamine have been used to validate M2-1 as a drug target.

We propose a method for the unsupervised clustering of hyperspectral images based on spatially regularized spectral clustering with ultrametric path distances. The proposed method efficiently combines data density and spectral-spatial geometry to distinguish between material classes in the data, without the need for training labels. The proposed method is efficient, with quasilinear scaling in the number of data points, and enjoys robust theoretical performance guarantees. Extensive experiments on synthetic and real HSI data demonstrate its strong performance compared to benchmark and state-of-the-art methods. Indeed, the proposed method not only achieves excellent labeling accuracy, but also efficiently estimates the number of clusters. Thus, unlike almost all existing hyperspectral clustering methods, the proposed algorithm is essentially parameter-free.

The data presented in this article are related to the research article entitled “A modelling approach to explore the critical environmental parameters influencing the growth and establishment of the invasive seaweed Undaria pinnatifida in Europe” [1]. This article describes raw simulation data output from a novel individual-based model of the invasive kelp species Undaria pinnatifida. It also includes field data of monthly abundance and recruitment values for a population of invasive U. pinnatifida (in Brest harbour, France) that were used to validate the model. The raw model output and field data are made publicly available in order to enable critical analysis of the model predictions and to inform future modelling efforts of the study species. Keywords: Macroalgae, Individual-based model, Invasive species, Seaweed, Kelp, Undaria pinnatifida, Recruitment, Abundance

Purpose: Treatments for locoregionally advanced head and neck cancer (LAHNC) negatively impact swallowing function, but the long-term incidence of severe toxicity requiring esophageal dilation is not well-documented in the population. The aim of this study was to compare the incidence of long-term esophageal dilation across varying treatments for LAHNC.Methods and Materials: We identified 5,223 patients with LAHNC diagnosed from 2000 to 2009 in the SEER-Medicare database. We compared the incidence of esophageal dilation for surgery alone vs. surgery plus adjuvant radiotherapy (RT) and chemoradiotherapy (CRT) vs. definitive RT or CRT.Results: The cumulative incidence of esophageal dilation for all sites at 10 years, according to treatment group were as follows: CRT, 14% (95% confidence interval (CI), 12–17%); definitive RT, 13% (95% CI, 10–16%); surgery alone, 5% (95% CI, 3–7%); surgery and CRT, 15% (95% CI, 11–19%); surgery and adjuvant RT: 10% (95% CI, 8–13%). There was no significant difference in the incidence of esophageal dilation between surgery plus adjuvant RT/CRT or definitive RT/CRT (p = 0.37), but the incidence was significantly increased in both groups compared to surgery alone (p = 0.003). On multivariable analysis, chemotherapy was associated with significantly increased incidence of esophageal dilation (HR 2.9, 95% CI 1.5–5.5, p < 0.001) in oropharyngeal cancers.Conclusions: The incidence of esophageal dilation is similar in LAHNC patients undergoing RT with or without surgery. Chemoradiotherapy increases the long-term risk of esophageal dilation events over surgery alone.

Viral-bacterial co-infections are associated with severe exacerbations of COPD. Epithelial antimicrobial peptides, including human β-defensin-2 (HBD-2), are integral to innate host defenses. In this study, we examined how co-infection of airway epithelial cells with rhinovirus and Pseudomonas aeruginosa modulates HBD-2 expression, and whether these responses are attenuated by cigarette smoke and in epithelial cells obtained by bronchial brushings from smokers with normal lung function or from COPD patients. When human airway epithelial cells from normal lungs were infected with rhinovirus, Pseudomonas aeruginosa, or the combination, co-infection with rhinovirus and bacteria resulted in synergistic induction of HBD-2 (p

The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed DFT1, was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015 a second transmissible cancer (DFT2) was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promote anti-tumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade anti-tumor immune responses. We developed recombinant proteins and monoclonal antibodies to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by monoclonal antibodies, which could be critical to understanding how the DFT allografts evade the immune system.

Integrating information from existing research, qualitative ethnographic interviews, and participant observation, we designed a field experiment that introduces idiosyncratic environmental risk and a voluntary sharing decision into a standard public goods game. Conducted with subsistence resource users in rural villages on the Kamchatka Peninsula in Northeast Siberia, we find evidence consistent with a model of indirect reciprocity and local social norms of helping the needy. When participants are allowed to develop reputations in the experiments, as is the case in most small-scale societies, we find that sharing is increasingly directed toward individuals experiencing hardship, good reputations increase aid, and the pooling of resources through voluntary sharing becomes more effective. We also find high levels of voluntary sharing without a strong commitment device; however, this form of cooperation does not increase contributions to the public good. Our results are consistent with previous experiments and theoretical models, suggesting strategic risks tied to rewards, punishments, and reputations are important. However, unlike studies that focus solely on strategic risks, we find the effects of rewards, punishments, and reputations are altered by the presence of environmental factors. Unexpected changes in resource abundance increase interdependence and may alter the costs and benefits of cooperation, relative to defection. We suggest environmental factors that increase interdependence are critically important to consider when developing and testing theories of cooperation.

Infection with Angiostrongylus cantonensis roundworms is endemic in Southeast Asia and the Pacific Basin. A. cantonensis meningitis and myelitis occurred in summer 2013 in a child with no history of travel outside of Texas, USA. Angiostrongyliasis is an emerging neurotropic helminthic disease in Texas and warrants increased awareness among healthcare providers.

Staphylococcus aureus es uno de los principales patógenos a nivel mundial. Durante los últimos años se ha reportado un incremento en el número de casos de S. aureus resistente a la meticilina adquiridos en la comunidad, tanto en niños como en adultos de los Estados Unidos y de otras partes del mundo. En el presente trabajo reportamos un caso de empiema necessitans y osteomielitis aguda en un niño de 19 meses de edad previamente sano. El presente reporte resalta la cambiante epidemiología de S. aureus tanto en la comunidad como en el medio hospitalario y la importancia de establecer guías apropiadas para el diagnóstico, el tratamiento y la vigilancia de este relevante problema de salud pública.

Several programmed lytic and necrotic-like cell death mechanisms have now been uncovered, including the recently described receptor interacting protein kinase-3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-dependent necroptosis pathway. Genetic experiments have shown that programmed necrosis, including necroptosis, can play a pivotal role in regulating host-resistance against microbial infections. Alternatively, excess or unwarranted necroptosis may be pathological in autoimmune and autoinflammatory diseases. This review highlights the recent advances in our understanding of the post-translational control of RIPK3-MLKL necroptotic signaling. We discuss the critical function of phosphorylation in the execution of necroptosis, and highlight the emerging regulatory roles for several ubiquitin ligases and deubiquitinating enzymes. Finally, based on current evidence, we discuss the potential mechanisms by which the essential, and possibly terminal, necroptotic effector, MLKL, triggers the disruption of cellular membranes to cause cell lysis.

The long-term trend toward decreased water clarity in Lake Tahoe is well documented, and is strongly linked to increased nitrogen and phosphorus loading from surrounding watersheds. Recent research has detected very high concentrations of biologically available nitrogen and phosphorus in overland/litter interflow from Sierra ecosystems. The objective of this study was to assess the effect of a localized wildfire on the nutrient content of such runoff. The wildfire increased the frequency and magnitude of elevated nutrient concentrations in discharge runoff for all three parameters studied (nitrate nitrogen, ammonium nitrogen and phosphate phosphorus). Although the mobilization of nutrients was increased due to wildfire, the lack of O horizon material (the surface organic layers of mineral soils) after burning may ultimately reduce discharge concentrations over time.