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Abstract Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12–1.64, P = 2×10−03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18–1.88, P = 9×10−04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07–4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Abstract 3′,5′-Cyclic adenosine monophosphate (cAMP), the first identified second messenger, is implicated in diverse cellular processes involving cellular metabolism, cell proliferation and differentiation, apoptosis, and gene expression. cAMP is synthesized by adenylyl cyclase (AC), which converts ATP to cAMP upon activation of Gαs-protein coupled receptors (GPCRs) in most cases and hydrolyzed by cyclic nucleotide phosphodiesterases (PDEs) to 5′-AMP. Dysregulation of cAMP signaling is implicated in a wide range of pathophysiological conditions such as cardiovascular diseases, neurodegenerative and behavioral disorders, cancers, diabetes, obesity, cataracts, and others. Therefore, cAMP targeted therapies have been and are still undergoing intense investigation for the treatment of these and other diseases. This highlights the need for developing assays to detect and monitor cAMP levels. In this study, we show cAMP Lumit assay as a highly specific homogeneous bioluminescent assay suitable for high throughput screenings with a large assay window and a wide dynamic range for cAMP detection. We believe that this assay will aid and simplify drug discovery screening efforts for cAMP signaling targeted therapies.

This paper provides an overview of the hydrology and water use in the Zayandeh Rud basin based on the data available over the 11- years period 1988-1998. The inflows into Chadegan reservoir, the releases from the reservoir, and the extractions along the river for irrigation and other purposes are considered, and a rapid water balance of the basin is performed. Inflows to the Chadegan reservoir, which serves to collect and regulate the runoff from the upper catchment of the basin to better meet the downstream water requirements for irrigation, urban and industrial uses, follow a regular pattern with moderate variability. But the limited year-to-year storage in the reservoir makes the basin vulnerable to prolonged periods of drought. Water releases from the Chadegan reservoir also show a predictable pattern, with the only deviations occurring during flood events. There is a high reliability of meeting the water requirements during periods of peak demand. But releases during the winter months, at the end of the irrigation season, are lower and more variable. This results in low discharges in the Zayandeh Rud and reduced water quality, especially in the lower reaches of the river. A simple water-balance approach was used to estimate the proportion of return flows in the basin. An average annual value of 30% was obtained, with the magnitude of return flows being particularly important in the lower reaches of the basin. But more investigation, especially including groundwater and water quality aspects, needs to be carried out before a definitive value can be advanced. Given the limited supply of fresh water in the Zayandeh Rud basin, further water resources development and water management improvements can only be envisaged in there is scope for real water savings in the basin. This can be assessed if a basin-wide approach, leading to a good understanding of water use (and reuse) at the farm, system and basin levels, is adopted.

Introduction – The study of informatics is multidisciplinary in nature. The informatics course, HSC 310: Health Care Informatics (HSC 310), for undergraduate health sciences students at the Massachusetts College of Pharmacy and Health Sciences (MCPHS) is an example of a librarian-led, multidisciplinary team functioning within a totally online environment. Description – The development and design of the course HSC 310 is reviewed. Issues and challenges are discussed, as well as the benefits of interdisciplinary expertise in the learning environment. Outcomes – Because informatics is fundamentally interdisciplinary in nature, librarians, instructional designers, statisticians, nurses, pharmacists, and other professionals can learn from each other and strengthen the learning experience of students. The “matrix” of informatics explains how diverse types of information interact with, and impact on, each other. This knowledge is crucial to the understanding of information and its role in one's professional life. There was a journey taken in the design of the course, its evolution cumulating in its final online form. Our unique design was an informatics exercise in itself. Student feedback confirmed that, in addition to the course content, the online environment was a positive educational experience. Discussion – Librarian involvement in teaching informatics at MCPHS began with a National Library of Medicine (NLM) fellowship in informatics at Woods Hole, Massachusetts. This resulted in the library's first for-credit course offered totally in-class and included the participation of faculty from other disciplines. Successful collaboration with the College instructional designer was essential in moving this librarian-led course to a totally virtual environment. In addition, the teaming of librarians with other faculty resulted in two nursing-led, hybrid courses on our Boston and Manchester campuses. During the past two years, interdisciplinary teams have provided informatics instruction to the Boston campus within a totally online environment. This paper discusses one of those courses, HSC 310: Health Care Informatics. The topics discussed in the course and the virtual platform have both provided a valuable learning experience for faculty and students. Informatics is an area where varied disciplines can join to achieve common goals.

The generation of distinct cell fates during development depends on asymmetric cell division of progenitor cells. In the central and peripheral nervous system of Drosophila, progenitor cells respectively called neuroblasts or sensory organ precursors use PAR polarity during mitosis to control cell fate determination in their daughter cells. How polarity and the cell cycle are coupled, and how the cell cycle machinery regulates PAR protein function and cell fate determination is poorly understood. Here, we generate an analog sensitive allele of CDK1 and reveal that its partial inhibition weakens but does not abolish apical polarity in embryonic and larval neuroblasts and leads to defects in polarisation of fate determinants. We describe a novel in vivo phosphorylation of Bazooka, the Drosophila homolog of PAR-3, on Serine180, a consensus CDK phosphorylation site. In some tissular contexts, phosphorylation of Serine180 occurs in asymmetrically dividing cells but not in their symmetrically dividing neighbours. In neuroblasts, Serine180 phosphomutants disrupt the timing of basal polarisation. Serine180 phosphomutants also affect the specification and binary cell fate determination of sensory organ precursors as well as Baz localisation during their asymmetric cell divisions. Finally, we show that CDK1 phosphorylates Serine-S180 and an equivalent Serine on human PAR-3 in vitro.

Abstract The COVID-19 pandemic demonstrated the need for rapid molecular diagnostics. Vaccination programs can provide protection and facilitate the opening of society, but newly emergent and existing viral variants capable of evading the immune system endanger their efficacy. Effective surveillance for Variants of Concern (VOC) is therefore important. Rapid and specific molecular diagnostics can provide speed and coverage advantages compared to genomic sequencing alone, benefitting the public health response and facilitating VOC containment. Here we expand the recently developed SARS-CoV-2 CRISPR-Cas detection technology (SHERLOCK) to provide rapid and sensitive discrimination of SARS-CoV-2 VOCs that can be used at point of care, implemented in the pipelines of small or large testing facilities, and even determine the proportion of VOCs in pooled population-level wastewater samples. This technology complements sequencing efforts to allow facile and rapid identification of individuals infected with VOCs to help break infection chains. We show the optimisation of our VarLOCK assays (Variant-specific SHERLOCK) for multiple specific mutations in the S gene of SARS-CoV-2 and validation with samples from the Cardiff University Testing Service. We also show the applicability of VarLOCK to national wastewater surveillance of SARS-CoV-2 variants and the rapid adaptability of the technique for new and emerging VOCs.

Background: Lutetium-177-prostate-specific membrane antigen- 617 (Lu-PSMA) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment responses are heterogeneous despite stringent positron emission tomography (PET)-based imaging selection criteria. Molecularly based biomarkers have potential to refine patient selection and optimise outcomes. Objective: To identify circulating tumour DNA (ctDNA) features associated with treatment outcomes for men treated with Lu-PSMA. Design, setting, and participants: ctDNA from men treated with Lu-PSMA in combination with idronoxil for progressive mCRPC were analysed using an 85-gene customised sequencing assay. ctDNA fractions, molecular profiles, and the presence of alterations in aggressive-variant prostate cancer (AVPC) genes were analysed at baseline, cycle 3 and at disease progression. Intervention: Men received Lu-PSMA with idronoxil every 6 wk for up to six cycles. Outcome measurements and statistical analysis: Baseline and exit PSMA and fluorodeoxyglucose PET/computed tomography (CT) imaging was conducted at baseline and study exit. Single-photon emission CT (SPECT) scans were performed 24 h after Lu-PSMA. Blood samples were collected at baseline,cycle 3 and at disease progression. Cox proportional-hazards models were used to assess associations and derive hazard ratios (HRs) and confidence intervals (CIs) for associations between molecular factors, imaging features, and clinical outcomes. Results and limitations: Sixty samples from 32 men were sequenced (32 at baseline, 24 at cycle 3, four from patients with disease progression); two samples (baseline, on-treatment) from one individual were excluded from analysis owing to poor quality of the baseline sequencing data. Alterations in AVPC genes were associated with shorter prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival (OS) in univariate (HR 3.4, 95% CI 1.5–7.7; p = 0.0036; and HR 3.3, 95% CI 1.4–7.7; p = 0.0063, respectively) and multivariate analyses (HR 4.8, 95% CI 1.8–13; p = 0.0014; and HR 4.1, 95% CI 1.6–11; p = 0.004). Conclusions: ctDNA alterations in AVPC genes were associated with shorter PSA PFS and OS among men treated with Lu-PSMA and intermittent idronoxil. These candidate molecular biomarkers warrant further study to determine whether they have predictive value and potential to guide synergistic combination strategies to enhance outcomes for men treated with Lu-PSMA for mCRPC. Patient summary: Certain DNA/gene changes detected in the blood of men with advanced prostate cancer were associated with shorter benefit from lutetium PSMA, a targeted radioactive therapy. This information may be useful in determining which men may benefit most from this treatment, but additional research is needed.

Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.

Populations of cells typically maintain a consistent size, despite cell division rarely being precisely symmetrical. Therefore, cells must possess a mechanism of "size control", whereby the cell volume at birth affects cell-cycle progression. While size control mechanisms have been elucidated in a number of other organisms, it is not yet clear how this mechanism functions in plants. Here, we present a mathematical model of the key interactions in the plant cell cycle. Model simulations reveal that the network of interactions exhibits limit-cycle solutions, with biological switches underpinning both the G1/S and G2/M cell-cycle transitions. Embedding this network model within growing cells, we test hypotheses as to how cell-cycle progression can depend on cell size. We investigate two different mechanisms at both the G1/S and G2/M transitions: (i) differential expression of cell-cycle activator and inhibitor proteins (with synthesis of inhibitor proteins being independent of cell size), and (ii) equal inheritance of inhibitor proteins after cell division. The model demonstrates that both these mechanisms can lead to larger daughter cells progressing through the cell cycle more rapidly, and can thus contribute to cell-size control. To test how these features enable size homeostasis over multiple generations, we then simulated these mechanisms in a cell-population model with multiple rounds of cell division. These simulations suggested that integration of size-control mechanisms at both G1/S and G2/M provides long-term cell-size homeostasis. We concluded that while both size independence and equal inheritance of inhibitor proteins can reduce variations in cell size across individual cell-cycle phases, combining size-control mechanisms at both G1/S and G2/M is essential to maintain size homeostasis over multiple generations. Thus, our study reveals how features of the cell-cycle network enable cell-cycle progression to depend on cell size, and provides a mechanistic understanding of how plant cell populations maintain consistent size over generations.

The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.

In cities throughout North America, sightings of coyotes (Canis latrans) have become common. Reports of human-coyote conflict are also rising, as is the public demand for proactive management to prevent negative human-coyote interactions. Effective and proactive management can be informed by the direct observations of community members, who can report their interactions with coyotes and describe the location, time, and context that led to their interactions. To better understand the circumstances that can predict human-coyote conflict, we used a web-based reporting system to collect 9134 community-supplied reports of coyotes in Edmonton, Canada, between January 2012 and December 2021. We used a standardized ordinal ranking system to score each report on two indicators of human-coyote conflict: coyote boldness, based on the reported coyote behavior, and human concern about coyotes, determined from the emotions or perceptions about coyotes expressed by reporters. We assigned greater scores to behaviors where coyotes followed, approached, charged, or contacted pets or people, and to perceptions where reporters expressed fear, worry, concern, discomfort or alarm. Using ordered logistic regression and chi-square tests, we compared boldness and concern scores to spatial, temporal, and contextual predictors. Our analysis showed that coyotes were bolder in less developed open areas and during the pup-rearing season, but human concern was higher in residential areas and during the dispersal season. Reports that mentioned dogs or cats were more likely to describe bolder coyote behavior, and those that mentioned pets or children had more negative perceptions about coyotes. Coyote boldness and human concern both indicated rising human-coyote conflict in Edmonton over the 10 years of reporting.

False discovery rates (FDR) are an essential component of statistical inference, representing the propensity for an observed result to be mistaken. FDR estimates should accompany observed results to help the user contextualize the relevance and potential impact of findings. This paper introduces a new user-friendly R pack-age for estimating FDRs and computing adjusted p-values for FDR control. The roles of these two quantities are often confused in practice and some software packages even report the adjusted p-values as the estimated FDRs. A key contribution of this package is that it distinguishes between these two quantities while also offering a broad array of refined algorithms for estimating them. For example, included are newly augmented methods for estimating the null proportion of findings - an important part of the FDR estimation procedure. The package is broad, encompassing a variety of adjustment methods for FDR estimation and FDR control, and includes plotting functions for easy display of results. Through extensive illustrations, we strongly encourage wider reporting of false discovery rates for observed findings.

False discovery rates (FDR) are an essential component of statistical inference, representing the propensity for an observed result to be mistaken. FDR estimates should accompany observed results to help the user contextualize the relevance and potential impact of findings. This paper introduces a new user-friendly R pack-age for estimating FDRs and computing adjusted p-values for FDR control. The roles of these two quantities are often confused in practice and some software packages even report the adjusted p-values as the estimated FDRs. A key contribution of this package is that it distinguishes between these two quantities while also offering a broad array of refined algorithms for estimating them. For example, included are newly augmented methods for estimating the null proportion of findings - an important part of the FDR estimation procedure. The package is broad, encompassing a variety of adjustment methods for FDR estimation and FDR control, and includes plotting functions for easy display of results. Through extensive illustrations, we strongly encourage wider reporting of false discovery rates for observed findings.