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Drilling for the International Continental Scientific Drilling Program (ICDP) Early Jurassic Earth System and Timescale project (JET) was undertaken between October 2020 and January 2021. The drill site is situated in a small-scale synformal basin of the latest Triassic to Early Jurassic age that formed above the major Permian–Triassic half-graben system of the Cheshire Basin. The borehole is located to recover an expanded and complete succession to complement the legacy core from the Llanbedr (Mochras Farm) borehole drilled through 1967–1969 on the edge of the Cardigan Bay Basin, North Wales. The overall aim of the project is to construct an astronomically calibrated integrated timescale for the Early Jurassic and to provide insights into the operation of the Early Jurassic Earth system. Core of Quaternary age cover and Early Jurassic mudstone was obtained from two shallow partially cored geotechnical holes (Prees 2A to 32.2 m below surface (m b.s.) and Prees 2B to 37.0 m b.s.) together with Early Jurassic and Late Triassic mudstone from the principal hole, Prees 2C, which was cored from 32.92 to 651.32 m (corrected core depth scale). Core recovery was 99.7 % for Prees 2C. The ages of the recovered stratigraphy range from the Late Triassic (probably Rhaetian) to the Early Jurassic, Early Pliensbachian (Ibex Ammonoid Chronozone). All ammonoid chronozones have been identified for the drilled Early Jurassic strata. The full lithological succession comprises the Branscombe Mudstone and Blue Anchor formations of the Mercia Mudstone Group, the Westbury and Lilstock formations of the Penarth Group, and the Redcar Mudstone Formation of the Lias Group. A distinct interval of siltstone is recognized within the Late Sinemurian of the Redcar Mudstone Formation, and the name “Prees Siltstone Member” is proposed. Depositional environments range from playa lake in the Late Triassic to distal offshore marine in the Early Jurassic. Initial datasets compiled from the core include radiography, natural gamma ray, density, magnetic susceptibility, and X-ray fluorescence (XRF). A full suite of downhole logs was also run. Intervals of organic carbon enrichment occur in the Rhaetian (Late Triassic) Westbury Formation and in the earliest Hettangian and earliest Pliensbachian strata of the Redcar Mudstone Formation, where up to 4 % total organic carbon (TOC) is recorded. Other parts of the succession are generally organic-lean, containing less than 1 % TOC. Carbon-isotope values from bulk organic matter have also been determined, initially at a resolution of ∼ 1 m, and these provide the basis for detailed correlation between the Prees 2 succession and adjacent boreholes and Global Stratotype Section and Point (GSSP) outcrops. Multiple complementary studies are currently underway and preliminary results promise an astronomically calibrated biostratigraphy, magnetostratigraphy, and chemostratigraphy for the combined Prees and Mochras successions as well as insights into the dynamics of background processes and major palaeo-environmental changes.

Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Background: The objective of this study was to determine whether postoperative pager alerts to the Hospital Elder Life Program (HELP), a delirium prevention service, would accelerate program enrollment for older surgical patients. This study also tested feasibility of family care partner interventions for delirium prevention., Methods: This single-center, pilot clinical trial factorially randomized 57 non-cardiac surgical patients ≥70 years of age to 4 arms: (1) standard care, (2) pager alerts to accelerate HELP enrollment, (3) family care partner-based delirium prevention interventions, or (4) a combined arm with both HELP and family interventions. The primary clinical outcome was delirium (assessed through the Confusion Assessment Method)., Results: In the pager alerting arms, 13/24 (54%) participants were enrolled by HELP on postoperative day 1 compared with 0/26 (0%, P<0.001) in the non-alerting arms. Median [interquartile range] time spent in delirium prevention protocols was significantly longer in pager alerting arms than in non-alerting arms (39 [5 to 75] min vs. 0 [0 to 0] min; P<0.001). Family care partners spent 18 [11 to 25)] hours at the bedside over the first 3 postoperative days. There was no significant difference in delirium occurrence in participants randomized to pager alert arms compared with non-alerting arms (odds ratio, 1.02, 95% CI, 0.97-1.07; P=0.390). Similarly, there was no significant difference in delirium occurrence in family intervention arms compared with nonintervention arms (odds ratio, 0.97; 95% CI 0.93-10.02; P=0.270)., Conclusions: Pager alerts significantly reduced time to HELP enrollment, albeit without reducing delirium incidence in this pilot study. Family care partners spent substantial time at the bedside during the study period., Competing Interests: P.E.V., A.M., and L.M. receive support from Blue Cross Blue Shield of Michigan (Detroit, MI) for quality improvement initiatives related to delirium. P.E.V. is a member of the Editorial Board of the Journal of Neurosurgical Anesthesiology. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

PIWI-interacting RNAs (piRNAs) are 24-32 nucleotide RNA sequences primarily expressed in germ cells and developing embryos that suppress transposable element expression to protect genomic integrity during epigenetic reprogramming events. We characterized the expression of piRNA sequences and their encoding clusters in sperm samples from an idiopathic fertility model of Holstein bulls with high and low Sire Conception Rates. The piRNA populations were determined to be mostly similar between fertility conditions when investigated by principal component and differential expression analysis, suggesting that a high degree of conservation in the piRNA system is likely necessary for the production of viable sperm. Both fertility conditions demonstrated evidence of 'ping-pong' activity - a secondary biogenesis pathway associated with active transposable element targeting and suppression. Most sperm-borne piRNAs were between 29-30 nucleotides in length and originated from 226 clusters across the genome, with the exception of chromosome 20. Mapping analysis revealed abundant targeting of several transposable element families, suggesting a suppressive function of sperm piRNAs consistent with their established roles. Expression of genes targeted by sperm-borne piRNAs is significantly reduced throughout early embryogenesis compared to the mRNA population. Limited transposable element expression is known to be essential for spermatogenesis, thus epigenetic regulation of this pathway is likely to influence sperm quality and fertilizing capacity.

The clinical laboratory uses commercial products with limited shelf life or certain expiry dates requiring frequent lot changes. Prior to implementation for clinical use, laboratories should determine the performance of the new reagent lot to ensure that there is no significant shift in reagent performance or reporting of patient data. This guideline has been written on behalf of the International Council for Standardization in Haematology (ICSH) to provide the framework and provisional guidance for clinical laboratories for evaluating and verifying the performance of new lot reagents used for coagulation testing. These ICSH Working Party consensus recommendations are based on good laboratory practice, regulatory recommendations, evidence emerged from scientific publications, and expert opinion and are meant to supplement regional standards, regulations, or requirements., Competing Interests: D.C. received honorarium from Whitehouse Webinar Speaker, Stago Webinar Speaker, Coagulation BLOG for Aniara. She served as an Executive Secretary, NASCOLA and is currently serving as a Chairperson, CLSI HILA Committee.K.M. received support from International Society of Laboratory Hematology (ISLH) and Canadian Society for Medical Laboratory Science (CSMLS) for attending meetings. She is also serving as a Vice President, Membership Engagement in ISLH and as a Board of Directors, Director, Ontario in CSMLS.R.C.G. received consultation fees from Sysmex America Inc.; University of California, Santa Cruz; University of California, Berkeley; and Diagnostica Grifols. He received honorarium from Diagnostica Stago; Pharmacy Innovations Conference on Antithrombotic Therapy; and Mindray Scientific Forum. He also participated on a Data Safety Monitoring Board or Advisory Board in University of California, Davis Health System, Thrombosis and Hemostasis Subcommittee of Pharmacy and Therapeutics Committee. He received reimbursement for expenses for leadership role from International Council for Standardization in Haematology., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Recycling of unnecessary or dysfunctional cellular structures through autophagy plays a critical role in cellular homeostasis and environmental resilience. Therefore, the autophagy trait may have been unintentionally selected in wheat breeding programs for higher yields in arid climates. This hypothesis was tested by measuring the response of three common autophagy markers, ATG7, ATG8, and NBR1, to a heat wave under reduced soil moisture content in 16 genetically diverse spring wheat landraces originating from different geographical locations. We observed in the greenhouse trials that ATG8 and NBR1 exhibited genotype-specific responses to a 1 h, 40 °C heat wave, while ATG7 did not show a consistent response. Three genotypes from Uruguay, Mozambique, and Afghanistan showed a pattern consistent with higher autophagic activity: decreased or stable abundance of both ATG8 and NBR1 proteins, coupled with increased transcription of ATG8 and NBR1 . In contrast, three genotypes from Pakistan, Ethiopia, and Egypt exhibited elevated ATG8 protein levels alongside reduced or unaltered ATG8 transcript levels, indicating a potential suppression or no change in autophagic activity. Principal component analysis demonstrated a correlation between lower abundance of ATG8 and NBR1 proteins and higher yield in the field trials. We found that (i) the combination of heat and drought activated autophagy only in several genotypes, suggesting that despite being a resilience mechanism, autophagy is a heat-sensitive process; (ii) higher autophagic activity correlates positively with greater yield; (iii) the lack of autophagic activity in some high-yielding genotypes suggests contribution of alternative stress-resilient mechanisms; and (iv) enhanced autophagic activity in response to heat and drought was independently selected by wheat breeding programs in different geographic locations.

Issue Addressed: This study assessed Australian adults' attitudes towards government actions to protect children from digital marketing of unhealthy food and drink products., Methods: An online survey was undertaken by Australian adults aged 18-64 recruited via two national panels in December 2019 (N = 2044)., Results: Most respondents (69%) agreed the Government should protect children from unhealthy food and drink marketing and advertising broadly. Those who agreed most commonly indicated children should be protected up to age 16 (34%) or 18 (24%). There was widespread support for government actions to stop unhealthy food and drink marketing on digital platforms (e.g., internet sites) (68%-69%) and various digital marketing techniques (e.g., advertising by brands on social media) (56%-71%). A total ban on targeting unhealthy food and drink marketing to children online received the highest level of support (76%). Most respondents (81%) disagreed unhealthy food and drink companies should be able to collect children's personal information for marketing purposes. Support for examined actions was generally higher among older adults, more educated adults and more frequent internet users, lower among males, and similar between parents and non-parents., Conclusions: There is public perception that the government is responsible for protecting children, well into adolescence, from unhealthy food and drink marketing broadly. Widespread public support extends to specific actions to reduce children's exposure to digital marketing of unhealthy food and drink products. SO WHAT?: Implementation of policies to protect children from digital marketing of unhealthy food and drink products would be well received by the Australian public., (© 2023 Australian Health Promotion Association.)

Competing Interests: None declared

Introduction and Aims: Mim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non-FVIII measuring haemostasis assays was assessed in plasma containing Mim8., Methods: Congenital severe HA plasma was spiked with increasing concentrations of Mim8 (0-20 μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D-dimer, anti-Xa, heparin induced thrombocytopenia (HIT), clotting factors II-XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT., Results and Conclusions: Less than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15 μg/mL Mim8 in all assays except thrombin time (-10.5%), APTT-based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (-26.4%) and LA2 (-16.9%). At the expected therapeutic steady state levels of Mim8 (5-8 μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo. APTT-based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management., (© 2023 John Wiley & Sons Ltd.)

Abiotic reduction by iron minerals is arguably the most important fate process for munition compounds (MCs) in subsurface environments. No model currently exists that can predict the abiotic reduction rates of structurally diverse MCs by iron (oxyhydr)oxides. We performed batch experiments to measure the rate constants for the reduction of three classes of MCs (poly-nitroaromatics, nitramines, and azoles) by hematite or goethite in the presence of aqueous Fe 2+ . The surface area-normalized reduction rate constant ( k SA ) depended on the aqueous-phase one-electron reduction potential ( E system. A linear free energy relationship (LFER), similar to that reported previously for nitrobenzene, successfully captures all MC reduction rate constants that span 6 orders of magnitude: log ( k S A ) = ( 1.12 ± 0.04 ) [ 0.53 E H 1 59 m V - ( p H + p e ) ] + ( 5.52 ± 0.23 ) . The finding that the rate constants of all the different classes of MCs can be described by a single LFER suggests that these structurally diverse nitro compounds are reduced by iron oxide-Fe H 1 ) of the MC and the thermodynamic state (i.e., pe and pH) of the iron oxide-Fe aq 2+ system. A linear free energy relationship (LFER), similar to that reported previously for nitrobenzene, successfully captures all MC reduction rate constants that span 6 orders of magnitude: log ( k S A ) = ( 1.12 ± 0.04 ) [ 0.53 E H 1 59 m V - ( p H + p e ) ] + ( 5.52 ± 0.23 ) . The finding that the rate constants of all the different classes of MCs can be described by a single LFER suggests that these structurally diverse nitro compounds are reduced by iron oxide-Fe aq 2+ couples through a common mechanism up to the rate-limiting step. Multiple mechanistic implications of the results are discussed. This study expands the applicability of the LFER model for predicting the reduction rates of legacy and emerging MCs and potentially other nitro compounds.

Bisphenol A (BPA) is an endocrine disrupting compound, used as the key monomer of polycarbonate plastics and epoxy resins. BPA has been detected in both humans and farm animals and has been correlated with decreased sperm counts and motility. BPS and BPF are structural analogs of BPA and are increasingly being used in manufacturing as BPA substitutes. In this study we aim to assess the direct outcomes of BPA, BPS and BPF exposure on bovine sperm parameters in vitro to elucidate how they affect sperm quality and fertilization potential, and to assess whether BPS and/or BPF are less harmful than BPA. Sperm from three or more bulls was obtained from either fresh samples or cryopreserved straws and exposed to 0.05 mg/mL of BPA, BPS and BPF in vitro. After 4h incubation, motility, capacitation, apoptosis/necrosis, and mitochondrial membrane potential levels were measured by CASA or computational flow cytometry. Results showed that BPA exposure significantly reduced both fresh and cryopreserved sperm motility, capacitation, viability and mitochondrial membrane potential levels. Furthermore, BPF significantly decreased motility, capacitation and mitochondrial membrane potential in cryopreserved sperm only. BPS did not have any significant effects on any of the parameters measured. Our results suggest that BPA is the most harmful to sperm, while BPF is toxic under certain conditions, and BPS seems to be the least detrimental. Overall, this study provides an understanding of how the ubiquitous environmental chemicals, bisphenols, may impact male fertility even after ejaculation.

Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody., Objective: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study., Methods: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection., Results: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C max in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after T max and a 97% reduction from C max in teclistamab concentration at a median time of 69 days (32-163 days) after T max . Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles., Conclusion: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM., Clinical Trial Registration: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020)., (© 2023. The Author(s).)

Organelles function as hubs of cellular metabolism and elements of cellular architecture. In addition to 3 spatial dimensions that describe the morphology and localization of each organelle, the time dimension describes complexity of the organelle life cycle, comprising formation, maturation, functioning, decay, and degradation. Thus, structurally identical organelles could be biochemically different. All organelles present in a biological system at a given moment of time constitute the organellome. The homeostasis of the organellome is maintained by complex feedback and feedforward interactions between cellular chemical reactions and by the energy demands. Synchronized changes of organelle structure, activity, and abundance in response to environmental cues generate the fourth dimension of plant polarity. Temporal variability of the organellome highlights the importance of organellomic parameters for understanding plant phenotypic plasticity and environmental resiliency. Organellomics involves experimental approaches for characterizing structural diversity and quantifying the abundance of organelles in individual cells, tissues, or organs. Expanding the arsenal of appropriate organellomics tools and determining parameters of the organellome complexity would complement existing -omics approaches in comprehending the phenomenon of plant polarity. To highlight the importance of the fourth dimension, this review provides examples of organellome plasticity during different developmental or environmental situations., Competing Interests: Conflict of interest. None declared., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

No single linear free energy relationship (LFER) exists that can predict reduction rate constants of all munition constituents (MCs). To address this knowledge gap, we measured the reduction rates of MCs and their surrogates including nitroaromatics [NACs; 2,4,6-trinitrotoluene (TNT), 2,4-dinitroanisole (DNAN), 2-amino-4,6-dinitrotoluene (2-A-DNT), 4-amino-2,6-dinitrotoluene (4-A-DNT), and 2,4-dinitrotoluene (DNT)], nitramines [hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and nitroguanidine (NQ)], and azoles [3-nitro-1,2,4-triazol-5-one (NTO) and 3,4-dinitropyrazole (DNP)] by three dithionite-reduced quinones (lawsone, AQDS, and AQS). All MCs/NACs were reduced by the hydroquinones except NQ. Hydroquinone and MC speciations were varied by controlling pH, permitting the application of a speciation model to determine second-order rate constants ( k ) from observed pseudo-first-order rate constants. The intrinsic reactivity of MCs (oxidants) decreased upon deprotonation, while the opposite was true for hydroquinones (reductants). The rate constants spanned ∼6 orders of magnitude in the order NTO ≈ TNT > DNP > DNT ≈ DNAN ≈ 2-A-DNT > DNP - > 4-A-DNT > NTO - > RDX. LFERs developed using density functional theory-calculated electron transfer and hydrogen atom transfer energies and reported one-electron reduction potentials successfully predicted k , suggesting that these structurally diverse MCs/NACs are all reduced by hydroquinones through the same mechanism and rate-limiting step. These results increase the applicability of LFER models for predicting the fate and half-lives of MCs and related nitro compounds in reducing environments.

Introduction: Adrenocortical carcinoma is a rare malignancy that typically presents with advanced features and carries a poor prognosis. Complete surgical resection offers patients the best survival outcomes, but this is not always achievable and many require additional therapy for advanced features. Some literature has explored the role of chemotherapy and radiation, but little has been conducted to explore the effects of multimodal therapy., Methods: We retrospectively reviewed the National Cancer Database for adults with primary nonmetastatic adrenocortical carcinoma (ACC) who underwent either partial or radical adrenalectomy. Excluded patients included those with metastatic disease and those with primary tumor >30 cm. Patients were categorized based on adjuvant treatment; chemotherapy, radiation therapy (RT), RT + chemotherapy, or no adjuvant therapy. Overall survival (OS) was compared using survival curves, log rank tests, and multivariate survival analysis., Results: We identified 1644 patients with localized ACC treated with adrenalectomy. The median tumor size was 10.6 cm. A total of 278 patients had positive margin status (R1), and 416 patients had nodal (pN+) disease. Out of all patients, a minority (39.4%) received adjuvant therapy, which was most commonly given as chemotherapy only. Statistically significant increase in OS was noted with the use of RT + chemotherapy in the node-negative, margins-positive (pN0/pNx; R1) subgroup versus patients who did not receive adjuvant therapy (5-year OS 60.5% and 28.2%, respectively [ P = 0.002]). This held true on multivariate analysis with significant improvement in OS in the pN0/pNx; R1 population with RT + chemotherapy compared to those who received no treatment (hazard ratio: 0.40 [95% confidence interval: 0.2-0.9], P = 0.02)., Conclusions: Our findings support the use of adjuvant chemotherapy plus RT in patients with positive surgical margins and no nodal disease. Additional studies are required to confirm these findings, clarify the objective benefit of multimodal therapy, and to determine the optimal chemotherapy/RT combination., Competing Interests: Conflicts of Interest: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Urology.)

CAS Common Chemistry (https://commonchemistry.cas.org/) is an open web resource that provides access to reliable chemical substance information for the scientific community. Having served millions of visitors since its creation in 2009, the resource was extensively updated in 2021 with significant enhancements. The underlying dataset was expanded from 8000 to 500,000 chemical substances and includes additional associated information, such as basic properties and computer-readable chemical structure information. New use cases are supported with enhanced search capabilities and an integrated application programming interface. Reusable licensing of the content is provided through a Creative Commons Attribution-Non-Commercial (CC-BY-NC 4.0) license allowing other public resources to integrate the data into their systems. This paper provides an overview of the enhancements to data and functionality, discusses the benefits of the contribution to the chemistry community, and summarizes recent progress in leveraging this resource to strengthen other information sources.

Drought resiliency strategies combine developmental, physiological, cellular, and molecular mechanisms. Here, we compare drought responses in two resilient spring wheat ( Triticum aestivum) genotypes: a well-studied drought-resilient Drysdale and a resilient genotype from the US Pacific North-West Hollis. While both genotypes utilize higher water use efficiency through the reduction of stomatal conductance, other mechanisms differ. First, Hollis deploys the drought escape mechanism to a greater extent than Drysdale by accelerating the flowering time and reducing root growth. Second, Drysdale uses physiological mechanisms such as non-photochemical quenching (NPQ) to dissipate the excess of harvested light energy and sustain higher F v /F m and ϕ PSII , whereas Hollis maintains constant NPQ but lower F v /F m and ϕ PSII values. Furthermore, more electron donors of the electron transport chain are in the oxidized state in Hollis than in Drysdale. Third, many ROS homeostasis parameters, including peroxisome abundance, transcription of peroxisome biogenesis genes PEX11 and CAT , catalase protein level, and enzymatic activity, are higher in Hollis than in Drysdale. Fourth, transcription of autophagy flux marker ATG8.4 is upregulated to a greater degree in Hollis than in Drysdale under drought, whereas relative ATG8 protein abundance under drought stress is lower in Hollis than in Drysdale. These data demonstrate the activation of autophagy in both genotypes and a greater autophagic flux in Hollis. In conclusion, wheat varieties utilize different drought tolerance mechanisms. Combining these mechanisms within one genotype offers a promising strategy to advance crop resiliency.

Small non-coding RNAs have been linked to different phenotypes in bovine sperm, however attempts to identify sperm-borne molecular biomarkers of male fertility have thus far failed to identify a robust profile of expressed miRNAs related to fertility. We hypothesized that some differences in bull fertility may be reflected in the levels of different miRNAs in sperm. To explore such differences in fertility that are not due to differences in visible metrics of sperm quality, we employed Next Generation Sequencing to compare the miRNA populations in Bos taurus sperm from bulls with comparable motility and morphology but varying Sire Conception Rates. We identified the most abundant miRNAs in both populations (miRs -34b-3p; -100-5p; -191-5p; -30d-4p; -21-5p) and evaluated differences in the overall levels and specific patterns of isomiR expression. We also explored correlations between specific pairs of miRNAs in each population and identified 10 distinct pairs of miRNAs that were positively correlated in bulls with higher fertility and negatively correlated in comparatively less fertile individuals. Furthermore, 8 additional miRNA pairs demonstrated the opposite trend; negatively correlated in high fertility animals and positively correlated in less fertile bulls. Finally, we performed pathway analysis to identify potential roles of miRNAs present in bull sperm in the regulation of specific genes that impact spermatogenesis and embryo development. Together, these results present a comprehensive picture of the bovine sperm miRNAome that suggests multiple potential roles in fertility., 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 Werry, Russell, Gillis, Miller, Hickey, Larmer, Lohuis, Librach and LaMarre.)

Aims: Digital health can transform the management of atrial fibrillation (AF) and enable patients to take a central role in detecting symptoms and self-managing AF. There is a gap in understanding factors that support sustained use of digital health tools for patients with AF. This study identified predictors of Alivecor® KardiaMobile ECG monitor usage among patients with AF enrolled in the iPhone®Helping Evaluate Atrial fibrillation Rhythm through Technology (iHEART) randomized controlled trial., Methods and Results: We analysed data from 105 English and Spanish-speaking adults with AF enrolled in the intervention arm of the iHEART trial. The iHEART intervention included smartphone-based electrocardiogram self-monitoring with Alivecor® KardiaMobile and triweekly text messages for 6 months. The primary outcome was use of Alivecor® categorized as: infrequent (≤5 times/week), moderate (>5 times and ≤11 times/week), and frequent (>11 times/week). We applied multinomial logistic regression modelling to characterize frequency and predictors of use. Of the 105 participants, 25% were female, 75% were White, and 45% were ≥65 years of age. Premature atrial contractions (PACs) [adjusted odds ratio (OR): 1.23, 1.08-1.40, P = 0.002] predicted frequent as compared to infrequent use. PACs (adjusted OR: 1.17, 95% confidence interval 1.06-1.30, P = 0.003), lower symptom burden (adjusted OR: 1.06, 1.01-1.11, P = 0.02), and less treatment concern (adjusted OR: 0.96, 0.93-0.99, P = 0.02) predicted moderate as compared to infrequent use., Conclusions: Frequent use of AliveCor® is associated with AF symptoms and potentially symptomatic cardiac events. Symptom burden and frequency should be measured and incorporated into analyses of future digital health trials for AF management., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)