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Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Abstract Background The Ultra-Low Emission Zone (ULEZ), introduced in Central London in April 2019, aims to enhance air quality and improve public health. The Children's Health in London and Luton (CHILL) study evaluates the impact of the ULEZ on children's health. This analysis focuses on the one-year impacts on the shift towards active travel to school. Methods CHILL is a prospective parallel cohort study of ethnically diverse children, aged 6–9 years attending 84 primary schools within or with catchment areas encompassing London’s ULEZ (intervention) and Luton (non-intervention area). Baseline (2018/19) and one-year follow-up (2019/20) data were collected at school visits from 1992 (58%) children who reported their mode of travel to school ‘today’ (day of assessment). Multilevel logistic regressions were performed to analyse associations between the introduction of the ULEZ and the likelihood of switching from inactive to active travel modes, and vice-versa. Interactions between intervention group status and pre-specified effect modifiers were also explored. Results Among children who took inactive modes at baseline, 42% of children in London and 20% of children in Luton switched to active modes. For children taking active modes at baseline, 5% of children in London and 21% of children in Luton switched to inactive modes. Relative to the children in Luton, children in London were more likely to have switched from inactive to active modes (OR 3.64, 95% CI 1.21–10.92). Children in the intervention group were also less likely to switch from active to inactive modes (OR 0.11, 0.05–0.24). Moderator analyses showed that children living further from school were more likely to switch from inactive to active modes (OR 6.06,1.87–19.68) compared to those living closer (OR 1.43, 0.27–7.54). Conclusions Implementation of clean air zones can increase uptake of active travel to school and was particularly associated with more sustainable and active travel in children living further from school.

Abstract Background Mandibular second premolar agenesis is a common problem in orthodontics and is often treated in conjunction with maxillary counterbalancing extractions. However, in cases without maxillary crowding or dental protrusion, space closure may pose challenges leading to compromised occlusal results or patient profile. Multiple techniques have been described to treat these patients; nevertheless, there is a paucity of data comparing effectiveness of space closure utilizing various anchorage techniques. The goal of this study is to assess the effectiveness of the Herbst device during mandibular molar protraction and compare it to the use of temporary anchorage device (TADs) in patients with mandibular second premolar agenesis. Materials and methods This retrospective study included 33 patients with mandibular premolar agenesis treated without maxillary extractions. Of these patients, 21 were treated with protraction Herbst devices and 12 with TADs. Changes in molar and incisor positions, skeletal base positions and occlusal plane angulations were assessed on pretreatment (T0) and post-treatment (T1) lateral cephalograms. Scans/photographs at T0 and T1 were used to evaluate canine relationship changes representing anchorage control. Space closure and breakage/failure rates were also compared. Data was analyzed with paired and unpaired t-tests at the significance level of 0.05. Results Within the Herbst group, changes in mandibular central incisor uprighting and mandibular molar crown angulations were statistically significant. However, no significant differences were noted between the Herbst and TAD groups. Protraction rates as well as overall treatment times were comparable (0.77 mm/month vs. 0.55 mm/month and 3.02 years vs. 2.67 years, respectively). Canine relationships were maintained or improved toward a class I in 82.85% of the Herbst sample, compared to in 66.7% of the TAD sample. Emergency visits occurred in 80.1% of the Herbst group, with cementation failures or appliance breakages as the most common reasons. Conclusion The Herbst device could be a viable modality in cases with missing mandibular premolars where maximum anterior anchorage is desired, or if patients/parents are resistant to TADs. Furthermore, they could be beneficial in skeletal class II patients with mandibular deficiency who also need molar protraction. However, the increased incidence of emergency visits must be considered when treatment is planned.

X-ray free-electron laser (XFEL) light sources have enabled the rapid growth of time-resolved structural experiments, which provide crucial information on the function of macromolecules and their mechanisms. Here, the aim was to commission the SwissMX fixed-target sample-delivery system at the SwissFEL Cristallina experimental station using the PSI-developed micro-structured polymer (MISP) chip for pump–probe time-resolved experiments. To characterize the system, crystals of the light-sensitive protein light–oxygen–voltage domain 1 (LOV1) from Chlamydomonas reinhardtii were used. Using different experimental settings, the accidental illumination, referred to as light contamination, of crystals mounted in wells adjacent to those illuminated by the pump laser was examined. It was crucial to control the light scattering from and through the solid supports otherwise significant contamination occurred. However, the results here show that the opaque MISP chips are suitable for defined pump–probe studies of a light-sensitive protein. The experiment also probed the sub-millisecond structural dynamics of LOV1 and indicated that at Δt = 10 µs a covalent thioether bond is established between reactive Cys57 and its flavin mononucleotide cofactor. This experiment validates the crystals to be suitable for in-depth follow-up studies of this still poorly understood signal-transduction mechanism. Importantly, the fixed-target delivery system also permitted a tenfold reduction in protein sample consumption compared with the more common high-viscosity extrusion-based delivery system. This development creates the prospect of an increase in XFEL project throughput for the field.

Abstract Background Abortion-related complications remain a main cause of maternal mortality. There is little evidence on the availability and quality of post-abortion care (PAC) in humanitarian settings. We assessed the quality of PAC in two hospitals supported by an international organization in Jigawa State (Nigeria) and Bangui (Central African Republic, CAR). Methods We mapped indicators corresponding to the eleven domains of the WHO Maternal and Newborn Health quality-of-care framework to assess inputs, processes (provision and experience of care), and outcomes of PAC. We measured these indicators in four components of a cross-sectional multi-methods study: 1) an assessment of the hospitals’ PAC signal functions, 2) a survey of the knowledge, attitudes, practices, and behavior of 140 Nigerian and 84 CAR clinicians providing PAC, 3) a prospective review of the medical records of 520 and 548 women presenting for abortion complications and, 4) a survey of 360 and 362 of these women who were hospitalized in the Nigerian and CAR hospitals, respectively. Results Among the total 27 PAC signal functions assessed, 25 were available in the Nigerian hospital and 26 in the CAR hospital. In both hospitals, less than 2.5% were treated with dilatation and sharp curettage. Over 80% of women received blood transfusion or curative antibiotics when indicated. However, antibiotics were given to about 30% of patients with no documented indication. Among discharged women in CAR, 99% received contraceptive counseling but only 39% did in Nigeria. Over 80% of women in Nigeria reported positive experiences of respect and preservation of dignity. Conversely, in CAR, 37% reported that their privacy was always respected during examination and 62% reported short or very short waiting time before seeing a health provider. In terms of communication, only 15% felt able to ask questions during treatment in both hospitals. The risk of abortion-near-miss happening ≥ 24h after presentation was 0.2% in Nigeria and 1.1% in CAR. Only 65% of women in the Nigerian hospital and 34% in the CAR hospital reported that the staff provided them best care all the time. Conclusion Our comprehensive assessment identified that these two hospitals in humanitarian settings provided lifesaving PAC. However, hospitals need to strengthen the patient-centered approach engaging patients in their own care and ensuring privacy, short waiting times and quality provider-patient communication. Health professionals would benefit from instituting antibiotic stewardships to prevent antibiotic-resistance.

Abstract Background Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood. Main text This study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed “chronic brain neutrophils” (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies. Conclusions In conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.

Abstract Background Netball is a sport with a large participation base and a high risk of injuries. Effective injury prevention strategies are dependent upon a clear understanding of injury issues, aetiology and mechanisms, requiring robust research methodologies to ensure a reliable evidence base. This scoping review aims to identify the characteristics and range of netball injury research methodologies, to inform recommendations for future research. Methods A systematic search of SPORTDiscus, MEDLINE, CINAHL and Academic Search Complete, PubMed, Scopus and Web of Science, from 1985 to May 2023 identified relevant studies. Inclusion criteria included peer-reviewed studies assessing injury incidence, aetiology and mechanisms in netball. Results Following screening, 65 studies were included (68% descriptive epidemiology, 32% analytic epidemiology). Descriptive epidemiology reported data from hospital/clinic and insurance databases (57%) and netball competitions (43%). Only two studies used ongoing, systematic injury surveillance in netball cohorts, and significant heterogeneity existed in study designs, data collection methods, injury definitions and injury incidence rates calculations. Studies assessed a limited number of risk factors (descriptive competition studies: median: n = 4; analytic studies median: n = 6), with 76% using a simplistic reductionist approach to determine causality. Basic descriptions and retrospective recall of injury mechanisms reduced accuracy. Only two studies conducted comprehensive assessments of injury mechanisms using video-based methods. Conclusion To establish an accurate netball injury evidence base, future research should prioritise the development of reliable, continuous surveillance systems. The International Olympic Committee (IOC) consensus statement guidelines are recommended for accurate injury data collection and reporting. A multifactorial approach should be adopted to assess the complex interaction between multiple risk factors, player load and the injury inciting event. Comprehensive descriptions of injury mechanisms using video methods, alongside descriptions from medical staff are recommended. This information is crucial for developing targeted prevention strategies.

Abstract Ventilator-associated pneumonia (VAP) affects up to 20% of critically ill patients and induces significant antibiotic prescription pressure, accounting for half of all antibiotic use in the ICU. VAP significantly increases hospital length of stay and healthcare costs yet is also associated with long-term morbidity and mortality. The diagnosis of VAP continues to present challenges and pitfalls for the currently available clinical, radiological and microbiological diagnostic armamentarium. Biomarkers and artificial intelligence offer an innovative potential direction for ongoing future research. In this Review, we summarise the pathobiological heterogeneity and diagnostic challenges associated with VAP.

Abstract Background Health system fragmentation directly contributes to poor health and social outcomes for older adults with multiple chronic conditions and their care partners. Older adults often require support from primary care, multiple specialists, home care, community support services, and other health-care sectors and communication between these providers is unstructured and not standardized. Integrated and interprofessional team-based models of care are a recommended strategy to improve health service delivery to older adults with complex needs. Standardized assessment instruments deployed on digital platforms are considered a necessary component of integrated care. The aim of this study was to develop strategies to leverage an electronic wellness instrument, interRAI Check Up Self Report, to support integrated health and social care for older adults and their care partners in a community in Southern Ontario, Canada. Methods Group concept mapping, a participatory mixed-methods approach, was conducted. Participants included older adults, care partners, and representatives from: home care, community support services, specialized geriatric services, primary care, and health informatics. In a series of virtual meetings, participants generated ideas to implement the interRAI Check Up and rated the relative importance of these ideas. Hierarchical cluster analysis was used to map the ideas into clusters of similar statements. Participants reviewed the map to co-create an action plan. Results Forty-one participants contributed to a cluster map of ten action areas (e.g., engagement of older adults and care partners, instrument’s ease of use, accessibility of the assessment process, person-centred process, training and education for providers, provider coordination, health information integration, health system decision support and quality improvement, and privacy and confidentiality). The health system decision support cluster was rated as the lowest relative importance and the health information integration was cluster rated as the highest relative importance. Conclusions Many person-, provider-, and system-level factors need to be considered when implementing and using an electronic wellness instrument across health- and social-care providers. These factors are highly relevant to the integration of other standardized instruments into interprofessional team care to ensure a compassionate care approach as technology is introduced.

Abstract The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.

Abstract Background Accurate detection of pheromones is crucial for chemical communication and reproduction in insects. In holometabolous flies and moths, the sensory neuron membrane protein 1 (SNMP1) is essential for detecting long-chain aliphatic pheromones by olfactory neurons. However, its function in hemimetabolous insects and its role for detecting pheromones of a different chemical nature remain elusive. Therefore, we investigated the relevance of SNMP1 for pheromone detection in a hemimetabolous insect pest of considerable economic importance, the desert locust Schistocerca gregaria, which moreover employs the aromatic pheromone phenylacetonitrile (PAN) to govern reproductive behaviors. Results Employing CRISPR/Cas-mediated gene editing, a mutant locust line lacking functional SNMP1 was established. In electroantennography experiments and single sensillum recordings, we found significantly decreased electrical responses to PAN in SNMP1-deficient (SNMP1−/−) locusts. Moreover, calcium imaging in the antennal lobe of the brain revealed a substantially reduced activation of projection neurons in SNMP1−/− individuals upon exposure to PAN, indicating that the diminished antennal responsiveness to PAN in mutants affects pheromone-evoked neuronal activity in the brain. Furthermore, in behavioral experiments, PAN-induced effects on pairing and mate choice were altered in SNMP1−/− locusts. Conclusions Our findings emphasize the importance of SNMP1 for chemical communication in a hemimetabolous insect pest. Moreover, they show that SNMP1 plays a crucial role in pheromone detection that goes beyond long-chain aliphatic substances and includes aromatic compounds controlling reproductive behaviors.

Abstract Background Alfalfa (Medicago sativa L.) experiences many negative effects under salinity stress, which may be mediated by recurrent selection. Salt-tolerant alfalfa may display unique adaptations in association with rhizobium under salt stress. Results To elucidate inoculation effects on salt-tolerant alfalfa under salt stress, this study leveraged a salt-tolerant alfalfa population selected through two cycles of recurrent selection under high salt stress. After experiencing 120-day salt stress, mRNA was extracted from 8 random genotypes either grown in 0 or 8 dS/m salt stress with or without inoculation by Ensifer meliloti. Results showed 320 and 176 differentially expressed genes (DEGs) modulated in response to salinity stress or inoculation x salinity stress, respectively. Notable results in plants under 8 dS/m stress included upregulation of a key gene involved in the Target of Rapamycin (TOR) signaling pathway with a concomitant decrease in expression of the SNrK pathway. Inoculation of salt-stressed plants stimulated increased transcription of a sulfate-uptake gene as well as upregulation of the Lysine-27-trimethyltransferase (EZH2), Histone 3 (H3), and argonaute (AGO, a component of miRISC silencing complexes) genes related to epigenetic and post-transcriptional gene control. Conclusions Salt-tolerant alfalfa may benefit from improved activity of TOR and decreased activity of SNrK1 in salt stress, while inoculation by rhizobiumstimulates production of sulfate uptake- and other unique genes.

Detailed explorations of the model organisms Caenorhabditis elegans (elegant worm) and Drosophila melanogaster (vinegar fly) have substantially improved our knowledge and understanding of biological processes and pathways in metazoan organisms. Extensive functional genomic and multi-omic data sets have enabled the discovery and characterisation of ‘essential’ genes that are critical for the survival of these organisms. Recently, we showed that a machine learning (ML)-based pipeline could be utilised to predict essential genes in both C. elegans and D. melanogaster using features from DNA, RNA, protein and/or cellular data or associated information. As these distantly-related species are within the Ecdysozoa, we hypothesised that this approach could be suited for non-model organisms within the same group (phylum) of protostome animals. In the present investigation, we cross-predicted essential genes within the phylum Nematoda – between C. elegans and the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus, and then ranked and prioritised these genes. Highly ranked genes were linked to key biological pathways or processes, such as ribosome biogenesis, translation and RNA processing, and were expressed at relatively high levels in the germline, gonad, hypodermis and/or nerves. The present in silico workflow is hoped to expedite the identification of drug targets in parasitic organisms for subsequent experimental validation in the laboratory.

Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans – a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes’ cellular and molecular biology – which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus – a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.

Abstract Background The demand for mental health services in Australia is substantial and has grown beyond the capacity of the current workforce. As a result, it is currently difficult for many to access secondary healthcare providers. Within the secondary healthcare sector, however, peer workers who have lived experience of managing mental health conditions have been increasingly employed to intentionally use their journey of recovery in supporting others living with mental health conditions and their communities. Currently, the presence of peer workers in primary care has been limited, despite the potential benefits of providing supports in conjunction with GPs and secondary healthcare providers. Methods This stepped-wedge cluster randomised controlled trial (RCT) aims to evaluate a lived experience peer support intervention for accessing mental health care in primary care (PS-PC). Four medical practices across Australia will be randomly allocated to switch from control to intervention, until all practices are delivering the PS-PC intervention. The study will enrol 66 patients at each practice (total sample size of 264). Over a period of 3–4 months, 12 h of practical and emotional support provided by lived experience peer workers will be available to participants. Scale-based questionnaires will inform intervention efficacy in terms of mental health outcomes (e.g., self-efficacy) and other health outcomes (e.g., healthcare-related costs) over four time points. Other perspectives will be explored through scales completed by approximately 150 family members or carers (carer burden) and 16 peer workers (self-efficacy) pre- and post-intervention, and 20 medical practice staff members (attitudes toward peer workers) at the end of each study site’s involvement in the intervention. Interviews (n = 60) and six focus groups held toward the end of each study site’s involvement will further explore the views of participants, family members or carers, peer workers, and practice staff to better understand the efficacy and acceptability of the intervention. Discussion This mixed-methods, multi-centre, stepped-wedge controlled study will be the first to evaluate the implementation of peer workers in the primary care mental health care sector. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623001189617. Registered on 17 November 2023, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386715

Abstract Background Genotype × environment interaction (GEI) slows genetic gains and complicates selection decisions in plant breeding programs. Forage breeding program seed sales often encompass large geographic regions to which the cultivars may not be adapted. An understanding of the extent of GEI in perennial, cool‐season forage grasses will facilitate improved selection decisions and end‐use in areas with harsh winters. Methods We evaluated the dry matter yield of nine meadow brome (Bromus biebersteinii Roemer & J. A. Schultes), nine orchardgrass (Dactylis glomerata L.), seven tall fescue (Lolium arundinaceum (Schreb.) Darbysh.), and 10 timothy (Phleum pratense L.) cultivars or breeding populations at seven high latitude and/or elevation locations in Canada and the United States from 2019 to 2021. Results For each of the species, we found significant differences among the genotypes for dry matter yield across environments and found significant levels of GEI. Using site regression analysis and GGE biplot visualizations, we then characterized the extent of the interactions in each species. Except for tall fescue, there was little evidence for the broad adaptation of genotypes across locations. Conclusions This research adds further evidence to the limitations of perennial, forage breeding programs to develop widely adapted cultivars and the need to maintain regional breeding efforts.

Abstract Estimating population changes of bats is important for their conservation. Population estimates of hibernating bats are often calculated by researchers entering hibernacula to count bats; however, the disturbance caused by these surveys can cause bats to arouse unnaturally, fly, and lose body mass. We conducted 17 hibernacula surveys in 9 caves from 2013 to 2018 and used acoustic detectors to document cave-exiting bats the night following our surveys. We predicted that cave-exiting flights (i.e., bats flying out and then back into caves) of Townsend’s big-eared bats (Corynorhinus townsendii) and western small-footed myotis (Myotis ciliolabrum) would be higher the night following hibernacula surveys than on nights following no surveys. Those two species, however, did not fly out of caves more than predicted the night following 82% of surveys. Nonetheless, the activity of bats flying out of caves following surveys was related to a disturbance factor (i.e., number of researchers × total time in a cave). We produced a parsimonious model for predicting the probability of Townsend’s big-eared bats flying out of caves as a function of disturbance factor and ambient temperature. That model can be used to help biologists plan for the number of researchers, and the length of time those individuals are in a cave to minimize disturbing bats.

Abstract The primary hurdles for small interference RNA (siRNA) in clinical use are targeted and cytosolic delivery. To overcome both challenges, we have established a novel platform based on phage display, called NNJA. In this approach, a lysosomal cathepsin substrate is engineered within the flexible loops of PIII, that is displaying a unique random sequence at its N-terminus. NNJA library selection targeting cell-expressed targets should yield specific peptides localized in the cytoplasm. That is because phage internalization and subsequent localization to lysosome, upon peptide binding to the cell expressed target, will result in cleavage of PIII, rendering phage non-infective. Such phage will be eliminated from the selected pool and only peptide-phage that escapes lysosomes will advance to the next round. Proof of concept studies with the NNJA library demonstrated cytosolic localization of selected peptide-phage and peptide-siRNA, confirmed through confocal microscopy. More importantly, conjugation of siHPRT to monomeric or multimeric NNJA peptides resulted in significant reduction in HPRT mRNA in various cell types without significant cytotoxicity. Sequence similarity and clustering analysis from NGS dataset provide insights into sequence composition facilitating cell penetration. NNJA platform offers a highly efficient peptide discovery engine for targeted delivery of oligonucleotides to cytosol.

Abstract Our nervous system contains billions of neurons that form precise connections with each other through interactions between cell surface proteins. In Drosophila, the Dpr and DIP immunoglobulin protein subfamilies form homophilic or heterophilic interactions to instruct synaptic connectivity, synaptic growth, and cell survival. However, the upstream regulatory mechanisms of Dprs and DIPs are not clear. On the other hand, while transcription factors have been implicated in target recognition, their downstream cell surface proteins remain mostly unknown. We conduct an F1 dominant modifier genetic screen to identify regulators of Dprs and DIPs. We identify huckebein (hkb), a transcription factor previously implicated in target recognition of the dorsal Is motor neuron. We show that hkb genetically interacts with DIP-α and loss of hkb leads to complete removal of DIP-α expression specifically in dorsal Is motor neurons. We then confirm that this specificity is through the dorsal Is motor neuron specific transcription factor, even-skipped (eve), which acts downstream of hkb. Analysis of the genetic interaction between hkb and eve reveals that they act in the same pathway to regulate dorsal Is motor neuron connectivity. Our study provides insight into the transcriptional regulation of DIP-α and suggests that distinct regulatory mechanisms exist for the same CSP in different neurons.

Abstract Animals employ different strategies to establish mating boundaries between closely related species, with sex pheromones often playing a crucial role in identifying conspecific mates. Many of these pheromones have carbon-carbon double bonds, making them vulnerable to oxidation by certain atmospheric oxidant pollutants, including ozone. Here, we investigate whether increased ozone compromises species boundaries in drosophilid flies. We show that short-term exposure to increased levels of ozone degrades pheromones of Drosophila melanogaster, D. simulans, D. mauritiana, as well as D. sechellia, and induces hybridization between some of these species. As many of the resulting hybrids are sterile, this could result in local population declines. However, hybridization between D. simulans and D. mauritiana as well as D. simulans and D. sechellia results in fertile hybrids, of which some female hybrids are even more attractive to the males of the parental species. Our experimental findings indicate that ozone pollution could potentially induce breakdown of species boundaries in insects.

Purpose – This literature review aims to assess the current research on healthcare job availability and skilled professionals. The objective of this research is to identify challenges caused by the imbalance between healthcare service demand and qualified professionals and propose potential solutions and future research directions. Design/methodology/approach – The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was employed as the guiding framework for conducting this review. A qualitative research design analyzed 38 peer-reviewed, evidence-based research works from 50 journal publications. Inclusion criteria focused on empirical studies, observational research and comprehensive reviews published within the last ten years. Thematic and discourse analysis categorized themes and factors explored in selected publications. Findings – The findings highlight significant challenges in the healthcare sector regarding job availability and skilled professionals. Developed countries face understaffed healthcare facilities, resulting in increased workloads and compromised care. Developing countries experience high rates of unemployment among healthcare graduates due to limited resources and mentorship. Practical implications – Improving educational infrastructure, expanding training opportunities and increasing healthcare investments are crucial for nurturing a skilled workforce. Implementing effective retention policies, fostering international collaborations and addressing socioeconomic determinants can create a sustainable job market. Originality/value – The healthcare sector faces critical challenges in balancing job availability and skilled professionals. Strategic solutions are proposed to create a sustainable and equitable healthcare workforce. By implementing recommendations and conducting further research, access to quality healthcare and global public health outcomes can be improved.

Abstract Background N‐acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4‐acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The role of NAT10 in driving the advancement of breast cancer remains uninvestigated. Methods We observed an increase in NAT10 expression, both at mRNA level through the analysis of the Cancer Genome Atlas (TCGA) database and at the protein level of tumor tissues from breast cancer patients. We determined that a heightened expression of NAT10 served as a predictor of an unfavorable clinical outcome. By screening the Cancer Cell Line Encyclopedia (CCLE) cell bank, this expression pattern of NAT10 was consistency found across almost all the classic breast cancer cell lines. Results Functionally, interference of NAT10 expression exerts an inhibitory effect on proliferation and invasion of breast cancer cells. By using ac4C RNA immunoprecipitation (ac4c‐RIP) and acRIP‐qPCR assays, we identified a reduction of ac4C enrichment within the ATP binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), consequent to NAT10 suppression. Expressions of MDR1 and BCRP exhibited a positive correlation with NAT10 expression in tumor tissues, and the inhibition of NAT10 in breast cancer cells resulted in a decrease of MDR1 and BCRP expression. Therefore, the overexpressing of MDR1 and BCRP could partially rescue the adverse consequences of NAT10 depletion. In addition, we found that, remodelin, a NAT10 inhibitor, reinstated the susceptibility of capecitabine‐resistant breast cancer cells to the chemotherapy, both in vitro and in vivo. Conclusion The results of our study demonstrated the essential role of NAT10‐mediated ac4c‐modification in breast cancer progression and provide a novel strategy for overcoming chemoresistance challenges.

In birds and insects, the female uptakes sperm for a specific duration post-copulation known as the ejaculate holding period (EHP) before expelling unused sperm and the mating plug through sperm ejection. In this study, we found that Drosophila melanogaster females shortens the EHP when incubated with males or mated females shortly after the first mating. This phenomenon, which we termed male-induced EHP shortening (MIES), requires Or47b+ olfactory and ppk23+ gustatory neurons, activated by 2-methyltetracosane and 7-tricosene, respectively. These odorants raise cAMP levels in pC1 neurons, responsible for processing male courtship cues and regulating female mating receptivity. Elevated cAMP levels in pC1 neurons reduce EHP and reinstate their responsiveness to male courtship cues, promoting re-mating with faster sperm ejection. This study established MIES as a genetically tractable model of sexual plasticity with a conserved neural mechanism.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. Up to now, no specific screening or diagnostic tests are available for early PDAC detection. As a result, most patients are diagnosed with advanced or metastatic disease, which leads to a poor prognosis. In this study, we aimed to evaluate the diagnostic value of urinary CRP (uCRP) alone and in combination with our previously established urine biomarker panel (REG1B, LYVE1 and TFF1) for early detection of PDAC. A total of 534 urine samples from multiple centres were analysed: 93 from healthy individuals, 265 from patients with benign hepatobiliary diseases and 176 from PDAC patients. The uCRP and the urinary biomarker panel were assessed using commercial ELISA assays, while plasma CA19-9 and blood CRP (bCRP) were measured using Roche Cobas platform. Multiple logistic regression and nonparametric Kruskal–Wallis test were used for statistical analysis. An internal validation approach was applied, and the validated AUC estimators were reported to ensure accuracy. A significant difference was observed in the medians of uCRP between healthy and benign controls and PDAC sample groups (p < 0.001). uCRP levels were not dependent on gender and age, as well as cancer stage. When uCRP was combined with the urinary biomarker panel, it achieved AUCs of 0.878 (95% CI: 0.802-0.931), 0.798 (95% CI: 0.738-0.859) and 0.813 (95% CI: 0.758-0.869) in healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC sample groups, respectively. However, adding plasma CA19-9 to the urinary biomarker panel yielded a better performance, with AUCs of 0.978 (95% CI: 0.959-0.996), 0.911 (95% CI: 0.873-0.949) and 0.919 (95% CI: 0.883-0.955) in the healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC comparisons, respectively. In conclusion, we show that measuring CRP in urine is a feasible analytical method, and that uCRP could potentially be a promising biomarker in various diseases including other cancer types.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

In a world grappling with climate change, understanding the enduring impact of changes in temperatures on insect adult traits is crucial. It is proposed that cold- and warm-adapted species exhibit specialized behavioural and physiological responses to their respective temperature ranges. In contrast, generalist species maintain more stable metabolic and developmental rates across a broader range of temperatures, reflecting their ability to exploit diverse thermal niches. Here, we explored this intricate response to temperature exposure in three Drosophila species: Drosophila ezoana originating in Arctic regions, D. novamexicana in arid, hot environments, and in the cosmopolitan species D. virilis. Rearing these flies at 15, 20, 25, and 30 °C revealed striking variations in their cuticular hydrocarbon (CHC) profiles, known to mediate mate recognition and prevent water loss in insects. The cold-adapted D. ezoana consistently exhibited reduced CHC levels with increasing temperatures, while the warm-adapted D. novamexicana and the cosmopolitan D. virilis displayed more nuanced responses. Additionally, we observed a significant influence of rearing temperature on the mating behaviour of these flies, where those reared at the extreme temperatures, 15 and 30 °C, exhibiting reduced mating success. Consequently, this led to a decrease in the production of adult offspring. Also, these adult offspring underwent notable alterations in life history traits, reaching adulthood more rapidly at 25 and 30 °C but with lower weight and reduced longevity. Furthermore, among these offspring, those produced by the cold-adapted D. ezoana were more vulnerable to desiccation and starvation than those from the warm-adapted D. novamexicana and the cosmopolitan D. virilis. In summary, our research demonstrates that Drosophila species from diverse ecological regions exhibit distinct responses to temperature changes, as evidenced by variations in CHC profiles, mating behaviours, fertility, and life history traits. This provides valuable insights into how environmental conditions shape the biology and ecology of insects.

Objectives To describe the epidemiological patterns and clinical characteristics of sports injuries treated at two hospitals in Douala.Methods This was a cross-sectional study conducted at the Douala General Hospital and Douala Laquintinie Hospital, involving medical records of patients treated for sports injuries from January 2012 to April 2022. Data extracted from records were entered into a data collection software and analysed using Microsoft Excel 2016. Severe injuries were defined as an injury score greater than or equal to 3 on the Abbreviated Injury Scale.Results The prevalence of sports injuries was 1.12% among all trauma cases. There was a male predominance with 62 (86.1%) males and 10 (13.9%) females. The mean age was 24.97±13.8 years. Most injured persons were students 35 (48.6%), followed by the employed 26 (36.1%), athletes 6 (8.3%) and the unemployed 5 (6.9%). Recreational sports accounted for 43 (59.7%) injuries while 16 (22.2%) injuries occurred during physical education, 8 (11.1%) during trainings and 5 (6.9%) during competitions. Football injuries were 48 (66.7%), running injuries 10 (13.9%) and 9 (12.5%) occurred during long, high and triple jump. Among all injuries, fractures were 43 (59.7%), 11 (15.3%) joint sprains, 5 (6.9%) muscle injuries, 4 (5.6%) brain injuries while 9 (12.5%) were contusions and lacerations. Lower extremity injuries were 34 (47.2%), 21 (29.2%) injuries were on the upper extremities, 4 (5.6%) abdominopelvic, 3 (4.2%) thoracic injuries, 9 (12.5%) head injuries and 1 (1.4%) on the neck. Overall, 53 (73.7%) were severe injuries.Conclusion The majority of sports injuries treated in these hospitals are fractures that occur during recreational sports, particularly football and predominantly involve the lower extremity. A significant proportion are severe injuries.

The research results presented in this paper were obtained as part of the D2KAB project (Data to Knowledge in Agriculture and Biodiversity) which aims to develop semantic web-based tools to describe and make agronomical data actionable and accessible following the FAIR principles. We focus on constructing domain-specific Knowledge Graphs (KGs) from textual data sources, using Natural Language Processing (NLP) techniques to extract and structure relevant entities. Our approach is based on the formalization of a semantic data model using common linked open vocabularies such as the Web Annotation Ontology (OA) and the Provenance Ontology (PROV). The model was developed by formulating motivating scenarios and competency questions from domain experts. This model has been used to construct three different KGs from three distinct corpora: PubMed scientific publications on wheat and rice genetics and phenotyping, and French agricultural alert bulletins. The named entities to be recognized include genes, phenotypes, traits, genetic markers, taxa and phenological stages normalized using semantic resources such as the Wheat Trait and Phenotype Ontology (WTO), the French Crop Usage (FCU) thesaurus and the Plant Phenological Description Ontology (PPDO). Named entities were extracted using different NLP approaches and tools. The relevance of the semantic model was validated by implementing experts questions as SPARQL queries to be answered on the constructed RDF knowledge graphs. Our work demonstrates how domain-specific vocabularies and systematic querying of KGs can reveal hidden interactions and support agronomists in navigating vast amounts of data. The resources and transformation pipelines developed are publicly available in Git repositories.

Summary: Learning, memorizing, and recalling of potential ovipositing sites can influence oviposition preference. Classical conditioning experiments have shown that vinegar flies can learn the association of olfactory, gustatory, or visual stimuli with either positive or negative unconditioned stimuli. However, less is known about whether similar associations are formed in an ecologically more relevant context like during oviposition. Our experiments reveal that Drosophila melanogaster females increase their preference for substrates they have already experienced. However, this change of preference requires that the flies not only smelled or touched the substrates but also oviposited on them. We furthermore show that such an experience results in long-term memory lasting for at least 4 days, i.e., a duration that so far was shown only for aversive conditioning. Our study thus reveals a different form of associative learning in D. melanogaster that might be highly relevant for settling novel ecological niches.

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, designated UMW-9729, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated UMW-9729's potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and the highly pathogenic, blood-feeding Haemonchus contortus (barber's pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested 25 analogues of UMW-9729 for their nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than UMW-9729, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a UMW-9729 analogue, designated 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with UMW-9729; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as possible targets of UMW-9729. Overall, the present study evaluates this anthelmintic candidate and highlights some challenges associated with early anthelmintic investigation.

Background:. Nurtec, a versatile migraine medication, has gained popularity. However, the awareness of migraine surgery remains uncertain. Methods:. Following a descriptive approach, this cross-sectional study used Google Trends data as of December 1, 2023, to analyze internet search patterns. Approval from Vanderbilt University’s institutional review board and adherence to Strengthening the Reporting of Observational Studies in Epidemiology guidelines were confirmed. Monthly relative search volume (RSV) data for “migraine surgery,” “Nurtec,” and “Rimegepant” were collected from January 1, 2004, to November 11, 2023, within the United States. Statistical analysis involved determining mean monthly RSV values and percentage changes for critical periods. Results:. For “Nurtec,” a significant surge in RSV occurred from March 2020 to April 2020 (344%). Additional peaks were observed from June 2020 to July 2020 (66%), October 2020 to December 2020 (169%), May 2021 to June 2021 (33%), and May 2023 to June 2023 (14%). “Migraine surgery” exhibited a notable 400% increase in RSV, from March 2005 to May 2005. However, post-2006, RSV for “migraine surgery” consistently remained low without noticeable peaks. Conclusions:. The analysis of RSV trends for “Nurtec” and “migraine surgery” from 2004 to 2023 reveals the impact of pivotal events and marketing strategies on public interest. The distinct peaks in “Nurtec” RSV align with Food & Drug Administration approvals and marketing campaigns, highlighting the medication’s accessibility. Conversely, the consistently low RSV for “migraine surgery” indicates limited awareness, emphasizing the need for enhanced promotion and education regarding surgical interventions.

The terms “offshore” and “open ocean” have been used to describe aquaculture sites that are further from the coast or in higher energy environments. Neither term has been clearly defined in the scientific literature nor in a legal context, and the terms are often used interchangeably. These and other related terms (for example “exposed”, “high-energy”) variously refer to aspects of a site such as the geographic distance from shore or infrastructure, the level of exposure to large waves and strong currents, the geographic fetch, the water depth, or some combination of these parameters. The ICES Working Group (ICES, 2024) on Open Ocean Aquaculture (WGOOA) therefore identified a need to define the terminology to reduce ambiguity for these types of aquaculture sites or more precisely, to: (1) promote a common understanding and avoid misuse for different classifications; (2) enable regulators to identify the characteristics of a marine site; (3) allow farmers to be able to assess or quantitatively compare sites for development; (4) equip developers and producers to identify operational parameters in which the equipment and vessels will need to operate; (5) provide insurers and investors with the terminology to consistently assess risk and premiums; and (6) circumvent the emergence of narratives that root in different cognitive interpretations of the terminology in public discourse. This paper describes the evolution of the use of the term “offshore aquaculture” and define the most relevant parameters to shift to a more definitive and robust term “exposed aquaculture” that can inherently relay clearer information. Adoption of this more definitive definition of “exposed” will allow the user to define a site with more than just distance from shore. Key differences and the importance of these terms are discussed that affect various interest groups. Follow-up articles in this compilation from scientific members of the WGOOA as well as other scientists outside ICES are incorporated that develop a set of definitions and a rigorous exposure index.

Given the expanding global population and finite resources, it is imperative to explore alternative technologies for food production. These technologies play a crucial role in ensuring the provision of safe, nutritious, and sustainable food options to meet the growing demand. Cellular agriculture plays an important in developing an alternative method for developing food products. While, cellular agriculture is emerging rapidly, food safety aspects and regulatory frameworks stayed behind. Despite developing several regulatory framework papers on cellular agriculture, there is no systematic approach for developing a comprehensive food safety plan (FSP), particularly for cultivated seafood. Thus, the overall goal of this article is to develop a FSP for cultivated seafood. The main differences between the food safety plan for cultivated seafood and the conventional seafood industries were the number of allergens in cultivated seafood products, including soy, wheat, and fish cells, compared to only fish for the conventional seafood industry. In addition, there are several hazards associated with mycoplasma in cultivated seafood, which should be considered. This guidance intends to help regulatory agencies, food safety experts, startup companies, and the cultivated seafood industry by providing a valuable platform to develop regulations, guidance, and food safety plans applicable to most cultivated seafood companies. This article will also help the industry to identify the hazards in their processing line and develop preventive controls, and as a comprehensive food safety plan, it could be easily adapted for other cultivated seafood products. This guidance applied systematic approaches to developing food safety plans using cell culture, pharmaceuticals, fermentation, seafood, meat, and aquaponics safety plans, collaborating with experts with different backgrounds, and working closely with the conventional and cultivated meat and seafood industries.

Abstract The hypergraph community detection problem seeks to identify groups of related vertices in hypergraph data. We propose an information-theoretic hypergraph community detection algorithm which compresses the observed data in terms of community labels and community-edge intersections. This algorithm can also be viewed as maximum-likelihood inference in a degree-corrected microcanonical stochastic blockmodel. We perform the compression/inference step via simulated annealing. Unlike several recent algorithms based on canonical models, our microcanonical algorithm does not require inference of statistical parameters such as vertex degrees or pairwise group connection rates. Through synthetic experiments, we find that our algorithm succeeds down to recently-conjectured thresholds for sparse random hypergraphs. We also find competitive performance in cluster recovery tasks on several hypergraph data sets.