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Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

Abstract Avian influenza A viruses (IAVs) pose a public health threat, as they are capable of triggering pandemics by crossing species barriers. Replication of avian IAVs in mammalian cells is hindered by species-specific variation in acidic nuclear phosphoprotein 32 (ANP32) proteins, which are essential for viral RNA genome replication. Adaptive mutations enable the IAV RNA polymerase (FluPolA) to surmount this barrier. Here, we present cryo-electron microscopy structures of monomeric and dimeric avian H5N1 FluPolA with human ANP32B. ANP32B interacts with the PA subunit of FluPolA in the monomeric form, at the site used for its docking onto the C-terminal domain of host RNA polymerase II during viral transcription. ANP32B acts as a chaperone, guiding FluPolA towards a ribonucleoprotein-associated FluPolA to form an asymmetric dimer—the replication platform for the viral genome. These findings offer insights into the molecular mechanisms governing IAV genome replication, while enhancing our understanding of the molecular processes underpinning mammalian adaptations in avian-origin FluPolA.

Abstract Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild–moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1–95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6–15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7– 63.3) against any COVID-19, and 95.3% (80.5–98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Abstract Background Disturbances alter the diversity and composition of microbial communities. Yet a generalized empirical assessment of microbiome responses to disturbance across different environments is needed to understand the factors driving microbiome recovery, and the role of the environment in driving these patterns. Results To this end, we combined null models with Bayesian generalized linear models to examine 86 time series of disturbed mammalian, aquatic, and soil microbiomes up to 50 days following disturbance. Overall, disturbances had the strongest effect on mammalian microbiomes, which lost taxa and later recovered their richness, but not their composition. In contrast, following disturbance, aquatic microbiomes tended away from their pre-disturbance composition over time. Surprisingly, across all environments, we found no evidence of increased compositional dispersion (i.e., variance) following disturbance, in contrast to the expectations of the Anna Karenina Principle. Conclusions This is the first study to systematically compare secondary successional dynamics across disturbed microbiomes, using a consistent temporal scale and modeling approach. Our findings show that the recovery of microbiomes is environment-specific, and helps to reconcile existing, environment-specific research into a unified perspective. Video Abstract

Abstract Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, $$\dot{{{\boldsymbol{V}}}}\!$$ V ° net , revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.

Introducción: Las osteotomías supramaleolares son una opción terapéutica para la artrosis asimétrica de tobillo. El objetivo de este artículo es describir los resultados clínicos, radiográficos y subjetivos obtenidos en pacientes con artrosis de tobillo sometidos a una osteotomía supramaleolar. Materiales y Métodos: Estudio observacional descriptivo retrospectivo de pacientes sometidos a una osteotomía supramaleolar por artrosis de tobillo entre enero de 2010 y julio de 2017. Se analizaron las historias clínicas para recabar datos clínicos y radiográficos preoperatorios y posoperatorios. Resultados: Se incluyó a 13 pacientes: 8 con una desalineación del tobillo y retropié en valgo (61,5%) y 5 (38,5%) en varo. El puntaje medio posoperatorio de la escala analógica visual del grupo con deformidad en varo disminuyó de 9 ± 0,45 a 3 ± 1 (p

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990–2017 in British Columbia, Canada. Individuals n = 2544, EoCRC) and a matched cohort >50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p < 0.0001) and LoCRC (p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8–1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

Abstract Background Rectal neuroendocrine tumors (RNETs) are often discovered on screening colonoscopy. Indications for staging and definitive resection are inconsistent in current guidelines. We evaluated the role of grade in guiding staging and procedural decision-making. Methods Patients with biopsy confirmed RNETs between 2004 and 2015 were reviewed. Baseline characteristics, staging investigations (biochemical and imaging), and endoscopic/surgical treatment were recorded. Associations between grade, preoperative staging, interventions, and survival were determined using Fisher-Freeman-Halton Exact, log-rank, and Kaplan-Meier analysis. Results Amongst 139 patients with RNETs, 9% were aged ≥ 75 years and 44% female. Tumor grade was: 73% grade 1 (G1), 18%, grade 2 (G2) and 9% grade 3 (G3). Staging investigations were performed in 52% of patients. All serum chromogranin A and 97% of 24-hour urine 5-hydroxyindoleacetic acid tests were normal. The large majority of staging computed tomography (CT) scans were negative (76%) with subgroup analysis showing no G1 patients with CT identified distant disease compared with 38% of G2 and 50% of G3 patients (p

Abstract Background Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Methods Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Results Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Conclusions Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.

Abstract Background Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. Methods Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. Results WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. Conclusions Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.

Abstract Introduction Surgical repair of obstetric fistula aims to restore the anatomical and functional integrity of the urinary tract, enabling affected women to regain their dignity and quality of life. However, such repairs can end in a failure. The aim of this study is to develop a predictive score to identify factors influencing failure of surgical repair of obstetric vesico-vaginal fistula (FSROVVF) in the Democratic Republic of the Congo. Methods This was an analytical cross-sectional study of 318 women with obstetric vesico-vaginal fistula (OVVF) who had undergone surgical management. A bivariate and then a multivariate analysis were performed. Score discrimination was assessed using the ROC curve and C-index, and score calibration using the Hosmer–Lemeshow test. Results Surgical repair of OVVF was unsuccessful in 16.98% of cases (54/318). After logistic modeling, six criteria emerged as predictive factors for FSROVVF: the presence of fibrosis (AOR = 5.01; 95% CI:1.73–14.49), the presence of 2 or more fistulas (AOR = 9.04; 95% CI:3.01–27.13), the association of OVVF with another anatomoclinical entity of fistula (AOR = 3.16; 95% CI:1.09–9.13), the fistula size > 3 cm (AOR = 3.65; 95% CI:1.36–9.76), the peri-operative hemorrhage (AOR = 7.01; 95% CI:2.33–21.03), and the post-operative infection (AOR = 178.89; 95% CI:26.09–1226.64). A score ranging from 0 to 13 points was obtained, of which a value ≤ 5 points defines a low risk of FSROVVF, a value between 6 and 8 points defines a moderate risk and value ≥ 9 points corresponds to a high risk of FSROVVF. The area under the ROC curve of the score is 0.925 with a sensitivity of 61.11%, a specificity of 96.59%, a positive predictive value of 78.57% and a negative predictive value of 92.39%. Conclusion This study demonstrated that the number of fistulas ≥ 2, fistula size > 3 cm, fibrosis, association of OVVF with other types of fistulas, peri-operative hemorrhage, and post-operative infection are factors predictive of FSROVVF. These six factors are key contributors to the score used to predict FSROVVF. Once validated, this score will inform and enable preoperative counseling regarding the prognosis and the chances of a successful outcome of surgical repair of OVVF.

We present a genome assembly from an individual female Anopheles marshallii (the malaria mosquito; Arthropoda; Insecta; Diptera; Culicidae) from Lopé, Gabon. The genome sequence is 225.7 megabases in span. Most of the assembly is scaffolded into three chromosomal pseudomolecules with the X sex chromosome assembled. The complete mitochondrial genome was also assembled and is 15.4 kilobases in length.

Background:. With neck, aging the cervicomental angle becomes obtuse and may be influenced by hyoid bone aging. An understanding of hyoid position changes with aging will further our understanding of its role in neck contour changes. Methods:. A 3D volumetric reconstruction of 282 neck computed tomography scans was performed. The cohort was categorized into three groups based on age: 20 years or older and younger than 40 years, 40 years or older and younger than 60 years, and 60 years or older and younger than 80 years. The vertical and horizontal hyoid distances in relation to the mandible were calculated for each patient. Results:. A total of 282 patients (153 women, 129 men) were included in the cohort. The age groups were evenly distributed in men and women. Mean hyoid vertical and horizontal distances differed between women and men in all age groups. There was a significant difference in the hyoid vertical distance between 20–39 years old to 40–59 years old in men (P < 0.01), and 20–39 years old to 60–79 years old in both genders (women P = 0.005, men P < 0.01). Hyoid horizontal distance was not affected by age and sex (age and sex: P > 0.05), but rather by body mass index (BMI). Every 5 BMI points corresponded to a forward movement of 2 mm. Conclusions:. As individuals age, the hyoid bone descends in both sexes, and an increase in BMI is associated with forward movement. Additional studies are needed to assess the correlation of the hyoid position between upright and supine positions.

Abstract Background With the burden of colorectal cancer in Canada, there is a need to address the psycho‐oncologic challenges, including mental health. This study aims to explore the lived mental health experiences in patients with CRC across the phases of the CRC care continuum. Methods We employed a patient‐oriented constructivist grounded theory design and recruited English speaking participants ≥18 years, diagnosed with CRC within the last 10 years, residing in Canada. We collected data through semi‐structured individual interviews using a guide co‐constructed with patient research partners. Data collection and analysis were iterative, employed theoretical sampling, and culminated in a theoretical model. Results Twenty‐eight participants diagnosed with CRC (18 females, 10 males), aged 18–63 years at time of diagnosis were interviewed, with representation across all CRC stages. There were 10 participants (36%) in treatment, 12 participants (43%) in follow‐up, and 6 participants (21%) in the beyond phase. We constructed a patient‐oriented theory illustrating the dynamic nature between one's self‐identity and their mental health experiences across the CRC care continuum. Mental health experiences encompass emotional and cognitive‐behavioral responses, expressed differently across phases. Mental health care experiences are also shaped by barriers, facilitators, and individual contextual factors, all of which influence their access to care. Conclusion Our theory provides insight into the mental health experiences of patients with CRC across phases of the CRC care continuum. Understanding patients' emotional and cognitive‐behavioral responses and care experiences can help identify opportunities to integrate mental health into CRC care.

Biological soil crusts (BSCs) play an essential role in soil stabilization and nutrient cycling in arid environments, being a hotspot of microbial activity including soil enzyme production. However, the changes in microbial communities of the BSCs from different age are poorly understood. In over a 60-year dune revegetation chronosequence (2021, 2016, 1973, and 1962) in the southeastern Tengger Desert, China, we compared the development of BSCs and underlying sands using metagenome sequencing and enzyme assays. In both BSCs and the underlying sand substrate, enzyme activity increased along the time series but was always greater for BSCs than the substrate, emphasizing the potential for nutrient cycling activity. A clear trend in community composition and co-occurrence network complexity was observed in the BSCs: the family-level taxonomic network of BSCs became more connected in the older age BSCs, while in the substrate, there was no such trend. Unexpectedly, considering their low relative abundance and diversity, archaea emerged as major keystones in establishing community networks, being key to network stability. In the underlying substrate, by contrast, archaea did not play this key role. During the time series of BSCs, the dominant archaeal groups were Nitrososphaeria, Methanomicrobia, Halobacteria, and an unclassified Thaumarchaeota, mainly linked to functional genes related to carbon and nitrogen, such as CHB2, xylA, amyA, amoB, nxrA, nxrB, and nirB. This suggests that in BSCs, the key role of archaea relates to their role in nitrogen cycling. This perspective adds to the emerging view that archaea play an important role in community structure and function in dryland environments.

Background: Hypertension affects approximately 1 in 2 adults in the US. Home blood pressure (BP) monitoring programs are effective in the diagnosis and management of hypertension. Free clinics serve as an integral safety net for millions of uninsured and economically disadvantaged patients in the US. The feasibility and effects of a free home BP monitoring and follow-up program in a free clinic setting is not well characterized. Methods: This was a prospective study of the implementation of a pilot BP monitoring and follow-up program between March 2021 and August 2023 at 2 free clinics in the San Francisco Bay Area. A total of 78 hypertensive patients were enrolled in the program and given a free BP monitor. We surveyed via telephone the change in systolic and diastolic BPs and BP monitor use and comfort at 3 weeks. Volunteers in clinic roles involved in the BP monitoring program were surveyed to assess their time spent and perceptions of the program. Results: Of the 78 patients, 37 provided responses to the 3-week survey. A total of 36 of 37 (97%) patients reported using their BP monitor. A total of 35 patients reported using it at least once a week (95%), with the majority reporting at least four uses a week (68%). A total of 36 patients (97%) planned on continuing to use their BP monitor. At 3 weeks, the mean systolic and diastolic BP changed by −6.40 mmHg (95% CI, −10.8 to −2.01 mmHg; P = .00577) and −2.72 mmHg (95% CI, −5.62 to 0.188 mmHg; P = .0657), respectively. The time commitment for this program ranged from 130 ± 51 min for program leaders to 16 ± 14 min per week for patient-facing roles. All volunteer roles (patient-facing, phone follow-up, program leaders) expressed that they had a clear understanding of their responsibilities in the program (median 4 on Likert scale, IQR 3-5). Conclusion: Home BP monitoring and follow-up is feasible to implement in free clinics, resulting in high rates of patient engagement among respondents. Our findings suggest that home BP monitoring and follow-up programs may be beneficial in vulnerable patient populations.

Abstract Rapid and accurate maps of floods across large domains, with high temporal resolution capturing event peaks, have applications for flood forecasting and resilience, damage assessment, and parametric insurance. Satellite imagery produces incomplete observations spatially and temporally, and hydrodynamic models require tradeoffs between computational efficiency and accuracy. We address these challenges with a novel flood model which predicts surface water area from the U.S. National Water Model using a convolutional neural network (NWM‐CNN). We trained NWM‐CNN on 780 flood events, at a 250 m resolution with an RMSE of 4.58% on held out validation geographies. We demonstrate NWM‐CNN across California during the 2023 atmospheric rivers, comparing predictions against Sentinel‐1 mapped flood observations. We compared historical predictions from 1979 to 2023 to flood damage reports in Sacramento County, California. Results show that NWM‐CNN captures inundation extent better than the Height Above Nearest Drainage (HAND) approach (25%–36% RMSE, respectively).

BackgroundData on clinical outcomes of infants with birthweights less than 501 g (ELBW

Background Left atrial appendage (LAA) slow‐flow may increase the risk of ischemic stroke. We studied LAA attenuation on cardiac computed tomography in patients with acute ischemic stroke. Methods and Results We used data from a prospective cohort of patients with acute ischemic stroke undergoing cardiac computed tomography during the acute stroke imaging protocol. We compared characteristics, functional outcome (modified Rankin scale: higher scores indicating worse outcome), stroke recurrence and major adverse cardiovascular events after 2‐year follow‐up between patients with LAA thrombus (filling defect

Climatic extremes, especially extreme droughts, are occurring more frequently and profoundly impacting biogeochemical processes. However, the relative importance of microbial communities on soil nutrient cycling and community maintenance under natural extreme drought events remains elusive. During a record-breaking drought in the Yangtze River Basin (YRB) in the summer of 2022, we collected ambient soils and drought-affected bare and vegetated soils in ecological buffer zones from two sites with similar soil and vegetation characteristics along the YRB, and examined the relative contribution of soil bacterial communities in supporting multi-nutrient cycling index (MNCI) involving carbon-, nitrate- and phosphorus-cycling and their associations with microbial network. Extreme drought decreased (p < 0.05) bacterial α-diversity but increased MNCI in vegetated soils at both sites, while both remained unchanged (p > 0.05) in bare soils, possibly as a result of vegetation releasing rhizodeposits under drought which selectively recruited bacterial communities. Bacterial community compositions were shifted (p < 0.05) only in vegetated soils, and they exerted more influence than α-diversity on soil MNCI. Notably, the Anaerolineae, identified as a biomarker enriched in vegetated soils, had close associations with enzyme activities and soil MNCI at both sites, suggesting their potential recruitment by vegetation to withstand drought. Furthermore, key ecological clusters (Module 1) in bacterial co-occurrence networks at both sites supported (p < 0.05) higher MNCI, despite no substantial variation in network structure due to drought. Specifically, the most important taxa within Module 1 for predicting soil MNCI revealed by random forest modeling analysis (R2 = 0.44 - 0.63, p < 0.001), such as B1-7BS, SBR1031 and Nocardioides, could be deeply involved in soil nitrogen-cycling, suggesting an essential role of specialized interactions of bacterial communities in maintaining soil multifunctionality. Overall, this study demonstrates that changes in biomarkers and functional taxa under extreme drought may better reflect the biological mechanisms involved in microbial communities impacting ecosystem function, which may aid in forecasting the ecological consequences of ongoing climate change in the ecological buffer zones along the YRB.

Summary: Following kidney removal, the remaining kidney enlarges and increases its function. The mechanism and signals driving this compensatory kidney hypertrophy and the enlargement of its constituent kidney cells remains elusive. RNA-seq studies in mice undergoing hypertrophy 24, 48, and 72 h following nephrectomy were undertaken to understand the early transcriptional changes. This revealed substantial enhancement of cholesterol biosynthesis pathways, increases in mitochondrial gene expression and cell cycle perturbations. Single nuclei RNA-seq delineated cell specific changes at 24 h post nephrectomy and showed that sterol binding protein 2 (SREBP2) activity increases in medullary thick ascending limb cells in keeping with promotion of cholesterol synthesis. Cultured renal tubular cells were examined for insulin-like growth factor-1 (IGF-1) stimulated hypertrophy and SREBP2 was found to be required for increase in cell size. This work describes the early cell specific growth pathways mediating cellular and kidney hypertrophy with an intriguing role for cholesterol synthesis.

Significant efforts have been made to characterize the biophysical properties of proteins. Small proteins have received less attention because their annotation has historically been less reliable. However, recent improvements in sequencing, proteomics, and bioinformatics techniques have led to the high-confidence annotation of small open reading frames (smORFs) that encode for functional proteins, producing smORF-encoded proteins (SEPs). SEPs have been found to perform critical functions in several species, including humans. While significant efforts have been made to annotate SEPs, less attention has been given to the biophysical properties of these proteins. We characterized the distributions of predicted and curated biophysical properties, including sequence composition, structure, localization, function, and disease association of a conservative list of previously identified human SEPs. We found significant differences between SEPs and both larger proteins and control sets. In addition, we provide an example of how our characterization of biophysical properties can contribute to distinguishing protein-coding smORFs from noncoding ones in otherwise ambiguous cases.

There is an increasing need for robust wildlife health programs that provide surveillance and management for diseases in wildlife and wild aquatic populations to manage associated risks. This paper illustrates the value of a systematic method to enhancing wildlife health programs. The U.S. Geological Survey and Mahidol University, Faculty of Veterinary Science, Thailand National Wildlife Health Center formally twinned under the auspices of the World Organisation for Animal Health to enhance wildlife health capacity in Thailand and the Southeast Asia Region. We used a system-wide approach to holistically and interdependently enhance capacity. The project commenced with a wildlife health program needs assessment, and capacity enhancement focused on strengthening the general wildlife health surveillance network and improving wildlife health information management. Activities included partner surveys, interactive and didactic workshops, and individual personnel training. Topics included development of wildlife health information management systems, analysis of the current surveillance network, development of a Theory of Change for a strengthened surveillance network, planning workshops to create a wildlife health network, training on wildlife disease outbreak investigation and field sample collection, leading networks, and individual training on bioinformatics and laboratory techniques. Engagement of stakeholders at all levels, continuous communication throughout the project, use of both strategic planning tools and pedagogical methods, and using iterative and adaptive approaches, were key factors to the success of this project.

The ROCO family is a family of GTPases characterized by a central ROC-COR tandem domain. Interest in the structure and function of ROCO proteins has increased with the identification of their important roles in human disease. Nevertheless, the functions of most ROCO proteins are still unknown. In the present study, we characterized the structure, evolution, and expression of ROCOs in four species of brown algae. Brown algae have a larger number of ROCO proteins than other organisms reported to date. Phylogenetic analyses showed that ROCOs have an ancient origin, likely originated in prokaryotes. ROCOs in brown algae clustered into four groups and showed no strong relationship with red algae or green algae. Brown algal ROCOs retain the ancestral LRR-ROC-COR domain arrangement, which is found in prokaryotes, plants and some basal metazoans. Remarkably, individual LRR motifs in ROCO genes are each encoded by separate exons and exhibit intense exon shuffling and diversifying selection. Furthermore, the tandem LRR exons exhibit alternative splicing to generate multiple transcripts. Both exon shuffling and alternative splicing of LRR repeats may be important mechanisms for generating diverse ligand-binding specificities as immune receptors. Besides their potential immune role, expression analysis shows that many ROCO genes are responsive to other stress conditions, suggesting they could participate in multiple signal pathways, not limited to the immune response. Our results substantially enhance our understanding of the structure and function of this mysterious gene family.

IntroductionDietary nitrate is potentially beneficial for cardiovascular, cerebrovascular, and nervous systems due to its role as a nitric oxide (NO) precursor. Increased nitrate intake improves cardiovascular health and therefore could protect against dementia, given the cardiovascular-dementia link.ObjectiveTo investigate the association between source-dependent nitrate intake and dementia-related mortality. As individuals with diabetes are at higher risk of dementia, a secondary aim was to investigate if the associations between nitrate and dementia varied by diabetes mellitus (DM) and pre-diabetes status.MethodsThis study involved 9,149 participants aged ≥25 years from the well-characterised Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study followed over a period of 17 years. Intakes of plant-sourced, vegetable-sourced, naturally occurring animal-sourced nitrate, and processed meat (where nitrate is an allowed additive)-sourced nitrate were assessed from a 74-item food frequency questionnaire completed by participants at baseline and nitrate databases were used to estimate nitrate from these different dietary sources. Associations between source-dependent nitrate intake and dementia-related mortality were assessed using multivariable-adjusted Cox proportional hazards models adjusted for demographics, lifestyle, and dietary factors.ResultsOver 17 years of follow-up, 93 (1.0%) dementia-related deaths occurred of 1,237 (13.5%) total deaths. In multivariable-adjusted models, participants with the highest intakes of plant-sourced nitrate (median intake 98 mg/day) had a 57% lower risk of dementia-related mortality [HR (95% CI): 0.43 (0.22, 0.87)] compared to participants with lowest intakes of plant-sourced nitrate (median intake 35 mg/day). A 66% lower risk was also seen for higher intakes of vegetable-sourced nitrate [HR (95% CI): 0.34 (0.17, 0.66)]. No association was observed for animal-sourced nitrate, but the risk was two times higher amongst those who consumed the most processed meat-sourced nitrate intake [HR (95%): 2.10 (1.07, 4.12)]. The highest intake of vegetable-sourced nitrate was associated with a lower risk of dementia-related mortality for those with and without DM and pre-diabetes.ConclusionEncouraging the intake of nitrate-rich vegetables, such as green leafy vegetables and beetroot, may lower the risk of dementia-related mortality, particularly in individuals with (pre-) diabetes who are at a higher dementia risk.

IntroductionCompanion animals offer a unique opportunity to investigate risk factors and exposures in our shared environment. Passive sampling techniques have proven effective in capturing environmental exposures in dogs and humans.MethodsIn a pilot study, we deployed silicone monitoring devices (tags) on the collars of a sample of 15 dogs from the Dog Aging Project Pack cohort for a period of 120 h (5 days). We extracted and analyzed the tags via gas chromatography–mass spectrometry for 119 chemical compounds in and around participants’ homes.ResultsAnalytes belonging to the following chemical classes were detected: brominated flame retardants (BFRs), organophosphate esters (OPEs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), pesticides, phthalates, and personal care products. The types and amounts of analytes detected varied substantially among participants.DiscussionData from this pilot study indicate that silicone dog tags are an effective means to detect and measure chemical exposure in and around pet dogs’ households. Having created a sound methodological infrastructure, we will deploy tags to a geographically diverse and larger sample size of Dog Aging Project participants with a goal of further assessing geographic variation in exposures.

IntroductionHemibiotrophic Phytophthora are a group of agriculturally and ecologically important pathogenic oomycetes causing severe decline in plant growth and fitness. The lifestyle of these pathogens consists of an initial biotrophic phase followed by a switch to a necrotrophic phase in the latter stages of infection. Between these two phases is the biotrophic to necrotrophic switch (BNS) phase, the timing and controls of which are not well understood particularly in Phytophthora spp. where host resistance has a purely quantitative genetic basis.MethodsTo investigate this we sequenced and annotated the genome of Phytophthora medicaginis, causal agent of root rot and substantial yield losses to Fabaceae hosts. We analyzed the transcriptome of P. medicaginis across three phases of colonization of a susceptible chickpea host (Cicer arietinum) and performed co-regulatory analysis to identify putative small secreted protein (SSP) effectors that influence timing of the BNS in a quantitative pathosystem.ResultsThe genome of P. medicaginis is ~78 Mb, comparable to P. fragariae and P. rubi which also cause root rot. Despite this, it encodes the second smallest number of RxLR (arginine-any amino acid-leucine-arginine) containing proteins of currently sequenced Phytophthora species. Only quantitative resistance is known in chickpea to P. medicaginis, however, we found that many RxLR, Crinkler (CRN), and Nep1-like protein (NLP) proteins and carbohydrate active enzymes (CAZymes) were regulated during infection. Characterization of one of these, Phytmed_10271, which encodes an RxLR effector demonstrates that it plays a role in the timing of the BNS phase and root cell death.DiscussionThese findings provide an important framework and resource for understanding the role of pathogenicity factors in purely quantitative Phytophthora pathosystems and their implications to the timing of the BNS phase.

Abstract Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro‐ and anti‐tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA‐producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial‐derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)‐induced proliferation and interleukin‐6 (IL‐6) expression in these cells. Gene expression correlations were assessed using the “Cancer Exploration” suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase‐2 and IL‐6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti‐tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

Skeletal muscle has a unique ability to remodel in response to stimuli such as contraction and aerobic exercise training. Phenotypic changes in muscle that occur with training such as a switch to a more oxidative fiber type, and increased capillary density contribute to the well-known health benefits of aerobic exercise. The muscle matrisome likely plays an important role in muscle remodeling with exercise. However, due to technical limitations in studying muscle ECM proteins, which are highly insoluble, little is known about the muscle matrisome and how it contributes to muscle remodeling. Here, we utilized two-fraction methodology to extract muscle proteins, combined with multiplexed tandem mass tag proteomic technology to identify 161 unique ECM proteins in mouse skeletal muscle. In addition, we demonstrate that aerobic exercise training induces remodeling of a significant proportion of the muscle matrisome. We performed follow-up experiments to validate exercise-regulated ECM targets in a separate cohort of mice using Western blotting and immunofluorescence imaging. Our data demonstrate that changes in several key ECM targets are strongly associated with muscle remodeling processes such as increased capillary density in mice. We also identify LOXL1 as a novel muscle ECM target associated with aerobic capacity in humans. In addition, publically available data and databases were used for in silico modeling to determine the likely cellular sources of exercise-induced ECM remodeling targets and identify ECM interaction networks. This work greatly enhances our understanding of ECM content and function in skeletal muscle and demonstrates an important role for ECM remodeling in the adaptive response to exercise. The raw MS data have been deposited to the ProteomeXchange with identifier PXD053003.

Background: Hip dysplasia is considered one of the leading etiologies contributing to hip degeneration and the eventual need for total hip arthroplasty (THA). We validated a deep learning (DL) algorithm to measure angles relevant to hip dysplasia and applied this algorithm to determine the prevalence of dysplasia in a large population based on incremental radiographic cutoffs. Methods: Patients from the Osteoarthritis Initiative with anteroposterior pelvis radiographs and without previous THAs were included. A DL algorithm automated 3 angles associated with hip dysplasia: modified lateral center-edge angle (LCEA), Tönnis angle, and modified Sharp angle. The algorithm was validated against manual measurements, and all angles were measured in a cohort of 3869 patients (61.2 ± 9.2 years, 57.1% female). The percentile distributions and prevalence of dysplastic hips were analyzed using each angle. Results: The algorithm had no significant difference (P > .05) in measurements (paired difference: 0.3°-0.7°) against readers and had excellent agreement for dysplasia classification (kappa = 0.78-0.88). In 140 minutes, 23,214 measurements were automated for 3869 patients. LCEA and Sharp angles were higher and the Tönnis angle was lower (P < .01) in females. The dysplastic hip prevalence varied from 2.5% to 20% utilizing the following cutoffs: 17.3°-25.5° (LCEA), 9.4°-15.6° (Tönnis), and 41.3°-45.9° (Sharp). Conclusions: A DL algorithm was developed to measure and classify hips with mild hip dysplasia. The reported prevalence of dysplasia in a large patient cohort was dependent on both the measurement and threshold, with 12.4% of patients having dysplasia radiographic indices indicative of higher THA risk.

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals responsible for economic losses that amount to >$20 billion annually. Rapid recognition of FMD cases provides vital information to guide control programmes. A range of point-of-need amplification technologies have been developed which allow sensitive detection of the causative virus (FMDV) in the field at locations remote from laboratories. Here we describe a novel system to detect FMDV RNA using loop-mediated isothermal amplification (LAMP). This test was evaluated using a panel of FMDV isolates (n = 79) and RNA standards demonstrating capability to amplify viral genome directly from clinical material in the absence of nucleic acid extraction. This extraction-free RT-LAMP assay was transferred to a bespoke closed-system lateral flow test (LFT) that was used in combination with a low-cost hand-held heater. Our results show that the RT-LAMP-LFT assay retains a high level of diagnostic and analytical sensitivity when using direct clinical material, with a limit of detection under 80 copies per reaction. Together, our data support the potential for the use of this assay at the point-of-need to facilitate rapid feedback on the status of suspect cases.

Abstract Urbanisation alters biodiversity patterns and threatens to disrupt mutualistic interactions. Aside from pollination, however, little is known about how mutualisms change in cities. Our study aimed to assess how urbanisation affects the protective mutualism between ants and aphids, investigating potential behavioural changes in mutualistic ants and their implications for aphids in urban environments. To do so, we studied the protective mutualism between the pink tansy aphid (Metopeurum fuscoviride) and the black garden ant (Lasius niger) along an urbanisation gradient in Berlin, Germany. In nine locations along this gradient, we measured aphid colony dynamics and proxies for parasitism, quantified the investment of ants in tending aphids and conducted behavioural assays to test the aggressiveness of ant responses to a simulated attack on the aphids. We found that aphid colonies flourished and were equally tended by ants across the urbanisation gradient, with a consistent positive density dependence between aphid and ant numbers. However, ants from more urbanised sites responded more aggressively to the simulated attack. Our findings suggest that this protective mutualism is not only maintained in the city, but that ants might even rely more on it and defend it more aggressively, as other food resources may become scarce and more unpredictable with urbanisation. We thereby provide unique insights into this type of mutualism in the city, further diversifying the growing body of work on mutualisms across urbanisation gradients.

Abstract Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity and other properties. Measuring how incorporation varies across a population of EVs is important for characterising such materials and understanding their function, yet it remains challenging to quantitatively characterise the absolute number of engineered proteins incorporated at single‐EV resolution. To address these needs, we developed a HaloTag‐based characterisation platform in which dyes or other synthetic species can be covalently and stoichiometrically attached to engineered proteins on the EV surface. To evaluate this system, we employed several orthogonal quantification methods, including flow cytometry and fluorescence microscopy, and found that HaloTag‐mediated quantification is generally robust across EV analysis methods. We compared HaloTag‐labelling to antibody‐labelling of EVs using single vesicle flow cytometry, enabling us to measure the substantial degree to which antibody labelling can underestimate proteins present on an EV. Finally, we demonstrate the use of HaloTag to compare between protein designs for EV bioengineering. Overall, the HaloTag system is a useful EV characterisation tool which complements and expands existing methods.

IntroductionThe human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets.Materials and methodsSnap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins).Results183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR

Background:. Lipedema is the progressive symmetrical deposition of subcutaneous fat and fluid in the lower body, ordinarily sparing the trunk, upper limbs, face, and neck. It may follow an autosomal dominant inheritance pattern. The gold standard treatment for lipedema is complete decongestive therapy, consisting of manual lymphatic drainage and compression garments. This scoping review assessed the existing literature on the effectiveness of liposuction as an alternative treatment for lipedema. Methods:. A scoping review of electronically available literature within PubMed, Scopus, and Cochrane focused on liposuction as a treatment for lipedema considering the following inclusion criteria: human studies, case series of 10 or more, controlled trials, randomized controlled trials, patient-reported outcome measurement studies, survey analyses, descriptive studies, retrospective analyses, recurrence included, follow-up of 6 months or more, age 18 years or older, and treatment modality being liposuction. Results:. Thirteen studies were selected. Nine studies reported decreased compression therapy use among patients following liposuction. No studies reported a long-term increase in compression therapy following liposuction. Studies found self-reported improvements in pain, mobility, bruising, and overall quality of life for patients following liposuction, many of whom had previously been on compressive therapy. Studies reported low rates of serious adverse events following liposuction, including deep vein thrombosis, pulmonary embolism, and infection. Conclusions:. These results suggest that liposuction can be a viable treatment alternative to compression therapy for lipedema in patients whose compression therapy has not been helpful. However, there is not enough evidence to say whether liposuction is as effective as compression for patients first presenting with lipedema.

Individuals harboring breast cancer gene 1/2 (BRCA1/2) pathogenic variants are at increased lifetime risk for developing cancer. Learning one’s BRCA1/2 carrier status is a watershed moment that can result in psychological distress, anxiety, and depression, as well as feelings of vulnerability and stigma. However, emotional and coping responses to learning one’s BRCA1/2 carrier status and after risk-reducing interventions (i.e., preventative bilateral mastectomy) are variable, and existing literature reveals mixed and sometimes contradictory results. Drawing on the concept of narrative identity from the field of psychology, we sought to examine if “identity theft” (the sudden overtaking of one’s narrative agency by an external force) may help explain the heterogeneity of emotional and coping responses following the revelation of BRCA carrier status and the subsequent medical intervention one may receive. This Perspective explores BRCA related identity theft using two case studies. Narrative analysis of qualitative interviews uncover the ways that patients experience the disintegration (theft) of their identity as well as their efforts to build and reintegrate a new BRCA carrier identity. This initial qualitative exploration provides preliminary support for the relevance of narrative identity and identity theft to hereditary cancer. We posit that applying the lens of identity theft may hold promise as a unifying concept, integrating across the variable emotional and coping responses among BRCA carriers. Employing a lens of identity theft may help inform the development of tailored narrative interventions as part of precision healthcare to support active coping and psychosocial wellbeing.

Background: Intussusception is the most common cause of preschool intestinal obstruction. International data suggest that following uncomplicated enema reduction, 4-hour observation with prompt return to oral diet is safe. We aimed to investigate the rate and timing of intussusception recurrence across Aotearoa New Zealand, compared to the cost of routine post-reduction observation. Methods: We performed a national 15-year retrospective, multicenter cohort study of all children treated for intussusception between 01 Jan 2007 and 01 Jan 2022 across AoNZ. A robust clinical dataset was collected using a REDCap proforma. We also investigated the financial and time costs of current in-hospital observation practices. Results: During this period, primary enema reduction without general anesthetic was successful in 339 cases, requiring a median of 2 attempts (1–8). The median age was 0.8 years; 70.8% were male, and 17.1% were Māori. The median length of hospital stay was 25.9 h, primarily comprised of post-reduction observation (21.6 h). Intussusception recurrence within 30 days occurred in 29 children (8.5%) at a median time of 24.7 h post-reduction. Of the 19 cases recurring before discharge, 12 (3.5%) recurred between 4 and 24 h. The median observation period for those with successful primary enema reduction was 21.6 h; if reduced to 4 h, savings of NZD 883,632 (USD 529,825) and 7342 ward hours were possible. Conclusions: Nationally, the intussusception recurrence rate after uncomplicated enema reduction was 8.5%, but only 3.5% occurred between the 4–24 hour period post-reduction. Expediting discharge by avoiding routine overnight observation appears safe and economically viable.

This study evaluated the effect of replacing fish meal (FM) with black soldier fly (Hermatia illucens) larvae meal (BSFLM) on growth performance and economic efficiency of Nile tilapia (Oreochromis niloticus) production. The BSFLM replaced FM at 0, 25, 50 and 75% (T1, T2, T3, and T4, respectively). One thousand two hundred (1,200) all-male Nile tilapia fry were stocked in twelve hapas at Kenya Marine and Fisheries Research Institute (KMFRI), Sangoro aquaculture research station in Kenya, and hand-fed four times daily for 21 weeks. Thirty (30) fish were sampled biweekly from each hapa for measurement of total length and weight. Findings indicated that diet T3 outperformed all the other treatments in respect to final body weight (23.20 ± 1.15 g), daily weight gain (0.13 ± 0.02 g), final weight gain (23.09 ± 1.15 g), survival rate (96.74 ± 3.18 %), SGR (1.31 ± 0.03 % day-1), FCR (1.57 ± 0.02), feed efficiency (0.64 ± 0.02), and condition factor (1.92 ± 0.01). The cost per kilogram of feed was highest for control diet (USD 0.91) and lowest for 75% BSFLM diet (USD 0.79). Economic Conversion Ratio (ECR) was lowest for the 50% BSFLM diet (1.26 ± 0.14) and highest for the control diet (1.44 ± 0.14). Economic Profit Index (EPI) was highest for the 50% BSFLM diet (141.82 ± 7.88) and lowest for the 25% BSFLM diet (106.64 ±6.63). The findings reveal that 50 to 75% BSFLM inclusion is an ideal replacement for FM in Nile tilapia diets, and is technically and economically efficient for Nile tilapia production. [Fundam Appl Agric 2024; 9(1.000): 1-9]

Abstract Background Neisseria meningitidis can cause life-threatening meningococcal meningitis and meningococcemia. Old standard microbiological results from CSF/blood cultures are time consuming. This study aimed to combine the sensitivity of loop-mediated isothermal nucleic acid amplification (LAMP) with the specificity of CRISPR/Cas12a cleavage to demonstrate a reliable diagnostic assay for rapid detection of N. meningitidis. Methods A total of n = 139 samples were collected from patients with suspected meningococcal disease and were used for evaluation. The extracted DNA was subjected to qualitative real-time PCR, targeting capsular transporter gene (ctrA) of N. meningitidis. LAMP-specific primer pairs, also targeting the ctrA, were designed and the LAMP products were subjected to CRISPR/Cas12 cleavage reaction. the readout was on a lateral flow strip. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of LAMP-CRISPR/Cas was compared with real-time PCR assays. The limit of detection (LOD) was established with serial dilutions of the target N. meningitidis DNA and calculated by Probit regression analysis. Results Six LAMP assay-specific primers were developed targeting the ctrA gene of N. meningitidis, which is conserved in all meningococcal serogroups. The LAMP primers did not amplify DNA from other bacterial DNA tested, showing 100% specificity. The use of 0.4 M betaine increased the sensitivity and stability of the reaction. LAMP-CRISPR/Cas detected meningococcal serogroups (B, C, W). The assay showed no cross-reactivity and was specific for N. meningitidis. The LOD was 74 (95% CI: 47–311) N. meningitidis copies. The LAMP-CRISPR/Cas performed well compared to the gold standard. In the 139 samples from suspected patients, the sensitivity and specificity of the test were 91% and 99% respectively. Conclusion This developed and optimized method can complement for the available gold standard for the timely diagnosis of meningococcal meningitis and meningococcemia.

Abstract Background Gestational weight gain (GWG) is a routinely monitored aspect of pregnancy health, yet critical gaps remain about optimal GWG in pregnant people from socially marginalized groups, or with pre-pregnancy body mass index (BMI) in the lower or upper extremes. The PROMISE study aims to determine overall and trimester-specific GWG associated with the lowest risk of adverse birth outcomes and detrimental infant and child growth in these underrepresented subgroups. This paper presents methods used to construct the PROMISE cohort using electronic health record data from a network of community-based healthcare organizations and characterize the cohort with respect to baseline characteristics, longitudinal data availability, and GWG. Methods We developed an algorithm to identify and date pregnancies based on outpatient clinical data for patients 15 years or older. The cohort included pregnancies delivered in 2005–2020 with gestational age between 20 weeks, 0 days and 42 weeks, 6 days; and with known height and adequate weight measures needed to examine GWG patterns. We linked offspring data from birth records and clinical records. We defined study variables with attention to timing relative to pregnancy and clinical data collection processes. Descriptive analyses characterize the sociodemographic, baseline, and longitudinal data characteristics of the cohort, overall and within BMI categories. Results The cohort includes 77,599 pregnancies: 53% had incomes below the federal poverty level, 82% had public insurance, and the largest race and ethnicity groups were Hispanic (56%), non-Hispanic White (23%) and non-Hispanic Black (12%). Pre-pregnancy BMI groups included 2% underweight, 34% normal weight, 31% overweight, and 19%, 8%, and 5% Class I, II, and III obesity. Longitudinal data enable the calculation of trimester-specific GWG; e.g., a median of 2, 4, and 6 valid weight measures were available in the first, second, and third trimesters, respectively. Weekly rate of GWG was 0.00, 0.46, and 0.51 kg per week in the first, second, and third trimesters; differences in GWG between BMI groups were greatest in the second trimester. Conclusions The PROMISE cohort enables characterization of GWG patterns and estimation of effects on child growth in underrepresented subgroups, ultimately improving the representativeness of GWG evidence and corresponding guidelines.

Abstract Background 16p11.2 proximal deletion and duplication syndromes (Break points 4–5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known propensity for lifelong psychiatric problems. This study aimed to contribute to a research gap by qualitatively exploring the challenges families with 16p11.2 deletion and duplication face by answering three research questions: (1) What are parents’ perceptions of the ongoing support needs of families with children who have 16p11.2 living in the UK?; (2) What are their experiences in trying to access support?; (3) In these regards, do the experiences of parents of children with duplication converge or vary from those of parents of children with 16p11.2 deletion? Methods 33 parents with children (aged 7–17 years) with 16p11.2 deletion or duplication participated in structured interviews, including the Autism Diagnostic Interview– Revised (ADI-R). Their answers to the ADI-R question ‘what are your current concerns’ were transcribed and subsequently analysed using Braun and Clarke’s six step reflexive thematic analysis framework. Results Three themes were identified: (1) Child is Behind Peers (subthemes: developmentally; academically; socially; emotionally); (2) Metabolism and Eating Patterns and; (3) Support (subthemes: insufficient support available; parent has to fight to access support; COVID-19 was a barrier to accessing support; 16p11.2 diagnosis can be a barrier to support, child is well-supported). Conclusions Parents of children with either 16p11.2 deletion or duplication shared similar experiences. However, metabolism concerns were specific to parents of children with 16p11.2 deletion. The theme Child is Behind Peers echoed concerns raised in previous Neurodevelopmental Copy Number Variant research. However, there were some key subthemes relating to research question (2) which were specific to this study. This included parents’ descriptions of diagnostic overshadowing and the impact of a lack of eponymous name and scant awareness of 16p11.2.

Abstract The deformation behavior of Ti-6Al-4V titanium alloy is significantly influenced by slip localized within crystallographic slip bands. Experimental observations reveal that intense slip bands in Ti-6Al-4V form at strains well below the macroscopic yield strain and may serially propagate across grain boundaries, resulting in long-range localization that percolates through the microstructure. These connected, localized slip bands serve as potential sites for crack initiation. Although slip localization in Ti-6Al-4V is known to be influenced by various factors, an investigation of optimal microstructures that limit localization remains lacking. In this work, we develop a novel strategy that integrates an explicit slip band crystal plasticity technique, graph networks, and neural network models to identify Ti-6Al-4V microstructures that reduce the propensity for strain localization. Simulations are conducted on a dataset of 3D polycrystals, each represented as a graph to account for grain neighborhood and connectivity. The results are then used to train neural network surrogate models that accurately predict localization-based properties of a polycrystal, given its microstructure. These properties include the ratio of slip accumulated in the band to that in the matrix, fraction of total applied strain accommodated by slip bands, and spatial connectivity of slip bands throughout the microstructure. The initial dataset is enriched by synthetic data generated by the surrogate models, and a grid search optimization is subsequently performed to find optimal microstructures. Describing a 3D polycrystal with only a few features and a combination of graph and neural network models offer robustness compared to the alternative approaches without compromising accuracy. We show that while each material property is optimized through a unique microstructure solution, elongated grain shape emerges as a recurring feature among all optimal microstructures. This finding suggests that designing microstructures with elongated grains could potentially mitigate strain localization without compromising strength.

Abstract Suncus etruscus is one of the world’s smallest mammals, with an average body mass of about 2 grams. The Etruscan shrew’s small body is accompanied by a very high energy demand and numerous metabolic adaptations. Here we report a chromosome-level genome assembly using PacBio long read sequencing, 10X Genomics linked short reads, optical mapping, and Hi-C linked reads. The assembly is partially phased, with the 2.472 Gbp primary pseudohaplotype and 1.515 Gbp alternate. We manually curated the primary assembly and identified 22 chromosomes, including X and Y sex chromosomes. The NCBI genome annotation pipeline identified 39,091 genes, 19,819 of them protein-coding. We also identified segmental duplications, inferred GO term annotations, and computed orthologs of human and mouse genes. This reference-quality genome will be an important resource for research on mammalian development, metabolism, and body size control.

Abstract The validity of venous ultrasound (V-US) for the diagnosis of deep vein thrombosis (DVT) during spaceflight is unknown and difficult to establish in diagnostic accuracy and diagnostic management studies in this context. We performed a systematic review of the use of V-US in the upper-body venous system in spaceflight to identify microgravity-related changes and the effect of venous interventions to reverse them, and to assess appropriateness of spaceflight V-US with terrestrial standards. An appropriateness tool was developed following expert panel discussions and review of terrestrial diagnostic studies, including criteria relevant to crew experience, in-flight equipment, assessment sites, ultrasound modalities, and DVT diagnosis. Microgravity-related findings reported as an increase in internal jugular vein (IJV) cross-sectional area and pressure were associated with reduced, stagnant, and retrograde flow. Changes were on average responsive to venous interventions using lower body negative pressure, Bracelets, Valsalva and Mueller manoeuvres, and contralateral IJV compression. In comparison with terrestrial standards, spaceflight V-US did not meet all appropriateness criteria. In DVT studies (n = 3), a single thrombosis was reported and only ultrasound modality criterion met the standards. In the other studies (n = 15), all the criteria were appropriate except crew experience criterion, which was appropriate in only four studies. Future practice and research should account for microgravity-related changes, evaluate individual effect of venous interventions, and adopt Earth-based V-US standards.

Abstract Journal editors have a large amount of power to advance open science in their respective fields by incentivising and mandating open policies and practices at their journals. The Data PASS Journal Editors Discussion Interface (JEDI, an online community for social science journal editors: www.dpjedi.org ) has collated several resources on embedding open science in journal editing ( www.dpjedi.org/resources ). However, it can be overwhelming as an editor new to open science practices to know where to start. For this reason, we created a guide for journal editors on how to get started with open science. The guide outlines steps that editors can take to implement open policies and practices within their journal, and goes through the what, why, how, and worries of each policy and practice. This manuscript introduces and summarizes the guide (full guide: https://doi.org/10.31219/osf.io/hstcx ).

Aims: Distal femoral resection in conventional total knee arthroplasty (TKA) utilizes an intramedullary guide to determine coronal alignment, commonly planned for 5° of valgus. However, a standard 5° resection angle may contribute to malalignment in patients with variability in the femoral anatomical and mechanical axis angle. The purpose of the study was to leverage deep learning (DL) to measure the femoral mechanical-anatomical axis angle (FMAA) in a heterogeneous cohort. Methods: Patients with full-limb radiographs from the Osteoarthritis Initiative were included. A DL workflow was created to measure the FMAA and validated against human measurements. To reflect potential intramedullary guide placement during manual TKA, two different FMAAs were calculated either using a line approximating the entire diaphyseal shaft, and a line connecting the apex of the femoral intercondylar sulcus to the centre of the diaphysis. The proportion of FMAAs outside a range of 5.0° (SD 2.0°) was calculated for both definitions, and FMAA was compared using univariate analyses across sex, BMI, knee alignment, and femur length. Results: The algorithm measured 1,078 radiographs at a rate of 12.6 s/image (2,156 unique measurements in 3.8 hours). There was no significant difference or bias between reader and algorithm measurements for the FMAA (p = 0.130 to 0.563). The FMAA was 6.3° (SD 1.0°; 25% outside range of 5.0° (SD 2.0°)) using definition one and 4.6° (SD 1.3°; 13% outside range of 5.0° (SD 2.0°)) using definition two. Differences between males and females were observed using definition two (males more valgus; p < 0.001). Conclusion: We developed a rapid and accurate DL tool to quantify the FMAA. Considerable variation with different measurement approaches for the FMAA supports that patient-specific anatomy and surgeon-dependent technique must be accounted for when correcting for the FMAA using an intramedullary guide. The angle between the mechanical and anatomical axes of the femur fell outside the range of 5.0° (SD 2.0°) for nearly a quarter of patients. Cite this article: Bone Jt Open 2024;5(2):101–108.