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Summary: The study of pattern formation has benefited from our ability to reverse-engineer gene regulatory network (GRN) structure from spatiotemporal quantitative gene expression data. Traditional approaches have focused on systems where the timescales of pattern formation and morphogenesis can be separated. Unfortunately, this is not the case in most animal patterning systems, where pattern formation and morphogenesis are co-occurring and tightly linked. To elucidate patterning mechanisms in such systems we need to adapt our GRN inference methodologies to include cell movements. In this work, we fill this gap by integrating quantitative data from live and fixed embryos to approximate gene expression trajectories (AGETs) in single cells and use these to reverse-engineer GRNs. This framework generates candidate GRNs that recapitulate pattern at the tissue level, gene expression dynamics at the single cell level, recover known genetic interactions and recapitulate experimental perturbations while incorporating cell movements explicitly for the first time.

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with body size has not been comprehensively studied. To address this gap in knowledge, we employed a systems approach including transcriptomics, proteomics, and measurement of in vitro and in vivo metabolic fluxes. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression according to body mass of genes related to cytosolic and mitochondrial metabolic processes, and to detoxication of oxidative damage. To determine whether flux through key metabolic pathways is ordered inversely to body size, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing C57BL/6 J mice with Sprague-Dawley rats, we demonstrate that while ordering of metabolic fluxes is not observed in in vitro cell-autonomous settings, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to other aspects of metabolism, and is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.

Accurate seasonal forecasts of sea ice are highly valuable, particularly in the context of sea ice loss due to global warming. A new machine learning tool for sea ice forecasting offers a substantial increase in accuracy over current physics-based dynamical model predictions.

Abstract We aimed to determine how a bout of resistance or aerobic exercise impacts physiological responses and performance during firefighting occupational tasks. Thirty-two non-firefighters completed two baseline assessments and three trials: resistance exercise (RE), aerobic exercise (AE), or a rested control (CON). Trials were followed by an occupational task assessment (OTA; four rounds of 10 deadlifts (38.6–61.4 kg) and 0.24-km 40lb-sandbag carry) in an environmental chamber (35 °C/50% humidity) while wearing standard municipal firefighter gear. Time to complete by condition was not statistically different (CON: 18.9 ± 4.4, AE: 20.0 ± 3.6, RE: 20.2 ± 5.0 min; p = 0.16). During the OTA average heart rate (CON: 149 ± 16, AE: 166 ± 12, RE: 160 ± 13 bpm; p

Abstract Disease-modifying therapies for Alzheimer’s disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients.

Abstract Glycans play critical roles in cellular signaling and function. Unlike proteins, glycan structures are not templated from genetic sequences but synthesized by the concerted activity of many genes, making them historically challenging to study. Here, we present a strategy that utilizes CRISPR screens and lectin microarrays to uncover and characterize regulators of glycosylation. We applied this approach to study the regulation of high mannose glycans – the starting structure of all asparagine(N)-linked-glycans. We used CRISPR screens to uncover the expanded network of genes controlling high mannose levels, followed by lectin microarrays to fully measure the complex effect of select regulators on glycosylation globally. Through this, we elucidated how two high mannose regulators – TM9SF3 and the CCC complex – control complex N-glycosylation via regulating Golgi morphology and function. Notably, this allows us to interrogate Golgi function in-depth and reveals that similar disruption to Golgi morphology can lead to drastically different glycosylation outcomes. Collectively, this work demonstrates a generalizable approach for systematically dissecting the regulatory network underlying glycosylation.

The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF), for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR), the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4) is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF) in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients). Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient) and vitreous (n = 3 patients) samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR.

In the Southern Hemisphere, humpback whales (Megaptera novaeangliae) migrate along the extended continental coastlines of Australia, South America, and South Africa. This study reports on photo-identification capture–recapture data from a long-term survey conducted in Hervey Bay, Queensland, where a substantial proportion of the population stop over early in the southern migration. Photo-identification data were collected over 10 weeks per year from 1997 to 2009. The migration through Hervey Bay is dominated and led by females with high fidelity to the site. Mature females, yearlings, and immature whales use the Bay during August, while mature lactating females with calves dominate during September and October. Complex social behaviours occur throughout the season and differ between the early and late cohorts. We argue that the composition of the two cohorts and their distinctively different behaviours indicate that Hervey Bay is not simply a resting site but an area of aggregation that serves important social and biological benefits. A multistate open robust design model was fitted to capture–recapture data to estimate the annual number of whales visiting the Bay, the permanent emigration rate, proportions of the visiting population that do not enter the Bay each year, the number present during each week, and their residency times. The number of annual visitors to the Bay increased approximately linearly from 857 in 1997 to 2175 at the end of sampling in 2009 with two-thirds migrating through during the first half of each season. The population rate of growth may have been slowing by 2009, but there was considerable uncertainty in the trajectory and little basis for projection into the future. While it is desirable to know the current status of the Hervey Bay population and what has occurred since 2009, the cost and effort required make further manual collection and matching of images unlikely. The development of AI algorithmic matching software may enable further research in future.

Accurate and high-throughput technologies are needed for identification of new therapeutic targets and for optimizing therapy in inflammatory bowel disease. Our aim was to assess multi-analyte protein-based assays of cytokines/chemokines using Luminex technology. We have reported that Luminex-based profiling was useful in assessing response to L-arginine therapy in the mouse model of dextran sulfate sodium colitis. Therefore, we studied prospectively collected samples from ulcerative colitis (UC) patients and control subjects. Serum, colon biopsies, and clinical information were obtained from subjects undergoing colonoscopy for evaluation of UC or for non-UC indications. In total, 38 normal controls and 137 UC cases completed the study. Histologic disease severity and the Mayo Disease Activity Index (DAI) were assessed. Serum and colonic tissue cytokine/chemokine profiles were measured by Luminex-based multiplex testing of 42 analytes. Only eotaxin-1 and G-CSF were increased in serum of patients with histologically active UC vs. controls. While 13 cytokines/chemokines were increased in active UC vs. controls in tissues, only eotaxin-1 was increased in all levels of active disease in both serum and tissue. In tissues, eotaxin-1 correlated with the DAI and with eosinophil counts. Increased eotaxin-1 levels were confirmed by real-time PCR. Tissue eotaxin-1 levels were also increased in experimental murine colitis induced by dextran sulfate sodium, oxazolone, or Citrobacter rodentium, but not in murine Helicobacter pylori infection. Our data implicate eotaxin-1 as an etiologic factor and therapeutic target in UC, and indicate that Luminex-based assays may be useful to assess IBD pathogenesis and to select patients for anti-cytokine/chemokine therapies.

Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis (UC), results in substantial morbidity and is difficult to treat. New strategies for adjunct therapies are needed. One candidate is the semi-essential amino acid, L-arginine (L-Arg), a complementary medicine purported to be an enhancer of immunity and vitality in the lay media. Using dextran sulfate sodium (DSS) as a murine colonic injury and repair model with similarities to human UC, we assessed the effect of L-Arg, as DSS induced increases in colonic expression of the y(+) cationic amino acid transporter 2 (CAT2) and L-Arg uptake. L-Arg supplementation improved the clinical parameters of survival, body weight loss, and colon weight, and reduced colonic permeability and the number of myeloperoxidase-positive neutrophils in DSS colitis. Luminex-based multi-analyte profiling demonstrated that there was a marked reduction in proinflammatory cytokine and chemokine expression with L-Arg treatment. Genomic analysis by microarray demonstrated that DSS-treated mice supplemented with L-Arg clustered more closely with mice not exposed to DSS than to those receiving DSS alone, and revealed that multiple genes that were upregulated or downregulated with DSS alone exhibited normalization of expression with L-Arg supplementation. Additionally, L-Arg treatment of mice with DSS colitis resulted in increased ex vivo migration of colonic epithelial cells, suggestive of increased capacity for wound repair. Because CAT2 induction was sustained during L-Arg treatment and inducible nitric oxide (NO) synthase (iNOS) requires uptake of L-Arg for generation of NO, we tested the effect of L-Arg in iNOS(-/-) mice and found that its benefits in DSS colitis were eliminated. These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity.

Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of L-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2(-/-) mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2(-/-) mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2(-/-) mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection.

Obesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance.Conventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in GF NF-kappaB(EGFP) mice.Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.

Se presenta una interesante aplicación de aprendizaje de máquina en la originación de créditos en microfinanzas. El objetivo de microfinanzas son las personas que no pueden construir un historial crediticio y, en consecuencia, no pueden acceder a préstamos de bancos u otras instituciones financieras. Usamos datos de una compañía microfinanciera mexicana que opera en varias regiones del país. De igual modo, se pretende guiar a prestamistas intermediarios para escoger sus clientes y alcanzar un menor riesgo de crédito. Usamos varios modelos estadísticos como análisis de componentes principales, análisis de grupos y árboles de regresión. Obtenemos, como resultado, una serie de recomendaciones basadas en las características de los clientes.

Abstract Synchronous interpersonal movements induce positive prosocial behaviors in adults and children. The processes that underlie this are debated. Here, we investigate the extent to which visual cues available during synchrony experience—particularly shared facial expressions and mutual eye contact—are necessary. Pairs of same-sex 4-year-olds (N = 216 children; 50% girls; 81% white) from the US were randomly assigned to synchronized versus asynchronized swinging experience. Access to visual information was experimentally manipulated by using a transparent versus translucent barrier between the children. The translucent barrier acted as a visual filter preventing children from monitoring facial cues while still enabling them to see whether the partner was swinging in synchrony. After the swinging experience, all pairs of children were administered the same tests of cooperation. The children administered synchronous movement performed better on the cooperation tasks, and there was no significant difference as a function of barrier transparency. This suggests that the positive effects of synchrony do not require visual resolution of the partner’s social-emotional facial cues. These findings advance our understanding about factors contributing to synchrony-induced cooperation between children.

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Abstract Superantigens (sAgs) are bacterial virulence factors that induce a state of immune hyperactivation by forming a bridge between certain subsets of T cell receptor (TCR) β chains on T lymphocytes, and class II major histocompatibility complex (MHC-II) molecules; this cross-linking leads to indiscriminate T cell activation, cytokine storm and toxic shock. Here we show that sAg exposure drives the preferential expansion of naive and central memory T cell subsets, but not effector or resident memory T cells, which instead, hyper release pro-inflammatory cytokines. A targeted therapeutic approach to minimise cytokine release by effector memory T cells attenuated sAg-induced cytokine release. Irrespective of antigen experience, sAg activation does not render mature T cells permanently dysfunctional, and full restoration of effector function is observed following a transient and reversible anergy. Moreover, we show that in the face of sAg induced immune hyperactivation, an intact bacterium-specific CD4+ T cell response can be mounted.

Abstract Onsite production of gigawatt-scale wind- and solar-sourced hydrogen (H2) at industrial locations depends on the ability to store and deliver otherwise-curtailed H2 during times of power shortages. Thousands of tonnes of H2 will require storage in regions where subsurface storage is scarce, which may only be possible using liquid organic H2 carriers. We evaluate aboveground system with a focus on providing technical insights into toluene/methylcyclohexane (TOL/MCH) storage systems in locations suitable for gigawatt-scale wind- and solar-powered electrolyzer systems in the United States. Here we show that the levelized cost of storage, at a national median of US dollar $1.84/kg-H2 is spatially heterogeneous, causing minor impact on the cost of H2 supply in the Midwest, and significant impact in Central California and the Southeast. While TOL/MCH may be the cheapest aboveground bulk storage solution evaluated, upfront capital costs, modest energy efficiency, reliance on critical materials and pre-sulfided catalysts, and greenhouse gas emissions from heating are opportunities for further development.

Abstract Exposure to ionizing radiation for oncological therapy increases the risk for late-onset fractures in survivors. However, the effects of total body irradiation (TBI) on adult bone are not well-characterized. The primary aim of this study was to quantify the long-term effects of TBI on bone microstructure, material composition, and mechanical behavior in skeletally mature rhesus macaque (Macaca mulatta) non-human primates. Femora were obtained post-mortem from animals exposed to an acute dose of TBI (6.0–6.75 Gy) nearly a decade earlier, age-matched non-irradiated controls, and non-irradiated young animals. The microstructure of femoral trabecular and cortical bone was assessed via micro-computed tomography. Material composition was evaluated by measuring total fluorescent advanced glycation end products (fAGEs). Cortical bone mechanical behavior was quantified via four-point bending and cyclic reference point indentation (cRPI). Animals exposed to TBI had slightly worse cortical microstructure, including lower cortical thickness (-11%, p = 0.037) and cortical area (-24%, p = 0.049), but similar fAGE content and mechanical properties as age-matched controls. Aging did not influence cortical microstructure, fAGE content, or cRPI measures but diminished femoral cortical post-yield properties, including toughness to fracture (-32%, p = 0.032). Because TBI was administered after the acquisition of peak bone mass, these results suggest that the skeletons of long-term survivors of adulthood TBI may be resilient, retaining or recovering their mechanical integrity during the post-treatment period, despite radiation-induced architectural deficits. Further investigation is necessary to better understand radiation-induced skeletal fragility in mature and immature bone to improve care for radiation patients of all ages.

Abstract Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d0–d8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H−/D− and H+/D+. The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro-methylphenidate were also prepared.

Abstract The diagnosis of prostate cancer using histopathology is reliant on the accurate interpretation of prostate tissue sections. Current standards rely on the assessment of Haematoxylin and Eosin (H&E) staining, which can be difficult to interpret and introduce inter-observer variability. Here, we present a digital pathology atlas and online resource of prostate cancer tissue micrographs for both H&E and the reinterpretation of samples using a novel set of three biomarkers as an interactive tool, where clinicians and scientists can explore high resolution histopathology from various case studies. The digital pathology prostate cancer atlas when used in conjunction with the biomarkers, will assist pathologists to accurately grade prostate cancer tissue samples.

Abstract Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization’s Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Abstract The Southern Ocean ecosystem has undergone extensive changes in the past two centuries driven by industrial sealing and whaling, climate change and commercial fishing. However, following the end of commercial whaling, some populations of whales in this region are recovering. Baleen whales are reliant on Antarctic krill, which is also the largest Southern Ocean fishery. Since 1993, krill catch has increased fourfold, buoyed by nutritional supplement and aquaculture industries. In this Perspective, we approximate baleen whale consumption of Antarctic krill before and after whaling to examine if the ecosystem can support both humans and whales as krill predators. Our back-of-the-envelope calculations suggest that current krill biomass cannot support both an expanding krill fishery and the recovery of whale populations to pre-whaling sizes, highlighting an emerging human-wildlife conflict. We then provide recommendations for enhancing sustainability in this region by reducing encounters with whales and bolstering the krill population.

Abstract How we move our bodies affects how we perceive sound. For instance, head movements help us to better localize the source of a sound and to compensate for asymmetric hearing loss. However, many auditory experiments are designed to restrict head and body movements. To study the role of movement in hearing, we developed a behavioral task called sound-seeking that rewarded freely moving mice for tracking down an ongoing sound source. Over the course of learning, mice more efficiently navigated to the sound. Next, we asked how sound-seeking was affected by hearing loss induced by surgical removal of the malleus from the middle ear. After bilateral hearing loss sound-seeking performance drastically declined and did not recover. In striking contrast, after unilateral hearing loss mice were only transiently impaired and then recovered their sound-seek ability over about a week. Throughout recovery, unilateral mice increasingly relied on a movement strategy of sequentially checking potential locations for the sound source. In contrast, the startle reflex (an innate auditory behavior) was preserved after unilateral hearing loss and abolished by bilateral hearing loss without recovery over time. In sum, mice compensate with body movement for permanent unilateral damage to the peripheral auditory system. Looking forward, this paradigm provides an opportunity to examine how movement enhances perception and enables resilient adaptation to sensory disorders.

Abstract The dynamic interaction between cliff, beach and shore-platform is key to assessing the sediment balance for coastal erosion risk assessments, but this is poorly understood. We present a dataset containing daily, 3D,colour LiDAR scans of a 450 m coastal section at Happisburgh, Norfolk, UK. This previously para-glaciated region comprises mixed sand-gravel sediments, which are less well-understood and well-studied than sandy beaches. From Apr-Dec 2019, 236 daily surveys were carried out. The dataset presented includes: survey areas, transects LiDAR scans, georeferenced orthophotos, meteorological- and oceanographical conditions during the Apr-Dec observation period. Full LiDAR point-clouds are available for 67 scans (Oct-Dec). Hourly time-series of offshore sea-state parameters (significant wave height, mean propagation direction, selected spectral periods) were obtained by downscaling the ERA5 global reanalysis data (global atmosphere, land surface and ocean waves) using the numerical model Simulating Waves Nearshore (SWAN). We indicate how to obtain hourly precipitation time-series by interpolating ERA5 data. This dataset is important for researchers understanding the interaction between cliff, beach and shore-platform in open-coast mixed-sand-gravel environments.

Abstract Recent advances in AI and intelligent vehicle technology hold the promise of revolutionizing mobility and transportation through advanced driver assistance systems (ADAS). Certain cognitive factors, such as impulsivity and inhibitory control have been shown to relate to risky driving behavior and on-road risk-taking. However, existing systems fail to leverage such factors in assistive driving technologies adequately. Varying the levels of these cognitive factors could influence the effectiveness and acceptance of ADAS interfaces. We demonstrate an approach for personalizing driver interaction via driver safety interfaces that are are triggered based on the inference of the driver’s latent cognitive states from their driving behavior. To accomplish this, we adopt a data-driven approach and train a recurrent neural network to infer impulsivity and inhibitory control from recent driving behavior. The network is trained on a population of human drivers to infer impulsivity and inhibitory control from recent driving behavior. Using data collected from a high-fidelity vehicle motion simulator experiment, we demonstrate the ability to deduce these factors from driver behavior. We then use these inferred factors to determine instantly whether or not to engage a driver safety interface. This approach was evaluated using leave-one-out cross validation using actual human data. Our evaluations reveal that our personalized driver safety interface that captures the cognitive profile of the driver is more effective in influencing driver behavior in yellow light zones by reducing their inclination to run through them.

Abstract The objective was to assess the impact of environmental complexity on affective state (anxiety) in fast- and slow-growing broilers (Gallus gallus domesticus) as they gain weight. Six hundred fast-growing broilers (Ross 708; “fast-growers”) and 600 slow-growing broilers (Hubbard Redbro Mini; “slow-growers”) were raised in 24 pens with simple (standard; SE) or complex (permanent and temporary enrichments; CE) environments. Six birds/pen underwent the attention bias test on day 23 (fast-growers only), 28–29, 35–36, 42–43, and 56–57 (slow-growers only), with individuals only tested once (n = 576). Proportion of birds feeding, time spent vigilant and latencies to eat and step were recorded. Greater vigilance and longer latencies indicate more anxiety. Slow-growers fed more (p = 0.001), were less vigilant (p = 0.003), and stepped sooner than fast-growers (p = 0.007). For both strains, likelihood of feeding was unrelated to weight in SE, but decreased with increasing weight in CE (p = 0.048). Birds in CE stepped sooner than birds in SE (p = 0.030). Vigilance increased with body weight (p = 0.024). These results indicate that affective state (anxiety) can change as birds gain weight, depending on environmental complexity and genetic strain. Overall, slow-growers showed reduced anxiety compared to fast-growers, across housing treatments or weights.

Abstract Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Abstract To accurately define the role of the gut microbiota in health and disease pathogenesis, the preservation of stool sample integrity, in terms of microbial community composition and metabolic function, is critical. This presents a challenge for any studies which rely on participants self-collecting and returning stool samples as this introduces variability and uncertainty of sample storage/handling. Here, we tested the performance of three stool sample collection/preservation buffers when storing human stool samples at different temperatures (room temperature [20 °C], 4 °C and – 80 °C) for up to three days. We compared and quantified differences in 16S rRNA sequencing composition and short-chain fatty acid profiles compared against immediately snap-frozen stool. We found that the choice of preservation buffer had the largest effect on the resulting microbial community and metabolomic profiles. Collectively analysis confirmed that PSP and RNAlater buffered samples most closely recapitulated the microbial diversity profile of the original (immediately – 80 °C frozen) sample and should be prioritised for human stool microbiome studies.

Abstract Occipital nerve decompression is effective in reducing headache symptoms in select patients with migraine and occipital neuralgia. Eligibility for surgery relies on subjective symptoms and responses to nerve blocks and Onabotulinum toxin A (Botox) injections. No validated objective method exists for detecting occipital headache pathologies. The purpose of the study is to explore the potential of high-resolution Magnetic Resolution Imaging (MRI) in identifying greater occipital nerve (GON) pathologies in chronic headache patients. The MRI protocol included three sequences targeting fat-suppressed fluid-sensitive T2-weighted signals. Visualization of the GON involved generating 2-D image slices with sequential rotation to track the nerve course. Twelve patients underwent pre-surgical MRI assessment. MRI identified four main pathologies that were validated against intra-operative examination: GON entanglement by the occipital artery, increased nerve thickness and hyperintensity suggesting inflammation compared to the non-symptomatic contralateral side, early GON branching with rejoining at a distal point, and a connection between the GON and the lesser occipital nerve. MRI possesses the ability to visualize the GON and identify suspected trigger points associated with headache symptoms. This case series highlights MRI's potential to provide objective evidence of nerve pathology. Further research is warranted to establish MRI as a gold standard for diagnosing extracranial contributors in headaches.

Abstract Oxide heterostructures exhibit a vast variety of unique physical properties. Examples are unconventional superconductivity in layered nickelates and topological polar order in (PbTiO3)n/(SrTiO3)n superlattices. Although it is clear that variations in oxygen content are crucial for the electronic correlation phenomena in oxides, it remains a major challenge to quantify their impact. Here, we measure the chemical composition in multiferroic (LuFeO3)9/(LuFe2O4)1 superlattices, mapping correlations between the distribution of oxygen vacancies and the electric and magnetic properties. Using atom probe tomography, we observe oxygen vacancies arranging in a layered three-dimensional structure with a local density on the order of 1014 cm−2, congruent with the formula-unit-thick ferrimagnetic LuFe2O4 layers. The vacancy order is promoted by the locally reduced formation energy and plays a key role in stabilizing the ferroelectric domains and ferrimagnetism in the LuFeO3 and LuFe2O4 layers, respectively. The results demonstrate pronounced interactions between oxygen vacancies and the multiferroic order in this system and establish an approach for quantifying the oxygen defects with atomic-scale precision in 3D, giving new opportunities for deterministic defect-enabled property control in oxide heterostructures.

Abstract In 2022, Houston, TX became a nexus for field campaigns aiming to further our understanding of the feedbacks between convective clouds, aerosols and atmospheric boundary layer (ABL) properties. Houston’s proximity to the Gulf of Mexico and Galveston Bay motivated the collection of spatially distributed observations to disentangle coastal and urban processes. This paper presents a value-added ABL dataset derived from observations collected by eight research teams over 46 days between 2 June - 18 September 2022. The dataset spans 14 sites distributed within a ~80-km radius around Houston. Measurements from three types of instruments are analyzed to objectively provide estimates of nine ABL parameters, both thermodynamic (potential temperature, and relative humidity profiles and thermodynamic ABL depth) and dynamic (horizontal wind speed and direction, mean vertical velocity, updraft and downdraft speed profiles, and dynamical ABL depth). Contextual information about cloud occurrence is also provided. The dataset is prepared on a uniform time-height grid of 1 h and 30 m resolution to facilitate its use as a benchmark for forthcoming numerical simulations and the fundamental study of atmospheric processes.

Abstract Myxovirus resistance (Mx) proteins are products of interferon stimulated genes (ISGs) and Mx proteins of different species have been reported to mediate antiviral activity against a number of viruses, including influenza A viruses (IAV). Ferrets are widely considered to represent the ‘gold standard’ small animal model for studying pathogenesis and immunity to human IAV infections, however little is known regarding the antiviral activity of ferret Mx proteins. Herein, we report induction of ferret (f)Mx1/2 in a ferret lung cell line and in airway tissues from IAV-infected ferrets, noting that fMx1 was induced to higher levels that fMx2 both in vitro and in vivo. Overexpression confirmed cytoplasmic expression of fMx1 as well as its ability to inhibit infection and replication of IAV, noting that this antiviral effect of fMx1was modest when compared to cells overexpressing either human MxA or mouse Mx1. Together, these studies provide the first insights regarding the role of fMx1 in cell innate antiviral immunity to influenza viruses. Understanding similarities and differences in the antiviral activities of human and ferret ISGs provides critical context for evaluating results when studying human IAV infections in the ferret model.

Abstract Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.

Abstract HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human β2m (hβ2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3−/−), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.

Abstract Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0–1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5–15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567).

Abstract Pseudomonas aeruginosa is a major cause of nosocomial infections and the leading cause of chronic lung infections in cystic fibrosis and chronic obstructive pulmonary disease patients. Antibiotic treatment remains challenging because P. aeruginosa is resistant to high concentrations of antibiotics and has a remarkable ability to acquire mutations conferring resistance to multiple groups of antimicrobial agents. Here we report that when P. aeruginosa is plated on ciprofloxacin (cipro) plates, the majority of cipro-resistant (ciproR) colonies observed at and after 48 h of incubation carry mutations in genes related to the Stringent Response (SR). Mutations in one of the major SR components, spoT, were present in approximately 40% of the ciproR isolates. Compared to the wild-type strain, most of these isolates had decreased growth rate, longer lag phase and altered intracellular ppGpp content. Also, 75% of all sequenced mutations were insertions and deletions, with short deletions being the most frequently occurring mutation type. We present evidence that most of the observed mutations are induced on the selective plates in a subpopulation of cells that are not instantly killed by cipro. Our results suggests that the SR may be an important contributor to antibiotic resistance acquisition in P. aeruginosa.

Abstract Halogen-containing molecules are ubiquitous in modern society and present unique chemical possibilities. As a whole, de novo fermentation and synthetic pathway construction for these molecules remain relatively underexplored and could unlock molecules with exciting new applications in industries ranging from textiles to agrochemicals to pharmaceuticals. Here, we report a mix-and-match co-culture platform to de novo generate a large array of halogenated tryptophan derivatives in Escherichia coli from glucose. First, we engineer E. coli to produce between 300 and 700 mg/L of six different halogenated tryptophan precursors. Second, we harness the native promiscuity of multiple downstream enzymes to access unexplored regions of metabolism. Finally, through modular co-culture fermentations, we demonstrate a plug-and-play bioproduction platform, culminating in the generation of 26 distinct halogenated molecules produced de novo including precursors to prodrugs 4-chloro- and 4-bromo-kynurenine and new-to-nature halogenated beta carbolines.

Microbial communities play a crucial role in the physiology of animal hosts; however, little is known about bacterial symbionts with the group cephalopods, specifically octopuses, and the function of these symbionts. The goal of this study was to determine if octopuses have a unique skin microbiome. The skin microbiome of two sympatric octopuses (Octopus vulgaris and Macrotritopus defilippi) was compared with the surrounding environment, sediment and seawater, to determine if octopus have a unique skin microbiome. High throughput sequencing of the bacterial 16S rRNA gene (V3-V4 region) amplicons was performed using an Illumina MiSeq. Sediment showed the greatest alpha diversity followed by octopus then seawater. Beta diversity revealed a difference in microbial composition between the octopus skin microbiome and sediment and seawater. While phylum Bacteroidetes appeared rare in environmental samples, it was most abundant for the octopus skin microbiome with the majority of the bacteria comprising the family Flavobacteriaceae. Proteobacteria, the largest group of bacteria, also constituted the octopus skin microbiome. Many of these groups occur on both octopus species; however, certain taxa differed in relative abundance between octopus species and may show species-specific host selection. Several bacteria that were identified for the octopus skin microbiome have been isolated from other marine animal hosts, identified as biodegraders and/or produce pigments and squalene, or act as predators of other bacteria. These groups may play a role in defense against environmental stressors or pathogenic bacteria. This is the first study to characterize the skin microbiome in two wild sympatric octopuses. Due to the importance of bacterial symbionts, this can provide insight to the physiology, behavior, ecology, and ultimately the health of these important animals in marine environments as well as care in captive or laboratory settings.

Body image disturbance is a both a risk factor for, and a symptom of, many eating disorders and refers to the misperception of and dissatisfaction with one's own body. Women with high body dissatisfaction have been shown to direct more attention to low body mass index (BMI) bodies, which results in the overestimation of body size via body size adaptation. Therefore, attention may have a causal role in body image disturbance. We conducted a novel training visual search task with 142 young adult women who we trained to attend to either high or low BMI bodies. We assessed the effects of this training on attention to bodies of different sizes, body size adaptation, and body dissatisfaction. Women trained to attend to low BMI bodies decreased their perceptions of a ‘normal’ body size via adaptation from pre- to post-training (p < 0.001); however, women trained to attend to high BMI bodies showed no change in their perception of a ‘normal’ body size. We found no lasting effects of the training on attention to body size or body dissatisfaction; however, our visual search task showed poor internal consistency as a measure of attention. These findings indicate that attention to low BMI bodies may exacerbate body image disturbance in women. However, more reliable measures of attentional are required to confirm this finding.

Summary: The oxytocinergic system has been suggested to make up an important part of the endocrine basis of group cohesion. However, controlled studies in open-group settings have not been performed. We here investigated the impact of exogenous intranasal oxytocin on the group-level social organization of 5 groups of horses (N = 58; 12 mares and 46 geldings) through GPS tracking and social network analysis. We find oxytocin flattened social differentiation across levels. Most strikingly, oxytocin did not simply reinforce existing bonds but selectively shifted social preferences toward homogenization – individuals and pairs who otherwise rarely associated spent more time close together, while individuals and pairs with the highest baseline association instead spent more time further apart. This resulted in a more distributed structure and lower clustering coefficient at the network level. These effects reinforce and extend oxytocin’s role in collective behavior, social organization, and the evolution of group-based sociality across taxa.

Ultrasound imaging can be used as an effective tool to measure the reproductive status and condition of sharks. This usually requires restraint of the subject, which is not feasible in the wild when the target species is of conservation concern and very large, as is the case for whale sharks. Our study invoked a behavioral response in free-swimming whale sharks that allowed snorkelers to image internal organs and structures using a submersible ultrasound scanner linked to an iPhone in an underwater housing. We were able to reliably locate and monitor the heart and other internal organs inside the body cavity, structures inside the head, and image skin and muscle in the dorsal surface of the sharks. The technique is evaluated as a means for assessing the condition and reproductive status of free-swimming whale sharks.

Abstract Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

Abstract Glycoproteins in urine have the potential to provide a rich class of informative molecules for studying human health and disease. Despite this promise, the urine glycoproteome has been largely uncharacterized. Here, we present the analysis of glycoproteins in human urine using LC–MS/MS-based intact glycopeptide analysis, providing both the identification of protein glycosites and characterization of the glycan composition at specific glycosites. Gene enrichment analysis reveals differences in biological processes, cellular components, and molecular functions in the urine glycoproteome versus the urine proteome, as well as differences based on the major glycan class observed on proteins. Meta-heterogeneity of glycosylation is examined on proteins to determine the variation in glycosylation across multiple sites of a given protein with specific examples of individual sites differing from the glycosylation trends in the overall protein. Taken together, this dataset represents a potentially valuable resource as a baseline characterization of glycoproteins in human urine for future urine glycoproteomics studies.

Abstract Problematic substance use and addiction is a growing crisis in the United States. As a result, identifying factors that effectively promote addiction recovery is, currently, of particular societal importance. Informed by evidence that—while addiction can be perpetuated by stress-related impulsivity and decreased self-regulation—perceived social support is protective against addiction, we test a model for addiction recovery as a form of posttraumatic growth (PTG), focused specifically on close relationships and personal strength—two domains of PTG. In an initial study, we found that perceived social support and impulsivity predicted number of relapses in individuals in a substance use disorder recovery program. Using experience sampling, we then observed that experiencing a stressful event predicted impulsive behavior. However, experiencing closeness with others—a domain of PTG—was directly associated with perceived social support, and both predicted positive emotional states, which were, in turn, inversely associated with experiencing a stressful event. Further, when experiencing a stressful event, personal strength—also a domain of PTG—was inversely associated with impulsive behavior and was predicted by both perceived social support and positive emotional states. Finally, in a follow-up experiment, we found that an ecological momentary intervention targeting perceived social support decreased impulsivity and increased self-regulation—an aspect of personal strength—in a dose-dependent fashion. Taken together, our findings: (1) support a PTG model for recovery; (2) provide evidence for processes by which close supportive relationships are protective against addiction and relapse; and (3) indicate that self-regulation is responsive to a short in-the-moment perceived social support intervention. We suggest that these findings support the theory that addiction is a social disease in the sense that close personal interactions and supportive relationships: (a) buffer against stress-related impulsivity, thereby protecting against addiction and relapse; and (b) increase personal strength, thereby decreasing the probability of impulsive—including addictive—behavior and promoting recovery.

Abstract The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.