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Quantum phases of solid-state electron systems can sustain exotic phenomena and a very rich spin physics. We utilize model-solid theory to show that Ge_{1−x}Sn_{x} alloys, an emerging group IV semiconductor, can be engineered into heterostructures that demonstrate a broken-gap alignment. Furthermore, the eight-band k·p method is used to disclose a quantum spin Hall phase in heterojunctions that accommodates the existence of gate-controlled chiral edge states. This proposal introduces a practical silicon-based architecture that spontaneously sustains topological properties, while being compatible with the high-volume manufacture of semiconductor technologies.

Introduction Frailty is defined as a clinical syndrome that encompasses a combination of decreased physiological reserve and low resistance to stressors. There is an association between mental illness and frailty among elderly cohorts. Frailty is also associated with obesity and smoking. There are high rates of treatment resistant schizophrenia among patients in secure forensic services. Patients with schizophrenia have high rates of morbidity and early mortality. Objectives The primary aim of this study was to examine the rates of frailty present in a complete cohort of forensic in-patients. Methods An assessment using Fried Frailty criteria was offered to all in-patients (n=95) in Ireland’s National Forensic Service, which included measures of walking speed, grip strength, low physical activity and exhaustion. Demographic details and details pertaining to diagnoses and medications were also gathered. Results Of the 95 in-patients, 92 patients agreed to participate. The majority were male (89%). The most common diagnosis was schizophrenia (71.7%). Mean age was 44.7 years (SD 11.42), and 58.2% met criteria for obesity. Of the total group, 47 patients met criteria for ‘pre-frail’ and 10 met criteria for ‘frail’ using Fried criteria. Conclusions This is the first study examining frailty in a cohort of patients in secure forensic settings. We found high rates of patients meeting frailty criteria at very young ages. Rates of frailty in this group were comparable to those found amongst elders in community settings. We consider this demonstrates significant medical vulnerability in this patient group. Disclosure No significant relationships.

A new generation of science curriculum materials is being developed and made widely available across K-12. These materials, along with their associated professional learning, are expected to play a pivotal role in transforming science instruction to meet the vision of A Framework for K-12 Science Education and the performance expectations of the Next Generation Science Standards. This study investigated one of the first widely available middle school curriculum programs designed for the NGSS, Amplify Science 6-8. The study team conducted a randomized experiment to examine the implementation and efficacy of the middle school curriculum program (materials plus teacher professional learning) for improving seventh grade students' learning in physical science. Findings show that students in schools where the program was implemented significantly outperformed peers in the comparison condition on an NGSS-focused physical science assessment. These findings underscore the importance of conducting additional research on NGSS-designed curriculum programs across other grade levels and within different science domains.

Abstract Microbial processing of atmospheric nitrogen (N) deposition regulates the retention and mobilization of N in soils, with important implications for water quality. Understanding the links between N deposition, microbial communities, N transformations, and water quality is critical as N deposition shifts toward reduced N and remains persistently high in many regions. Here, we investigated these connections along an elevation transect in the Colorado Front Range. Although rates of N deposition and pools of extractable N increased down the elevation transect, soil microbial communities and N transformation rates did not follow clear elevational patterns. The subalpine microbial community was distinct, corresponding to a high C:N ratio and low pH, while the microbial communities at the lower elevation sites were all very similar. Net nitrification, mineralization, and nitrification potential rates were highest at the Plains (1,700 m) and Montane (2,527 m) sites, suggesting that these ecosystems mobilize N. In contrast, the net immobilization of N observed at the Foothills (1,978 m) and Subalpine (3,015 m) sites suggests that these ecosystems retain N deposition. The contrast in N transformation rates between the plains and foothills, both of which receive elevated N deposition, may be due to spatial heterogeneity not captured in this study and warrants further investigation. Stream N concentrations from the subalpine to the foothills were consistently low, indicating that these soils are currently able to process and retain N deposition, but this may be disrupted if drought, wildfire, or land‐use change alter the ability of the soils to retain N.

Introduction: Guidelines regarding postsurgical dental care have been common in adult total joint arthroplasty patients despite limited supporting evidence in the literature. There is anecdotal evidence that similar precautions are implemented frequently in postoperative pediatric orthopaedic patients without any published evidence to guide clinicians. Methods: A survey of the Active Members of the Pediatric Orthopaedic Society of North America (POSNA) was performed to assess the use of postsurgical guidelines regarding dental care (procedures and prophylaxis) in pediatric patients. A 20-question survey regarding this subject was developed with the input of, and approved by, the Evidence-Based Practice Committee of POSNA, and a link to participate was distributed to the Active Membership. Results: One hundred seventy-three POSNA Members opened the link to the survey. One hundred sixty-three respondents self-identified as Active, for a response rate of 19.8%. One hundred fifty-seven (96.3%) reported direct involvement in surgical and postsurgical care of pediatric orthopaedic patients. Sixty-two (39.4%) indicated use of a postoperative protocol regarding dental interventions. Forty percent of those indicating use of guidelines were uncertain of the specifics of the protocol(s) used at their institution. Eighty-five percent of those utilizing protocols felt that the use of guidelines was a valuable topic for investigation. Conclusions: These results demonstrate that many of the active Members of POSNA utilize postsurgical guidelines for dental care, particularly for those patients who have undergone spinal surgery with permanent implants. This is despite the fact that there is limited evidence to support their use in adult total joint patients and no literature regarding use of such guidelines in pediatric orthopaedic patients. Key Concepts: (1) There is limited and contradictory evidence that postsurgical dental guidelines are indicated in adult orthopaedic patients. (2) There is no published evidence supporting postsurgical dental guidelines in pediatric orthopaedic patients. (3) Almost 40% of active Pediatric Orthopaedic Society of North America Members responding to a survey appear to utilize postsurgical dental care guidelines in pediatric patients, particularly after spinal procedures utilizing implants. Level of Evidence: Level V

This study focusses on knowledge absorption in SMEs and their abilities to develop innovations. It does so by examining SMEs in three different economic sectors, namely, manufacturing, high-tech and services. In doing so it provides one of the first comparative studies of SMEs within these different sectors. It also examines variations by place and compares the performance of SMEs across four distinct places within the UK. The research is based around both a quantitative analysis of firm performances followed by a detailed in-depth qualitative study. Our results focussed on the stages of knowledge transfer from acquisition, assimilation, through to the transformation and exploitation of knowledge. The findings draw attention to the significance. of management practices within SMEs and recognised the importance of open innovation. The study indicates that place alone does not play a key role, compared with the industry sector.

Iron Age settlement in Wales is dominated by defended settlements, ranging in size from large multivallate hillforts to small farmsteads protected by a simple bank and ditch. There are a total of 787 defended settlements in southwest Wales (Carmarthenshire, Ceredigion and Pembrokeshire) alone, which include 59 definite or possible hillforts, 166 definite or possible promontory forts and 562 definite or possible defended enclosures. This short article summarises the results of several years' survey, during which all those defended settlement sites that had no statutory protection as Scheduled Ancient Monuments were visited and recorded, and one in ten scheduled sites were visited. A list of all sites, including those that are Scheduled Ancient Monuments, is presented in an appendix. It is not possible in such a short article to provide a complete analysis and synthesis of Iron Age settlement in southwest Wales, but the results of the survey are presented in as concise a form as possible, using tables and distribution maps accompanied by a short commentary and some contextual information.

Brain health is largely dependent on the metabolic regulation of amino acids. Brain injuries, diseases, and disorders can be detected through alterations in free amino acid (FAA) concentrations; and thus, mapping the changes has high diagnostic potential. Common methods focus on optimizing neurotransmitter quantification; however, recent focus has expanded to investigate the roles of molecular precursors in brain metabolism. An isocratic method using high performance liquid chromatography with electrochemical cell detection was developed to quantify a wide range of molecular precursors and neurotransmitters: alanine, arginine, aspartate, serine, taurine, threonine, tyrosine, glycine, glutamate, glutamine, and γ-Aminobutyric acid (GABA) following traumatic brain injury. First, baseline concentrations were determined in the serum, cerebrospinal fluid, hippocampus, cortex, and cerebellum of naïve male Sprague Dawley rats. A subsequent study was performed investigating acute changes in FAA concentrations following blast-induced traumatic brain injury (bTBI). Molecular precursor associated FAAs decreased in concentration at 4 h after injury in both the cortex and hippocampus while those serving as neurotransmitters remained unchanged. In particular, the influence of oxidative stress on the observed changes within alanine and arginine pathways following bTBI should be further investigated to elucidate the full therapeutic potential of these molecular precursors at acute time points.

Abstract Here, we describe a new national tide gauge‐based sea level dataset for monitoring sea level changes around Australia, and the novel homogenization methodology used to develop it. Homogenization is a two‐step process that involves the detection of jumps or steps in the data (inhomogeneities) followed by a correction applied to remove the change. This new dataset is called the Australian National Collection of Homogenized Observations of Relative Sea Level (ANCHORS). ANCHORS provides coastal sea levels at hourly resolution with homogenization performed on annual means. ANCHORS is intended to be a national tide gauge‐based sea level dataset to monitor changes in mean sea level and resultant coastal flood frequency changes around Australia. Whilst sea levels are rising around Australia in response to global mean sea level changes, coastal water levels represent a notable gap in the suite of in situ high‐quality datasets available for researchers, governments and industry. Tide gauge datasets are well suited to impact‐based assessments of changes in flood frequency, duration and risk. In this regard, ANCHORS will sit alongside existing satellite‐ and numerical modelling‐based sea level datasets to provide enhanced insights into the physical impacts of sea level rise on Australian coastlines. We have adapted established homogenization techniques to develop a national collection of homogenous long tide gauge records. The dataset comprises 38 tide gauge records from around Australia, varying in length from 34 to 123 years, with an average of 57 years. Finally, we discuss limitations and potential applications for ANCHORS and how these have informed the design of this coastal sea level dataset.

Abstract Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784

Abstract We present the first global estimates of annual average exceedances of contemporary minor, moderate, and major flood levels under sea‐level rise (SLR). Applying established methods, we show that minor flooding will occur most days worldwide under 0.7 m global SLR. Moderate flooding occurs at the same frequency under 1.0 m SLR. Local and regional differences in flood threshold elevations, tidal ranges, and non‐tidal variability lead to differences in the SLR required for this chronic flooding to emerge. Lower flood thresholds, smaller tidal ranges, and larger extreme skew surges mean chronic flooding can emerge with less SLR. We discuss several implications of these findings for coastal flood hazard assessments. First, tide‐driven water level variability dominates weather‐driven water level variability when determining locations' propensities for frequent and chronic flooding under SLR. Second, centimeter‐accurate flood threshold information is necessary to accurately estimate present and future flood hazards. Third, locations with the most frequent floods at present may not be those that have the most frequent floods under SLR. We develop the Rapid Assessment Framework for Frequent Flood Transitions under SLR (RAFFFTS) to apply these findings to locations not previously considered in global coastal flood hazard studies. RAFFFTS can robustly identify potential future tidal flooding hotspots using only 1‐year observational records. We anticipate RAFFFTS will be a valuable tool for identifying locations at risk of chronic flooding under SLR, complementing existing tools for identifying changes in less frequent episodic floods.

BackgroundMicrobial dysbiosis in infancy can influence long-term health outcomes such as childhood obesity. The aim of this study is to explore relationships among maternal well-being during pregnancy, breastfeeding, and the infant gut microbiome.MethodsThis is a secondary analysis of healthy pregnant women from the MicrobeMom study, a double-blind randomized control trial of maternal probiotic supplementation (Bifidobacterium breve 702258) versus placebo antenatally and up to 3 months postpartum. Maternal well-being was assessed using the WHO-5 well-being index at 16 weeks’ and 34 weeks’ gestation. Breastfeeding practices were recorded at discharge from hospital and at 1 month postpartum. Infant stool samples were obtained at 1 month of age. Next generation shotgun sequencing determined infant microbial diversity. Independent sample t-tests and Mann-Whitney U tests informed adjusted regression analysis, which was adjusted for delivery mode, antibiotics during delivery, maternal age and body mass index (BMI), and probiotic vs. control study group.ResultsWomen (n = 118) with at least one measure of well-being were on average 33 years (SD 3.93) of age and 25.09 kg/m2 (SD 3.28) BMI. Exclusive breastfeeding was initiated by 65% (n = 74). Any breastfeeding was continued by 69% (n = 81) after 1 month. In early and late pregnancy, 87% (n = 97/111) and 94% (n = 107/114) had high well-being scores. Well-being was not associated with infant microbial diversity at 1 month. In adjusted analysis, exclusive breastfeeding at discharge from hospital was associated with infant microbial beta diversity (PC2; 0.254, 95% CI 0.006, 0.038). At 1 month postpartum, any breastfeeding was associated with infant microbial alpha diversity (Shannon index; −0.241, 95% CI −0.498, −0.060) and observed species; (−0.325, 95% CI −0.307, −0.060), and infant microbial beta diversity (PC2; 0.319, 95% CI 0.013, 0.045). Exclusive breastfeeding at 1 month postpartum was associated with infant alpha diversity (Shannon index −0.364, 95% CI −0.573, −0.194; Simpson index 0.339, 95% CI 0.027, 0.091), and infant’s number of observed microbial species (−0.271, 95% CI −0.172, −0.037).ConclusionBreastfeeding practices at 1 month postpartum were associated with lower microbial diversity and observed species in infants at 1 month postpartum, which is potentially beneficial to allow greater abundance of Bifidobacterium.Clinical trial registrationISRCTN53023014.

Mycotic pseudoaneurysms (PA) are an infrequent complication of infective endocarditis (IE). However, due to advanced imaging modality and early therapy, this complication has been seen less frequently in the past few years. The reported incidence is 5%–15% of the patients, with the most common site being intracranial vessels (up to 65%), followed by abdominal and then peripheral vessels. We describe a young patient with a bicuspid aortic valve complicated by IE, who developed a giant mycotic PA. This was treated with a cover stent of the aneurysmal segment, which was complicated by distal stent migration and eventually managed with bypass surgery.

The human microbiome has emerged as an intriguing field of scientific research. Its role in human physiology impacts both health and disease, contributing to the enhancement or impairment of metabolic and immune functions. Sometimes referred to as our body’s “second genome”, the alteration of the microbiome’s bacterial ecology (dysbiosis), is linked to increasing numbers of illnesses, including cancer. The tumor microenvironment (TME) is the environment in which tumors grow and modulate the tumorigenic process depending on a myriad of distinct factors, including cell types, vascular system, and cytokines. Given the emerging relationship between the microbiome and the TME, this perspective aims to distill some of the key factors regulating the crosstalk between the microbiome and the TME. It also outlines why manipulating the microbiome may be a feasible strategy for anti-cancer therapy.

The effects of fertiliser from intensive agriculture are well recognised, but not so well for fine-sediment. Here we show how widespread ingress of agriculturally derived fine-sediment since the 1940s markedly amplifies methane emissions from streams.

Extreme rainfall in Puerto Rico leads to some of the highest particulate organic carbon yields. Here the authors find that global estimates of carbon export may be underestimated by up to 9% because of a lack of studies in the tropics.

Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.

Wildfires pose a risk to water supplies in the western U.S. and many other parts of the world, due to the potential for degradation of water quality. However, a lack of adequate data hinders prediction and assessment of post-wildfire impacts and recovery. The dearth of such data is related to lack of funding for monitoring extreme events and the challenge of measuring the outsized hydrologic and erosive response after wildfire. Assessment and prediction of post-wildfire surface water quality would be strengthened by the strategic monitoring of key parameters, and the selection of sampling locations based on the following criteria: (1) streamgage with pre-wildfire data; (2) ability to install equipment that can measure water quality at high temporal resolution, with a focus on storm sampling; (3) minimum of 10% drainage area burned at moderate to high severity; (4) lack of major water management; (5) high-frequency precipitation; and (6) availability of pre-wildfire water-quality data and (or) water-quality data from a comparable unburned basin. Water-quality data focused on parameters that are critical to human and (or) ecosystem health, relevant to water-treatment processes and drinking-water quality, and (or) inform the role of precipitation and discharge on flow paths and water quality are most useful. We discuss strategic post-wildfire water-quality monitoring and identify opportunities for advancing assessment and prediction. Improved estimates of the magnitude, timing, and duration of post-wildfire effects on water quality would aid the water resources community prepare for and mitigate against impacts to water supplies.

Summary: Background and Aims: Oesophagectomy is the primary curative treatment for oesophageal cancer but is associated with considerable postoperative morbidity and mortality. To better understand the aetiology of impaired health-related quality of life (HRQL) in oesophageal cancer survivors (OCS), this study sought to determine the longitudinal changes in nutritional status, nutrition-impact symptoms (NIS), and HRQL in this cohort, and to determine which variables have the greatest impact on postoperative HRQL decline. Methods: Data, derived from St. James' Hospital, Dublin, included patients who underwent oesophagectomy from October 2017 to May 2019 and attended clinic preoperatively and 6 months postoperatively. A subset attended a further 12-month appointment. HRQL and symptom data were collected using validated questionnaires and anthropometric measures were completed by clinicians. Data were analysed using SPSS. Results: A total of 66 patients were studied preoperatively and 6 months postoperatively, of whom 37 were studied at 12 months postoperatively. Malnutrition remained prevalent at each time-point, although rates did not significantly change longitudinally. Conversely, the prevalence of malabsorption (7.6%–14.3%, P

Abstract Wildfire is a growing concern as climate shifts. The hydrologic effects of wildfire, which include elevated hazards and changes in water quantity and quality, are increasingly assessed using numerical models. Post‐wildfire application of physically based distributed models provides unique insight into the underlying processes that affect water resources after wildfire. This work reviews and synthesizes post‐wildfire applications of physically based distributed models by examining the scales and geographic/ecohydrologic distribution of model applications, hydrologic response process representation, model parameterization, and model performance metrics. Highlighted gaps and opportunities for advancing physically based distributed hydrologic response modeling after wildfire include the following: (a) applying models in under‐represented geographic (S. America, Africa, Asia) and ecohydrologic regions (arid or dry subhumid climates), (b) incorporating all four major streamflow generation mechanisms (infiltration excess, saturation excess, subsurface storm flow, and groundwater flow), (c) representing integrated vadose zone and saturated zone processes to better capture subsurface streamflow generation, (d) building new remotely sensed model parameterization methods for precipitation interception, infiltration, and overland flow that account for burn severity and recovery, (e) incorporating distributed state variables (e.g., soil moisture, groundwater levels) in model performance assessment, (f) designing model intercomparison studies, including field datasets specifically for post‐wildfire model development and validation, (g) linking mechanistic vegetation regrowth models with hydrologic models to improve simulation of process shifts as ecosystems recover, and (h) creating a new community modeling framework to integrate modeling advances across the wildfire science community.

Rhinovirus causes many types of respiratory illnesses, ranging from minor colds to exacerbations of asthma. Moraxella catarrhalis is an opportunistic pathogen that is increased in abundance during rhinovirus illnesses and asthma exacerbations and is associated with increased severity of illness through mechanisms that are ill-defined. We used a co-infection model of human airway epithelium differentiated at the air-liquid interface to test the hypothesis that rhinovirus infection promotes M. catarrhalis adhesion and survival on the respiratory epithelium. Initial experiments showed that infection with M. catarrhalis alone did not damage the epithelium or induce cytokine production, but increased trans-epithelial electrical resistance, indicative of increased barrier function. In a co-infection model, infection with the more virulent rhinovirus-A and rhinovirus-C, but not the less virulent rhinovirus-B types, increased cell-associated M. catarrhalis. Immunofluorescent staining demonstrated that M. catarrhalis adhered to rhinovirus-infected ciliated epithelial cells and infected cells being extruded from the epithelium. Rhinovirus induced pronounced changes in gene expression and secretion of inflammatory cytokines. In contrast, M. catarrhalis caused minimal effects and did not enhance RV-induced responses. Our results indicate that rhinovirus-A or C infection increases M. catarrhalis survival and cell association while M. catarrhalis infection alone does not cause cytopathology or epithelial inflammation. Our findings suggest that rhinovirus and M. catarrhalis co-infection could promote epithelial damage and more severe illness by amplifying leukocyte inflammatory responses at the epithelial surface.

Background:: The field of tissue engineering has provided valuable three-dimensional species-specific models of the human myocardium in the form of human Engineered Cardiac Tissues (hECTs) and similar constructs. However, hECT systems are often bottlenecked by a lack of openly available software that can collect data from multiple tissues at a time, even in multi-tissue bioreactors, which limits throughput in phenotypic and therapeutic screening applications. Methods:: We developed Rianú, an open-source web application capable of simultaneously tracking multiple hECTs on flexible end-posts. This software is operating system agnostic and deployable on a remote server, accessible via a web browser with no local hardware or software requirements. The software incorporates object-tracking capabilities for multiple objects simultaneously, an algorithm for twitch tracing analysis and contractile force calculation, and a data compilation system for comparative analysis within and amongst groups. Validation tests were performed using in-silico and in-vitro experiments for comparison with established methods and interventions. Results:: Rianú was able to detect the displacement of the flexible end-posts with a sub-pixel sensitivity of 0.555 px/post (minimum increment in post displacement) and a lower limit of 1.665 px/post (minimum post displacement). Compared to our established reference for contractility assessment, Rianú had a high correlation for all parameters analyzed (ranging from R2=0.7514 to R2=0.9695), demonstrating its high accuracy and reliability. Conclusions:: Rianú provides simultaneous tracking of multiple hECTs, expediting the recording and analysis processes, and simplifies time-based intervention studies. It also allows data collection from different formats and has scale-up capabilities proportional to the number of tissues per field of view. These capabilities will enhance throughput of hECTs and similar assays for in-vitro analysis in disease modeling and drug screening applications.

T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct, with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation.

Abstract Obesity and its sequelae have a major impact on human health. The stomach contributes to obesity in ways that extend beyond its role in digestion, including through effects on the microbiome. Gastrokine-1 (GKN1) is an anti-amyloidogenic protein abundantly and specifically secreted into the stomach lumen. We examined whether GKN1 plays a role in the development of obesity and regulation of the gut microbiome. Gkn1−/− mice were resistant to diet-induced obesity and hepatic steatosis (high fat diet (HFD) fat mass (g) = 10.4 ± 3.0 (WT) versus 2.9 ± 2.3 (Gkn1−/−) p

Spitz neoplasms are a diverse group of molecularly and histologically defined melanocytic tumors with varying biologic potentials. The precise classification of Spitz neoplasms can be challenging. Recent studies have revealed recurrent fusions involving multiple kinases in a large proportion of Spitz tumors. In this study, we generated a transgenic zebrafish model of Spitz melanoma using a previously identified ZCCHC8-ROS1 fusion gene. Animals developed grossly apparent melanocytic proliferations as early as 3 weeks of age and overt melanoma as early as 5 weeks. By 7 weeks, ZCCHC8-ROS1 induced a histologic spectrum of neoplasms ranging from hyperpigmented patches to melanoma. Given the swift onset of these tumors during development, we extended this approach into adult fish using a recently described electroporation technique. Tissue-specific expression of ZCCHC8-ROS1 in adults led to melanocyte expansion without overt progression to melanoma. Subsequent electroporation with tissue-specific CRISPR, targeting only tp53 was sufficient to induce transformation to melanoma. Our model exhibits the use of sequential mutagenesis in the adult zebrafish, and demonstrates that ZCCHC8-ROS1 induces a spectrum of melanocytic lesions that closely mimics human Spitz neoplasms.

Abstract As humans increasingly dominate the nitrogen cycle, deposition of reactive nitrogen (Nr) will continue to have adverse consequences for ecosystems. In the Rocky Mountains, Nr deposition remains elevated and has become increasingly dominated by ammonium, despite efforts to reduce emissions. Currently, spatial models of Nr deposition do not fully account for urban and agricultural emissions, sources that contribute to the observed high rates of ammonium deposition in adjacent ecosystems. To address this gap in the Colorado Front Range, we measured Nr deposition along a transect from urban and agricultural plains to subalpine forests. We found elevated values of wet Nr deposition at the urban and foothill sites (4.7 and 4.4 kg N ha−1 yr−1, respectively), and lower values at the montane and subalpine sites (2.5–2.8 kg N ha−1 yr−1). Ammonium dominated wet and bulk Nr deposition, accounting for approximately 69% of bulk Nr deposition. Seasonally, bulk Nr deposition was highest in the spring months, when air masses from the plains are transported west into the mountains. Previous work has demonstrated that high elevations of the Colorado Front Range are especially sensitive to Nr deposition due to thin soil and minimal vegetation. Our results indicate that despite lower precipitation, the fire‐prone forested foothills receive even greater Nr deposition than higher elevations, due to proximity to urban and agricultural Nr sources. The interaction between elevated Nr deposition and wildfire in this region may pose a risk to water supplies and ecosystems, and is an important topic for future research.

Abstract Shotgun metagenomic sequencing is a valuable tool for the taxonomic and functional profiling of microbial communities. However, this approach is challenging in samples, such as milk, where a low microbial abundance, combined with high levels of host DNA, result in inefficient and uneconomical sequencing. Here we evaluate approaches to deplete host DNA or enrich microbial DNA prior to sequencing using three commercially available kits. We compared the percentage of microbial reads obtained from each kit after shotgun metagenomic sequencing. Using bovine and human milk samples, we determined that host depletion with the MolYsis complete5 kit significantly improved microbial sequencing depth compared to other approaches tested. Importantly, no biases were introduced. Additionally, the increased microbial sequencing depth allowed for further characterization of the microbiome through the generation of metagenome-assembled genomes (MAGs). Furthermore, with the use of a mock community, we compared three common classifiers and determined that Kraken2 was the optimal classifier for these samples. This evaluation shows that microbiome analysis can be performed on both bovine and human milk samples at a much greater resolution without the need for more expensive deep-sequencing approaches.

Conserved Moraxella catarrhalis (Mcat) proteins, oligopeptide permease (Opp)A, hemagglutinin (Hag), outer membrane protein (OMP) CD, Pilin A clade 2 (PilA2), and Moraxella surface protein (Msp) 22 have been studied as vaccine candidates. Children who experience frequent acute otitis media (AOM) confirmed with pathogen identification by tympanocentesis are referred to as stringently-defined otitis prone (sOP). Synchrony of serum antibody responses against 5 Mcat proteins, OppA, Hag, OMP CD, PilA2, and Msp22 resulting from nasopharyngeal colonization and AOM was studied for 85 non-otitis prone (NOP) children and 34 sOP children. Changes in serum IgG were quantitated with ELISA. Serum IgG antibody levels against OppA, Hag, OMP CD, and Msp22 rose in synchrony in NOP and sOP children; that is, the proteins appeared equally and highly immunogenic in children at age 6 to 22–25 months old and then leveled off in their rise at 22–25 to 30 months old. In contrast, rises of PilA2 were slow from 6 months old and kept constant and did not level off significantly before 30 months old. OppA, Hag, OMP CD, and Msp22 elicited a synchronous acquisition of naturally-induced serum antibody in young children. A multi-valent Mcat protein vaccine combining OppA, Hag, OMP CD, and Msp22 may exhibit less antigen competition when administered as a combination vaccine in young children.

OBJECTIVES/GOALS: This study proposes a pragmatic approach for tracking institutional changes in research teamwork and productivity in real time using common institutional electronic databases such as eCV and grant management systems. Dissemination of this approach could provide a standard metric for comparing teamwork productivity across different programs. METHODS/STUDY POPULATION: This study tracks research teamwork and productivity using commonly available institutional electronic databases such as eCV and grant management systems. We tested several definitions of interdisciplinary collaborations based on number of collaborations and their fields of discipline. Publication characteristics were compared by faculty seniority and appointment type using non-parametric Wilcoxon Rank Sum Test (p RESULTS/ANTICIPATED RESULTS: Interdisciplinary grants constitute 24% of all grants but the trend has significantly increased over the last five years. Tenure track faculty collaborated with more organizations (3.5, SD 2.5 vs 2.3, SD 1.1, p DISCUSSION/SIGNIFICANCE: This study provides empirical evidence of the benefits of interdisciplinary collaboration in research and identifies an important role that senior faculty may be playing in creating the culture of interdisciplinary teamwork. More research is needed to improve efficiency of interdisciplinary collaborations.

A significant number of chronic venous ulcers (CVUs) fail to heal despite guideline-conform standards of care. Skin-derived ABCB5+ mesenchymal stem cells can dampen the sustained IL-1β‒driven inflammation present in chronic wounds. On the basis of their wound healing‒facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ mesenchymal stem cells have emerged as a potential candidate for cell-based advanced therapy of nonhealing CVUs. In this interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVUs had emerged as standard therapy resistant received one or two topical applications of 1 × 106 allogeneic ABCB5+ mesenchymal stem cells per cm2 wound area, in addition to standard treatment. Of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, n = 31), 78% (per-protocol set, n = 27), and 87% (subset of responders, n = 21). In conclusion, the study treatment was well-tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ mesenchymal stem cells as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.

The African American population of Buffalo, New York experiences striking race-based health disparities due to adverse social determinants of health. A team of community leaders and university faculty determined that a community dialogue was needed to focus research and advocacy on the root causes of these disparities. In response, we organized the annual Igniting Hope conference series that has become the premier conference on health disparities in the region. The series, now supported by an R13 conference grant from NCATS, has been held four times (2018–2021) and has attracted community members, community leaders, university faculty, and trainees. The agenda includes talks by national leaders and breakout/working groups that led to a new state law that has reduced disproportionate traffic-ticketing and drivers' license suspensions in Black neighborhoods; mitigation of the disproportionate COVID-19 fatalities in Black communities; and the launching of a university-supported institute. We describe the key elements of success for a conference series designed by a community–university partnership to catalyze initiatives that are having an impact on social determinants of health in Buffalo.

Long-term neuropsychiatric impairments have become a growing concern following blast-related traumatic brain injury (bTBI) in active military personnel and Veterans. Neuropsychiatric impairments such as anxiety and depression are common comorbidities that Veterans report months, even years following injury. To understand these chronic behavioral outcomes following blast injury, there is a need to study the link between anxiety, depression, and neuropathology. The hippocampus and motor cortex (MC) have been regions of interest when studying cognitive deficits following blast exposure, but clinical studies of mood disorders such as major depressive disorder (MDD) report that these two regions also play a role in the manifestation of anxiety and depression. With anxiety and depression being common long-term outcomes following bTBI, it is imperative to study how chronic pathological changes within the hippocampus and/or MC due to blast contribute to the development of these psychiatric impairments. In this study, we exposed male rats to a repeated blast overpressure (~17 psi) and evaluated the chronic behavioral and pathological effects on the hippocampus and MC. Results demonstrated that the repeated blast exposure led to depression-like behaviors 36 weeks following injury, and anxiety-like behaviors 2-, and 52-weeks following injury. These behaviors were also correlated with astrocyte pathology (glial-fibrillary acid protein, GFAP) and dendritic alterations (Microtubule-Associated Proteins, MAP2) within the hippocampus and MC regions at 52 weeks. Overall, these findings support the premise that chronic glial pathological changes within the brain contribute to neuropsychiatric impairments following blast exposure.

The purpose of this study is to comprehensively review the extant literature on the application of management accounting practices (MAPs) to the sustainable development of family businesses (FBs), and to identify future research avenues. Academic interest in the field of MAPs in family businesses as well as the concept of sustainable development has been growing rapidly due to the fast-moving business landscape associated with environmental dynamism, particularly over the past two decades. Consequently, some authors claim that the heterogeneous characteristics of FBs apparently lead to a lower degree of information asymmetry, and that this, in-turn, may weaken the need for MAPs. On the other hand, some studies emphasise that the distinctive conflicts of interest in FBs and some contingent factors (for example, intense competition in the industry) are triggers for the adoption of MAPs by FBs. Given these mixed research outcomes and the absence of a comprehensive study that demonstrates the state-of-the-art in this research stream, this paper aims to review previously reported key works to thoroughly investigate the above mentioned factors with a view to exploring the existing knowledge gap. The holistic conclusion arrived at by the study points to the fact that there seems to have a considerable impact of family involvement on business performance achieved through the application of MAPs. Nonetheless, the impact of certain heterogeneous characteristics of FBs on the application of environmental management accounting (EMA) practices, which is a sub-stream of MAPs, is yet to be explored.

BackgroundThe Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial.MethodsPatients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA).ResultsThirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p

Abstract Background Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs) on contractile function of human engineered cardiac tissues (hECTs) as a species-specific model of the human myocardium. Methods Human induced pluripotent stem cell-derived cardiomyoctes (hCMs) were mixed with Collagen/Matrigel to fabricate control hECTs, with an experimental group of hCSC-supplemented hECT fabricated using a 9:1 ratio of hCM to hCSC. Functional testing was performed starting on culture day 6, under spontaneous conditions and also during electrical pacing from 0.25 to 1.0 Hz, measurements repeated at days 8 and 10. hECTs were then frozen and processed for gene analysis using a Nanostring assay with a cardiac targeted custom panel. Results The hCSC-supplemented hECTs displayed a twofold higher developed force vs. hCM-only controls by day 6, with approximately threefold higher developed stress and maximum rates of contraction and relaxation during pacing at 0.75 Hz. The spontaneous beat rate characteristics were similar between groups, and hCSC supplementation did not adversely impact beat rate variability. The increased contractility persisted through days 8 and 10, albeit with some decrease in the magnitude of the difference of the force by day 10, but with developed stress still significantly higher in hCSC-supplemented hECT; these findings were confirmed with multiple hCSC and hCM cell lines. The force-frequency relationship, while negative for both, control (− 0.687 Hz− 1; p = 0.013 vs. zero) and hCSC-supplemented (− 0.233 Hz− 1;p = 0.067 vs. zero) hECTs, showed a significant rectification in the regression slope in hCSC-supplemented hECT (p = 0.011 vs. control). Targeted gene exploration (59 genes) identified a total of 14 differentially expressed genes, with increases in the ratios of MYH7/MHY6, MYL2/MYL7, and TNNI3/TNNI1 in hCSC-supplemented hECT versus controls. Conclusions For the first time, hCSC supplementation was shown to significantly improve human cardiac tissue contractility in vitro, without evidence of proarrhythmic effects, and was associated with increased expression of markers of cardiac maturation. These findings provide new insights about adult cardiac stem cells as contributors to functional improvement of human myocardium.