Search

Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.

Abstract Background Many ecologically and commercially important species occur in the epipelagic marine environment and have been observed to spend a considerable amount of time associating with surface structure. The bottom depth of this habitat often exceeds transmission (~ 500-1000 m) and receiver (500–750 m) range specifications for commonly used acoustic telemetry methods that rely on an array of receivers deployed on the seafloor with overlapping fields of detection to provide positioning of acoustically tagged individuals. This poses logistical challenges for tracking the fine-scale movements, behaviors, and associations to moored and free-floating structure of these species. Acoustic telemetry can provide high resolution positioning data for tagged animals within an array of receivers with overlapping fields of detection; however, this technique has not been applied in deep open-ocean environments off the benthos. Results Herein, we detail the development of a novel vertical acoustic telemetry array that can be mounted on, or suspended from, various moored and free-floating structures in the open ocean, thus facilitating high resolution tracking of structure-associated epipelagic animals. This new ‘vertical acoustic array’ (VAR) allows for the calculation of a transmitter’s distance from the array and depth with average error around these metrics ranging from 16.2 to 54.8 m (distance error) and 8.6 to 61.5 m (depth error) within the tested range (~ 500 m radius around the array, ~ 300 m deep). We also validated the ability of the VAR to inform the association of an epipelagic species to surface structure by calculating fine-scale positioning for a great barracuda around a fish aggregating device (FAD), which on average was 27.9 ± 2.9 m away at a depth of 9.3 ± 0.4 m over a 9-day tracking period, demonstrating high association with the structure. Conclusions This new array is able to provide two-dimensional (distance away and depth) animal behavior data around natural and anthropogenic moored and free-floating structures in open-ocean environments where bottom depths often exceed transmission (~ 1000 m) and receiver (~ 500 m) range specifications of traditional bottom moored positioning arrays. This array can also be used to quantitatively assess associations of epipelagic species beyond presence/absence using a single receiver, advancing the potential to improve understanding of the interactions between pelagic fauna and anthropogenic structures such as wind turbines, oil rigs, and fish aggregation devices.

Abstract Introduction Diarrhoeagenic Escherichia coli (DEC) persistently challenges public health in Africa, contributing substantially to the diarrhoeal disease burden. This systematic review and meta-analysis illuminate the distribution and antimicrobial resistance (AMR) patterns of DEC pathotypes across the continent. Methods The review selectively focused on pathotype-specific studies reporting prevalence and/or AMR of human-derived DEC pathotypes from African nations, excluding data from extra-intestinal, animal, and environmental sources and studies focused on drug and mechanism experiments. Pertinent studies were retrieved from SCOPUS, PubMed, and EBSCOhost, processed with Covidence, and screened in alignment with PRISMA guidelines. Results The reviewed studies were predominantly hospital-based (80%) and paediatric-focused (91%), with a meagre 4.4% documenting DEC outbreaks. Seven DEC pathotypes were discerned, with Enteroaggregative E. coli (EAEC) being notably prevalent (43%, 95% CI 30–55%) and Enteroinvasive E. coli (EIEC) least prevalent (24%, 95% CI 17–32%). Identified non-susceptibilities were noted against essential antibiotics including ciprofloxacin, ceftriaxone, and ampicillin, while instances of carbapenem and Extended-Spectrum ß-Lactamase (ESBL) resistance were scarce. Conclusion Despite sporadic data on DEC prevalence and AMR in Africa, particularly in community settings, a palpable gap remains in real-time outbreak surveillance and comprehensive data documentation. Augmenting surveillance and embracing advancements in molecular/genomic characterisation techniques are crucial to precisely discerning DEC's actual impact and resistance continuum in Africa.

Summary: The role of genomics in public health surveillance has been accentuated by its crucial contributions during the COVID-19 pandemic, demonstrating its potential in addressing global disease outbreaks. While Africa has made strides in expanding multi-pathogen genomic surveillance, the integration into foodborne disease (FBD) surveillance remains nascent. Here we highlight the critical components to strengthen and scale-up the integration of whole genome sequencing (WGS) in foodborne disease surveillance across the continent. We discuss priority use-cases for FBD, and strategies for the implementation. We also highlight the major challenges such as data management, policy and regulatory frameworks, stakeholder engagement, the need for multidisciplinary collaborations and the importance of robust monitoring and evaluation, aiming to bolster Africa's preparedness and response to future health threats.

Introduction: As prevalence of patients with steatotic liver diseases increases throughout the world, it is necessary to have accurate and accessible methods to estimate liver fat content. Using quantitative ultrasound parameters, such as attenuation and backscatter, it is possible to estimate liver fat with MRI proton density fat fraction as the reference standard. Velacur determined fat fraction (VDFF) is a new output measurement on Velacur (Sonic Incytes Medical Corp, Vancouver, BC). Methods: This study described the results of parameter fitting and validation of VDFF, which is a combination of quantitative ultrasound parameters. Patients were recruited from sites within the US and Canada. All patients had contemporaneous Velacur and MRI proton density fat fraction scans. The quantitative ultrasound parameter fitting was completed using linear regression on a random sub-sample approach, and a separate cohort was used for validation. The AUC for detection of 5 % liver fat based on MRI-PDFF and the correlation between MRI-PDFF and VDFF was measured in both cohorts. Results: VDFF had an AUROC of 0.97 for the detection of MRI-PDFF >5 % in the parameter fitting cohort, and 0.99 in the validation cohort. The correlation [95 % CI] between MRI-PDFF and VDFF was r = 0.84 [0.78–0.89] for the parameter fitting cohort and r = 0.90 [0.82–0.95] for the validation cohort. Conclusion: The Velacur Determined Fat Fraction (VDFF) is an accurate and accessible way to estimate steatosis as measured by MRI-PDFF. Velacur VDFF can fill the unmet need of an accurate means to diagnosis hepatic steatosis and serve as a potential alternative to biopsy or MRI-PDFF.

Abstract In this study, optical photothermal infrared (O-PTIR) spectroscopy combined with machine learning algorithms were used to evaluate 46 tissue cores of surgically resected cervical lymph nodes, some of which harboured oral squamous cell carcinoma nodal metastasis. The ratios obtained between O-PTIR chemical images at 1252 cm−1 and 1285 cm−1 were able to reveal morphological details from tissue samples that are comparable to the information achieved by a pathologist’s interpretation of optical microscopy of haematoxylin and eosin (H&E) stained samples. Additionally, when used as input data for a hybrid convolutional neural network (CNN) and random forest (RF) analyses, these yielded sensitivities, specificities and precision of 98.6 ± 0.3%, 92 ± 4% and 94 ± 5%, respectively, and an area under receiver operator characteristic (AUC) of 94 ± 2%. Our findings show the potential of O-PTIR technology as a tool to study cancer on tissue samples.

Abstract Regulatory T cells (Tregs) are a type of lymphocyte that is key to maintaining immunological self-tolerance, with great potential for therapeutic applications. A long-standing challenge in the study of Tregs is that the only way they can be unambiguously identified is by using invasive intracellular markers. Practically, the purification of live Tregs is often compromised by other cell types since only surrogate surface markers can be used. We present here a non-invasive method based on Raman spectroscopy that can detect live unaltered Tregs by coupling optical detection with machine learning implemented with regularized logistic regression. We demonstrate the validity of this approach first on murine cells expressing a surface Foxp3 reporter, and then on peripheral blood human T cells. By including methods to account for sample purity, we could generate reliable models that can identify Tregs with an accuracy higher than 80%, which is already comparable with typical sorting purities achievable with standard methods that use proxy surface markers. We could also demonstrate that it is possible to reliably detect Tregs in fully independent donors that are not part of the model training, a key milestone for practical applications.

Abstract Background Anthrax is a non-contagious zoonotic disease caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. Infection is common in livestock and wild animals such as cattle, goats, sheep, camels, and antelopes. In humans, anthrax may occur after contact with contaminated carcasses or animal products like milk and meat. The best method to prevent anthrax in people is to ensure livestock are vaccinated, which significantly limits the risk of zoonotic spread to humans. However, the rate of vaccination of domesticated animals kept by nomadic pastoralists in West Africa is low. These groups regularly cross over national boundaries with their grazing herds. Nigeria is a country that historically has done comparatively well to contain this public health threat. However, in 2023 several outbreaks of human disease appear linked to the consumption of anthrax-contaminated animal products brought into Nigeria by pastoralists from neighboring countries. Clinical manifestations include skin sores or ulcers, nausea, vomiting, and fever. This article aims to raise awareness of recent outbreaks of anthrax in West Africa and to call for a renewed focus on measures to combat this neglected public health concern to the region. Main body The imperative to pinpoint pivotal issues relating to the ongoing emergence of anthrax cases in Nigeria cannot be overstated. By delving into the prevalence of anthrax in both livestock and human populations residing along Nigeria’s borders, unraveling the genetic diversity and potential sources of B. anthracis strains, and identifying the primary animal host(s) responsible for transmission, we stand to enhance our understanding of this critical issue. Furthermore, investigating the multifaceted factors contributing to anthrax transmission, assessing community knowledge and practices, mapping common migratory routes of pastoralists, and formulating targeted intervention strategies tailored to the challenges of border communities, are each crucial steps towards effective control and prevention. Conclusion Closing these knowledge gaps on anthrax is not only essential for safeguarding both animal and human health but also for fostering sustainable and resilient communities. Addressing research questions on these interdisciplinary concerns will undoubtedly pave the way for informed decision-making, proactive measures, and a more secure future for Nigeria and its border regions. Graphical Abstract

Objective: Families enrolled in the Supplemental Nutrition Assistance Program (SNAP) report persistent barriers to purchasing nutritious foods. This mixed-methods study explored SNAP users’ food and beverage purchasing patterns and perspectives regarding potential modifications to SNAP to inform the design of SNAP+, a healthy incentive program to increase fruit and vegetable (FV) and decrease sugar-sweetened beverage (SSB) purchases. Methods: Participants were recruited through a non-profit organizational network to participate in an online survey. Survey measures included: SNAP usage patterns, meal/shopping patterns, and perceptions of potential changes to SNAP. A subset (N = 28) was invited to participate in an interview to further explore these domains. Frequencies were calculated to explore trends in quantitative data, with thematic analysis applied to qualitative data. Results: Participants (N = 278) identified as female (81.0 %), head of household (90.8 %) and mothers (70.5 %), with most (66.5 %) using SNAP ≥ 1 year. Most spend >$15 of SNAP (87.1 %) and >$15 of non-SNAP (60.8 %) dollars on FVs/month. Respondents spend

Abstract Background Estimation of prognosis of oral squamous cell carcinoma (OSCC) is inaccurate prior to surgery, only being effected following subsequent pathological analysis of the primary tumour and excised lymph nodes. Consequently, a proportion of patients are overtreated, with an increase in morbidity, or undertreated, with inadequate margins and risk of recurrence. We hypothesise that it is possible to accurately characterise clinical outcomes from infrared spectra arising from diagnostic biopsies. In this first step, we correlate survival with IR spectra derived from the primary tumour. Methods Infrared spectra were collected from tumour tissue from 29 patients with OSCC and subject to classification modelling. Results The model had a median AUROC of 0.89 with regard to prognosis, a median specificity of 0.83, and a hazard ratio of 6.29 in univariate Cox proportional hazard modelling. Conclusion The data suggest that FTIR spectra may be a useful early biomarker of prognosis in OSCC.

Abstract Recently nitrogen-hydrogen compounds have successfully been applied as co-catalysts for mild conditions ammonia synthesis. Ca2NH was shown to act as a H2 sink during reaction, with H atoms from its lattice being incorporated into the NH3(g) product. Thus the ionic transport and diffusion properties of the N–H co-catalyst are fundamentally important to understanding and developing such syntheses. Here we show hydride ion conduction in these materials. Two distinct calcium nitride-hydride Ca2NH phases, prepared via different synthetic paths are found to show dramatically different properties. One phase (β) shows fast hydride ionic conduction properties (0.08 S/cm at 600 °C), on a par with the best binary ionic hydrides and 10 times higher than CaH2, whilst the other (α) is 100 times less conductive. An in situ combined analysis techniques reveals that the effective β-phase conducts ions via a vacancy-mediated phenomenon in which the charge carrier concentration is dependent on the ion concentration in the secondary site and by extension the vacancy concentration in the main site.

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with singletons were fed 100% (CON) or 60% (RES) of requirements until day 90 of gestation, when a subset of ewes (n = 7/treatment) were euthanized, and fetal samples were collected. The remaining ewes were maintained on a current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to an alternative diet (CON-RES, RES-CON; n = 7/treatment). On day 130 of gestation, the remaining ewes were euthanized, and fetal samples were collected. Fetal liver, longissimus dorsi (LD), and blood metabolites were analyzed using LC-MS/MS, and pathway enrichment analysis was conducted using MetaboAnalyst. Then, 600, 518, and 524 metabolites were identified in the liver, LD, and blood, respectively, including 345 metabolites that were present in all three. Nutrient restriction was associated with changes in amino acid, carbohydrate, lipid, and transulfuration/methionine metabolic pathways, some of which were alleviated by realimentation. Fetal age also affected metabolite abundance. The differential abundance of metabolites involved in amino acid, methionine, betaine, and bile acid metabolism could impact fetal epigenetic regulation, protein synthesis, lipid metabolism, and signaling associated with glucose and lipid metabolism.

IntroductionWe aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use.MethodsWe interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach.ResultsClinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools).Discussion and conclusionFindings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.

IntroductionForecasting range shifts in response to climate change requires accurate species distribution models (SDMs), particularly at the margins of species' ranges. However, most studies producing SDMs rely on sparse species occurrence datasets from herbarium records and public databases, along with random pseudoabsences. While environmental covariates used to fit SDMS are increasingly precise due to satellite data, the availability of species occurrence records is still a large source of bias in model predictions. We developed distribution models for hybridizing sister species of western and eastern Joshua trees (Yucca brevifolia and Y. jaegeriana, respectively), iconic Mojave Desert species that are threatened by climate change and habitat loss.MethodsWe conducted an intensive visual grid search of online satellite imagery for 672,043 0.25 km2 grid cells to identify the two species' presences and absences on the landscape with exceptional resolution, and field validated 29,050 cells in 15,001 km of driving. We used the resulting presence/absence data to train SDMs for each Joshua tree species, revealing the contemporary environmental gradients (during the past 40 years) with greatest influence on the current distribution of adult trees.ResultsWhile the environments occupied by Y. brevifolia and Y. jaegeriana were similar in total aridity, they differed with respect to seasonal precipitation and temperature ranges, suggesting the two species may have differing responses to climate change. Moreover, the species showed differing potential to occupy each other's geographic ranges: modeled potential habitat for Y. jaegeriana extends throughout the range of Y. brevifolia, while potential habitat for Y. brevifolia is not well represented within the range of Y. jaegeriana.DiscussionBy reproducing the current range of the Joshua trees with high fidelity, our dataset can serve as a baseline for future research, monitoring, and management of this species, including an increased understanding of dynamics at the trailing and leading margins of the species' ranges and potential for climate refugia.

Abstract Topochemistry enables step-by-step conversions of solid-state materials often leading to metastable structures that retain initial structural motifs. Recent advances in this field revealed many examples where relatively bulky anionic constituents were actively involved in redox reactions during (de)intercalation processes. Such reactions are often accompanied by anion-anion bond formation, which heralds possibilities to design novel structure types disparate from known precursors, in a controlled manner. Here we present the multistep conversion of layered oxychalcogenides Sr2MnO2Cu1.5 Ch 2 (Ch = S, Se) into Cu-deintercalated phases where antifluorite type [Cu1.5 Ch 2]2.5- slabs collapsed into two-dimensional arrays of chalcogen dimers. The collapse of the chalcogenide layers on deintercalation led to various stacking types of Sr2MnO2 Ch 2 slabs, which formed polychalcogenide structures unattainable by conventional high-temperature syntheses. Anion-redox topochemistry is demonstrated to be of interest not only for electrochemical applications but also as a means to design complex layered architectures.

Adequate fluid resuscitation in adults with major burns is crucial to prevent or minimize burn shock, but needs to be balanced against the complications of over-resuscitation. A single-center, retrospective review of 95 ICU patients with severe burns from Jan 2014 to Aug 2021 was performed. Some 52 patients were managed with a liberal targeted fluid goal of 4 mL/kg/%TBSA, and 43 patients were managed after we incorporated a restricted fluid goal of 2 mL/kg/%TBSA into our standard resuscitation strategy. Of the 95 patients included in this analysis, 76 patients (80%) survived admission. The median age was 41 years, and the median TBSA was 36%. All patients received Ringer’s lactate as the primary fluid for resuscitation, and 40 of the 95 patients (42%) received colloids as a rescue infusion within 24 h of injury. Some 44 of the 95 patients (46.3%) had a concurrent inhalational injury. The median length of hospital stay was 37 days, and the median ICU length of stay was 18 days. A total of 17 of the 95 patients developed ARDS (17.9%), 51 of the 95 (53.7%) patients developed pneumonia, and 34 of the 95 patients (35.8%) developed AKI within the first 7 days of admission. The median fluid administered during the first day of hospitalization from 2019 onwards remained close to 4 mL/kg/%TBSA, despite transitioning to a 2 mL/kg/%TBSA formula for a 24 h fluid goal (unless there was an electrical burn, in which case the 4 cc/kg formula was utilized). Further exploratory analyses also suggested that under-resuscitation and administration of albumin may be associated with increased mortality, though this did not reach statistical significance. ARDS development was associated with increased age and TBSA as well as increased fluid intake within the first 24 h. A change in the targeted fluid goal from liberal (4 mL/kg/%TBSA) to a restricted (2 mL/kg/%TBSA) formula did not change the actual fluids administered over 24 h when guided by clinical criteria. Our review did suggest that under-resuscitation contributed to mortality, but that excessive fluid resuscitation likely contributed to ARDS risks for large TBSA patients. Our data suggest that strategies to optimize fluid administration are important to improve patient outcomes, but should focus on clinical parameters rather than calculated fluid goals.

Abstract Background Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer’s Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD. Methods Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations. Results Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications. Conclusion The evaluation of modifications to MTM recommendations demonstrated that pharmacists’ initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations. Trial registration Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016.

Abstract The monitoring of dynamic cellular behaviors remains a technical challenge for most established techniques used nowadays for single-cell analysis, as most of them are either destructive, or rely on labels that can affect the long-term functions of cells. We employ here label-free optical techniques to non-invasively monitor the changes that occur in murine naive T cells upon activation and subsequent differentiation into effector cells. Based on spontaneous Raman single-cell spectra, we develop statistical models that allow the detection of activation, and employ non-linear projection methods to delineate the changes occurring over a several day period spanning early differentiation. We show that these label-free results have very high correlation with known surface markers of activation and differentiation, while also providing spectral models that allow the identification of the underlying molecular species that are representative of the biological process under study.

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Impact and implications: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 and 2 (IDH1/2) are genes involved in epigenetic regulation, each mutated in 7–23% of patients with acute myeloid leukemia. Here, we investigated whether hotspot mutations in these genes encode neoantigens that can be targeted by immunotherapy. Five human B-lymphoblastoid cell lines expressing common HLA class I alleles were transduced with a minigene construct containing mutations that often occur in DNMT3A or IDH1/2. From these minigene-transduced cell lines, peptides were eluted from HLA class I alleles and analyzed using tandem mass spectrometry. The resulting data are available via ProteomeXchange under the identifier PXD050560. Mass spectrometry revealed an HLA-A*01:01-binding DNMT3AR882H peptide and an HLA-B*07:02-binding IDH2R140Q peptide as potential neoantigens. For these neopeptides, peptide–HLA tetramers were produced to search for specific T-cells in healthy individuals. Various T-cell clones were isolated showing specific reactivity against cell lines transduced with full-length DNMT3AR882H or IDH2R140Q genes, while cell lines transduced with wildtype genes were not recognized. One T-cell clone for DNMT3AR882H also reacted against patient-derived acute myeloid leukemia cells with the mutation, while patient samples without the mutation were not recognized, thereby validating the surface presentation of a DNMT3AR882H neoantigen that can potentially be targeted in acute myeloid leukemia via immunotherapy.

The in vitro study demonstrates wirelessly controlled modulation of neural activity using magnetoelectric nanoparticles (MENPs), synchronized to magnetic field application with a sub-25-msec temporal response. Herein, MENPs are sub-30-nm CoFe2O4@BaTiO3 core-shell nanostructures. MENPs were added to E18 rat hippocampal cell cultures (0.5 μg of MENPs per 100,000 neurons) tagged with fluorescent Ca2+ sensitive indicator cal520. MENPs were shown to wirelessly induce calcium transients which were synchronized with application of 1200-Oe bipolar 25-msec magnetic pulses at a rate of 20 pulses/sec. The observed calcium transients were similar, in shape and magnitude, to those generated through the control electric field stimulation with a 50-μA current, and they were inhibited by the sodium channel blocker tetrodotoxin. The observed MENP-based magnetic excitation of neural activity is in agreement with the non-linear M − H hysteresis loop of the MENPs, wherein the MENPs’ coercivity value sets the threshold for the externally applied magnetic field.

Cholera caused by Vibrio cholerae remains endemic and recurrent in Nigeria resulting in morbidity and mortality on annual basis. Vibrio cholerae O1 and non-O1/O139 are reported causative agents of the disease outbreak in Nigeria and some of these strains circulating the country acquired multidrug resistance potential. Several factors including socioeconomic and environmental among other factors drive this trend. Some regions in the country have been identified as hot spots most especially the north where insurgency has exacerbated outbreaks and management/control difficult. Surveillance and response to cholera outbreaks has been suboptimal which in turn has always increased the number of fatalities. Coordinated and harmonized approach involving all needed components (education, WASH, vaccination, surveillance, human capacity building and strengthening capacity of laboratories) has been advocated as a viable option to tackle the scourge.

Abstract Background Good quality colostrum is characterized by high immunoglobulin concentration and low pathogen load. Some methods of pathogen reduction can decrease immunoglobulin concentration and potentially affect their function. Objectives were to determine the effect of formic acid treatment on colostral bacterial and immunoglobulin (IgG) levels before feeding, and serum immunoglobulin concentration and neutralizing capabilities after feeding. Fifteen female Holstein calf pairs born

ABSTRACT Basic combat training (BCT) is a physically rigorous period at the beginning of a soldier's career that induces bone formation in the tibia. Race and sex are determinants of bone properties in young adults but their influences on changes in bone microarchitecture during BCT are unknown. The purpose of this work was to determine the influence of sex and race on changes in bone microarchitecture during BCT. Bone microarchitecture was assessed at the distal tibia via high‐resolution peripheral quantitative computed tomography at the beginning and end of 8 weeks of BCT in a multiracial cohort of trainees (552 female, 1053 male; mean ± standard deviation [SD] age = 20.7 ± 3.7 years) of which 25.4% self‐identified as black, 19.5% as race other than black or white (other races combined), and 55.1% as white. We used linear regression models to determine whether changes in bone microarchitecture due to BCT differed by race or sex, after adjusting for age, height, weight, physical activity, and tobacco use. We found that trabecular bone density (Tb.BMD), thickness (Tb.Th), and volume (Tb.BV/TV), as well as cortical BMD (Ct.BMD) and thickness (Ct.Th) increased following BCT in both sexes and across racial groups (+0.32% to +1.87%, all p

Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.

Approximately half of the world’s population is estimated to be infected with Helicobacter pylori [...]

Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair. Here, we examine the pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies.

Hyaluronan is a naturally occurring linear polysaccharide that together with collagens, enzymes, and glycoproteins forms the extracellular matrix. Here the authors show that adipose tissue overproduction of Hyaluronan reduces fat accumulation in mice fed high-fat diet and improves systemic glucose homeostasis.

Spin-ice physics in frustrated magnets is constrained by the energy scale of magnetic interactions, which typically translates to temperatures of a few Kelvin. Here, the authors demonstrate that similar physics can be observed in the system of frustrated electric dipoles in Cd(CN)2 even at room temperature.

Abstract Objective Prompt diagnosis of Helicobacter pylori infection is essential for proper treatment and eradication of the pathogen because prolonged infection could lead to gastric cancer. Sensitive and cost effective diagnostic methods are key to guiding treatment options that will reduce mortality. This study was aimed at detecting H. pylori from biopsies of peptic ulcer patients. Real-time PCR using TaqMan and EvaGreen assays targeting 16S rRNA and ureA genes were used to detect H. pylori DNA extracted from 40 biopsy samples comprising 20 biopsies obtained from the antrum and 20 from the corpus of 20 patients undergoing endoscopy for duodenal ulcer investigation in Lagos, Nigeria. Results H. pylori was detected in 80% of the biopsy samples by combined cycle threshold (C t ) and melting temperature (T m ) values. Mean C t value for ureA gene ranged from 21.40 to 37.53 and 22.71 to 35.44 for 16SrRNA gene. Average melting temperatures (T m ) of 81.57 and 82.90 °C among amplicons of ureA and 16S rRNA were observed respectively. H. pylori DNA was generally detected in biopsies collected from antrum and corpus. Real-time PCR in the diagnosis of H. pylori can be considered a simple, low cost and efficient alternative or addition to the gold standard.

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveals more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

Abstract We describe experiments and simulations to investigate the dynamics of a ball bouncing on a rough vibrating surface. Directly measuring the impulse due to each bounce we find that the frictional interaction with the surface is strongly enhanced near to the side wall. The enhanced dissipation arises as a consequence of the coupling between the collision, rotation and surface friction. This dissipation, which for our experimental conditions was estimated to be up to three times larger than the more obvious inelastic collision, can result in an enhanced probability density near boundaries and particle–particle spatial correlations. Our findings imply that the effective particle collision properties cannot be considered independently of the surface’s frictional properties.

The development of the all solid-state battery requires the formation of stable solid/solid interfaces between different battery components. Here the authors tailor the composition to form both electrolyte and anode from the same novel family of perovskites with shared crystal chemistry.

Abstract Background Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn’s disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset. Methods Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15–40-fold increased risk of developing CD in homozygous or compound heterozygous individuals. Results Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae. Conclusions This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.

Introduction and objectives: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. Materials and methods: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. Results: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p = 0.02) or diagnosis of HBV (p = 0.02). Conclusions: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5–15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Abstract Objective Nosocomial and community acquired multidrug resistant Klebsiella infections are wide spread resulting in high morbidity and mortality due to limited number of antibiotics treatment options. This study investigated efflux pump activity, biofilm forming potential and antibiotic susceptibility profile of Klebsiella spp. isolated from clinical samples in a tertiary hospital in Lagos Nigeria. Eighteen clinical Klebsiella spp. isolated from urine, blood and sputum were subjected to antibiotic susceptibility testing using the disc diffusion method. Efflux pump activity was evaluated by the ethidium bromide cartwheel method and biofilm forming ability was determined by the tissue culture plate technique. Results All 18 (100%) Klebsiella isolates were resistant to cefuroxime, cefixime, amoxicillin − clavulanate, ampicillin + cloxacillin, cefotaxime, and imipenem. Seventeen (94.4%) were resistant to ofloxacin while sixteen (88.9%) were resistance to nalidixic acid, Gentamicin and levofloxacin. All Klebsiella isolates possessed active efflux pump with the ability to form biofilm. However, their biofilm forming capabilities varied as 4 (22.2%) were strong, 3 (16.7%) were moderate and 11 (61.1%) were weak biofilm formers. Findings in this study reveal multiple factors at play in mediating the high level of antibiotic resistance observed in Klebsiella isolates. Hence a multifaceted approach is advocated in managing the infections caused by the pathogen.

Helicobacter pylori (H. pylori) infection is ubiquitous worldwide, with prevalence rates of greater than 70% in Africa. Symptomatic patients present with foregut gastrointestinal symptoms which can be readily diagnosed with standardized non-invasive or invasive tests. The biggest challenge, however, is in the management of this condition with rising antimicrobial resistance rates to most of the antibiotics recommended for therapy. This is a problem worldwide, but more specifically in Africa, where the socio-economic and political climate is such that eradication of this organism seems impossible. Furthermore, the recommended antimicrobial susceptibility testing for drug resistance is not widely available in Africa due to the lack of infrastructural as well as human resources. With the widespread unregulated use of antibiotics in some parts of Africa, the figures of antimicrobial resistance are likely to soar. In the face of these significant challenges, this ‘perspectives’ article aims to address the issue of antimicrobial resistance in Africa, by providing achievable and targeted goals to curb the spread of infection and rising antimicrobial resistance.

Invasive insects pose an increasing risk to global agriculture, environmental stability, and public health. Giant pine scale (GPS), Marchalina hellenica Gennadius (Hemiptera: Marchalinidae), is a phloem feeding scale insect endemic to the Eastern Mediterranean Basin, where it primarily feeds on Pinus halepensis and other Pinaceae. In 2014, GPS was detected in the southeast of Melbourne, Victoria, Australia, infesting the novel host Pinus radiata. An eradication program was unsuccessful, and with this insect now established within the state, containment and management efforts are underway to stop its spread; however, there remains a need to understand the insect’s phenology and behaviour in Australia to better inform control efforts. We documented the annual life cycle and seasonal fluctuations in activity of GPS in Australia over a 32 month period at two contrasting field sites. Onset and duration of life stages were comparable to seasons in Mediterranean conspecifics, although the results imply the timing of GPS life stage progression is broadening or accelerating. GPS density was higher in Australia compared to Mediterranean reports, possibly due to the absence of key natural predators, such as the silver fly, Neoleucopis kartliana Tanasijtshuk (Diptera, Chamaemyiidae). Insect density and honeydew production in the Australian GPS population studied varied among locations and between generations. Although insect activity was well explained by climate, conditions recorded inside infested bark fissures often provided the weakest explanation of GPS activity. Our findings suggest that GPS activity is strongly influenced by climate, and this may in part be related to changes in host quality. An improved understanding of how our changing climate is influencing the phenology of phloem feeding insects such as GPS will help with predictions as to where these insects are likely to flourish and assist with management programs for pest species.

Background It is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity.Methods We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D).Results Glucose-stimulated insulin secretion (GSIS), an assessment of β cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration.Conclusion Increased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in β cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D.CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560.FUNDING NIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559).

Oral epithelial dysplasia (OED) is a histopathologically-defined, potentially premalignant condition of the oral cavity. The rate of transformation to frank carcinoma is relatively low (12% within 2 years) and prediction based on histopathological grade is unreliable, leading to both over- and under-treatment. Alternative approaches include infrared (IR) spectroscopy, which is able to classify cancerous and non-cancerous tissue in a number of cancers, including oral. The aim of this study was to explore the capability of FTIR (Fourier-transform IR) microscopy and machine learning as a means of predicting malignant transformation of OED. Supervised, retrospective analysis of longitudinally-collected OED biopsy samples from 17 patients with high risk OED lesions: 10 lesions transformed and 7 did not over a follow-up period of more than 3 years. FTIR spectra were collected from routine, unstained histopathological sections and machine learning used to predict malignant transformation, irrespective of OED classification. PCA-LDA (principal component analysis followed by linear discriminant analysis) provided evidence that the subsequent transforming status of these 17 lesions could be predicted from FTIR data with a sensitivity of 79 ± 5% and a specificity of 76 ± 5%. Six key wavenumbers were identified as most important in this classification. Although this pilot study used a small cohort, the strict inclusion criteria and classification based on known outcome, rather than OED grade, make this a novel study in the field of FTIR in oral cancer and support the clinical potential of this technology in the surveillance of OED.

We developed the Physics Inventory of Quantitative Literacy (PIQL) to assess students’ quantitative reasoning in introductory physics contexts. The PIQL includes several “multiple-choice-multiple-response” (MCMR) items (i.e., multiple-choice questions for which more than one response may be selected) as well as traditional single-response multiple-choice items. In this paper, we discuss differences in performance on MCMR items that seems to result from differences in administration method (paper versus online). In particular, we find a tendency for “clickiness” in online administration: students choose more responses to MCMR items when taking the electronic version of the assessment. Student performance on single-response multiple-choice items was not affected by administration method. These results suggest that MCMR items may provide a unique opportunity to probe differences in online and on-paper administration of low-stakes assessments.

This study critically evaluates a recent machine learning method called the X-Learner, that aims to estimate treatment effects by predicting counterfactual quantities. It uses information from the treated group to predict counterfactuals for the control group and vice versa. The problem is that studies have either only been applied to real world data without knowing the ground truth treatment effects, or have not been compared with the traditional regression methods for estimating treatment effects. This study therefore critically evaluates this method by simulating various scenarios that include observed confounding and non-linearity in the data. Although the regression X-Learner performs just as well as the traditional regression model, the other base learners performed worse. Additionally, when non-linearity was introduced into the data, the results of the X-Learner became inaccurate.

We describe pynucastro 2.0, an open-source library for interactively creating and exploring astrophysical nuclear reaction networks. We demonstrate new methods for approximating rates and use detailed balance to create reverse rates, show how to build networks and determine whether they are appropriate for a particular science application, and discuss the changes made to the library over the past few years. Finally, we demonstrate the validity of the networks produced and share how we use pynucastro networks in simulation codes.

Abstract Background High risk human papillomaviruses (HPV) plays important roles in the development of cervical cancer, a number of other anogenital cancer and they are increasingly found in oropharyngeal squamous cell carcinoma (OPSCC), however there has not been comprehensive analysis about the role how these viruses play in the development of OPSCC. Methods To characterize the physical status of HPV within OPSCC and to determine the effect this has throughout the host genome, we have performed 30-40X whole genome sequencing (WGS) on the BGI sequencing platform on 34 OPSCCs: 28 of which were HPV positive. We then examined the sequencing data to characterize the HPV copy number and HPV physical status to determine what effect they have on both HPV and human genome structural changes. Results WGS determined the HPV copy number across the viral genome. HPV copy number ranged from 1 copy to as high as 150 copies in each individual OPSCC. Independent of HPV copy number, most tumors had either a small or a very large deletion in the viral genome. We discovered that these deletions were the result of either HPV integration into the human genome or HPV-HPV sequence junctions. WGS revealed that ~ 70% of these tumors had HPV integrations within the human genome and HPV integration occurred independent of HPV copy number. Individual HPV integrations were found to be highly disruptive resulting in structural variations and copy number changes at or around the integration sites. Conclusions WGS reveals that there is a great complexity in both HPV sequences present and the HPV integrations events in HPV positive OPSCCs tumors. Thus HPV may be playing different roles in the development of different OPSCCs and this further challenge the HPV-driven carcinogenesis model first proposed for cervical cancer.

Intestinal epithelial cell tight junctions (TJs) contribute to the integrity of the intestinal barrier allowing for control of the physical barrier between external antigens or bacterial products and the internal environment. Zonula occludens-1 (ZO-1) is a protein that modulates intestinal TJs, and serum levels of ZO-1 has been suggested as a biomarker of disrupted barrier function in humans. Previous studies suggested that increased intestinal permeability was associated with evidence of TJ abnormalities. However, there is limited information on the serological measurement of ZO-1 and its relation to other tests of barrier function in healthy subjects. We investigated the correlation of serum ZO-1, with physiologic measures of intestinal permeability (as the ratio of the fractional excretion of lactulose-mannitol or LMR) in a cohort of 39 healthy FDRs of Crohn's disease (CD) patients. No significant correlation was found between LMR and ZO-1 levels (r2 = 0.004, P < 0.71), or intestinal fatty acid binding proteins (I-FABP) (r2 = 0.004, P < 0.71). In conclusion, our data show that ZO-1 and I-FABP are not a marker of gut permeability as defined by LMR.