bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognition and nutrition: the role of dietary protein and amino acids in cognitive health
Authors: Nagao Kenji
Published: October 2023

Purpose of review

This review underscores recent advancements in the role of protein and amino acid nutrition on cognitive health. Given the escalating prevalence of neurodegenerative disorders, particularly Alzheimer's disease, it is essential to understand nonpharmaceutical interventions that could potentially counteract their development and progression.

Recent findings

Emerging research indicates that moderate protein intake may offer protective benefits against dementia. Studies also emphasize the importance of considering not just the quantity, but also the quality and source of dietary protein. The role of essential amino acids in nutrition is gaining attention in the field of cognitive health. Moreover, plasma-free amino acid concentrations, particularly branched-chain amino acids, are being explored as potential biomarkers for cognitive health and Alzheimer's disease. Mechanistic studies suggest that proteins and amino acids help maintain neuronal integrity, reduce inflammation, and support muscle retention, all essential factors for cognitive health.

Recent findings emphasize the complex relationship between protein, amino acids, and cognitive health, highlighting the potential of dietary interventions in warding off neurodegenerative diseases. Given the observational nature of these findings, further interventional and longitudinal studies are needed to ascertain causality and elucidate the mechanisms involved.
The colitis may be microscopic, but the diarrhea is not: update on the treatment of microscopic colitis and immune checkpoint inhibitor colitis
Authors: Enwerem Ngozi Y. , Yen Eugene F.
Published: October 2023

Purpose of review

Microscopic colitis is an inflammatory disease of the colon that presents as watery diarrhea with minimal to normal endoscopic changes on colonoscopy. It encompasses two common subtypes, lymphocytic colitis and collagenous colitis, which are both treated similarly.

Immune checkpoint inhibitor colitis is among the most common immune-related adverse events. Endoscopic and histological findings range from normal colonic mucosa to inflammatory bowel like changes. This review article provides update in treatment and management of microscopic colitis and immune checkpoint inhibitor colitis (ICPi colitis).

Recent findings

Recent studies on microscopic colitis have focused on the successful use of immunomodulators such as biologics for treatment of budesonide refractory microscopic colitis cases. Microscopic colitis does not confer an added risk for colorectal cancer.

With the increasing usage of immunotherapy agents, immune checkpoint inhibitor colitis is becoming more common. ICPi colitis can be successfully managed with steroids, with treatment stepped up to biologics for moderate to severe cases or for mild cases that do not respond to steroids. Immunotherapy agents can be carefully re-introduced in mild cases, after treatment of ICPi colitis.

Biologics can be used to treat budesonide refractory microscopic colitis. ICPi colitis can be managed with steroids and biologics in moderate to severe cases.
Sociocultural Framework for Psychiatric Case Formulation
Authors: Weiss Mitchell G. , Deshmukh Ankita , Sarmukaddam Sanjeev B. , Paralikar Vasudeo P.
Published: October 2023

A Cultural Formulation Interview (CFI) field trial in India, widely reported racist violence in the United States, and casteist and religious communal conflicts in India highlighted inattention to structural issues affecting mental health problems in the Outline for Cultural Formulation (OCF) and the CFI in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Consequently, we revised the OCF as a sociocultural formulation (SCF) to better consider structures of society and culture. We studied and compared clinicians' ratings of SCF case formulations from a constructed assessment instrument (SCF Interview [SCFI]) and the CFI. Socio-cultural formulations from SCFI interviews were rated higher for details of societal structural impact, and overall interrater agreement was better. CFI interviews were rated higher for clinical rapport. Revision of the CFI should enhance consideration of structural issues and incorporate them in SCFs that better integrate assessment process and case formulation content. The need to acknowledge structural sources of mental health problems is clear, and our study indicates how a sociocultural framework may be used for that.
Addressing Workplace Violence With Evidence
Authors: Bauersfeld Sara , Majers Joan Sevy
Published: October 2023

AIM

The purpose of this article is to describe how regional community assessment survey data specific to healthcare workers' (HCWs') attitudes and actions related to workplace violence (WPV) from 1 participating urban tertiary hospital was compared with current evidence to identify evidence-based interventions to promote a safer work environment. The regional survey assessed real-time data regarding the state of WPV and its impact on HCWs, and to drive proposed interventions to prevent and reduce WPV in the healthcare community.

BACKGROUND

Incidents of WPV in healthcare continue to increase, resulting in calls for action from staff, leadership, and regulatory organizations.

METHODS

Data were collected from the HCWs who completed the survey. Experiences with WPV were analyzed. Qualitative data were evaluated for themes. A review of external evidence was conducted to identify best practices in preparing proposed next steps for the organization.

RESULTS

Healthcare worker attitudes and practices related to WPV were described as unreported and not addressed. Violence was more readily perceived as a part of the job. External evidence indicated that education and training alone seemed to have minimal effect on preventing WPV. Evidence from best practices and staff feedback were recommended to be incorporated into plans for the organization.
Chemical Corneal Burn After Short Exposure to Alcohol-Containing Chlorhexidine Antiseptic
Authors: Lee Jun Hyeok , Jun Dai Won , Lee Jung Ho
Published: October 2023

Chlorhexidine is used routinely for asepsis in craniofacial surgeries. A solution containing a lower concentration of chlorhexidine diluted with alcohol has been developed to decrease chlorhexidine-related side effects. Herein, we report a case of chemical corneal burn caused by hexitanol solution (2% chlorhexidine + 72% ethanol) in a patient after undergoing closed reduction for nasal fracture under general anesthesia. Although the presumptive exposure time of the cornea was short, slit-lamp examination revealed epithelial defects. The patient received conservative care with extensive saline irrigation and conservative treatment with 0.3% gatifloxacin, 1% prednisolone, and carbomer eye drops. Among the various antiseptic solutions, ethanol markedly decreases cell viability in a concentration-dependent manner by inducing cell lysis, even after short exposure. Moreover, chlorhexidine induces corneal toxicity, necessitating corneal transplantation. Therefore, surgeons should be aware of the complications associated with the use of chlorhexidine or alcohol-containing antiseptics and the use povidone for its low ocular toxicity.
A Comparative Analysis of Tranexamic Acid Dosing Strategies in Traumatic Major Hemorrhage
Authors: Gunn Finn , Stevenson Rheanna , Almuwallad Ateeq , Rossetto Andrea , Vulliamy Paul , Brohi Karim , Davenport Ross ,   London, United Kingdom
Published: October 2023

Introduction

Tranexamic acid (TXA) is a life-saving treatment for traumatic hemorrhage, but the optimal dosing regimen remains unknown. Different doses and treatment strategies have been proposed, including single bolus, repeated bolus or bolus plus infusion. The aim of this study was to determine the effect of different TXA dosing strategies on clinical outcomes in bleeding trauma patients.

Methods

Secondary analysis of a perpetual cohort study from a UK Level 1 trauma center. Adult patients who activated the local major hemorrhage protocol and received TXA were included. The primary outcome was 28-day mortality. Secondary outcomes were 24-hour mortality, multiple organ dysfunction syndrome (MODS), venous thromboembolism (VTE) and ROTEM fibrinolysis.

Results

Over an 11-year period, 525 patients were included. Three dosing groups were identified: 1 g bolus only (n = 317), 1 g bolus +1 g infusion over 8 hours (n = 80), and 2 g bolus (n = 128). Demographics and admission physiology were similar, but there were differences in injury severity (median ISS: 25, 29 & 25); and admission systolic blood pressure (median SBP: 99, 108, 99 mmHg) across the 1 g, 1 g + 1 g and 2 g groups. 28-day mortality was 21% in each treatment group. The incidence of MODS was significantly higher in the bolus plus infusion group (84%) vs 1 g bolus (64%) and 2 g bolus (62%) group, p = 0.002, but on multivariable analysis was non-significant. VTE rates were similar in the 1 g bolus (4%), 2 g bolus (8%) and bolus plus infusion groups (7%). There was no difference in ROTEM Maximum Lysis at 24 hours: 5% in both the 1 g and 2 g bolus groups vs 4% in bolus plus infusion group.

Conclusion

Clinical outcomes and 24-hour fibrinolysis state were equivalent across three different dosing strategies of TXA. Single bolus administration is likely preferable to a bolus plus infusion regimen.

Level of Evidence

Level IV, Therapeutic/Care Management
Persistent Long-Term Opioid Use After Trauma: Incidence and Risk Factors
Authors: Benns Matthew V. , Gaskins Jeremy T. , Miller Keith R. , Nash Nicholas A. , Bozeman Matthew C. , Pera Samuel J. , Marshall G. Ryne , Coleman Jamie J. , Harbrecht Brian G.
Published: October 2023

Background

The opioid epidemic in the United States continues to lead to a substantial number of preventable deaths and disability. The development of opioid dependence has been strongly linked to previous opioid exposure. Trauma patients are at particular risk since opioids are frequently required to control pain after injury. The purpose to this study was to examine the prevalence of opioid use before and after injury and to identify risk factors for persistent long-term opioid use after trauma.

Methods

Records for all patients admitted to a Level 1 trauma center over a one-year period were analyzed. Demographics, injury characteristics, and hospital course were recorded. A multi-state Prescription Controlled Drug Monitoring Program (PDMP) database was queried to obtain records of all controlled substances prescribed from 6 months prior to the date of injury to 12 months after hospital discharge. Patients still receiving narcotics at 1 year were defined as persistent long-term users and were compared against those who were not.

Results

2992 patients were analyzed. 20.4% of patients had filled a narcotic prescription within the 6 months prior to injury. 53.5% of patients received opioids at hospital discharge. 12.5% of patients had persistent long-term use after trauma with the majority demonstrating pre-injury use. Univariate risk factors for long term use included female sex, longer length of stay, higher injury severity score, anxiety, depression, orthopedic surgeries, spine injuries, multiple surgical locations, discharge to acute inpatient rehab, and pre-injury opioid use. On multi-variate analysis, the only significant predictors of persistent long-term prescription opioid use were pre-injury use, as well as a much smaller effect associated with use at discharge.

Conclusion

During a sustained opioid epidemic, concerns and caution are warranted in the use of prescription narcotics for trauma patients. However, persistent long-term opioid use among opioid naïve patients is rare and difficult to predict after trauma.

Level of Evidence

III, Prognostic/Epidemiological
Contemporary Left Ventricular Assist Device Therapy as a Bridge or Alternative to Transplantation
Authors: Boulet Jacinthe , Wanderley Mauro R.B. , Mehra Mandeep R.
Published: October 2023

Left ventricular assist devices (LVADs), which were introduced as a bridge to heart transplantation, are now an established alternative to heart transplantation (HT) for patients with advanced heart failure. These devices have undergone significant technological advancements over the years, and contemporary LVADs prolong life substantially in patients dependent on inotropic therapy or in those with severe ambulatory advanced heart failure with a median survival that exceeds 5 y, and most patients benefit from a doubling in functional capacity, even among those intended as destination therapy because of ineligibility for transplantation. Other intended goals for LVAD implantation consist of (1) bridge to remission or recovery and (2) bridge to transplant or candidacy for transplant. In the former situation, few selected patients underwent LVAD implantation, facilitating myocardial remission to recovery that allowed explantation. Among those bridged to transplantation, survival in the intended goal was excellent, with 80% success at 5 y (with a 50% rate of transplantation). In this review, we provide a brief historical background on the evolution of LVADs and discuss outcomes with contemporary pumps, immunological and infection-related impact of such devices, impact of bridging in HT, and use of devices for facilitating myocardial recovery and remission. Furthermore, we discuss implications of HT allocation policies, with a specific focus within the United States, and outline future perspectives and novel device in development.
A post-transplant infection by Nocardia cyriacigeorgica
Authors: GANDHAM NAGESWARI , Kannuri Sriram , Gupta Aryan , Mukhida Sahjid , DAS NIKUNJA , Mirza Shahzad
Published: October 2023

Nocardia are gram-positive bacilli that cause opportunistic infections in susceptible populations. We describe a case of post-transplant infection of pulmonary Nocardiosis caused by the rare strain Nocardia cyriacigeorgica and the challenges faced in reaching a definitive diagnosis. This case report emphasizes on keeping Nocardiosis as a differential diagnosis in transplant recipients as this disease is largely underdiagnosed and underreported.
ICTV Virus Taxonomy Profile: Tosoviridae 2023
Authors: Wolf Yuri I. , Krupovic Mart , Kuhn Jens H. , Koonin Eugene V.
Published: October 2023

Tosoviridae is a family of negative-sense RNA viruses with genomes totaling about 12.3 kb that have been found in turtles. The tosovirid genome consists of two segments, each with two open reading frames (ORFs) in ambisense orientation. The small (S) segment encodes a nucleoprotein (NP) and a glycoprotein precursor (GPC); the large (L) segment encodes an L protein containing an RNA-directed RNA polymerase (RdRP) domain and a zinc-binding (Z) protein. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Tosoviridae, which is available at ictv.global/report/tosoviridae.
Facemask wearing in COVID-19 pandemic: Correlates and prevalence; A survey after COVID-19 second wave in Uganda
Authors: Alema Nelson Onira , Okot Christopher , Olal Emmanuel , Ikoona Eric Nzirakaindi , Oyat Freddy Wathum Drinkwater , Baguma Steven , Ochula Denish Omoya , Olwedo Patrick Odong , Oloya Johnson Nyeko , Pebolo Francis Pebalo , Atim Pamela Okot , Okot Godfrey Smart , Nantale Ritah , Aloyo Judith , Kitara David Lagoro
Published: October 2023

Background

The WHO and the US. CDC documented that facemask-wearing in public situations is one of the most important prevention measures that can limit the acquisition and spread of COVID-19. Considering this, WHO and US. CDC developed guidelines for using facemasks in public settings. This study aimed to determine correlates and prevalence of facemask wearing during COVID-19 pandemic among adult population of Northern Uganda.

Methods

We conducted a cross-sectional study on five hundred and eighty-seven adult population of northern Uganda. A single stage stratified, and systematic sampling methods were used to select respondents from twenty-four Acholi subregion’s health facilities. Data was collected in a face-to-face questionnaire interview with an internal validity of Cronbach’s α=0.72. A local IRB approved the study, and Stata 18 was used for data analysis at multivariable Poisson regression with a p-value set at ≤0.05.

Results

The most substantial findings from this study were the high prevalence of face mask-wearing in public among respondents [88.7%,95%CI:86%-91%]. At a multivariable Poisson regression analysis, we found that obese respondents were 1.12 times more likely to wear facemasks than those who were not, [adjusted Interval Rates Ratios, aIRR=1.12,95%CI:1.04-1.19;p<0.01], and respondent who agreed to the lockdown measures were 1.23 times more likely to wear facemasks during COVID-19 pandemic than those who did not, [aIRR=1.23, 95%CI:1.07-1.41;p<0.01]. Other sociodemographic characteristics such as sex, age, occupation, level of education, religion, tribes, marital status, nationality, race, and comorbidities were not statistically significant at 95% Confidence Intervals.

Conclusion

The most significant findings from this study were the high prevalence of face mask-wearing among adult community members in northern Uganda. The correlates of facemask wearing in public were the obese and respondents who agreed with the presidential directives on the lockdown measures. Although this was within acceptable prevalence rates, the strict enforcement of face mask-wearing by security forces raised concerns among many community members and human rights advocates. We recommend more studies on communities’ perspectives on the challenges and benefits of facemask-wearing during the COVID-19 pandemic.
Systematic assessment of early brain injury severity at admission with aneurysmal subarachnoid hemorrhage
Authors: Tuzi Sheri , Kranawetter Beate , Mielke Dorothee , Rohde Veit , Malinova Vesna
Published: October 2023

Background

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) has been increasingly recognized as a risk factor for delayed cerebral ischemia (DCI). While several clinical and radiological EBI biomarkers have been identified, no tool for systematic assessment of EBI severity has been established so far. This study aimed to develop an EBI grading system based on clinical signs and neuroimaging for estimation of EBI severity at admission.

Methods

This is a retrospective observational study assessing imaging parameters (intracranial blood amount, global cerebral edema (GCE)), and clinical signs (persistent loss of consciousness [LOC]) representative for EBI. The intracranial blood amount was semi-quantitatively assessed. One point was added for GCE and LOC, respectively. All points were summed up resulting in an EBI grading ranging from 1-5. The estimated EBI severity was correlated with progressive GCE requiring decompressive hemicraniectomy (DHC), DCI-associated infarction, and outcome according to the modified Rankin scale (mRS) at 3-month-follow up.

Results

A consecutive cohort including 324 aSAH-patients with a mean age of 55.9 years, was analyzed. The probability of developing progressive GCE was 9% for EBI grade 1, 28% for EBI grade 2, 43% for EBI grade 3, 61% for EBI grade 4, and 89% for EBI grade 5. The EBI grading correlated significantly with the need for DHC (r=0.25,p<0.0001), delayed infarction (r=0.30,p<0.0001), and outcome (r=0.31,p<0.0001).

Conclusions

An EBI grading based on clinical and imaging parameters allowed an early systematic estimation of EBI severity with a higher EBI grade associated not only with a progressive GCE but also with DCI and poor outcome.
Parental awareness and attitudes towards prevention of respiratory syncytial virus in infants and young children in Australia
Authors: Holland Charlie , Baker Megan , Bates Amber , Hughes Catherine , Richmond Peter C , Carlson Samantha , Moore Hannah C
Published: October 2023

Aims

To assess parental awareness of respiratory syncytial virus (RSV) and the level of acceptance of future RSV prevention strategies.

Methods

A cross-sectional online survey was implemented targeting “future” and “current” parents of children aged ≤5 years in Australia.

Results

From 1,992 eligible participants, two non-mutually exclusive subgroups were formed; “current” parents (N=1931) and “pregnant/planning” parents (N=464; 403 also “current” parents; 61 “future” parents). Participants were predominantly (86.6%) aged 25-39 years and 68.5% with university education. The majority (89.6% current; 78.7% future) had heard of RSV. Of those, 64.2% (current) and 50.0% (future) were aware that pneumonia is associated with RSV; 71.8% (current) and 52.1% (future) were aware that bronchiolitis is associated. In multivariable logistic regression analyses, Australian-born parents (aOR=2.47 [95%CI:1.48-4.12]), living in the Eastern States (e.g., New South Wales: aOR=6.15 [95%CI:2.10-18.04]), with a university level education (aOR=2.61 [95%CI:1.38-4.94]) and being a current parent (aOR=12.26 [95%CI:2.82-53.28]) were associated with higher RSV awareness. There was a high level of acceptance for maternal vaccines (future: 79.3%) and infant immunisation (all: 81.7%).

Conclusion

While RSV awareness and immunisation acceptance was high, there was limited knowledge of severity of RSV, especially in future parents. Education campaigns need to be developed to increase RSV knowledge.

Key notes

The success of RSV immunisation programs is dependent on the community having sufficient disease awareness and acceptance of new immunisation strategies. Majority of parents in the study had heard of RSV, however lacked awareness on associated conditions and disease severity, particularly future parents. Education and awareness campaigns are required to inform parents about RSV and future immunisations; there is a critical opportunity to increase awareness prior to immunisation arrival.
Low-flow in aortic valve stenosis patients with reduced ejection fraction does not depend on left ventricular function
Authors: Gersch Svante , Lange Torben , Beuthner Bo Eric , Elkenani Manar , Paul Niels , Schnelle Moritz , Zeisberg Elisabeth , Puls Miriam , Hasenfuß Gerd , Schuster Andreas , Toischer Karl
Published: October 2023

Background

Patients with severe aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF) can be distinguished into high-(HG) and low-gradient (LG) subgroups. However, less is known about their characteristics and underlying (pathophysiological) hemodynamic mechanisms.

Methods

98 AS patients with reduced LVEF were included. Subgroup characteristics were analyzed by a multimodal approach using clinical and histological data, next-generation sequencing (NGS) and applying echocardiography as well as cardiovascular magnetic resonance (CMR) imaging. Biopsy samples were analyzed with respect to fibrosis and mRNA expression profiles.

Results

40 patients were classified as HG-AS and 58 patients as LG-AS. Severity of AS was comparable between the subgroups. Comparison of both subgroups revealed no differences in LVEF (p=0.1), LV mass (p=0.6) or end-diastolic LV diameter (p=0.12). Neither histological (HG: 23.2% vs. LG: 25.6%, p=0.73) and circulating biomarker-based assessment (HG: 2.6 ± 2.2 % vs. LG: 3.2 ± 3.1 %; p= 0.46) of myocardial fibrosis nor global gene expression patterns differed between subgroups. Mitral regurgitation (MR), atrial fibrillation (AF) and impaired right ventricular function (MR: HG: 8% vs. LG: 24%; p<0.001; AF: HG: 30% vs. LG: 51.7%; p=0.03; RVSVi: HG 36.7 vs. LG 31.1 ml/m2, p=0.045; TAPSE: HG 20.2 vs. LG 17.3 mm, p=0.002) were more frequent in LG-AS patients compared to HG-AS. These pathologies could explain the higher mortality of LG vs. HG-AS patients.

Conclusion

In patients with low-flow severe aortic stenosis, low transaortic gradient and cardiac output are not primarily due to LV dysfunction or global changes in gene expression, but may be attributed to other additional cardiac pathologies like mitral regurgitation, atrial fibrillation or right ventricular dysfunction. These factors should also be considered during planning of aortic valve replacement.
Kynurenic acid promotes activity-dependent synaptic pruning in schizophrenia
Authors: Orhan Funda , Malwade Susmita , Khanlarkhani Neda , Gkoga Asimenia , Jungholm Oscar , Koskuvi Marja , Lehtonen Šárka , Schwieler Lilly , Jardemark Kent , Tiihonen Jari , Koistinaho Jari , Erhardt Sophie , Engberg Göran , Samudyata Samudyata , Sellgren Carl M.
Published: October 2023

Schizophrenia is a neurodevelopmental disorder characterized by an excessive loss of synapses. Recent data suggest that this is due to increased microglia-mediated synaptic pruning. Here, we utilize human induced pluripotent stem cell-derived models to show that kynurenic acid (KYNA), an endogenous NMDA-receptor antagonist observed to be increased in the brains of individuals with schizophrenia, reduces neuronal activity and promote microglial uptake of synapses. In a human brain organoid model, we confirm reduced microglia-mediated synaptic pruning upon inhibiting the endogenous KYNA production. To verify our experimental data in a clinical context, we integrate large-scale transcriptomic and genetic datasets and show that KYNA-producing kynurenine aminotransferases (KATs) enrich for genes governing synaptic activity and genetic risk variants for schizophrenia. Together, these results link genetic risk variants for schizophrenia to elevated production of KYNA and excessive activity-dependent synaptic pruning, while implicating pharmacological inhibition of KATs as a strategy to avoid synapse loss in schizophrenia.
A dynamic scale-mixture model of motion in natural scenes
Authors: Salisbury Jared M. , Palmer Stephanie E.
Published: October 2023

Some of the most important tasks of visual and motor systems involve estimating the motion of objects and tracking them over time. Such systems evolved to meet the behavioral needs of the organism in its natural environment, and may therefore be adapted to the statistics of motion it is likely to encounter. By tracking the movement of individual points in movies of natural scenes, we begin to identify common properties of natural motion across scenes. As expected, objects in natural scenes move in a persistent fashion, with velocity correlations lasting hundreds of milliseconds. More subtly, but crucially, we find that the observed velocity distributions are heavy-tailed and can be modeled as a Gaussian scale-mixture. Extending this model to the time domain leads to a dynamic scale-mixture model, consisting of a Gaussian process multiplied by a positive scalar quantity with its own independent dynamics. Dynamic scaling of velocity arises naturally as a consequence of changes in object distance from the observer, and may approximate the effects of changes in other parameters governing the motion in a given scene. This modeling and estimation framework has implications for the neurobiology of sensory and motor systems, which need to cope with these fluctuations in scale in order to represent motion efficiently and drive fast and accurate tracking behavior.
A High-Fat and Fructose Diet in Dogs Mirrors Insulin Resistance and β-cell Dysfunction Characteristic of Impaired Glucose Tolerance in Humans
Authors: Gregory Justin M. , Kraft Guillaume , Man Chiara Dalla , Slaughter James C , Scott Melanie F. , Hastings Jon R. , Edgerton Dale S. , Moore Mary C. , Cherrington Alan D.
Published: October 2023

This study examined the impact of a hypercaloric high-fat high-fructose diet (HFFD) in dogs as a potential model for human impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). The HFFD not only led to weight gain but also triggered metabolic alterations akin to the precursors of human T2DM, notably insulin resistance and β-cell dysfunction. Following the HFFD intervention, the dogs exhibited a 50% decrease in insulin sensitivity within the first four weeks, paralleling observations in the progression from normal to IGT in humans. Calculations of the insulinogenic index using both insulin and C-peptide revealed a significant and sustained decrease in early-phase insulin release, with partial compensation in the later phase, predominantly stemming from reduced hepatic insulin clearance. In addition, the Disposition Index, representing the β-cell’s capacity to compensate for diminished insulin sensitivity, fell dramatically. These results confirm that a HFFD can instigate metabolic changes in dogs akin to the early stages of progression to T2DM in humans. The study underscores the potential of using dogs subjected to a HFFD as a model organism for studying human IGT and T2DM.
Montane Central Appalachian Forests Provide Refuge for the Critically Endangered Rusty Patched Bumble Bee (Bombus affinis)
Authors: Hepner Mark J. , Orcutt Ellison , Price Kyle , Goodell Karen , Roulston T’ai , Jean Robert P. , Richardson Rodney T.
Published: October 2023

The mountains of Central Appalachia are rich with environmental variance and host a wide variety of community types and diverse flora and fauna. The once common Rusty-Patched Bumble Bee (RPBB,Bombus affinis) has experienced widespread declines and was believed to have been extirpated throughout the Lower Midwest, Northeast and Appalachian regions of the United States (U.S.). We document the occurrence and environmental associations of a contemporary population within Central Appalachia using a dataset of 274 observations spanning nine years and over 2,000 surveys. We show that Appalachian RPBB are strongly associated with high elevation, heavily forested landscapes, especially those with West to Northwest facing aspects. Measures of forest species composition are also associated with RPBB observations. While only 38 percent of surveys occurred on U.S. National Forest lands, 84 percent of observations occurred in these areas, suggesting distinct forest habitat conditions associated with U.S. Forest Service lands play a role in the persistence of this species. The Appalachian region is rugged and difficult to systematically survey, and our analysis represents the first assessment of the species presence and habitat associations within the region. Appalachian RPBB populations are likely geographically and genetically isolated from Upper Midwest populations and additional research is needed to prioritize future conservation efforts across the current and potential range of the species.
Visual impairment cell non-autonomously dysregulates brain-wide proteostasis
Authors: Shekhar Shashank , Wert Katherine J , Krämer Helmut
Published: October 2023

Loss of hearing or vision has been identified as a significant risk factor for dementia but underlying molecular mechanisms are unknown. In different Drosophila models of blindness, we observe non-autonomous induction of stress granules in the brain and their reversal upon restoration of vision. Stress granules include cytosolic condensates of p62, ATF4 and XRP1. This cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets during cellular stress. Cytosolic condensates of p62 and ATF4 were also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate conservation of the link between loss of sensory input and dysregulation of stress responses critical for protein quality control in the brain.

One-sentence summary

Drosophila and mouse models link loss of visual input to dysregulated stress responses of neurons and glia in the brain.
Endothelial Cell Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Mediates Vascular Stiffening
Authors: Zhang Liping , Sun Zhe , Yang Yan , Mack Austin , Rodgers Mackenna , Aroor Annayya , Jia Guanghong , Sowers James R. , Hill Michael A.
Published: October 2023

Background

Excess dietary salt increases vascular stiffness in humans, especially in salt- sensitive populations. While we recently suggested that the endothelial sodium channel (EnNaC) contributes to salt-sensitivity related endothelial cell (EC) and arterial stiffening, mechanistic understanding is incomplete. This study thus aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a regulator of sodium channels, in EC and arterial stiffening.

Methods and Results

A mouse model of salt sensitivity-associated vascular stiffening was produced by subcutaneous implantation of slow-release deoxycorticosterone acetate (DOCA) pellets, with salt (1% NaCl, 0.2% KCl) administered via drinking water. Preliminary data showed that global SGK1 deletion caused significantly decreased blood pressure, EnNaC activity and aortic endothelium stiffness as compared to control mice following DOCA-salt treatment. To probe EC signaling pathways, selective deletion of EC-SGK1 was performed by cross-breeding cadherin 5-Cre mice with sgk1flox/floxmice. DOCA-salt treated control mice had significantly increased blood pressure, EC and aortic stiffness in vivo and ex vivo, which were attenuated by EC-SGK1 deficiency. To demonstrate relevance to humans, human aortic ECs were cultured in the absence or presence of aldosterone and high salt with or without the SGK1 inhibitor, EMD638683 (10uM or 25uM). Treatment with aldosterone and high salt increased intrinsic stiffness of ECs, which was prevented by SGK1 inhibition. Further, the SGK1 inhibitor prevented aldosterone and high salt induced actin polymerization, a key mechanism in cellular stiffening.

Conclusion

EC-SGK1 mediates salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation actin polymerization.

Graphical Abstract
Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug
Authors: Vilca Samara J , Margetts Alexander V , Fleites Isabella , Wahlestedt Claes , Tuesta Luis M
Published: October 2023

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation, and that post-methamphetamine microglial repopulation attenuates drug-seeking following a 21-day period of abstinence. In contrast, microglial depletion during abstinence did not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.
Variational Bayesian Phylogenies through Matrix Representation of Tree Space
Authors: Bouckaert Remco R.
Published: October 2023

In this paper, we study the distance matrix as a representation of a phylogeny by way of hierarchical clustering. By defining a multivariate normal distribution on (a subset of) the entries in a matrix, this allows us to represent a distribution over rooted time trees. Here, we demonstrate tree distributions can be represented accurately this way for a number of published tree distributions. Though such a representation does not map to unique trees, restriction to a subspace, in particular one we call a “cube”, makes the representation bijective at the cost of not being able to represent all possible trees. We introduce an algorithm “cubeVB” specifically for cubes and show through well calibrated simulation study that it is possible to recover parameters of interest like tree height and length. Although a cube cannot represent all of tree space, it is a great improvement over a single summary tree, and it opens up exciting new opportunities for scaling up Bayesian phylogenetic inference. We also demonstrate how to use a matrix representation of a tree distribution to get better summary trees than commonly used maximum clade credibility trees. An open source implementation of the cubeVB algorithm is available fromhttps://github.com/rbouckaert/cubevbas thecubevbpackage for BEAST 2.
Selective Cancellation of Reactive and Anticipated Movement: Differences in Speed of Action Reprogramming, but not Stopping
Authors: Weber Simon , Salomoni Sauro E. , Hinder Mark R.
Published: October 2023

The ability to inhibit movements is an essential component of a healthy executive control system. Two distinct but commonly used tasks to assess motor inhibition are the stop signal task (SST) and the anticipated response inhibition (ARI) task. The SST and ARI tasks are similar in that they both require cancelation of a prepotent movement; however, the SST involves cancelation of a speeded reaction to a temporally unpredictable signal, while the ARI task involves cancelation of an anticipated response that the participant has prepared to enact at a wholly predictable time.

33 participants (mean age = 33.3 years, range = 18-55 years) completed variants of the SST and ARI task. In each task, the majority of trials required bimanual button presses, while on a subset of trials a stop signal indicated that one of the presses should be cancelled (i.e., motor selective inhibition). Additional variants of the tasks also included trials featuring signals which were to be ignored, allowing for insights into the attentional component of the inhibitory response. Electromyographic (EMG) recordings allowed detailed comparison of the characteristics of voluntary action and cancellation.

The speed of the inhibitory process was not influenced by whether the enacted movement was reactive (SST) or anticipated (ARI task). However, the ongoing (non-cancelled) component of anticipated movements was more efficient than reactive movements, as a result of faster action reprogramming (i.e., faster ongoing actions following successful selective inhibition). Older age was associated with both slower inhibition and slower action reprogramming across all reactive and anticipated tasks.
Robust and Adaptive Deep Model Ensemble Framework Fine-tuned by Structural Information for Drug-Target Interactions
Authors: Wei Jinhang , Zhuo Linlin , Fu Xiangzheng , Zhang Junmin , Zeng Xiangxiang , Zou Quan
Published: October 2023

In the fields of new drug development and drug repositioning, drug-target interactions (DTI) play a pivotal role. Although deep learning models have already made significant contributions in this domain, the state-of-the-art models still exhibit shortcomings in predictive performance and issues of false-negative errors. Based on these observations, we constructed a streamlined yet effective base learner model. With our designed adaptive feature weight network, the model can capture key features within drugs (targets). Furthermore, by cross-partitioning the training data, multiple base learners are integrated into a powerful ensemble model named EADTN. The performance of the model is further enhanced as the number of base learners increases. Additionally, we employed a single-linkage clustering algorithm to cluster drugs and proteins and leveraged this clustering information to fine-tune the base learners, which elevates the value of EADTN in real-world applications like drug repositioning and targeted drug development. Our designed substructure importance ranking method also demonstrates the model’s exceptional capability to recognize key substructures. Benefiting from the model’s low generalization error capability, we successfully identified false-negative samples within the dataset, revealing new interaction relationships. Experimental results indicate that EADTN consistently outperforms existing state-of-the-art models across multiple datasets. More importantly, the ensemble learning and clustering fine-tuning approaches adopted by our model offer a fresh perspective for related fields.
Ecdysone Orchestrates Notch and Broad Symphony to Craft Epithelial Cell Shape Change
Authors: Ghosh Gaurab , Halder Sudipta , Sahu Aresh , Prasad Mohit
Published: October 2023

Morphogenesis in the metazoans relies on cell shape transformations that forms an integral component of organ development, form generation and maintenance of tissue homeostasis. Nevertheless, a comprehensive grasp of how the epithelial morphogenesis is modulated in the metazoans remain still elusive. The Steroid hormones play a pivotal role in morphogenesis spanning several organs including the gonads, urogenital tracts, and mammary glands. Employing theDrosophilaoogenesis model, we investigated the the role of steroid hormone receptor, Ecdysone receptor (EcR) involvement in transforming anterior epithelial follicle cells (AFCs) from cuboidal to squamous shape. Consistent with the fact that the activity of EcR in the AFCs coincides with the timing of cuboidal-to-squamous shape transition, we found that depletion of EcR function impedes the shape transformation of AFCs. We report that EcR doesn’t impair the follicle cell fate, but impedes the morphological change by restricting the remodelling of lateral and adherens junctions. Employing the classical genetic tools and immnohistochemistry, we show that EcR limits the Notch-Broad axis to facilitate alteration of the shape of AFCs. Our study suggests a mechanistic model where Ecdysone signalling, via the Notch pathway, finetunes the activity of non-muscle myosin heavy chain zipper, prompting AFC shape transition. In sum, our work illuminates how Ecdysone signalling orchestrates epithelial follicle cell morphogenesis during metazoan development.
Generation of circulating autoreactive pre-plasma cells fueled by naïve B cells in celiac disease
Authors: Lindeman Ida , Høydahl Lene S. , Christophersen Asbjørn , Risnes Louise F. , Jahnsen Jørgen , Lundin Knut E. A. , Sollid Ludvig M. , Iversen Rasmus
Published: October 2023

Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific IgA plasma cells are abundant in gut biopsies of patients. We here describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells were found in untreated patients on a gluten-containing diet but not in controls. They were clonally related to TG2-specific small intestinal plasma cells, and they expressed gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells were negative for CD27, placing them in the double negative (IgD-CD27-) category. They had a plasmablast or activated memory B-cell phenotype, and they harbored fewer variable region mutations than other IgA cells. Based on their similarity to naïve B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naïve B cells via an extrafollicular response involving gluten-specific CD4+ T cells.
A novel amphibian sex determination candidate gene, evolved by structural variation in the regulatory region between X and Y
Authors: Kuhl Heiner , Tan Wen Hui , Klopp Christophe , Kleiner Wibke , Koyun Baturalp , Ciorpac Mitica , Feron Romain , Knytl Martin , Kloas Werner , Schartl Manfred , Winkler Christoph , Stöck Matthias
Published: October 2023

Most vertebrates develop distinct females and males, where sex is determined by repeatedly-evolved environmental or genetic triggers. Undifferentiated sex chromosomes and large genomes have caused major knowledge gaps in amphibians. Only a single master gene is known in >8650 species, thedmrt1-paralogue (dm-w) of female-heterogametic clawed frogs (Xenopus; ZW♀/ZZ♂). Combining a chromosome-scale genome of a non-model amphibian, the European green toad,Bufo(tes)viridis, with ddRAD- and whole genome pool-sequencing revealed a novel candidate master gene (bod1l), governing a male-heterogametic system (XX♀/XY♂). Targeted sequencing across multiple taxa and a male long-read assembly uncovered structural X/Y-variation in the 5’-regulatory region, where a Y-specific non-coding RNA, only expressed in males, suggests regional enhancer-properties. Developmental transcriptomes and RNAin-situhybridization provide evidence for timely and spatially relevant, sex-specificbod1l-gene expression in primordial gonads with coinciding differentialH3K4me-methylation in pre-granulosa/pre-Sertoli cells, pointing to a novel mechanism of amphibian sex determination.
Body-part specificity for learning of multiple prior distributions in human coincidence timing
Authors: Matsumura Yoshiki , Roach Neil W. , Heron James , Miyazaki Makoto
Published: October 2023

During timing tasks, the brain learns the statistical distribution of target intervals and integrates this prior knowledge with sensory inputs to optimise task performance. Daily events can have different temporal statistics (e.g. fastball/slowball in baseball batting), making it important to learn and retain multiple priors. However, the rules governing this process are not yet understood. Here, we demonstrate that the learning of multiple prior distributions in a coincidence timing task is characterised by body-part specificity. In our experiments, two prior distributions (short and long intervals) were imposed on participants. When using only one body part for timing responses, regardless of the priors, participants learned a single prior by generalising over the two distributions. However, when the two priors were assigned to different body parts, participants concurrently learned the two independent priors. Moreover, body-part specific prior acquisition was faster when the priors were assigned to anatomically distant body parts (e.g. hand/foot) than when they were assigned to close body parts (e.g. index/middle fingers). This suggests that the body-part specific learning of priors is organised according to somatotopy.