bluuebunny/crossref_metadata_2025 huggingface dataset:
An shRNA screen in primary human beta cells identifies the serotonin 1F receptor as a negative regulator of survival during transplant
Authors: Lee Rebecca A. , Chopra Deeksha G. , Nguyen Vinh , Huang Xi-Ping , Zhang Yaohuan , Shariati Kaavian , Yiv Nicholas , Schugar Rebecca , Annes Justin , Roth Bryan , Ku Gregory M.
Published: May 2024

Islet transplantation can cure type 1 diabetes, but peri-transplant beta cell death limits this procedure to those with low insulin requirements. Improving human beta cell survival or proliferation may make islet transplantation a possibility for more type 1 patients. To identify novel regulators of beta cell survival and proliferation, we conducted a pooled small hairpin RNA (shRNA) screen in primary human beta cells transplanted into immunocompromised mice. shRNAs targeting several cyclin dependent kinase inhibitors were enriched after transplant. Here, we focused on the Gi/o-coupled GPCR, serotonin 1F receptor (HTR1F,5-HT1F) which our screen identified as a negative regulator of beta cell numbers after transplant.In vitro, 5-HT1Fknockdown induced human beta cell proliferation but only when combined with harmine and exendin-4.In vivo, knockdown of 5-HT1Freduced beta cell death during transplant. To demonstrate the feasibility of targeting 5-HT1Fin islet transplant, we identified and validated a small molecule 5-HT1Fantagonist. This antagonist increased glucose stimulated insulin secretion from primary human islets and cAMP accumulation in primary human beta cells. Finally, the 5-HT1Fantagonist improved glycemia in marginal mass, human islet transplants into immunocompromised mice. We identify 5-HT1Fas a novel druggable target to improve human beta cell survival in the setting of islet transplantation.

One Sentence Summary

Serotonin 1F receptor (5-HT1F) negatively regulates insulin secretion and beta cell survival during transplant.
Identification and Expression Analysis of CDPK Family inEriobotrya japonica, revealsEjCDPK25in Response to Freezing Stress in Fruitlets
Authors: Xiong Yifan , Lin Shunquan , Wu Jincheng , Lin Shoukai
Published: May 2024

The fruitlets of loquat (Eriobotrya japonicaLindl.) are susceptible to freezing injury due to their developmental cycle encountering winter. Freezing stress severely damages the fruitlets, resulting in loss of fruit yield and quality. Studies have shown that Ca2+, as a second messenger, is involved in signal transduction in loquat fruitlets under freezing stress. However, the mechanism of downstream calcium signal transduction in loquat fruitlets under freezing stress is currently unclear. Calcium-depend protein kinase (CDPK) as the most particular calcium sensor family in plants, play an important role in multiple stress signal transduction including freezing. In this study, we identified the loquat CDPK family on a genome-wide scale. A total of 34EjCDPKgenes were identified and studied for basic structural and phylogenetic features. EjCDPKs can be divided into four subgroups phylogenetically. The patterns of exon-intron and protein motif are highly conserved among the subgroups. Collinearity analysis identified several segmental duplicate events in EjCDPK family. RNA-seq based transcription analysis indicated that partial ofEjCDPKs differently expressed in response to freezing stress with tissue-specific. Moreover, we preformed correlation analysis between expression value and trait data of loquat fruitlet under freezing stress by weighted co-expression gene network. After that,EjCDPK25was selected as the candidate because of its potential freezing stress response function. Protein kinase related GO terms were enriched inEjCDPK25co-expression genes, and then QPCR was performed to examine the target gene’s expression pattern. In addition,EjCDPK25was cloned to construct overexpression vector to obtain transgenicArabidopsisplants. Transgenic and wild-typeArabidopsiswere suffered freezing stress treatments (-5°C). The results showed that the survival rate ofEjCDPK25overexpressing transgenicArabidopsiswas significantly higher than WT. In summary, this study identified loquat CDPK family firstly, and our data provide significant insights into the evolution and function of loquat CDPKs. Above all, a freezing stress response geneEjCDPK25was verified can increase the resistance of freezing stress inArabidopsis.
The Ithildin library for efficient numerical solution of anisotropic reaction-diffusion problems in excitable media
Authors: Kabus Desmond , Cloet Marie , Zemlin Christian , Bernus Olivier , Dierckx Hans
Published: May 2024

Ithildin is an open-source library and framework for efficient parallelized simulations of excitable media, written in the C++ programming language. It uses parallelization on multiple CPU processors via the message passing interface (MPI). We demonstrate the library’s versatility through a series of simulations in the context of the mono-domain description of cardiac electrophysiology, including the S1S2 protocol, spiral break-up, and spiral waves in ventricular geometry. Our work demonstrates the power of Ithildin as a tool for studying complex wave patterns in cardiac tissue and its potential to inform future experimental and theoretical studies. We publish our full code with this paper in the name of open science.

Author summary

We present Ithildin, an open-source library for reaction-diffusion systems such as the electrical waves in cardiac tissue controlling the heart beat. We demonstrate the versatility of Ithildin by example simulations in various tissue models and geometries, from simple 2D simulations to detailed ones in ventricular geometry. Our simulations highlight key features of Ithildin, such as recording pseudo-electrograms or filament trajectories. We hope that our work will contribute to the growing understanding of cardiac electrophysiology and inform future experimental and theoretical studies.
PfHT1 controls glucose uptake in malaria parasite: molecular dynamics study in plasma membrane like environment reveals ligand induced conformational changes trigger closed conformation and alters binding pocket geometry
Authors: Ganguly Manisha , Maitra Hriddhi , Roychowdhury Amlan , Hazra Ditipriya
Published: May 2024

Plasmodium falciparumhexose transporter 1 protein or PfHT1 is the major glucose transporter of the parasite and indispensable for its survival at the blood stage of infection. PfHT1 transports the hexose sugar to meet the energy demand of the parasite. Studying the mechanism of transport and designing structure specific inhibitors against PfHT1 is an intelligent strategy to kill malaria parasite by starving it out because at the blood stage the sole carbon source ofPlasmodium falciparumis glucose. In this study the conformational dynamics of PfHT1 has been studied in detail in the apo and holo (inhibitor bound) form using Molecular Dynamics Simulation. Which reveals that PfHT1 undergoes ligand induced closed state if compared with the apo form. The geometry of ligand binding pocket also shifts from the apo form in the presence of inhibitors. A de novo drug designing approach based on the skeleton of leads obtained from screening nearly 4500 compounds, has produced inhibitors of PfHT1 with higher specificity and affinity. The drug screening data as well as the conformational dynamics study was validated using Molecular Dynamics Simulation platform where a near physiological atmosphere was created for PfHT1 by constructing a lipid phase (phospholipid bilayer) sandwiched between aqueous phases (mimics extracellular and cytosolic polar environment).
The effect of climate change on the spread of predicted bluetongue in Australian livestock
Authors: Al-Riyami S , Firestone SM , Eagles D , Bradhurst R , Stevenson MA
Published: May 2024

Introduction

The frequency of vector-borne disease in human and animal populations has increased in recent years leading to concerns that even greater increases will occur as a result of climate change, driven by changes in the geographic distribution of insect vector habitat areas. In this study we investigate the effect of climate change on the expected spread of bluetongue (a viral disease of ruminants spread byCulicoidesmidges) using the Australian Animal Disease Spread model (AADIS).

Methods

Estimates of average daily temperature across Australia for 2015 were obtained from the Australian Bureau of Meteorology. Predicted average daily temperatures using the CanESM2 model (emission scenario RCP 8.5) for 2025 and 2035 at a resolution of 5 km × 5 km were obtained from the Australian Climate Futures decision-support tool, managed by CSIRO. Two study areas in Australia were selected: the first in North Queensland and the second in Northern New South Wales. A total of 24 outbreak scenarios were run: mid-summer and mid-winter incursions for each study area for 2015, 2025 and 2035 with direct movement of animals in the AADIS model disabled and enabled for each. Model results were expressed as the number bluetongue-positive herds, (herds in which at least one animal was BTV positive) at the end of each 365 day simulation period.

Results

For North Queensland, there was little change in the median predicted number of bluetongue positive herds for mid-summer and mid-winter 2025 and 2035 incursions (compared with 2015) and a moderate increase in the variability of predicted outbreak sizes when direct animal movements were disabled. For Northern New South Wales there were moderate increases in both the predicted number of bluetongue positive herds and the variability of predicted outbreak sizes for 2025 and 2035, compared with 2015. Compared with the direct animal movement disabled scenarios, there were marked increases in the predicted number of bluetongue positive herds as a function of simulation year for North Queensland. For Northern New south Wales this trend was not as distinct, but as for the direct movement disabled scenarios, the variability of predicted outbreak sizes for the 2035 incursions were greater than the variability of predicted outbreak sizes for the 2015 incursions.

Conclusion

Climate change will result in a greater portion of the land area of Australia with conditions suitable forCulicoidesmidges. Our findings show that under conditions of climate change and an outbreak of virulent bluetongue in Australia, the rapid imposition of effective restrictions of animal movement will be the single most important control measure to limit further spread of disease.
PATHOGEN GROWTH AND VIRULENCE DYNAMICS DRIVE THE HOST EVOLUTION AGAINST COINFECTIONS
Authors: Seal Srijan , Basu Dipendra Nath , Ghosh Kripanjali , Ramachandran Aryan , Kutum Rintu , Shelke Triveni , Gupta Ishaan , Khan Imroze
Published: May 2024

Coinfections, or the simultaneous infection of hosts by multiple pathogens, are widespread in nature with significant negative impacts on global health. Can hosts evolve against such coinfections as effectively as they would against individual pathogens? Also, what roles do individual pathogens play during such evolution? Here, we combined theoretical models and experiments withTribolium castaneumpopulations evolving against two coinfecting bacterial pathogens, with contrasting growth and virulence dynamics, to reveal that fast-growing pathogens inflicting rapid mortality surges (i.e., fast-acting) restrict adaptive success against coinfections. While hosts rapidly evolved better survival against slow-growing bacteria causing long-lasting infections, evolution against coinfection was significantly delayed and resembled slow adaptation against fast-acting pathogens. Moreover, limited scopes of immunomodulation against fast-acting pathogens during coinfections can drive the observed adaptive patterns. Overall, we provide new insights into how adaptive dynamics and mechanistic bases against coinfections are critically regulated by individual pathogens’ growth and virulence dynamics.
SLAYER: A Computational Framework for Identifying Synthetic Lethal Interactions through Integrated Analysis of Cancer Dependencies
Authors: Cohen Ziv , Petrenko Ekaterina , Barisaac Alma Sophia , Abu-Zhayia Enas R. , Yanovich-Ben-Uriel Chen , Ayoub Nabieh , Aran Dvir
Published: May 2024

Synthetic lethality represents a promising therapeutic approach in precision oncology, yet systematic identification of clinically relevant synthetic lethal interactions remains challenging. Here we present SLAYER (Synthetic Lethality AnalYsis for Enhanced taRgeted therapy), a computational framework that integrates cancer genomic data and genome-wide CRISPR knockout screens to identify potential synthetic lethal interactions. SLAYER employs parallel analytical approaches examining both direct mutation-dependency associations and pathway-mediated relationships across 808 cancer cell lines. Our integrative method identified 4,332 statistically significant interactions, which were refined to 142 high-confidence candidates through stringent filtering for effect size, druggability, and clinical prevalence. Systematic validation against protein interaction databases revealed a 15-fold enrichment of known associations among SLAYER predictions compared to random gene pairs. Through pathway-level analysis, we identified inhibition of the aryl hydrocarbon receptor (AhR) as potentially synthetically lethal with RB1 mutations in bladder cancer. Experimental studies demonstrated selective sensitivity to AhR inhibition in RB1-mutant versus wild-type bladder cancer cells, which probably operates through indirect pathway-mediated mechanisms rather than direct genetic interaction. In summary, by integrating mutation profiles, gene dependencies, and pathway relationships, our approach provides a resource for investigating genetic vulnerabilities across cancer types.
An FDA-Approved Assay Platform Can Detect Biomarkers of Neuronal and Glial Injury in the Blood of COVID-19 Patients
Authors: Glushakov Alexander V. , Vittor Amy Y. , Lewis Lawrence , House Stacey , Bartlett Maggie L. , Glushakova Olena Y. , Urbine Dan , Smith Darci R. , Hayes Ronald L
Published: May 2024

Employing assays approved by the U.S. Food and Drug Administration (FDA) to assist in detection of brain injury in mild traumatic brain injury (TBI) patients, this study demonstrated that the astroglial protein, glial fibrillary acidic protein (GFAP) and the neuronal protein, ubiquitin C-terminal hydrolase (UCH-L1) were positively associated with age in COVID-19 patients. Controlling for age, UCH-L1 and GFAP were significantly elevated in COVID-19 patients compared to non-COVID-19 controls, and UCH-L1, but not GFAP, was elevated in patients with neurological alterations. Data from this study are also compared to historical data on levels of UCH-L1 and GFAP in brain injured and healthy normal patients. These data support further studies of an FDA approved assay format that could facilitate timely development, validation, and FDA approval of blood tests to detect neuronal and glial cell injuries following infection by SARS-CoV-2. Moreover, appropriately validated blood tests could detect brain injury originating from any systemic pathogen.
RANDOMIZED CONTROL STUDY TO ANALYSE THE EFFICACY BUDESONIDE NASAL DOUCHING ON ALLERGIC FUNGAL RHINOSINUSITIS
Authors: TR Sowparnika , Ramaneeshwaran  , Bhalla Ashu Seith , Madan Karan , Gupta Yashdeep , Srivastava Rupesh K , Viswanathan Ganesh Kumar , Singh Gagandeep , Thakar Alok , Kumar Rakesh , Sikka Kapil , Pachaury Shuchita Singh , Verma Hitesh
Published: May 2024

INTRODUCTION

Allergic Fungal Rhinosinusitis is a hypersensitivity against fungal antigens. Primary surgical management is complimented with medical management in preoperative and postoperative phases for better intraoperative field & to limit the recurrence. The effect of systemic steroids & itraconazole showed promising outcomes as a solo agent or in combination under preoperative status. Recent studies showed auspicious conclusions with steroid-based nasal douches. The current study aims to assess the effectiveness of medical management in combination with steroid-based nasal douches.

METHODOLOGY

This prospective study will recruit 40 clinico-radiological proven cases of AFRS after ethical approval. The study population will be randomized into two groups based on a computer program. Group A will receive systemic itraconazole and steroids & Group B will receive additional budesonide nasal douching. The outcomes will be studied clinically by SNOT-22 scoring system & Meltzer nasal polyp scoring system, biochemically with absolute eosinophil counts, aspergillus specific IgE and total IgE, radiologically with Lund-Mackay system and 20-point CT scoring system after 6 weeks of initiation of the treatment.

ETHICS AND DISSEMINATION

We received an AIIMS ethical board. Ref no-AIIMSA00641 dated 21.03.24 & CTRI (Clinical Trial Registry India) acknowledgement number - REF/2024/03/081566 dated 29. 03.24. We will follow the ethical committee protocol and instructions received from reviewers.

STRENGTHS

AFRS is a bothersome illness both for treating doctors and patients. This study is a pilot study on a combination of past and recently proven medical therapies for AFRS.

The study will generate data on new or complete medical management for AFRS.

The duration of planned treatment is 6 weeks. The study will generate data for future studies where prolonged medical treatment can be planned.

LIMITATIONS

This will be a single-centred study. The validation for the expected outcome will require a multicentric study.

The study topic is planned for an MS student thesis so the follow-up period will be 3-6 months.
Relapse prediction in multiple myeloma patients treated with isatuximab, carfilzomib, and dexamethasone
Authors: Myklebust Even Moa , Schjesvold Fredrik , Frigessi Arnoldo , Leder Kevin , Foo Jasmine , Köhn-Luque Alvaro
Published: May 2024

Multiple myeloma (MM) patients experience repeated cycles of treatment response and relapse, yet despite close monitoring of disease status through M protein measurements, no standard model exists for relapse prediction in MM. We investigate the feasibility of predicting relapse using a hierarchical Bayesian model of subpopulation dynamics by training and testing the model on 229 patients from the IKEMA trial.

After observing between 11 and 18 treatment cycles, the model predicted relapse within six cycles with an average sensitivity between 60 and 80 %, and an average specificity between 60 and 90 %. A model of linear extrapolation is preferable when patients have been observed for less than 6 cycles, but for longer observation windows the hierarchical Bayesian model is preferred. Including available baseline and longitudinal covariate information did not improve predictive accuracy. A survival analysis showed that two model parameters separated patients into groups with significantly different PFS (p <0.001).

Statement of Significance

Currently, no standard model exists for relapse prediction in multiple myeloma. A personalized model of M protein development could guide the frequency of follow-up measurements, reduce uncertainty for patients, and give clinicians more time to choose the best subsequent treatment for each patient. Furthermore, models that predict relapse are required to study the effect of changing treatment in advance of relapse rather than in response to it. Our work addresses this need by developing a hierarchical Bayesian model of subpopulation dynamics for prediction of future M protein values. We validate the model on a patient cohort treated with state-of-theart CD38 inhibitor therapy and show that it can accurately predict relapse within the next six treatment cycles, highlighting the promise of mathematical modeling in multiple myeloma and for personalized medicine in general.

Declaration of Interests

F.S. received honorarium from Sanofi, Janssen, BMS, Oncopeptides, Abbvie, GSK, and Pfizer. The authors declare that they have no other conflicts of interest.
Explanations for higher-than-expected mortality from April 2021: a scoping review
Authors: Scott Fiona , McCartney Gerry , Walsh David , Wild Sarah , Rae David , Ramsay Julie , Donaghy Grant , Douglas Margaret
Published: May 2024

Objectives

Many countries have continued to experience a higher-than-expected number of deaths following the peaks in mortality observed in the first year of the Covid-19 pandemic. This scoping review aims to identify the different explanations proposed for sustained higher-than-expected mortality beyond the first pandemic year.

Study design

Scoping review

Methods

A systematic search of databases and grey literature sources was completed to identify English-language records proposing or investigating hypotheses for higher-than-expected mortality from April 2021 onwards in (sub)populations of high-income countries. Papers focused on survival following a diagnosis or intervention were excluded. Results were summarised narratively, and existing research prioritisation frameworks were adapted and applied to identify the hypotheses proposed as highest priority for further research.

Results

Seventy eligible papers were identified. Most were opinion pieces or simply presented trends; few included investigation of suggested hypotheses. Numerous explanations for higher-than-expected mortality were proposed, with hypotheses relating to direct Covid-19 mortality, sequalae of Covid-19 infection, the health service impacts of the pandemic, wider pandemic impacts and socioeconomic factors identified as highest-priority for further research.

Conclusions

The causes of continued higher-than-expected mortality are likely to be multiple and potentially interactive. This review will help to shape research into current mortality trends, with a critical understanding of this topic essential for achieving evidence-informed policy.
Circulation of DENV-2 serotype associated with increased risk of cumulative incidence of severe dengue and dengue with warning signs: A 16-year retrospective study in Peru
Authors: Cañari-Casaño Jorge L. , Paz-Soldan Valerie A. , Lescano Andres G. , Morrison Amy C.
Published: May 2024

Background

Dengue poses a significant public health challenge in Peru and other endemic countries worldwide. While severe dengue is known to be associated with secondary infection at the individual level, the factors that elevate the risk of severe dengue at the population level remain poorly understood. This study leverages over 16 years of secondary data from a Peruvian dengue surveillance system to assess which type of serotype-specific circulation is associated with an increased risk of cumulative incidence of severe dengue or dengue with warning signs (SD-DWS).

Methodology

This is a retrospective analysis of secondary data using the Peruvian Ministry of Health databases of dengue cases and serotyping. A mixed negative binomial regression model for repeated measures over time was employed to estimate the association between the cumulative incidence of reported SD-DWS cases per 100,000 inhabitants and serotype-specific circulation. Crude and adjusted incidence ratios (IRR) were estimated.

Principal findings

The study analyzed data from 2007 to 2022 across 19 regions of Peru, totaling 304 region-years. Data from nearly 58,000 serotype identification reports and 57,966 cases of SD-DWS were analyzed. The regions with most cumulative incidence of SD-DWS per 100,000 inhabitants during 2007 to 2022 were Madre de Dios (3859), Loreto (1518), Ucayali (1492), Tumbes (1335), and Piura (722). The adjusted model revealed a higher risk of cumulative incidence of SD-DWS when there was specific circulation of DENV-123 (aIRR 7.57 CI 4.00 – 14.31), DENV-12 (aIRR 4.66 CI 2.57 – 8.44), DENV-23 (aIRR 3.55 CI 1.75 – 7.21), or when there was circulation of DENV-2 alone or co-circulating with other serotypes (aIRR 27.7 CI 15.46 -49.63).

Conclusions

Circulation of DENV-2 was associated with higher average incidence rate ratios of SD-DWS.

Author summary

We investigated how the circulation of different dengue virus (DENV) serotypes are associated with the incidence of severe dengue and dengue with warning signs in Peru, a country where dengue is endemic. We analyzed 16 years of data from the dengue surveillance system, including nearly 58,000 serotype identification reports and 57,966 cases of severe dengue and dengue with warning signs. We found that regions with specific circulation of DENV-2, either alone or in combination with other serotypes, had higher incidence rates of severe dengue and dengue with warning signs. Our findings highlight the importance of monitoring DENV serotype circulation to manage and prevent severe dengue, especially in regions where DENV-2 is prevalent.
X-Chromosome-wide association study for Alzheimer’s disease
Authors: Le Borgne Julie , Gomez Lissette , Heikkinen Sami , Amin Najaf , Ahmad Shahzad , Choi Seung Hoan , Bis Joshua , Grenier-Boley Benjamin , Rodriguez Omar Garcia , Kleineidam Luca , Young Juan , Tripathi Kumar Parijat , Wang Lily , Varma Achintya , van der Lee Sven , Damotte Vincent , de Rojas Itziar , Palmal Sagnik , Giedraitis Vilmantas , Ghidoni Roberta , Fernandez Victoria , Kehoe Patrick Gavin , Frikke-Schmidt Ruth , Tsolaki Magda , Sánchez-Juan Pascual , Sleegers Kristel , Ingelsson Martin , Haines Jonathan , Farrer Lindsay , Mayeux Richard , Wang Li-San , Sims Rebecca , DeStefano Anita , Schellenberg Gerard D. , Seshadri Sudha , Amouyel Philippe , Williams Julie , van der Flier Wiesje , Ramirez Alfredo , Pericak-Vance Margaret , Andreassen Ole , Van Duijn Cornelia , Hiltunen Mikko , Ruiz Agustín , Dupuis Josée , Martin Eden , Lambert Jean-Charles , Kunkle Brian , Bellenguez Céline
Published: May 2024

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To finally address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified four X-chromosome-wide significant loci (P ≤ 1.7 × 10−6). Two signals locate in theFRMPD4andDMDgenes, while the two others are more than 300 kb away from the closest protein coding genesNLGN4XandGRIA3. Overall, this XWAS found no common genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
Prevalence and Factors Associated with Moderate-to-Severe Anaemia Among Virally Suppressed People with HIV at a Tertiary Hospital in Zambia
Authors: Kamvuma Kingsley , Masenga Sepiso K. , Hamooya Benson M. , Chanda Warren , Munsaka Sody
Published: May 2024

Objective

Anaemia is associated with an increased risk of disease progression and all-cause mortality among HIV-infected individuals, regardless of the type of anaemia, but the magnitude of the risk is greater with more severe anaemia. Although anaemia PLWH has been extensively studied, the focus has primarily been on its prevalence and association with disease progression in untreated or poorly controlled HIV cases. This study aimed to investigate the prevalence, and factors associated with moderate-to-severe anaemia among virally suppressed HIV patients at a tertiary hospital in Zambia.

Methods

We conducted a cross-sectional study of ART treated PLWH for at least 6 months between October 2023 and February 2024 at Livingstone University Teaching Hospital (LUTH). Sociodemographic, clinical, and laboratory were the data collected. Anaemia was defined based on the World Health Organisation (WHO) classification, as haemoglobin concentration lower than normal i.e. <12 g/dl in females and <13 g/dl in males. The primary outcome was moderate-to-severe anaemia defined as haemoglobin level below 10.9 g/dl based World Health Organisation (WHO) classification. Logistic regression was performed to identify factors associated with moderate-to-severe anaemia.

Results

Among 823 participants with viral suppression, the overall prevalence of anaemia and moderate-to-severe anaemia was 29.4% (n=242; 95% confidence interval (CI): 26.3-32.6) and 14.2% (n=117, 95% CI: 11.7-18), respectively. Females exhibited significantly higher odds of moderate-to-severe anaemia compared to males (adjusted odds ratio (AOR) 2.65; 95% confidence interval (CI): 1.21-5.81). Lower lymphocyte count (AOR 0.542; 95% CI: 0.33-0.90), higher BMI (AOR 1.06; 95% CI: 1.01-1.12), and Microcytosis (AOR 14.35; 95% CI: 7.33 - 28.08) were associated with increased odds of anaemia. Participants on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens had a higher likelihood of anaemia compared to those on integrase strand transfer inhibitor (INSTI) regimens (AOR 5.16; 95% CI: 1.02-26.24).

Conclusion

We found a higher prevalence of anaemia and moderate-to-severe anaemia in virally suppressed PLWH, suggesting factors beyond HIV contribute to the persistence of anaemia in this cohort. Female gender, lower lymphocyte count, higher BMI, low mean corpuscular volume, and NNRTI-based ART regimens were independently associated with moderate-to-severe anaemia. Further research is warranted to explain the underlying mechanisms and optimize clinical management to improve outcomes among virally suppressed PLWH.
Optimised oxygenation improves functional capacity during daily activities in patients with COPD on long-term oxygen therapy – a randomised crossover trial
Authors: Kofod Linette Marie , Hansen Ejvind Frausing , Brocki Barbara Cristina , Kristensen Morten Tange , Roberts Nassim , Westerdahl Elisabeth
Published: May 2024

Background

Minimising hypoxemia during submaximal walking tests has a positive effect on exercise capacity and dyspnea in patients with COPD on long-term oxygen therapy (LTOT). However, the impact of optimising oxygenation during everyday tasks remains unexplored. Therefore, we investigated the effects of maintaining a target saturation on activities of daily living (ADL) using automated oxygen titration compared to conventional fixed oxygen flow.

Methods

In a double-blinded, randomised crossover trial, 31 patients with COPD on LTOT performed two GlittreADL tests to assess the functional capacity of everyday activities using a) their fixed oxygen dose and b) an adjusted flow from 0-8 L/min targeting a SpO2of 90-94%. A closed-loop device automatically titrated the oxygen based on information from a Bluetooth wrist pulse oximeter.

Results

The patients reduced the time to perform the ADL-test by median (IQR) 38 (12–73) seconds, p<0.001, using automated titration compared to the fixed oxygen flow. The oxygen flow in the automated arm more than tripled to 5.4 (4.1–6.8) vs. 1.6 (1.1–2.1) L/min (fixed) during the test, p<0.001, while the time spent within SpO2-target was increased from 19% to 49%, p=0.002. Correspondingly, the patients experienced less dyspnea (BorgCR10); 5 (3–7) vs. 6 (4–8), p<0.001, in favour of the automated oxygen titration.

Conclusions

Improving oxygenation and extending the time spent within target saturation reduced dyspnea and improved functional capacity in activities of daily living in patients with COPD on LTOT.

Trial registration number

NCT05553847
Home and wild food procurement was associated with greater intake of fruits and vegetables during the COVID-19 pandemic in northern New England
Authors: McCarthy Ashley C. , Angle Ashleigh , Bliss Sam , Bertmann Farryl , Belarmino Emily H. , Rose Kelsey , Niles Meredith T.
Published: May 2024

Objective

This study examined the effect of home and wild food procurement (HWFP) activities (i.e., gardening, hunting, fishing, foraging, preserving food, raising livestock, and raising poultry for eggs) on food security status, fruit and vegetable intake, and meat consumption.

Design

We used data collected in 2021 and 2022 through two statewide representative surveys (n = 2,001). Dietary intake was assessed using the Dietary Screener Questionnaire. We analyzed the data using linear regression, logistic regression, and ordinal logistic regression models.

Setting

Maine and Vermont, United States

Participants

2,001 adults (18 years and older)

Results

Sixty-one percent of respondents engaged in HWFP activities; the majority of those gardened. Households engaging in most individual HWFP activities had greater odds of being food insecure. HWFP engagement was positively associated with fruit and vegetable consumption. Specifically, gardening was associated with an additional one cup-equivalent in fruit and vegetable consumption per week compared to respondents that did not garden. Furthermore, when exploring these relationships disaggregated by food security status, we find that this effect is stronger for food insecure households than food secure households. Respondents from households that hunted were more likely to eat wild game meat and also consumed red and white meat more frequently compared to households that did not hunt.

Conclusion

Overall, our results indicate potential public health and food security benefits from engaging in HWFP activities. Future research should continue to examine a full suite of HWFP activities and their relationship to diet, health, and food security.
Brain lesions causing parkinsonism versus seizures map to opposite brain networks
Authors: Schaper Frederic L.W.V.J. , Morton-Dutton Mae , Drew William , Khosravani Sanaz , Joutsa Juho , Fox Michael D.
Published: May 2024

Recent epidemiological studies propose an association between parkinsonism and seizures, but the direction of this association is unclear. Focal brain lesions causing new-onset parkinsonism versus seizures may provide a unique perspective on the causal relationship between the two symptoms and involved brain networks. We studied lesions causing parkinsonism versus lesions causing seizures and utilized human connectome data to identify their connected brain networks. Brain networks for parkinsonism and seizures were compared using spatial correlations on a group and individual lesion level. Lesions not associated with either symptom were used as controls. Lesion locations from 29 patients with parkinsonism were connected to a brain network with the opposite spatial topography (spatialr=-0.85) compared to 347 patients with lesions causing seizures. A similar inverse relationship was found when comparing the connections that were most specific for lesions causing parkinsonism versus seizures on a group level (spatialr=- 0.51) and on an individual lesion level (average spatialr=-0.042; p<0.001). The substantia nigra was found to be most positively correlated to the parkinsonism network but most negatively correlated to the seizure network (spatialr>0.8). Brain lesions causing parkinsonism versus seizures map to opposite brain networks, providing neuroanatomical insight into conflicting epidemiological evidence.
Why do different people with Spinal Cord Injury have differing severity of symptoms with Autonomic Dysreflexia? Exploring relationships of vascular alpha-1 adrenoreceptor and baroreflex sensitivity after SCI
Authors: Higano Jennifer Dens , Burns Kathryn , Smith Geoffrey , Solinsky Ryan
Published: May 2024

Introduction

Individuals with spinal cord injury (SCI) commonly have autonomic dysreflexia (AD) with increased sympathetic activity. After SCI, individuals have decreased baroreflex sensitivity and increased vascular responsiveness.

Objective

To evalate relationship between baroreflex and blood vessel sensitivity with autonomic dysreflexia symptoms.

Design

Case control

Setting

Tertiary academic center

Patients

14 individuals with SCI, 17 matched uninjured controls

Interventions

All participants quantified AD symptoms using the Autonomic Dysfunction Following SCI (ADFSCI)-AD survey. Participants received three intravenous phenylephrine boluses, reproducibly increasing systolic blood pressure (SBP) 15-40 mmHg. Continuous heart rate (R-R interval, ECG), beat-to-beat blood pressures (finapres), and popliteal artery flow velocity were recorded. Vascular responsiveness (α1 adrenoreceptor sensitivity) and heart rate responsiveness to increased SBP (baroreflex sensitivity) were calculated.

Main outcome measures

Baroreflex sensitivity after increased SBP; Vascular responsiveness through quantified mean arterial pressure (MAP) 2-minute area under the curve and change in vascular resistance.

Results

SCI and control cohorts were well-matched with mean age 31.9 and 29.6 years (p=0.41), 21.4% and 17.6% female respectively. Baseline MAP (p=0.83) and R-R interval (p=0.39) were similar. ADFSCI-AD scores were higher following SCI (27.9+/-22.9 vs 4.2+/-2.9 in controls, p=0.002).

To quantify SBP response, MAP area under the curve was normalized to dose/bodyweight. Individuals with SCI had significantly larger responses (0.26+/-0.19 mmHg*s/kg*ug) than controls (0.06+/-0.06 mmHg*s/kg*ug, p=0.002). Similarly, leg vascular resistance increased after SCI (24% vs 6% to a normalized dose, p=0.007). Baroreflex sensitivity was significantly lower after SCI (15.0+/-8.3 vs 23.7+/-9.3 ms/mmHg, p=0.01). ADFSCI-AD subscore had no meaningful correlation with vascular responsiveness (R2=0.008) or baroreflex sensitivity (R2=0.092) after SCI.

Conclusions

While this confirms smaller previous studies suggesting increased α1 adrenoreceptor sensitivity and lower baroreflex sensitivity in individuals with SCI, these differences lacked correlation to increased symptoms of AD. Further research into physiologic mechanisms to explain why some individuals with SCI develop symptoms is needed.
Self-determination in minoritized autistic adolescents and adults
Authors: Girolamo Teresa , Birmingham Marissa , Patel Karina , Ghali Samantha , Campos Iván , Greene-Pendelton Kyle , Canale Rebecca , Larson Caroline , Sterling Audra , Shogren Karrie A.
Published: May 2024

Self-determination plays an important role in outcomes in autism and shows intersectional disparities. Yet, little is known about the role of individual differences or social drivers of health in the development of self-determination. Understanding these factors is key for developing effective supports. This mixed-methods convergent study examined self-determination in racially and ethnically minoritized autistic individuals and caregivers. Participants ages 13 to 30 (N= 73) varying widely in language and cognitive ability and caregivers (n=52) completed the Self-Determination Inventory. Autism traits and sense of community predicted caregiver report of self-determination, and autism traits and language predicted self-report of self-determination, consistent with DisCrit and Diversity Science. Self-Determination Inventory interviews of a subset of participants (n= 13) and caregivers (n= 9) were analyzed using inductive thematic analysis. Themes pointed to the role of the intersection of race and disability in shaping self-determination. Altogether, findings point to the importance of these frameworks, environmental influences, and multi-informant perspectives in characterizing self-determination. Future work should focus on the impact of environmental factors in self-determination in minoritized autistic individuals during the transition to adulthood.
The IQGAP-related RasGAP IqgC regulates cell-substratum adhesion in Dictyostelium discoideum
Authors: Mijanovic Lucija , Putar Darija , Mimica Lucija , Klajn Sabina , Filic Vedrana , Weber Igor
Published: May 2024

Proper adhesion of cells to their environment is essential for the normal functioning of single cells and multicellular organisms. To attach to the extracellular matrix (ECM), mammalian cells form integrin adhesion complexes consisting of many proteins that together link the ECM and the actin cytoskeleton. Similar to mammalian cells, the amoeboid cells of the protist Dictyostelium discoideum also use multiprotein adhesion complexes to control their attachment to the underlying surface. However, the exact composition of the multiprotein complexes and the signaling pathways involved in the regulation of adhesion in D. discoideum have not yet been elucidated. Here we show that the IQGAP-related protein IqgC is important for normal attachment of D. discoideum cells to the substratum. Mutant iqgC-null cells have impaired adhesion, whereas overexpression of IqgC promotes directional migration. A RasGAP C-terminal (RGCt) domain of IqgC is sufficient for its localization in the ventral adhesion focal complexes, while RasGAP activity of a GAP-related domain (GRD) is additionally required for the proper function of IqgC in adhesion. We identify the small GTPase RapA as a novel direct IqgC interactor and show that IqgC participates in a RapA-regulated signaling pathway targeting the adhesion complexes that include talin A, myosin VII and paxillin B. Based on our results, we propose that IqgC is a positive regulator of adhesion, responsible for the strengthening of ventral adhesion structures and for the temporal control of their subsequent degradation.
Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder
Authors: Tian Yuan , Qiao Hui , Zhu Ling-Qiang , Man Heng-Ye
Published: May 2024

Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral challenges.UBE3Ais one of the most common ASD genes. ASDs display a remarkable sex difference with a 4:1 male to female prevalence ratio; however, the underlying mechanism remains largely unknown. Using the UBE3A-overexpressing mouse model for ASD, we studied sex differences at behavioral, genetic, and molecular levels. We found that male mice with extra copies ofUbe3Aexhibited greater impairments in social interaction, repetitive self-grooming behavior, memory, and pain sensitivity, whereas female mice with UBE3A overexpression displayed greater olfactory defects. Social communication was impaired in both sexes, with males making more calls and females preferring complex syllables. At the molecular level, androgen receptor (AR) levels were reduced in both sexes due to enhanced degradation mediated by UBE3A. However, AR reduction significantly dysregulated AR target genes only in male, not female, UBE3A-overexpressing mice. Importantly, restoring AR levels in the brain effectively normalized the expression of AR target genes, and rescued the deficits in social preference, grooming behavior, and memory in male UBE3A-overexpressing mice, without affecting females. These findings suggest that AR and its signaling cascade play an essential role in mediating the sexually dimorphic changes in UBE3A-dependent ASD.
Context specific ubiquitin modification of ribosomes regulates translation under oxidative stress
Authors: Dougherty Shannon E. , Barros Géssica C. , Foster Matthew W. , Teo Guoshou , Choi Hyungwon , Silva Gustavo M.
Published: May 2024

Cellular exposure to stress is known to activate several translational control pathways through ribosome ubiquitination. However, how unique patterns of ribosome ubiquitination act at the site-specific level to drive distinct modes of translation regulation remains unclear. To further understand the complexity of these ubiquitin signals, we developed a new targeted proteomics approach to quantify site-specific ubiquitin modification across the ribosome. This method increased the sensitivity and throughput of current approaches and allowed us to systematically measure the ubiquitin status of 78 ribosome peptides and ubiquitin linkages in response to stress. Using this method, we were able to detect the ubiquitination of several ribosome sites even in steady-state conditions, and to show that their modification increases non-stoichiometrically in a dynamic range of >4 orders of magnitude in response to hydrogen peroxide. Besides demonstrating new patterns of global ribosome ubiquitination, our study also revealed an unexpected increase of ubiquitination of ribosomal protein uS10/Rps20 and uS3/Rps3 independent of the canonical E3 ubiquitin ligase Hel2. Furthermore, we show that unique and mixed patterns of ribosome ubiquitination occur in a stress specific manner, depending on the nature of stressor and the enzymes involved. Finally, we showed that while deletion ofHEL2further induces the integrated stress response in response to the nucleotide alkylating agent 4-NQO, deletion of the E2 conjugaseRAD6leads to sustained translation only in response to H2O2. Our findings contribute to deciphering the complexity of the stress response at the translational level, revealing the induction of dynamic and selective ubiquitin codes, which shed light on the integration of important quality control pathways during cellular response to stress.
Data-driven prediction of spinal cord injury recovery: an exploration of current status and future perspectives
Authors: Håkansson Samuel , Tuci Miklovana , Bolliger Marc , Curt Armin , Jutzeler Catherine R. , Brüningk Sarah
Published: May 2024

Spinal Cord Injury (SCI) presents a significant challenge in rehabilitation medicine, with recovery outcomes varying widely among individuals. Machine learning (ML) is a promising approach to enhance the prediction of recovery trajectories, but its integration into clinical practice requires a thorough understanding of its efficacy and applicability. We systematically reviewed the current literature on data-driven models of SCI recovery prediction. The included studies were evaluated based on a range of criteria assessing the approach, implementation, input data preferences, and the clinical outcomes aimed to forecast. We observe a tendency to utilize routinely acquired data, such as International Standards for Neurological Classification of SCI (ISNCSCI), imaging, and demographics, for the prediction of functional outcomes derived from the Spinal Cord Independence Measure (SCIM) III and Functional Independence Measure (FIM) scores with a focus on motor ability. Although there has been an increasing interest in data-driven studies over time, traditional machine learning architectures, such as linear regression and tree-based approaches, remained the overwhelmingly popular choices for implementation. This implies ample opportunities for exploring architectures addressing the challenges of predicting SCI recovery, including techniques for learning from limited longitudinal data, improving generalizability, and enhancing reproducibility. We conclude with a perspective, highlighting possible future directions for data-driven SCI recovery prediction and drawing parallels to other application fields in terms of diverse data types (imaging, tabular, sequential, multimodal), data challenges (limited, missing, longitudinal data), and algorithmic needs (causal inference, robustness).