bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue-resident NK cells support survival in pancreatic cancer through promotion of cDC1-CD8T activity
Authors: Go Simei , Demetriou Constantinos , Valenzano Giampiero , Hughes Sophie , Lanfredini Simone , Ferry Helen , Arbe-Barnes Edward , Sivakumar Shivan , Bashford-Rogers Rachael , Middleton Mark R. , Mukherjee Somnath , Morton Jennifer , Jones Keaton , O’Neill Eric
Published: October 2023

The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T cell activity) have had limited success. Here we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident NK (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypoactive NKG2D-veNK population, phenotypically reminiscent of trNK cells, that supports CD8 T cell involvement. We show an equivalent population in human PDAC cohorts that represents immunomodulatory trNK cells that could similarly support CD8 T cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5i/αPD1 and IR-induced damage as a novel therapeutic approach.
hkbis required forDIP-αexpression and target recognition in theDrosophilaneuromuscular circuit
Authors: Wang Yupu , Salazar Rio , Simonetta Luciano , Sorrentino Violet , Gatton Terrence J. , Wu Bill , Vecsey Christopher G. , Carrillo Robert A.
Published: October 2023

Our nervous system contains billions of neurons that form precise connections with each other through interactions between cell surface proteins (CSPs). InDrosophila, the Dpr and DIP immunoglobulin protein subfamilies form homophilic or heterophilic interactions to instruct synaptic connectivity, synaptic growth and cell survival. However, the upstream regulation and downstream signaling mechanisms of Dprs and DIPs are not clear. In theDrosophilalarval neuromuscular system,DIP-αis expressed in the dorsal and ventral type-Is motor neurons (MNs). We conducted an F1 dominant modifier genetic screen to identify regulators of Dprs and DIPs. We found that the transcription factor,huckebein(hkb), genetically interacts withDIP-αand is important for target recognition specifically in the dorsal Is MN, but not the ventral Is MN. Loss ofhkbled to complete removal ofDIP-αexpression. We then confirmed that this specificity is through the dorsal Is MN specific transcription factor,even-skipped(eve), which acts downstream ofhkb. Genetic interaction betweenhkbandeverevealed that they act in the same pathway to regulate dorsal Is MN connectivity. Our study provides insight into the transcriptional regulation ofDIP-αand suggests that distinct regulatory mechanisms exist for the same CSP in different neurons.
Detecting copy number variations from single-cell chromatin sequencing data by AtaCNV
Authors: Wang Xiaochen , Jin Zijie , Shi Yang , Xi Ruibin
Published: October 2023

Singe-cell assay of transposase accessible chromatin sequencing (scATAC-seq) can unbiasedly profile genome-wide chromatin accessibility in single cells. In single-cell tumor studies, identification of normal cells or tumor clonal structures often rely on copy number variations (CNVs). However, CNV detection from scATAC-seq is difficult due to the high noise, sparsity, and confounding factors. Here, we describe AtaCNV, a computational algorithm that accurately detects high resolution CNVs from scATAC-seq data. We benchmark AtaCNV using simulation and real data and find AtaCNV’s superior performance. Analyses of 10 scATAC-seq datasets shows that AtaCNV could effectively distinguish malignant from non-malignant cells. In glioblastoma, endometrial and ovarian cancer samples, AtaCNV identifies subclones at distinct cellular states, suggesting important interplay between genetic and epigenetic plasticity. Some tumor subclones only differ in small-scale CNVs, demonstrating the importance of high-resolution CNV detection. These data show that AtaCNV can aid the integrative analysis for understanding the complex heterogeneity in cancer.
Transitions in dynamical regime and neural mode underlie perceptual decision-making
Authors: Luo Thomas Zhihao , Kim Timothy Doyeon , Gupta Diksha , Bondy Adrian G. , Kopec Charles D. , Elliot Verity A. , DePasquale Brian , Brody Carlos D.
Published: October 2023

Perceptual decision-making is the process by which an animal uses sensory stimuli to choose an action or mental proposition. This process is thought to be mediated by neurons organized as attractor networks1,2. However, whether attractor dynamics underlie decision behavior and the complex neuronal responses remains unclear. Here we use an unsupervised, deep learning-based method to discover decision-related dynamics from the simultaneous activity of neurons in frontal cortex and striatum of rats while they accumulate pulsatile auditory evidence. We found that trajectories evolved along two sequential regimes, the first dominated by sensory inputs, and the second dominated by the autonomous dynamics, with flow in a direction (i.e., “neural mode”) largely orthogonal to that in the first regime. We propose that the second regime corresponds to decision commitment. We developed a simplified model that approximates the coupled transition in dynamics and neural mode and allows precise inference, from each trial’s neural activity, of a putative internal decision commitment time in that trial. The simplified model captures diverse and complex single-neuron temporal profiles, such as ramping and stepping3–5. It also captures trial-averaged curved trajectories6–8, and reveals distinctions between brain regions. The putative neurally-inferred commitment times (“nTc”) occurred at times broadly distributed across trials, and not time-locked to stimulus onset, offset, or response onset. Nevertheless, when trials were aligned to nTc, behavioral analysis showed that, as predicted by a decision commitment time, sensory evidence before nTc affected the subjects’ decision, but evidence after nTc did not. Our results show that the formation of a perceptual choice involves a rapid, coordinated transition in both the dynamical regime and the neural mode of the decision process, and suggest the moment of commitment to be a useful entry point for dissecting mechanisms underlying rapid changes in internal state.
Longitudinal prevalence of neurogenic orthostatic hypotension in the idiopathic Parkinson Progression Marker Initiative (PPMI) cohort
Authors: Beach Paul , McKay J. Lucas
Published: October 2023

Background

Reported orthostatic hypotension (OH) prevalence in Parkinson disease (PD) varies widely, with few studies evaluating specifically neurogenic-OH (nOH). The ratio of orthostatic heart rate (HR) to systolic blood pressure (SBP) change (Δ) is a valid screening method to stratify nOH/non-nOH but had minimal epidemiologic application.

Objective

To estimate the prevalence of nOH and non-nOH in the PPMI using the ΔHR/ΔSBP ratio and examine associations between nOH and various motor and non-motor measures.

Methods

Longitudinal orthostatic vitals and motor and non-motor measures were extracted (baseline-month 48). Patients were consensus criteria classified as OH+/-, with ΔHR/ΔSBP sub-classification to nOH (ΔHR/ΔSBP<0.5) or non-nOH (ratio≥0.5). Prevalence was determined across visits. Independent linear mixed models tested associations between nOH/non-nOH and clinical variables.

Results

Of N=907 PD with baseline orthostatic vitals, 3.9% and 1.8% exhibited nOH and non-nOH, respectively. Prevalence of nOH/non-nOH increased yearly (P=0.012, chi-square), though with modest magnitude (baseline: 5.6% [95% CI: 4.3-7.3%]; month 48: 8.6% [6.4-11.5%]). nOH patients were older than PD with no OH and nOH was associated with greater impairment of motor and independent functioning than non-nOH/OH-groups. Cognitive function and typical OH symptoms were worse in PD+OH, generally.

Conclusions

nOH prevalence was greater than non-nOH in the PPMI early PD cohort, with modest prevalence increase over time. Our findings are consistent with prior studies of larges cohorts that evaluated nOH, specifically. Early PD with nOH were likelier to be older and suffer from greater motor and functional impairment, but OH presence was generally associated with more cognitive impairment.
Cognitive Impairment and Noncommunicable Diseases in Egypt’s Aging Population: Insights and Implications from the pilot of the Longitudinal Study of Egyptian Healthy Aging “AL-SEHA”
Authors: Moustafa Sara A. , Deif Reem , Gaballah Nada , Salama Mohamed
Published: October 2023

As the global population ages, the prevalence of cognitive impairment among older individuals has been steadily rising. Egypt, like many countries, is grappling with the challenges posed by an aging demographic. Cognitive impairment not only affects the quality of life of older adults but also imposes significant burdens on healthcare systems and societies as a whole. This paper presents findings from the pilot phase of the Longitudinal Study of Egyptian Healthy Aging, known as “AL-SEHA,” shedding light on the intricate relationship between cognitive impairment and noncommunicable diseases (NCDs) in Egypt’s aging population.

KEY MESSAGES

The increasing prevalence of cognitive impairment among the aging population creates a need for a comprehensive understanding of its implications on the individuals’ quality of life

A significant association between cognitive impairment and non-communicable diseases exists and further research can help in the strategic allocation of resources for designing the most effective interventions
Cardiopulmonary resuscitation (CPR) competency retention among registered nurses in critical care versus general care unit
Authors: AL-Helih Yahia , AL-Ruzzieh Majeda , AL-Yatim Sami , Alawneh Mohammad , Haija Saleh Abu-AL , Odeh Faten
Published: October 2023

Background

Cardiac arrest is a sudden and life-threatening event resulting in an end of cardiac activity, necessitating immediate intervention to prevent fatalities. In-hospital cardiac arrest (IHCA) presents a critical medical emergency, demanding swift and competent response. Cardiopulmonary resuscitation (CPR) is a key lifesaving intervention for IHCA, but the frequency of CPR events and the decay of CPR skills and knowledge among healthcare professionals (HCPs) raise concerns.

Methods and Results

In a prospective quasi-experimental study with no control group, 263 registered nurses (121 in critical care units and 144 in general care units) were assessed for CPR skills and knowledge retention at various time intervals. The result showed that overall decay after six months are almost the same for both groups. Knowledge decay started for both groups after one month and for both groups the highest level of decay was reported after three months, however the decay pattern was quite different. General units mean differences showed sudden sharp decline on three months which was not reported with critical care nurses who showed steady decay reaching to six months.

Conclusions

In this study, it is noteworthy that nurses in critical care units exhibited consistent decay in skills and knowledge, while those in general care units demonstrated a progressive decline over time.
Direct delivery of Cas9 or base editor protein and guide RNA complex enables genome editing in the retina
Authors: Botto Catherine , Pulman Juliette , Malki Hugo , Ren Duohao , Oudin Paul , Cian Anne De , As Marie , Izabelle Charlotte , Saubamea Bruno , Fouquet Stéphane , Robert Camille , El-Amraoui Aziz , Fisson Sylvain , Concordet Jean-Paul , Dalkara Deniz
Published: October 2023

Genome editing by CRISPR-Cas holds promise for the treatment of retinal dystrophies. For therapeutic gene editing, transient delivery of CRISPR- Cas9 is preferable to viral delivery which leads to long-term expression with potential adverse consequences. Successful delivery of Cas9 protein and its guide RNA as ribonucleoprotein (RNP) complexes has been reported in the retinal pigment epitheliumin vivobut not into photoreceptors, the main target of retinal dystrophies. Here, we investigate the feasibility of direct RNP delivery to photoreceptors and RPE cells. We show that RNPs composed of Cas9 or adenine- base editor and guide RNA, without addition of any carrier compounds, induce gene editing in retinal cells at variable rates depending on the guide RNA efficiency and on the locus. But Cas9 RNP delivery at high concentrations leads to outer retinal toxicity indicating a need to improve delivery efficiency for future therapeutic use.
Reversible inhibition of GluN2B-containing NMDA receptors with anin situred-shifted, photoswitchable antagonist
Authors: Geoffroy Chloé , Berraud-Pache Romain , Chéron Nicolas , McCort-Tranchepain Isabelle , Paoletti Pierre , Mony Laetitia
Published: October 2023

NMDA receptors (NMDARs) are glutamate-gated ion channels playing a central role in synaptic transmission and plasticity. Dysregulation of NMDARs is linked to various neuropsychiatric disorders, emphasizing the need to understand the functional roles of individual NMDAR subtypes in the brain. GluN2B-containing NMDARs (GluN2B-NMDARs) are particularly important due to both pro-cognitive and pro-excitotoxic roles, although these functions remain under debate. Traditional pharmacological and genetic approaches have important shortcomings in terms of specificity and spatio-temporal resolution, limiting their use in native tissues. We therefore turned to optopharmacology, a technique based on the use of photosensitive ligands, whose activity can be reversibly tuned via illumination with different wavelengths. We developed OptoNAM-3, an azobenzene-based, photoswitchable negative allosteric modulator selective for GluN2B-NMDARs. OptoNAM-3 is a potent inhibitor of GluN2B-NMDARs in itstransconfiguration and inactive in itscisconfiguration. When bound to GluN2B-NMDARs, OptoNAM-3 displays remarkable red-shifting of its photoswitching properties that we attributed to geometric constraints imposed by the binding site onto the ligand azobenzene moiety. OptoNAM-3 allowed fast and reversible photomodulation of GluN2B-NMDAR activityin vitrousing either UV/green or blue/green light illumination cycles. OptoNAM-3 furthermore acted as a reversible, red-shiftedin vivophotomodulator of Xenopus tadpole locomotion. By enabling fast and reversible photocontrol of endogenous GluN2B-NMDARs within vivocompatible photochemical properties, OptoNAM-3 should advance our understanding of the role of this class of NMDARs in brain function and dysfunction.

Significance statement

This article presents the development and characterization of a photoswitchable negative allosteric modulator (NAM) targeting GluN2B-containing NMDA receptors (GluN2B-NMDARs). Traditional GluN2B-selective NAMs suffer from slow kinetics and irreversible effects, limiting their use in native tissues. OptoNAM-3 emerged as a potent and selective inhibitor of GluN2B-NMDARs, exhibiting fast temporal resolution of action and reversibility bothin vitroandin vivo. OptoNAM-3 furthermore exhibited different spectral properties when in solution or bound to its target, thus behaving as anin situ“red-shifted” photodependent antagonist with improvedin vivocompatibility. This study therefore provides a valuable photoswitchable tool for precise control of NMDAR activity in native tissues. It furthermore reveals the importance of the protein environment on the spectral properties of photosensitive molecules.
Analysis of Social Determinants of Hypertension Outcomes among Asian Americans in Los Angeles
Authors: Yu Megan R. , Liu Haoyuan , Kung Madyllen , Tran Caitlyn , Mitra Shameek , Dang Preston , Woo Benjamin K.
Published: October 2023

Asian Americans are a diverse and significant group within the United States and encompass a wide range of social demographics. Research on social determinants of hypertension within this population is limited, despite a notable burden of illness. Asian American attendees at health fairs held in Monterey Park and Rosemead, California in Los Angeles County were surveyed on various social demographics and screened for presence of hypertension outcomes. Logistic regression modeling was employed to determine major demographic contributors to the prevalence of prehypertensive or higher outcomes, ultimately finding that health fair location was a significant predictor (OR: 3.41; 95% CI: 1.54, 7.58; P-Value: 0.003). Further analysis of only attendees exhibiting prehypertensive or higher outcomes showed a significant distribution in the conditional distribution of education levels between Monterey Park and Rosemead attendees. Study findings uncover further areas for research into both Asian American and Chinese American populations and contribute to an overall gap in research within these demographic groups.
Socioeconomic inequalities in COVID-19 infection and vaccine uptake among children and adolescents in Catalonia, Spain
Authors: López-Sánchez Irene , Perramon Aida , Soriano-Arandes Antoni , Prats Clara , Duarte-Salles Talita , Raventós Berta , Roel Elena
Published: October 2023

IMPORTANCE

The relationship between socioeconomic deprivation and COVID-19 infection and vaccination among children and adolescents remains unclear.

OBJECTIVE

To investigate the association between deprivation and COVID-19 vaccine uptake and infection among children and adolescents before and after the vaccination rollout in Catalonia, Spain.

DESIGN AND SETTING

Population-based cohort study using primary care electronic health records from the Information System for Research in Primary Care. Individuals were followed 3 months before the start of the vaccination campaign in Spain and 3 months after the vaccination rollout among adolescents and children.

PARTICIPANTS

Children (5-11 years) and adolescents (12-15 years) with at least 1 year of prior history observation available and without missing deprivation data.

EXPOSURE

Deprivation, assessed using an ecological socioeconomic deprivation index (SDI) score for census tract urban areas and categorized into quintiles.

MAIN OUTCOMES AND MEASURES

COVID-19 infection and COVID-19 vaccination. For each outcome, we calculated cumulative incidence and crude Cox proportional-hazard models by SDI quintiles, and estimated hazard ratios (HRs) of COVID-19 infection and vaccine uptake relative to the least deprived quintile, Q1.

RESULTS

Before COVID-19 vaccination rollout, 290,625 children and 179,685 adolescents were analyzed. Increased HR of deprivation was associated with a higher risk of COVID-19 infection in both children (Q5: 1.55 [95% CI, 1.47 - 1.63]) and adolescents (Q5: 1.36 [95% CI, 1.29 - 1.43]). After the rollout, this pattern changed among children, with lower risk of infection in more deprived areas (Q5: 0.62 [95% CI, 0.61 - 0.64]). Vaccine uptake was higher among adolescents (72.6%) than children (44.8%), but in both age groups, non-vaccination was more common among those living in more deprived areas (39.3% and 74.6% in Q1 vs. 26.5% and 66.9% in Q5 among children and adolescents, respectively).

CONCLUSIONS AND RELEVANCE

In this cohort study, children and adolescents living in deprived areas were at higher risk of COVID-19 non-vaccination. Socioeconomic disparities in COVID-19 infection were also evident before vaccine rollout, with a higher infection risk in deprived areas across age groups. Our findings suggest that changes in the association between deprivation and infections among children after the vaccine rollout were likely due to testing disparities.
HIV prevalence and associated factors among adolescent boys and young men in South Africa, 2017
Authors: Makusha Tawanda , Mabaso Musawenkosi , Zungu Nompumelelo , Moyo Sizulu , Naidoo Inbarani , Jooste Sean , Mohapanele Karabo , Zuma Khangelani , Simbayi Leickness
Published: October 2023

Introduction

In South Africa, current epidemic control efforts include strategies to reach all young people and leave no one behind. Hence there is a need to track HIV among adolescent boys and young men (ABYM) to support these efforts. We examined HIV prevalence and associated factors among ABYM aged 15-24 years using the 2017 South African National HIV Prevalence, Incidence, Behaviour, and Communication Survey.

Methods

The cross-sectional survey used a multi-stage stratified cluster randomised sample. Descriptive statistics were used to characterise HIV prevalence among ABYM. Multivariate backward stepwise logistic regression was used to determine factors associated with HIV prevalence.

Results

A total of 4792 ABYM aged 15-24 years were interviewed of whom 4.01% [95% CI: 3.28-4.90] were HIV positive, translating to 255 366 ABYM living with HIV in the country in 2017. The odds of being HIV positive were significantly lower among ABYM with tertiary education level (AOR=0.06 [95% CI 0.01-0.50], p=0.009, employed (AOR=0.34 [95% CI: 0.14-0.81], p=0.015), and those who had tested and were aware of their HIV status (AOR=0.29 [95% CI: 0.10-0.83], p=0.015).

Conclusion

These findings suggest that ABYM with low educational attainment and those unemployed need to be reached with sexual and reproductive health interventions, including the promotion of uptake of HIV testing and awareness for this population group.
The SHOW COVID-19 cohort: methods and rationale for examining the statewide impact of COVID-19 on the social determinants of health
Authors: Schultz Amy A. , Nelson-Bakkum Erin , Nikodemova Maria , Luongo Sarah , Barnet Jodi H , Walsh Matthew C. , Bersch Andrew , Cadmus-Bertram Lisa , Engelman Corinne D. , Lubsen Julia , Peppard Paul , Sethi Ajay , Malecki Kristen MC
Published: October 2023

Background

National and large city mortality and morbidity data emerged during the early years of the COVID-19 pandemic, yet statewide data to assess the impact COVID-19 had across urban and rural landscapes on subpopulations was lacking. The SHOW COVID-19 cohort was established to provide descriptive and longitudinal data to examine the influence the social determinants of health had on COVID-19 related outcomes.

Methods

Participants were recruited from the 5,742 adults in the Survey of the Health of Wisconsin (SHOW) cohort who were all residents of Wisconsin, United States when they joined the cohort between 2008-2019. Online surveys were administered at three timepoints during 2020-2021. Survey topics included COVID-19 exposure, testing and vaccination, COVID-19 impact on economic wellbeing, healthcare access, mental and emotional health, caregiving, diet, lifestyle behaviors, social cohesion, and resilience.

Results

A total of 2,304 adults completed at least one COVID-19 online survey, with n=1,090 completing all three survey timepoints. Non-Whites were 2-3 times more likely to report having had COVID-19 compared to Whites, females were more likely than males to experience disruptions in their employment, and those with children in the home were more likely to report moderate to high levels of stress compared to adults without children.

Conclusion

Longitudinal, statewide cohorts are important for investigating how the social determinants of health affect people’s lives, health, and well-being during the first years of a pandemic and offer insight into future pandemic preparation. The data are available for researchers and cohort is active for continued and future follow-up.

Key Messages

Mortality and morbidity data emerged during the early years of the COVID-19 pandemic at the national scale and in large cities, yet comprehensive social, cultural, and economic population-level data at the state level was lacking for identifying sub-population trends.

COVID-19 disrupted lives and affected people differently based on socio-economic status, demographics, family dynamics, geography, health status, and employment.

SHOW COVID-19 cohort is a unique non-clinical, non-hospital-based sample with pre-COVID-19 baseline survey data and biospecimen and three waves of COVID-19 data and specimen available to examine effects of COVID-19 on the social determinants of health.
Can diffuse reflectance spectroscopy identify shuntodynia in pediatric hydrocephalus patients?
Authors: Kline Olivia , Vishwanath Karthik , Colbrunn Boyd , Peachman Andrew , Zhang Jing , Vadivelu Sudhakar
Published: October 2023

Significance

Shuntodynia is patient reported pain at the site of the implanted ventriculo-peritoneal (VP) shunt. Pediatric hydrocephalus requiring shunt placement is a chronic and prevalent standard of care treatment and requiring lifetime management. Shuntodynia is a subjective measure of shunt dysfunction. Quantitative, white-light tissue spectroscopy could be used to objectively identify this condition in the clinic.

Aim

Pediatric subjects were recruited for optical sensing during routine clinical follow-up visits, post VP shunt implantations. Acquired optical signals were translated into skin-hemodynamic signatures and were compared between subjects that reported shuntodynia vs. those that did not.

Approach

Diffuse reflectance spectroscopy (DRS) measurements were collected between 450-700 nm using a single-channel fiber-optical probe from (N=35) patients. Multiple reflectance spectra were obtained by the attending physician from regions both proximal and distal to the VP shunt sites, and from a matched contralateral site for each subject. Acquired reflectance spectra were processed quantitatively into functional tissue optical endpoints. A two- way, repeated measures analysis of variance (ANOVA) was used to assess whether and which of the optical variables were statistically separable, across subjects with shuntodynia vs. those without.

Results

Results showed that vascular oxygen saturation was significantly lower in subjects reporting shuntodynia, when measured proximal to shunt sites. Subjects with shuntodynia also had lower total hemoglobin at the shunt site relative to distal sites. Both patient groups showed higher tissue scattering at the shunt sites in comparison to the contralateral sites.

Conclusions

Optically derived hemodynamic variables were statistically significantly different in subjects presenting with shuntodynia relative to those without. DRS could provide a viable mode in routine bedside monitoring of subjects with VP shunts for clinical management and risk assessment of shuntodynia.
HAI-VECT(SCD): AI-Humanoid Enabled Virtual Clinical Trial for Sickle Cell Disease
Authors: Danter WR
Published: October 2023

Background

Sickle Cell Disease (SCD) remains a globally important disorder with limited therapeutic options. This study utilizes the advanced capabilities of the DeepNEU© platform v8.2 and aiHumanoid (Pat. Pend.) simulations to evaluate potential drug combinations for treating SCD, focusing on vaso-occlusive events (VOE) and associated secondary outcomes.

Methods

Using data from 25 virtual patients in each of six treatment groups, therapeutic responses to each treatment were investigated. The study evaluated the primary outcome of VOE and secondary outcomes, including HbA, HbF, Quality of Life (QoL), RBC hemolysis, and Pain. Treatment toxicities were also assessed across all dosage levels.

Results

The combination of Endari (L-glutamine powder) plus Crizanlizumab (a P-selectin antibody) demonstrated superior efficacy, with significant improvements in primary and secondary endpoints. This regimen, along with Voxelotor (a hemoglobin S polymerization inhibitor) plus Crizanlizumab, showed promising reductions in VOE, RBC hemolysis, and enhanced QoL scores. Notably, these results align with existing literature emphasizing the benefits of combination therapies in SCD management. Furthermore, aiHumanoid simulations indicated that these treatment combinations present lower cumulative multi-organoid toxicity, potentially translating to better patient outcomes and reduced healthcare costs.

Conclusion

AI-driven virtual clinical trials offer an innovative approach in evaluating drug combinations, presenting a robust case for the efficacy of Endari plus Crizanlizumab in managing SCD. The results warrant further research and real-world trials, potentially reshaping clinical guidelines for SCD treatment.
Disentangling the link between maternal influences on birth weight and disease risk in 36,211 genotyped mother-child pairs
Authors: Leinonen Jaakko T. ,   FinnGen, Pirinen Matti , Tukiainen Taru
Published: October 2023

Epidemiological studies have robustly linked lower birth weight to later-life disease risks. These observations may reflect the adverse impact of intrauterine growth restriction on a child’s health. However, causal evidence supporting such a mechanism in humans is largely lacking.

Using Mendelian Randomization and 36,211 genotyped mother-child pairs from the FinnGen study, we assessed the relationship between intrauterine growth restriction and five common health outcomes (coronary heart disease (CHD), hypertension, statin use, type 2 diabetes and cancer). We proxied intrauterine growth restriction with polygenic scores for maternal effects on birth weight and took into account transmission of genetic variants between a mother and a child in the analyses.

We find limited evidence for contribution of normal variation in maternally influenced intrauterine growth on later-life disease. Instead, we find support for genetic pleiotropy in the child genome linking birth weight to CHD and hypertension. Our study illustrates the opportunities that data from genotyped parent-child pairs from a population-based biobank provides for addressing causality of maternal influences.
Disease-specific prioritization of non-coding GWAS variants based on chromatin accessibility
Authors: Liang Qianqian , Abraham Abin , Capra John A , Kostka Dennis
Published: October 2023

Non-protein-coding genetic variants are a major driver of the genetic risk for human disease; however, identifying which non-coding variants contribute to which diseases, and their mechanisms, remains challenging. In-silico variant prioritization methods quantify a variant’s severity in the context of having a phenotypic effect; but for most methods the specific phenotype and disease context of the prediction are poorly defined. For example, many commonly used methods provide a single organism-wide score for each variant, while other methods summarize a variant’s impact specifically in certain tissues and/or cell-types. Here we propose a complementary disease-specific variant prioritization scheme, which is motivated by the observation that the variants contributing to different diseases often operate through different biological mechanisms.

We combine tissue/cell-type specific scores into disease-specific scores with a logistic regression approach and apply it to 25,000 non-coding variants spanning 111 diseases. We show that disease-specific aggregation of tissue/cell-type specific scores (GenoSkyline, Fit-Cons2, DNA accessibility) signifiantly improves the association of common non-coding genetic variants with disease (average precision: 0.151, baseline=0.09), compared with organism-wide scores (GenoCanyon, LINSIGHT, GWAVA, eigen, CADD; average precision: 0.129, base-line=0.09). Calculating disease similari-ties based on data-driven aggregation weights highlights meaningful disease groups (e.g., immune system related diseases and mental/behavioral disorders), and it provides information about tissues and cell-types that drive these similarities (e.g., lymphoblastoid T-cells for immune-system diseases). We also show that so-learned similarities are complementary to genetic similarities as quantified by genetic correlation. Overall, our aggregation approach demonstrates the strengths of disease-specific variant prioritization, leads to improvement in non-coding variant prioritization, and it enables interpretable models that link variants to disease via specific tissues and/or cell-types.
Persistent high mortality rates for Diabetes Mellitus and Hypertension after excluding deaths associated with COVID-19 in Brazil, 2020-2022
Authors: Moreira Rodrigo , Bastos Leonardo S , Carvalho Luiz Max , Freitas Laís Picinini , Pacheco Antonio G
Published: October 2023

Background

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a significant public health challenge globally, with Brazil being no exception. Excess mortality during this period reached alarming levels. Cardiovascular diseases (CVD), Systemic Hypertension (HTN), and Diabetes Mellitus (DM) were associated with increased mortality. However, the specific impact of DM and HTN on mortality during the pandemic remains poorly understood.

Methods

This study analyzed mortality data from Brazil’s mortality system, covering the period from 2015 to 2022. Data included all causes of death as listed on death certificates, categorized by International Classification of Diseases 10th edition (ICD-10) codes. Population data were obtained from the Brazilian Census. Mortality ratios (MRs) were calculated by comparing death rates in 2020, 2021, and 2022 to the average rates from 2015 to 2019. Adjusted MRs were calculated using Poisson models.

Results

Between 2015 and 2022, Brazil recorded a total of 11,423,288 deaths. Death rates remained relatively stable until 2019 but experienced a sharp increase in 2020 and 2021. In 2022, although a decrease was observed, it did not return to pre-pandemic levels. This trend persisted even when analyzing records mentioning DM, HTN, or CVD. Excluding death certificates mentioning COVID-19 codes, the trends still showed increases from 2020 through 2022, though less pronounced.

Conclusion

This study highlights the persistent high mortality rates for DM and HTN in Brazil during the years 2020-2022, even after excluding deaths associated with COVID-19. These findings emphasize the need for continued attention to managing and preventing DM and HTN as part of public health strategies, both during and beyond the COVID-19 pandemic. There are complex interactions between these conditions and the pandemic’s impact on mortality rates.
Partial elimination ofWolbachiain the Asian citrus psyllid,Diaphorina citri, increases phytopathogen acquisition and decreases fitness
Authors: Roldán Erik L. , Stelinski Lukasz , Pelz-Stelinski Kirsten S.
Published: October 2023

Wolbachiais a maternally inherited intracellular bacterium that infects a wide range of arthropods.Wolbachiacan have a significant impact on host biology and development, often due to its effects on reproduction. We investigatedWolbachiainfection in the Asian citrus psyllid,Diaphorina citri, which transmitsCandidatusLiberibacter asiaticus (CLas), the causal agent of citrus greening disease.D. citriare naturally infected withWolbachia; therefore, investigatingWolbachia-mediated effects onD. citrifitness andCLas transmission required artificial elimination of this endosymbiont with application of doxycycline. Doxycycline treatment of psyllids reducedWolbachiainfection by approximately 60% in both male and femaleD. citri; however, this reduction varied between generations of treated psyllids. Psyllids treated with doxycycline exhibited higherCLas acquisition as both adults and nymphs as compared with negative controls. In addition, doxycycline-treated psyllids exhibited decreased fitness as measured by reduced egg and nymph production as well as adult emergence as compared with controls lines whereWolbachiawas not manipulated. Our results indicate thatWolbachiabenefitsD. citriby improving fitness and potentially competes withCLas by interfering with phytopathogen acquisition. Targeted manipulation of endosymbionts in this phytopathogen vector may yield disease management tools.

Importance of the study

This study provides insights into the critical role ofWolbachiain the Asian citrus psyllid,Diaphorina citri, a known vector of the presumed causal agent of citrus greening disease. Our data indicate a beneficial role ofWolbachiainD. citri, whereby the bacteria greatly enhance overall fitness and affect sex ratio of the host but interfere with acquisition of the phytopathogen,CandidatusLiberibacter asiaticus (CLas). By artificially eliminatingWolbachiafrom psyllids, the study confirms its endosymbiotic role and opens potential avenues for development of disease control methods. Specifically, our data suggest that targeted manipulation of insect endosymbionts likeWolbachiamay potentially contribute new tools for management of this economically devastating and globally widespread disease of citrus.
Zinc-dependent Nucleosome Reorganization by PARP2
Authors: Maluchenko Natalya , Saulina Alexandra , Geraskina Olga , Kotova Elena , Korovina Anna , Feofanov Alexey , Studitsky Vasily
Published: October 2023

Poly(ADP-ribose)polymerase 2 (PARP2) is a nuclear protein that acts as a DNA damage sensor; it recruits the repair enzymes to a DNA damage site and facilitates formation of the repair complex. Using single particle Förster resonance energy transfer microscopy and electrophoretic mobility shift assay (EMSA) we demonstrated that PARP2 forms complexes with a nucleosome containing different number of PARP2 molecules without altering conformation of nucleosomal DNA both in the presence and in the absence of Mg2+or Ca2+ions. In contrast, Zn2+ions directly interact with PARP2 inducing a local alteration of the secondary structure of the protein and PARP2-mediated, reversible structural reorganization of nucleosomal DNA. AutoPARylation activity of PARP2 is enhanced by Mg2+ions and modulated by Zn2+ions: suppressed or enhanced depending on the occupancy of two functionally different Zn2+binding sites. The data suggest that Zn2+/PARP2-induced nucleosome reorganization and transient changes in the concentration of the cations could modulate PARP2 activity and the DNA damage response.

Significance Statement

PARP2 recognizes and binds DNA damage sites, recruits the repair enzymes to these sites and facilitates formation of the repair complex. Zn2+-induced structural reorganization of nucleosomal DNA in the complex with PARP2, which is reported in the paper, could modulate the DNA damage response. The obtained data indicate the existence of specific binding sites of Mg2+and Zn2+ions in and/or near the catalytic domain of PARP2, which modulate strongly, differently and ion-specifically PARylation activity of PARP2, which is important for maintaining genome stability, adaptation of cells to stress, regulation of gene expression and antioxidant defense.
Sparse-view synchrotron X-ray tomographic reconstruction with learning-based sinogram synthesis
Authors: Cheng Chang-Chieh , Chiang Ming-Hsuan , Yeh Chao-Hong , Lee Tsung-Tse , Ching Yu-Tai , Hwu Yeukuang , Chiang Ann-Shyn
Published: October 2023

Synchrotron radiation can be used as a light source in X-ray microscopy to acquire a high-resolution image of a microscale object for tomography. However, numerous projections must be captured for a high-quality tomographic image to be reconstructed; thus, image acquisition is time consuming. Such dense imaging is not only expensive and time consuming but also results in the target receiving a large dose of radiation. To resolve these problems, sparse acquisition techniques have been proposed; however, the generated images often have many artefacts and are noisy. In this study, a deep-learning-based approach is proposed for the tomographic reconstruction of sparse-view projections that are acquired with a synchrotron light source; this approach proceeds as follows. A convolutional neural network (CNN) is used to first interpolate sparse X-ray projections and then synthesize a sufficiently large set of images to produce a sinogram. After the sinogram is constructed, a second CNN is used for error correction. In experiments, this method successfully produced high-quality tomography images from sparse-view projections for two data sets comprising Drosophila and mouse tomography images. However, the initial results for the smaller mouse data set were poor; therefore, transfer learning was used to apply the Drosophila model to the mouse data set, greatly improving the quality of the reconstructed sinogram. The method could be used to achieve high-quality tomography while reducing the radiation dose to imaging subjects and the imaging time and cost.
Impact of digital capabilities of countries on the pedagogical transitions in business schools
Authors: Pandya Bharti , Cho BooYun , Patterson Louise
Published: October 2023

Purpose

During the COVID-19 pandemic, the importance of digital infrastructure in higher education surged. This study aims to analyze how a country’s digital capabilities influence pedagogical transitions in business schools and compare the impacts between digitally advanced and advancing countries.

Design/methodology/approach

The authors applied the job demands–resources model and the IMD World Digital Competition Ranking 2021 to analyze the impact of nations’ digital capabilities on the pedagogical transitions experienced by 121 business faculty members from 20 nations. The countries were categorized into digitally advanced countries and advancing countries. The snowball sampling method was used to gather data through an online survey consisting of 24 items. SPSS was used to statistically analyze the data in two stages using paired t-test and group comparison.

Findings

Significant shifts between face-to-face and online lectures occurred in both groups. Advanced countries witnessed positive shifts in discussions, presentations, oral assessment, independent learning opportunities, online teaching methods, technical support and faculties’ readiness, whereas advancing countries mainly noted alterations in professional development and communication technologies.

Originality/value

This study offers insights into optimizing digital capabilities and enhancing business schools’ readiness for effective pedagogical shifts during crises. Both the theoretical contribution and the findings will benefit national education policies, higher education institution leaders, scholars and educators.
Gender, external financing and firm performance: evidence from Chinese private firms
Authors: Huang Lingyun , Liu Jiankun , Huang Zhigang
Published: October 2023

Purpose

The operational framework of external financing in the correlation between the gender of entrepreneurs and firm performance remains to be resolved. This study aims to investigate the mediating effect of external financing on gender-based disparities in private firm performance and to explore its heterogeneity within the Chinese context.

Design/methodology/approach

Based on national data from the 10th to 13th Chinese Private Enterprise Survey, this study used a bootstrap-based mediation effect model to analyze the role of external financing as a mediator in the relationship between entrepreneur gender and firm performance.

Findings

This study found that external financing is a constructive mediator between entrepreneur gender and firm performance. Heterogeneity analysis revealed that external financing plays a complementary mediation role in the impact of entrepreneur gender on performance in West China. In the tertiary industry, external financing acts as the sole mediator for the impact of gender on firm performance. Notably, this mediating effect is present in non-startups but not in startups.

Practical implications

The findings suggest that external financing can improve the firm performance of female entrepreneurs. Governments and policymakers should strengthen financial support for female entrepreneurs in West China, tertiary industry and non-startup enterprises.

Originality/value

This paper contributes to the literature on gender and corporate governance by shedding light on the mediating role of external financing in the relationship between the gender of business owners and firm performance.
The influences of psychosocial work environment on the turnovers of civil service cadre officers in rural Bangladesh: an empirical study
Authors: Huynh Thanh , Sheikh Md Mahabur Rahman
Published: October 2023

Purpose

The purpose of this study is to determine the effects of the psychosocial work environment on the turnover of civil service cadre officers in rural areas in Bangladesh.

Design/methodology/approach

Physical intimidation, mental health and well-being, organisational impediments, decision latitude, psychological job demands and social interaction were developed as variables to examine in relation to job satisfaction and turnover. This study gathers 406 responses from Bangladesh Civil Service (BCS) cadre officers in rural areas to test the hypotheses.

Findings

The findings indicate that physical intimidation increases employee turnover, whereas psychosocial job demand decreases it. Physical intimidation reduces job satisfaction, whereas decision flexibility and social interaction enhance job satisfaction, hence reducing the turnover of civil service cadre officers in rural Bangladesh.

Originality/value

This research contributes to the creation of context-specific and targeted public sector support, particularly the interventions and policies addressing the work environment in rural areas.
Adopting blockchain-based traceability in the fruit supply chain in a developing economy: facilitators and barriers
Authors: Yap Teck Lee , Nayak Rajkishore , Vu Nhung T.H. , Bui Duy Tung , Pham Thi Thu Tra , Allen Darcy W.E.
Published: October 2023

Purpose

Blockchain-based traceability technology (BTT) is an emerging digital technology that claims to have the potential to fulfil the demand for traceability to safeguard fruit safety. Drawing on the technological, organisational and environmental (TOE) framework, this study aims to investigate the perceived facilitators and barriers that influence the behavioural intentions of multiple stakeholders in the Vietnamese fruit supply chain (i.e., farmers, trading enterprises and consumers) to adopt BTT.

Design/methodology/approach

This study utilised a qualitative approach of semi-structured in-depth interviews with 60 stakeholders in the Vietnamese fruit supply chain to achieve the research objectives. NVivo 12 was employed to analyse the collected data using content and thematic analysis.

Findings

The findings identify several perceived facilitators that motivate BTT adoption. These include trust, transparency, business performance, the formation of alliances, consumer awareness of food safety and ethical agricultural practices, fruit branding and the pivotal role of farmers' cooperatives. Meanwhile, the perceived barriers to BTT adoption include a lack of digital literacy amongst the stakeholders, poor organisational culture, the high cost of traceability-enabled products and data privacy and security governance.

Practical implications

This study suggests that technology awareness and perceived facilitators and barriers should be incorporated into the design and deployment of blockchain-based traceability technology in the agri-food supply chain in developing countries.

Originality/value

To the best of the authors' knowledge, this study is the first qualitative paper that attempts to fill the research gap of understanding the perceived facilitators and barriers that influence the intentions of multiple stakeholders in the fruit supply chain to adopt BTT in the context of a developing economy.