bluuebunny/crossref_metadata_2025 huggingface dataset:
All-Optical Multimodal Mapping of Single Cell Type-Specific Metabolic Activities via REDCAT
Authors: Li Yajuan , Zhang Zhaojun , Enninful Archibald , Nam Jungmin , Qin Xiaoyu , Villazon Jorge , Fazard Negin , Fung Anthony A. , Xu Mina L. , Jang Hongje , Zhang Nancy R. , Fan Rong , Ma Zongming , Shi Lingyan
Published: November 2024

Metabolism dictates a range of physiological functions in human health and disease. Metabolic activities vary substantially in different cell types and are influenced by local tissue environments. Despite latest advent in spatial omics to map cellular heterogeneity and neighborhoods, it is yet to connect cell type or state to metabolic function, ideally, cell-by-cell in same tissue section to unveil metabolic mechanisms in a cell-type-specific manner in complex tissue. Here we present Raman Enhanced Delineation of Cell Atlases in Tissues (REDCAT) for spatially co-profiling metabolic activities and cell types via integration of all-optical multi-modal chemical imaging with high-plex immunofluorescence imaging on the same tissue section. Application to human normal and malignant lymphoid tissues maps metabolic processes including protein, nucleic acid, and lipid metabolism as well as intra-cellular lipid droplet (LD) diversity to all cell types and unveils metabolic reprogramming in lymphoma development and progression. Hyperspectral imaging further revealed subcellular chemical composition changes in individual cancer cells. REDCAT enables the mapping of single-cell type-specific metabolic activities in complex tissues to explore the landscape of cellular phenotype–function relationship, providing rich biological information potentially for clinical pathology and disease diagnosis.
Ecological response ofAngelica dahuricaand its rhizosphere microorganisms to the treatment ofAlternanthera philoxeroidesextracts
Authors: Huang Yongjie , Huang Yufeng , Cai Yuting , Li Xinmeng , Zhang Jie
Published: November 2024

To explore the ecological adaptation mechanism of the medicinal plantAngelica dahuricaand its rhizosphere microorganisms to the invasion of Alternantheraphiloxeroides. This study analysed the physiological and biochemical indexes ofA. dahuricaseedlings and soil enzyme activities under a series concentration of root, stem and leaf extracts fromA. philoxeroides.Furthermore, high-throughput sequencing technology was used to detect the rhizosphere microorganism diversity ofA. dahurica.Results showed that with the increase of extract concentration and the extension of treatment time, the activity of antioxidant enzymes (SOD, POD, CAT) in seedlings increased and then decreased, and the inhibitory effect of root extract was the most significant. The extract effect on soil enzyme activity followed the descending sequence: root ˃ stem ˃ leaf. The activities of soil enzymes S-β-GC, S-LAP and S-ALP showed an upward trend with the increase of extract concentration, and the highest enzyme activity was found at 80 g/L.Proteobacteria,Acidobacteria,BacteroidesandSphingomonaswere the dominant species of rhizosphere soil bacteria under the treatment of each extract at phyla level. With the increasing concentration of different organ extracts, the relative abundance ofProteobacteria,BacteroidesandSphingomonasgradually increased, while the abundance ofAcidobacteriadecreased. PcoA principal component analysis revealed a significant differentiation between rhizosphere bacterial community structure under the extract and control treatments. These results indicated that different concentrations ofA. philoxeroidesextract could affect the growth and soil enzyme activity ofA. dahuricaand change the community structure of rhizosphere microorganisms.
A post-translational cysteine-to-serine conversion in human and mouse insulin generates a diabetogenic neoepitope
Authors: Srivastava Neetu , Vomund Anthony N. , Peterson Orion J. , Abousaway Omar , Li Tiandao , Kain Lisa , Stone Pamela , Clement Cristina C. , Sharma Siddhartha , Zhang Bo , Liu Chang , Joglekar Alok V. , Campisi Laura , Hsieh Chyi-Song , Santambrogio Laura , Teyton Luc , Arbelaez Ana Maria , Lichti Cheryl F. , Wan Xiaoxiao
Published: November 2024

Type 1 diabetes (T1D) affects a genetically susceptible population that develops autoreactive T cells attacking insulin-producing pancreatic β cells. Increasingly, neoantigens are recognized as critical drivers of this autoimmune response. Here, we report a novel insulin neoepitope generated via post-translational cysteine-to-serine conversion (C>S) in human patients, which is also seen in the autoimmune-prone non-obese diabetic (NOD) mice. This modification is driven by oxidative stress within the microenvironment of pancreatic β cells and is further amplified by T1D-relevant inflammatory cytokines, enhancing neoantigen formation in both pancreatic β cells and dendritic cells. We discover that C>S-modified insulin is specifically recognized by CD4+T cells in human T1D patients and NOD mice. In humans with established T1D, HLA-DQ8-restricted, C>S-specific CD4+T cells exhibit an activated memory phenotype and lack regulatory signatures. In NOD mice, these neoepitope-specific T cells can orchestrate islet infiltration and promote diabetes progression. Collectively, these data advance a concept that microenvironment-driven and context-dependent post-translational modifications (PTMs) can generate neoantigens that contribute to organ-specific autoimmunity.
Predicting the Pathway Involvement of Compounds Annotated in the Reactome Knowledge-base
Authors: Huckvale Erik D. , Moseley Hunter N.B.
Published: November 2024

Motivation

Pathway annotations of non-macromolecular (relatively small) biomolecules facilitate biological and biomedical interpretation of metabolomics datasets. However, low pathway annotation levels of detected biomolecules hinder this type of interpretation. Thus, predicting the pathway involvement of detected but unannotated biomolecules has high potential to improve metabolomics data analysis and omics integration. Past publications have only made use of the Kyoto Encyclopedia of Genes and Genomes derived datasets to develop machine learning models to predict pathway involvement. However, to our knowledge, the Reactome knowledgebase has not been utilized to develop these types of predictive models.

Results

We created a dataset ready for machine learning using chemical representations of all path-way-annotated compounds available from the Reactome knowledgebase. Next, we trained and evaluated a single multilayer perceptron binary classifier using combined metabolite-pathway paired feature vectors engineered from this new dataset. While models trained on a prior corresponding KEGG dataset with 502 pathways scored a mean Matthew’s correlation coefficient (MCC) of 0.847 and 0.0098 standard deviation, the models trained on the Reactome dataset with 3,985 pathways demonstrated improved performance with a mean MCC of 0.916, but with a higher 0.0149 standard deviation. These results indicate that the pathways in Reactome can also be effectively predicted, greatly increasing the number of human-defined pathways available for prediction.

Availability

Code and data for fully reproducing the results in this work are available athttps://doi.org/10.6084/m9.figshare.27478065.

Contact

hunter.moseley@uky.edu.
Clinical effectiveness of computer-based psychoeducational self-help platforms for eating disorders (with or without an associated app): A systematic review
Authors: Gentile Alessandra Diana , Kritian Yosua Yan , Cini Erica
Published: November 2024

Background

Following the COVID-19 pandemic, computer-based self-help platforms for eating disorders (EDs) became increasingly prevalent as a tool to effectively prevent and treat ED symptoms and related behaviours. This systematic review explored the clinical effectiveness of computer-based self-help platforms for EDs.

Methods

From inception to the 31stof May 2024, a systematic search of Ovid MEDLINE, Embase, Global Health, and APA PsycInfo was conducted. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Outcome quality assessments were conducted according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Results

14 RCTs, with a total of 4195 participants, were included. 4 studies explored the effectiveness as primary prevention, 7 as secondary prevention, and 3 as tertiary intervention. The gathered literature demonstrated computer-based self-help platforms as clinically effective in reducing ED core symptoms and related behaviours, with psychoeducation, cognitive behavioural, and dissonance-based approaches being the most prevalent approaches.

Conclusions

Computer-based self-help platforms are effective in the short-term reduction of ED symptoms and associated behaviours and should be implemented in the early stages of a tiered healthcare system for ED treatments.

Trial Registration

Prospero (CRD42024520866).
Post-discharge mortality in suspected pediatric sepsis: insights from rural and urban healthcare settings in Rwanda
Authors: Umuhoza Christian , Hooft Anneka , Zhang Cherri , Trawin Jessica , Mfuranziza Cynthia , Uwiragiye Emmanuel , Nguyen Vuong , Kornblith Aaron , Mugisha Nathan Kenya , Ansermino J Mark , Wiens Matthew O.
Published: November 2024

Post-discharge death is increasingly recognized as an important contributor to pediatric mortality in sub-Saharan Africa. To address morbidity and mortality during this period, a representative evidence base is needed to inform resource prioritization, policy, and guideline development. To date, no studies have been conducted in Rwanda, limiting understanding of post-discharge mortality in this region. We conducted a prospective cohort study of children ages 0-60 months in two Rwandan hospitals, one rural (Ruhengeri) and one urban (Kigali), from May 2022 to February 2023. We collected clinical, laboratory, and sociodemographic data on admission and follow-up data on vital statistics at 2-, 4-, and 6-months post-discharge. Of 1218 children enrolled, 115 (9.4%) died, with half occurring in-hospital (n=57, 4.7%) and half after discharge (n=58, 4.7%). Post-discharge mortality was lower in the 6-60-month cohort (n=30, 3.5%) than in the 0-6-month cohort (10%) and higher in Kigali (n=37, 10.3%) vs. Ruhengeri (n=21, 2.7%). Median time to post-discharge death was 38 days (IQR: 16-97.5) in the 0–6-month cohort and 33 days (IQR: 12-76) in the 6– 60-month cohort. In the 0-6 months cohort, malnutrition (weight-for-age z-score <-3) was associated with increased odds of post-discharge death (aOR 3.31, 95% CI 1.28-8.04), while higher maternal education was protective (aOR 0.15, 95% CI 0.03-0.85). Significant factors associated with post-discharge death in the 6-60-month cohort included an abnormal Blantyre Coma Scale (aOR 3.28, 95% CI 1.47-7.34), travel time to care >1 hour (aOR 3.54, 95% CI 1.26-9.93), and referral for higher levels of care (aOR 4.13, 95% CI 1.05-16.27). Children aged <2 months exhibited the highest cumulative mortality risk. Post-discharge mortality among Rwandan children remains a significant burden, necessitating targeted interventions for post-discharge care and follow up to reduce mortality.
Gene-diet interaction analysis in UK Biobank identified genetic loci that modify the association between fish oil supplementation and the incidence of dementia
Authors: Lu Yueqi , Xu Huifang , Sun Yitang , Ihejirika Susan Adanna , Chiang Charleston W. K. , Darst Burcu F. , Song Suhang , Shen Ye , Ye Kaixiong
Published: November 2024

Background

Dementia is a common disease influenced by both genetic and environmental factors.APOEε4 is well-known to increase the risk of dementia, and it has been shown to attenuate the protective association of fish oil supplementation and the incidence of dementia. To identify more genetic factors with similar modifying effects, we performed a genome-wide scan.

Methods

We first performed time-to-event genome-wide association study (GWAS) of all-cause dementia and two of its subtypes, Alzheimer’s disease (AD) and vascular dementia, in the UK Biobank. GWAS were performed in all participants (N = 357,631) and in two subgroups with or without fish oil supplementation (N = 113,267 and 244,364, respectively). Single nucleotide polymorphisms (SNPs) suggestively associated with dementia were then evaluated for their interactions with fish oil status in Cox-regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals.

Results

Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (p < 5e-8) for the incidence of all-cause dementia, AD, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for AD and related dementia. A total of 178 suggestive GWAS loci (p < 1e-5) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between fish oil supplementation and dementia incidence (p < 2.8e-4 with Bonferroni correction). One locus overlapped with a known AD GWAS locus (EED/PICALM) and two overlapped with GWAS loci for circulating omega-3 fatty acids (SRSF4,PSMG1). Gene set enrichment analysis found that candidate genes of interaction signals demonstrated tissue or cell-type specificity in the brain.

Conclusion

We identified 43 genetic loci that modify the association between fish oil supplementation and dementia. These findings indicate a need for genome-informed personalized nutrition of fish oil supplementation for the purpose of dementia prevention.
Comparing the Canadian front-of-pack labeling regulations with other mandatory approaches in the Americas and their ability to identify ultra-processed products
Authors: Flexner Nadia , Gomes Fabio S. , Mulligan Christine , Ahmed Mavra , Vergeer Laura , Lee Jennifer J. , Jeong Hayun , L’Abbe Mary R.
Published: November 2024

Background

Front-of-pack labeling (FOPL) has been implemented in several countries in the Americas, with Chile being the first to introduce a mandatory ‘high in’ warning FOPL in 2016. The Pan American Health Organization (PAHO) food classification criteria, considered a best practice for FOPL regulations, has been adopted by Mexico, Argentina, and Colombia. Canada’s FOPL regulations were recently approved and will take effect in January 2026, but it is unknown how these regulations compare to FOPL regulations that have already been implemented in other parts of the region.

Objectives

To compare the Canadian criteria for FOPL regulations with other FOPL criteria implemented in the Americas, and to determine their ability to identify ultra-processed products (UPPs).

Methods

Packaged foods and beverages (n=17,094) from the University of Toronto’s Food Label Information and Price (FLIP) 2017 database were analyzed using three FOPL criteria (Canadian, Chilean and PAHO criteria) and the NOVA classification system. The proportions of products that would be subject to displaying a ‘high in/excess’ FOPL and UPPs that would not be subject to FOPL regulations were examined under each system’s criteria. Agreement patterns were modeled using a nested sequence of hierarchical Poisson log-linear models. The Wald statistics for homogeneity were used to test whether proportional distributions differ significantly.

Results

Under the Canadian, Chilean and PAHO criteria, 54.4%, 68.4%, and 81.3% of packaged products would be required to display a ‘high in/excess’ FOPL, respectively. Disagreements between the Chilean and the Canadian criteria with PAHO’s were significant, but the greatest disagreement was between the Canadian and PAHO criteria. According to the Canadian, Chilean, and PAHO criteria, 33.4%, 18.4%, 2.3% of UPPs would not be subject to FOPL regulations, respectively.

Conclusions

A significant proportion of products that should be subject to FOPL regulations according to the PAHO criteria would not be regulated under Chilean and Canadian criteria, resulting in high proportion of UPPs that would not be subject to FOPL regulations. The Canadian FOPL criteria are the most lenient, with the highest proportion of UPPs that would not display a FOPL. Results can inform improvements for FOPL regulations in Canada, Chile and other countries.
Sex differences in the cardiopulmonary and neuromuscular response to high-intensity interval exercise
Authors: Wilson Hannah , Bernert Lina , Spillane Padraig , Squires Emma , Crawford Lorna , Piasecki Jessica , Julian Ross , Wilhelm Eurico N. , Hicks Kirsty M , Ansdell Paul
Published: November 2024

Sex differences exist in the integrative response to exercise, however, these are typically researched during constant-load exercise. Interval exercise involves high-intensity efforts interspersed with recovery periods to repeatedly stress physiological systems, and it is currently unknown whether the response to this form of exercise differs between sexes.

Ten males and ten females (age: 25±3 years) completed two experimental visits. First, an incremental treadmill exercise test was performed to obtain submaximal (lactate threshold) and maximal (O2peak) data. Thereafter, visit two involved 4 × 3-min running intervals at 90% of the final incremental test velocity (vO2peak), with 90 secs rest between intervals. Before exercise and after each interval, maximal voluntary contraction (MVC), quadriceps potentiated twitch (Qtw.pot), and voluntary activation (VA) were recorded. The rates of oxygen uptake (O2), carbon dioxide production (CO2) and ventilation (E) were continuously recorded throughout.

There was no sex difference in relativeO2peak(males: 47.2±6.0 vs. females: 44.4±5.8 ml.kg-1.min-1, p=0.292). When expressed relative to peak values, there were no sex differences in theO2orCO2response to the interval task (p≥0.781). Females had greaterE,E/O2, andE/CO2values during the first two intervals (p≤0.046). There were no sex differences in the reductions in MVC, Qtw.pot, and VA during the interval task (p≥0.150), however females had lesser reductions in Qtw.potvalues post-exercise (−24±9 vs. −15±8%, p=0.044).

Sex differences exist in the physiological response to interval exercise. Compared to males, females experienced greater hyperpnoea during the initial stages, and had lesser decreases in contractile function post-exercise.
The energetic cost of human walking as a function of uneven terrain amplitude
Authors: Hosseini-Yazdi Seyed-Saleh , Kuo Arthur D.
Published: November 2024

Humans expend more energy walking on uneven terrain, but the exact cost varies across terrains. Few experimental characterizations exist, each describing terrain qualitatively without any relation to others or flat ground. This precludes mechanistic explanation of the energy costs. Here we show that energy cost varies smoothly and approximately quadratically as a function of terrain amplitude. We tested this with healthy adults (N=10) walking on synthetic uneven terrain with random step heights of parametrically controlled maximum amplitude (four conditions 0 – 0.045 m), and at four walking speeds (0.8 – 1.4 m · s−1). Both net metabolic rate and the rate of positive work increased approximately with amplitude squared and speed cubed (R2= 0.74, 0.82 respectively), as predicted by a simple walking model. The model requires work to redirect the body center of mass velocity between successive arcs described by pendulum-like legs, at proportional metabolic cost. Humans performed most of the greater work with terrain amplitude early in the single stance phase, and with faster walking late in stance during push-off. Work and energy rates changed with approximately linear proportionality, with a ratio or delta efficiency of 49.5% (R2= 0.68). The efficiency was high enough to suggest substantial work performed passively by elastic tendon and not only by active muscle. Simple kinematic measures such as mid-swing foot clearance also increased with terrain amplitude (R2= 0.65), possibly costing energy as well. Nevertheless, most of the metabolic cost of walking faster or on more uneven terrain can be explained mechanistically by the work performed.

Summary statement

Humans perform more work and expend more energy on uneven terrain, increasing with the square of terrain amplitude and the cube of walking speed.
iPAR: A framework for modelling and inferring information about disease spread when the populations at risk are unknown
Authors: Catterall Stephen , Porphyre Thibaud , Marion Glenn
Published: November 2024

We introduce the inference for populations at risk (iPAR) framework which enables modelling and estimation of spatial disease dynamics in scenarios where the population at risk is unknown or poorly quantified. This framework addresses a gap in spatial infectious disease modelling approaches, with current methods typically requiring knowledge of the spatial distribution of the population at risk or making simplifying assumptions that are not supported in many real-world outbreaks where only case-report data are available. The principles for iPAR are demonstrated in the context of a susceptible-infected disease dynamics model coupled with Bayesian inference implemented via data-augmentation Markov chain Monte Carlo (MCMC). This implementation of iPAR is tested for a range of scenarios using simulated outbreak data. Results indicate that the method can effectively estimate key properties of disease spread from spatio-temporal case reports and make useful predictions of future spread. The method is then applied to a case study exploring the 2015-2019 Estonian outbreak of African Swine Fever (ASF) in wild boar. Estimates of epidemiological parameters reveal evidence for long distance transmission, as well as disease control via reduction of the wild boar population in Estonia.
Safety concerns following the use of ketamine as a potential antidepressant for adolescent rats of both sexes
Authors: Jornet-Plaza Jordi , Ledesma-Corvi Sandra , García-Fuster M. Julia
Published: November 2024

While ketamine is already approved for treatment resistant depression in adult patients, its efficacy and safety profile for its use in adolescence still needs further investigations. Preclinical studies proved dose- and sex-dependent effects induced by ketamine during adolescence, but few studies have evaluated the short- and long-term safety profile of ketamine at the doses necessary to induce its antidepressant-like effects. The present study aimed at evaluating the antidepressant-like effects of ketamine (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naïve or early-life stressed (i.e., maternal deprivation) rats of both sexes in the forced-swim or novelty-suppressed feeding tests. Safety was evaluated by measuring the psychomotor- and reinforcing-like responses induced by adolescent ketamine. In addition, long-term safety was evaluated in adulthood at the level of cognitive performance, or addiction liability (induced by a challenge dose of ketamine in rats treated with adolescent ketamine). The main results reinforced the potential for ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged for adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) and adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting the need for caution and further research before moving forward the use of ketamine as an antidepressant for adolescence.
Measurement of Real Time Serotonin Dynamics from Human Derived Gut Organoids
Authors: Bohl B. , Lei Y. , Bewick G A. , Hashemi P.
Published: November 2024

The importance of the gut in regulating the brain-body-immune axis is becoming increasingly evident. Interestingly, the brain and gut share many common signalling molecules, with serotonin being one of the most notable. In fact, the gut is the primary source of serotonin in the body. However, studying serotonin dynamics in a human-specific context remains a challenge. Human stem cell-derived models provide a promising avenue for studying signal transmission in well-controlled,in vitroenvironments. In this study, we report the first fast-scan cyclic voltammetry (FSCV) measurements of serotonin signalling in a newly developed enterochromaffin cell (ECC)-enriched gut organoid model. First, we characterize the stem cell-derived gut organoids and confirmed they are enriched with ECCs - the key cell type responsible for producing and releasing serotonin in the gut. We then optimize anin vitrobuffer that maintains cell viability while supporting FSCV measurements. Using this system, we detect spontaneous release events, which increase in frequency and amplitude following stimulation with forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX). Finally, we confirm the identity of the signal as serotonin by using a selective serotonin reuptake inhibitor (SSRI), which significantly delayed the reuptake profile. Our study introduces the first real time measurement of serotonin signalling in a human-derived gut model. We believe this system will be essential for future research on serotonin’s role in the gut and for potential novel drug target identification.
A whole-genome scan for evidence of recent positive and balancing selection in aye-ayes (Daubentonia madagascariensis) utilizing a well-fit evolutionary baseline model
Authors: Soni Vivak , Terbot John W. , Versoza Cyril J. , Pfeifer Susanne P. , Jensen Jeffrey D.
Published: November 2024

The aye-aye (Daubentonia madagascariensis) is one of the 25 most endangered primate species in the world, maintaining amongst the lowest genetic diversity of any primate measured to date. Characterizing patterns of genetic variation within aye-aye populations, and the relative influences of neutral and selective processes in shaping that variation, is thus important for future conservation efforts. In this study, we performed the first whole-genome scans for recent positive and balancing selection in the species, utilizing high-coverage population genomic data from newly sequenced individuals. We generated null thresholds for our genomic scans by creating an evolutionarily appropriate baseline model that incorporates the demographic history of this aye-aye population, and identified a small number of candidate genes. Most notably, a suite of genes involved in olfaction — a key trait in these nocturnal primates — were identified as experiencing long-term balancing selection. We also conducted analyses to quantify the expected statistical power to detect positive and balancing selection in this population using site frequency spectrum-based inference methods, once accounting for the potentially confounding contributions of population history, recombination and mutation rate variation, and purifying and background selection. This work, presenting the first high-quality, genome-wide polymorphism data across the functional regions of the aye-aye genome, thus provides important insights into the landscape of episodic selective forces in this highly endangered species.
Bone marrow microenvironment signatures associate with patient survival after guadecitabine and atezolizumab therapy in HMA-resistant MDS
Authors: Jang H. Josh , Urrutia Guillermo , Orskov Andreas Due , Kim Hyeon Jin , Nelson Seth A. , Nguyen Anh Van , Lee Hyein , Burgos Ryan S. , Johnson Benjamin K. , Wegener Marc , Becker Katelyn , Adams Marie , Sheridan Rachael , Ramjan Zachary H. , Givan Scott A. , Zebley Caitlin C. , Youngblood Benjamin A. , Issa Jean-Pierre J. , Topper Michael J. , Baylin Stephen B. , Baer Maria R. , Triche Timothy J. , O’Connell Casey L. , Gronbaek Kirsten , Jones Peter A.
Published: November 2024

Almost 50% of patients with myelodysplastic syndrome (MDS) are refractory to first-line hypomethylating agents (HMAs), which presents a significant clinical challenge considering the lack of options for salvage. Past work revealed that immune checkpoint molecules on peripheral myeloblasts and immune cells are up-regulated after HMA treatment. Therefore, we conducted a Phase I/II clinical trial combining guadecitabine (an HMA) and atezolizumab (an immune checkpoint inhibitor) to treat HMA-relapsed or refractory (HMA-R/R) MDS patients. This combination therapy showed median overall survival of 15.1 months relative to historical controls (4-6 months). Here, we profiled the cell composition and gene expression signatures of cells from bone marrow aspirates from trial participants with short-term (<15 months) or long-term (>15 months) survival at single-cell resolution. Long-term survivors showed a significant reduction of immunosuppressive monocytes, and an expansion of effector lymphocytes after combination therapy. Further immune profiling suggests that gamma delta T cell activation through primed dendritic cells was associated with global interferon activation in the bone marrow microenvironment of long-term survivors. Short-term survivors exhibited elevated inflammation and senescence-like gene signatures that were not resolved by combination therapy. We propose that distinct bone marrow microenvironment features, such as senescence-associated inflammation or immunosuppressive monocyte presence, could improve patient stratification for HMA and immunotherapy combinations in HMA-R/R MDS patients.
Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins
Authors: Rosencrans William M. , Khuntia Harisankar , Larimi Motahareh Ghahari , Mahalakshmi Radhakrishnan , Yu Tsyr-Yan Dharma , Bezrukov Sergey M. , Rostovtseva Tatiana K.
Published: November 2024

The Voltage Dependent Anion Channel (VDAC) is the major conduit of water-soluble metabolites and small ions into and out of the mitochondria. In mammals, VDAC exists in three isoforms, VDAC1, VDAC2, and VDAC3, each characterized by distinct tissue-dependent distribution and physiological role. VDAC2 is the most notable among the three isoforms because its knockout results in embryonic lethality and regulates the BAK/BAX-dependent apoptosis pathways. Yet, understanding of the biophysical underpinnings of VDAC2 functions remains limited. In this study, we reevaluate VDAC2’s properties, utilizing recombinant human VDAC2 WT and its three mutants – cysteine-less VDAC2, VDAC2 with truncated first 11 residues, and E84A - to explore the biophysical basis that distinguishes VDAC2 from the other isoforms using single-molecule electrophysiology. We found that contrary to VDAC1 and VDAC3, which are characterized by a unique open state, VDAC2 displays dynamic switching between a few high-conductive anion-selective substates. We employed α-synuclein (αSyn) – a known potent cytosolic regulator of VDAC1 and VDAC3 – as a sensitive molecular probe to show that it induces characteristic blockage events in all open substates of VDAC2 but with up to ten-fold different on-rates and blockage times. A substate with higher conductance always corresponds to a higher on-rate of the αSyn-VDAC2 interaction but proportionally lower blockage times. This gives the same equilibrium constant for all substates, thus resulting in the same affinity of the αSyn-VDAC2 interaction. The pronounced difference is limited to the kinetic parameters, suggesting that once the αSyn molecule is captured, its physical state and free energy are the same for all substates. These striking results imply that the αSyn molecule senses the dynamic structural variations within the channel prior to its final capture by the pore. We propose that the discovered conformational flexibility may allow VDAC2 to recognize a larger number of binding partners, thus explaining the physiological significance of this isoform, namely, its ability to adapt to mitochondrial metabolic conditions in cells dynamically.
Early Prediction of Preeclampsia Based on Transposable Elements signature in cell-free RNA
Authors: Patel Manthan , Saleh Ahmed , Dabrowska Adrianna , Boulet Fanny , Sinha Ajay K , Madapura Pradeepa
Published: November 2024

Preeclampsia (PE) is a pregnancy-associated hypertension disorder affecting 5 to 10% of pregnant women each year worldwide, which leads to adverse maternal and child outcomes. PE remains inadequately predicted, prevented and treated. Here, we comprehensively investigated altered transcriptomic and epigenetic changes in the PE placenta and maternal cell free RNA (cfRNA). We show that many transposable elements (TEs) in sub-families are deregulated in the gestational age-matched PE placenta. Increased expression of endogenous retrovirus (ERV) and long interspersed nuclear element 1 (L1, LINE1) subfamilies of TEs is associated with higher histone acetylation levels at their regulatory elements. A higher TE transcript level correlates with the type I interferon (IFN I) pathway, suggesting inflammation associated with PE could be due to the sensing of TE transcripts by the antiviral innate immune system. Consistent with higher TE transcript levels in the PE placentas, analysis of maternal cfRNA data revealed differential levels of TE subfamilies in PE compared to healthy controls. Machine learning-based training for TE transcripts for early prediction of PE showed a robust performance in the validation cohort, with an area under the curve (AUC) of 0.88, 81% sensitivity, and 74% positive predictive value (PPV). Overall, we show TE deregulation in the placenta is associated with PE, and maternal cfRNA TE signature accurately predicts early diagnosis of PE, which can improve prophylaxis and obstetric outcomes.
A chromosome-level genome of the giant vinegaroonMastigoproctus giganteusexhibits the signature of pre-Silurian whole genome duplication
Authors: Kulkarni Siddharth S. , Klementz Benjamin C. , Sharma Prashant P.
Published: November 2024

Within the arachnids, chromosome-level genome assemblies have greatly accelerated the understanding of gene family evolution and developmental genomics in key groups, such as spiders (Araneae), mites and ticks (Acariformes and Parasitiformes). Among other poorly studied arachnid orders that lack genome assemblies altogether are the clade Pedipalpi, which is comprised of three orders that form the sister group of spiders, which diverged over 400 Mya. We close this gap by generating the first chromosome-level assembly from a single specimen of the vinegaroonMastigoproctus giganteus(Uropygi). We show that this highly complete genome retains plesiomorphic conditions for many gene families that have undergone lineage-specific derivations within the more diverse spiders. Consistent with the phylogenetic position of Uropygi, macrosynteny in theM. giganteusgenome substantiates the signature of an ancient whole genome duplication.
Effects ofPseudomonas aeruginosapyocyanin and 1-hydroxyphenazine on intracellular calcium, mitochondrial function, and viability in human nasal epithelial cells
Authors: Thompson Joel C. , Kouakou Yobouet Ines , Miller Zoey A. , Adappa Nithin D. , Palmer James N. , Lee Robert J.
Published: November 2024

Pseudomonas aeruginosais an opportunistic pathogen that produces phenazine metabolites pyocyanin and 1-hydroxyphenazine that have been suggested to have detrimental effects on mitochondrial function and reactive oxygen species (ROS) production. Prior studies have suggested activation of Ca2+signaling by pyocyanin in an airway cell line. Ca2+is tightly linked to both normal mitochondrial function as well as mitochondrial ROS and apoptosis during mitochondrial Ca2+overload. We found that pyocyanin but not 1-hydroxyphenazine induced both cytosolic and mitochondrial Ca2+increases. Despite this, both pyocyanin and 1-hydroxyphenazine decreased in cell viability in RPMI 2650 nasal carcinoma cells but not in primary human nasal epithelial cells (HNECs) at 24 hours. However, in both RPMI 2650 and HNEC, mitochondrial membrane potential acutely decreased after treatment with either pyocyanin or 1-hydroxyphenazine. Our data suggest that Ca2+signaling is not required for acute effects of 1-hydroxyphenazine or pyocyanin on mitochondrial function. The greater sensitivity of RPMI 2650 cells to pyocyanin-induced and 1-hydroxyphenzine-induced cytotoxicty compared with primary cells suggests that these compounds might have some applicability in treating nasal squamous carcinoma or other types of head and neck squamous carcinoma.
Variants in NR6A1 cause a novel oculo-vertebral-renal (OVR) syndrome
Authors: Neelathi Uma M , Ullah Ehsan , George Aman , Maftei Mara I , Elangovan Elangovan , Sanchez-Mendoza Daniel , Adams Chloe , McGaughey David , Sergeev Yuri V , AI Rawi Ranya , Naik Amelia , Bender Chelsea , Maumenee Irene H , Michaelides Michel , Tan Tun Giap , Lin Siying , Villasmil Rafael , Blain Delphine , Hufnagel Robert B , Arno Gavin , Young Rodrigo M , Guan Bin , Brooks Brian P
Published: November 2024

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.
Antidepressant switching as a proxy phenotype for drug non-response: investigating clinical, demographic and genetic characteristics
Authors: Lo Chris Wai Hang , Gillett Alexandra C. , Iveson Matthew H. , Kamp Michelle , Fabbri Chiara , Wong Win Lee Edwin , Handley Dale , Pain Oliver , Vassos Evangelos , Wray Naomi R. , Whalley Heather C. , Li Danyang , Young Allan H. , Mcintosh Andrew M. ,   AMBER Research Team, Lewis Cathryn M.
Published: November 2024

Background

Selective serotonin reuptake inhibitors (SSRIs) are a first-line pharmacological therapy in major depressive disorder (MDD), but treatment response rates are low. Clinical trials lack the power to study the genetic contribution to SSRI response. Real-world evidence from electronic health records provides larger sample sizes, but novel response definitions are needed to accurately define SSRI non-responders.

Methods

In UK Biobank (UKB) and Generation Scotland, SSRI switching was defined using a ≤ 90-day gap between prescriptions for an SSRI and another antidepressant in primary care. Non-switchers were participants with ≥ 3 consecutive prescriptions for an SSRI. In UKB, clinical, demographic and polygenic score (PGS) associations with switching were determined, and the common-variant heritability was estimated.

Results

In UKB, 5,133 (13.2 %) SSRI switchers and 33,680 non-switchers were defined. The mean time to switch was 28 days. Switching patterns were consistent across UKB and Generation Scotland (n = 498 switchers). Higher annual income and educational levels (OR [95% CI] for university degree compared to no qualifications: 0.727 [0.666-0.794]) were associated with lower levels of switching. PGS for non-remission, based on clinical studies, were associated with increased risk of switching (OR: 1.07 [1.02-1.12], p = 0.007). MDD PGS and family history of depression were not significantly associated with switching. The heritability (h2) of SSRI switching was approximately 4% on the observed scale.

Conclusion

This study identified SSRI switching as a proxy of drug non-response, scalable across biobanks, capturing demographic and genetics of treatment non-response, and independent of the genetics of MDD.
Differential Impacts of the COVID-19 Pandemic on Sociodemographic Groups in England: A Mathematical Model Framework
Authors: Oyedele Gbeminiyi J. , Vlaev Ivo , Tildesley Michael J.
Published: November 2024

The Coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on the world, redefining how we work, respond to public health emergencies and control efforts, and sparking increased research efforts. In this study, we have developed a deterministic, ordinary differential equation multi-risk structured model of the disease outcomes, with a focus on the total number of infections, reported cases, hospitalised individuals, and deaths in the population. The model takes into account sociodemographic risk-structure and age structured dynamics, as well as time-sensitive nonpharmaceutical interventions (lockdowns) to help observe the disease trajectory following the implementation of control measures. The primary focus of this study is to demonstrate the impact of different patterns of social mixing within and between deprivation deciles in England, to understand disparities in disease outcomes. Our analysis reveals that the diagonal kind of mixing, similar to “within-group homogenous” type of mixing assumption, results in a higher number of disease outcome compared to other types of mixing assumptions. We also explore the effectiveness of movement restriction (the first national lockdown) in controlling the spread of the virus in each social group, in order to understand how to target interventions in the future. Our analysis confirms significant disparities in infection outcomes between sociodemographic groups in England.

Author summary

The global impact of the coronavirus pandemic 2019 was evident, but different sociodemographic groups experienced disproportionate disease outcomes. In this paper, we present results from a mathematical model that simulates COVID-19 outcomes across diverse sociodemographic groups in England. Our work uses a mathematical framework that combines age and deprivation decile, to examine the disproportionate outcome in the number of infection, hospitalisation, and mortality based on social mixing patterns. Our work demonstrated the elevated risk for more deprived groups, where social and occupational factors increase contact rates, therefore intensifying disease spread. By distinguishing disease dynamics among deprivation deciles, this model offers insights for policymakers to design more equitable health strategies. This approach emphasis the need for policies that address the vulnerabilities of specific social groups to mitigate the effects of pandemics.
Health care worker's perspective on the MDR-TB treatment guidelines in South Africa
Authors: Ramasir Serisha , Oosthuizen Frasia , Bangalee Varsha
Published: November 2024

Background Treatment guidelines are developed and updated according to evidence-based research. Healthcare workers in the public health sector are responsible for the implementation of said guidelines. The multi-drug resistant tuberculosis (MDR-TB) guideline has undergone major changes over the past 5 years. These changes included shorter treatment regimens and the introduction of novel drugs. These changes have consequently impacted the management of MDR-TB patients. Objectives To establish healthcare workers' perspectives on the MDR-TB guidelines and managing patients with MDR-TB. Methods Healthcare workers employed in MDR-TB departments at Murchison District Hospital in KwaZulu-Natal were invited to complete a written questionnaire. These healthcare workers comprised of doctors, nurses, pharmacists, and data capturers. The questionnaire consisted of both open- and closed-ended questions. Descriptive statistics were generated for closed-ended questions using SPSS (version 25). Open-ended questions were transcribed onto Microsoft Excel and analyzed for common and emerging themes. Results There were 44 staff employed in the inpatient and outpatient MDR-TB unit. Thirty-four of participants agreed to participate in the questionnaire. HIV co-infection was highlighted as a contributor to complicating the management of MDR-TB patients. The most common co-morbidities associated with MDR-TB patients were diabetes, anaemia and hypertension. The socioeconomic influence on outcomes were highlighted throughout patient responses.  Conclusion The MDR-TB program has come been progressive in its approach to gaining control over MDR-TB. The SBR is an effective regimen with a few safety concerns. The nature of ADRs associated with the regimen are serious with myelosuppression highlighted as a common ADR.  The impact of socio-economic factors on treatment outcomes is an important factor that should be considered in addition to MDR-TB regimens. The BPaL regimen may offer benefits of a shorter duration and reduced pill burden but there are concerns over the safety of the regimen. The success of the MDR-TB program requires a holistic approach combining patient factors with an effective, safe and convenient regimen.
Medical Students’ Knowledge, Attitudes, and Motivation towards Antimicrobial Resistance Efforts in Eastern Uganda
Authors: Babuya Jonathan , Waruingi Daniel , Mungujakisa Douglas , Ahimbisibwe Osmas , Kako Victoria Ruth , Aporu Faith , Mugume Emmanuel , Nyamupachitu Julian , Kiyimba Kenedy
Published: November 2024

Introduction

To promote holistic learning about Antimicrobial Resistance (AMR), catalyze multidisciplinary engagement, and innovative AMR interventions, it is important that learning goes beyond the classroom and students embrace different extracurricular interventions. This study aimed to determine knowledge, attitudes, and motivations influencing medical students’ engagement in AMR Club Initiatives at Busitema University in Uganda.

Methodology

This was descriptive cross-sectional study conducted at Busitema University among undergraduate student pursuing Bachelors of Medicine and Surgery, Bachelor of Nursing, and Bachelor of Science in Anesthesia and Critical care. A semi structured pre-tested questionnaire was shared among the study participants. Bloom cut-off method was used to analyse the knowledge of the participants, chi square test used for bivariate analysis and multivariable logistic regression used for determining factors independently associated to students’ engagement in AMR club activities.

Results

71.5% of the 193 students had sufficient knowledge (determined using Bloom’s cutoff categories from 60% and above as sufficient and below 60% as insufficient) on AMR with an average score of 68.18% (SD= ±16.12). 90% of participants recognized the significance of incorporating AMR within their curriculum, and 87.5% appreciated the need for training AMR using a One Health ApproachThe most common reasons why students engaged in extracurricular efforts to address AMR such as forming AMR clubs were found to be; influence from peers (n= 42), university support (n=35), and inspiration from peer mentors’ work (n=35).

Conclusion

The students were found to have a high level of knowledge and positive attitudes towards AMR but reported the need for further in-depth training. Extra-curricular engagement such as participation in an AMR Club was found to positively influence students’ engagement in AMR interventions.