bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundDementia 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.MethodsWe 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.ResultsTime-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.ConclusionWe 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

ABSTRACTBackgroundFront-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.ObjectivesTo 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).MethodsPackaged 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.ResultsUnder 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.ConclusionsA 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

AbstractSex 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

AbstractHumans 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 statementHumans 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

AbstractWe 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

AbstractWhile 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

AbstractThe 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

ABSTRACTThe 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

AbstractAlmost 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

AbstractThe 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.
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

AbstractWithin 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

AbstractPseudomonas 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.