bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-linear mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol
Authors: Hamilton Fergus W , Hughes David A , Spiller Wes , Tilling Kate , Smith George Davey 
Published: August 2023

AbstractMendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the “residual” exposure). These “local” causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method - the doubly-ranked method – has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects - that of low density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest that until there is extensive simulation and empirical methodological work demonstrating that these methods generally produce meaningful findings use of them is suspended. If authors feel it is imperative that they report results from them there should be strong justification for this, and a number of sanity checks (such as analysis of negative and positive control outcomes) should be provided.
Visceral adipose macrophage content does not associate with body mass index or systemic inflammation in COVID-19: an autopsy study
Authors: Su Steven H. , Nobel Yael R. , Besharati Sepideh , del Portillo Armando , Anderson Michaela R. , Freedberg Daniel E. 
Published: August 2023

ABSTRACTIntroductionAdiposity, especially visceral adiposity with elevated body mass index (BMI), is associated with a hyperinflammatory syndrome and poor outcomes in patients with COVID-19. In other diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, systemic inflammation is driven directly by visceral adipose macrophages which release pro-inflammatory cytokines. Currently it is unknown whether visceral adipose tissue macrophage content may similarly explain the observation that COVID-19 patients with elevated BMI are at risk for a hyperinflammatory syndrome and death.MethodsThis was a retrospective study of hospitalized adults who died of COVID-19 between March 2020 and June 2020 and underwent autopsy. Visceral adipose tissue macrophage content was quantified by histological staining of visceral adipose tissue samples with CD68, using pericolic fat gathered at autopsy from each subject. Clinical data including inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive Protein (CRP), Troponin, D-dimer, Interleukin-6 (IL-6), and ferritin as well as BMI were collected from electronic medical records.ResultsA total of 39 subjects were included in this study. There was no association between BMI and visceral adipose tissue macrophage content (Spearman R=0.025, p=0.88). Additionally, there was no association between adipose tissue macrophage content and any of the systemic markers of inflammation measured including ESR, CRP, Troponin, D-dimer, IL-6, and Ferritin (p>0.05 for all markers).ConclusionUnlike chronic diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, elevated BMI is not associated with increased visceral adipose tissue macrophage content in patients who died of COVID-19. Additionally, among patients who died of COVID-19, visceral adipose tissue macrophage content is not associated with markers of systemic inflammation. These results suggest that the elevations in systemic markers of inflammation—and the hyperinflammatory syndrome often observed during acute COVID-19—does not directly originate from visceral adipose macrophages as it seems to in chronic disease states.
Preventing tuberculosis with community-based care in an HIV-endemic setting: a modeling analysis
Authors: Ross Jennifer M. , Greene Chelsea , Bayer Cara J. , Dowdy David W. , van Heerden Alastair , Heitner Jesse , Rao Darcy W. , Roberts D. Allen , Shapiro Adrienne E. , Zabinsky Zelda B. , Barnabas Ruanne V. 
Published: August 2023

AbstractIntroductionAntiretroviral therapy (ART) and TB preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men.MethodsWe developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programs during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e., ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for ten years. We projected the number of TB cases, deaths, and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated program costs and incremental cost-effectiveness ratios from the provider perspective.ResultsIf community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3% - 34.1%) and TB mortality by 36.0% (range 26.9% - 43.8%) after ten years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9% - 36.0%) and TB mortality by 36.0% (range 26.9% - 43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates by reducing TB mortality among men by a projected 39.8% (range 32.2% - 46.3%) and by 30.9% (range 25.3% - 36.5%) among women. Over ten years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709 - $1,012).ConclusionsBy substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.
Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single cell resolution
Authors: Caporale Nicolò , Castaldi Davide , Rigoli Marco Tullio , Cheroni Cristina , Trattaro Sebastiano , Valenti Alessia , Bonfanti Matteo , Stucchi Sarah , Tobon Alejandro Lopez , Ricca Dario , Lessi Manuel , Pezzali Martina , Vitriolo Alessandro , Schmid Katharina T. , Heinig Matthias , Theis Fabian J. , Villa Carlo Emanuele , Testa Giuseppe 
Published: August 2023

AbstractThe combination of brain organoid and single cell omic technologies holds transformative potential to dissect human neurobiology at high resolution and with mechanistic precision. Delivering this promise in the context of human neurodiversity, physiological and pathological alike, requires however a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we implemented and benchmarked complementary strategies to multiplex brain organoids. Following an extended longitudinal design with a uniquely informative set of timepoints, we pooled cells from different induced pluripotent stem cell lines either during organoids generation (upstream multiplexing in mosaic models) or before single cell-RNAseq library preparation (downstream multiplexing). We developed a new method, SCanSNP, and an aggregated call to deconvolve organoids cell identities, overcoming current criticalities in doublets prediction and low quality cells identification and improving accuracy over state of the art algorithms. Integrating single cell transcriptomes and analysing cell types across neurodevelopmental stages and multiplexing modalities, we validated the feasibility of both multiplexing methods in charting neurodevelopmental trajectories at high resolution, linking their specificity to genetic variation between individual lines. Together, this multiplexing suite of experimental and computational methods provides an enabling resource for disease modelling at scale and paves the way towards anin vitroepidemiology paradigm.
The essential roles of Dicer-mediated mTORC1 signaling in parathyroid gland integrity and function: Insights from genetic mouse models and clinical data
Authors: Hassan Alia , Khalaily Nareman , Kilav-Levin Rachel , Castello Barbara Del , Manley Nancy Ruth , Ben-Dov Iddo Z. , Naveh-Many Tally 
Published: August 2023

AbstractSecondary hyperparathyroidism (SHP) frequently accompanies chronic kidney disease (CKD), contributing to morbidity and mortality in patients. Our previous findings demonstrated that PT-Dicer-/-mice, with parathyroid specific deletion ofDicerand consequently microRNA, maintained normal serum PTH levels but failed to increase serum PTH in response to the major inducers of PTH secretion, hypocalcemia and CKD. Additionally, we elucidated a critical role of mTORC1 in CKD-induced SHP. We now explored the roles of Dicer and mTORC1 in parathyroid development and function. Despite sustaining normal serum PTH levels, PT-Dicer-/-mice displayed apoptotic loss of intact parathyroid glands postnatally, which were replaced by scattered cell clusters, and reduced mTORC1 activity. PT-mTORC1-/-mice exhibited the absence of intact parathyroid glands, while retaining normal serum PTH levels, mirroring the characteristics of PT-Dicer-/-mice. Conversely, PT-Tsc1-/-mice with hyperactivated mTORC1 exhibited enlarged glands and elevated serum PTH and calcium levels. Significantly, PT-Dicer-/-;Tsc1-/-double knockout mice demonstrated a reversal of the aparathyroidism of PT-Dicer-/-mice, preserving intact parathyroid glands and reinstating CKD-induced SHP. Lastly, data collected from a network of 106 healthcare organizations demonstrated that drug-induced mTOR inhibition is associated with reduced elevation of serum PTH levels in kidney transplant recipients. The latter findings offer physiological validation for our observations in genetically modified mouse models, highlighting the central role of mTORC1 signaling in CKD-SHP. Altogether, our results indicate that mTOR operates downstream of Dicer and miRNA. Consequently, Dicer, miRNA and mTORC1 collectively play a crucial role in maintaining the postnatal integrity and function of the parathyroid glands.
‘Mindin Vitro’ platforms: Versatile, scalable, robust and open solutions to interfacing with living neurons
Authors: Zhang Xiaotian , Dou Zhi , Kim Seung-Hyun , Upadhyay Gaurav , Havert Daniel , Kang Sehong , Kazemi Kimia , Huang Kai-Yu , Aydin Onur , Huang Raymond , Rahman Saeedur , Ellis-Mohr Austin , Noblet Hayden A. , Lim Ki H. , Chung Hee Jung , Gritton Howard J. , Saif M. Taher A. , Kong Hyun Joon , Beggs John M. , Gazzola Mattia 
Published: August 2023

AbstractMotivated by the unexplored potential ofin vitroneural systems for computing, and by the corresponding need of versatile, scalable interfaces for multimodal interaction, we present an accurate, modular, fully customizable and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated. A reconfigurable platform that works across multiple industry standards enables a complete signal chain, from neural substrates sampled through high-density Micro-Electrode Arrays (MEAs) to data acquisition, downstream analysis and cloud storage. Built-in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations and spatial topologies. Through a native analysis and management software suite, the utility and robustness of our system is demonstrated across neural cultures and applications, including embryonic stem cell-derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging and long-term recording. Overall, our technology, termed ‘Mindin Vitro’ to underscore the computing inspiration, provides an end-to-end solution that can be widely deployed due to its affordable (>10X cost-reduction) and open-source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.
Non-antibiotic pharmaceuticals exhibit toxicity againstEscherichia coliat environmentally relevant concentrations with no evolution of cross-resistance to antibiotics
Authors: Hall Rebecca J , Snaith Ann E , Element Sarah J , Moran Robert A , Smith Hannah , Cummins Elizabeth A , Bottery Michael J , Chowdhury Kaniz F , Sareen Dipti , Ahmad Iqbal , Blair Jessica M A , Carter Laura J , McNally Alan 
Published: August 2023

AbstractAntimicrobial resistance can arise in the natural environment via prolonged exposure to the effluent surrounding manufacturing facilities. These facilities also produce non-antibiotic pharmaceuticals, and the effect of these on the surrounding microbial communities is less clear; whether they have inherent toxicity, or whether long-term exposure might select for cross-resistance to antibiotics. To this end, we screened four non-antibiotic pharmaceuticals (acetaminophen, ibuprofen, propranolol, met formin) and titanium dioxide for toxicity againstEscherichia coliK-12 MG1655 and conducted a 30 day selection experiment to assess the effect of long-term exposure. All compounds reduced the maximum optical density reached byE. coliat a range of concentrations including one of environmental relevance, with transcriptome analysis identifying upregulated genes related to stress response and multidrug efflux in response ibuprofen treatment. The non-antibiotic pharmaceuticals did not select for significant genetic changes following a 30 day exposure, and no evidence of selection for cross-resistance to antibiotics was observed for population evolved in the presence of ibuprofen in spite of the differential gene expression after exposure to this compound. This work suggests that these non-antibiotic pharmaceuticals, at environmental concentrations, do not select for cross-resistance to antibiotics inE. coli.
Ecological drift during colonization drives within- and between-host heterogeneity in animal symbiont populations
Authors: Chen Jason Z. , Kwong Zeeyong , Gerardo Nicole M. , Vega Nic M. 
Published: August 2023

AbstractHost-associated microbiomes vary greatly in composition both within and between host individuals, providing the raw material for natural selection to act on host-microbe associations. Nonetheless, the drivers of compositional heterogeneity in host-associated microbiomes have only rarely been examined. To understand how this heterogeneity arises, we utilize the squash bug,Anasa tristis, and its bacterial symbionts in the genusCaballeronia. We artificially modulate symbiont bottleneck size and strain diversity during colonization to demonstrate the significance of ecological drift, which causes stochastic fluctuations in community composition. Consistent with predictions from the neutral theory of biodiversity, ecological drift alone can account for heterogeneity in symbiont community composition between hosts, even when two strains are nearly genetically identical. When acting on competing, unrelated strains, ecological drift can maintain symbiont genetic diversity among different hosts by stochastically determining the dominant strain within each host. Finally, ecological drift mediates heterogeneity in isogenic symbiont populations even within a single host, along a consistent gradient running the anterior-posterior axis of the symbiotic organ. Our results demonstrate that symbiont population structure across scales does not necessarily require host-mediated selection, but emerges as a result of ecological drift acting on both isogenic and unrelated competitors. Our findings illuminate the processes that might affect symbiont transmission, coinfection, and population structure in nature, which can drive the evolution of host-microbe symbiosis and microbe-microbe interactions within host-associated microbiomes.
Gaming expertise induces meso-scale brain plasticity and efficiency mechanisms as revealed by whole-brain modeling
Authors: Coronel-Oliveros Carlos , Medel Vicente , Orellana Sebastián , Rodiño Julio , Lehue Fernando , Cruzat Josephine , Tagliazucchi Enzo , Brzezicka Aneta , Orio Patricio , Kowalczyk-Grębska Natalia , Ibáñez Agustín 
Published: August 2023

AbstractVideo games are a valuable tool for studying the effects of training and neural plasticity on the brain. However, the underlaying mechanisms related to plasticity-induced brain structural changes and their impact in brain dynamics are unknown. Here, we used a semi-empirical whole-brain model to study structural neural plasticity mechanisms linked to video game expertise. We hypothesized that video game expertise is associated with neural plasticity-mediated changes in structural connectivity that manifest at the meso-scale level, resulting in a more segregated functional network topology. To test this hypothesis, we combined structural connectivity data of StarCraft II video game players (VGPs, n = 31) and non-players (NVGPs, n = 31), with generic fMRI data from the Human Connectome Project and computational models, with the aim of generating simulated fMRI recordings. Graph theory analysis on simulated data was performed during both resting-state conditions and external stimulation. VGPs’ simulated functional connectivity was characterized by a meso-scale integration, with increased local connectivity in frontal, parietal and occipital brain regions. The same analyses at the level of structural connectivity showed no differences between VGPs and NVGPs. Regions that increased their connectivity strength in VGPs are known to be involved in cognitive processes crucial for task performance such as attention, reasoning, and inference. In-silico stimulation suggested that differences in FC between VGPs and NVGPs emerge in noisy contexts, specifically when the noisy level of stimulation is increased. This indicates that the connectomes of VGPs may facilitate the filtering of noise from stimuli. These structural alterations drive the meso-scale functional changes observed in individuals with gaming expertise. Overall, our work sheds light into the mechanisms underlying structural neural plasticity triggered by video game experiences.
AI identifies potent inducers of breast cancer stem cell differentiation based on adversarial learning from gene expression data
Authors: Li Zhongxiao , Napolitano Antonella , Fedele Monica , Gao Xin , Napolitano Francesco 
Published: August 2023

AbstractCancer stem cells (CSCs) are a subpopulation of cancer cells within tumors that exhibit stem-like properties, and represent a potentially effective therapeutic target towards long-term remission by means of differentiation induction. By leveraging an Artificial Intelligence (AI) approach solely based on transcriptomics data, this study scored a large library of small molecules based on their predicted ability to induce differentiation in stem-like cells. In particular, a deep neural network model was trained using publicly available single-cell RNA-Seq data obtained from untreated human induced pluripotent stem cells at various differentiation stages and subsequently utilized to screen drug-induced gene expression profiles from the LINCS database. The challenge of adapting such different data domains was tackled by devising an adversarial learning approach that was able to effectively identify and remove domain-specific bias during the training phase. Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of 5 out of 6 tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron, and A-443654 offer a potential avenue for targeted therapies against breast CSCs.
Yeast TLDc domain-containing proteins control assembly and subcellular localization of the V-ATPase
Authors: Klössel Samira , Zhu Ying , Amado Lucia , Bisinski Daniel D. , Ruta Julia , Liu Fan , González Montoro Ayelén 
Published: August 2023

AbstractYeast vacuoles, equivalent to lysosomes in other eukaryotes, are important acidic degradative organelles as well as storage compartments and signaling hubs. To perform these functions, they rely on important protein complexes, including the V-ATPase, responsible for organelle acidification. In this study, we used cross-linking mass spectrometry to characterize the protein complexes of isolated vacuoles. We were able to detect many known protein-protein interactions, including known protein complexes, as well as undescribed ones. Among these, we identified the uncharacterized TLDc domain-containing protein Rtc5 as a novel interactor of the V-ATPase. We show that Rtc5 localizes to the vacuole membrane depending on N-myristoylation and on its interactions with the V-ATPase. We further analyzed the influence of this protein, and the second yeast TLDc domain-containing protein, Oxr1, on V-ATPase function. We find that both Rtc5 and Oxr1 promote the disassembly of the vacuolar V-ATPasein vivo, counteracting the role of the assembly chaperone, the RAVE complex. Finally, Oxr1 is necessary for the retention in the late Golgi complex of an organelle-specific subunit of the V-ATPase. Collectively, our results shed light on thein vivoroles of yeast TLDc domain-containing proteins in relation to the V-ATPase, highlighting the multifaceted regulation of this crucial protein complex.