bluuebunny/crossref_metadata_2025_split huggingface dataset:
Montane rain forest dynamics under changes in climate and human impact during the past millennia in northern Madagascar
Authors: Montade Vincent , Bremond Laurent , Teixeira Helena , Kasper Thomas , Daut Gerhard , Rasoamanana Elysée , Ramavovolona Perle , Favier Charly , Arnaud Fabien , Radespiel Ute , Behling Hermann 
Published: June 2023

AbstractMadagascar comprises one of the Earth’s biologically richest, but also one of most endangered, terrestrial ecoregions. Although it is obvious that humans substantially altered its natural ecosystems during the past decades, the timing of arrival of humans on Madagascar as well as their environmental impact is not well resolved. In this context, this research aims to study and compare the influence of early human impact and climate change on rain forests and wildlife in northern Madagascar during the past Millennia. By using palaeoenvironmental reconstructions from lake sediment cores in a montane environment (Montagne d’Ambre), results indicate a major drought, starting approximately 1,100 years ago. This drought caused significant changes in lake levels and vegetation dynamics. Human impact, evidenced by fires, started a few decades later. Anthropogenic burning, limited to the low-altitude areas, was therefore not the driving force behind these early changes observed in the lake catchment areas. Although this does not dismiss the strong impacts humans had subsequently on these ecosystems, this work demonstrates that the late Holocene natural drought that intensified regionally about one thousand years ago, significantly impacted the ecosystems independently and prior to anthropogenic activities. At a regional scale, a review of demographic studies revealed a substantial number of inferred population bottlenecks in various wildlife species during the last millennia, likely resulting from this combination of both human-related impact and natural environmental changes (i.e., precipitation decline). This research highlights that the current state of ecosystems in northern Madagascar results from both human impact and natural climate changes. It also points to the importance of a multi-site and multi-proxy comparison for deciphering the nature and succession of past environmental changes.
Heritable epigenetic changes are constrained by the dynamics of regulatory architectures
Authors: Jose Antony M 
Published: June 2023

ABSTRACTInteracting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Such stable changes can (1) alter steady-state levels while preserving the architecture, (2) induce different architectures that persist for many generations, or (3) collapse the entire architecture. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that the evolution of mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of regulatory architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematodeC. elegans, which range from permanent silencing to recovery from silencing within a few generations and subsequent resistance to silencing. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.
Light-induced condensates show accumulation-prone and less dynamic properties in the nucleus compared to the cytoplasm
Authors: Hamada Yuta , Kitamura Akira 
Published: June 2023

AbstractBiomolecular condensates, including membraneless organelles, are ubiquitously observed in subcellular compartments. However, the accumulation and dynamic properties of arbitrarily induced condensates remain elusive. Here, we show the size, amount, and dynamic properties of subcellular condensates using various fluorescence spectroscopic imaging analyses. Spatial image correlation spectroscopy showed that the size of blue-light-induced condensates of cryptochrome 2-derived oligomerization tag (CRY2olig) tagged with a red fluorescent protein in the nucleus was not different from that in the cytoplasm. Fluorescence intensity measurements showed that the condensates in the nucleus were more prone to accumulation than those in the cytoplasm. Single-particle tracking analysis showed that the condensates in the nucleus are predisposed to be stationary dynamics compared to those in the cytoplasm. Therefore, the subcellular compartment may, in part, affect the characteristics of self-recruitment of biomolecules in the condensates and their movement property.
Random effects adjustment in machine learning models for cardiac surgery risk prediction: a benchmarking study
Authors: Dong Tim , Sinha Shubhra , Fudulu Daniel P , Chan Jeremy , Zhai Ben , Narayan Pradeep Narayan , Caputo Massimo , Judge Andy , Dimagli Arnaldo , Benedetto Umberto , Angelini Gianni D. 
Published: June 2023

ABSTRACTObjectivesThere is an ongoing debate over whether a procedural specific (e.g. Society of Thoracic Surgeons (STS)) or universal model (e.g. EuroSCORE II (ES II)) should be used for patient selection in cardiac surgery. Recently, we showed that ES II suffers from severe performance drift across several important metrics and that ML approaches such as Xgboost and Random Forest are substantially more resistant to dataset drift. With the growing interest in big data and its leverage through the use of ML approaches that are not limited by linear statistical assumptions, the number of clinical variables can theoretically increase exponentially. In addition, the variations and residual confounding that historically hindered the usefulness of cardiac risk stratification scores can potentially be taken into account. Here, we assess these possibilities on a large United Kingdom (UK) database.MethodsA retrospective analysis of prospectively routinely gathered data on adult patients undergoing cardiac surgery in the UK between 2012-2019. We temporally split the data 70:30 into a training and validation subset. Two sets of seven ML mortality prediction models, with and without variable selection were assessed for consensus Clinical Effective Metric (CEM) overall performance and performance within each of CEM’s consistuent metrics. Confounding and potential causal relationships between covariates and outcomes were evaluated using bayesian network analysis.ResultsA total of 227,087 adults underwent cardiac surgery during the study period with a mortality rate of 2.76%. For non-variable selected (NVS) risk scores with 102 variables, Xgboost with adjustment for hospital variation was superior to the Xgboost without adjustment (p < 2e-16). Both NVS and the 18 variables selected (VS) Xgboost with adjustment for hospital variation risk scores were superior to the Xgboost (ES II 18 variables) model (p < 6.3e-15), with NVS Xgboost with adjustment for hospital variation having the best performance, followed by the VS Xgboost with adjustment for hospital variation (CEM Difference: 0.0150 and 0.0023, respectively).ConclusionsWe have identified an ML adjusted risk score comprising 102 variables that increases risk stratification performance on hold out dataset, removing the need to perform variable selection and reduction. This paves the way for further research that utilises this new set of variables with hospital-based adjustments for the safer selection of patients undergoing cardiac surgery.
Medical Devises Regulation in Zimbabwe: An Evaluation of operational readiness
Authors: Chiku Charles , Maruta Talkmore , Mbiba Fredrick , Manasa Justen 
Published: June 2023

BackgroundRegulation of medical devices has seriously lagged, especially in Resource-Limited Settings (RLS). There are disparities in regulating medical devices; in the African region, it is below the global average. This may translate into poor access to quality-assured medical devices and result in undesirable health outcomes. Operational readiness to regulate medical devices in Zimbabwe at the Medicines Control Authority of Zimbabwe (MCAZ), the designated National Regulatory Authority (NRA), is vital for planning and implementation. The study aimed to assess the readiness of the MCAZ to regulate medical devices by identifying the strengths and gaps and proposing an institutional development plan that can be monitored and evaluated to assess progress over time.MethodsQuantitative study was conducted using the World Health Organization (WHO) Global Benchmarking Tool+ medical devices (GBT+ medical devices) methodology to evaluate the medical devices regulatory oversight at the MCAZ. Data were collected between June and August 2022 using standard checklists to assess the quality of implementation of medical devices’ regulatory functions; National Regulatory System (RS), Registration and Market Authorisation (MA), Vigilance (VL), Market Surveillance and Control (MC), Licensing Establishment (LI), Regulatory Inspection (RI), Laboratory Testing(LT), and Clinical Trials (CTs) Oversight.ResultsThe MCAZ attained maturity level 1, with an RS score of 79%, MA-44%, VL-27%, MC-40%, LI-62%, RI-68%, LT-88%, and CT-18%. Condoms and gloves were the only regulated medical devices. Indicators on legal provisions, regulations, and guidelines across the regulatory functions were below the optimum requirement.ConclusionThe legal provisions, regulations, and guidelines are inadequate for effectively regulating medical devices. The medical devices regulation requires review for it to be robust and fit-for-purpose, responsive, oriented to the outcome, predictable based on a standard and transparent approach, and the level of scrutiny proportionate to the risk classification of the medical device.
Machine learning of dissection photographs and surface scanning for quantitative 3D neuropathology
Authors: Gazula Harshvardhan , Tregidgo Henry F. J. , Billot Benjamin , Balbastre Yael , William-Ramirez Jonathan , Herisse Rogeny , Deden-Binder Lucas J , Casamitjana Adrià , Melief Erica J. , Latimer Caitlin S. , Kilgore Mitchell D. , Montine Mark , Robinson Eleanor , Blackburn Emily , Marshall Michael S. , Connors Theresa R. , Oakley Derek H. , Frosch Matthew P. , Young Sean I. , Van Leemput Koen , Dalca Adrian V. , FIschl Bruce , Mac Donald Christine L. , Keene C. Dirk , Hyman Bradley T. , Iglesias Juan Eugenio 
Published: June 2023

AbstractWe present open-source tools for 3D analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can:(i)3D reconstruct a volume from the photographs and, optionally, a surface scan; and(ii)produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute forex vivomagnetic resonance imaging (MRI), which requires access to an MRI scanner,ex vivoscanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimer’s Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences betweenpost mortemconfirmed Alzheimer’s disease cases and controls. The tools are available in our widespread neuroimaging suite “FreeSurfer” (https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools).
Ketamine rescues anhedonia by cell-type and input specific adaptations in the Nucleus Accumbens
Authors: Lucantonio Federica , Li Shuwen , Lu Jaden , Roeglin Jacob , Bontempi Leonardo , Shields Brenda C. , Zarate Carlos A. , Tadross Michael R. , Pignatelli Marco 
Published: June 2023

AbstractKetamine’s role in providing a rapid and sustained antidepressant response, particularly for patients unresponsive to conventional treatments, is increasingly recognized. A core symptom of depression, anhedonia, or the loss of enjoyment or interest in previously pleasurable activities, is known to be significantly alleviated by ketamine. While several hypotheses have been proposed regarding the mechanisms by which ketamine alleviates anhedonia, the specific circuits and synaptic changes responsible for its sustained therapeutic effects are not yet understood. Here, we show that the nucleus accumbens (NAc), a major hub of the reward circuitry, is essential for ketamine’s effect in rescuing anhedonia in mice subjected to chronic stress, a critical risk factor in the genesis of depression in humans. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). By using a novel cell-specific pharmacology method, we demonstrate that this cell-type specific neuroadaptation is necessary for the sustained therapeutic effects of ketamine. To test for causal sufficiency, we artificially mimicked ketamine-induced increase in excitatory strength on D1-MSNs and found that this recapitulates the behavioral amelioration induced by ketamine. Finally, to determine the presynaptic origin of the relevant glutamatergic inputs for ketamine-elicited synaptic and behavioral effects, we used a combination of opto- and chemogenetics. We found that ketamine rescues stress-induced reduction in excitatory strength at medial prefrontal cortex and ventral hippocampus inputs to NAc D1-MSNs. Chemogenetically preventing ketamine-evoked plasticity at those unique inputs to the NAc reveals a ketamine-operated input-specific control of hedonic behavior. These results establish that ketamine rescues stress-induced anhedonia via cell-type-specific adaptations as well as information integration in the NAc via discrete excitatory synapses.
Formation of Müller glia-derived progenitor cells in retinas depleted of microglia
Authors: El-Hodiri Heithem M. , Bentley James , Reske Alana , Palazzo Isabella , Campbell Warren A. , Halloy Nicklaus R. , Fischer Andy J. 
Published: June 2023

AbstractRecent studies have demonstrated the complex coordination of pro-inflammatory signaling and reactive microglia/macrophage on the formation Müller glial-derived progenitor cells (MGPCs) in the retinas of fish, birds and mice. We generated scRNA-seq libraries to identify transcriptional changes in Müller glia (MG) that result from the depletion of microglia from the chick retina. We found significant changes in different networks of genes in MG in normal and damaged retinas when the microglia are ablated. We identified a failure of MG to upregulate Wnt-ligands, Heparin binding epidermal growth factor (HBEGF), Fibroblast growth factor (FGF), retinoic acid receptors and genes related to Notch-signaling. Inhibition of GSK3β, to simulate Wnt-signaling, failed to rescue the deficit in formation of proliferating MGPCs in damaged retinas missing microglia. By comparison, application of HBEGF or FGF2 completely rescued the formation of proliferating MGPCs in microglia-depleted retinas. Similarly, injection of a small molecule inhibitor to Smad3 or agonist to retinoic acid receptors partially rescued the formation of proliferating MGPCs in microglia-depleted damaged retinas. According to scRNA-seq libraries, patterns of expression of ligands, receptors, signal transducers and/or processing enzymes to cell-signaling via HBEGF, FGF, retinoic acid and TGFβ are rapidly and transiently upregulated by MG after neuronal damage, consistent with important roles for these cell-signaling pathways in regulating the formation of MGPCs. We conclude that quiescent and activated microglia have a significant impact upon the transcriptomic profile of MG. We conclude that signals produced by reactive microglia in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFβ/Smad3 to promote the reprogramming on MG into proliferating MGPCs.
A translational rodent model of individual differences in sensitivity to the aversive properties of ethanol
Authors: Przybysz Kathryn R , Ramirez Lindsey A , Pitock Joseph R , Starr E Margaret , Yang Hyerim , Glover Elizabeth J 
Published: June 2023

AbstractBackgroundA strong relationship exists between individual sensitivity to the aversive properties of ethanol and risk for alcohol use disorder (AUD). Despite this, our understanding of the neurobiological mechanisms underlying subjective response to ethanol is relatively poor. A major contributor to this is the absence of preclinical models that enable exploration of this individual variability similar to studies performed in humans.MethodsAdult male and female Long-Evans rats were trained to associate a novel tastant (saccharin) with acute exposure to either saline or ethanol (1.5 g/kg or 2.0 g/kg i.p.) over three conditioning days using a standard conditioned taste aversion (CTA) procedure. Variability in sensitivity to ethanol-induced CTA was phenotypically characterized using a median split across the populations studied.ResultsWhen examining group averages, both male and female rats that had saccharin paired with either dose of ethanol exhibited reduced saccharin intake relative to saline controls of ethanol-induced CTA. Examination of individual data revealed a bimodal distribution of responses uncovering two distinct phenotypes present in both sexes. CTA-sensitive rats exhibited a rapid and progressive reduction in saccharin intake with each successive ethanol pairing. In contrast, saccharin intake was unchanged or maintained after an initial decrease from baseline levels in CTA-resistant rats. While CTA magnitude was similar between male and female CTA-sensitive rats, CTA-resistant females were more resistant to the development of ethanol-induced CTA than their male counterparts. Phenotypic differences were not driven by differences in baseline saccharin intake. CTA sensitivity correlated with behavioral signs of intoxication in only a subset of rats.ConclusionsThese data parallel work in humans by revealing individual differences in sensitivity to the aversive properties of ethanol that emerge immediately after initial exposure to ethanol in both sexes. This model can be leveraged in future studies to investigate the neurobiological mechanisms that confer risk for AUD.
TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis
Authors: Guise Amanda J. , Misal Santosh A. , Carson Richard , Boekweg Hannah , Van Der Watt Daisha , Truong Thy , Liang Yiran , Chu Jen-Hwa , Welsh Nora C. , Gagnon Jake , Payne Samuel H. , Plowey Edward D. , Kelly Ryan T. 
Published: June 2023

SummaryUnbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is that motor neuron (MN) proteome signals may be confounded by admixed non-MN proteins. Recent advances in trace sample proteomics have enabled quantitative protein abundance datasets from single human MNs (Cong et al., 2020b). In this study, we leveraged laser capture microdissection (LCM) and nanoPOTS (Zhu et al., 2018c) single-cell mass spectrometry (MS)-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control donor spinal cord tissues, leading to the identification of 2515 proteins across MNs samples (>900 per single MN) and quantitative comparison of 1870 proteins between disease groups. Furthermore, we studied the impact of enriching/stratifying MN proteome samples based on the presence and extent of immunoreactive, cytoplasmic TDP-43 inclusions, allowing identification of 3368 proteins across MNs samples and profiling of 2238 proteins across TDP-43 strata. We found extensive overlap in differential protein abundance profiles between MNs with or without obvious TDP-43 cytoplasmic inclusions that together point to early and sustained dysregulation of oxidative phosphorylation, mRNA splicing and translation, and retromer-mediated vesicular transport in ALS. Our data are the first unbiased quantification of single MN protein abundance changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein abundance changes in human neurologic diseases.
Condition-dependent fitness effects of large synthetic chromosome amplifications
Authors: Keller Abigail , Gao Lucy L. , Witten Daniela , Dunham Maitreya J. 
Published: June 2023

AbstractWhole-chromosome aneuploidy and large segmental amplifications can have devastating effects in multicellular organisms, from developmental disorders and miscarriage to cancer. Aneuploidy in single-celled organisms such as yeast also results in proliferative defects and reduced viability. Yet, paradoxically, CNVs are routinely observed in laboratory evolution experiments with microbes grown in stressful conditions. The defects associated with aneuploidy are often attributed to the imbalance of many differentially expressed genes on the affected chromosomes, with many genes each contributing incremental effects. An alternate hypothesis is that a small number of individual genes are large effect ‘drivers’ of these fitness changes when present in an altered copy number. To test these two views, we have employed a collection of strains bearing large chromosomal amplifications that we previously assayed in nutrient-limited chemostat competitions. In this study, we focus on conditions known to be poorly tolerated by aneuploid yeast—high temperature, treatment with the Hsp90 inhibitor radicicol, and growth in extended stationary phase. To identify potential genes with a large impact on fitness, we fit a piecewise constant model to fitness data across chromosome arms, filtering breakpoints in this model by magnitude to focus on regions with a large impact on fitness in each condition. While fitness generally decreased as the length of the amplification increased, we were able to identify 91 candidate regions that disproportionately impacted fitness when amplified. Consistent with our previous work with this strain collection, nearly all candidate regions were condition specific, with only five regions impacting fitness in multiple conditions.