bluuebunny/crossref_metadata_2025_split huggingface dataset:
Death by Round Numbers: Glass-Box Machine Learning Uncovers Biases in Medical Practice
Authors: Lengerich Benjamin J. , Caruana Rich , Nunnally Mark E. , Kellis Manolis 
Published: May 2022

AbstractReal-world evidence is confounded by treatments, so data-driven systems can learn to recapitulate biases that influenced treatment decisions. This confounding presents a challenge: uninterpretable black-box systems can put patients at risk by confusing treatment benefits with intrinsic risk, but also an opportunity: interpretable “glass-box” models can improve medical practice by highlighting unexpected patterns which suggest biases in medical practice. We propose a glass-box model that enables clinical experts to find unexpected changes in patient mortality risk. By applying this model to four datasets, we identify two characteristic types of biases: (1) discontinuities where sharp treatment thresholds produce step-function changes in risk near clinically-important round-number cutoffs, and (2) counter-causal paradoxes where aggressive treatment produces non-monotone risk curves that contradict underlying causal risk by lowering the risk of treated patients below that of healthier, but untreated, patients. While these effects are learned by all accurate models, they are only revealed by interpretable models. We show that because these effects are the result of clinical practice rather than statistical aberration, they are pervasive even in large, canonical datasets. Finally, we apply this method to uncover opportunities for improvements in clinical practice, including 8000 excess deaths per year in the US, where paradoxically, patients with moderately-elevated serum creatinine have higher mortality risk than patients with severely-elevated serum creatinine.
A ratchet-like apical constriction drives cell ingression during the mouse gastrulation EMT
Authors: Francou Alexandre , Anderson Kathryn V. , Hadjantonakis Anna-Katerina 
Published: May 2022

ABSTRACTEpithelial-to-Mesenchymal Transition (EMT) is a fundamental process in which epithelial cells acquire mesenchymal phenotypes and the ability to migrate. EMT is the hallmark of gastrulation, an evolutionarily conserved developmental process. In mammals, epiblast cells lose pluripotency and ingress at the primitive streak to form mesoderm. Cell exit from the epiblast epithelial layer and the associated EMT are dynamically regulated processes involving a stereotypical sequence of cell behaviors. 3D time-lapse imaging of gastrulating mouse embryos combined with cell and tissue scale data analyses revealed the stochastic-like ingression of epiblast cells at the primitive streak. Ingressing cells constrict their apical surfaces in a pulsed ratchet-like fashion through asynchronous shrinkage of apical junctions. A quantitative analyses of the distribution of apical proteins, revealed the anisotropic and complementary distribution of members of the actomyosin network and Crumbs2 complexes, potential regulators of asynchronous shrinkage of cell junctions. The analysis of mutants demonstrated a requirement for Crumbs2 in Myosin2 localization and activity at apical junctions, and as a candidate for regulating actomyosin anisotropy.
Rebound Excitation of Epileptiform Activities by Transcranial Focused Ultrasound Stimulation
Authors: Choi Taewon , Koo Minseok , Joo Jaesoon , Kim Taekyung , Shon Young-Min , Park Jinhyoung 
Published: May 2022

AbstractBackgroundConventional neurostimulations to treat epilepsy have adverse effects caused by post-inhibitory rebound excitations. Although ultrasound brain stimulation is feasible in inducing anticonvulsant effects, its association with paradoxical rebound excitations is unknown.ObjectiveThis study aimed at demonstrating rebound excitations with transcranial focused ultrasound. The modulations of epileptiform activities toward both suppressive and excitatory responses were investigated by changing ultrasonic transmit sequences.MethodsIn a pentylenetetrazol-injected acute epilepsy rat model, transcranial focused ultrasound stimulation was applied on the thalamus to modulate epileptiform activities. The parameters differentiated for pulse sequences were the pulse length, pulse pressure, and interval between the pulses. Sonication effects were assessed by electroencephalography (n=38), immuno-histochemical analysis (n=24), and optical measurement of cerebral blood volume changes (n=18).ResultsWhile ultrasonic patterns of stimuli at long intervals showed antiepileptic effects on electroencephalography, those at short intervals showed rebound excitatory responses followed by inhibitory activities. Further, suppressive states induced by inhibitory stimulations were transformed into excitatory states by applying a consecutive series of short bursts at higher acoustic pressure. Cerebral blood volume changes demonstrated consistent results with electroencephalography. Immunohistochemistry revealed that both inhibitory and excitatory neuronal cells were activated to generate rebound excitatory conditions, while inhibitory cells were activated for suppressive conditions.ConclusionsIn our study, variations in ultrasound stimulation patterns could modulate epileptiform activities in both upregulated and downregulated directions.
A CXCL12 morphogen gradient uncovers lung endothelial heterogeneity and promotes distal vascular growth
Authors: Chandrasekaran Prashant , Negretti Nicholas M. , Sivakumar Aravind , Peers de Nieuburgh Maureen , Wang Joanna , Michki Nigel S. , Chaudhry Fatima N. , Wen Hongbo , Kaur Sukhmani , Lu MinQi , Zepp Jarod A. , Young Lisa R. , Sucre Jennifer M.S. , Frank David B. 
Published: May 2022

AbstractIn adults, there is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury, however, molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to a large number of lung diseases in children, indicating a need to uncover fetal programs that promote pulmonary vascular growth. To address this, we used a transgenic mouse reporter for expression ofCxcl12, an arterial hallmark gene, and performed single-cell RNA sequencing on isolatedCxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation, gene ontology analysis, and spatial transcriptomics allowed us to segregate the developing artery into spatially and functionally distinct novel subpopulations. In addition, expression ofCxcl12suggests a morphogen gradient from arteries to capillaries, suggesting directed cell migration for pulmonary vascular development. Disruption of this gradient led to abnormal branching and pulmonary vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.
Toxicology assessment of manganese oxide nanomaterials with enhanced electrochemical properties using human in vitro models representing different exposure routes
Authors: Fernández-Pampin Natalia , Plaza Juan José González , García Alejandra , Peña Elisa , Rumbo Carlos , Barros Rocío , Martel Sonia , Aparicio Santiago , Tamayo-Ramos Juan Antonio 
Published: May 2022

AbstractIn the present study, a comparative human toxicity assessment between newly developed Mn3O4 nanoparticles with enhanced electrochemical properties (GNA35) and their precursor material (Mn3O4) was performed, employing different in vitro cellular models representing alveolar, oral and dermal exposure routes, namely the human alveolar carcinoma epithelial cell line (A549), the human colorectal adenocarcinoma cell line (HT29), and the reconstructed 3D human epidermal model EpiDerm™ (RhE). The obtained results showed that Mn3O4 and GNA35 harbour similar morphological characteristics, while differences were observed in relation to their thermal stability and electrochemical properties. In regard to their toxicological properties, both nanomaterials induced oxidative stress in the A549 and HT29 cell lines that have demonstrated that manganese oxide nanoparticles reduce the cell viability in A549 cells while they do not produce any negative effect on that of HT29 cells. On the other hand, it was observed that Mn3O4 and GNA35 induce oxidative stress in both cell lines. Finally, it was noticed that none of the nanoparticles caused a reduction of the viability on the skin tissue so that they could not be classified as irritants. Our findings demonstrate that the evaluation of the toxicity of nanoparticles using different models is a critical aspect to increase the knowledge on their potential impact on human health.
Hippocampal cAMP-dependent synaptic potentiation, ERK-dependent immediate-early gene activation, and context-dependent fear conditioning in mice are linked through dependence on the guanine nucleotide exchange factor RapGEF2
Authors: Jiang Sunny Zhihong , Shahoha Meishar , Tejeda Hugo A. , Ashery Uri , Eiden Lee E. 
Published: May 2022

ABSTRACTThe MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for ERK activation in hippocampus are still largely undetermined. RapGEF2 has emerged as a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether RapGEF2 might also be required for cAMP-dependent ERK activation leading to synaptic potentiation, and how this involvement might be penetrant to hippocampus-dependent learned behavior. We demonstrate that conditional knockout of Rapgef2 in forebrain neurons, specifically in dentate gyrus and CA1 of the hippocampus, leads to an attenuation of context-dependent fear conditioning, but not of cue-dependent fear conditioning, in mice. RapGEF2 knockout is associated with a reduction in cAMP-dependent synaptic potentiation at two central hippocampal synapses-the entorhinal cortex-granule cell synapse and the CA3-CA1 synapse. Furthermore, cAMP-induced postsynaptic potentiation requires both RapGEF2 and activation of ERK. Induction of Egr-1/Zif268 (and pERK), but not of c-Fos, immediately following fear conditioning, was abolished in CA1 and detate gyrus, in the absence of RapGEF2 expression in these hippocampal regions, thus revealing a link between learning (conditioning) and molecular pathways activated during conditioned fear memory formation. Hence, we suggest that contextual fear conditioning is mediated via RapGEF2-dependent ERK activation and downstream induction of Egr-1, via an underlying mechanism of cAMP-dependent long-term potentiation at hippocampal synapses. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. This study provides a functional link between one of these cAMP-dependent GEFs, RapGEF2, and cognitive processes involved in associative learning.
Continued Emergence and Evolution of Omicron in South Africa: New BA.4 and BA.5 lineages
Authors: Tegally Houriiyah , Moir Monika , Everatt Josie , Giovanetti Marta , Scheepers Cathrine , Wilkinson Eduan , Subramoney Kathleen , Moyo Sikhulile , Amoako Daniel G. , Baxter Cheryl , Althaus Christian L. , Anyaneji Ugochukwu J. , Kekana Dikeledi , Viana Raquel , Giandhari Jennifer , Lessells Richard J. , Maponga Tongai , Maruapula Dorcas , Choga Wonderful , Matshaba Mogomotsi , Mayaphi Simnikiwe , Mbhele Nokuzola , Mbulawa Mpaphi B. , Msomi Nokukhanya ,   NGS-SA consortium, Naidoo Yeshnee , Pillay Sureshnee , Sanko Tomasz Janusz , San James E. , Scott Lesley , Singh Lavanya , Magini Nonkululeko A. , Smith-Lawrence Pamela , Stevens Wendy , Dor Graeme , Tshiabuila Derek , Wolter Nicole , Preiser Wolfgang , Treurnicht Florette K. , Venter Marietjie , Davids Michaela , Chiloane Georginah , Mendes Adriano , McIntyre Caitlyn , O’Toole Aine , Ruis Christopher , Peacock Thomas P. , Roemer Cornelius , Williamson Carolyn , Pybus Oliver G. , Bhiman Jinal , Glass Allison , Martin Darren P. , Rambaut Andrew , Gaseitsiwe Simani , Gottberg Anne von , de Oliveira Tulio 
Published: May 2022

AbstractSouth Africa’s fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath™ COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa.
Predicting longitudinal brain atrophy in Parkinson’s disease using a Susceptible-Infected-Removed agent-based model
Authors: Abdelgawad Alaa , Rahayel Shady , Zheng Ying-Qiu , Tremblay Christina , Vo Andrew , Misic Bratislav , Dagher Alain 
Published: May 2022

ABSTRACTParkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in PD: in its misfolded pathologic state it favours the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal or synaptic damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation and toxicity of alpha-synuclein molecules in the brain. Here we test this model with longitudinal MRI collected over four years from the Parkinson Progression Markers Initiative (1068 T1 MRI scans, 790 PD, 278 matched controls). We find that brain deformation progresses in subcortical and cortical regions. The SIR model, using structural connectivity from diffusion MRI, recapitulates the spatiotemporal distribution of brain atrophy observed in PD. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in PD is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.
A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE
Authors: Watts Jason A. , Grunseich Christopher , Rodriguez Yesenia , Liu Yaojuan , Li Dongjun , Burdick Joshua T , Bruzel Alan , Crouch Robert J. , Mahley Robert W. , Wilson Samuel H. , Cheung Vivian G. 
Published: May 2022

AbstractThe DNA genetic code and the RNA regulatory code determine phenotypes from gene expression to disease susceptibility. DNA sequence variants lead to phenotypic differences among individuals, while within an individual, RNA dynamically confers cell identity and responds to cellular and environmental signals. To provide regulation for different cell types and conditions, the nucleotides of RNA are modified by hundreds of chemical reactions, and RNA folds into innumerable shapes. To decipher the RNA regulatory code is to understand how RNA sequence and structure respond to cellular needs. Here, we deciphered one part of the RNA code where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We uncovered an enhancer RNA, AANCR, that regulates the transcription and expression of APOE. When AANCR is folded into an R-loop, which is then modified by N6-adenine methylation and N-glycosidic cleavage, it is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in some cell types and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. By genetic analysis, we confirmed that AANCR regulates APOE expression. DNA sequence variants in AANCR are associated with APOE expression and also with Alzheimer’s disease. Our data show that DNA and RNA sequence and structure jointly regulate gene expression that influence disease risk.Highlightsm6A, RNA abasic sites and R-loops jointly regulate transcription by pausing RNA Polymerase II.An enhancer RNA regulates APOE expression.Enhancer RNA of APOE modifies susceptibility to Alzheimer’s disease.
Genome-wide identification ofSINAgene family in sugarcane and functional analysis ofSsSINA1ain drought response
Authors: Zhang Jinxu , Jiang Xialan , Xiao Shenghua , Jiang Shuo , Yao Wei , Zhang Muqing 
Published: May 2022

ABSTRACTSugarcane (Saccharumspp. hybrid) is a crucial sugar and energy crop that provides majority of the raw material for sugar and ethanol production globally. Drought represents one of the most critical constraints of sugarcane production in the subtropical parts of China. SEVEN IN ABSENTIA (SINA) act as an important E3 ubiquitin ligase and play a significant role in plant stress responses. However, the characteristics of the sugarcaneSINAgene family have not been previously studied currently. Here, we identified 15SsSINAinSaccharum spontaneum, 5ShSINAinSaccharum spp. hybrid and 6SbSINAinSorghum bicolorbased on their conserved N□terminal RING and C-terminal SINA domains, and these genes were distributed into three phylogenetic groups (I, □ and □). Collinearity analysis showed a close genetic relationship between theSINAgenes ofS. spontaneumandS. bicolor. The cis-regulatory elements in the promoter regions of theSINAgenes were involved in a variety of plant physiological responses. Further, we identified aSINAgeneSsSINA1athat significantly induced by drought stress. Overexpression ofSsSINA1aenhanced drought tolerance in Arabidopsis through reducing leaf water loss rate. These finding indicate that SsSINA1a mediates plant drought tolerance and this study provides a new potential candidate gene for sugarcane drought-resistant breeding.
Tension-Tuned SynNotch Receptors for Synthetic Mechanotranduction and Intercellular Force Detection
Authors: Sloas D. Christopher , Tran Jeremy C. , Marzilli Alexander M. , Ngo John T. 
Published: May 2022

ABSTRACTCells can sense and interpret mechanical stimuli from their environments and neighbors, but the ability to engineer customized mechanosensing capabilities has remained a synthetic and mechanobiology challenge. Here, we introduce tension-tuned synthetic Notch (SynNotch) receptors that can be used to convert extracellular and intercellular forces into specifiable gene expression changes. By elevating the tension requirements of SynNotch activation, in combination with structure-guided mutagenesis, we designed a set of receptors with mechanical sensitivities spanning the physiologically relevant picoNewton (pN) range. Cells expressing these receptors can distinguish between varying tensile forces and respond by enacting customizable transcriptional programs. The synthetic utility of these tools is demonstrated by designing a decision-making circuit, through which fibroblasts can be made to differentiate into myoblasts upon stimulation with distinct tension magnitudes. Mechanobiological utility is also demonstrated by characterizing cell-generated forces transmitted between cells during Notch signaling. Overall, this work provides insight regarding how mechanically induced changes in protein structure can be used to transduce physical forces into biochemical signals. The system should facilitate the further programming and dissection of force-related phenomena in biological systems.
A role for the anterior hippocampus in autobiographical memory construction regardless of temporal distance
Authors: Audrain Sam , Gilmore Adrian W. , Wilson Jenna M. , Schacter Daniel L. , Martin Alex 
Published: May 2022

AbstractMounting evidence suggests distinct functional contributions of the anterior and posterior hippocampus to autobiographical memory retrieval, but how these subregions function under different retrieval demands as memories age is not yet understood. Specifically, autobiographical memory retrieval is not a homogenous process, rather, it is thought to consist of multiple stages: an early stage of memory construction and a later stage of detailed elaboration, which may differently engage the hippocampus over time. In the present study, we analyzed data from 40 participants who constructed and overtly elaborated upon recent and remote memories in response to picture cues in the fMRI scanner. We previously reported a temporal gradient in the posterior hippocampus during the elaboration period of autobiographical retrieval, with posterior hippocampal activation observed for recent but not remote timepoints. Here, we consider the previously unanalyzed construction stage of retrieval, where participants searched for and selected a memory. We found no evidence of a temporal gradient during memory construction, instead observing strong anterior hippocampus activity regardless of memory remoteness. Our findings suggest a unique contribution of the anterior hippocampus to the construction process of autobiographical retrieval over time. These findings highlight that retrieval processes, which have yet to be considered in current models of systems consolidation, offer novel insights to hippocampal subregion function over time.
Coordinated control of neuronal differentiation and wiring by a sustained code of transcription factors
Authors: Özel Mehmet Neset , Gibbs Claudia Skok , Holguera Isabel , Soliman Mennah , Bonneau Richard , Desplan Claude 
Published: May 2022

AbstractThe enormous diversity of cell types in nervous systems presents a challenge in identifying the genetic mechanisms that encode it. Here, we report that nearly 200 distinct neurons in the Drosophila visual system can each be defined by unique combinations of ∼10 transcription factors that are continuously expressed by them. We show that targeted modifications of this ‘selector’ code induce predictable conversions of cell fates between neurons in vivo. These conversions appear morphologically and transcriptionally complete, arguing for a conserved gene regulatory program that jointly instructs both the type-specific development and the terminal features of neurons. Cis-regulatory sequence analysis of open chromatin links one of these selectors to an upstream patterning gene in stem cells that specifies neuronal fates. Experimentally validated network models show that selectors interact with ecdysone signaling to regulate downstream effectors controlling brain wiring. Our results provide a generalizable framework of how specific fates are initiated and maintained in postmitotic neurons.