bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia
Authors: Wen Kailong , Shi Zhuoyue , Yu Peijia , Mo Lillian , Sullere Shivang , Yang Victor , Westneat Nate , Beeler Jeff A , McGehee Daniel S , Doiron Brent , Zhuang Xiaoxi 
Published: February 2024

AbstractLoss of dopamine neurons causes motor deterioration in Parkinson’s disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m6A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion ofYthdf1in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinson’s disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.
Genome concentration limits cell growth and modulates proteome composition inEscherichia coli
Authors: Mäkelä Jarno , Papagiannakis Alexandros , Lin Wei-Hsiang , Lanz Michael C. , Glenn Skye , Swaffer Matthew , Marinov Georgi K. , Skotheim Jan M. , Jacobs-Wagner Christine 
Published: February 2024

ABSTRACTDefining the cellular factors that drive growth rate and proteome composition is essential for understanding and manipulating cellular systems. In bacteria, ribosome concentration is known to be a constraining factor of cell growth rate, while gene concentration is usually assumed not to be limiting. Here, using single-molecule tracking, quantitative single-cell microscopy, and modeling, we show that genome dilution inEscherichia colicells arrested for DNA replication limits total RNA polymerase activity within physiological cell sizes across tested nutrient conditions. This rapid-onset limitation on bulk transcription results in sub-linear scaling of total active ribosomes with cell size and sub-exponential growth. Such downstream effects on bulk translation and cell growth are near-immediately detectable in a nutrient-rich medium, but delayed in nutrient-poor conditions, presumably due to cellular buffering activities. RNA sequencing and tandem-mass-tag mass spectrometry experiments further reveal that genome dilution remodels the relative abundance of mRNAs and proteins with cell size at a global level. Altogether, our findings indicate that chromosome concentration is a limiting factor of transcription and a global modulator of the transcriptome and proteome composition inE. coli. Experiments inCaulobacter crescentusand comparison with eukaryotic cell studies identify broadly conserved DNA concentration-dependent scaling principles of gene expression.
Bayesian Hierarchical Hypothesis Testing in Large-Scale Genome-Wide Association Analysis
Authors: Samaddar Anirban , Maiti Tapabrata , de los Campos Gustavo 
Published: February 2024

AbstractVariable selection and large-scale hypothesis testing are techniques commonly used to analyze high-dimensional genomic data. Despite recent advances in theory and methodology, variable selection and inference with highly collinear features remain challenging. For instance, collinearity poses a great challenge in Genome-Wide Association Studies (GWAS) involving millions of variants, many of which may be in high linkage disequilibrium. In such settings, collinearity can significantly reduce the power of variable selection methods to identify individual variants associated with an outcome. To address such challenges, we developed a Bayesian Hierarchical Hypothesis Testing (BHHT)–a novel multi-resolution testing procedure that offers high power with adequate error control and fine-mapping resolution. We demonstrate through simulations that the proposed methodology has a power-FDR performance that is competitive with (and in many scenarios better than) state-of-the-art methods. Finally, we demonstrate the feasibility of using the proposed methodology with big data to map risk variants for serum urate using data (n∼300,000) on phenotype and ultra-high-dimensional genotypes (∼15 million SNPs) from the UK-Biobank. Our results show that the proposed methodology leads to many more discoveries than those obtained using traditional feature-centered inference procedures. The article is accompanied by open-source software that implements the methods described in this study using algorithms that scale to biobank-size ultra-high-dimensional data.
Reactivated past decisions repel early sensory processing and attract late decision-making
Authors: Luo Minghao , Zhang Huihui , Luo Huan 
Published: February 2024

AbstractAutomatic shaping of perception by past experiences is common in many cognitive functions, reflecting the exploitation of temporal regularities in environments. A striking example is serial dependence, i.e., current perception is biased by previous trials. However, the neural implementation of its operational circle in human brains remains unclear. In two experiments with Electroencephalography (EEG) / Magnetoencephalography (MEG) recordings and delayed-response tasks, we demonstrate a two-stage ’repulsive-then-attractive’ past-present interaction mechanism underlying serial dependence. First, past-trial reports serve as a prior to be reactivated during both encoding and decision-making. Crucially, past reactivation interacts with current information processing in a two-stage manner: repelling and attracting the present during encoding and decision-making, and arising in the sensory cortex and prefrontal cortex, respectively. Finally, while the early stage occurs automatically, the late stage is modulated by task and predicts bias behavior. Our findings might also illustrate general mechanisms of past-present influences in neural operations.
CD34-positive monocytes are highly susceptible to HIV-1
Authors: Takahashi Naofumi , Noyori Osamu , Komohara Yoshihiro , Eltalkhawy Youssef M. , Hirayama Masatoshi , Yoshida Ryoji , Nakayama Hideki , Kuroda Marcelo J. , Nomura Takushi , Ishii Hiroshi , Matano Tetsuro , Gatanaga Hiroyuki , Oka Shinichi , Takiguchi Masafumi , Suzu Shinya 
Published: February 2024

AbstractHIV-1 persists in cellular reservoirs despite effective combined antiretroviral therapy (cART). CD4+T cells are a well-known reservoir, but there is evidence suggesting that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is not fully understood which subsets of monocytes are preferentially infected in vivo. Here, we show that a monocyte fraction expressing a stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In cART-untreated viremic individuals, the CD34+fraction increased in the percentage in total monocytes, and harbored higher copies of proviral DNA than the major subset. Consistent with this, the CD34+fraction expressed HIV-1 receptors CD4 and CCR5 at higher levels and HIV-1 restriction factors MX2 and SAMHD1 at lower levels. Interestingly, proviral DNA was still detectable in the CD34+fraction of cART-treated virologically suppressed individuals. CD34+monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed in peripheral blood. Moreover, CD34+monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Collectively, our findings raise the new possibility that lymph node CD34+monocytes, which originate from the circulation, are infected with HIV-1 owing to their high susceptibility to HIV-1, and return to circulation, which explains the detection of proviral DNA in peripheral CD34+monocytes even after long-term cART.
Development and Validation of a Deep Learning Model for Detecting Signs of Tuberculosis on Chest Radiographs among US-bound Immigrants and Refugees
Authors: Lee Scott , Fox Shannon , Smith Raheem , Skrobarcek Kimberly A. , Keyserling Harold , Phares Christina R. , Lee Deborah , Posey Drew L. 
Published: February 2024

AbstractImmigrants and refugees seeking admission to the United States must first undergo an overseas medical exam, overseen by the US Centers for Disease Control and Prevention (CDC), during which all persons ≥15 years old receive a chest x-ray to look for signs of tuberculosis. Although individual screening sites often implement quality control (QC) programs to ensure radiographs are interpreted correctly, the CDC does not currently have a method for conducting similar QC reviews at scale.We obtained digitized chest radiographs collected as part of the overseas immigration medical exam. Using radiographs from applicants 15 years old and older, we trained deep learning models to perform three tasks: identifying abnormal radiographs; identifying abnormal radiographs suggestive of tuberculosis; and identifying the specific findings (e.g., cavities or infiltrates) in abnormal radiographs. We then evaluated the models on both internal and external testing datasets, focusing on two classes of performance metrics: individual-level metrics, like sensitivity and specificity, and sample-level metrics, like accuracy in predicting the prevalence of abnormal radiographs.A total of 152,012 images (one image per applicant; mean applicant age 39 years) were used for model training. On our internal test dataset, our models performed well both in identifying abnormalities suggestive of TB (area under the curve [AUC] of 0.97; 95% confidence interval [CI]: 0.95, 0.98) and in estimating sample-level counts of the same (−2% absolute percentage error; 95% CIC: −8%, 6%). On the external test datasets, our models performed similarly well in identifying both generic abnormalities (AUCs ranging from 0.89 to 0.92) and those suggestive of TB (AUCs from 0.94 to 0.99). This performance was consistent across metrics, including those based on thresholded class predictions, like sensitivity, specificity, and F1 score.Strong performance relative to high-quality radiological reference standards across a variety of datasets suggests our models may make reliable tools for supporting chest radiography QC activities at CDC.
Carboxylated graphene: A novel approach for enhanced IgA-SARS-CoV-2 electrochemical biosensing
Authors: Freire Luciana de Souza , Ruzo Camila Macena , Salgado Barbara Batista , Gandarilla Ariamna María Dip , Barcelay Yonny Romaguera , Tavares Ana P.M. , Nobre Francisco Xavier , Lalwani Pritesh , Astofi-Filho Spartaco , Brito Walter Ricardo 
Published: February 2024

AbstractBiosensors comprise devices that use a material of biological nature as receptors connected to transducers, these devices are capable of capturing biorecognition signals, called a primary signal, and converting it to a measurable signal. In this study, we report the synthesis of carboxylated graphene (CG) through a carboxylation method in acid medium and further characterization of the materials by different techniques such as scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), Raman spectroscopy, thermal gravimetric analysis (TGA), and X-ray diffraction (DRX). Also, the surface of the screen-printed carbon electrodes (SPCEs) was modified with CG for subsequent immobilization of N-protein of SARS-CoV-2, which allowed the detection of antibodies (IgA-SARS-CoV-2). The electrical properties and response of the biosensor were investigated using electrochemical techniques (cyclic voltammetry and electrochemical impedance spectroscopy). Through the chemical characterization techniques, it was possible to confirm the success of the CG synthesis process. The biosensor fabricated shown to be able to detect IgA-SARS-CoV-2 in the range of 1:1000 to1:200 v/v in phosphate buffer solution (PBS) and the limit of detection calculated was 1:1601 v/v. this perspective they comprise a wide range of applications due to its advantages, such as the possibility of a shorter response time, reproducibility, the miniaturization of detection devices such as the use of screen-printed electrodes, the use of small amounts of sample, the high sensitivity and specificity, low limits of detection and the integration of nano materials that make it possible to improve the detected signal.
Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants
Authors: Bowman Jacob , Lynch Vincent J. 
Published: February 2024

AbstractElephants have emerged as a model system to study the evolution of body size and cancer resistance because, despite their immense size, they have a very low prevalence of cancer. Previous studies have found that duplication of tumor suppressors at least partly contributes to the evolution of anti-cancer cellular phenotypes in elephants. Still, many other mechanisms must have contributed to their augmented cancer resistance. Here, we use a suite of codon-based maximum-likelihood methods and a dataset of 13,310 protein-coding gene alignments from 261Eutherianmammals to identify positively selected and rapidly evolving elephant genes. We found 496 genes (3.73% of alignments tested) with statistically significant evidence for positive selection and 660 genes (4.96% of alignments tested) that likely evolved rapidly in elephants. Positively selected and rapidly evolving genes are statistically enriched in gene ontology terms and biological pathways related to regulated cell death mechanisms, DNA damage repair, cell cycle regulation, epidermal growth factor receptor (EGFR) signaling, and immune functions, particularly neutrophil granules and degranulation. All of these biological factors are plausibly related to the evolution of cancer resistance. Thus, these positively selected and rapidly evolving genes are promising candidates for genes contributing to elephant-specific traits, including the evolution of molecular and cellular characteristics that enhance cancer resistance.
Inhibition of SARS-CoV-2 infection byPorphyromonas gingivalisand the oral microbiome
Authors: Bontempo Alexander , Chirino Alexandra , Heidari Alireza , Lugo Alexandra , Shindo Satoru , Pastore Maria R. , Antonson Sibel A. , Godoy Cristina , Nichols Frank C. , Potempa Jan , Davey Mary Ellen , Kawai Toshihisa , Cayabyab Mark J. 
Published: February 2024

AbstractThe COVID-19 pandemic persists despite the availability of vaccines, and it is therefore crucial to develop new therapeutic and preventive approaches. In this study, we investigated the potential role of the oral microbiome in SARS-CoV-2 infection. Using anin vitroSARS-CoV-2 pseudovirus infection assay, we found a potent inhibitory effect exerted byPorphyromonas gingivalison SARS-CoV-2 infection mediated by knownP. gingivaliscompounds such as phosphoglycerol dihydroceramide (PGDHC) and gingipains as well as by unknown bacterial factors. We found that the gingipain-mediated inhibition of infection is likely due to cytotoxicity, while PGDHC inhibited virus infection by an unknown mechanism. Unidentified factors present inP. gingivalissupernatant inhibited SARS-CoV-2 likely via the fusion step of the virus life cycle. We addressed the role of other oral bacteria and found certain periodontal pathogens capable of inhibiting SARS-CoV-2 pseudovirus infection by inducing cytotoxicity on target cells. In the human oral cavity, we observed the modulatory activity of oral microbial communities varied among individuals in that some saliva-based cultures were capable of inhibiting while others were enhancing infection. These findings contribute to our understanding of the complex relationship between the oral microbiome and viral infections, offering potential avenues for innovative therapeutic strategies in combating COVID-19.
Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder
Authors: Hristova Katerina , Fasol Melissa C. , McLaughlin Niamh , Nawaz Sarfaraz , Taskiran Mehmet , Buller-Peralta Ingrid , Bassi Alejandro , Ocampo-Garces Adrian , Escudero Javier , Kind Peter C. , Gonzalez-Sulser Alfredo 
Published: February 2024

AbstractPathogenic mutations inGRIN2Bare an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability.GRIN2Bencodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novelGRIN2Bheterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous absence seizures than wild-type rats (Grin2b+/+). Spike and wave discharges, the electrographic correlate of absences seizures, were longer in duration and displayed increased higher overall spectral power inGrin2b+/-animals than those inGrin2b+/+. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep inGrin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options forGRIN2Brelated epilepsy. Our data shows the new ratGRIN2Bhaploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies forGRIN2Bneurodevelopmental disorders.
Distinct Dendritic Morphological Changes in the Nucleus Accumbens of Microbiota-deficient Male Mice
Authors: García-Cabrerizo Rubén , Viola Maria Francesca , Luczynski Pauline , Clarke Gerard , Cryan John F. 
Published: February 2024

AbstractThe gut microbiota has been shown to be an important regulator of brain and behaviour. Germ-free rodents are a key model to study the microbiome-gut-brain axis to reveal the microbial underpinnings of diseases, including those related to psychiatric illnesses. The present study evaluated whether the absence of gut microbiota could alter the morphological development of the nucleus accumbens, a brain region located in the ventral striatum involved in stress, mood and addiction. In germ-free mice, there was dendritic hypertrophy of medium spiny neurons in the shell and dendritic elongation in the core. This led to an increase in the number of stubby dendritic spines within the shell and an increase in both stubby and thin spines in the core. Taken together, these results indicate that the gut microbiota is essential for the normal development of the dendritic structure of medium spiny neurons in the nucleus accumbens and that altered remodelling may contribute to maladaptive psychiatric disorders.
The Douglas Bell Canada Brain Bank Post-mortem Brain Imaging Protocol
Authors: Dadar Mahsa , Sanches Liana , Fouqouet Jeremie , Moqadam Roqaie , Alasmar Zaki , Miraut Dominique , Maranzano Josefina , Mechawar Naguib , Chakravarty M. Mallar , Zeighami Yashar 
Published: February 2024

AbstractMagnetic resonance imaging (MRI) is a valuable non-invasive tool that has been widely used for in vivo investigations of brain morphometry and microstructural characteristics. Postmortem MRIs can provide complementary anatomical and microstructural information to in vivo imaging and ex vivo neuropathological assessments without compromising the sample for future investigations. We have developed a postmortem MRI protocol for the brain specimens of the Douglas-Bell Canada Brain Bank (DBCBB), the largest brain bank in Canada housing over 3000 neurotypical and diseased brain specimens, that allows for acquisition of high-resolution 3T and 7T MRIs. Our protocol can be used to scan DBCBB specimens with minimal tissue manipulation, allowing for feasibly scanning large numbers of postmortem specimens while retaining the quality of the tissue for downstream histology and immunohistochemistry assessments. We demonstrate the robustness of this protocol in spite of the dependency of image quality on fixation by acquiring data on the first day of extraction and fixation, to over twenty years post fixation. The acquired images can be used to perform volumetric segmentations, cortical thickness measurements, and quantitative analyses which can be potentially used to link MRI-derived and ex vivo histological measures, assaying both the normative organization of the brain and ex vivo measures of pathology.