bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ventral hippocampus and nucleus accumbens as neural substrates for cocaine contextual memory reconsolidation
Authors: Rivera Carolina Caban , Price Rachael , Fortuna Ricardo P. , Li Chen , Do Chau , Shinkle Justin , Ghilotti Marco G. , Shi Xiangdang , Kirby Lynn G. , Smith George M. , Unterwald Ellen M. 
Published: December 2023

ABSTRACTDrug craving triggered by cues that were once associated with drug intoxication is a major contributor to continued drug-seeking behaviors. Addictive drugs engage molecular pathways of associative learning and memory. Reactivated memories are vulnerable to disruption by interference with the process of reconsolidation, hence targeting reconsolidation could be a strategy to reduce cue-induced drug craving and relapse. Here we examined the circuitry of cocaine contextual memory reconsolidation and explored neuroplasticity following memory reactivation. Mice underwent chemogenetic inhibition of either nucleus accumbens (NA) neurons or the glutamatergic projection neurons from the ventral hippocampus (vHPC) to NA using inhibitory designer receptors exclusively activated by designer drugs (iDREADD). Mice underwent cocaine conditioned place preference followed by reactivation of the cocaine contextual memory. Clozapine-N-oxide (CNO) was administered after memory reactivation to inhibit either NA neurons or the accumbens–projecting vHPC neurons during the reconsolidation period. When retested 3 days later, a significant reduction in the previously established preference for the cocaine context was found in both conditions. FosTRAP2-Ai14 mice were used to identify neurons activated by cocaine memory recall and to evaluate plasticity in NA medium spiny neurons (MSNs) and vHPC pyramidal neurons upon recall of cocaine memories. Results indicate a significant increase in dendritic spine density in NA MSNs activated by cocaine memory recall, particularly of the thin spine type. Sholl analysis indicated longer dendritic length and more branching of NA MSNs after cocaine memory recall than without memory reactivation. vHPC neurons showed increased spine density, with the most robust change in stubby spines. These results implicate a circuit involving glutamatergic projections from the vHPC onto NA neurons which is necessary for the reconsolidation of cocaine memories. Interruption of cocaine memory reconsolidation reduced drug-seeking behavior.
Spatiotemporal Rhythmic Seizure Sources Can be Imaged by means of Biophysically Constrained Deep Neural Networks
Authors: Sun Rui , Sohrabpour Abbas , Joseph Boney , Worrell Gregory , He Bin 
Published: December 2023

AbstractNoninvasive dynamic brain imaging of neural oscillations provides valuable insights into both physiological and pathological brain states. Yet, challenges remain due to the ill-posed nature of the problem and high complexity of the solution space, which can be alleviated by advanced computational models. Here, we investigated the capability of a novel deep learning-based source imaging framework (DeepSIF) for imaging ictal activities from high-density electroencephalogram (EEG) recordings in drug-resistant focal epilepsy patients. The neural mass model of ictal oscillations was adopted to generate synthetic training data with spatio-temporal-spectra features similar to ictal dynamics. We rigorously validated the trained DeepSIF model using computer simulations and in a cohort of 33 drug-resistant focal epilepsy patients. The DeepSIF ictal source imaging was compared with interictal source imaging and three conventional imaging methods as benchmark comparisons. Our findings show that the trained DeepSIF model outperforms other methods in estimating the spatial and temporal information of ictal sources. It achieves a high spatial specificity of 96% and a low spatial dispersion of 3.80 ± 5.74 mm when compared to the resection region. The noninvasive source imaging results also demonstrate good coverage of seizure-onset-zone (SOZ), with an average distance of 10.89 ± 10.14 mm (from the SOZ to the reconstruction). These promising results suggest that DeepSIF has significant potential for advancing noninvasive imaging of ictal activities in patients with focal epilepsy. By providing valuable insights into the spatiotemporal dynamics of seizure activity, DeepSIF promises to help guide clinical decisions and improve treatment outcomes for epilepsy patients.
Scalable Incident Detection via Natural Language Processing and Probabilistic Language Models
Authors: Walsh Colin G. , Wilimitis Drew , Chen Qingxia , Wright Aileen , Kolli Jhansi , Robinson Katelyn , Ripperger Michael A. , Johnson Kevin B. , Carrell David , Desai Rishi J. , Mosholder Andrew , Dharmarajan Sai , Adimadhyam Sruthi , Fabbri Daniel , Stojanovic Danijela , Matheny Michael E. , Bejan Cosmin A. 
Published: December 2023

AbstractPost marketing safety surveillance depends in part on the ability to detect concerning clinical events at scale. Spontaneous reporting might be an effective component of safety surveillance, but it requires awareness and understanding among healthcare professionals to achieve its potential. Reliance on readily available structured data such as diagnostic codes risk under-coding and imprecision. Clinical textual data might bridge these gaps, and natural language processing (NLP) has been shown to aid in scalable phenotyping across healthcare records in multiple clinical domains. In this study, we developed and validated a novel incident phenotyping approach using unstructured clinical textual data agnostic to Electronic Health Record (EHR) and note type. It’s based on a published, validated approach (PheRe) used to ascertain social determinants of health and suicidality across entire healthcare records. To demonstrate generalizability, we validated this approach on two separate phenotypes that share common challenges with respect to accurate ascertainment: 1) suicide attempt; 2) sleep-related behaviors. With samples of 89,428 records and 35,863 records for suicide attempt and sleep-related behaviors, respectively, we conducted silver standard (diagnostic coding) and gold standard (manual chart review) validation. We showed Area Under the Precision-Recall Curve of ∼ 0.77 (95% CI 0.75-0.78) for suicide attempt and AUPR ∼ 0.31 (95% CI 0.28-0.34) for sleep-related behaviors. We also evaluated performance by coded race and demonstrated differences in performance by race were dissimilar across phenotypes and require algorithmovigilance and debiasing prior to implementation.
Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway
Authors: Bose Mahima , Talwar Ishita , Suresh Varun , Mishra Urvi , Biswas Shiona , Yadav Anuradha , Suryavanshi Shital T. , Hippenmeyer Simon , Tole Shubha 
Published: December 2023

AbstractIn the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and in postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss ofFoxg1in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway componentFgfr3, that is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons.Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated inFoxg1null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.
Structural mechanism of HP1α-dependent transcriptional repression and chromatin compaction
Authors: Sokolova Vladyslava , Miratsky Jacob , Svetlov Vladimir , Brenowitz Michael , Vant John , Lewis Tyler , Dryden Kelly , Lee Gahyun , Sarkar Shayan , Nudler Evgeny , Singharoy Abhishek , Tan Dongyan 
Published: December 2023

AbstractHeterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. In this study, we employed a multidisciplinary approach to unravel the interactions between human HP1α and nucleosomes. We have elucidated the cryo-EM structure of an HP1α dimer bound to an H2A.Z nucleosome, revealing that the HP1α dimer interfaces with nucleosomes at two distinct sites. The primary binding site is located at the N-terminus of histone H3, specifically at the trimethylated K9 (K9me3) region, while a novel secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. This study offers a model that explains how HP1α functions in heterochromatin maintenance and gene silencing, particularly in the context of H3K9me-dependent mechanisms. Additionally, it sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.
The historical ecological background of West Nile virus in Portugal provides One Health opportunities into the future
Authors: Geraldes Martim Afonso , Cunha Mónica V. , Godinho Carlos , Faustino de Lima Ricardo , Giovanetti Marta , Lourenço José 
Published: December 2023

AbstractWest Nile (WNV) is a zoonotic arbovirus with an expanding geographical range and epidemic activity in Europe. Not having yet experienced a human-associated epidemic, Portugal remains an outlier in the Mediterranean basin. In this study, we apply ecological niche modelling informed by WNV historical evidence (1969-2022) and a multitude of environmental variables from across Portugal. We identify that ecological backgrounds compatible with WNV historical circulation are mostly restricted to the south, characterized by a warmer and drier climate, high avian diversity, specific avian species and land types. We estimate WNV ecological suitability across the country, identifying overlaps with the distributions of the three relevant hosts (humans, birds, equines) for public and animal health. From this, we propose a category-based spatial framework providing first of a kind valuable insights for future WNV surveillance under the One Health nexus. We also forecast that climate trends alone will contribute to pushing adequate WNV ecological suitability northwards, toward regions with higher human density. This unique perspective on the past, present and future ecology of WNV addresses existing national knowledge gaps, enhances our understanding of the evolving emergence of WNV, and offers opportunities to prepare and respond to the first human-associated epidemic in Portugal.
Spatiotemporal Metabolic Responses to Water Deficit Stress in Distinct Leaf Cell-types of Poplar
Authors: Balasubramanian Vimal Kumar , Velickovic Dusan , Rubio Wilhelmi Maria Del Mar , Anderton Christopher R , Stewart C. Neal , DiFazio Stephen , Blumwald Eduardo , Ahkami Amir H. 
Published: December 2023

AbstractThe impact of water-deficit (WD) stress on plant metabolism has been predominantly studied at the whole tissue level. However, plant tissues are made of several distinct cell types with unique and differentiated functions, which limits whole tissue ‘omics’-based studies to determine only an averaged molecular signature arising from multiple cell types. Advancements in spatial omics technologies provide an opportunity to understand the molecular mechanisms underlying plant responses to WD stress at distinct cell-type levels. Here, we studied the spatiotemporal metabolic responses of two poplar leaf cell types-palisade and vascular cells-to WD stress using matrix-assisted laser desorption Ionization-mass spectrometry imaging (MALDI-MSI). We identified unique WD stress-mediated metabolic shifts in each leaf cell type when exposed to early and prolonged WD and recovery from stress. During stress, flavonoids and phenolic metabolites were exclusively accumulated in leaf palisade cells. However, vascular cells mainly accumulated sugars during stress and fatty acids during recovery conditions, highlighting a possibility of interconversion between sugars and fatty acids under stress and recovery conditions in vascular cells. By comparing our MALDI-MSI metabolic data with whole leaf tissue gas chromatography-mass spectrometry (GC-MS)-based metabolic profile, we identified only a few metabolites that showed a similar accumulation trend at both cell-type and whole leaf tissue levels. Overall, this work highlights the potential of the MSI approach to complement the whole tissue-based metabolomics techniques and provides a novel spatiotemporal understanding of plant metabolic responses to WD stress. This will help engineer specific metabolic pathways at a cellular level in strategic perennial trees like poplars to help withstand future aberrations in environmental conditions and to increase bioenergy sustainability.
High-Throughput Evolution Unravels Landscapes of High-Level Antibiotic Resistance Induced by Low-Level Antibiotic Exposure
Authors: Wang Hanqing , Lu Hui , Jiang Chao , Zhu Lizhong , Lu Huijie 
Published: December 2023

AbstractPotential pathogens exposed to low-level environmental antibiotics could develop high-level clinically relevant antibiotic resistance detrimental to the health of the general population. However, the underlying evolutionary landscapes remain poorly understood. We conducted a high-throughput experimental evolution study by exposing an environmentally isolated pathogenicEscherichia colistrain to 96 typical antibiotics at 10 μg l−1for 20 days. Antibiotic resistance phenotypic (IC90against 8 clinically used antibiotics) and genetic changes of the evolved populations were systematically investigated, revealing a universal increase in antibiotic resistance (up to 349-fold), and mutations in 2,432 genes. Transposon sequencing was further employed to verify genes potentially associated with resistance. A core set of mutant genes conferring high-level resistance was analyzed to elucidate their resistance mechanisms by analyzing the functions of interacted genes within the gene co-fitness network and performing gene knockout validations. We developed machine-learning models to predict antibiotic resistance phenotypes from antibiotic structures and genomic mutations, enabling the resistance predictions for another 569 antibiotics. Importantly, 14.6% of the 481 key mutations were observed in clinical and environmentalE. coliisolates retrieved from the NCBI database, and several were over-represented in clinical isolates. Deciphering the evolutionary landscapes underlying resistance exposed to low-level environmental antibiotics is crucial for evaluating the emergence and risks of environment-originated clinical antibiotic resistance.
A PhyloFisher utility for nucleotide-based phylogenomic matrix construction;nucl_matrix_constructor.py
Authors: Jones Robert E. , Jones Erin P. , Tice Alexander K. , Brown Matthew W. 
Published: December 2023

ABSTRACTPhylogenies built from multiple genes have become a common component of evolutionary biology studies. Molecular phylogenomic matrices used to build multi-gene phylogenies can be built from either nucleotide or protein matrices. Nucleotide-based analyses are often more appropriate for addressing phylogenetic questions in evolutionarily shallow timescales (i.e., less than 100 million years) while protein-based analyses are often more appropriate for addressing deep phylogenetic questions. PhyloFisher is a phylogenomic software package written in Python3. The manually curated PhyloFisher database contains 240 protein-coding genes from 304 eukaryotic taxa. Here we presentnucl_matrix_constructor.py, an expansion of the PhyloFisher starting database, and an update to PhyloFisher that maintains DNA sequences. This combination will allow users the ability to easily build nucleotide phylogenomic matrices while retaining the benefits of protein-based pre-processing used to identify contaminants and paralogy.
Cortical sensory aging is layer-specific
Authors: Liu Peng , Doehler Juliane , Henschke Julia U. , Northall Alicia , Serian Angela , Loaiza-Carvajal Laura C. , Budinger Eike , Schwarzkopf Dietrich S. , Speck Oliver , Pakan Janelle M.P. , Kuehn Esther 
Published: December 2023

AbstractThe segregation of processes into cortical layers is a convergent feature in animal evolution. However, how changes in the cortical layer architecture interact with sensory system function and dysfunction remains unclear. We conducted functional and structural layer-specific in-vivo 7T-MRI of the primary somatosensory cortex in two cohorts of healthy younger and older adults. Input layer IV is enlarged and more myelinated in older adults, and associated with extended sensory input signals. Age-related cortical thinning is driven by deep layers, and accompanied by altered functional modulation and preserved inhibition. Calcium imaging and histology in younger and older mice reveal increased sensory-evoked neuronal activity accompanied by increased parvalbumin expression as a potential inhibitory balance, with dynamic changes in layer-specific myelination across age groups. Using multimodal imaging, we demonstrate that middle and deep layers show specific vulnerability to aging across species.
A Mouse Model of the Protease Activated Receptor 4 (PAR4) Pro310Leu Variant has Reduced Platelet Reactivity
Authors: Han Xu , Knauss Elizabeth A. , de la Fuente Maria , Li Wei , Conlon Ronald A , LePage David F. , Jiang Weihong , Renna Stephanie A. , McKenzie Steven E. , Nieman Marvin T. 
Published: December 2023

AbstractBackgroundProtease activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated a single nucleotide polymorphism in extracellular loop 3 (ECL3), PAR4-P310L (rs2227376) leads to a hypo-reactive receptor.ObjectivesThe goal of this study was to determine how the hypo-reactive PAR4 variant in ECL3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L).MethodsA point mutation was introduced into the PAR4 gene, F2rl3, via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbβ3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model.ResultsPAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbβ3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis.ConclusionsPAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.EssentialsA mouse model was created to represent the PAR4-P310L sequence variant.PAR4-P322L leads to reduced platelet reactivity in response to PAR4-activation peptide and thrombin, while the ADP and GPVI signaling pathways were unaffected.The PAR4-P322L mutation decreases time to occlusion in a mouse model of arterial thrombosis.The PAR4-P322L mouse model provides a foundation to further explore the role of PAR4 in hemostasis and thrombosis.
Epithelial organoid supports resident memory CD8 T cell differentiation
Authors: Ulibarri Max R. , Lin Ying , Ramprashad Julian R. , Han Geongoo , Hasan Mohammad H. , Mithila Farha J. , Ma Chaoyu , Gopinath Smita , Zhang Nu , Milner J. Justin , Beura Lalit K. 
Published: December 2023

AbstractResident Memory T cells (TRM) play a vital role in regional immune defense in barrier organs. Although laboratory rodents have been extensively used to study fundamental TRM biology, poor isolation efficiency, sampling bias and low cell survival rates have limited our ability to conduct TRM-focused high-throughput assays. Here, we engineered a murine vaginal epithelial organoid (VEO)-CD8 T cell co-culture system that supports CD8 TRM differentiationin vitro. The three-dimensional VEOs established from murine adult stem cells resembled stratified squamous vaginal epithelium and induced gradual differentiation of activated CD8 T cells into epithelial TRM. Thesein vitrogenerated TRM were phenotypically and transcriptionally similar toin vivoTRM, and key tissue residency features were reinforced with a second cognate-antigen exposure during co-culture. TRM differentiation was not affected even when VEOs and CD8 T cells were separated by a semipermeable barrier, indicating soluble factors’ involvement. Pharmacological and genetic approaches showed that TGF-β signaling played a crucial role in their differentiation. We found that the VEOs in our model remained susceptible to viral infections and the CD8 T cells were amenable to genetic manipulation; both of which will allow detailed interrogation of antiviral CD8 T cell biology in a reductionist setting. In summary, we established a robust model which captures bonafide TRM differentiation that is scalable, open to iterative sampling, and can be subjected to high throughput assays that will rapidly add to our understanding of TRM.