bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flotillin-2 dampens T cell antigen-sensitivity and functionality
Authors: Moon Sookjin , Zhao Fei , Uddin Mohammad N. , Tucker Charles J. , Karmaus Peer W. F. , Fessler Michael B. 
Published: April 2024

AbstractT cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen sensitivity, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+T cells exhibited increased T helper 1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and LCK upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single cell-RNA sequencing suggested that Flot2-null CD4+T cells follow a similar route of activation as wild-type CD4+T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naïve CD4+T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.
5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation
Authors: Conde Kristine M. , Wong HueyZhong , Fang Shuzheng , Li Yongxiang , Yu Meng , Deng Yue , Liu Qingzhuo , Fang Xing , Wang Mengjie , Shi Yuhan , Ginnard Olivia Z. , Yang Yuxue , Tu Longlong , Liu Hesong , Liu Hailan , Yin Na , Bean Jonathan C. , Han Junying , Burt Megan E. , Jossy Sanika V. , Yang Yongjie , Tong Qingchun , Arenkiel Benjamin R. , Wang Chunmei , He Yang , Xu Yong 
Published: April 2024

ABSTRACTObesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN◊arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRNneurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAAreceptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRNneurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRNneurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.
Evaluating the breeding potential of cultivated lentils for increasing protein and amino acid concentration in the Northern Great Plains
Authors: Wright Derek M. , Hang Jiayi , House James D. , Bett Kirstin E. 
Published: April 2024

ABSTRACTThe rising demand for plant-based proteins has intensified interest in pulse crops due to their high protein concentration. However, few studies have evaluated protein and amino acid composition/variability in cultivated lentil (Lens culinarisMedik.). We evaluated protein and amino acid composition using near-infrared reflectance spectroscopy (NIRS) in a diversity panel grown in four site-years in Saskatchewan, Canada, followed by genome-wide association analyses with phenology-related traits as covariates. We found little correlation between days from sowing to flowering, region of origin, cotyledon color, or seed size, and protein concentration. Reproductive period was correlated with protein concentration. We also observed large variability between environments and more variability within market classes than among them. Our results demonstrate the potential for breeders to identify germplasm and select for increased protein and amino acid concentration and quality using a high-throughput NIRS method. We were able to identify numerous molecular markers for use in marker-assisted breeding. Our approach could be replicated by breeders from other regions or with other pulse crops to help meet the demand for plant-based protein and improvements in protein quality.
Towards EEG-to-Text: Handwritten Character Classification via Continuous Kinematic Decoding
Authors: Crell Markus R. , Müller-Putz Gernot R. 
Published: April 2024

AbstractThe classification of handwritten letters from invasive neural signals has lately been subject of research to restore communication abilities in people with limited movement capacities. This study explores the classification of ten letters (a,d,e,f,j,n,o,s,t,v) from non-invasive neural signals of 20 participants using two methods: the direct classification from low-frequency and broadband electroencephalogram (EEG) and a two-step approach comprising the continuous decoding of hand kinematics and the application of those in subsequent classification. When using low-frequency EEG, results show moderate accuracies of 23.1 % for ten letters and 39.0 % for a subset of five letters with highest discriminability of the trajectories. The two-step approach yielded significantly higher performances of 26.2 % for ten letters and 46.7 % for the subset of five letters. Hand kinematics could be reconstructed with a correlation of 0.10 to 0.57 (average chance level: 0.04) between the decoded and original kinematic. The study shows the general feasibility of extracting handwritten letters from non-invasively recorded neural signals and indicates that the proposed two-step approach can improve performances. As an exploratory investigation of the neural mechanisms of handwriting in EEG, results suggest movement speed as the most informative kinematic for the decoding of short hand movements.
Mechanisms Of Meristem Maintenance By Maize Transcriptional Corepressors
Authors: Gregory Jason , Liu Xue , Chen Zongliang , Gallardo Cecilia , Punskovsky Jason , Koslow Gabriel , Galli Mary , Gallavotti Andrea 
Published: April 2024

ABSTRACTThe formation of the plant body proceeds in a sequential post-embryonic manner through the action of meristems. Tightly coordinated meristem regulation is required for development and reproductive success, eventually determining yield in crop species. In maize, the REL2 family of transcriptional corepressors includes four members, REL2, RELK1 (REL2-LIKE1), RELK2, and RELK3. In a screen forrel2enhancers, we identified shorter double mutants with enlarged female inflorescence meristems (IMs) carrying mutations inRELK1. Expression and genetic analysis indicate thatREL2andRELK1cooperatively regulate female IM development by controlling genes involved in redox balance, hormone homeostasis, and differentiation, ultimately tipping the meristem toward an environment favorable to expanded expression of theZmWUSCHEL1gene, a key stem-cell promoting transcription factor. We further demonstrate thatRELKgenes have partially redundant yet diverse functions in the maintenance of various meristem types during development. By exploiting subtle increases in ear IM size inrel2heterozygous plants, we also show that extra rows of kernels are formed across a diverse set of F1 hybrids. Our findings reveal that the REL2 family maintains development from embryonic initiation to reproductive growth and can potentially be harnessed for increasing seed yield in a major crop species.One sentence summaryREL2-RELKs fine tune hormone and chemical cues to prevent expanded expression of ZmWUSCHEL1 in maize inflorescence meristems, and can potentially be harnessed for increasing seed yield in hybrids.
Reduced Levels of Lagging Strand Polymerases Shape Stem Cell Chromatin
Authors: Snedeker Jonathan , Davis Brendon E. M. , Ranjan Rajesh , Wooten Matthew , Blundon Joshua , Chen Xin 
Published: April 2024

AbstractStem cells display asymmetric histone inheritance while non-stem progenitor cells exhibit symmetric patterns in theDrosophilamale germline lineage. Here, we report that components involved in lagging strand synthesis, such as DNA polymerase α and δ (Polα and Polδ), have significantly reduced levels in stem cells compared to progenitor cells. Compromising Polα genetically induces the replication-coupled histone incorporation pattern in progenitor cells to be indistinguishable from that in stem cells, which can be recapitulated using a Polα inhibitor in a concentration-dependent manner. Furthermore, stem cell-derived chromatin fibers display a higher degree of old histone recycling by the leading strand compared to progenitor cell-derived chromatin fibers. However, upon reducing Polα levels in progenitor cells, the chromatin fibers now display asymmetric old histone recycling just like GSC-derived fibers. The oldversusnew histone asymmetry is comparable between stem cells and progenitor cells at both S-phase and M-phase. Together, these results indicate that developmentally programmed expression of key DNA replication components is important to shape stem cell chromatin. Furthermore, manipulating one crucial DNA replication component can induce replication-coupled histone dynamics in non-stem cells in a manner similar to that in stem cells.One Sentence SummaryDelayed lagging strand synthesis regulates asymmetric histone incorporation.
IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum
Authors: Yadav Rashi , Vague Morgan , Rettig Malia , Loo Christopher P. , Brown Kasidy , Samiea Abrar , Moreau Joshua M. , Ortega-Loayza Alex G 
Published: April 2024

AbstractPyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.
GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons
Authors: Yuan Zixuan , Pavel Mahmud Arif , Hansen Scott B. 
Published: April 2024

AbstractThe γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions enhance endocytosis and delay desensitization. Our findings suggest intercellular signaling from astrocytes regulates GABAAR location based on lipid uptake in neurons. The findings have implications for treating mood disorders associated with altered neural excitability.
Design principles to tailor Hsp104 therapeutics
Authors: Lin JiaBei , Carman Peter J. , Gambogi Craig W. , Kendsersky Nathan M. , Chuang Edward , Gates Stephanie N. , Yokom Adam L. , Rizo Alexandrea N. , Southworth Daniel R. , Shorter James 
Published: April 2024

AbstractThe hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting the NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off- target toxicity, and counteract FUS proteinopathy in human cells. Thus, we establish important design principles to tailor Hsp104 therapeutics.Graphical Abstract
Assembly, comparative analysis, and utilization of a single haplotype reference genome for soybean
Authors: Espina Mary Jane C. , Lovell John T. , Jenkins Jerry , Shu Shengqiang , Sreedasyam Avinash , Jordan Brandon D. , Webber Jenell , Boston LoriBeth , Brůna Tomáš , Talag Jayson , Goodstein David , Grimwood Jane , Stacey Gary , Cannon Steven B. , Lorenz Aaron J. , Schmutz Jeremy , Stupar Robert M. 
Published: April 2024

ABSTRACTCultivar ‘Williams 82’ has served as the reference genome for the soybean research community since 2008, but is known to have areas of genomic heterogeneity among different sub-lines. This work provides an updated assembly (version Wm82.a6) derived from a specific sub-line known as ‘Wm82-ISU-01’ (seeds available under USDA accession PI 704477). The genome was assembled using Pacific BioSciences HiFi reads and integrated into chromosomes using HiC. The 20 soybean chromosomes assembled into a genome of 1.01Gb, consisting of 36 contigs. The genome annotation identified 48,387 gene models, named in accordance with previous assembly versions Wm82.a2 and Wm82.a4. Comparisons of Wm82.a6 with other near-gapless assemblies of ‘Williams 82’ reveal large regions of genomic heterogeneity, including regions of differential introgression from the genotype ‘Kingwa’ within approximately 30 Mb and 25 Mb segments on chromosomes 03 and 07, respectively. Additionally, our analysis revealed a previously unknown large (∼20 Mb) heterogeneous region in the pericentromeric region of chromosome 12, where Wm82.a6 matches the ‘Williams’ haplotype while the other two near-gapless assemblies do not match the haplotype of either parent of ‘Williams 82’. In addition to the Wm82.a6 assembly, we also assembled the genome of soybean line ‘Fiskeby III’, a rich resource for abiotic stress resistance genes. A genome comparison of Wm82.a6 with ‘Fiskeby III’ revealed the nucleotide and structural polymorphisms between the two genomes within a QTL region for iron deficiency chlorosis resistance. The Wm82.a6 and ‘Fiskeby III’ genomes described here will enhance comparative and functional genomics capacities and applications in the soybean community.
GraSP Gene Targets to Hierarchically Infer Sub-Classes with CuttleNet
Authors: Budoff Samuel A. , Poleg-Polsky Alon 
Published: April 2024

AbstractThis paper introduces a machine learning approach, GraSP, for retinal cell classification that addresses key challenges in spatial biology, alongside a novel neural network architecture, CuttleNet, tailored for class and subclass inference with incomplete datasets. We propose an innovative, unbiased gene selection method that utilizes simple neural networks for each target cell subclass, such thatGradientSelectedPredictors (GraSP) corresponding to gene importance are found for each. This approach significantly outperforms traditional machine learning techniques and expert-selected gene targets, reducing the necessary genes for classification from over 18k to 300 within the murine retina. Such reduction is crucial for advancing spatial biology, particularly in mapping retinal cell subclasses. Furthermore, our hierarchical architecture inspired by the organization of the cephalopod nervous system, CuttleNet, adeptly handles the pervasive issue of missing data in disjointed single-cell RNA sequencing datasets. CuttleNet operates by first classifying cell classes using consistently measured genes, then dynamically routing to subclass-specific subnetworks that leverage all available data for subclass classification. CuttleNet establishes a new standard in handling systematically missing data, offering substantial improvements over existing models in our targeted application.
Large Language Models for Pathway Curation: A Preliminary Investigation
Authors: Karkera Nikitha , Karkera Nikshita , Kumar Mahanash , Ghosh Samik , Palaniappan Sucheendra K. 
Published: April 2024

The pathway curation task involves analyzing scientific literature to identify and represent cellular processes as pathways. This process, often time-consuming and labor-intensive, requires significant curation efforts amidst the rapidly growing biomedical literature. Natural Language Processing (NLP) offers a promising method to automatically extract these interactions from scientific texts. Despite immense progress, there remains room for improvement in these systems. The emergence of Large Language Models (LLMs) provides a promising solution for this challenge. Our study conducts a preliminary investigation into leveraging LLMs for the pathway curation task. This paper first presents a review of the current state-of-the-art algorithms for the pathway curation task. Our objective is to check the feasibility and formulate strategies of using these LLMs to improve the accuracy of pathway curation task. Our experiments demonstrate that our GPT-3.5 based fine-tuned models outperforms existing state-of-the-art methods. Specifically, our model achieved a 10 basis point improvement in over-all recall and F1 score compared to the best existing algorithms. These findings highlight the potential of LLMs in pathway curation tasks, warranting further research and substantial efforts in this direction.Keypoints/ObjectivesStudy evaluates the feasibility of using Large Language Models (LLMs) for pathway curation in scientific literature.Using GPT-3.5 based fine tuned models for pathway curation, we compare its performance with existing methods, focusing on precision, recall and F1 score metrics.Emphasize the promise and need for further research on using LLMs for pathway curation.
Endothelial SHP-1 regulates diabetes-induced abnormal collateral vessel formation and endothelial cell senescence
Authors: Nadeau Alexandre , Ouellet Marike , Béland Raphaël , Mercier Clément , Robillard Stéphanie , Lizotte Farah , Despatis Marc-Antoine , Benzinger C. Florian , Geraldes Pedro 
Published: April 2024

AbstractObjectiveIschemia due to narrowing of the femoral artery and distal vessels is a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Diabetes-induced premature senescence of endothelial cells (EC) has been proposed as a mechanism leading to impaired ischemia-driven angiogenesis. Importantly, our previous work has shown that hyperglycemia reduced vascular endothelial growth factor (VEGF) activity in ischemic muscle of diabetic mice, which was associated with increased expression of the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1). Here, we evaluate the impact of SHP-1 deletion on EC function and senescence.Approach and ResultsLigation of the femoral artery was performed in nondiabetic (NDM) and 3 months diabetic (DM) mice with EC-specific deletion of SHP-1 and blood flow reperfusion was measured for 4 weeks. Blood flow reperfusion and limb function during voluntary wheel running were reduced by 43% and 82%, respectively in DM mice as compared to NDM mice. EC-specific deletion of SHP-1 in DM mice restored blood flow reperfusion by 60%, limb function by 86%, while capillary density was similar to NDM mice. Moreover, ablation of SHP-1 in EC prevented diabetes-induced expression of the senescence markers p53 and p21 and counteracted Nrf2 downregulation. In cultured EC, overexpression of dominant negative of SHP-1 prevented HG-induced inhibition of proliferation, migration, tubule formation and VEGFR2/Akt phosphorylation following VEGF stimulation. In addition, the expression of senescence markers and suppression of Nrf2 in EC exposed to HG levels were reversed by overexpression of dominant negative SHP-1.ConclusionSHP-1 in ECs is a central effector of diabetes-induced senescence that blocks VEGF action, and induces aberrant collateral vessel formation and blood flow reperfusion. Reduced SHP-1 expression counteracts these pathologic features suggesting the notion that it represents a promising therapeutic target.HIGHLIGHTSEndothelial specific deletion of SHP-1 (Scr homology 2-containing phosphatase-1) improves blood flow reperfusion, limb motricity and vessel density in the diabetic ischemic limb.Diabetes-induced SHP-1 protein expression inhibits VEGF proangiogenic actions and promotes endothelial senescence.Endothelial specific deletion of SHP-1 restores VEGF proangiogenic actions and prevents senescence in ischemic muscle and artery of diabetic mice and patients.