bluuebunny/crossref_metadata_2025_split huggingface dataset:
An alpha- to gamma-motoneurone collateral can mitigate velocity-dependent stretch reflexes during voluntary movement: A computational study
Authors: Niyo Grace , Almofeez Lama I , Erwin Andrew , Valero-Cuevas Francisco J 
Published: December 2023

AbstractThe primary motor cortex does not uniquely or directly produce alpha motoneurone (α-MN) drive to muscles during voluntary movement. Rather,α-MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input is velocity-dependent stretch reflexes in lengthening muscles, which should be inhibited to enable voluntary movement. It remains an open question, however, the extent to which unmodulated stretch reflexes disrupt voluntary movement, and whether and how they are inhibited in limbs with numerous multi-articular muscles. We used a computational model of aRhesus Macaquearm to simulate movements with feedforwardα-MN commands only, and with added velocity-dependent stretch reflex feedback. We found that velocity-dependent stretch reflex caused movement-specific, typically large and variable disruptions to arm movements. These disruptions were greatly reduced when modulating velocity-dependent stretch reflex feedback (i) as per the commonly proposed (but yet to be clarified) idealized alpha-gamma (α-γ) co-activation or (ii) an alternativeα-MN collateral projection to homonymousγ-MNs. We conclude that suchα-MN collaterals are a physiologically tenable, but previously unrecognized, propriospinal circuit in the mammalian fusimotor system. These collaterals could still collaborate withα-γco-activation, and the few skeletofusimotor fibers (β-MNs) in mammals, to create a flexible fusimotor ecosystem to enable voluntary movement. By locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb, these collaterals could be a critical low-level enabler of learning, adaptation, and performance via higher-level brainstem, cerebellar and cortical mechanisms.SignificanceMuscles have velocity sensors controlled byγ-MNs that produce stretch reflexes which could disrupt voluntary limb movements. Whether and how severely those unmodulated stretch reflexes disrupt voluntary movement remains unclear, especially in realistic multi-articular limbs. Our neuromechanical simulations demonstrate that unmodulated stretch reflexes greatly disrupt movements. Modulating the stretch reflex by implementing an idealized version of a long-posited (but yet unclear)α-γco-activation greatly mitigates those perturbations. However, a collateral from theα-MN to theγ-MN (which has been reported among motoneurones but not interpreted in this way) achieves similar functionality. Our results suggest this modulation of the intensity of the stretch reflex by theα-MN collateral provides an effective mechanism to locally stabilize the disruptions from stretch reflexes.
Large Language Models for Detecting Body Weight Changes as Side Effects of Antidepressants in User-Generated Online Content
Authors: Yokoyama Taïoh , Natter Johan , Godet Julien 
Published: December 2023

ObjectiveHealthcare websites allow patients to share their experiences with their treatments. Drug testimonials provide useful information for real-world evidence, particularly on the occurrence of side effects that may be underreported. We investigated the potential of large language models (LLMs) for detecting signals of body weight change as under-reported side effect of antidepressants in user-generated online content.Materials and MethodsA database of 8,000 user-generated comments about the 32 FDA-approved antidepressants was collected from healthcare social websites. These comments were manually annotated under the supervision of drug experts. Several pre-trained LLMs derived from BERT were fine-tuned to automatically classify comments describing weight gain, weight loss, or the absence of reference to a weight change. Zero-shot classification was also performed. Performance was evaluated on a test set by measuring the weighted precision, recall, F1-score and the prediction accuracy.ResultsAfter fine-tuning, most of the BERT-derived LLMs showed weighted F1-scores above 97%. LLMs with higher number of parameters used in zero-shot classification almost reached the same performance. The main source of errors in predictions came from situations where the machine predicted falsely weight gain or loss, because the text mentioned these elements but for a different molecule than the one for which the comment was written.ConclusionEven fine-tuned LLMs with limited numbers of parameters showed interesting results for the detection of adverse events from online patient testimonials, suggesting they can be used at scale for real-world evidence.
Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology
Authors: Maharjan Sunita , Gamper Howard , Yamaki Yuka , Henley Robert Y. , Li Nan-Sheng , Suzuki Takeo , Suzuki Tsutomu , Piccirilli Joseph A. , Wanunu Meni , Seifert Erin , Wallace Douglas C. , Hou Ya-Ming 
Published: December 2023

SUMMARYHuman mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA structure would also stabilize its pathogenic variants is unknown. Here we show that theN1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m1G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that theN1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
ST-GEARS: Advancing 3D Downstream Research through Accurate Spatial Information Recovery
Authors: Xia Tianyi , Hu Luni , Zuo Lulu , Zhang Yunjia , Xu Mengyang , Lu Qin , Zhang Lei , Cao Lei , Pan Taotao , Zhang Bohan , Ma Bowen , Chen Chuan , Guo Junfu , Shi Chang , Li Mei , Liu Chao , Li Yuxiang , Zhang Yong , Fang Shuangsang 
Published: December 2023

AbstractThree-dimensional Spatial Transcriptomics has revolutionized our understanding of tissue regionalization, organogenesis, and development. However, to reconstruct single sections back to theirin situthree-dimensional morphology, existing approaches either only adopt gene expression information to guide reconstruction or overlook shape correction against experiment-induced section distortions. This leads to significant discrepancies between reconstruction results and the actualin vivolocations of cells, imposing unreliable spatial profiles to downstream analysis. To address these challenges, we propose ST-GEARS (Spatial Transcriptomics GEospatial profile recovery system through AnchoRS), which solves optimized ‘anchors’ betweenin situclosest spots utilizing expression and structural similarity across sections and recoversin vivospatial information under the guidance of anchors. By employing innovative Distributive Constraints into the Optimization scheme, it retrieves anchors with higher precision compared to existing methods. Taking these anchors as reference points, ST-GEARS first rigidly aligns sections, then introduces and infers Elastic Fields to counteract distortions. ST-GEARS denoises the fields using context information by Gaussian Denoising. Utilizing the denoised fields, it eliminates distortions and eventually recovers original spatial profile through innovative and mathematically proved Bi-sectional Fields Application. Studying ST-GEARS on both bi-sectional registration and complete tissue reconstruction across sectional distances and sequencing platforms, we observed its outstanding performance in spatial information recovery across tissue, cell, and gene levels compared to current approaches. Through this recovery, ST-GEARS provides precise and well-explainable ‘gears’ betweenin vivosituations and 3Din vitroanalysis, powerfully fueling the potential of biological discoveries.
Investigation of ice nucleation properties ofPseudomonas syringaebacterium and insoluble low molecular weight substances
Authors: Vorobeva D.E. , Majorina M.A. , Marchenko N.U. , Melnik B.S. 
Published: December 2023

AbstractControl of the water freezing process is considerable in different fields of science and technology: from the artificial snow production to the cryopreservation of biological materials. To date, there is no conventional theory that predicts the influence of various biological and non-biological ice nucleators on the formation of ice and, accordingly, on the freezing point of supercooled water. In this work, we investigated the influence of bacteriumPseudomonas syringae, a biological ice nucleator, and heterodisperse insoluble powders of low molecular weight substances on the process of water freezing. AgCl, ZnO and SnO2were found to be ice nucleators. This property has not been described previously in the literature. It has also been established that insoluble low molecular weight substances affect both the freezing point of water and the temperature of coexistence of water and ice.
Maternal dietary deficiencies in folic acid or choline reduce primary neuron viability after exposure to hypoxia through increased levels of apoptosis
Authors: Yaldiko Alice , Coonrod Sarah , Marella Purvaja , Hurley Lauren , Jadavji Nafisa M. 
Published: December 2023

AbstractStoke is the leading cause of death and disability globally. By addressing modifiable risk factors, particularly nutrition, the prevalence of stroke and its dire consequences can be mitigated. One-carbon (1C) metabolism is a critical biosynthetic process that is involved in neural tube closure, neuronal plasticity, and cellular proliferation in the developing embryo. Folic acid and choline are two active components of 1C metabolism, we have previously demonstrated that maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in offspring. However, there is insufficient data to understand the neuronal mechanisms involved. We exposed embryonic neurons of offspring, whom mothers were on folic acid or choline deficient diets, to hypoxia conditions for 6 hours and return to normoxic conditions for 24 hours to model an ischemic stroke and reperfusion injury. To determine whether increased levels of either folic acid or choline can rescue reduced neuronal viability, we supplemented cell media with folic acid and choline prior to and after exposure to hypoxia. Our results suggest that maternal dietary deficiencies in either folic acid or choline during pregnancy negatively impacts offspring neuronal viability after hypoxia. Furthermore, increasing levels of folic acid or choline prior to and after hypoxia have a beneficial impact on neuronal viability. The findings contribute to our understanding of the intricate interplay between maternal dietary factors, 1C metabolism, and the outcome of offspring to hypoxic events, emphasizing the potential for nutritional interventions in mitigating adverse outcomes.
Peribacillus frigoritoleransT7-IITJ, a potential biofertilizer, induces plant growth-promoting genes ofArabidopsis thaliana
Authors: Marik Debankona , Sharma Pinki , Chauhan Nar Singh , Jangir Neelam , Shekhawat Rajveer Singh , Verma Devanshu , Mukherjee Manasi , Abiala Moses , Roy Chandan , Yadav Pankaj , Sadhukhan Ayan 
Published: December 2023

AbstractThis study aimed to isolate plant growth and drought tolerance-promoting bacteria from the nutrient- poor rhizosphere soil of several plant species from the Thar desert and unravel their molecular mechanisms of plant growth promotion, to develop effective biofertilizers for arid agriculture. Among our isolates of Thar desert rhizobacteria,Enterobacter cloacaeC1P-IITJ,Kalamiella piersoniiJ4-IITJ, andPeribacillus frigoritoleransT7-IITJ, significantly enhanced root and shoot growth in the model plantArabidopsis thalianaunder PEG-induced drought stress in the lab. Whole genome sequencing and biochemical analyses of the non-pathogenic bacterium T7-IITJ revealed its plant growth-promoting traits, viz., solubilization of phosphate, iron, and nitrate and production of exopolysaccharides and auxin. Transcriptome analysis ofArabidopsis thalianainoculated with T7-IITJ and exposure to drought revealed the induction of plant genes for photosynthesis, auxin and jasmonate signaling, nutrient mining and sequestration, redox homeostasis, and secondary metabolite biosynthesis pathways related to beneficial bacteria-plant interaction, but repression of many stress-responsive genes. Biochemical analyses indicated enhanced proline, chlorophyll, iron, phosphorous, and nitrogen content and reduced reactive oxygen species in plant tissues due to T7-IITJ inoculation. This bacterium could also improve the germination and seedling growth ofTephrosia purpurea,Triticum aestivum,andSetaria italicaunder drought. Additionally, T7-IITJ inhibited the growth of two plant pathogenic fungi,Rhizoctonia solani,andFusarium oxysporum. These results suggestP. frigoritoleransT7-IITJ is a potent biofertilizer which can regulate plant genes promoting growth and drought tolerance.
Discovery of anthelmintic small molecules in the Medicines for Malaria Venture’s COVID and Global Health Priority Boxes using an infrared-based assay forCaenorhabditis elegansmotility
Authors: Sun Yujie Uli , Liu Lawrence J. , Caffrey Conor R. 
Published: December 2023

AbstractBackgroundParasitic nematodes are a public health problem globally, and an economic burden on animal and plant agricultural industries. With their ability to generate drug resistance, new anthelmintic compounds must be constantly sourced.MethodsUsing the free-living nematode,Caenorhabditis elegans,in an infrared-based motility assay, we screened 400 compounds from two open-source, small-molecule collections distributed by the Medicines for Malaria Venture, namely, the COVID Box and Global Health Priority Box. The screening assay was first validated for worm number, DMSO concentration and final volume.ResultsPrimary and secondary (time- and concentration-dependent) screens of both boxes, identified twelve compounds as hits; nine of which were known anthelmintics. Three novel anthelmintic hits, flufenerim, flucofuron and indomethacin were identified with EC50values ranging from 0.211 to 23.174 µM. Counter toxicity screens with HEK293 cells indicated varying degrees of toxicity with EC50values ranging from 0.453 to >100 µM.ConclusionsAC. elegansmotility assay was optimized and used to screen two recently-released, small molecule libraries. One or more of these three novel active compounds might serve as starting points for the development of new anthelmintics.
Toward Best Practice in Identifying Subtle Differential Expression with RNA-seq: A Real-World Multi-Center Benchmarking Study Using Quartet and MAQC Reference Materials
Authors: Wang Duo , Liu Yaqing , Zhang Yuanfeng , Chen Qingwang , Han Yanxi , Hou Wanwan , Liu Cong , Yu Yin , Li Ziyang , Li Ziqiang , Zhao Jiaxin , Zheng Yuanting , Shi Leming , Li Jinming , Zhang Rui 
Published: December 2023

AbstractTranslating RNA-seq into clinical diagnostics requires ensuring the reliability of detecting clinically relevant subtle differential expressions, such as those between different disease subtypes or stages. Moreover, cross-laboratory reproducibility and consistency under diverse experimental and bioinformatics workflows urgently need to be addressed. As part of the Quartet project, we presented a comprehensive RNA-seq benchmarking study utilizing Quartet and MAQC RNA reference samples spiked with ERCC controls in 45 independent laboratories, each employing their in-house RNA-seq workflows. We assessed the data quality, accuracy and reproducibility of gene expression and differential gene expression and compared over 40 experimental processes and 140 combined differential analysis pipelines based on multiple ‘ground truths’. Here we show that real-world RNA-seq exhibited greater inter-laboratory variations when detecting subtle differential expressions between Quartet samples. Experimental factors including mRNA enrichment methods and strandedness, and each bioinformatics step, particularly normalization, emerged as primary sources of variations in gene expression and have a more pronounced impact on the subtle differential expression measurement. We underscored the pivotal role of experimental execution over the choice of experimental protocols, the importance of strategies for filtering low-expression genes, and optimal gene annotation and analysis tools. In summary, this study provided best practice recommendations for the development, optimization, and quality control of RNA-seq for clinical diagnostic purposes.
Isotope geolocation and population genomics inVanessa cardui:Short- and long-distance migrants are genetically undifferentiated
Authors: Reich Megan S. , Shipilina Daria , Talla Venkat , Bahleman Farid , Kébé Khadim , Berger Johanna L. , Backström Niclas , Talavera Gerard , Bataille Clément P. 
Published: December 2023

AbstractThe painted lady butterflyVanessa carduiis renowned for its virtually cosmopolitan distribution and the remarkable long-distance migrations that are part of its annual, multi-generational migratory cycle. Recently,V. carduiindividuals were found north and south of the Sahara in the autumn, suggesting distinct migratory behaviours within the species. However, the evolutionary and ecological factors shaping these differences in migratory behaviour remain largely unexplored. Here, we performed whole-genome resequencing and analysed the hydrogen and strontium isotopes of 40V. carduiindividuals simultaneously collected in the autumn from regions both north and south of the Sahara. Our investigation revealed two main migratory groups: (i) short-distance migrants, journeying from temperate Europe to the circum-Mediterranean region and (ii) long-distance migrants, originating from Europe, crossing the Mediterranean Sea and Sahara, and reaching West Africa, covering up to over 4,000 km. Despite these stark differences in migration distance, a genome-wide analysis revealed that both short- and long-distance migrants belong to a single intercontinental panmictic population extending from northern Europe to sub-Saharan Africa. Contrary to common biogeographic patterns, the Sahara is not a catalyst for population structuring in this species. No significant genetic differentiation or signs of adaptation and selection were observed between the two migratory phenotypes (pairwise FST= 0.001 ± 0.006). Nonetheless, two individuals, which were early arrivals to West Africa and covered longer migration distances, exhibited some genetic differentiation. The lack of genetic structure between short- and long-distance migrants suggests that migration distance inV. carduiis a plastic response to environmental conditions.Significance statementAlthough migratory insects dominate living biomass fluxes and impact agriculture, ecosystems, and human communities, little is known about the controls of their migratory behavior. Our study develops an interdisciplinary framework, applied to the migratory butterflyV.cardui, to explore the genetic basis of variation in insect migration behavior. We leverage new generation isotope geolocation techniques to uncover striking differences in butterfly behaviour, with some individuals migrating short distances within the circum-Mediterranean region and others migrating thousands of kilometers across the Mediterranean Sea and Sahara. This major difference does not coincide with genetic differentiation or population structure and is likely a plastic response to environmental cues. This study provides a ground-breaking framework to study migration in insects.
Switching circuits: Modulating NK cell response to TGF-β using novel receptors
Authors: Turk Rebekah , Guo Lan , Belmont Brian J. , Bogard Nick , Chen Aye T. , Williams Maddie D. , Young Mary , Stone Matthew R. , Daines Bryce , Darnell Max 
Published: December 2023

ABSTRACTEngineered natural killer (NK) cells offer a promising treatment strategy for multiple therapeutic areas, yet tuning cell function to diverse environmental and inhibitory contexts remains a significant challenge. An attractive strategy for functional rescue in the presence of inhibitory ligands is the use of switch receptors, surface-expressed chimeric receptors that convert an external inhibitory cue into an intracellular activation signal. Here, we discover novel engineered switch receptors in NK cells that are responsive to TGF-β, a soluble inhibitory factor present in many therapeutic contexts. Through a pooled screen of an 11,131 member library, we identified multiple novel signaling endodomains and endodomain combinations that improve both the acute cytotoxicity and persistence of NK cells in the presence of TGF-β, demonstrating a novel and flexible approach to switch receptor discovery.
RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4
Authors: Weinstein Hannah N.W. , Hu Kevin , Fish Lisa , Chen Yih-An , Allegakoen Paul , Hui Keliana S. F. , Pham Julia H. , Baco Maria B. , Song Hanbing , Giacomelli Andrew O. , Vazquez Francisca , Ghandi Mahmoud , Goodarzi Hani , Huang Franklin W. 
Published: December 2023

SummaryMicrosatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intactTP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation inRPL22, a ribosomal protein. Here, we identifiedRPL22as a modulator ofMDM4splicing through an alternative splicing switch in exon 6.RPL22loss increasesMDM4exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
Morphological signatures of neurogenesis and neuronal migration in hypothalamic vasopressinergic magnocellular nuclei of the adult rat
Authors: Zhang Limei , Zetter Mario A. , Hernández Vito S. , Hernández-Pérez Oscar R. , Jáuregui-Huerta Fernando , Krabichler Quirin , Grinevich Valery 
Published: December 2023

AbstractArginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker Iba1, and 5′-bromo-2′-deoxyuridine (BrdU), we report morphological evidence that low rate neurogenesis and migration occur in adult AVPMNS in rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the SON and PVN. These findings raise new questions about AVPMNS’s potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.