bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eye movements organize excitability state, information coding and network connectivity in the human hippocampus
Authors: Leszczynski Marcin , Espinal Elizabeth , Smith Elliot , Schevon Catherine , Sheth Sameer , Schroeder Charles E. 
Published: January 2025

AbstractNatural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.One-Sentence SummarySaccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network activation
Structures of the human adult muscle-type nicotinic receptor in resting and desensitised states
Authors: Li Anna , Pike Ashley C. W. , Webster Richard , Maxwell Susan , Liu Wei-Wei , Chi Gamma , Palace Jacqueline , Beeson David , Sauer David B. , Dong Yin Yao 
Published: January 2025

AbstractMuscle-type nicotinic acetylcholine receptor (AChR) is the key signalling molecule in neuromuscular junctions. Here we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states, and in acetylcholine (ACh)-bound desensitised states. In addition to identifying the conformational changes during recovery from desensitisation, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in congenital myasthenic syndrome (CMS) patients, revealing they cause either slow- or fast-channel CMS characterised by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both AChR state transition and the pathogenic mechanisms of disease variants.
Identification of specific lipid-protein interactions in dividing cells using lipid-trap mass spectrometry
Authors: Paquola Andrea , Ozbalci Cagakan , Storck Elisabeth M. , Terry Stephen J. , Benson Clare E. , Eggert Ulrike S. 
Published: January 2025

AbstractCells actively maintain complex lipidomes that encompass thousands of lipids, however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason for the evolutionary conservation of complex lipidomes. We report the development of a technique, named lipid-trap mass spectrometry (LTMS), to systematically study protein-lipid interactions directly captured from mammalian cells. LTMS uses immunoprecipitation of GFP-tagged proteins expressed in HeLa, followed by lipidomic analysis of lipids bound to the GFP-tagged protein. We applied LTMS to cell division to illustrate the technique. We chose this process because membranes regulate their lipid composition as they undergo major changes during cytokinesis and many cytokinetic proteins, including RACGAP1 and ESCRTIII components CHMP4B and CHMP2A, are membrane-associated. Using LTMS, we found that RACGAP1 and CHMP4B associate with specific lipid species in dividing compared to non-dividing cells. We expand our understanding of lipid diversity during cell division and present a general approach to explore lipid-protein interactions to further our understanding of the roles of lipids in mammalian cells.
Reduced enteric BDNF-TrkB signaling drives glucocorticoid-mediated GI dysmotility
Authors: Slosberg Jared , Puttapaka Srinivas N. , Seika Philippa , Hong Su Min , Singh Alpana , Kulkarni Subhash 
Published: January 2025

AbstractStress affects gastrointestinal (GI) function causing dysmotility, especially indisorders of gut-brain interactions (DGBI)patients. GI motility is regulated by the enteric nervous system (ENS), suggesting that stress alters ENS biology to cause dysmotility. While stress increases glucocorticoid levels through the hypothalamus-pituitary-adrenal axis, how glucocorticoids affect GI motility is not known. Glucocorticoid signaling reduces expression of specific transcriptional isoforms of brain-derived neurotrophic factor (BDNF) in the central nervous system, altering signaling through its receptor Tropomyosin-related kinase B (TrkB) to cause behavioral defects. However, since the nature of ENS-specificBdnfisoforms and their response to glucocorticoids remains unknown, we are limited in studying how stress impacts the ENS to cause dysmotility. Here, in male and female mice, we establish that stress-responsiveBdnfisoforms that are transcriptionally regulated at exons 4 and 6 represent >85% of allBdnfisoforms in the post-natal ENS, and thatBdnfandNtrk2(TrkB) are expressed by enteric neurons. We further show using male mice dosed with a synthetic glucocorticoid receptor (GR) agonist dexamethasone (Dexa), that increased glucocorticoid signaling in ENS significantly reduces the expression ofBdnftranscripts and protein and that it significantly reduces GI motility. Finally, by using HIOC, a specific synthetic agonist of TrkB, we observe that HIOC treatment significantly improved GI motility of a cohort of Dexa-treated male mice, when compared to Dexa-treated and HIOC-untreated mice. Our results implicate BDNF- TrkB signaling in the etiology of stress-associated dysmotility and suggest that TrkB is a putative therapeutic target for dysmotility in DGBI patients.Significance statementThe mechanism through which stress-associated increase in glucocorticoid signaling causes gastrointestinal (GI) dysmotility is not well understood. GI motility is regulated by the enteric nervous system, which depends on optimal signaling between brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin related kinase B (TrkB). The lack of clarity on whether glucocorticoid impact BDNF signaling in the ENS, analogous to the manner they affect BDNF in brain, has limited our understanding of stress-associated dysmotility. Here, by identifying the nature ofBdnfisoforms expressed in ENS, studying their response to increased glucocorticoid signaling, and testing the effect of TrkB agonist to promote healthy gut motility in a model of glucocorticoid-driven dysmotility, we implicate altered BDNF-TrkB signaling as the mechanism driving stress-associated dysmotility.
Bouncer’s receptor on sperm: Investigating sperm-egg compatibility in fish
Authors: Blaha Andreas , Pauli Andrea 
Published: January 2025

AbstractFertilization requires the successful binding and fusion of sperm and egg. In zebrafish, sperm-egg binding is mediated by the Spaca6-Izumo1-Tmem81 complex on sperm interacting with Bouncer on the egg. We previously found that expressing medaka Bouncer on zebrafish eggs andvice versaallows hybridization between medaka and zebrafish, two species that can normally not hybridize. Here, we tested whether providing zebrafish Spaca6 and Izumo1 on medaka sperm and vice versa enables cross-species compatibility from the side of the sperm. To this end, we generatedspaca6andizumo1knock-out (KO) lines in medaka, which are male sterile, and introduced zebrafishspaca6andizumo1transgenes. Transgenic medaka males did not fertilize zebrafish or medaka eggs with zebrafish Bouncer. Similarly, zebrafish males expressing medaka Spaca6 and Izumo1 failed to fertilize zebrafish eggs presenting medaka Bouncer. Unexpectedly, providing either full-length medaka Spaca6 or the Bouncer binding site of medaka Izumo1 in zebrafish sperm rescued the sterility ofspaca6andizumo1KO, respectively. Therefore, medaka Spaca6 and Izumo1 can interact with zebrafish Bouncer when paired with their zebrafish sperm complex members underscoring the nuanced interplay between molecular restrictions and compatibilities during sperm-egg interaction across teleosts.
The dual coding geneSLC35A4protects against oxidative stress
Authors: Ajala Ikram , Tiaiba Imadeddine , Grondin Benoît , Lipuma Damien , Jmii Souleimen , Benlyamani Hiba , Cappadocia Laurent , Vanderperre Benoît 
Published: January 2025

AbstractAlternative proteins (AltProts) represent a newly recognized class of biologically active proteins encoded from alternative open reading frames (AltORFs) within already annotated genes. This study focuses on theSLC35A4gene, which encodes both the reference protein SLC35A4 and the alternative protein AltSLC35A4. Using a combination of microscopy and biochemical analyses, we confirmed the presence of AltSLC35A4 in the inner mitochondrial membrane, resolving previous conflicting reports. Previous studies employing ribosome profiling have revealed that during oxidative stress induced by sodium arsenite, the reference coding sequence ofSLC35A4exhibits the largest increase in translational efficiency among all cellular mRNAs. Our results confirmed this translational upregulation, with the emergence of SLC35A4 protein isoforms during oxidative stress in an upstream ORF-dependent manner. Notably, the expression of AltSLC35A4 remained unchanged during oxidative stress. Knock- out of SLC35A4 enhanced sensitivity to oxidative stress in a rescuable manner, indicating a direct implication for SLC35A4 in stress resistance. In conclusion, our research provides compelling evidence for the functional significance of the dual-coding nature ofSLC35A4for resistance to oxidative stress and highlights the importance of considering AltProts in the functional study of eukaryotic genes.
Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Authors: Copley Katie E. , Mauna Jocelyn C. , Danielson Helen , Ngo Marilyn , Xie Longxin , Smirnov Ashleigh , Davis Matt , Mayne Leland , Linsenmeier Miriam , Rubien Jack D. , Portz Bede , Lee Bo Lim , Odeh Hana M. , Hallegger Martina , Ule Jernej , Pasinelli Piera , Poon Yan , Fawzi Nicolas L. , Black Ben E. , Donnelly Christopher J. , Jensen Brigid K. , Shorter James 
Published: January 2025

AbstractAberrant aggregation of the prion-like, RNA-binding protein TDP-43 underlies several debilitating neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). Here, we define how short, specific RNAs antagonize TDP-43 aggregation. Short, specific RNAs engage and stabilize the TDP-43 RNA-recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. By mining sequence space, we uncover short RNAs with enhanced activity against TDP-43 and diverse disease-linked variants. The solubilizing activity of enhanced short RNA chaperones corrects aberrant TDP-43 phenotypes in optogenetic models and ALS patient-derived neurons. Remarkably, an enhanced short RNA chaperone mitigates TDP-43 proteinopathy and neurodegeneration in mice. Our studies reveal mechanisms of short RNA chaperones and pave the way for the development of short RNA therapeutics for fatal TDP-43 proteinopathies.
The 8-nm spaghetti: well-structured glycans coating linear tetrapeptide repeats discovered from freshwater with CryoSeek
Authors: Wang Tongtong , Sun Yitong , Li Zhangqiang , Yan Nieng 
Published: January 2025

AbstractWe recently developed a research strategy, termed CryoSeek, to identify uncharacterized bio-entities from natural or endogenous resources using cryo-electron microscopy (cryo-EM). Here we report the discovery of a glycofibril whose primary molecular mass is attributed to a thick glycan shell. The 3.3-Å resolution cryo-EM reconstruction reveals that the only protein component of the glycofibril, which is approximately 8 nm in diameter, is a linear chain of tetrapeptide repeats. Each tetrapeptide repeat consists of a 3,4-dihydroxyproline (diHyp), a Ser or Thr, and two less conserved residues. Two and one glycan chains are respectively O-linked to the diHyp and Ser/Thr residues. The protein sequence pattern of this glycofibril is similar to that of our recently observed TLP-4, although the glycan chains are different. We rename the previously characterized glycofibril as TLP-4a and designate this one as TLP-4b. Our discoveries reveal the critical role of glycans in structural folding of glycoconjugates and shed light on understanding the carbon/nitrogen ratio in biospheres.
Reproduction and preference to macronutrients have different relations to biological or chronological age inDrosophila
Authors: Lushchak Oleh , Strilbytska Olha , Petakh Pavlo , Kamyshnyi Oleksandr , Koliada Oleksandr , Semaniuk Uliana 
Published: January 2025

AbstractGenetic manipulations, dietary composition and supplementations with varied drugs and natural compounds were shown to extend both the life- and health-span in different model organisms. An understanding of the mechanisms behind the beneficial properties of intervention includes the evaluation of physiological and molecular traits at certain time points that reflect the values at distinguished chronological age. Thus, if one cohort has a long-lived phenotype than measurements at certain time points represent the difference between organisms of different biological ages. We have compared reproduction and consumption of specific macronutrients for flies of the same cohort but related to different quartiles of chronological and biological age. We found that the decline in carbohydrate or protein consumption was stronger in the case of chronological rather than biological age. However, flies of biological or chronological quartile 4 consumed virtually the same amounts of macronutrients. The decline in reproduction was significantly reduced in relation to biological age. Thus, the decline was about 38-68% when within chronological quartiles 2 and 1 but only 4-31% for biological ones. The reproductive capacity was reduced by 86-93% in flies of chronological Q4 as compared to a 60-77% decrease for those of biological. Starting from quartile 2 biologically aged flies laid significantly higher number of eggs than flies of the same chronological quartile. Our results point out the significant difference in flies of the same biological and chronological quartile and raise the question about the suitability of comparison traits of organisms with different lifespans same chronological age.
Lifespan Normative Modeling of Brain Microstructure
Authors: Villalón-Reina Julio E. , Zhu Alyssa H. , Benavidez Sebastian , Moreau Clara A. , Feng Yixue , Chattopadhyay Tamoghna , Nabulsi Leila , Kushan Leila , John John P. , Joshi Himanshu , Thomopoulos Sophia I. , Lawrence Katherine E. , Nir Talia M. , Jahanshad Neda , Bearden Carrie E. , Kia Seyed Mostafa , Marquand Andre F. , Thompson Paul M. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractNormative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain’s white matter (WM) microstructure. Here we present the first large-scale normative model of brain WM microstructure–based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N=54,583 individuals; age: 4-91 years). We extracted regional diffusion tensor imaging (DTI) metrics using a standardized analysis and quality control protocol and used hierarchical Bayesian regression (HBR) to model the statistical distribution of derived WM metrics as a function of age and sex. We extracted the average lifespan trajectories and corresponding centile curves for each WM region. We illustrate the utility of the method by applying it to detect and visualize profiles of WM microstructural deviations in a variety of contexts: in mild cognitive impairment, Alzheimer’s disease, and 22q11.2 deletion syndrome – a neurogenetic condition that markedly increases risk for schizophrenia. The resulting large-scale model provides a common reference to identify disease effects on the brain’s microstructure in individuals or groups, and to compare disorders, and discover factors affecting WM abnormalities. The derived normative models are a new resource publicly available to the community, adaptable and extendable to future datasets as the available data expands.
Lysine deacetylation inhibition reverses TDP-43 mislocalization and in combination with arimoclomol ameliorates neuromuscular pathology
Authors: Scozzari Serena , Columbro Stefano Fabrizio , Favagrossa Monica , Tortarolo Massimo , Cagnotto Alfredo , Salmona Mario , De Marco Giovanni , Bendotti Caterina , Calvo Andrea , Pasetto Laura , Bonetto Valentina 
Published: January 2025

AbstractBackgroundCytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but more recently have been associated with several neurodegenerative conditions. Cyclophilin A (PPIA), a foldase and molecular chaperone, interacts with TDP-43 and influences its aggregation and function. The interaction between PPIA and TDP-43 is facilitated by PPIA Lys-acetylation, which is reduced in peripheral blood mononuclear cells (PBMCs) of ALS patients showing signs of TDP-43 proteinopathy. In this study, we investigated the effect of lysine deacetylation inhibition to uncover the underlying mechanisms of TDP-43 proteinopathy in relation to PPIA acetylation, and to identify new therapeutic avenues.MethodsThrough a screening of histone deacetylase (HDAC) inhibitors in a cellular model of TDP-43 proteinopathy, we identified vorinostat/SAHA, capable of increasing PPIA acetylation, as the most effective in reversing TDP-43 mislocalization. We confirmed its effect in PBMCs from ALS patients. Next, we explored its impact on proteinopathy and PPIA acetylation in a severe and fast-progressing TDP-43-overexpressing mouse model (Thy1-hTDP-43), using several molecular biomarkers as outcome measures, including neurofilament light chain (NfL) in plasma.ResultsThy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower levels of neurodegeneration and neuroinflammation markers, and improved neuromuscular function markers. However, over time, the broad-spectrum inhibitor SAHA was unable to counteract the two-fold overexpression of TDP-43 and led to the accumulation of side effects. When combined with the heat shock protein (HSP) co-inducer arimoclomol, a mitigation of the neurodegeneration was sustained. Moreover, a synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing pTDP-43 accumulation in the sciatic nerve. This resulted in a more pronounced reduction of NfL in plasma and acetylcholine receptor (AChR) γ-subunit expression in gastrocnemius muscle, indicating reduced axonal transport impairment and muscle denervation.ConclusionsThis study suggests that HDAC inhibition, by increasing acetylated PPIA, could be beneficial in restoring TDP-43 localization and function. The combination of lysine deacetylation inhibition and HSP induction shows a synergistic effectin vivoand has potential as a therapeutic approach for patients.
Mechanistic Insights into Dengue Virus Inhibition by a Clinical Trial Compound NITD-688
Authors: Wang Yan , Sun Long , Fernandes Luciana , Wang Yu-Hsiu , Zou Jing , Franklin Samuel J. , Hu Yanping , Palmer Lee K. , Yeung Jason , Barriga Daniela , Russell William K. , Moquin Stephanie A. , Shi Pei-Yong , Skepper Colin , Xie Xuping 
Published: January 2025

AbstractDengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent pan-serotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts pre-existing complexes invitroand DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.
A novel pan class-I glucose transporter inhibitor DRB18 exhibits synergistic effectsin vitroandin vivowith paclitaxel against human non-small cell lung cancer
Authors: Shriwas Pratik , Bachmann Lindsey , Ward Ryan , Adhicary Subhodip , Nielsen Corinne M. , Li Yunsheng , Zhang Haiyun , Song Jingwen , Roberts Dennis , Bergmeier Stephen , Chen Xiaozhuo 
Published: January 2025

AbstractCancer cells depend on glucose for biomass synthesis, cell proliferation, and drug resistance. Glucose transporter (GLUT) transcripts as well as proteins are upregulated in human lungs and other cancers and are negatively correlated with patient survival. Thus, inhibiting GLUT function has been an attractive anticancer strategy. We previously characterized WZB117 and DRB18, first- and second-generation pan-class I GLUT inhibitors, respectively. DRB18 strongly inhibits glucose transport mediated by GLUT1-4 in non-small lung cancer (NSCLC) A549 cellsin vitroandin vivo. Here, we report DRB18 as a more stable and potent anticancer compound, compared to WZB117. DRB18 reduced glucose uptake in NSCLC A549, pancreatic Panc1, and cervical Hela cancer cells with varied but strong anticancer potencies in the presence or absence of extracellular nutrients such as ATP and glucose. Combined with different clinical and pre-clinical anticancer compounds such as V9302, CB839, Sutent, Brigatinib, DRB18 significantly increased death of A549 and Panc1 cells. Noteworthy, DRB18 exhibited strong anticancer synergy with paclitaxel, an approved chemo drug for NSCLC, drastically reducing cancer cell proliferationin vitroand growth of A549 tumors grafted on the flank of nude mice without increased side effects, compared to single drug treatments. Mechanistically, dual treatment of DRB18 with paclitaxel elevated the expression of Caspases 3 and 9, suggesting GLUT-inhibiting and apoptosis-inducing anticancer mechanisms of DRB18 with paclitaxel. Collectively, our results demonstrate anticancer efficacy of DRB18 either working alone or in combination with paclitaxel, providing a potentially more efficacious therapeutic strategy for treating advanced NSCLC and other cancers.