bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecules targeting the structural dynamics of AR-V7 partially disordered protein using deep learning and physics based models
Authors: Karatzas Pantelis , Brotzakis Z. Faidon , Sarimveis Haralambos 
Published: February 2024

AbstractPartially disordered proteins can contain both stable and unstable secondary structure segments and are involved in various (mis)functions in the cell. The extensive conformational dynamics of partially disordered proteins scaling with extent of disorder and length of the protein hampers the efficiency of traditional experimental and in-silico structure-based drug discovery approaches. Therefore new efficient paradigms in drug discovery taking into account conformational ensembles of proteins need to emerge. In this study, using as a test case the AR-V7 transcription factor splicing variant related to prostate cancer, we present an automated methodology that can accelerate the screening of small molecule binders targeting partially disordered proteins. By swiftly identifying the conformational ensemble of AR-V7, and reducing the dimension of binding-sites by a factor of 90 by applying appropriate physicochemical filters, we combine physics based molecular docking and multi-objective classification machine learning models that speed up the screening of thousands of compounds targeting AR-V7 multiple binding sites. Our method not only identifies previously known binding sites of AR-V7, but also discovers new ones, as well as increases the multi-binding site hit-rate of small molecules by a factor of 10 compared to naive physics-based molecular docking.
Spatiotemporal dynamics of NF-κB/Dorsal inhibitor IκBα/Cactus inDrosophilablastoderm embryos
Authors: Schloop Allison E. , Hiremath Sharva , Shaikh Razeen , Williams Cranos M. , Reeves Gregory T. 
Published: February 2024

AbstractThe NF-κB signaling pathway is a key regulatory network in mammals that controls many cellular processes, including immunity and inflammation. Of particular note is the relationship between NF-κB and its inhibitor IκBα, which sequesters NF-κB to the cytoplasm of cells until needed. It is also known that IκBα can enter nuclei, disrupt NF-κB binding to DNA, and shuttle it out to again sequester NF-κB in the cytoplasm. InDrosophila melanogaster, a homologous system between the proteins Dorsal (homologous to NF-κB) and Cactus (homologous to IκBα) is important in embryo development, specifically in establishment of the Dorsal nuclear concentration gradient. Previous work suggests Cactus also enters the nucleus; mathematical models of the Dorsal gradient fail to accurately predict the normal range of the gradient without nuclear Cactus. However, direct,in vivovisualization of Cactus spatiotemporal dynamics, including its localization to the nuclei, has been difficult to gather. Previously, imaging Cactus in live embryos was complicated by rapid protein turnover, preventing fluorescent protein fusions from fully maturing. To address this, we used the CRISPR/Cas9 system to tag Cactus with the recently developed “LlamaTag” (LT), a genetically encodable nanobody from llamas that dynamically binds to GFPin vivo. We then employed standard confocal imaging, as well as advanced optical techniques such as raster image correlation spectroscopy (RICS) and fluorescent recovery after photobleaching (FRAP) to investigate the spatiotemporal distribution of Cactus-LlamaTag inDrosophilaembryos at the blastoderm stage. Our results demonstrate that Cactus can be found in the nuclei of early embryos, consistent with its role as a transcription factor regulator. Moreover, by using the data from FRAP and RICS, we were able to estimate biophysical parameters of Cactus dynamicsin vivo, including its nuclear transport rate constants and fraction bound to GFP. These data were further used to constrain a mathematical model that allowed us to infer experimentally inaccessible biophysical parameters, such as the concentration of Cact protein and the dissociation constant of LT and GFP. Our study provides new insights into the regulation of the NF-κB pathway in earlyDrosophilaembryos and highlights the power of advanced optical techniques for investigating complex biological dynamics.
The lipidome of posttraumatic stress disorder
Authors: Bhargava Aditi , Knapp Johannes D. , Fiehn Oliver , Neylan Thomas C. , Inslicht Sabra S. 
Published: February 2024

ABSTRACTPosttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 individuals with PTSD and 40 trauma-exposed non-PTSD individuals. Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ∼ 90 measures were collected, on sleep, mental and physical health indices. Sleep quality worsened as PTSD severity increased in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 classes of lipids. After adjusting for sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The triglycerides and ceramide metabolites that were most highly increased were correlated with cholesterol metabolites and systolic blood pressure in men but not always in women with PTSD. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher weight may have contributed to changes in the lipidome found in PTSD.
Object motion representation in the macaque ventral stream – a gateway to understanding the brain’s intuitive physics engine
Authors: Ramezanpour Hamidreza , Ilic Filip , Wildes Richard P. , Kar Kohitij 
Published: February 2024

AbstractEffective interaction with moving objects and the ability to infer and predict their motion (a core component of “intuitive physics”) is essential for survival in the dynamic world. How does the primate visual system process such stimuli, enabling predictive capabilities for dynamic stimuli statistics like motion velocity and expected trajectories? In this study, we probed brain areas in the ventral visual pathway of rhesus macaques implicated in object recognition (areas V4 and inferior temporal, IT, cortex) to evaluate how they represent object motion speed and direction. We assessed the relationship between the distributed population activity in the ventral stream and two distinct object motion-based behaviors—one reliant on information directly available in videos (speed discrimination) and the other predicated on predictive motion estimates from videos (future event predictions). Further, employing microstimulation strategies, we confirm the causal, functional role of the IT cortex in these behaviors. Our results underscore the need to re-examine the traditional functional segregation of the primate visual cortices into “what” and “where” pathways and provide empirical constraints to model their interaction for a better circuit-level understanding of visual motion and intuitive physics.
Ribonanza: deep learning of RNA structure through dual crowdsourcing
Authors: He Shujun , Huang Rui , Townley Jill , Kretsch Rachael C. , Karagianes Thomas G. , Cox David B.T. , Blair Hamish , Penzar Dmitry , Vyaltsev Valeriy , Aristova Elizaveta , Zinkevich Arsenii , Bakulin Artemy , Sohn Hoyeol , Krstevski Daniel , Fukui Takaaki , Tatematsu Fumiya , Uchida Yusuke , Jang Donghoon , Lee Jun Seong , Shieh Roger , Ma Tom , Martynov Eduard , Shugaev Maxim V. , Bukhari Habib S.T. , Fujikawa Kazuki , Onodera Kazuki , Henkel Christof , Ron Shlomo , Romano Jonathan , Nicol John J. , Nye Grace P. , Wu Yuan , Choe Christian , Reade Walter ,   Eterna participants, Das Rhiju 
Published: February 2024

AbstractPrediction of RNA structure from sequence remains an unsolved problem, and progress has been slowed by a paucity of experimental data. Here, we present Ribonanza, a dataset of chemical mapping measurements on two million diverse RNA sequences collected through Eterna and other crowdsourced initiatives. Ribonanza measurements enabled solicitation, training, and prospective evaluation of diverse deep neural networks through a Kaggle challenge, followed by distillation into a single, self-contained model called RibonanzaNet. When fine tuned on auxiliary datasets, RibonanzaNet achieves state-of-the-art performance in modeling experimental sequence dropout, RNA hydrolytic degradation, and RNA secondary structure, with implications for modeling RNA tertiary structure.
Enhanced microbiota profiling in patients with quiescent Crohn’s disease through comparison with paired healthy first-degree relatives using fecal metagenomics and metabolomics
Authors: Chen Wanning , Li Yichen , Wang Wenxia , Gao Sheng , Wu Dingfeng , Jiao Na , Xu Tao , Zhi Min , Zhu Lixin , Zhu Ruixin 
Published: February 2024

AbstractPrior studies indicate no correlation between gut microbiota of healthy first-degree relatives (HFDRs) of Crohn’s disease (CD) patients and development of CD. Here, we utilized HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. Compared to non-relative controls, the use of HFDR controls identified fewer differential taxa.Faecalibacterium, Dorea,andFusicatenibactershowed decreased abundances in CD-R, independent of inflammation, and correlated with fecal SCFAs. Validation with a large multi-center cohort confirmed decreased abundances inFaecalibacteriumand other SCFA-producing genera in CD-R. Classification models based on these genera distinguished CD-R and CD-A from healthy individuals, in both the discovery and validation cohorts. Thus, the decreased presence ofFaecalibacterium, Dorea,andFusicatenibacterin CD-R likely contributed to disease relapse through reduced SCFA production, highlighting their potential as diagnostic markers and therapeutic targets for CD.
Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2
Authors: Wortham Matthew , Ramms Bastian , Zeng Chun , Benthuysen Jacqueline R. , Sai Somesh , Pollow Dennis P. , Liu Fenfen , Schlichting Michael , Harrington Austin R. , Liu Bradley , Prakash Thazha P. , Pirie Elaine C , Zhu Han , Baghdasarian Siyouneh , Auwerx Johan , Shirihai Orian S. , Sander Maike 
Published: February 2024

ABSTRACTSelective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2).Sirt2deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level,Sirt2inactivation has context-dependent effects on β-cells, withSirt2controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupledSirt2-targeting antisense oligonucleotide achieves β-cell selectiveSirt2inactivation and stimulates β-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation.
Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells
Authors: Kasap Corynn , Izgutdina Adila , Patiño-Escobar Bonell , Kang Amrik , Chilakapati Nikhil , Akagi Naomi , Johnson Haley , Rashid Tasfia , Werner Juwita , Barpanda Abhilash , Geng Huimin , Lin Yu-Hsiu T. , Rampersaud Sham , Gil-Alós Daniel , Sobh Amin , Dupéré-Richer Daphné , Wicaksono Gianina , Kawehi Kelii K.M. , Dalal Radhika , Ramos Emilio , Vijayanarayanan Anjanaa , Salangsang Fernando , Phojanakong Paul , Serrano Juan Antonio Camara , Zakraoui Ons , Tariq Isa , Steri Veronica , Shanmugam Mala , Boise Lawrence H. , Kortemme Tanja , Stieglitz Elliot , Licht Jonathan D. , Karlon William J. , Barwick Benjamin G. , Wiita Arun P. 
Published: February 2024

AbstractDespite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.One sentence summaryStructure-optimized CD27-based CAR-T cells targeting CD70 are a promising therapeutic option for high-risk multiple myeloma patients who are most likely to relapse on current BCMA-targeting cellular therapies.
Wake EEG oscillation dynamics reflect both sleep need and brain maturation across childhood and adolescence
Authors: Snipes Sophia , Krugliakova Elena , Jaramillo Valeria , Volk Carina , Furrer Melanie , Studler Mirjam , LeBourgeois Monique , Kurth Salome , Jenni Oskar G. , Huber Reto 
Published: February 2024

ABSTRACTAn objective measure of brain maturation is highly insightful for monitoring both typical and atypical development. Slow wave activity, recorded in the sleep electroencephalogram (EEG), reliably indexes changes in brain plasticity with age, as well as deficits related to developmental disorders such as attention-deficit hyperactivity disorder (ADHD). Unfortunately, measuring sleep EEG is resource-intensive and burdensome for participants. We therefore aimed to determine whether wake EEG could likewise index developmental changes in brain plasticity. We analyzed high-density wake EEG collected from 163 participants 3-25 years old, before and after a night of sleep. We compared two measures of oscillatory EEG activity, amplitudes and density, as well as two measures of aperiodic activity, intercepts and slopes. Furthermore, we compared these measures in patients with ADHD (8-17 y.o., N=58) to neurotypical controls. We found that wake oscillation amplitudes behaved the same as sleep slow wave activity: amplitudes decreased with age, decreased after sleep, and this overnight decrease decreased with age. Oscillation densities were also substantially age-dependent, decreasing overnight in children and increasing overnight in adolescents and adults. While both aperiodic intercepts and slopes decreased linearly with age, intercepts decreased overnight, and slopes increased overnight. Overall, our results indicate that wake oscillation amplitudes track both development and sleep need, and overnight changes in oscillation density reflect some yet-unknown shift in neural activity around puberty. No wake measure showed significant effects of ADHD, thus indicating that wake EEG measures, while easier to record, are not as sensitive as those during sleep.
Recurrent cortical networks encode natural sensory statistics via sequence filtering
Authors: Deveau Ciana E. , Zhou Zhishang , LaFosse Paul K. , Deng Yanting , Mirbagheri Saghar , Steinmetz Nicholas , Histed Mark H. 
Published: February 2024

AbstractRecurrent neural networks can generate dynamics, but in sensory cortex it has been unclear if any dynamic processing is supported by the dense recurrent excitatory-excitatory network. Here we show a new role for recurrent connections in mouse visual cortex: they support powerful dynamical computations, but by filtering sequences of input instead of generating sequences. Using two-photon optogenetics, we measure neural responses to natural images and play them back, finding inputs are amplified when played back during the correct movie dynamic context— when the preceding sequence corresponds to natural vision. This sequence selectivity depends on a network mechanism: earlier input patterns produce responses in other local neurons, which interact with later input patterns. We confirm this mechanism by designing sequences of inputs that are amplified or suppressed by the network. These data suggest recurrent cortical connections perform predictive processing, encoding the statistics of the natural world in input-output transformations.
ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer’s Disease
Authors: Hu Wen , Foord Careen , Hsu Justine , Fan Li , Corley Michael J , Bhatia Tarun N , Xu Siwei , Belchikov Natan , He Yi , Pang Alina PS , Lanjewar Samantha N , Jarroux Julien , Joglekar Anoushka , Milner Teresa A , Ndhlovu Lishomwa C , Zhang Jing , Butelman Eduardo , Sloan Steven A , Lee Virginia MY , Gan Li , Tilgner Hagen U 
Published: February 2024

AbstractMultimodal measurements have become widespread in genomics, however measuring open chromatin accessibility and splicing simultaneously in frozen brain tissues remains unconquered. Hence, we devised Single-Cell-ISOform-RNA sequencing coupled with the Assay-for-Transposase-Accessible-Chromatin (ScISOr-ATAC). We utilized ScISOr-ATAC to assess whether chromatin and splicing alterations in the brain convergently affect the same cell types or divergently different ones. We applied ScISOr-ATAC to three major conditions: comparing (i) the Rhesus macaque (Macaca mulatta) prefrontal cortex (PFC) and visual cortex (VIS), (ii) cross species divergence of Rhesus macaque versus human PFC, as well as (iii) dysregulation in Alzheimer’s disease in human PFC. We found that among cortical-layer biased excitatory neuron subtypes, splicing is highly brain-region specific for L3-5/L6 IT_RORBneurons, moderately specific in L2-3 IT_CUX2.RORBneurons and unspecific in L2-3 IT_CUX2neurons. In contrast, at the chromatin level, L2-3 IT_CUX2.RORBneurons show the highest brain-region specificity compared to other subtypes. Likewise, when comparing human and macaque PFC, strong evolutionary divergence on one molecular modality does not necessarily imply strong such divergence on another molecular level in the same cell type. Finally, in Alzheimer’s disease, oligodendrocytes show convergently high dysregulation in both chromatin and splicing. However, chromatin and splicing dysregulation most strongly affect distinct oligodendrocyte subtypes. Overall, these results indicate that chromatin and splicing can show convergent or divergent results depending on the performed comparison, justifying the need for their concurrent measurement to investigate complex systems. Taken together, ScISOr-ATAC allows for the characterization of single-cell splicing and chromatin patterns and the comparison of sample groups in frozen brain samples.
Dietary bacteria controlC. elegansfat content through pathways converging at phosphatidylcholine
Authors: Han Hsiao-Fen , Nien Shao-Fu , Jiang Hang-Shiang , Wu Jui-Ching , Chiang Chia-Yi , Li Man-Tzu , Huang Leng-Jie , Chiang Sufeng , Lin Lien-Chieh , Chuang Yi-Ting , Lin Yu-Ho , Wang Chao-Wen , Wu Yi-Chun 
Published: February 2024

AbstractDietary factors play a pivotal role in regulating metabolism in both health and disease. Lipid metabolism is particularly important for organismal health and longevity. However, the mechanisms by which dietary factors influence lipid metabolism remain poorly understood. Here, using the nematodeC. elegansas a model system, we investigated the influence of distinct bacterial diets on fat metabolism. We found that dietary vitamin B12 activates the S-adenosyl methionine (SAM) and phosphatidylcholine (PC) biosynthetic pathways. This activation leads to elevated levels of PC, which in turn suppresses the expression of the genefat-7and modulates lipid droplet dynamics through the regulatory proteins SBP-1/SREBP1 and SEIP-1/SEIPIN, respectively. Additionally, we identified a feedback loop involving SBP-1-mediated regulation of acid sphingomyelinase ASM-3, which enhances the production of phospho-choline and further stimulates PC synthesis. Our localization studies further suggest that ASM-3 may act as a signaling mediator between the intestine and coelomocytes, coordinating their roles in vitamin B12-mediated fat regulation. Overall, our findings shed new light on the complex interplay between diet and metabolic regulation, with a particular emphasis on the central role of phosphatidylcholine.HighlightsAnimals govern PC level to regulate lipid homeostasis in response to dietsB12 regulates SAM-PC axis to affect lipogenic genes expression and LD biogenesisCoelomocytes regulate diets-induced lipid homeostasis throughasm-3asm-3constructs a positive feedback loop to participate in PC metabolism