bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design of a systemic small molecule clinical STING agonist using physics-based simulations and artificial intelligence
Authors: Allen Bryce K. , Kulkarni Meghana M. , Chamberlain Brian , Dwight Timothy , Koh Cheryl , Samant Ramya , Jernigan Finith , Rice Jamie , Tan Dazhi , Li Stella , Marino Kristen , Huang Huang , Chiswick Evan , Tesar Bethany , Sparks Sam , Lin Zhixiong , McGee T. Dwight , Kolossváry István , Lin Charles , Shechter Sharon , Soutter Holly , Bastos Cecilia , Taimi Mohammed , Lai Sujen , Petrin Alicia , Kane Tracy , Swann Steven , Gardner Humphrey , Winter Christopher , Sherman Woody 
Published: May 2022

AbstractThe protein STING (stimulator of interferon genes) is a central regulator of the innate immune system and plays an important role in antitumor immunity by inducing the production of cytokines such as type I interferon (IFN). Activation of STING stems from the selective recognition of endogenous cyclic dinucleotides (CDNs) by the large, polar, and flexible binding site, thus posing challenges to the design of small molecule agonists with drug-like physicochemical properties. In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where the ligand dimer approximates the size and shape of a cyclic dinucleotide while maintaining drug-like small molecule properties. SNX281 exhibits systemic exposure, STING-mediated cytokine release, strong induction of type I IFN, potent in vivo antitumor activity, durable immune memory, and single-dose tumor elimination in mouse models via a Cmax-driven pharmacologic response. Bespoke computational methods – a combination of quantum mechanics, molecular dynamics, binding free energy simulations, and artificial intelligence – were developed during the course of the project to design SNX281 by explicitly accounting for the unique self-dimerization mechanism and the large-scale conformational change of the STING protein upon activation. Over the course of the project, we explored millions of virtual molecules while synthesizing and testing only 208 molecules in the lab. This work highlights the value of a multifaceted computationally-driven approach anchored by methods tailored to address target-specific problems encountered along the project progression from initial hit to the clinic.
TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
Authors: Pérez-Berlanga Manuela , Wiersma Vera I. , Zbinden Aurélie , De Vos Laura , Wagner Ulrich , Foglieni Chiara , Mallona Izaskun , Betz Katharina M. , Cléry Antoine , Weber Julien , Guo Zhongning , Rigort Ruben , de Rossi Pierre , Manglunia Ruchi , Tantardini Elena , Sahadevan Sonu , Stach Oliver , Hruska-Plochan Marian , Allain Frederic H.-T. , Paganetti Paolo , Polymenidou Magdalini 
Published: May 2022

AbstractAggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state –monomeric/oligomeric, RNA-bound/-unbound– and the subcellular environment –nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.
Privacy-preserving integration of multiple institutional data for single-cell type identification with scPrivacy
Authors: Chen Shaoqi , Duan Bin , Zhu Chenyu , Tang Chen , Wang Shuguang , Gao Yicheng , Fu Shaliu , Fan Lixin , Yang Qiang , Liu Qi 
Published: May 2022

AbstractThe rapid accumulation of large-scale single-cell RNA-seq datasets from multiple institutions presents remarkable opportunities for automatically cell annotations through integrative analyses. However, the privacy issue has existed but being ignored, since we are limited to access and utilize all the reference datasets distributed in different institutions globally due to the prohibited data transmission across institutions by data regulation laws. To this end, we presentscPrivacy, which is the first and generalized automatically single-cell type identification prototype to facilitate single cell annotations in a data privacy-preserving collaboration manner. We evaluatedscPrivacyon a comprehensive set of publicly available benchmark datasets for single-cell type identification to stimulate the scenario that the reference datasets are rapidly generated and distributed in multiple institutions, while they are prohibited to be integrated directly or exposed to each other due to the data privacy regulations, demonstrating its effectiveness, time efficiency and robustness for privacy-preserving integration of multiple institutional datasets in single cell annotations.
Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect
Authors: Wang Wei , Xie Xueyi , Zhuang Xiaowen , Huang Yufei , Tan Tao , Gangal Himanshu , Huang Zhenbo , Purvines William , Wang Xuehua , Stefanov Alexander , Chen Ruifeng , Yu Emily , Hook Michelle , Huang Yun , Darcq Emmanuel , Wang Jun 
Published: May 2022

SUMMARYWithdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse.HighlightsRepeated administration of morphine potentiates IPSCdMSN◊GPhneurotransmission.Repeated administration of fentanyl potentiates IPSCdMSN◊SNcneurotransmission.Fentanyl withdrawal induces negative emotional states, which drive relapse.
The effects of combined action observation and motor imagery on corticospinal excitability and movement outcomes: Two meta-analyses
Authors: Chye Samantha , Valappil Ashika Chembila , Wright David J. , Frank Cornelia , Shearer David A. , Tyler Christopher J. , Diss Ceri E. , Mian Omar S. , Tillin Neale A. , Bruton Adam M. 
Published: May 2022

AbstractMotor simulation interventions involving motor imagery (MI) and action observation (AO) have received considerable interest in the behavioral sciences. A growing body of research has focused on using AO and MI simultaneously, termed ‘combined action observation and motor imagery’ (AOMI). The current paper includes two meta-analyses that quantify changes in corticospinal excitability and motor skill performance for AOMI compared to AO, MI and control conditions. Specifically, the first meta-analysis collated and synthesized existing motor evoked potential (MEP) amplitude data from transcranial magnetic stimulation studies and the second meta-analysis collated and synthesized existing movement outcome data from behavioral studies. AOMI had a positive effect compared to control and AO but not MI conditions for both MEP amplitudes and movement outcomes. No methodological factors moderated the effects of AOMI, indicating a robust effect of AOMI across the two outcome variables. The results of the meta-analyses are discussed in relation to existing literature on motor simulation and skill acquisition, before providing viable directions for future research on this topic.HighlightsMotor imagery (MI) and action observation (AO) can be combined (AOMI)This paper synthesizes neurophysiological and behavioral evidence for AOMIAOMI had increased corticospinal excitability compared to AO and control but not MIAOMI led to improved movement outcomes compared to AO and control but not MIThe reported effects of AOMI were maintained across all moderators
Connecting human voice profiling to genomics: A predictive algorithm for linking speech phenotypes to genetic microdeletion syndromes
Authors: Singh Rita 
Published: May 2022

AbstractChanges in vocal acoustic patterns are known to correlate with the occurrence of several diseases and syndromes, many of which do not directly affect the structures or processes that control voice production. In such cases, it is difficult to support the existence of correlated changes in voice. This paper presents a methodology for identifying potential genomic bases for such correlations, by finding links between specific genes involved in the conditions under study, and those involved in voice, speech or language generation. Syndromes associated with chromosomal microdeletions are examined as an illustrative case, with focus on their linkage to the FOXP2 gene which has been strongly implicated in speech and language disorders. A novel path-finding graph algorithm to detect pathway chains that connect the the former to the latter is proposed. Statistical analysis of ensembles of “voice” chains detected by this algorithm indicates that they are predictive of speech phenotypes for the syndromes. Algorithmic findings are validated against clinical findings in the literature pertaining to the actual speech phenotypes that have been found to be associated with these syndromes. This methodology may also potentially be used to predict the existence of voice biomarkers in naїve cases where the existence of voice biomarkers has not already been established.
Reconstitution of the SARS-CoV-2 ribonucleosome provides insights into genomic RNA packaging and regulation by phosphorylation
Authors: Carlson Christopher R. , Adly Armin N. , Bi Maxine , Cheng Yifan , Morgan David O. 
Published: May 2022

AbstractThe nucleocapsid (N) protein of coronaviruses is responsible for compaction of the ∼30-kb RNA genome in the ∼100-nm virion. Cryo-electron tomography suggests that each virion contains 35-40 viral ribonucleoprotein (vRNP) complexes, or ribonucleosomes, arrayed along the genome. There is, however, little mechanistic understanding of the vRNP complex. Here, we show that N protein, when combined with viral RNA fragments in vitro, forms cylindrical 15-nm particles similar to the vRNP structures observed within coronavirus virions. These vRNPs form in the presence of stem-loop-containing RNA and depend on regions of N protein that promote protein-RNA and protein-protein interactions. Phosphorylation of N protein in its disordered serine/arginine (SR) region weakens these interactions and disrupts vRNP assembly. We propose that unmodified N binds stem-loop-rich regions in genomic RNA to form compact vRNP complexes within the nucleocapsid, while phosphorylated N maintains uncompacted viral RNA to promote the protein’s transcriptional function.
SALMA: Scalable ALignment using MAFFT-Add
Authors: Shen Chengze , Liu Baqiao , Williams Kelly P. , Warnow Tandy 
Published: May 2022

AbstractMultiple sequence alignment is essential for many biological downstream analyses, but accurate alignment of large datasets, especially those exhibiting high rates of evolution or sequence length heterogeneity, is still unsolved. We present SALMA, a new multiple sequence alignment that provides high accuracy and scalability, even for datasets exhibiting high rates of evolution and great sequence length heterogeneity that arises from evolutionary processes. Like some prior methods (e.g., UPP, WITCH, and MAFFT-sparsecore), SALMA operates in two distinct stages: the first stage computes a “backbone alignment” for a subset of the sequences, and the second stage adds the remaining sequences into the backbone alignment. The main novelty in SALMA is how it adds the remaining (“query”) sequences into the backbone alignment. For this step, which we refer to as SALMA-add, we use divide-and-conquer to scale MAFFT-linsi--add to enable it to add sequences into large backbone alignments. We show that SALMA-add has an advantage over other sequence-adding techniques for many realistic conditions and can scale to very large datasets with high accuracy (hundreds of thousands of sequences). We also show that SALMA is one of the most accurate compared to standard alignment methods. Our open source software for SALMA is available at https://github.com/c5shen/SALMA.
Targeting Pulmonary Fibrosis by SLC1A5 dependent Glutamine Transport Blockade
Authors: Choudhury Malay , Schaefbauer Kyle J. , Kottom Theodore J. , Yi Eunhee S. , Tschumperlin Daniel J. , Limper Andrew H. 
Published: May 2022

AbstractThe neutral amino acid glutamine plays a central role in TGF-β-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5. In this current work, we demonstrated that profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from IPF lungs. The expression of profibrotic targets, cell migration, and anchorage independent growth by TGF-β required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy, suppressed mTOR, HIF, Myc signaling, and impaired mitochondrial function, ATP production and glycolysis. Pharmacological inhibition of SLC1A5 by small molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving, and attenuated fibrosis in a bleomycin treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, laying a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.
Clinical heterogeneity based on race and sex within a large cohort of inclusion body myositis patients
Authors: Michelle E. Harlan , Pinal-Fernandez Iago , Casal-Dominguez Maria , Albayda Jemima , Paik Julie J. , Tiniakou Eleni , Adler Brittany , Mecoli Christopher A. , Danoff Sonye K. , Christopher-Stine Lisa , Mammen Andrew L , Lloyd Thomas E. 
Published: May 2022

ABSTRACTBackground and ObjectivesSporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals over age 50. The disorder is slowly progressive and while many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM is limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort, as well as prognostic factors for disease progression.MethodsClinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003-2018. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in IBM patients.ResultsAmong the 335 IBM patients meeting inclusion criteria, 64% were male with an average age of disease onset of 58.7 years and a delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients but were less likely to develop dysphagia. Female patients had stronger finger flexors and knee extensors compared to their male counterparts but were more likely to develop dysphagia. A significant number (20%) of patients had an age of onset less than 50 years. This group of younger patients was weaker at their first visit; however, this may be accounted for by a longer disease duration at first visit.DiscussionAlthough IBM has long been considered a disorder predominately of older, White men, female, and non-White patients comprise a significant proportion of the IBM population. Our study demonstrates that female and Black patients have distinct clinical phenotypes within the overarching IBM clinical phenotype.
A central role of sibling sRNAs NgncR_162/163 in main metabolic pathways of Neisseria gonorrhoeae
Authors: Steiner Thomas , Zachary Marie , Bauer Susanne , Müller Martin J. , Krischke Markus , Radziej Sandra , Klepsch Maximilian , Huettel Bruno , Eisenreich Wolfgang , Rudel Thomas , Beier Dagmar 
Published: May 2022

SummaryBacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in very few cases has the role in metabolism been demonstrated. We performed here a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR_162 and NgncR_163 and their impact on the metabolism of the major human pathogen Neisseria gonorrhoeae. These sRNA have previously been shown to control genes of the citric acid and methylcitrate cycle by post-transcriptional negative regulation. By transcriptome analysis we expand the NgncR_162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR_162/163 targets are mostly involved in transport processes, especially the uptake of glycine, branched chain amino acids and phenylalanine. NgncR_162/163 also play key roles in the control of serine-glycine metabolism and hence probably affect biosynthesis of nucleotides, vitamins and other amino acids via the supply of C1-units. Metabolic flux analysis demonstrated a bipartite metabolism with glucose degradation providing intermediates for anabolic pathways, while energy metabolism via the citric acid cycle is mainly driven by amino acids, which feed into the cycle. Thus, by combined RNA-seq and metabolomics we significantly extended the regulon of NgncR_162/163 and demonstrate their role in the regulation of central metabolic pathways of the gonococcus.ImportanceNeisseria gonorrhoeae is a major human pathogen which infects more than 100 million people every year. An alarming development is the emergence of gonococcal strains resistant against virtually all of the antibiotics used for their treatment. Despite the medical importance and the vanishing treatment options of gonococcal infections, the bacterial metabolism and its regulation is only ill defined until today. We investigate here the regulation of the gonococcal metabolism by two previously studied sRNAs, NgncR_162/163 using RNA-seq and metabolomics. The results provided in this study demonstrate the regulation of transport processes and metabolic pathways involved in the biosynthesis of nucleotides, vitamins and amino acids by NgncR_162/163. Combined transcriptome and metabolome analyses provide a thus far unreached depth in the regulation of metabolic pathways by the neisserial sibling sRNAs and may therefore also be suitable for functional analysis of a growing number of other bacterial metabolic sRNA regulators.
The transcription regulator Lmo3 is required for cell fate specification in the external globus pallidus
Authors: Biswas Shiona , Chan C. Savio , Rubenstein John L.R. , Gan Lin 
Published: May 2022

ABSTRACTThe external globus pallidus (GPe) is an essential component of the basal ganglia, a group of subcortical nuclei that are involved in control of action. Changes in the firing of GPe neurons are associated with both passive and active body movements. Aberrant activity of GPe neurons has been linked to motor symptoms of a variety of movement disorders, such as Parkinson’s Disease, Huntington’s disease and dystonia. Recent studies have helped delineate functionally distinct sub types of GABAergic GPe projection neurons. However, little remains known about specific molecular mechanisms underlying the development of GPe neuronal subtypes. We show that the transcriptional regulator Lmo3 is required for the development of medial ganglionic eminence derived Nkx2.1+ and PV+ GPe neurons, but not FoxP2+ neurons or Npas1+ neurons. As a consequence of the reduction in PV+ neurons, Lmo3-null mice have a reduced pallidal input to the subthalamic nucleus.SIGNIFICANCE STATEMENTThe external globus pallidus (GPe) is a critical component of the basal ganglia and can coordinate neuronal activity across the basal ganglia by virtue of its widespread projections to almost all other basal ganglia nuclei. Aberrant activity of GPe neurons has been linked to motor symptoms of a wide variety of movement disorders. Recent advances have delineated functionally distinct sub types of GABAergic GPe projection neurons. However, little remains known about molecular mechanisms underlying their development. Here, we demonstrate that the transcription regulator Lmo3 is required for the development of specific subtypes of GPe neurons, and for their appropriate connectivity with other parts of the basal ganglia.