bluuebunny/crossref_metadata_2025_split huggingface dataset:
mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations
Authors: Gasparski Alexander N. , Moissoglu Konstadinos , Pallikkuth Sandeep , Meydan Sezen , Guydosh Nicholas R. , Mili Stavroula 
Published: April 2023

SummaryNumerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that protein targeting can additionally be determined by mRNA location and translation rate, through modulating protein binding to specific interacting partners. Peripheral localization of theNET1mRNA and fast translation lead to higher cytosolic retention of the NET1 protein, through promoting its binding to the membrane-associated scaffold protein CASK. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting, through promoting binding to importins. This mRNA location-dependent mechanism is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. These results reveal that the location of protein synthesis and the rate of translation elongation act in coordination as a ‘partner-selection’ mechanism that robustly influences protein distribution and function.
Structurally-informed human interactome reveals proteome-wide perturbations by disease mutations
Authors: Xiong Dapeng , Qiu Yunguang , Zhao Junfei , Zhou Yadi , Lee Dongjin , Gupta Shobhita , Torres Mateo , Lu Weiqiang , Liang Siqi , Kang Jin Joo , Eng Charis , Loscalzo Joseph , Cheng Feixiong , Yu Haiyuan 
Published: April 2023

AbstractHuman genome sequencing studies have identified numerous loci associated with complex diseases. However, translating human genetic and genomic findings to disease pathobiology and therapeutic discovery remains a major challenge at multiscale interactome network levels. Here, we present a deep-learning-based ensemble framework, termed PIONEER (Protein-proteinInteractiOn iNtErfacEpRediction), that accurately predicts protein binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms, generating comprehensive structurally-informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods. We further systematically validated PIONEER predictions experimentally through generating 2,395 mutations and testing their impact on 6,754 mutation-interaction pairs, confirming the high quality and validity of PIONEER predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces after mapping mutations from ∼60,000 germline exomes and ∼36,000 somatic genomes. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from pan-cancer analysis of ∼11,000 tumor whole-exomes across 33 cancer types. We show that PIONEER-predicted oncoPPIs are significantly associated with patient survival and drug responses from both cancer cell lines and patient-derived xenograft mouse models. We identify a landscape of PPI-perturbing tumor alleles upon ubiquitination by E3 ligases, and we experimentally validate the tumorigenic KEAP1-NRF2 interface mutation p.Thr80Lys in non-small cell lung cancer. We show that PIONEER-predicted PPI-perturbing alleles alter protein abundance and correlates with drug responses and patient survival in colon and uterine cancers as demonstrated by proteogenomic data from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels.
Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus
Authors: A.B. Leithead , A. Godino , M. Barbier , H. Harony-Nicolas 
Published: April 2023

ABSTRACTBackgroundThe posterior intralaminar (PIL) complex of the thalamus is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed.MethodsWe used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real-time during social and non-social interactions. Finally, we used inhibitory DREADDs in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation.ResultsWe observed significantly morec-fos-positive cells in the PIL of mice exposed to social versus object or no stimuli. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time it took female mice to form social habituation.ConclusionsTogether these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.
Pathogenic Mutations in the C2A Domain of Dysferlin form Amyloid that Activates the Inflammasome
Authors: Scott Isaac L. , Dominguez Matthew J. , Snow Adam , Harsini Faraz M. , Williams Justin , Fuson Kerry L. , Thapa Roshan , Bhattacharjee Pushpak , Cornwall Gail A. , Keyel Peter A. , Sutton R. Bryan 
Published: April 2023

AbstractLimb-Girdle Muscular Dystrophy Type-2B/2R is caused by mutations in thedysferlingene (DYSF). This disease has two known pathogenic missense mutations that occur within dysferlin’s C2A domain, namely C2AW52Rand C2AV67D. Yet, the etiological rationale to explain the disease linkage for these two mutations is still unclear. In this study, we have presented evidence from biophysical, computational, and immunological experiments which suggest that these missense mutations interfere with dysferlin’s ability to repair cells. The failure of C2AW52Rand C2AV67Dto initiate membrane repair arises from their propensity to form stable amyloid. The misfolding of the C2A domain caused by either mutation exposes β-strands, which are predicted to nucleate classical amyloid structures. When dysferlin C2A amyloid is formed, it triggers the NLRP3 inflammasome, leading to the secretion of inflammatory cytokines, including IL-1β. The present study suggests that the muscle dysfunction and inflammation evident in Limb-Girdle Muscular Dystrophy types-2B/2R, specifically in cases involving C2AW52Rand C2AV67D, as well as other C2 domain mutations with considerable hydrophobic core involvement, may be attributed to this mechanism.
Discovery of microsized RNA-derived RNAs and proteins in human cells
Authors: Huang Xiaoqiang , Wu Haidong , Zhong Weilong , Li Wenbo , Liu Zhiyong , Zhao Min , Xi Xiaonan , Cao Bo , Pu Yong , Kong Xiangxu , Zhao Huan , Zhang Ronghua , Lai Keguan , Lv Xinze , Lv Yue , Bao Jingyu , Wang Meimei , Xiong Yanan , Dong Lijie , Zhang Jifeng , Zhang Guangling , Hu Yuanjing , Xu Jie , Chen Y. Eugene , Chen Shuang 
Published: April 2023

AbstractMicroRNAs (miRNAs) are a class of short noncoding RNAs that can regulate gene expression through the binding of their 5’-end to mRNA. However, the biological effects of miRNA’s 3’-end binding to mRNA remain unclear. Here we discover that the exact reverse pairing of the 3’-ends of miRNAs or miRNA-like RNAs, collectively referred to as microsized RNAs (msRNAs), with template RNAs could initiate the production of msRNA-derived RNAs (msdRs), which consequently translate into msRNA-derived proteins (msdPs). Starting with 2,632 human miRNAs or miRNA-like msRNAs taken from the miRBase database, we predicted 11,121 and 1,239 unique msdRs and msdPs respectively using a 15-nt pairing threshold. We verified the authentic presence of example msdRs and msdPs in human cells. Of clinical relevance, we demonstrated that msdP0188 is highly expressed in human lung and breast cancer tissues and cells, and its corresponding msdRs represent novel anti-cancer targets. Intriguingly, inhibiting the human telomerase reverse transcriptase, a putative RNA-dependent RNA polymerase suggested by bioinformatic screening, led to reduced levels of msdP0188 in human cells. Our findings propose a novel “msRNA → msdR → msdP” axis that not only represents an augmentation to the central dogma of molecular biology but also predicts thousands of previously unknown RNAs and proteins that may have significant biological and pathological roles in human cells as well as in other biological systems.One-Sentence SummaryThis work reports the discovery of msRNA-derived RNAs and proteins that may have significant roles in biology and medicine.
Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein Kinase 1
Authors: Harold Rachel L. , Tulsian Nikhil K. , Narasimamurthy Rajesh , Yaitanes Noelle , Ayala Hernandez Maria G. , Lee Hsiau-Wei , Crosby Priya , Tripathi Sarvind M. , Virshup David M. , Partch Carrie L. 
Published: April 2023

AbstractCasein kinase 1 δ (CK1δ) controls essential biological processes including circadian rhythms and Wnt signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C-termini (XCT), but with marked changes in potential phosphorylation sites. Here we test if the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and HDX-MS, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity bothin vitroand in cells and leads to changes in circadian period, similar to what is reportedin vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase.SignificanceSubtle control of kinase activity is critical to physiologic modulation of multiple physiological processes including circadian rhythms. CK1δ and the closely related CK1ε regulate circadian rhythms by phosphorylation of PER2, but how kinase activity itself is controlled is not clear. Building on the prior observation that two splice isoforms of CK1δ regulate the clock differently, we show that the difference maps to three phosphorylation sites in the variably spliced region (XCT) that cause feedback inhibition of the kinase domain. More broadly, the data suggest a general model where CK1 activity on diverse substrates can be controlled by signaling pathways that alter tail phosphorylation. These inhibitory phosphorylation sites could also be targets for new therapeutic interventions.
Differences in AD-related pathology profiles across APOE groups
Authors: Morrison Cassandra , Dadar Mahsa , Kamal Farooq , Collins D. Louis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2023

AbstractBACKGROUNDThe apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer’s disease (AD), while the e2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype and results are inconsistent for those with an e2 allele.METHODSWe analyzed Alzheimer’s Disease Neuroimaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load, ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV-45), and phosphorylated tau (pTau). Participants were divided into one of four APOE allele profiles (E4=e4e4 or e3e4; E2=e2e2 or e2e3; E3=e3e3; or E24=e2e4, Fig.1). Linear mixed models examined the relationship between APOE profiles and each pathology (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures). while controlling for age, sex, education, and diagnostic status at baseline and over time.RESULTSAPOE ε4 is associated with increased pathology while ε2 positivity is associated with reduced baseline and lower accumulation of pathologies and rates of neurodegeneration. APOE ε2ε4 is similar to ε4 (increased neurodegeneration) but with a slower rate of change.CONCLUSIONSThe strong associations observed between APOE and pathology in this study show the importance of how genetic factors influence structural brain changes. These findings suggest that ε2ε4 genotype is related to increased declines associated with the ε4 as opposed to the protective effects of the ε2. These findings have important implications for initiating treatments and interventions. Given that people who have the ε2ε4 genotype can expect to have increased atrophy, they must be included (alongside those with an ε4 profile) in targeted interventions to reduce brain changes that occur with AD.
TRANS-AORTIC VALVULAR FLOW DYNAMICS AND LEFT VENTRICULAR EJECTION FRACTION FOR MONITORING RECOVERY OF PATIENTS WITH LEFT VENTRICULAR SYSTOLIC HEART FAILURE
Authors: Vasudevan Viswajith S. , Rajagopal Keshava , Rame Jesus E. , Antaki James F. 
Published: April 2023

AbstractDurable mechanical circulatory support in the form of left ventricular (LV) assist device (LVAD) therapy is increasingly considered in the context of the recovery of native cardiac function. Progressive improvement in LV function may facilitate LVAD explantation and a resultant reduction in device-related risk. However, ascertaining LV recovery remains a challenge. In this study, we investigated the use of trans-aortic valvular flow rate and trans-LVAD flow rate to assess native LV systolic function using a well-established lumped parameter model of the mechanically assisted LV with pre-existing systolic dysfunction. Trans Aortic Valvular Ejection Fraction (TAVEF) was specifically found to characterize the preload-independent contractility of the LV. It demonstrated excellent sensitivity to simulated pharmacodynamic stress tests and volume infusion tests. TAVEF may prove to be useful in the ascertainment of LV recovery in LVAD-supported LVs with pre-existing LV systolic dysfunction.
VODKA2: A fast and accurate method to detect non-standard viral genomes from large RNA-seq datasets
Authors: Achouri Emna , Felt Sébastien A. , Hackbart Matthew , Rivera-Espinal Nicole S. , López Carolina B. 
Published: April 2023

ABSTRACTDuring viral replication, viruses carrying an RNA genome produce non-standard viral genomes (nsVGs), including copy-back viral genomes (cbVGs) and deletion viral genomes (delVGs), that play a crucial role in regulating viral replication and pathogenesis. Because of their critical roles in determining the outcome of RNA virus infections, the study of nsVGs has flourished in recent years exposing a need for bioinformatic tools that can accurately identify them within Next-Generation Sequencing data obtained from infected samples. Here, we present our data analysis pipeline, Viral Opensource DVG Key Algorithm2 (VODKA2), that is optimized to run on a High Performance Computing (HPC) environment for fast and accurate detection of nsVGs from large data sets.Availability and implementationVODKA2 is freely available at GitHub (https://github.com/lopezlab-washu/VODKA2)
Synaptopodin is necessary forShigella flexneriintercellular spread
Authors: Vickery Jenna M. , Toperzer Jody D. , Raab Julie E. , Lenz Laurel L. , Colgan Sean P. , Russo Brian C. 
Published: April 2023

AbstractFor many intracellular pathogens, their virulence depends on an ability to spread between cells of an epithelial layer. For intercellular spread to occur, these pathogens deform the plasma membrane into a protrusion structure that is engulfed by the neighboring cell. Although the polymerization of actin is essential for spread, how these pathogens manipulate the actin cytoskeleton in a manner that enables protrusion formation is still incompletely understood. Here, we identify the mammalian actin binding protein synaptopodin as required for efficient intercellular spread. Using a model cytosolic pathogen,Shigella flexneri, we show that synaptopodin contributes to organization of actin around bacteria and increases the length of the actin tail at the posterior pole of the bacteria. We show that synaptopodin presence enables protrusions to form and to resolve at a greater rate, indicating that greater stability of the actin tail enables the bacteria to push against the membrane with greater force. We demonstrate that synaptopodin recruitment around bacteria requires the bacterial protein IcsA, and we show that this recruitment is further enhanced in a type 3 secretion system dependent manner. These data establish synaptopodin as required for intracellular bacteria to reprogram the actin cytoskeleton in a manner that enables efficient protrusion formation and enhance our understanding of the cellular function of synaptopodin.Authors SummaryIntercellular spread is essential for many cytosolic dwelling pathogens during their infectious life cycle. Despite knowing the steps required for intercellular spread, relatively little is known about the host-pathogen interactions that enable these steps to occur. Here, we identify a requirement for the actin binding protein synaptopodin during intercellular spread by cytosolic bacteria. We show synaptopodin is necessary for the stability and recruitment of polymerized actin around bacteria. We also demonstrate synaptopodin is necessary to form plasma membrane structures known as protrusions that are necessary for the movement of these bacteria between cells. Thus, these findings implicate synaptopodin as an important actin-binding protein for the virulence of intracellular pathogens that require the actin cytoskeleton for their spread between cells.
Members of an array of zinc finger proteins specify distinctHoxchromatin boundaries
Authors: Ortabozkoyun Havva , Huang Pin-Yao , Gonzalez-Buendia Edgar , Cho Hyein , Kim Sang Y. , Tsirigos Aristotelis , Mazzoni Esteban O. , Reinberg Danny 
Published: April 2023

SUMMARYPartitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type specific gene expression patterns. While this partitioning is reconstructed during differentiation, the chromatin occupancy of the key insulator, CTCF, is unchanged at the developmentally importantHoxclusters. Thus, dynamic changes in chromatin boundaries must entail other activities. Given its requirement for chromatin loop formation, we examined cohesin-based chromatin occupancy without known insulators, CTCF and MAZ, and identified a family of zinc finger proteins (ZNFs), some of which exhibit tissue-specific expression. Two such ZNFs foster chromatin boundaries at theHoxclusters that are distinct from each other and from MAZ. PATZ1 was critical to the thoracolumbar boundary in differentiating motor neurons and mouse skeleton, while ZNF263 contributed to cervicothoracic boundaries. We propose that these insulating activities act with cohesin, alone or combinatorially, with or without CTCF, to implement precise positional identity and cell fate during development.
Environmental RNA as a non-invasive tool for assessing toxic effects in fish: a proof-of-concept study using Japanese medaka exposed to pyrene
Authors: Hiki Kyoshiro , Yamagishi Takahiro , Yamamoto Hiroshi 
Published: April 2023

ABSTRACTAlthough environmental RNA (eRNA) is emerging as a non-invasive tool to assess the health status of aquatic macro-organisms, the potential of eRNA remains largely untested. In this study, we investigated the ability of eRNA to detect changes in gene expression in Japanese medaka fish (Oryzias latipes) in response to sub-lethal pyrene exposure, as a model toxic chemical. We performed standardized acute toxicity tests and collected eRNA from tank water and RNA from fish tissue after 96 h of exposure. Our results showed that over 1000 genes were detected in eRNA and the sequenced read counts of these genes correlated with those in fish tissue (r= 0.50). Moreover, eRNA detected 86 differentially expressed genes in response to pyrene, some of which were shared by fish RNA, including suppression of collagen fiber genes. These results suggest that eRNA has the potential to detect changes in gene expression in fish in response to environmental stressors without the need for sacrificing or causing pain to fish. However, we also found that the majority of sequenced reads of eRNA (> 99%) were not mapped to the reference medaka genome and they originated from bacteria and fungi, resulting in low sequencing-depth. In addition, eRNA, in particular nuclear genes, was highly degraded with a median transcript integrity number (TIN) of < 20. These limitations highlight the need for future studies to improve the analytical methods of eRNA application.TOC Art
Human Attention during Goal-directed Reading Comprehension Relies on Task Optimization
Authors: Zou Jiajie , Zhang Yuran , Li Jialu , Tian Xing , Ding Nai 
Published: April 2023

AbstractThe computational principles underlying attention allocation in complex goal-directed tasks remain elusive. Goal-directed reading, i.e., reading a passage to answer a question in mind, is a common real-world task that strongly engages attention. Here, we investigate what computational models can explain attention distribution in this complex task. We show that the reading time on each word is predicted by the attention weights in transformer-based deep neural networks (DNNs) optimized to perform the same reading task. Eye-tracking further reveals that readers separately attend to basic text features and question-relevant information during first-pass reading and rereading, respectively. Similarly, text features and question relevance separately modulate attention weights in shallow and deep DNN layers. Furthermore, when readers scan a passage without a question in mind, their reading time is predicted by DNNs optimized for a word prediction task. Therefore, we offer a computational account of how task optimization modulates attention distribution during real-world reading.