bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of functional HLA class I groups with HIV viral load in a heterogeneous cohort
Authors: Zucco Adrian G. , Bennedbæk Marc , Ekenberg Christina , Gabrielaite Migle , Leung Preston , Polizzotto Mark N. , Kan Virginia , Murray Daniel D. , Lundgren Jens D. , Macpherson Cameron R. ,   the INSIGHT START study group
Published: June 2022

AbstractHuman Leucocyte Antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort from the Strategic Timing of AntiRetroviral Treatment (START) study. We imputed HLA class I alleles from host genetic data (2,546 HIV+ participants) and sampled immunopeptidomes from 2,079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL. We identified four clades totalling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B*57:01 and B*57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β −0.25; adj. p-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies. The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data.Abstract Figure
ERBB4Mutant Alleles Found inBRAFWT Melanomas That Drive the Proliferation of aBRAFWT Melanoma Cell Line
Authors: Lucas Lauren M. , Cullum Richard L. , Woggerman Joelle N. , Dwivedi Vipasha , Markham Jessica A. , Kelley Connor M. , Knerr Elizabeth L. , Cook Laura J. , Jacobi Megan A. , Taylor Darby C. , Rael Cristina C. , Lucas Howard C. , Waits Damien S. , Ghosh Taraswi M. , Halanych Kenneth M. , Gupta Ram B. , Riese David J. 
Published: June 2022

AbstractMetastatic skin cutaneous melanomas that contain wild-typeBRAFalleles (“BRAFWT melanomas”) remain a significant clinical challenge, primarily because of the paucity of targets for therapeutic intervention. In prior work,in silicoanalyses of The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) dataset suggested that elevated transcription of the gene that encodes the ERBB4 receptor tyrosine kinase may driveBRAFWT melanomas. Moreover, that prior work demonstrated that expression of the wild-type ERBB4 gene (WTERBB4) stimulates clonogenic proliferation by the IPC-298, MEL-JUSO, MeWo, and SK-MEL-2 humanBRAFWT melanoma cell lines. Moreover, expression of a dominant-negative (K751M)ERBB4mutant (ERBB4DN) inhibits clonogenic proliferation by these same cell lines.Here we have extended these findings by investigating the role ofERBB4mutant alleles inBRAFWT melanomas.In silicoanalyses of the TCGA-SKCMBRAFWT melanoma dataset indicates thatERBB4missense mutant alleles occur in a non-random manner, suggesting that melanomagenesis selects for theERBB4missense mutant alleles. Specifically,ERBB4missense mutant alleles affect amino acid residues that are weakly correlated with residues conserved in the ERBB3 extracellular domains and the EGFR tyrosine kinase domain. The occurrence ofERBB4missense mutant alleles in the TCGA-SKCMBRAFWT melanoma dataset is weakly inversely correlated with events that cause ERBB4-independent PI3K pathway signaling and is strongly correlated with events that cause elevated RAS pathway signaling. Thus, thein silicoanalyses suggest thatERBB4mutant alleles encode proteins that stimulate PI3K signaling, which cooperates with elevated RAS signaling to driveBRAFWT melanomas. Moreover, thein silicoanalyses have prioritized theERBB4mutant alleles as candidate drivers ofBRAFWT melanomas. TwoERBB4mutant alleles (G85S and G741E) found inBRAFWT melanomas stimulate clonogenic proliferation of MEL-JUSOBRAFWT melanoma cells. We discuss these findings in the context of strategies for identifying and treatingERBB4-dependentBRAFWT melanomas.
U.S. state-level COVID-19 transmission insights from a mechanistic mobility-incidence model
Authors: Thommes Edward W. , Mohammadi Zahra , Flynn-Primrose Darren , Smook Sarah , Gomez Gabriela , Chaves Sandra S. , Coudeville Laurent , Van Aalst Robertus , Mahé Cedric , Cojocaru Monica G. 
Published: June 2022

SummaryBackgroundThroughout the COVID-19 pandemic, human mobility has played a central role in shaping disease transmission. In this study, we develop a mechanistic model to calculate disease incidence from commercially-available US mobility data over the course of 2020. We use it to study, at the US state level, the lag between infection and case report. We examine the evolution of per-contact transmission probability, and its dependence on mean air temperature. Finally, we evaluate the potential of the model to produce short-term incidence forecasts from mobility data.MethodsWe develop a mechanistic model that relates COVID-19 incidence to time series contact index (CCI) data collected by mobility data vendor Cuebiq. From this, we perform maximum-likelihood estimates of the transmission probability per CCI event. Finally, we retrospectively conduct forecasts from multiple dates in 2020 forward.FindingsAcross US states, we find a median lag of 19 days between transmission and case report. We find that the median transmission probability from May onward was about 20% lower than it was during March and April. We find a moderate, statistically significant negative correlation between mean state temperature and transmission probability, r = − .57, N = 49, p = 2 × 10−5. We conclude that for short-range forecasting, CCI data would likely have performed best overall during the first few months of the pandemic.InterpretationOur results are consistent with associations between colder temperatures and stronger COVID-19 burden reported in previous studies, and suggest that changes in the per-contact transmission probability play an important role. Our model displays good potential as a short-range (2 to 3 week) forecasting tool during the early stages of a future pandemic, before non-pharmaceutical interventions (NPIs) that modify per-contact transmission probability, principally face masks, come into widespread use. Hence, future development should also incorporate time series data of NPI use.
Waterlogging stress induces antioxidant defense responses and aerenchyma formation and alters metabolisms of banana plants
Authors: Teoh Ee Yang , Teo Chee How , Baharum Nadiya Akmal , Pua Teen-Lee , Tan Boon Chin 
Published: June 2022

AbstractFlooding caused or exacerbated by climate change has threatened plant growth and food production worldwide. The lack of knowledge on how crops respond and adapt to flooding stress imposes a major barrier to enhancing their productivity. Hence, understanding the flooding-responsive mechanisms of crops is indispensable for developing new flooding-tolerant varieties. Here, we examined the banana (Musa acuminata cv. Berangan) responses to soil waterlogging for 1, 3, 5, 7, 14, and 24 days. After waterlogging stress, banana root samples were analyzed for their molecular and biochemical changes. We found that waterlogging treatment induced the formation of adventitious roots and aerenchyma with conspicuous gas spaces. In addition, the antioxidant activities, hydrogen peroxide and malondialdehyde contents of the waterlogged bananas increased in response to waterlogging stress. To assess the initial response of bananas toward waterlogging stress, we analyzed the transcriptome changes of banana roots. A total of 3,508 unigenes were differentially expressed under 1-day waterlogging conditions. These unigenes comprise abiotic stress-related transcription factors, such as ethylene response factors, basic helix-loop-helix, myeloblastosis, plant signal transduction, and carbohydrate metabolisms. The findings of the study provide insight into the complex molecular events of bananas in response to waterlogging stress, which could later help develop waterlogging resilient crops for the future climate.
Convergence of Ras- and Rac-regulated formin pathways is pivotal for phagosome formation and particle uptake in Dictyostelium
Authors: Körber Sarah , Junemann Alexander , Litschko Christof , Winterhoff Moritz , Faix Jan 
Published: June 2022

AbstractMacroendocytosis comprising phagocytosis and macropinocytosis are actin-driven processes regulated by small GTPases that depend on the dynamic reorganization of the membrane that protrudes and internalizes extracellular material by cup-shaped structures. To effectively capture, enwrap, and internalize their targets, these cups are arranged into a peripheral ring or ruffle of protruding actin sheets emerging from an actin-rich, non-protrusive zone at its base. Despite extensive knowledge of the mechanism driving actin assembly of the branched network at the protrusive cup edge, which is initiated by the actin-related protein (Arp) 2/3 complex downstream of Rac signaling, our understanding of actin assembly in the base is still incomplete. In the Dictyostelium model system, the Ras-regulated formin ForG was previously shown to specifically contribute to actin assembly at the cup base. Loss of ForG is associated with a strongly impaired macroendocytosis and a 50% reduction of F-actin content at the base of phagocytic cups, in turn indicating the presence of additional factors that specifically contribute to actin formation at the base. Here, we show that ForG synergizes with the Rac-regulated formin ForB to form the bulk of linear filaments at the cup base. Consistently, combined loss of both formins virtually abolishes cup formation and leads to severe defects of macroendocytosis, emphasizing the relevance of converging Ras- and Rac-regulated formin pathways in assembly of linear filaments in the cup base, which apparently provide mechanical support to the entire structure. Remarkably, we finally show that active ForB, unlike ForG, additionally drives phagosome rocketing to aid particle internalization.Significance StatementCup formation in macroendocytosis is a decisive, actin-dependent process that relies on distinct actin assembly factors generating the necessary mechanical forces to drive rearrangements of the plasma membrane and engulfment of extracellular material. Hitherto, in Dictyostelium the Arp2/3 complex and VASP were shown to promote actin assembly at the protrusive rim of phagocytic cups, while the Ras-regulated formin ForG generates about half of the actin filament mass at the base. Here, we show that ForG synergizes with the Rac-regulated formin ForB to form the bulk of filaments at the cup base. Loss of both formins virtually abolishes cup formation and leads to dramatic defects in macroendocytosis, illustrating the relevance of converging Ras- and Rac-regulated signaling pathways in this process.
Oxidative stress potentiates the therapeutic action of a mitochondrial complex I inhibitor in MYC-driven B-cell lymphoma
Authors: Donati Giulio , Nicoli Paola , Verrecchia Alessandro , Vallelonga Veronica , Croci Ottavio , Rodighiero Simona , Audano Matteo , Cassina Laura , Ghsein Aya , Binelli Giorgio , Boletta Alessandra , Mitro Nico , Amati Bruno 
Published: June 2022

ABSTRACTMYC is a key oncogenic driver and an adverse prognostic factor in multiple types of cancer, including diffuse large B-cell lymphoma (DLBCL). Yet, MYC activation also endows cancer cells with a series of metabolic dependencies, which can provide strategic points for targeted pharmacological intervention. We recently reported that targeting the mitochondrial electron transport chain (ETC) complex I with the small molecule inhibitor IACS-010759 selectively killed MYC-overexpressing lymphoid cells. Here, we unravel the mechanistic basis for this synthetic-lethal interaction and exploit it to improve the anti-tumoral effects of ETC inhibition. In a mouse B-cell line, MYC hyperactivation and IACS-010759 treatment added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced by targeted pharmacological intervention, with either inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to contribute pro-oxidant effects when administered at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, ETC inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and other MYC-driven cancers.Key point #1MYC and the ETC complex I inhibitor IACS-010759 elicit different reactive oxygen species (ROS) that cooperate to disrupt redox homeostasis.Key point #2Further boosting of oxidative stress with high doses of ascorbate increases the killing of MYC-driven lymphoma xenografts by IACS-010759.
Heads in the clouds: marine viruses disperse bidirectionally along the natural water cycle
Authors: Rahlff Janina , Esser Sarah P. , Plewka Julia , Heinrichs Mara Elena , Soares André , Scarchilli Claudio , Grigioni Paolo , Wex Heike , Giebel Helge-Ansgar , Probst Alexander J. 
Published: June 2022

AbstractMarine viruses have thoroughly been studied in seawater, yet their dispersal from neuston ecosystems at the air-sea interface towards the atmosphere remains a knowledge gap. Here, we show that 6.2 % of the studied virus population were shared between air-sea interface ecosystems and rainwater. Virus enrichment in the 1-mm thin surface microlayer and sea foams happened selectively, and variant analysis proved virus transfer to aerosols and rain. Viruses detected in rain and aerosols showed a significantly higher percent G/C base content compared to marine viruses, and a genetically distinct rain virome supports that those viruses could inhabit higher air masses. CRISPR spacer matches of marine prokaryotes to “foreign” viruses from rainwater prove regular virus-host encounters at the air-sea interface. Our findings on aerosolization and long-range atmospheric dispersal implicate virus-mediated carbon turnover in remote areas, viral dispersal mechanisms relevant to human health, and involvement of viruses in atmospheric processes like ice-nucleation.
Dopamine in the Dorsal Bed Nucleus of Stria Terminalis signals Pavlovian sign-tracking and reward violations
Authors: Gyawali Utsav , Martin David A. , Sun Fangmiao , Li Yulong , Calu Donna J. 
Published: June 2022

AbstractMidbrain and striatal dopamine signals have been extremely well characterized over the past several decades, yet novel dopamine signals and functions in reward learning and motivation continue to emerge. A similar characterization of real-time sub-second dopamine signals in areas outside of the striatum has been limited. Recent advances in fluorescent sensor technology and fiber photometry permit measurement of dopamine binding correlates, which can divulge basic functions of dopamine signaling in non-striatal dopamine terminal regions, like the dorsal bed nucleus of the stria terminalis (dBNST). Here, we record GRABDAsignals in the dBNST during a Pavlovian lever autoshaping task. We observe greater Pavlovian cue-evoked dBNST GRABDAsignals in sign-tracking (ST) compared to goal-tracking/intermediate (GT/INT) rats and the magnitude of cue-evoked dBNST GRABDAsignals decrease immediately following reinforcer-specific satiety. When we deliver unexpected reward or omit expected reward, we find that dBNST dopamine signals encode bidirectional reward prediction errors in GT/INT rats, but only positive prediction errors in ST rats. Since sign- and goal-tracking approach strategies are associated with distinct drug relapse vulnerabilities, we examined the effects of experimenter-administered fentanyl on dBNST dopamine associative encoding. Systemic fentanyl injections do not disrupt dBNST cue discrimination but generally potentiate dBNST dopamine signals. These results reveal multiple dBNST dopamine correlates of learning and motivation that depend on the Pavlovian approach strategy employed.
OrganelX Web Server for Sub-Peroxisomal and Sub-Mitochondrial protein localisation
Authors: Anteghini Marco , Haja Asmaa , Martins dos Santos Vitor AP , Schomaker Lambert , Saccenti Edoardo 
Published: June 2022

AbstractComputational approaches for sub-organelle protein localisation and identification are often neglected while general methods, not suitable for specific use cases, are promoted instead. In particular, organelle-specific research lacks user-friendly and easily accessible computational tools that allow researchers to perform computational analysis before starting time-consuming and expensive wet-lab experiments. We present the Organelx e-Science Web Server which hosts three sequence localisation predictive algorithms: In-Pero and In-Mito for classifying sub-peroxisomal and sub-mitochondrial protein localisations given their FASTA sequences, as well as the Is-PTS1 algorithm for detecting and validating potential peroxisomal proteins carrying a PTS1 signal. These tools can be used for a fast and accurate screening while looking for new peroxisomal and mitochondrial proteins. To our knowledge, this is the only service that provides these functionalities and can fasten the daily research of the peroxisomal science community.
Differential roles of delta and theta oscillations in understanding semantic gist during natural audiovisual speech perception: Functional and anatomical evidence
Authors: Park Hyojin , Ince Robin A. A. , Gross Joachim 
Published: June 2022

AbstractUnderstanding the main topic of naturalistic speech in a multi-speaker environment is demanding though the availability of visual speech can be beneficial for speech comprehension. Recent studies provided evidence that low-frequency brain rhythms play an important role in the processing of acoustic speech features. However, at present, the neural dynamics of brain rhythms implementing a higher-order semantic system during naturalistic audiovisual speech perception is unknown. Here we investigated information processing carried by low-frequency oscillations in delta and theta bands for audiovisual speech integration for high-level semantic gist processing using a representational interaction approach. By manipulating the degree of high-level semantic content (speech chunks with high versus low topic probability) using Latent Dirichlet Allocation (LDA) topic modelling algorithm and complexity of speaker environment (single versus multi-speaker), we first found that delta and theta phase exert distinctive roles in high-level semantic processing where delta phase represents auditory and visual inputs synergistically whereas theta band does so redundantly. Next, we show both forms of representational interaction are observed to be greater for speech with low semantic gist, supported by speech comprehension and white matter tractography. Furthermore, we show that the delta phase-specific synergistic interaction in the right auditory, temporal, and inferior frontal areas is sensitive to the speaker environment, whereas theta band activity showing redundant representations is sensitive to semantic content. Our results shed new light on dynamic neural mechanisms of implementing higher-order semantic systems through representational interactions between audiovisual speech information and differential roles of delta and theta bands depending on the speaker environment.
Arginine methylation of Puf4 drives diverse protein functions
Authors: Kalem Murat C. , Duffy Sean , Shen Shichen , Kaur Jan Naseer , Qu Jun , Panepinto John C. 
Published: June 2022

SummaryThe evolutionarily conserved Pumilio domain-containing RNA binding proteins (RBPs) are involved in many steps of post-transcriptional gene regulation, including RNA stability, polyadenylation, deadenylation, and translation. RBPs are post-translationally modified by methylation of arginine/glycine-rich domains, though the consequences of these modifications are not well known. We determined the arginine methylation and phosphorylation landscape of the Pumilio domain-containing RBP Puf4 from the basidiomycete fungus Cryptococcus neoformans. We found that methyl-deficient Puf4 mutants do not complement critical PUF4 deletion phenotypes, such as resistances to endoplasmic reticulum stress and antifungals, and cell wall remodeling. Methyl-deficient mutants also exhibit unique RNA and protein interactions. Lastly, we identified intra-protein cross talk between post-translationally modified methylated and phosphorylated residues. Overall, we show that post-translational modifications, particularly arginine methylation, of Puf4 regulate the functions of this RBP.
VPS13A and VPS13C influence lipid droplet abundance
Authors: Chen Shuliang , Roberts Melissa A. , Chen Chun-Yuan , Markmiller Sebastian , Wei Hong-Guang , Yeo Gene W. , Granneman James G , Olzmann James A. , Ferro-Novick Susan 
Published: June 2022

ABSTRACTLipid transfer proteins mediate the exchange of lipids between closely apposed membranes at organelle contact sites and play key roles in lipid metabolism, membrane homeostasis, and cellular signaling. A recently discovered novel family of lipid transfer proteins, which includes the VPS13 proteins (VPS13A-D), adopt a rod-like bridge conformation with an extended hydrophobic groove that enables the bulk transfer of membrane lipids for membrane growth. Loss of function mutations in VPS13A and VPS13C cause chorea acanthocytosis and Parkinson’s disease, respectively. VPS13A and VPS13C localize to multiple organelle contact sites, including endoplasmic reticulum (ER) – lipid droplet (LD) contact sites, but the functional roles of these proteins in LD regulation remains mostly unexplored. Here, we employ CRISPR-Cas9 genome editing to generate VPS13A and VPS13C knockout cell lines in U-2 OS cells via deletion of exon 2 and introduction of an early frameshift. Analysis of LD content in these cell lines revealed that loss of either VPS13A or VPS13C results in reduced LD abundance under oleate-stimulated conditions. These data implicate VPS13A and VPS13C in LD regulation and raise the intriguing possibility that VPS13A and VPS13C-mediated lipid transfer facilitates LD biogenesis.