bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding Antibody-Target Antigen Interactions and the Avidity Effect Using Mathematical Modelling
Authors: Heirene Luke A. , Byrne Helen M. , Gaffney Eamonn A. , Yates James W. T. 
Published: May 2024

AbstractBackground and PurposeImmunotherapies are designed to exploit the immune system to target pathologies, for instance, but not exclusively, cancer. Monoclonal antibodies (mAbs) are an important class of immunotherapies that induce anti-tumour effects in numerous ways. Fundamental to the success of mAbs in cancer treatments are their interactions with target antigens. For example, binding multiple antigens, which increases binding affinity, termed the avidity effect, has been shown to impact treatment outcomes. However, there has been limited theoretical analysis addressing the impacts of antibody-antigen interactions on avidity, potency, and efficacy. Hence, our aim is to develop a mathematical model to develop insight on these impacts.Experimental ApproachWe analyse an ordinary differential equation model of bivalent, monospecific IgG antibodies binding to membrane bound antigens. We obtain equilibrium solutions of the model and conduct a global parameter sensitivity analysis to identify which antibody-antigen interactions impact quantities, such as antigen occupancy, that contribute to mAb potency and efficacy.Key ResultsWe show that the ratio of antibody to antigen number impacts antigen occupancy, bound antibody number and whether an antibody can bind both its antigen-binding arms. A sensitivity analysis reveals that antigen occupancy and the ratio of bound antibody to total antigen number are sensitive to the antibody-antigen binding rates only for high antibody concentrations. We identify parameter ranges in which the avidity effect is predicted to be large for antigen occupancy and bound antibody numbers.Conclusion and ImplicationsThese results could be used in the preclinical development of mAb therapies by predicting conditions which enhance mAb potency, efficacy, and the avidity effect.
Multiple Unfolded Protein Response pathways cooperate to link cytosolic dsDNA release to Stimulator of Interferon Gene (STING) activation
Authors: Hu Tiancheng , Liu Yiping , Fleck Jeremy , King Cason , Schalk Elaine , Zhang Zhenyu , Mehle Andrew , Smith Judith A 
Published: May 2024

AbstractThe double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to “sterile” endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-β expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-β induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-β, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-β mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-β via mitochondrial dsDNA release.
Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression
Authors: Tcyganov Evgenii N. , Kwak Taekyoung , Yang Xue , Poli Adi Narayana Reddy , Hart Colin , Bhuniya Avishek , Cassel Joel , Kossenkov Andrew , Auslander Noam , Lu Lily , Sharma Paridhima , Mendoza Maria De Grecia Cauti , Zhigarev Dmitry , Cadungog Mark Gregory , Jean Stephanie , Chatterjee-Paer Sudeshna , Weiner David , Donthireddy Laxminarasimha , Bristow Bryan , Zhang Rugang , Tyurin Vladimir A. , Tyurina Yulia Y. , Bayir Hülya , Kagan Valerian E. , Salvino Joseph M. , Montaner Luis J. 
Published: May 2024

AbstractOvarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor RbhighM2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape.Statement of significanceCurrently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.
Personalized transcriptome signatures in a cardiomyopathy stem cell biobank
Authors: Monte Emma , Furihata Takaaki , Wang Guangwen , Perea-Gil Isaac , Wei Eric , Chaib Hassan , Nair Ramesh , Guevara Julio Vicente , Mares Rene , Cheng Xun , Zhuge Yan , Black Katelyn , Serrano Ricardo , Dagan-Rosenfeld Orit , Maguire Peter , Mercola Mark , Karakikes Ioannis , Wu Joseph C. , Snyder Michael P. 
Published: May 2024

AbstractBACKGROUNDThere is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient’s genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines.METHODSWe recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility.RESULTSWe generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment.CONCLUSIONSWe have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role forADCY5in cardiomyopathy.
Tendon-associated gene expression precedes osteogenesis in mid-palatal suture establishment
Authors: Roth Daniela M. , Oliver Piña Jeremie , Raju Resmi , Iben James , Faucz Fabio R. , Makareeva Elena , Leikin Sergey , Graf Daniel , D’Souza Rena N. 
Published: May 2024

AbstractOrthodontic maxillary expansion relies on intrinsic mid-palatal suture mechanobiology to induce guided osteogenesis, yet establishment of the mid-palatal suture within the continuous secondary palate and causes of maxillary insufficiency remain poorly understood. In contrast, advances in cranial suture research hold promise to improve surgical repair of prematurely fused cranial sutures in craniosynostosis to potentially restore the obliterated signaling environment and ensure continual success of the intervention. We hypothesized that mid-palatal suture establishment is governed by shared principles with calvarial sutures and involves functional linkage between expanding primary ossification centres with the midline mesenchyme. We characterized establishment of the mid-palatal suture from late embryonic to early postnatal timepoints. Suture establishment was visualized using histological techniques and multimodal transcriptomics. We identified that mid-palatal suture formation depends on a spatiotemporally controlled signalling milieu in which tendon-associated genes play a significant role. We mapped relationships between extracellular matrix-encoding gene expression, tenocyte markers, and novel suture patency candidate genes. We identified similar expression patterns in FaceBase-deposited scRNA-seq datasets from cranial sutures. These findings demonstrate shared biological principles for suture establishment, providing further avenues for future development and understanding of maxillofacial interventions.
Natural selection and evolution of mitochondrial genome in terrestrial and aquatic turbellarians
Authors: Li Rong , Feng Hui , Cao Pinglin , Wang Jianxing 
Published: May 2024

AbstractMitochondrial energy metabolism may be directly influenced by natural selection pressures in response to the energy demands of an organism’s specific ecological niche. Here, we hypothesized that the mitochondrial genome of turbellarian animals was influenced by the metabolic requirements of various habitats We used selection pressure and phylogenetic independent contrasts (PIC) analyses to detect the selection pressure of protein-coding genes in the mitochondrial genome of turbellarian living in aquatic and terrestrial habitats. The results indicated turbellarians in aquatic habitats experienced greater selection pressure, resulting in the evolution of several genes at a lower ω value compared to their terrestrial counterparts. The NAD4 was identified as having positive selection sites in all site models analyzed. Among all genes, the equilibrium constant (ionization of COOH) was the most frequently detected amino acid characteristic with significant positive selection changes, followed by hydropathy and molecular volume. The equilibrium constant (ionization of COOH) was found to be the amino acid characteristic with the greatest magnitude of change in NAD4. This suggests that it plays a crucial role in the adaptive evolution of turbellarians to varying habitats. The study found a significant positive correlation (R = 0.61, p < 0.05) between the ω value of turbellarian and their habitats by PIC analysis. These findings shed light on the adaptive evolution of turbellarian mtDNAs and their influence on the oxidative phosphorylation molecular mechanism.0.Significance statementThe adaptive evolution of mitochondrial genes is closely related to environmental temperature, high energy metabolism demand, altitude, and oxygen availability. Mitochondrial energy metabolism may be directly influenced by natural selection pressures in response to the energy demands of an organism’s specific ecological niche. Here, we investigated the evolution of mtDNA PCGs in turbellarians across different habitats, and identified purifying selection as the main evolutionary pattern of the turbellarian mitochondrial genome. Additionally, we found that NAD4 played an important role in the adaptive evolution of turbellarians to different habitats.
N-acetylcysteine as a treatment for substance use cravings: A meta-analysis
Authors: Winterlind Emma L. , Malone Samantha G. , Setzer Michael R. , Murphy Mikela A. , Saunders David , Gray Joshua C. 
Published: May 2024

AbstractN-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC’s efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, andClinicalTrials.govwere conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger’s tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.
Data-driven neuroanatomical subtypes of primary progressive aphasia
Authors: Taylor Beatrice , Bocchetta Martina , Shand Cameron , Todd Emily G , Chokesuwattanaskul Anthipa , Crutch Sebastian J , Warren Jason D , Hardy Chris JD , Rohrer Jonathan D , Oxtoby Neil P 
Published: May 2024

AbstractThe primary progressive aphasias are rare, language-led dementias, with three main variants: semantic, non-fluent/agrammatic, and logopenic. Whilst semantic variant has a clear neuroanatomical profile, the non-fluent/agrammatic and logopenic variants are difficult to discriminate from neuroimaging. Previous phenotype-driven studies have characterised neuroanatomical profiles of each variant on MRI. In this work we used a machine learning algorithm known as SuStaIn to discover data-driven neuroanatomical “subtype” progression profiles and performed an in-depth subtype–phenotype analysis to characterise the heterogeneity of primary progressive aphasia.Our study included 270 participants with primary progressive aphasia seen for research in the UCL Queen Square Institute of Neurology Dementia Research Centre, with follow-up scans available for 137 participants. This dataset included individuals diagnosed with all three main variants (semantic: n=94, non-fluent/agrammatic: n=109, logopenic: n=51) as well as individuals with un-specified primary progressive aphasia (n=16). A data set of 66 patients (semantic n=37, non-fluent/agrammatic: n=29) from the ALLFTD North American cohort study, was used to validate our results. MRI scans were segmented and SuStaIn was employed on 19 regions of interest to identify neuroanatomical profiles independent of the diagnosis. We assessed the assignment of subtypes and stages, as well as their longitudinal consistency.We discovered four neuroanatomical subtypes of primary progressive aphasia, labelled S1, S2, S3, S4, exhibiting robustness to statistical scrutiny. S1 correlated strongly with semantic variant, while S2, S3, and S4 showed mixed associations with the logopenic and non-fluent/agrammatic variants. Notably, S3 displayed a neuroanatomical signature akin to a logopenic only signature, yet a significant proportion of logopenic cases were allocated to S2. The non-fluent/agrammatic variant demonstrated diverse associations with S2, S3, and S4. No clear relationship emerged between any of the neuroanatomical subtypes and the unspecified cases. At first follow up 84% of patients subtype assignment was stable, and 91.9% of patients stage assignment was stable. The ALLFTD dataset validated the findings.Our study, leveraging machine learning on a large primary progressive aphasia dataset, delineated four distinct neuroanatomical patterns. The identification of multiple profiles within the logopenic and non-fluent/agrammatic variants, alongside intra-phenotypic overlap, supports recent conceptualisations of primary progressive aphasia as a spectrum of disorders rather than discrete entities. Understanding the multifaceted profiles of the disease, encompassing neuroanatomical, molecular, clinical, and cognitive dimensions, holds potential implications for clinical decision support.
Persistent lung inflammation and alveolar-bronchiolization due to Notch signaling dysregulation in SARS-CoV-2 infected hamster
Authors: Li Can , Xiao Na , Song Wenchen , Lam Alvin Hiu-Chung , Liu Feifei , Cui Xinrui , Ye Zhanhong , Chen Yanxia , Ren Peidi , Cai Jianpiao , Lee Andrew Chak-Yiu , Chen Honglin , Ou Zhihua , Chan Jasper Fuk-Woo , Yuen Kwok-Yung , Chu Hin , Zhang Anna Jin-Xia 
Published: May 2024

AbstractLong COVID or Post-acute sequalae of COVID-19 (PASC) defines the persistent signs, symptoms, and conditions long after initial SARS-CoV-2 infection which affecting over 10% of COVID-19 patients, with 40% of them affecting respiratory system. The lung histopathological changes and underlying mechanism remain elusive. Here we systemically investigate histopathological and transcriptional changes at 7, 14, 42, 84 and 120 days-post-SARS-CoV-2-infection (dpi) in hamster. We demonstrate persistent viral residues, chronic inflammatory and fibrotic changes from 42dpi to 120dpi. The most prominent lung histopathological lesion is multifocal alveolar-bronchiolization observed in every animal from 14dpi until 120dpi. However, none of the above are observed in hamsters recovered from influenza A infection. We show airway progenitor CK14+ basal cells actively proliferate, differentiate into SCGB1A+ club cell or Tubulin+ ciliated cells, leading to alveolar-bronchiolization. Most importantly, Notch pathway is persistently upregulated. Intensive Notch3 and Hes1 protein expression are detected in alveolar-bronchiolization foci, suggesting the association of sustained Notch signaling with dysregulated lung regeneration. Lung spatial transcriptomics show upregulation of genes positively regulating Notch signaling is spatially overlapping with alveolar-bronchiolization region. To be noted, significant upregulation of tumor-related genes was detected in abnormal bronchiolization region by spatial transcriptomics analysis, indicating possible risk of lung carcinoma. Collectively, our data suggests SARS-CoV-2 infection caused chronic inflammatory and fibrotic tissue damages in hamster lung, sustained upregulation of Notch pathway signaling contributed to the dysregulated lung regeneration and CK14+ basal cells-driven alveolar-bronchiolization. The study provides important information for potential therapeutic approaches and probable long-term surveillance of malignancy in PASC management.
Residues Neighboring an SH3-Binding Motif Participate in the InteractionIn Vivo
Authors: Jordan David F. , Dubé Alexandre K. , Dionne Ugo , Bradley David , Landry Christian R. 
Published: May 2024

AbstractIn signaling networks, protein-protein interactions are often mediated by modular domains that bind short linear motifs. The motifs’ sequences affect many factors, among them affinity and specificity, or the ability to bind strongly and to bind the appropriate partners. Using Deep Mutational Scanning to create a mutant library, and protein complementation assays to measure protein-protein interactions, we determined thein vivobinding strength of a library of mutants of a binding motif on the MAP kinase kinase Pbs2, which binds the SH3 domain of the osmosensor protein Sho1 inSaccharomyces cerevisiae. These measurements were made using the full-length endogenous proteins, in their native cellular environment. We find that along with residues within the canonical motif, many mutations in the residues neighboring the motif also modulate binding strength. Interestingly, all Pbs2 mutations which increase affinity are situated outside of the Pbs2 region that interacts with the canonical SH3 binding pocket, suggesting that other surfaces on Sho1 contribute to binding. We use predicted structures to hypothesize a model of binding which involves residues neighboring the canonical Pbs2 motif binding outside of the canonical SH3 binding pocket. We compared this predicted structure with known structures of SH3 domains binding peptides through residues outside of the motif, and put forth possible mechanisms through which Pbs2 can bind specifically to Sho1. We propose that for certain SH3 domain-motif pairs, affinity and specificity are determined by a broader range of sequences than what has previously been considered, potentially allowing easier differentiation between otherwise similar partners.SummaryProtein-protein interactions are often mediated by a binding domain on one protein and a short disordered binding motif on another protein. We measured the binding strength of a mutant library of a binding motif situated in the yeast protein Pbs2 to the SH3 domain of Sho1. Many mutations in the residues neighboring the binding motif affect binding. A protein structure prediction of the interaction partners shows that residues neighboring the motif bind residues outside the known binding pocket on the SH3 domain. The Sho1-Pbs2 interaction differs enough from other known SH3-motif pairs to allow specific binding.