bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Inter-Subject Alignment of the Lumbosacral Cord for Group-Level In Vivo Gray and White Matter Assessments: A Scan-Rescan MRI Study at 3T
Authors: Büeler Silvan , Freund Patrick , Kessler Thomas M. , Liechti Martina D. , David Gergely 
Published: October 2023

AbstractIntroductionMagnetic resonance imaging (MRI) enables the investigation of pathological changes in gray and white matter at the lumbosacral enlargement (LSE) and conus medullaris (CM). However, conducting group-level analyses of MRI metrics in the lumbosacral spinal cord is challenging due to variability in CM size, lack of established image-based landmarks, and unknown scan-rescan reliability. This study aimed to improve inter-subject alignment of the lumbosacral cord to facilitate group-level analyses of MRI metrics. Additionally, we evaluated the scan-rescan reliability of MRI-based cross-sectional area (CSA) measurements and diffusion tensor imaging (DTI) metrics.MethodsFifteen participants (10 healthy volunteers and 5 patients with spinal cord injury) underwent axial T2*-weighted and diffusion MRI at 3T. We assessed (i) the reliability of spinal cord and gray matter based landmarks for consistent inter-subject alignment of the lumbosacral cord, (ii) the inter-subject variability of MRI metrics before and after adjusting for the CM length, (iii) the intra- and inter-rater reliability of CSA measurements, and (iv) the scan-rescan reliability of CSA measurements and DTI metrics.ResultsThe slice with the largest gray matter CSA as an LSE landmark exhibited the highest reliability, both within and across raters. Adjusting for the CM length greatly reduced the inter-subject variability of MRI metrics. The intra-rater, inter-rater, and scan-rescan reliability of MRI metrics were the highest at and around the LSE (scan-rescan coefficient of variation <3% for CSA measurements and <7% for DTI metrics within the white matter) and decreased considerably caudal to it.ConclusionTo facilitate group-level analysis of corresponding spinal cord levels, we recommend using the slice with the largest gray matter CSA as a reliable LSE landmark, along with an adjustment for the CM length. We also stress the significance of the anatomical location within the lumbosacral cord in relation to the reliability of MRI metrics. The scan-rescan reliability values serve as valuable guides for power and sample size calculations in future longitudinal studies.
Multivariate Age-related Analysis of Variance in quantitative MRI maps: Widespread age-related differences revisited
Authors: Moallemian Soodeh , Bastin Christine , Callaghan Martina F. , Phillips Christophe 
Published: October 2023

AbstractThis study utilized multivariate ANOVA analysis to investigate age-related microstructural changes in the brain tissues driven primarily by myelin, iron, and water content. Voxel-wise analyses were performed on gray matter (GM) and white matter (WM), in addition to region of interest (ROI) analyses. The multivariate approach identified brain regions showing coordinated alterations in multiple tissue properties and demonstrated bidirectional correlations between age and all examined modalities in various brain regions, including the caudate nucleus, putamen, insula, cerebellum, lingual gyri, hippocampus, and olfactory bulb. The multivariate model was more sensitive than univariate analyses as evidenced by detecting a larger number of significant voxels within clusters in the supplementary motor area, frontal cortex, hippocampus, amygdala, occipital cortex, and cerebellum bilaterally. The examination of normalized, smoothed, and z-transformed maps within the ROIs revealed age-dependent differences in myelin, iron, and water content. These findings contribute to our understanding of age-related brain differences and provide insights into the underlying mechanisms of aging. The study emphasizes the importance of multivariate analysis for detecting subtle microstructural changes associated with aging that may motivate interventions to mitigate cognitive decline in older adults.
ER procollagen storage defect without coupled unfolded protein response drives precocious arthritis
Authors: Yammine Kathryn M. , Abularach Sophia Mirda , Kim Seo-yeon , Bikovtseva Agata A. , Lilianty Jinia , Butty Vincent L. , Schiavoni Richard P. , Bateman John F. , Lamandé Shireen R. , Shoulders Matthew D. 
Published: October 2023

AbstractCollagenopathies are a group of clinically diverse disorders caused by defects in collagen folding and secretion. For example, mutations in the gene encoding collagen type-II, the primary collagen in cartilage, can lead to diverse chondrodysplasias. One example is the Gly1170Ser substitution in procollagen-II, which causes precocious osteoarthritis. Here, we biochemically and mechanistically characterize an induced pluripotent stem cell-based cartilage model of this disease, including both hetero- and homozygous genotypes. We show that Gly1170Ser procollagen-II is notably slow to fold and secrete. Instead, procollagen-II accumulates intracellularly, consistent with an endoplasmic reticulum (ER) storage disorder. Owing to unique features of the collagen triple helix, this accumulation is not recognized by the unfolded protein response. Gly1170Ser procollagen-II interacts to a greater extent than wild-type with specific proteostasis network components, consistent with its slow folding. These findings provide mechanistic elucidation into the etiology of this disease. Moreover, the cartilage model will enable rapid testing of therapeutic strategies to restore proteostasis in the collagenopathies.
HDL regulates TGFß-receptor lipid raft partitioning, restoring contractile features of cholesterol-loaded vascular smooth muscle cells
Authors: Thevkar Nagesh Prashanth , Nishi Hitoo , Rawal Shruti , Zahr Tarik , Miano Joseph M. , Sorci-Thomas Mary , Xu Hao , Akbar Naveed , Choudhury Robin P , Misra Ashish , Fisher Edward A 
Published: October 2023

AbstractBackgroundCholesterol-loading of mouse aortic vascular smooth muscle cells (mVSMCs) downregulatesmiR-143/145, a master regulator of the contractile state downstream of TGFβ signaling.In vitro,this results in transitioning from a contractile mVSMC to a macrophage-like state. This process likely occursin vivobased on studies in mouse and human atherosclerotic plaques.ObjectivesTo test whether cholesterol-loading reduces VSMC TGFβ signaling and if cholesterol efflux will restore signaling and the contractile statein vitroandin vivo.MethodsHuman coronary artery (h)VSMCs were cholesterol-loaded, then treated with HDL (to promote cholesterol efflux). Forin vivostudies, partial conditional deletion ofTgfβr2in lineage-traced VSMC mice was induced. Mice wild-type for VSMCTgfβr2or partially deficient (Tgfβr2+/-) were made hypercholesterolemic to establish atherosclerosis. Mice were then treated with apoA1 (which forms HDL).ResultsCholesterol-loading of hVSMCs downregulated TGFβ signaling and contractile gene expression; macrophage markers were induced. TGFβ signaling positively regulatedmiR-143/145expression, increasingActa2expression and suppressing KLF4. Cholesterol-loading localized TGFβ receptors into lipid rafts, with consequent TGFβ signaling downregulation. Notably, in cholesterol-loaded hVSMCs HDL particles displaced receptors from lipid rafts and increased TGFβ signaling, resulting in enhancedmiR-145expression and decreased KLF4-dependent macrophage features. ApoA1 infusion intoTgfβr2+/-mice restoredActa2expression and decreased macrophage-marker expression in plaque VSMCs, with evidence of increased TGFβ signaling.ConclusionsCholesterol suppresses TGFβ signaling and the contractile state in hVSMC through partitioning of TGFβ receptors into lipid rafts. These changes can be reversed by promotion of cholesterol efflux, consistent with evidencein vivo.Condensed abstractMany cells identified as macrophage-like in human and mouse atherosclerotic plaques are thought to be of VSMC origin. We identified cholesterol-mediated downregulation of TGFβ signalingin vitroin human (h)VSMCs by localization of TGFβ receptors in membrane lipid rafts, which was reversed by HDL-mediated cholesterol efflux. This restored VSMC contractile marker (Acta2) and suppressed macrophage marker (CD68) expression by promoting TGFβ enhancement ofmiR-145expression.In vivo, administration of apoA1 (which forms HDL) to atherosclerotic mice also promoted VSMCActa2expression and reduced CD68 expression. Because macrophage-like VSMC are thought to have adverse properties, our studies not only show mechanistically how cholesterol causes their transition, but also suggest that efflux-competent HDL particles may have a therapeutic role by restoring a more favorable phenotypic state of VSMC in atherosclerotic plaques.
3D Bioprinting Using Poly(ethylene-glycol)-dimethacrylate (PEGDMA) Composite
Authors: Chang Shu-Yung , Lee Joseph Zhi Wei , Ranganath Anupama Sargur , Ching Terry , Hashimoto Michinao 
Published: October 2023

AbstractRecent progress in additive manufacturing has enabled rapid printing of bioinspired structures such as vasculature and alveoli using stereolithography (SLA) bioprinting. Bioinks for SLA often require synthetic polymers as additives to ensure the structural integrity of the printed cell-laden constructs. To this end, high molecular weight (MW) poly(ethylene-glycol)- diacrylate (PEGDA) (MW = 3400) is commonly used to enhance the mechanical property of crosslinked hydrogels, which requires in-house polymer synthesis or the acquisition of costly reagents. This research investigated the use of poly(ethylene-glycol)-dimethacrylate (PEGDMA) (MW = 1000) as a component of a composite bioink to enhance the mechanical properties of the SLA-printed constructs. We successfully demonstrated the fabrication of three-dimensional (3D) constructs with overhang and complex architecture, while human colorectal cancer cells (Caco-2) embedded in the crosslinked bioink exhibited the capability to proliferate on Day 6 ofin vitrocell culture. Our study suggested PEGDMA as a viable alternative to high MW PEGDA used in SLA bioprinting. The accessibility to PEGDMA will facilitate the advance in 3D bioprinting to fabricate complex bioinspired structures and tissue surrogates for biomedical applications.Article HighlightsPoly(ethylene-glycol)-dimethacrylate (PEGDMA) can be used in cell-laden bioprinting to enhance the mechanical property of bioinks.PEGDMA-based bioink was non-cytotoxic and conducive to cell proliferation.The facile preparation of PEGDMA composite ink will help to accelerate the research in tissue engineering via bioprinting.
Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer
Authors: Ravenscroft Benjamin , Yolmo Priyanka , Chenard Stephen , Rahimi Sadaf , Pace Keiran , Sachdeva Kartik , Jamaspishvilli Tamara , Ghaedi Hamid , Garven Andrew , Tyryshkin Kathrin , Berman David M. , Jackson Chelsea , Robert D. Siemens , Koti Madhuri 
Published: October 2023

AbstractNon-muscle invasive bladder cancer (NMIBC) constitutes a significant clinical challenge, with over 50% of patients experiencing poor clinical outcomes in the form of early recurrence or progression following treatment with Bacillus Calmette-Guerin (BCG) immunotherapy. The pre-treatment tumor immune microenvironment (TIME) is an established determinant of response to BCG. This study explores the spatial profiles of CD79a+ B cells, CD163+ M2-like macrophages, proliferating and tissue-resident phenotypes of T cells, along with PD-1/PD-L1 checkpoint expression in pre-BCG treatment tumors of 173 patients (139 males, 34 females). Multiplex immunofluorescence staining of a tumor tissue microarray, revealed elevated infiltration of CD79a+ B cells, CD163+ M2-like macrophages, CD103+ cells, and CD8+ T cells at the tumor invasive margins. Increased epithelial PD-L1 immune-checkpoint expression in tumors was observed in female and male patients who exhibited significantly shorter recurrence-free survival (RFS). Importantly, high CD79a+ B cell density in BCG-treated females in both stromal and epithelial compartments exhibited significantly shorter RFS and progression-free survival compared to males. Stromal CD79a+ B cell density was positively correlated with M2-like macrophages, CD8+ T cells, CD103+ cells and PD-1 expressing cells. CD79a+ B cells, CD103+ cells, and M2-like macrophage density were associated with higher grade and enriched in basal subtype tumor. This study highlights the significance of an understudied role of B cells and their cellular neighborhoods in the pre-treatment TIME and BCG-therapy response. Overall, findings from this study underscore the importance of considering sex-related immunobiological differences in the stromal compartments of bladder tumors towards the development of optimal therapeutic targeting strategies.
Evolution of microRNAs in Amoebozoa and implications for the origin of multicellularity
Authors: Edelbroek Bart , Kjellin Jonas , Biryukova Inna , Liao Zhen , Lundberg Torgny , Noegel Angelika A. , Eichinger Ludwig , Friedländer Marc R. , Söderbom Fredrik 
Published: October 2023

AbstractMicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression in both plants and animals. They are thought to have evolved convergently in these lineages and hypothesized to have played a role in the evolution of multicellularity. In line with this hypothesis, miRNAs have so far only been described in few unicellular eukaryotes. Here, we investigate the presence and evolution of miRNAs in Amoebozoa, focusing on species belonging toAcanthamoeba,Physarum, and dictyostelid taxonomic groups, representing a range of unicellular and multicellular lifestyles. miRNAs that adhere to both the stringent plant and animal miRNA criteria were identified in all examined amoebae, greatly expanding the total number of protists harbouring miRNAs. We found conserved miRNAs between closely related species, but the majority of species feature only unique miRNAs. Our results show that miRNAs are rapidly lost and gained in Amoebozoa, and that miRNAs were not required for transition from uni- to multicellular life.
Growth inhibitory factor/metallothionein-3 is a sulfane sulfur-binding protein
Authors: Shinkai Yasuhiro , Ding Yunjie , Matsui Toru , Devitt George , Akiyama Masahiro , Shen Tang-Long , Nishida Motohiro , Ida Tomoaki , Akaike Takaaki , Mahajan Sumeet , Fukuto Jon M. , Shigeta Yasuteru , Kumagai Yoshito 
Published: October 2023

AbstractCysteine-bound sulfane sulfur atoms in proteins have received much attention as key factors in cellular redox homeostasis. However, the role of sulfane sulfur in zinc regulation has been underinvestigated. We report here that cysteine-bound sulfane sulfur atoms serve as ligands to hold and release zinc ions in growth inhibitory factor (GIF)/metallothionein-3 (MT-3) with an unexpected C– S–S–Zn structure. Oxidation of such a zinc/persulfide cluster in Zn7GIF/MT-3 results in the release of zinc ions, and intramolecular tetrasulfide bridges in apo-GIF/MT-3 efficiently undergo S–S bond cleavage by thioredoxin to regenerate Zn7GIF/MT-3. Three-dimensional molecular modeling confirmed the critical role of the persulfide group in the thermostability and Zn-binding affinity of GIF/MT-3. The present discovery raises the fascinating possibility that the function of other Zn-binding proteins is controlled by sulfane sulfur.
An Antibiotic Degrading Engineered Living Material Platform to Combat Environmental Antibiotic Resistance
Authors: Özkul Gökçe , Kehribar Ebru Şahin , Şeker Urartu Özgür Şafak 
Published: October 2023

ABSTRACTPresence of antibiotics in natural water bodies is a growing problem regarding the occurrence of antibiotic resistance among various species. This is mainly caused due to excessive use of medical and veterinary antibiotics as well as the lack of effective treatment processes for eliminating residual antibiotic from wastewaters. In this study, we introduce a genetically engineered biomaterial as a solution for effective degradation of one of the dominantly found antibiotics in natural water bodies. Our biomaterial harnesses laccase type enzymes which are known to attack specific type of antibiotics, i.e. fluoroquinolone type synthetic antibiotics, and as a result degradation occurs. The engineered biomaterial is built usingEscherichia colibiofilm protein CsgA as a scaffold, which is fused separately to two different laccase enzymes with the SpyTag – SpyCatcher peptide-protein duo. The final material is implemented as a part of a living material system. Our proposed system can be integrated as living antibiotic degrading materials to help the combat with antibiotic resistance.
FAKHRAVAC and BBIBP-CorV vaccine seeds’ binding to angiotensin-converting enzyme 2: A comparative molecular dynamics study
Authors: Setareh Soroush , Rad Iman , Meghdadi Jafar , Khodayari Kaveh , Karimi Rahjerdi Ahmad 
Published: October 2023

AbstractBackgroundSafety and efficacy of the SARS-CoV-2 inactivated vaccines have been question since the emergence of SARS-CoV-2 variants of concern (VOCs). Using residue fluctuations and statistically comparing RMSF values, have escalated the understanding of the binding dynamics of the viral proteins to their receptors and here in this study, we compared the interaction between inactivated spike proteins (representing FAKHRAVAC and BBIBP-CorV vaccines seed) and the human Angiotensin-Converting Enzyme 2 (hACE2) receptor.MethodologyThrough 100 set of accelerated 1 ns comparative molecular dynamics simulations, we analyze the binding dynamics and energy components of these interactions and compared residue backbone fluctuations using entropy and statistics including KL-Divergence and KS-test.Principal FindingsOur results reveal that FAKHRAVAC and Sinopharm exhibit similar binding dynamics and affinity to hACE2. Further examination of residue-wise fluctuations highlights the common behavior of binding key residues and mutation sites between the two vaccines. However, subtle differences in residue fluctuations, especially at critical sites like Q24, Y435, L455, S477, Y505, and F486, raise the possibility of distinct efficacy profiles.ConclusionThese variations may influence vaccine immunogenicity and safety in response to evolving SARS-CoV-2 variants. The study underscores the importance of considering residue-wise fluctuations for understanding vaccine-pathogen interactions and their implications for vaccine design.Author summaryIt is fundamentally important to ensure the safety and efficacy of the FAKHRAVAC, as an inactivated vaccine candidate for SARS-CoV-2. Considering the previously published pre-clinical and clinical findings about the similarity of the FAKHRAVAC’s safety and efficacy in comparison to the BBIBP-CorV vaccine seed (which is recalled as Sinopharm), it is necessary to gain more insights into structure and function of this vaccine at the molecular level, as well. Since the binding dynamics of the viral proteins to their receptor can imply the vaccine’s immunogenicity and mechanism-of-action, binding dynamics of a vaccine candidate must be studied comprehensively. Hereby, we have compared binding dynamics of the FAKHRAVAC and Sinopharm vaccine seeds to the SARS-CoV-2 spike protein’s receptor, the ACE2. We took advantage of a comparative molecular dynamics simulation approach to effectively compare binding dynamics using atom fluctuations and at the residue level to ensure the resolution of this study. We have found similar binding dynamics and binding mechanics between these two vaccines, validating the pre-clinical and clinical findings computationally, as well as highlighting residues with different fluctuations and discussed their potential roles.
Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling
Authors: Soya Naoto , Xu Haijin , Roldan Ariel , Yang Zhengrong , Ye Haoxin , Jiang Fan , Premchandar Aiswarya , Veit Guido , Cole Susan P.C. , Kappes John , Hegedus Tamas , Lukacs Gergely L. 
Published: October 2023

AbstractThe folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. The ABCC transporters core consists of two nucleotide binding domains (NBD1,2) and transmembrane domains (TMD1,2). Using molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization of NBD1-TMD1/2 interfaces can compromise or facilitate the CFTR(ABCC7)-, MRP1(ABCC1)-, and ABCC6-transporters posttranslational coupled domain-folding in the endoplasmic reticulum. Allosteric or orthosteric binding of VX-809 and/or VX-445 folding correctors to TMD1/2 can rescue kinetically trapped CFTR post-translational folding intermediates of cystic fibrosis (CF) mutants of NBD1 or TMD1 by global rewiring inter-domain allosteric-networks. We propose that dynamic allosteric domain-domain communications not only regulate ABCC-transporters function but are indispensable to tune the folding landscape of their post-translational intermediates. These allosteric networks can be compromised by CF-mutations, and reinstated by correctors, offering a framework for mechanistic understanding of ABCC-transporters (mis)folding.One-Sentence SummaryAllosteric interdomain communication and its modulation are critical determinants of ABCC-transporters post-translational conformational biogenesis, misfolding, and pharmacological rescue.
CENP-E initiates chromosome congression by opposing Aurora kinases to promote end-on attachments
Authors: Vukušić Kruno , Tolić Iva M. 
Published: October 2023

ABSTRACTChromosome congression to the spindle equator is crucial for accurate cell division. The kinetochore motor protein CENP-E/kinesin-7 is uniquely required for the rapid congression of chromosomes near centrosomes. Current models suggest that CENP-E drives congression by gliding kinetochores along microtubules independently of chromosome biorientation. Here, by studying chromosome movement under different levels of CENP-E activity, we propose an alternative model in which CENP-E initiates congression by promoting the formation or stabilization of end-on attachments at kinetochores, rather than by directly propelling the chromosomes. CENP-E accelerates congression initiation by opposing Aurora kinase activity, but subsequent chromosome movement toward the equator does not depend on CENP-E. Without CENP-E, stabilization of end-on attachments is delayed due to Aurora kinase-mediated phosphorylation of microtubule-binding proteins on kinetochores and the expansion of the fibrous corona. We propose that CENP-E counters this inhibition by reducing Aurora B-mediated phosphorylation of outer kinetochore proteins in a BubR1-dependent manner, thereby stabilizing end-on attachments, facilitating the removal of the fibrous corona, and initiating biorientation-dependent chromosome movement.