bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoplasmic Reticulum Alterations in Living Cells Expressing INF2 Variants Causing Glomerulosclerosis and Peripheral Neuropathy
Authors: Tran Quynh Thuy Huong , Kondo Naoyuki , Ueda Hiroko , Matsuo Yoshiyuki , Tsukaguchi Hiroyasu 
Published: May 2024

ABSTRACTThe endoplasmic reticulum (ER) is a single dynamic, and continuous network, which mediates a variety of biological processes. The ER spreads throughout the cytoplasm as an interconnected network mainly consisting of flat (sheets) or reticular (tubules) networks. Such ER integrity is regulated by actin-microtubule interaction. INF2 is an actin assembly factor that exclusively located in ER and is mutated in hereditary form of glomerulopathy (focal segmental glomerulosclerosis, FSGS) and peripheral neuropathy (Charcot-Marie Tooth, CMT-DIE, MIM 614455). It remains unclear how INF2 variants could affect ER morphology.High-resolution, live-imaging of HeLa cells revealed that pathogenic INF2-CAAX variants disrupt peripheral ER complexity, generating focal clustering of polygonal tubules and preferential sheet-like appearance. G73D (causing CMT+FSGS) induced more remarkable alterations than T161N, N202S and R218W (leading to FSGS). Both actin and microtubule inhibitors shifted the ER balance towards sheet predominance and focal compaction of ER tubules, suggesting the role of cytoskeleton in shaping tubular ER networks. INF2 variants induced mitochondria fragmentation with peripheral mis-distribution. The mitochondrial alterations correlated with the degree of cytoskeletal disorganization, leading to defective respiratory function. Moreover, lysosomal trafficking was restricted by INF2 variants in the cell cortex. These organelle-cytoskeletal interactions were more remarkably impaired by CMT+FSGS variant than in FSGS variants.Our observations underscore that INF2 variants disrupt ER integrity by disorganizing cytoskeletons, which leads to defective mitochondria function and vesicle trafficking in INF2 disorders. INF2 CMT+FSGS variants impair ER-organelles interaction more prominent than FSGS variants, suggesting the existence of specific mediators for CMT+FSGS variants.
CD44/Integrin β1 association drives fast motility on HA substrates
Authors: Roy Tanusri , Dutta Sarbajeet , Sthanam Lakshmi Kavitha , Sen Shamik 
Published: May 2024

AbstractIn addition to proteins such as collagen (Col) and fibronectin, the extracellular matrix (ECM) is enriched with bulky proteoglycan molecules such as hyaluronic acid (HA). However, how ECM proteins and proteoglycans collectively regulate cellular processes has not been adequately explored. Here, we address this question by studying cytoskeletal and focal adhesion organization and dynamics on cells cultured on polyacrylamide hydrogels functionalized with Col, HA and a combination of Col and HA (Col/HA). We show that fastest migration on HA substrates is attributed to the presence of smaller and weaker focal adhesions. Integrinβ1 co-localization and its association with CD44—which is the receptor for HA, and insensitivity of cell spreading to RGD on HA substrates suggests that focal adhesions on HA substrates are formed via integrin association with HA bound CD44. Consistent with this, adhesion formation and cell motility were inhibited when CD44 was knocked out. Collectively, our results suggest that association of integrinβ1 with CD44 drives fast motility on HA substrates.
Elastic tethers remain functional during anaphase arrest in partially-lysed crane-fly spermatocytes: a possible approach for studying mitotic tethers
Authors: Aidil Aisha , Malick Samir A. , Forer Arthur 
Published: May 2024

ABSTRACTMitotic tethers connect partner telomeres of all segregating anaphase chromosomes in all animal cells that have been tested, as detected by laser-cutting chromosome arms during anaphase and seeing that the arm fragments move rapidly across the equator to their partner chromosome moving to the opposite pole, telomere moving towards telomere. Tethers exert anti-poleward forces on the poleward separating telomeres, but tether elasticity (that produces the backwards forces) diminishes during anaphase: as determined by the behavior of arm fragments; short tethers (early anaphase) are elastic, long tethers (late anaphase) are not elastic, and medium-length tethers transition between the two states. We developed a procedure in which the tethers still functioned after we partially-lysed anaphase crane-fly spermatocytes. The partial lysis consistently arrested chromosome movements, after which the tethers moved the chromosomes backwards, potentially allowing the elastic tethers to be studied biochemically. To ensure that tether function was not altered by the partial cell-lysis procedure, we compared backward chromosome movements in partially-lysed cells with arm fragment movements in control cells. In the partially-lysed cells the backward chromosomal movements had characteristics identical to those of arm fragments in non-lysed (control) cells. In particular, in both control and partially-lysed cells shorter tethers caused backward movements more often than did longer tethers; shorter tethers caused backward movements over greater fractional distances (of the tether) than did longer tethers; and velocities of the backwards movements were the same for tethers of different lengths. We also compared the effects of Calyculin A (an inhibitor of Protein Phosphatase1) in controlversusin partially-lysed cells. Calyculin A (CalA) added to control cells in early anaphase blocks dephosphorylation, thereby maintaining tether elasticity throughout anaphase: after the chromosomes reach the poles they move backwards when the usual poleward forces are reduced. Partial lysis preserves this tether functionality: after partial lysis of CalA-treated cells the chromosomes move backward and reach the partner telomeres at even very long tether lengths. We conclude that partial cell-lysis arrests anaphase chromosome poleward movement but does not affect tether function.
Rational design of HER2-targeted combination therapies to reverse drug resistance in fibroblast-protected HER2+ breast cancer cells
Authors: Poskus Matthew D. , McDonald Jacob , Laird Matthew , Li Ruxuan , Norcoss Kyle , Zervantonakis Ioannis K. 
Published: May 2024

AbstractIntroductionFibroblasts, an abundant cell type in the breast tumor microenvironment, interact with cancer cells and orchestrate tumor progression and drug resistance. However, the mechanisms by which fibroblast-derived factors impact drug sensitivity remain poorly understood. Here, we develop rational combination therapies that are informed by proteomic profiling to overcome fibroblast-mediated therapeutic resistance in HER2+ breast cancer cells.MethodsDrug sensitivity to the HER2 kinase inhibitor lapatinib was characterized under conditions of monoculture and exposure to breast fibroblast-conditioned medium. Protein expression was measured using reverse phase protein arrays. Candidate targets for combination therapy were identified using differential expression and multivariate regression modeling. Follow-up experiments were performed to evaluate the effects of HER2 kinase combination therapies in fibroblast-protected cancer cell lines and fibroblasts.ResultsCompared to monoculture, fibroblast-conditioned medium increased the expression of plasminogen activator inhibitor-1 (PAI1) and cell cycle regulator polo like kinase 1 (PLK1) in lapatinib-treated breast cancer cells. Combination therapy of lapatinib with inhibitors targeting either PAI1 or PLK1, eliminated fibroblast-protected cancer cells, under both conditions of direct coculture with fibroblasts and protection by fibroblast-conditioned medium. Analysis of publicly available, clinical transcriptomic datasets revealed that HER2-targeted therapy fails to suppress PLK1 expression in stroma-rich HER2+ breast tumors and that high PAI1 gene expression associates with high stroma density. Furthermore, we showed that an epigenetics-directed approach using a bromodomain and extraterminal inhibitor to globally target fibroblast-induced proteomic adaptions in cancer cells, also restored lapatinib sensitivity.ConclusionsOur data-driven framework of proteomic profiling in breast cancer cells identified the proteolytic degradation regulator PAI1 and the cell cycle regulator PLK1 as predictors of fibroblast-mediated treatment resistance. Combination therapies targeting HER2 kinase and these fibroblast-induced signaling adaptations eliminates fibroblast-protected HER2+ breast cancer cells.
Elastic mitotic tethers remain functional after microtubules are inhibited
Authors: Adil Aisha , Janan Maral , Forer Arthur 
Published: May 2024

ABSTRACTDuring normal anaphase in animal cells, elastic tethers connect partner telomeres of segregating chromosomes and exert backward (anti-poleward) forces on those chromosomes. The experiments reported herein test whether microtubules need to be present in order for tethers to produce backwards forces. We disassembled spindle microtubules by treating anaphase crane-fly primary spermatocytes separately with nocodazole, colcemid, or podophyllotoxin. The drug treatments caused anaphase chromosomes to stop moving poleward; almost immediately thereafter they moved backward. The characteristics of the backward movements of the half-bivalents match those of the backwards movements of arm fragments formed by cutting chromosome arms during anaphase – for example the occurrence and lengths of backward movements were a function of tether length. The only difference from movement of arm fragments is that the chromosomes in the treated cells moved backwards slower than arm fragments did. Immunofluorescence of spindle tubulin after the drug treatments indicated that acetylated kinetochore microtubules were not depolymerized by the drugs, though the non-kinetochore spindle microtubules were depolymerized. Our data indicate that tethers move anaphase chromosomes backwards in the absence of functioning spindle microtubules. We suggest that the backward movements that take place when poleward forces are absent are due to tethers, and that the backward movements are slowed by the presence of acetylated kinetochore microtubules.
Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes
Authors: Sadis Hagit , Peles David , Hussein Yara , Stern Shani 
Published: May 2024

AbstractNeurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite diverse etiologies, patients with these disorders may share symptoms.In this study, we aimed to explore potential common mechanisms between seven neurological disorders spanning three categories: neurodegenerative diseases, neuropsychiatric disorders, and neurodevelopmental disorders, by comparing gene expression profiles and focusing on the most prominent dysregulated genes consistently reported within and across disorders. Our results demonstrate 31 genes that are commonly differentially expressed in brain cells and tissues derived from human disease models when compared to healthy controls. These genes were enriched in brain Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, and External encapsulating structure. Remarkedly, dysregulation of ECM genes was evident separately in each of the three categories of disorders. This suggests a notable distinction in the brain ECM in disease states. Furthermore, we identified that the most frequently reported genes among all disorders wereGFAP, andIFITM3.Key PointsAnalysis of 41 human studies revealed 31 significantly dysregulated genes shared among seven neurological disorders when compared to healthy controls, spanning three distinct categories: Neurodegenerative diseases, Neuropsychiatric disorders, and Neurodevelopmental disorders.These shared Differentially Expressed Genes (DEGs) demonstrated significant enrichment for Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, Blood vessel development, and External encapsulating structure. Particularly,SSTandBCL6were the most frequently reported shared DEGs.Notably, each of the three categories of neurological disorders exhibited significant cellular component enrichment for ECM pathways.In order to distinguish noise genes (false-positive genes) from disease-relevant genes, we identified the DEGs that were reported the highest number of times per disorder.GFAP, followed byIFITM3, were found to be the most reported genes.Furthermore, due to partially shared symptoms, we explored commonalities between Autism Spectrum Disorders (ASD) and Schizophrenia. DEGs shared between both disorders were specifically enriched with ECM pathways, External encapsulating structure, Growth factor binding, Cell adhesion molecule binding, and PI3K-Akt signaling pathway. Noteworthy,IFITM2, HSPB1, IFITM3, HSPA1A, MKNK2, GFAPandCOL4A1were among the most frequently reported shared DEGs.The central aspects of our findings suggest a substantial distinction between the Central Nervous System (CNS) ECM in health and disease.
The PVD neuron has male-specific structure and mating function inC. elegans
Authors: Iosilevskii Yael , Hall David H. , Katz Menachem , Podbilewicz Benjamin 
Published: May 2024

AbstractNeurons display unique shapes and establish intricate networks, which may differ between sexes. In complex organisms, studying sex differences in structure and function of individual neurons is difficult. The nematodeCaenorhabditis eleganshermaphrodites and males present an exceptional model for studying neuronal morphogenesis in a simple, sexually-dimorphic system. We focus on the polymodal sensory bilateral neuron pair PVD, which forms a complex but stereotypic dendritic tree composed of multiple subunits that resemble candelabra. PVD is well studied in hermaphrodites, but not in males. We show here that during larval development, male PVDs extend a similar architecture to the hermaphrodite utilizing the sexually-shared Menorin patterning mechanism. In early adulthood, however, male PVD develops a unique extension into the copulatory tail structure. Alongside established tail ray neurons RnA and RnB, we show PVD is a third, previously unrecognized, neuron within the tail rays. Unlike RnA and RnB, PVD extends anterogradely, branches and turns within the ray hypodermis, and is non-ciliated. This PVD sexually-dimorphic arborization is absent in mutant backgrounds which perturb the Menorin guidance complex. SAX-7/L1CAM, a hypodermal component of this complex, shows a male-specific expression pattern which precedes PVD extension, and its presence allows PVD to enter the tail rays. Further, our results reveal that genetically altered arborization or ablation of the PVD result in male mating behavioral defects, particularly as males turn around the hermaphrodite. These results uncover an adult-stage sexual dimorphism of dendritic branching and uncover a function for PVD in male sexual behavior.Significance StatementNeurons form intricate shapes and networks, which may display sexual differences. Pinpointing these changes at the single cell level, however, is challenging. InC. elegans, the PVD neuron is a powerful model for stereotypical neuron shaping, yet most studies concern only one of two sexes. Our research focuses on the understudied male, where we show an adult-stage extension of PVD into the male copulatory tail organ. We further show how this stems from a sex-shared patterning complex, progressing independently and in a different environment compared with nearby male-specific neurons. We further find PVD has a role in the male adult-specific mating behavior. PVD thus presents a unique example of a highly arborized neuron showing sexually dimorphic behavioral function and structure.
Intra-amygdala circuits of sleep disruption-induced anxiety in female mice
Authors: Peng Beibei , Foilb Allison R. , Manasian Yunona , Li Yan , Deng Xin , Meloni Edward G. , Ressler Kerry J. , Carlezon William A. , Bolshakov Vadim Y. 
Published: May 2024

AbstractCombining mouse genetics, electrophysiology, and behavioral training and testing, we explored how sleep disruption may affect the function of anxiety-controlling circuits, focusing on projections from the basolateral nucleus of the amygdala (BLA) to CRF-positive cells in the lateral division of the central amygdala (CeL). We found in Crh-IRES-Cre::Ai14(tdTomato) reporter female mice that 6 hours of sleep disruption during their non-active (light) cycle may be anxiogenic. Notably, the AMPAR/NMDAR EPSC amplitude ratio at the BLA inputs to CRF-CeL cells (CRFCeL), assessed with whole-cell recordings inex vivoexperiments, was enhanced in slices from sleep-disrupted mice, whereas paired-pulse ratio (PPR) of the EPSCs induced by two closely spaced presynaptic stimuli remained unchanged. These findings indicate that sleep disruption-associated synaptic enhancements in glutamatergic projections from the BLA to CRF-CeL neurons may be postsynaptically expressed. We found also that the excitation/inhibition (E/I) ratio in the BLA to CRFCeLinputs was increased in sleep-disrupted mice, suggesting that the functional efficiency of excitation in BLA inputs to CRFCeLcells has increased following sleep disruption, thus resulting in their enhanced activation. The latter could be translated into enhanced anxiogenesis as activation of CRF cells in the CeL was shown to promote anxiety-like behaviors.
Differential Control of Inhibitory and Excitatory Nerve Terminal Function by Mitochondria
Authors: Bredvik Kirsten , Ryan Timothy A. 
Published: May 2024

AbstractInhibitory neurons shape the brain’s computational landscape and rely on different cellular architectures and intrinsic properties than excitatory neurons. Maintenance of the overall balance of excitatory (E) versus inhibitory (I) drive is essential, as disruptions can lead to neuropathological conditions, including autism and epilepsy. Metabolic perturbations are a common driver of E/I imbalance but differential sensitivity of these two neuron types to metabolic lesions is not well understood. Here, we characterized differences in presynaptic bioenergetic regulation between excitatory and inhibitory nerve terminals using genetically encoded indicators expressed in primary dissociated neuronal cultures. Our experiments showed that inhibitory nerve terminals sustain higher ATP levels than excitatory nerve terminals arising from increased mitochondrial metabolism. Additionally, mitochondria in inhibitory neurons play a greater role in buffering presynaptic Ca2+and inhibitory mitochondrial Ca2+handling is differentially regulated by TMEM65-mediated acceleration of mitochondrial Ca2+extrusion following bursts of activity. These experiments thus identify differential reliance on mitochondrial function across two major neuron types.
Sustainable admixtures to enhance long-term strength and durability properties of eco-concrete: an innovative use of Saudi agro-industrial by-products
Authors: Amran Mugahed , Onaizi Ali 
Published: May 2024

PurposeLow-carbon concrete represents a new direction in mitigating the global warming effects caused by clinker manufacturing. Utilizing Saudi agro-industrial by-products as an alternative to cement is a key support in reducing clinker production and promoting innovation in infrastructure and circular economy concepts, toward decarbonization in the construction industry. The use of fly ash (FA) as a cement alternative has been researched and proven effective in enhancing the durability of FA-based concrete, especially at lower replacement levels. However, at higher replacement levels, a noticeable impediment in mechanical strength indicators limits the use of this material.Design/methodology/approachIn this study, low-carbon concrete mixes were designed by replacing 50% of the cement with FA. Varying ratios of nano-sized glass powder (4 and 6% of cement weight) were used as nanomaterial additives to enhance the mechanical properties and durability of the designed concrete. In addition, a 10% of the mixing water was replaced with EMs dosage.FindingsThe results obtained showed a significant positive impact on resistance and durability properties when replacing 10% of the mixing water with effective microorganisms (EMs) broth and incorporating nanomaterial additives. The optimal mix ratios were those designed with 10% EMs and 4–6% nano-sized glass powder additives. However, it can be concluded that advancements in eco-friendly concrete additive technologies have made significant contributions to the development of sophisticated concrete varieties.Originality/valueThis study focused at developing nanomaterial additives from Saudi industrial wastes and at presenting a cost-effective and feasible solution for enhancing the properties of FA-based concrete. It has also been found that the inclusion of EMs contributes effectively to enhancing the concrete's resistance properties.
An investigation on the rationales to internationalize higher education in public universities in Kenya
Authors: Mutinda Gladys Ndunge , Gichuki Castro , Liu Zhimin , Shan Xue 
Published: May 2024

PurposeThe converging global trends for countries and educational institutions is to push the boundaries of science and develop new technologies through the application of internationalization strategies. However, the extent to which higher education institutions (HEIs) participate and apply internationalization strategies in higher education (IOHE) varies by institution and region.Design/methodology/approachThe study employed the multi-level ordinal regression to estimate how various factors influence the rationales to internationalize higher education.FindingsThe study revealed that the salience of HEIs choice of a specific rationale for the IOHE stems from either the academic, administrative and socio-cultural levels.Research limitations/implicationsThis article posits, particularly for Kenyan universities, that proper identification of their needs and wants for their higher education is key to successfully engage in IOHE. This recognition of needs and wants places them in the right position to identify appropriate rationales to engage in this complex process.Originality/valueThe novelty of this study is based on the fact that in Sub-Saharan Africa, research on the rationales for the IOHE in universities is highly lacking. A focus on more localized contexts is a critical starting point for these institutions to own and situate the internationalization process in a way that meets their needs.
Development of research-intensive universities in Tanzania
Authors: Fussy Daniel Sidney 
Published: May 2024

PurposeThis article reports on a study that explored how the Tanzanian government can support the development of research-intensive universities in its higher education system.Design/methodology/approachData were collected through document analysis and in-depth semi-structured interviews with participants obtained from national higher education departments, senior university leadership offices and academic staff in both public and private universities.FindingsThe study identified four essential systemic elements for developing research-intensive universities (RIUs): diversification of universities based on their core functions, allocation of financial resources according to research performance, relaxation of university governing systems and accrediting universities based on research outcomes.Practical implicationsThe study identified essential systemic elements that could address the issue of developing RIUs in low- and middle-income countries (LMICs). These elements present a potential solution for developing a diverse higher education system capable of sustaining RIUs, offering opportunities to produce innovative knowledge, develop diverse skills and meet the needs of a range of students, employers and businesses.Originality/valueThis study adds to the body of knowledge on how LMICs can develop well-functioning RIUs. The study also contributes to the ongoing debates among higher education stakeholders, including governments, academics, students and the community, on the changing dynamics of higher education and its role in national and regional development.