bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model
Authors: Gicquel Tristan , Marchiano Fabio , Reyes-Castellanos Gabriela , Audebert Stéphane , Camoin Luc , Habermann Bianca , Giannesini Benoit , Carrier Alice 
Published: December 2022

ABSTRACTAimsPancreatic Ductal AdenoCarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. The objective of this work was to investigate the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative study combining functional, morphological and omics-based evaluation of gastrocnemius muscle from genetically-engineered mice developing autochthonous pancreatic tumor and cachexia (KIC GEMM).ResultsKIC cachectic PDAC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. While the number of mitochondria per cell is not altered, mitochondrial mass is decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis.InnovationMuscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrate, protein and redox metabolism, but concern also lipid and nucleic acid metabolism.ConclusionThis work provides a framework to guide towards the most relevant targets in the clinic to limit PDAC-induced cachexia, in particular mitochondrial fatty acid metabolism.
Interfacial dynamics and growth modes ofβ2-microglobulin dimers
Authors: Oliveira Nuno F. B. , Rodrigues Filipe E. P. , Vitorino João N. M. , Faísca Patrícia F. N. , Machuqueiro Miguel 
Published: December 2022

AbstractProtein aggregation is a complex process that strongly depends on environmental conditions and has considerable structural heterogeneity, not only at the level of fibril structure but also at the level of molecular oligomerization. Since the first step in aggregation is the formation of a dimer, it is important to clarify how certain properties (e.g., stability or the interface geometry) of the latter may determine the outcome of aggregation. Here, we developed a simple model that represents the dimer’s interfacial region by two angles (spanning the so-called growth landscape), and investigate how modulations of the interfacial region occurring on the ns–μs timescale change the dimer’s growth mode. We applied this methodology to 15 different dimer configurations of theβ2m D76N mutant protein equilibrated with long MD simulations and identified which of them have limited and unlimited growth modes, with different consequences to their aggregation potential. We found that despite the highly dynamic nature of the starting configurations, most polymeric growth modes tend to be conserved within the studied time scale. The proposed methodology performs remarkably well taking into consideration that theβ2m dimers are formed by monomers with detached termini, and their interfaces are stabilized by non-specific apolar interactions, leading to relatively weak binding affinities.
Defining ancestry, heritability and plasticity of cellular phenotypes in somatic evolution
Authors: Schiffman Joshua S. , D’Avino Andrew R. , Prieto Tamara , Pang Yakun , Fan Yilin , Rajagopalan Srinivas , Potenski Catherine , Hara Toshiro , Suvà Mario L. , Gawad Charles , Landau Dan A. 
Published: December 2022

SummaryThe broad application of single-cell RNA sequencing has revealed transcriptional cell state heterogeneity across diverse healthy and malignant somatic tissues. Recent advances in lineage tracing technologies have further enabled the simultaneous capture of cell transcriptional state along with cellular ancestry thus enabling the study of somatic evolution at an unprecedented resolution; however, new analytical approaches are needed to fully harness these data. Here we introduce PATH (Phylogenetic Analysis of Transcriptional Heritability), an analytical framework, which draws upon classic approaches in species evolution, to quantify heritability and plasticity of somatic phenotypes, including transcriptional states. The PATH framework further allows for the inference of cell state transition dynamics by linking a model of cellular evolutionary dynamics with our measure of heritability versus plasticity. We evaluate the robustness of this approach by testing a range of biological and technical features in simulations of somatic evolution. We then apply PATH to characterize previously published and newly generated single-cell phylogenies, reconstructed from either native or artificial lineage markers, with matching cellular state profiling. PATH recovered developmental relationships in mouse embryogenesis, and revealed how anatomic proximity influences neural relatedness in the developing zebrafish brain. In cancer, PATH dissected the heritability of the epithelial-to-mesenchymal transition in a mouse model of pancreatic cancer, and the heritability versus plasticity of transcriptionally-defined cell states in human glioblastoma. Finally, PATH revealed phenotypic heritability patterns in a phylogeny reconstructed from single-cell whole genome sequencing of a B-cell acute lymphoblastic leukemia patient sample. Altogether, by bringing together perspectives from evolutionary biology and emerging single-cell technologies, PATH formally connects the analysis of cell state diversity and somatic evolution, providing quantification of critical aspects of these processes and replacingqualitativeconceptions of “plasticity” withquantitativemeasures of cell state transitions and heritability.
Neuron types in the developing mouse brain are divided into partially matching epigenomic and transcriptomic classes
Authors: Kilpinen Sami , Heliölä Heidi , Achim Kaia 
Published: December 2022

AbstractIn recent single-cell -omics studies, both the differential activity of transcription factors regulating cell fate determination and differential genome activation have been tested for utility as descriptors of cell types. Naturally, genome accessibility and gene expression are interlinked. To understand the variability in genomic feature activation in the GABAergic neurons of different spatial origins, we have mapped accessible chromatin regions and mRNA expression in single cells derived from the developing mouse central nervous system (CNS). We first defined a reference set of open chromatin regions for scATAC-seq read quantitation across samples, allowing comparison of chromatin accessibility between brain regions and cell types directly. Second, we integrated the scATAC-seq and scRNA-seq data to form a unified resource of transcriptome and chromatin accessibility landscape for the cell types in di- and telencephalon, midbrain and anterior hindbrain of E14.5 mouse embryo. Importantly, we implemented resolution optimization at the clustering, and automatized the cell typing step. We show high level of concordance between the cell clustering based on the chromatin accessibility and the transcriptome in analyzed neuronal lineages, indicating that both genome and transcriptome features can be used for cell type definition. Hierarchical clustering by the similarity in accessible chromatin reveals that the genomic feature activation correlates with neurotransmitter phenotype, selector gene expression, cell differentiation stage and neuromere origins.
Evolutionary divergence of basal and activity-dependent exon splicing in cortical neurons
Authors: Dando Owen , Qiu Jing , Chandran Siddharthan , Hardingham Giles E. 
Published: December 2022

AbstractAlternative splicing of mRNA exons in mammalian neurons increases diversity of the proteome and is regulatable by signaling pathways. However, the degree of conservation of basal and signal-dependent exon usage between human neurons and those from experimental models such as mice is incompletely understood. We previously showed that cortical neuronal activity-dependent gene transcription exhibits human/mouse differences, driven by evolutionary divergence of cis-acting promoter elements (Qiu et al. 2016). Since alternative exon usage influences brain development and cognition, is controlled by neuronal activity, and is disturbed in brain disorders, we investigated human/mouse differences in exon usage in cortical neurons. Comparing orthologous exons, basal exon inclusion levels showed human-mouse conservation, but also significant differences determined by cis-acting sequences: human-mouse conservation and divergence in exon usage was recapitulated in neurons from Tc1 mice carrying human chromosome-21 (hCh21). Activity-dependent changes in exon usage also exhibited significant conservation: gene structure was more likely to be conserved in activity-regulated exons, and exons regulated in both human and mouse neurons were enriched in RBFOX and SAM68 targets, and genes were centred on cytoskeletal organisation, mRNA transcription/processing, and synaptic signaling. However, divergence was also evident, and human-specific activity-dependent exon usage was dominated by genes involved in lipid biosynthesis, signaling and trafficking. Notably, the pattern of activity-dependent usage of hCh21 exons in human neurons was not recapitulated in mouse Tc1 neurons. Thus, unlike species-specific differences in activity-dependent gene transcription, cis-acting DNA sequence divergence is insufficient to explain inter-species differences in activity-regulated exon usage. Trans-acting factors involved in activity-responsive splicing have likely also diverged.
FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1
Authors: Wang Dongyang , Zheng Xiaojing , Chai Lihong , Zhao Junli , Zhu Jiuling , Li Yanqing , Yang Peiyan , Mao Qinwen , Xia Haibin 
Published: December 2022

AbstractFAM76B has been reported to be a nuclear speckle localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-κB-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1in vitro.We further showed that FAM76B suppressed inflammation by regulating the NF-κB pathwayin vivousing a traumatic brain injury (TBI) model in FAM76B knockout mice. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediates neuroinflammation by influencing the translocation of hnRNPA2B1in vivoduring TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-κB-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.
A new type of transcriptional reprogramming by an IRF4 mutation in lymphoma
Authors: Schleussner Nikolai , Cauchy Pierre , Franke Vedran , Giefing Maciej , Fornes Oriol , Vankadari Naveen , Assi Salam , Costanza Mariantonia , Weniger Marc A. , Akalin Altuna , Anagnostopoulos Ioannis , Bukur Thomas , Casarotto Marco G. , Damm Frederik , Daumke Oliver , Edginton-White Benjamin , Gebhardt J. Christof M. , Grau Michael , Grunwald Stephan , Hansmann Martin-Leo , Hartmann Sylvia , Huber Lionel , Kärgel Eva , Lusatis Simone , Noerenberg Daniel , Obier Nadine , Pannicke Ulrich , Pfaus Anja , Reisser Anja , Rosenwald Andreas , Schwarz Klaus , Sundararaj Srinivasan , Weilemann Andre , Winkler Wiebke , Xu Wendan , Lenz Georg , Rajewsky Klaus , Wasserman Wyeth W. , Cockerill Peter N. , Scheidereit Claus , Siebert Reiner , Küppers Ralf , Grosschedl Rudolf , Janz Martin , Bonifer Constanze , Mathas Stephan 
Published: December 2022

SUMMARY PARAGRAPHDisease-causing mutations in genes encoding transcription factors (TFs) are a recurrent finding in hematopoietic malignancies and might involve key regulators of lineage adherence and cellular differentiation1–3. Such mutations can affect TF-interactions with their cognate DNA-binding motifs4, 5. Whether and how TF-mutations impact upon the nature of binding to TF composite elements (CE) and influence their interaction with other TFs is unclear. Here, we report a new mechanism of TF alteration in human lymphomas with perturbed B cell identity. It is caused by a recurrent somatic missense mutation c.295T>C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cell-differentiation and -activation6, 7. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF composite elements (CEs). Furthermore, IRF4-C99R thoroughly modifies IRF4 function, by blocking IRF4-dependent plasma cell induction, and up-regulating disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single arginine mutation creates a complex switch of TF specificity and gene regulation. These data open the possibility of designing specific inhibitors to block the neomorphic, disease-causing DNA-binding activities of a mutant transcription factor.
Repurposing of the antibiotic nitroxoline for the treatment of mpox
Authors: Bojkova Denisa , Zöller Nadja , Tietgen Manuela , Steinhorst Katja , Bechtel Marco , Rothenburger Tamara , Kandler Joshua D. , Schneider Julia , Corman Victor M. , Ciesek Sandra , Rabenau Holger F. , Wass Mark N. , Kippenberger Stefan , Göttig Stephan , Michaelis Martin , Cinatl Jindrich 
Published: December 2022

AbstractThe antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.
A broad matrix metalloproteinase inhibitor with designed loop extension exhibits ultrahigh specificity for MMP-14
Authors: Bonadio Alessandro , Wenig Bernhard L. , Hockla Alexandra , Radisky Evette S. , Shifman Julia M. 
Published: December 2022

AbstractMatrix metalloproteinases (MMPs) are key drivers of various diseases, including cancer. While several antibodies against MMPs are in development, our goal is to construct therapeutic anti-MMP inhibitors based on a natural broad MMP inhibitor, tissue inhibitor of metalloproteinases-2 (N-TIMP2). To confer high binding specificity toward one MMP type, we extend one of the N-TIMP2 loops, allowing it to interact with the non-conserved MMP surface. Multiple computational designs of the loop were used to design a focused library for yeast surface display, which was sorted for high binding to the target MMP-14 and low binding to off-target MMP-3. Deep sequencing of the two selected populations followed by comparative data analysis was used to identify the most promising variants, which were expressed, purified, and tested for inhibition of MMP-14 and off-target MMPs. Our best N-TIMP2 variant exhibited 29 pM binding affinity to MMP-14 and 2.4 µM affinity to MMP-3, 7500-fold more specific than WT N-TIMP2. Furthermore, the variant inhibited cell invasion with increased potency relative to WT N-TIMP2 in two breast cancer cell lines. We obtained the engineered variant high-accuracy model by including NGS data as input to AlphaFold multiple sequence alignment (MSA). Modeling results together with experimental mutagenesis demonstrate that the loop packs tightly against non-conserved residues on MMP-14 and clashes with MMP-3. This study demonstrates that introduction of loop extensions into inhibitors to stretch to the non-conserved surface of the target proteins is an attractive strategy for conferring high binding specificity in design of MMP inhibitors and other therapeutic proteins.
Antibiotic-induced dysbiosis does not potentiate the effect of lipopolysaccharide insult in male Wistar rats
Authors: Tejkalová Hana , Jakob Lea , Kvasnová Simona , Klaschka Jan , Sechovcová Hana , Mrázek Jakub , Páleníček Tomáš , Fliegerová Kateřina Olša 
Published: December 2022

AbstractThe present study investigated whether neonatal exposure to the proinflammatory endotoxin lipopolysaccharide (LPS) followed by antibiotic (ATB)-induced dysbiosis in early adulthood could induce schizophrenia-like behavioral changes in adult male rats. The combination of these two stressors resulted in decreased weight gain, but no significant behavioral abnormalities were observed. LPS treatment resulted in adult rats hypoactivity and induced anxiety-like behavior in the social recognition paradigm, but these behavioral changes were not exacerbated by ATB-induced gut dysbiosis. ATB treatment seriously disrupted the gut bacterial community, but dysbiosis did not affect locomotor activity, social recognition, and acoustic reactivity in adult rats. Fecal bacterial community analyzes showed no differences between the LPS challenge exposed/unexposed rats, while the effect of ATB administration was decisive regardless of prior LPS exposure. ATB treatment resulted in significantly decreased bacterial diversity, suppression of Clostridiales and Bacteroidales, and increases in Lactobacillales, Enterobacteriales, and Burkholderiales. The persistent effect of LPS on some aspects of behavior suggests a long-term effect of early toxin exposure that was not observed in ATB-treated animals. However, an anti-inflammatory protective effect of ATB cannot be assumed because of the increased abundance of pro-inflammatory, potentially pathogenic bacteria (Proteus, Suttrella) and the elimination of the bacterial familiesRuminococcaceaeandLachnospiraceae, which are generally considered beneficial for gut health.
Using principal component analysis to identify latent factors affecting cost and time overrun in public construction projects
Authors: Wyke Simon , Lindhard Søren Munch , Larsen Jesper Kranker 
Published: December 2022

PurposeCost and time are two of the primary benchmarks in which construction projects are measured. A variety of factors, however, affect cost and time on construction projects, as identified in previous research. This has led to a need for better understanding how factors affecting cost and time overruns on public construction projects can be managed more efficiently. The purpose of this paper is to address these issues.Design/methodology/approachIn this study 26 factors affecting cost and time overruns on construction projects were identified, through qualitative interviews with project managers from Danish governmental agencies and through a literature review. Through principal component analyses the 26 factors were subsequently narrowed down to four primary latent factors.FindingsThe identified four latent factors affecting cost and time overruns on public construction projects were lack of quality management, lack of project pre-planning, lack of user management and lack of project management.Originality/valuePrevious research has focussed on increasing knowledge by identifying and ranking factors affecting time and cost performance. This has led to the identification of an overwhelming number of factors to use for managing construction projects. The present research reduced the number of factors by clustering them into key latent factors responsible for most of the deviation in performance, narrowing the scope of construction cost and time management into a few tangible key focus areas. This supports and improves fast decision-making that is necessary in a changeable environment such as construction.
Indigenous knowledge, climate change and transformations of Gwadar fishing community
Authors: Ullah Shakir , Khan Usman , Begum Abida , Han Heesup , Mohamed Abdullah 
Published: December 2022

Purpose
This paper explores the indigenous climate knowledge (ICK) of the Gwadar fishing community in Pakistan. The main purpose of this paper is to explore the accuracy of ICK and how climatic change brings changes to it and the social lives of local fishers.

Design/methodology/approach
Qualitative research methods, including participant observation, in-depth interviews and oral histories, were used to collect the data.

Findings
Finding from this long fieldwork shows that this fishing community has a harmonious relationship with nature and local ecology. Their knowledge of local ecology enables them to have equal access to natural resources, sustainable resource management, disaster risk reduction and strong social organization on the coast of Gwadar. Recently their deep relationship with local ecology and sociocultural organization has been disturbed due to huge climate changes caused by human manipulation of the environment. Their ability to foresee climatic events has been reduced. They are finding it impossible to estimate fish availability due to massive climate changes. Local communities are losing their traditional livelihoods and socioeconomic autonomy as a result of growing climate change. Climatic change adds to the existing poverty situation and increases political instability in the region.

Practical implications
The study suggests using the fishermen’s valuable indigenous knowledge of local ecology, climate and its ties to local traditions, culture and resource management for a scientific understanding of climate change and marine resource management in Gwadar, Pakistan.

Originality/value
This is an ethnographic study based on a long term field work. Fishing community is passing through catastrophic climatic changes in the region. This community has been ignored by both government and researchers to record their problems and bring them to academia and media. Therefore, this study will help them raise their voices.