bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein disulfide isomerase disassembles stress granules and blocks cytoplasmic aggregation of TDP-43 in ALS
Authors: Liu Jia-Qi , Liu Hao , Li Yuying , Liu Xiangyi , Wang Li-Qiang , Wang Kan , Yang Zhaofei , Fu Qi , Xu Xiaojiao , Chen Jie , Zhang Yingshuang , Zhou Jun , Lei Weidong , Cui Mengchao , Liang Yi 
Published: March 2024

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimer’s patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimer’s patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid–liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS patients and some Alzheimer’s patients.TeaserPDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS.
Unraveling the Evolutionary Trajectory of LHCI in Red-Lineage Algae: Conservation, Diversification, and Neolocalization
Authors: Kumazawa Minoru , Ifuku Kentaro 
Published: March 2024

AbstractRed algae and the secondary symbiotic algae that engulfed a red alga as an endosymbiont are called red-lineage algae. They comprise key marine taxa including diatoms, Haptophyta, and Cryptophyta. Several photosystem (PS) I–light-harvesting complex I (LHCI) structures have been reported from red-lineage algae —two red algaeCyanidioschyzon merolae(Cyanidiophyceae),Porphyridium purpureum(Rhodophytina), a diatomChaetoceros gracilisand a CryptophyteChroomonas placoidea. Here, we clarified the orthologous relation of LHCIs in red-lineage algae by combining a detailed phylogenetic analysis of LHCIs and the structural information of PSI–LHCI. We found that the seven Lhcr groups in LHCI are conserved in Rhodophytina; Furthermore, during both genome reduction in Cyanidioschyzonales of red algae and endosymbiosis leading to Cryptophyta, some LHCIs were lost and replaced by existing or differentiated LHCIs. Especially in Cryptophyta, uniquely diversified Lhcrs form three sets of heterotrimers contributed to the expansion of the antenna size of PSI, supporting the modern ecological success of this taxon. We denominated “neolocalization” to these examples of flexible reorganization of LHCIs. This study provides new insights into the evolutionary process of LHCIs associated with PSI in the red-lineage algae and clarifies the need for both molecular phylogeny and structural information to elucidate the plausible evolutionary history of LHCI.
IMMUNOPHENOTYPING AND FUNCTIONAL ANALYSIS OF NK CELL SUBSETS INMycobacterium tuberculosis-INFECTED INDIVIDUALS
Authors: Silva Carolina S. , Folkesson Elin , Foroogh Fariba , Gower Maia S. , Kleberg Linn , Xi Pengjun , Sahran Dhifaf , Bruchfeld Judith , Correia-Neves Margarida , Källenius Gunilla , Sundling Christopher 
Published: March 2024

ABSTRACTInfection withMycobacterium tuberculosisremains a global health challenge, with diverse clinical outcomes ranging from latent TB (LTB) infection to active TB disease (ATB). We conducted a comprehensive analysis of NK cell subsets and function in individuals with LTB, ATB, and healthy controls to elucidate their potential association with TB pathogenesis. Peripheral blood mononuclear cells (PBMCs) were isolated from Mtb-infected individuals and analyzed by mass cytometry and flow cytometry. We identified distinct NK cell subsets and evaluated their functional responses to stimulation. Our findings revealed comparable frequencies of total and NK cell subsets across LTB, ATB, and controls. Functional assays demonstrated similar degranulation, cytokine production, and proliferation capabilities among NK cell subsets across the three groups. This study provides insights into the heterogeneity of NK cell responses in TB and highlights the need for standardized methodologies with well-characterized cohorts controlling for donor background. Further investigations are warranted to delineate the specific roles of NK cells in TB immunity and pathogenesis.
Neurodevelopmental Subtypes of Functional Brain Organization in the ABCD Study Using a Rigorous Analytic Framework
Authors: DeRosa Jacob , Friedman Naomi P. , Calhoun Vince , Banich Marie T. 
Published: March 2024

SummaryThe current study demonstrates that an individual’s resting-state functional connectivity (RSFC) is a dependable biomarker for identifying differential patterns of cognitive and emotional functioning during late childhood. Using baseline RSFC data from the Adolescent Brain Cognitive Development (ABCD) study, which includes children aged 9-11, we identified four distinct RSFC subtypes We introduce an integrated methodological pipeline for testing the reliability and importance of these subtypes. In the Identification phase, Leiden Community Detection defined RSFC subtypes, with their reproducibility confirmed through a split-sample technique in the Validation stage. The Evaluation phase showed that distinct cognitive and mental health profiles are associated with each subtype, with the Predictive phase indicating that subtypes better predict various cognitive and mental health characteristics than individual RSFC connections. The Replication stage employed bootstrapping and down-sampling methods to substantiate the reproducibility of these subtypes further. This work allows future explorations of developmental trajectories of these RSFC subtypes.
Rapid evolution ofKlebsiella pneumoniaebiofilmsin vitrodelineates adaptive changes selected during infection
Authors: Zaborskytė Greta , Coelho Patrícia , Wrande Marie , Sandegren Linus 
Published: March 2024

AbstractBiofilm formation facilitates infection by the opportunistic pathogenKlebsiella pneumoniae, primarily through indwelling medical devices. Here, we address howK. pneumoniaecan increase its biofilm capacity by experimental evolution of surface-attached biofilms to mimic catheter-associated infections. We observed rapid convergent evolution that altered or abolished capsule, modified the fimbrial adhesin MrkD, or increased production of fimbriae and cellulose via upregulated c-di-GMP-dependent pathways. However, evolutionary trajectories and resulting phenotypes showed strain differences, illustrating the importance of genetic background on biofilm adaptation. Multiple biofilm aspects, such as early attachment, biofilm topology, surface preference, and extracellular matrix composition, were affected in a mutation-specific manner. Acute virulence was linked to the underlying genetic change rather than the overall biofilm capacity. Single mutations conferring hypermucoidy and c-di-GMP-related changes extensively overlapped with previously identified adaptive changes in UTI and wound isolates, confirming biofilm as an important selective traitin vivo.
PPIscreenML: Structure-based screening for protein-protein interactions using AlphaFold
Authors: Mischley Victoria , Maier Johannes , Chen Jesse , Karanicolas John 
Published: March 2024

AbstractProtein-protein interactions underlie nearly all cellular processes. With the advent of protein structure prediction methods such as AlphaFold2 (AF2), models of specific protein pairs can be built extremely accurately in most cases. However, determining the relevance of a given protein pair remains an open question. It is presently unclear how to use best structure-based tools to infer whether a pair of candidate proteins indeed interact with one another: ideally, one might even use such information to screen amongst candidate pairings to build up protein interaction networks. Whereas methods for evaluating quality of modeled protein complexes have been co-opted for determining which pairings interact (e.g., pDockQ and iPTM), there have been no rigorously benchmarked methods for this task. Here we introduce PPIscreenML, a classification model trained to distinguish AF2 models of interacting protein pairs from AF2 models of compelling decoy pairings. We find that PPIscreenML out-performs methods such as pDockQ and iPTM for this task, and further that PPIscreenML exhibits impressive performance when identifying which ligand/receptor pairings engage one another across the structurally conserved tumor necrosis factor superfamily (TNFSF). Analysis of benchmark results using complexes not seen in PPIscreenML development strongly suggest that the model generalizes beyond training data, making it broadly applicable for identifying new protein complexes based on structural models built with AF2.
Wildlife as a sentinel for pathogen introduction in nonendemic areas: first detection ofLeishmania tropicain wildlife in Spain
Authors: Azami-Conesa Iris , Matas Méndez Pablo , Pérez-Moreno Paula , Carrión Javier , Alunda J.M. , Mateo Barrientos Marta , Gómez-Muñoz María Teresa 
Published: March 2024

AbstractLeishmaniasis is a chronic global arthropod-borne zoonotic disease produced by several species ofLeishmania, with cutaneous, mucocutaneous, and visceral clinical manifestations. In Spain, onlyLeishmania infantumhas been reported so far, although other species ofLeishmania, such asL. tropicaandL. major, are present in surrounding countries.The aim of this work is to analyze the occurrence ofLeishmaniaspp. infection in European wildcats (Felis silvestris) as sentinels, including their genotypic characterization. Necropsies of 18 road killed wildcats were conducted. Samples of ear skin and spleen were taken for DNA isolation and PCR of the highly sensitiveSSUrDNAtarget. Subsequent PCR tests were performed using more specific targets for the determination ofLeishmaniaspecies:hsp70andITS1. Positive samples were sequenced, and phylogenetic trees constructed. Seven wildcats were found positive forLeishmaniaspp.. Based on thehsp70andITS1sequences, an animal was found to be infected only withL. tropicain ear skin samples, while two cats were found to be infected withL. infantumin both the ear skin and the spleen. In one animal, a clear sequence ofL. infantumITS1 and a sequence ofL. tropica hsp70were obtained from the ear skin. Since hsp70 and ITS1 sequencing was not possible in three cats, the species ofLeishmaniainfecting them was not determined.This is the first report of autochthonous infection withL. tropicain the Iberian Peninsula. Health care professionals, including physicians, dermatologists, and veterinarians, must be aware of this for a correct diagnosis, treatment, and management of possible co-infections.
Human circulatory system response to changes in alveolar pressure and lung volume
Authors: Semenov Yu.S. , Dyachenko A.I. , Melnikov I.S. , Zaripov R.N. 
Published: March 2024

AbstractThe response of hemodynamic parameters in healthy volunteers to changes in alveolar pressure and lung volume was studied by noninvasive methods during respiratory maneuvers similar to Valsalva and Müller maneuvers (in a sitting position and lying on the back horizontally). The following lung volumes and values of pressure (relative to atmospheric pressure) were considered in various combinations: total lung capacity, functional residual capacity, residual volume, -30, -15, 0, +15, +30 mmHg. Changes in hemodynamic parameters averaged over the duration of a maneuver were studied (the duration of a maneuver was 30 s). Changes in alveolar and, accordingly, intrathoracic pressure influenced hemodynamic more strongly than changes in lung volume or body position. Stroke volume decreased with increasing alveolar pressure and increased with decreasing pressure regardless of lung volume and body position; changes ranged from -35 to +15 ml. The effect of changes in alveolar pressure was more pronounced in a sitting position. Heart rate increased with increasing alveolar pressure (up to +20 bpm) but changed little with decrease in pressure. Mean arterial pressure decreased with decreasing alveolar pressure regardless of lung volume and body position; with increasing alveolar pressure, the result depended on lung volume. When performing maneuvers at total lung capacity, mean arterial pressure remained below baseline values, in other cases it increased. Changes in mean arterial pressure were within ±20 mmHg. Regardless of lung volume and body position, total peripheral resistance decreased with decreasing alveolar pressure and increased with increasing alveolar pressure; the range of changes in total peripheral resistance was -0.3 to +0.7 mmHg·s/ml.
The Area-law of Molecular Entropy: Moving beyond Harmonic Approximation
Authors: Roy Amitava , Venkatraman Vishwesh , Ali Tibra 
Published: March 2024

AbstractInspired by black hole thermodynamics, the area law that entropy is proportional to horizon area has been proposed in quantum entanglement entropy and has largely maintained its validity. This article shows that the area law is also valid for the thermodynamic entropy of molecules. We showed that the gas-phase entropy of molecules obeys the area law with our proposed correction for the different curvatures of the molecular surface. The coefficient for the ultraviolet cutoff for the molecular entropy, calculated from our curated experimental data, is tantalizingly close to the valueproposed by Hawking [Hawking, 1976]. The ability to estimate gas-phase entropy by the area law also allows us to calculate molecular entropy faster and more accurately than currently popular methods of estimating molecular entropy with harmonic oscillator approximation. The speed and accuracy of our method will open up new possibilities for the explicit inclusion of entropy in computational biology methods, such as virtual screening applications.
A mathematical model for pancreatic cancer during intraepithelial neoplasia
Authors: Briones-Andrade Joshua , Ramírez-Santiago Guillermo , Romero-Arias J. Roberto 
Published: March 2024

AbstractCancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. To understand the evolution of any type of cancer it is necessary to understand the role of the microenvironmental conditions and the impact of some molecular complexes and mechanisms on certain signalling pathways. As in most cancer quantitative models, the understanding of the early onset of cancer requires a multiscale analysis of the cellular microenvironment. In this paper we analyse a multiscale model of pancreatic adenocarcinoma by modelling the cellular microenvironment through elastic cell interactions and their intercellular communication mechanisms, such as growth factors and cytokines. We focus on the low-grade dysplasia (PanIN 1) and moderate dysplasia (PanIN 2) stages of the pancreatic adenocarcinoma. To this end we propose a gene regulatory network associated with the processes of proliferation and apoptosis of pancreatic cells and its kinetics in terms delayed differential equations to mimic cell development. Likewise, we couple the cell cycle with the spatial distribution of cells and the transport of growth factors to show that the adenocarcinoma evolution is triggered by inflammatory processes. We show that the oncogene RAS may be an important target to develop anti-inflammatory strategies that limit the emergence of more aggressive adenocarcinomas.
Neurosphere culture derived from aged hippocampal dentate gyrus
Authors: Vafaeva Olga , Namchaiw Poommaree , Murray Karl , Diaz Elva , Cheng Hwai-Jong 
Published: March 2024

AbstractThe neurosphere assay is the gold standard for determining proliferative and differentiation potential of neural progenitor cells (NPCs) in neurogenesis studies1–3. While severalin vitroassays have been developed to model the process of neurogenesis, they have predominantly used embryonic and early postnatal NPCs derived from the dentate gyrus (DG). A limitation of these approaches is that they do not provide insight into adult-born NPCs, which are modeled to affect hippocampal function and diseases later in life. Here, we show a novel free-floating neurosphere culture system using NPCs isolated from the DG of mature adult and aged mice.The protocol outlines detailed steps on the isolation, propagation, and maintenance of neurospheres from adult and aged (>12 months old) mouse brain and how to differentiate cultured neurospheres into neurons and astrocytes. Culturing adult and aged NPCs provides an importantin vitromodel to (1) investigate cellular and molecular properties of this unique cell population and (2) expand the understanding of plasticity in the adult and aging brain. This protocol requires ∼2 hours to complete dissection, dissociation and culture plating, while differentiation to neuronal and astrocytic lineages takes 9 days.By focusing on neurospheres obtained from animals at later ages this model facilitates investigation of important biological questions related to development and differentiation of hippocampal neurons generated throughout adult life.
Tuft cells act as regenerative stem cells in the human intestine
Authors: Huang Lulu , Bernink Jochem H. , Giladi Amir , Krueger Daniel , van Son Gijs J.F. , Geurts Maarten H. , Busslinger Georg , Lin Lin , Zandvliet Maurice , Peters Peter J. , López-Iglesias Carmen , Buskens Christianne J. , Bemelman Willem A. , Begthel Harry , Clevers Hans 
Published: March 2024

ABSTRACTIn mice, intestinal tuft cells have been described as a long-lived, post-mitotic cell type of which two distinct subsets have been identified, named tuft-1 and tuft-21. By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase upon interleukin (IL)-4 and IL-13 exposure, as reported previously in mouse2–4. This occurs through proliferation of pre-existing tuft cells, rather than through increasedde novogeneration from stem cells. Indeed, proliferative tuft cells occurin vivoboth in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem- and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.
Whole-body connectome of a segmented annelid larva
Authors: Verasztó Csaba , Jasek Sanja , Gühmann Martin , Bezares-Calderón Luis Alberto , Williams Elizabeth A. , Shahidi Réza , Jékely Gáspár 
Published: March 2024

AbstractNervous systems coordinate effectors across the body during movements. We know little about the cellular-level structure of synaptic circuits for such body-wide control. Here we describe the whole-body synaptic connectome of a segmented larva of the marine annelidPlatynereis dumerilii. We reconstructed and annotated over 9,000 neuronal and non-neuronal cells in a whole-body serial electron microscopy dataset. Differentiated cells were classified into 202 neuronal and 92 non-neuronal cell types. We analyse modularity, multisensory integration, left-right and intersegmental connectivity and motor circuits for ciliated cells, glands, pigment cells and muscles. We identify several segment-specific cell types, demonstrating the heteromery of the annelid larval trunk. At the same time, segmentally repeated cell types across the head, the trunk segments and the pygidium suggest the serial homology of all segmental body regions. We also report descending and ascending pathways, peptidergic circuits and a multi-modal mechanosensory girdle. Our work provides the basis for understanding whole-body coordination in an entire segmented animal.
Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations
Authors: Fernández Ester Calvo , Tomassoni Lorenzo , Zhang Xu , Wang Junqiang , Obradovic Aleksandar , Laise Pasquale , Griffin Aaron T. , Vlahos Lukas , Minns Hanna E. , Morales Diana V. , Simmons Christian , Gallitto Matthew , Wei Hong-Jian , Martins Timothy J. , Becker Pamela S. , Crawford John R. , Tzaridis Theophilos , Wechsler-Reya Robert J. , Garvin James , Gartrell Robyn D. , Szalontay Luca , Zacharoulis Stergios , Wu Cheng-Chia , Zhang Zhiguo , Califano Andrea , Pavisic Jovana 
Published: March 2024

AbstractDiffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis—whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-upin vivovalidation. While individual drugs predicted to target individual subpopulations—including avapritinib, larotrectinib, and ruxolitinib—produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.