bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation
Authors: Bershteyn Marina , Zhou Hongjun , Fuentealba Luis , Chen Chun , Subramanyam Geetha , Cherkowsky Daniel , Salvatierra Juan , Sezan Meliz , Maury Yves , Havlicek Steven , Kriks Sonja , Lee Seonok , Watson Michael , Au Wai , Qiu Yuechen , Nesterova Anastasia , Anderson Derek , Feld Brianna G , Kuzmenko Olga , Grimmett Maria Elena , Hosford Victoria , Jung Ji-Hye , Kowal Tia , Bulfone Alessandro , Banik Gautam , Priest Catherine , Palop Jorge , Nicholas Cory R. 
Published: December 2024

SUMMARYMedial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential regulators of cortical circuits; their dysfunction is associated with numerous neurological disorders. We developed human (h) MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted hMGE-pINs over the lifespan of host mice using single nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer’s disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diversebona-fidehuman SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation as well as a compositional atlas for regenerative cell therapy applications.
An algorithm for predicting per-cell proteomic properties
Authors: Arroyo José Ignacio , Kempes Chris 
Published: December 2024

AbstractProteomic studies have traditionally focused on population-level analyses with an emphasis on the relative abundance of various proteins. Such studies have been useful in uncovering physiological differences across diverse species, the physiological response of individual species to distinct environmental conditions, and the function of individual proteins in the context of cellular networks. However, the absolute value of protein abundance in a cell is important for understanding single-cell physiology, detailed biophysical considerations, connecting diverse quantitative data, and for comparisons across species. Such detailed quantification will naturally occur as singlecell proteomics becomes more prevalent, but it is also of current interest to leverage population studies. There are several challenges here. First, most population studies do not measure the quantity of cells associated with a proteome. Second, recent work has shown that cell physiology radically shifts with cell size, and these effects need to be accounted for in going from population to single-cell estimates. Here we develop and implement a method to estimate the basic properties of proteomes, based on well-established scaling relationships among cell components, including genome size, cell size, and proteome volume. Our method estimates similar but higher total proteins per cell compared to previous theoretical and empirical estimations. Our algorithm has applications for interpreting proteomes, analyzing environmental samples, and designing artificial cells. While focusing on prokaryotes, we discuss how the method can be extended to unicellular and multicellular eukaryotes.
Age-specific control and Alzheimer’s disease reference curves and z-scores for glial fibrillary acidic protein in blood
Authors: Halbgebauer Steffen , Fazeli Badrieh , Klose Veronika , Nagel Gabriele , Rosenbohm Angela , Rothenbacher Dietrich , Bachhuber Franziska , Jesse Sarah , Otto Markus , Landwehrmeyer G. Bernhard , Abdelhak Ahmed , Petzold Axel , Ludolph Albert C. , Tumani Hayrettin ,   the ALS Registry Swabia study group
Published: December 2024

AbstractBackgroundSerum glial fibrillary acidic protein (GFAP) is a biomarker for astrocytic injury and astrogliosis. Concentrations are elevated in numerous neurological disorders, including a pronounced increase in Alzheimer’s disease (AD). However, GFAP levels in the serum also increase with age. Consequently, the integration of GFAP levels into clinical routine and their interpretation demands age-adjusted reference values.MethodsSerum from 1273 subjects (952 non-inflammatory and non-neurodegenerative neurological controls and 321 subjects with AD) were analyzed for GFAP using the microfluidic Ella system. Age-dependent serum GFAP reference values were calculated by additive quantile regression analysis. Percentiles and z-scores were employed for the presentation of GFAP levels as a function of age.ResultsAll patients within the AD continuum exhibited statistically elevated serum GFAP levels in comparison to the control cohort (p<0.0001). This remained the case when the newly generated age-corrected z-scores were applied (p<0.0001). In the control cohort, a non-linear elevation of serum GFAP with increasing age was observed (Spearman correlation coefficient (r) 0.62, 95%CI 0.58-0.66, p<0.0001). In contrast, the AD cohort exhibited a more linear increase in serum GFAP levels (0.16, 95%CI 0.05-0.26, p=0.004). Age-dependent cut-offs for serum GFAP were calculated for different AD age groups. The calculated areas under the curve (AUC 0.97) demonstrated excellent diagnostic test performance in the early onset age group. This effect was less marked in the elderly subjects (AUC 0.72).ConclusionsOur novel GFAP z-scores enable the integration and interpretation of serum GFAP levels in clinical practice, moving from group to individual level. They support both intra- and interindividual interpretation of single GFAP levels in neurological diseases with astrocytic pathology, including an accurate discrimination of Alzheimer’s disease.
Transcriptome regulation analysis in osteoarthritis primary tissues identifies high-confidence effector genes
Authors: Katsoula Georgia , Arruda Ana Luiza , Tutino Mauro , Kreitmaier Peter , Shah Karan M , Swift Diane , Southam Lorraine , Wilkinson J Mark , Zeggini Eleftheria 
Published: December 2024

SummaryOsteoarthritis, a whole-joint degenerative disorder, is a major public health burden that affects nearly 600 million individuals worldwide. Molecular profiling of relevant tissues is crucial for understanding the biological mechanisms underlying disease development. We present the first comprehensive map of transcriptional regulation of disease-relevant primary tissues from knee osteoarthritis patients: macroscopically intact (low-grade, N=263) and degenerated (high-grade, N=216) cartilage, synovium (N=278), and fat pad (N=94). Of 9,738 unique expression quantitative trait loci (eQTL)-associated genes, 60.6% have not been reported previously. We identify 51 genes with directional evidence of tissue-specific colocalization and causal association with knee osteoarthritis, 25 of which are new high-confidence effector genes for osteoarthritis (includingMUSTN1, which is implicated in cartilage integrity). Our study provides valuable insights into the tissue-specific and shared molecular mechanisms underlying osteoarthritis and offers drug repurposing opportunities.Graphical abstract
Optimal intervention strategies for a new pandemic: The case of Covid-19*
Authors: Holden Steinar , Rø Gunnar , Hjort Ingrid 
Published: December 2024

AbstractWe present an age-stratified SEIR-type model of the Norwegian population, which is extended to include the effects of broad types of Non-Pharmaceutical Interventions (NPIs) like general lockdown-policies, contact tracing and quarantine and border control. The model can be used to explore the spread of a new virus with given virulence and transmissibility, and to assess the main costs of the disease and the NPIs in terms of lost health and welfare as well as economic losses. We define the optimal strategy as the intervention policy which minimizes the total costs from the pandemic, including health, economic and other welfare effects. We find that the optimal policy typically is a “bang-bang-strategy”, where costly interventions are either so strict that the pandemic is suppressed to a low level, or they are not used at all. Strict interventions may be used to stop the disease at the herd immunity level (i.e prevent pandemic overshoot), while mitigation policies aimed at merely slowing the spread of the pandemic are not optimal in our baseline simulations. We explore how the optimal strategy depends on the properties of the virus, healthcare capacity, intervention costs, population behavior and other relevant variables. These results are informative for decisions regarding costly investments and interventions. In addition, we explore the consequences of policy errors and delays, providing guidance for decision making in the uncertain early stages of a new pandemic.
The essential host genome forCryptosporidiumintracellular survival exposes metabolic dependencies that can be leveraged for treatment
Authors: Marzook N. Bishara , Song Ok-Ryul , Baumgärtel Lotta , Bernitz Netanya , Mkandawire Tapoka T. , Watson Lucy C. , Nunes Vanessa , Warchal Scott , MacRae James I. , Howell Michael , Sateriale Adam 
Published: December 2024

ABSTRACTMapping how pathogens interact with their host cells can reveal unexpected pathogen and host cell biology, paving the way for new treatments.Cryptosporidiumis an intracellular parasite of intestinal epithelial cells, and a leading cause of diarrheal death and disease in infants worldwide. Despite this, very little is known about the cell biology of infection of this eukaryotic pathogen. Here, we designed and implemented a unique microscopy-based arrayed CRISPR-Cas9 screen to interrogate the effects of the loss of every protein-coding human gene on aCryptosporidiuminfection. As the experimental readout is image-based, we extracted multiple phenotypic features of infection, including parasite growth, progression of the parasite to its sexual life stage, and recruitment of host actin to ‘pedestals’ beneath the parasite vacuole. Using this dataset, we discovered a tipping point in the host cholesterol biosynthesis pathway that controlsCryptosporidiuminfection. Parasite growth can either be inhibited or promoted by the intermediary metabolite squalene. A build-up of squalene in epithelial cells creates a reducing environment, with more reduced host glutathione available for uptake by the parasite. BecauseCryptosporidiumhas lost the ability to synthesise glutathione, this uptake from the host cell is required for growth and progression through its life cycle. We demonstrate that this dependency can be leveraged for treatment with the abandoned drug lapaquistat, an inhibitor of host squalene synthase that has efficacy againstCryptosporidium in vitroandin vivo.
PITHD1: An Endogenous Inhibitor of the 26S Proteasome During Cellular Dormancy
Authors: Amann Sascha J. , Dong Ken , Roehsner Josef , Krall Dominik , Grishkovskaya Irina , Kotisch Harald , Schleiffer Alexander , Roitinger Elisabeth , Pauli Andrea , Martin Andreas , Haselbach David 
Published: December 2024

AbstractCellular dormancy represents a state of regulated growth arrest essential for diverse biological processes, from reproduction to cancer progression. While mechanisms controlling protein synthesis in dormant cells have been identified, how cells regulate protein degradation during dormancy remains unclear. Using zebrafish oocytes, eggs and embryos as a model system, we discovered PITHD1 as an endogenous inhibitor of the 26S proteasome. Our high-resolution cryoEM structure reveals that PITHD1 simultaneously blocks three crucial functional sites on the 19S regulatory particle which are required for ubiquitin recognition, processing, and substrate translocation. This triple-lock mechanism effectively prevents protein degradation in dormant cells. Given PITHD1’s evolutionary conservation across species, this mechanism likely represents a general strategy for reversible proteasome regulation during cellular dormancy. Our findings establish a new paradigm for controlling proteostasis in quiescent states.
Glucose-Sensing ChREBP Protein in the Pathogenesis of Diabetic Retinopathy
Authors: Starr Christopher R. , Zhylkibayev Assylbek , Gorbatyuk Oleg , Nuotio-Antar Alli M. , Mobley James , Grant Maria B. , Gorbatyuk Marina 
Published: December 2024

AbstractGlucose-sensing ChREBP and MondoA are transcriptional factors involved in lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRPmice with constitutively active (ca) ChREBP. These mice underwent retinal function testing, followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both pro-teins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photo-receptor degeneration as we observed diminished scotopic ERG amplitudes detected in caChREB-PRPmice at P35. The retinal proteomic landscape indicated a decline in KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific ca-ChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBPcells displayed a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprograming triggering retinal functional loss in mice
High resolution imaging and interpretation of three-dimensional RPE sheet structure
Authors: Donaldson Kevin J. , Chrenek Micah A. , Boatright Jeffrey H. , Nickerson John M. 
Published: December 2024

AbstractThe retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell to cell contact, barrier function, and conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers.We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (alpha-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misinterpreting multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO3 oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes.
Convergence of autism proteins at the cilium
Authors: Kostyanovskaya Elina , Lasser Micaela C. , Wang Belinda , Schmidt James , Bader Ethel , Buteo Chad , Arbelaez Juan , Sindledecker Aria Rani , McCluskey Kate E. , Castillo Octavio , Wang Sheng , Dea Jeanselle , Helde Kathryn A. , Graglia J. Michael , Brimble Elise , Kastner David B. , Ehrlich Aliza T. , State Matthew W. , Willsey A. Jeremy , Willsey Helen Rankin 
Published: December 2024

AbstractHundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete. Our recent autism functional genetics work has suggested that these genes may share a common mechanism at the cilium, a membrane-bound organelle critical for neurogenesis, brain patterning, and neuronal activity–all processes strongly implicated in autism. Moreover, autism commonly co-occurs with conditions that are known to involve ciliary-related pathologies, including congenital heart disease, hydrocephalus, and blindness. However, the role of autism genes at the cilium has not been systematically investigated. Here we demonstrate that autism proteins spanning disparate functional annotations converge in expression, localization, and function at cilia, and that patients with pathogenic variants in these genes have cilia-related co-occurring conditions and biomarkers of disrupted ciliary function. This degree of convergence among genes spanning diverse functional annotations strongly suggests that cilia are relevant to autism, as well as to commonly co-occurring conditions, and that this organelle should be explored further for therapeutic potential.One-Sentence SummaryAutism genes of diverse functional annotations converge at cilia, deepening our understanding of underlying autism biology and co-occurring conditions.
GET3B interacts with the thylakoidal ALB3 and ALB4 insertases and is involved in the initial stages of chloroplast biogenesis
Authors: Bodensohn Uwe , Dünschede Beatrix , Kuhlmann Chiara , Kumari Khushbu , Ladig Roman , Grefen Christopher , Schleiff Enrico , Fernandez Donna , Schünemann Danja 
Published: December 2024

AbstractProtein targeting and insertion into membranes are essential for cellular organization and organelle function. The Guided Entry of Tail-anchored (GET) pathway facilitates the post-translational targeting and insertion of tail-anchored (TA) membrane proteins.Arabidopsis thalianahas four GET3 homologues, includingAtGET3B andAtGET3D localized to chloroplasts. These photosynthetic organelles possess complex membrane systems, and the mechanisms underlying their protein targeting and membrane biogenesis are not fully understood. This study conducted a comprehensive proteomic analysis ofget3bmutant plastids, which displayed significant alterations. Fluorometric based complex assembly as well as CO2assimilation analyses confirmed that disruption of GET3B function displayed a significant impact on photosystem II assembly as well as carbon fixation, respectively, indicating a functional role in chloroplast biogenesis. Additionally, genetic interactions were found between GET3B and the two component STIC system, which cooperates with the cpSRP pathway and is involved in the co-translational sorting of thylakoid proteins. Further, physical interactions were observed between GET3B and the C-terminus of ALB3 and ALB4in vitroand the full length proteinsin vivo, indicating a role of GET3B in protein targeting and membrane integration within chloroplasts. These findings enhance our understanding of GET3B’s involvement in stromal protein targeting and thylakoidal biogenesis.
The impact of organisational resilience and government communication on the well-being of tourism SME operators
Authors: Natoli Riccardo , Nguyen Van K. , Gamage Ancy , Pyke Joanne , de Lacy Terry , Nguyen Thu-Huong , Drake Colin 
Published: December 2024

Purpose
Drawing on crisis management theory and complexity theory, the purpose of this study is to examine the impact of a prolonged COVID-19 induced lockdown on tourism small and medium enterprise (SME) operators’ well-being.

Design/methodology/approach
A mixed methods approach was used, with survey data from 226 SME tourism operators located in Victoria (Australia) and 33 interviews with a cross-representative selection of tourism stakeholders.

Findings
The findings of this study show that planned resilience, adaptive resilience, government communication (i.e. Roadmap to Recovery announcement) and revenue status are positively linked to well-being.

Research limitations/implications
The cross-sectional nature of this study is not able to provide evidence of a temporal relationship between exposure and outcome, as both are examined at the same time. This study is restricted to one Australian State and may have limited generalisability.

Practical implications
The findings identify strategies to improve tourism SMEs resilience and their operator well-being. Programs designed to meet the needs of tourism SME owners and enhance access to well-being services, while training for SME tourism operators should focus on improving the diversification potential of the business.

Originality/value
To the best of the authors’ knowledge, this is among the first studies applying crisis management and complexity theories as theoretical lenses to explore the joint effect of organisational resilience and government communication on SME tourism operators’ well-being. The inclusion of communication on SME well-being is an area hitherto unexplored in the tourism literature.
Grand Challengers: the exemplars of Follett and Barnard
Authors: S. O’Connor Ellen 
Published: December 2024

Purpose
This study aims to present a new contribution from recognized historical sources that gives proven knowledge on how to develop individuals to meet Grand Challenges.

Design/methodology/approach
Textual analysis and interpretive synthesis of little-known biographical and autobiographical data on Mary Parker Follett and Chester Barnard showing a method for meeting Grand Challenges.

Findings
Follett and Barnard developed a method of self-development for making significant societal contributions.

Research limitations/implications
The major limitation is a claim that there is sufficient empirical evidence to document a strictly internal process of Follett’s and Barnard’s.

Practical implications
A method that is teachable and replicable.

Social implications
A method that could scale to a curriculum enabling better and faster development of Grand Challengers.

Originality/value
A new contribution, from historically recognized sources, which responds to a leadership crisis in general and particularly where Grand Challenges are concerned.