bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population genomic analysis reveals genetic structure and thermal-tolerant genotypes in remnant Tasmanian giant kelp populations
Authors: Iha Cintia , Layton Cayne , Amancio Carlos E. , Flentje Warren , Lenton Andrew , Fraser Ceridwen I. , Johnson Craig , Willis Anusuya 
Published: October 2023

AbstractGiant kelp,Macrocystis pyrifera, is a foundation species that forms dense forests of complex physical habitat and supports coastal biodiversity, productivity, and other essential ecosystem services. Tasmanian coasts have suffered a massive decline in giant kelp forests due to changes in regional oceanography and environmental conditions, but efforts are being made to restore these disappearing populations using identification and selective breeding for lineages that are more tolerant to warmer temperatures. Here, we used gametophytes that originated from remnant populations collected at three sites in northeastern and three sites in southeastern Tasmania to determine the genetic structure of the giant kelp population via genotyping-by-sequencing (GBS) and assembled a draft genome from a Tasmanian giant kelp sporophyte individual. Previous research identified seven strain lines that were tolerant to warm temperatures, and we used the GBS data to test whether genotypes were associated with warm tolerance. Kelps from the north were genetically distinct from the southern ones, with much lower gene flow between regions than within regions. These results revealed that giant kelp populations from Tasmania are more genetically structured than previously thought. Two loci were significantly associated with warm temperature tolerance. They are population-specific: the alternative allele from one of the loci was found only in the northern populations, while the other was found in the southern populations. This could suggest that thermal tolerance is adapting locally or drifting given large changes in population demography, but further research is needed to confirm this hypothesis. Our research sheds light on genetic patterns in this critical habitat-forming kelp and will help inform conservation management, including selective breeding.
Volumetric Compression Shifts Rho GTPase Balance and Induces Mechanobiological Cell State Transition
Authors: Gong Xiangyu , Nguyen Ryan , Chen Zehua , Wen Zhang , Zhang Xingjian , Mak Michael 
Published: October 2023

AbstractDuring development and disease progression, cells are subject to osmotic and mechanical stresses that modulate cell volume, which fundamentally influences cell homeostasis and has been linked to a variety of cellular functions. It is not well understood how the mechanobiological state of cells is programmed by the interplay of intracellular organization and complex extracellular mechanics when stimulated by cell volume modulation. Here, by controlling cell volume via osmotic pressure, we evaluate physical phenotypes (including cell shape, morphodynamics, traction force, and extracellular matrix (ECM) remodeling) and molecular signaling (YAP), and we uncover fundamental transitions in active biophysical states. We demonstrate that volumetric compression shifts the ratiometric balance of Rho GTPase activities, thereby altering mechanosensing and cytoskeletal organization in a reversible manner. Specifically, volumetric compression controls cell spreading, adhesion formation, and YAP nuclear translocation, while maintaining cell contractile activity. Furthermore, we show that on physiologically relevant fibrillar collagen I matrices, which are highly non-elastic, cells exhibit additional modes of cell volume-dependent mechanosensing that are not observable on elastic substrates. Notably, volumetric compression regulates the dynamics of cell-ECM interactions and irreversible ECM remodeling via Rac-directed protrusion dynamics, at both the single-cell level and the multicellular level. Our findings support that cell volume is a master biophysical regulator and reveal its roles in cell mechanical state transition, cell-ECM interactions, and biophysical tissue programming.
Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype
Authors: Gong Xiangyu , Ogino Noriyoshi , Leite M. Fatima , Chen Zehua , Nguyen Ryan , Liu Raymond , Kruglov Emma , Flores Kaitlin , Cabral Aiden , Mendes Gabriel M. M. , Ehrlich Barbara E. , Mak Michael 
Published: October 2023

AbstractLiver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and β-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells.Significance statementCompression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.
The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience
Authors: Pabis Kamil , Barardo Diogo , Gruber Jan , Sirbu Olga , Selvarajoo Kumar , Kaeberlein Matt , Kennedy Brian K. 
Published: October 2023

ABSTRACTAlthough lifespan extension remains the gold standard for assessing interventions hypothesized to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that the use of short-lived control cohorts tends to exaggerate the relative efficacy of putative longevity interventions. Moreover, due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups.To facilitate identification of successful interventions, we propose an alternative approach. The level of confidence we can have in an intervention is proportional to the degree of lifespan extension above the strain- and species-specific upper limit of lifespan, which we can estimate from comparison to historical controls. In the absence of independent replication, a putative mouse longevity intervention should only be considered with high confidence when control lifespans are close to 900 days or if the final lifespan of the treated group is considerably above 900 days. Using this “900-day rule” we identified several candidate interventions from the literature that merit follow-up studies.
Cortical networks of parkinsonian gait: a metabolic and functional connectivity study
Authors: Pellegrini Franziska , Pozzi Nicoló G. , Palmisano Chiara , Marotta Giorgio , Buck Andreas , Haufe Stefan , Isaias Ioannis U. 
Published: October 2023

AbstractObjectiveLocomotion is an automated voluntary movement sustained by coordinated neural synchronization across a distributed brain network. The cerebral cortex is central for adapting the locomotion pattern to the environment and alterations of cortical network dynamics can lead to gait impairments. Gait problems are a common symptom with a still unclear pathophysiology and represent an unmet therapeutical need in Parkinson’s disease. Little is known about the cortical network dynamics of locomotor control in these patients.MethodsWe studied the cortical basis of parkinsonian gait by combining metabolic brain imaging with high-density EEG recordings and kinematic measurements performed at rest and during unperturbed overground walking.ResultsWe found significant changes in functional connectivity between frontal, sensorimotor and visuomotor cortical areas during walking as compared to resting. Specifically, hypokinetic gait was associated with poor information flow from the supplementary motor area (SMA) to precuneus and from calcarine to lingual gyrus as well as high information flow from calcarine to cuneus.InterpretationOur findings support a role for visuomotor integration processes in PD-related hypokinetic gait and suggest that reinforcing visual information may act as a compensatory strategy to allow SMA-related feedforward locomotor control in PD.
Influence of socioeconomic status on functional outcomes after stroke: a systematic review and meta-analysis
Authors: Nguyen Mai T H , Sakamoto Yuki , Maeda Toshiki , Woodward Mark , Anderson Craig S. , Catiwa Jayson , Yazidjoglou Amelia , Carcel Cheryl , Yang Min , Wang Xia 
Published: October 2023

AbstractBackgroundDespite advances in stroke treatment and rehabilitation, socioeconomic factors have an important impact on recovery from stroke. This review aimed to quantify the impact of socioeconomic status (SES) on functional outcomes from stroke and identify the SES indicators that exhibit the highest magnitude of association.MethodsWe performed a systematic literature search across Medline and Embase databases up to May 2022, for studies fulfilling the following criteria: observational studies with ≥100, patients aged ≥18 years with stroke diagnosis based on clinical examination or in combination with neuroimaging, reported data on the association between SES and functional outcome, assessed functional outcomes with the modified Rankin Scale (mRS) or Barthel index tools, provided estimates of association (odds ratios [OR] or equivalent), and published in English. Risk of bias was assessed using the modified Newcastle Ottawa Scale.FindingsWe identified 7,698 potentially eligible records through the search after removing duplicates. Of these, 19 studies (157,715 patients, 47.7% women) met our selection criteria and were included in the meta-analyses. Ten studies (53%) were assessed as low risk of bias. Measures of SES reported were education (11 studies), income (8), occupation (4), health insurance status (3), and neighbourhood socioeconomic deprivation (3). Random-effect meta-analyses revealed low SES was significantly associated with poor functional outcomes: incomplete education or below high school level versus high school attainment and above (OR [95% CI]: 1.66 [1.40, 1.95]), lowest income versus highest income (1.36 [1.02, 1.83], a manual job/unemployed versus a non-manual job/employed (1.62 [1.29, 2.02]), and living in the most disadvantaged socioeconomic neighbourhood versus the least disadvantaged (1.55 [1.25, 1.92]). Low health insurance status was also associated with an increased risk of poor functional outcomes (1.32 [0.95, 1.84]), although not statistically significant.ConclusionsSocioeconomic disadvantage remains a risk factor for poor functional outcomes after an acute stroke. Further research is needed to better understand causal mechanisms and disparities.FundingThis study is supported by an NHMRC Investigator grant (APP1195237).
Testing the sensitivity of diagnosis-derived patterns in functional brain networks to symptom burden in a Norwegian youth sample
Authors: Voldsbekk Irene , Kjelkenes Rikka , Frogner Erik R. , Westlye Lars T. , Alnæs Dag 
Published: October 2023

AbstractAberrant brain network development represents a putative aetiological component in mental disorders, which typically emerge during childhood and adolescence. Previous studies have identified resting-state functional connectivity (RSFC) patterns reflecting psychopathology, but the generalisability to other samples and politico-cultural contexts has not been established.We investigated whether a previously identified cross-diagnostic case-control and autism spectrum disorder (ASD)-specific pattern of RSFC (discovery sample; aged 5-21 from New York City, USA; n=1666) could be validated in a Norwegian convenience-based youth sample (validation sample; aged 9-25 from Oslo, Norway; n=531). As a test of generalisability, we investigated if these diagnosis-derived RSFC patterns were sensitive to levels of symptom burden in both samples, based on an independent measure of symptom burden.Both the cross-diagnostic and ASD-specific RSFC pattern were validated across samples. Connectivity patterns were significantly associated with thematically appropriate symptom dimensions in the discovery sample. In the validation sample, the ASD-specific RSFC pattern showed a weak, inverse relationship with symptoms of conduct problems, hyperactivity, and prosociality, while the cross-diagnostic pattern was not significantly linked to symptoms.Diagnosis-derived connectivity patterns in a developmental clinical US sample were validated in a convenience sample of Norwegian youth, however, they were not associated with mental health symptoms.
The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity
Authors: Richenberg George , Francis Amy , Owen Carina N. , Gray Victoria , Robinson Timothy , AG Gabriel Aurélie , Lawrenson Kate , Crosbie Emma J. , Schildkraut Joellen M. , Mckay James D. , Gaunt Tom R. , Relton Caroline L. , Vincent Emma E. , Kar Siddhartha P. 
Published: October 2023

ABSTRACTHigh body mass index (BMI) is a causal risk factor for endometrial cancer but the tumor molecular mechanisms affected by adiposity and their therapeutic relevance remain poorly understood. Here we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic exposure to elevated BMI. We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted life-course BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. High BMI germline PGS was associated with (i) upregulated tumor gene expression in theIL6-JAK-STAT3pathway (FDR=4.2×10−7); (ii) increased estimated intra-tumor activated mast cell infiltration (FDR=0.008); (iii) increased single base substitution (SBS) mutational signatures 1 (FDR=0.03) and 5 (FDR=0.09) and decreased SBS13 (FDR=0.09), implicating age-related and APOBEC mutagenesis, respectively; and (iv) decreased tumor EGFR protein expression (FDR=0.07). Alterations inIL6-JAK-STAT3signaling gene and EGFR protein expression were, in turn, significantly associated with both overall survival and progression-free interval. Thus, we integrated germline and somatic data using a novel study design to identify associations between genetically predicted lifelong exposure to higher BMI and potentially actionable endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development and progression of this cancer, impacting endometrial tumor biology and clinical outcomes.
Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells
Authors: Hammer Quirin , Perica Karlo , van Ooijen Hanna , Mbofung Rina , Momayyezi Pouria , Varady Erika , Martin Karen E. , Pan Yijia , Jelcic Mark , Groff Brian , Abujarour Ramzey , Krokeide Silje , Lee Tom , Williams Alan , Goodridge Jode P. , Valamehr Bahram , Önfelt Björn , Sadelain Michel , Malmberg Karl-Johan 
Published: October 2023

SUMMARYAllogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection, although absence ofB2Mtriggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligandsCD54andCD58on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion ofCD54andCD58inB2M-deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cellsin vitroandin vivowithout affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.
MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death
Authors: Van Kessel Antonius T. M. , Cosa Gonzalo 
Published: October 2023

AbstractFerroptosis is a regulated form of cell death characterized by lipid peroxidation and lipid hydroperoxide (LOOH) generation that offers new therapeutic opportunities. However, the molecular mechanism through which LOOH accumulation leads to cell death remains poorly understood. Importantly, LOOH breakdown forms truncated phospholipids (PLs) and highly reactive lipid-derived electrophiles (LDEs) capable of altering protein function through cysteine alkylation. While truncated PLs have been shown to mediate ferroptotic membrane permeabilization, a functional role for LDEs in the ferroptotic cell death mechanism has not been established. Here, using multidrug resistance protein 1 (MRP1) activity as an example, we demonstrate that LDEs mediate altered protein functionduring ferroptosis. Applying live cell fluorescence imaging, we first identified that inhibition of MRP1-mediated LDE detoxification occurs across a panel of ferroptosis inducers (FINs) with differing mechanisms of ferroptosis induction (Types I-IV FINs erastin, RSL3, FIN56 and FINO2). This MRP1 inhibition was recreated by both initiation of lipid peroxidation and treatment with the LDE 4-hydroxy-2-nonenal (4-HNE). Importantly, treatment with radical-trapping antioxidants prevented impaired MRP1 activity when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of inhibited MRP1 activity during ferroptosis. Our findings, when combined with reports of widespread LDE-alkylation of key proteins during ferroptosis, sets a precedent for LDEs as critical mediators of ferroptotic cell death. LOOH breakdown to truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function during late stage ferroptosis, offering a unified explanation of the molecular ferroptotic cell death mechanism.
Nanoscale Structural Mapping of Protein Aggregates in Live Cells Modeling Huntington’s Disease
Authors: Guo Zhongyue , Chiesa Giulio , Yin Jiaze , Sanford Adam , Meier Stefan , Khalil Ahmad S. , Cheng Ji-Xin 
Published: October 2023

AbstractProtein aggregation, in the form of amyloid fibrils, is intimately correlated with many neurodegenerative diseases. Despite recent advances in structural biology, it remains challenging to acquire structural information of proteins in live cells. Tagging with fluorescent proteins, like green fluorescent protein (GFP), is routinely used for protein visualization. Yet, this method alone cannot provide detailed structural information on the protein system of interest, and tagging proteins has the potential to perturb native structure and function. Here, by fluorescence-detected as well as label-free scattering-based mid-infrared photothermal (MIP) microscopy, we demonstrate nanoscale mapping of secondary structure of protein aggregates in a yeast model of Huntington’s disease. We first used GFP as a highly sensitive photothermal reporter to validate β-sheet enrichment in huntingtin (htt) protein aggregates. We then obtained label-free structural maps of protein aggregates. Our data showed that the fluorescent protein tag indeed perturbed the secondary structure of the aggregate, evident by a spectral shift. Live cell MIP spectroscopy further revealed the fine spatial distribution of structurally distinct components in protein aggregates, featuring a 246-nm diameter core highly enriched in β-sheet surrounded by a ɑ-helix-rich shell. Interestingly, this structural partition exists only in presence of the [RNQ+] prion, a prion that acts to facilitate the formation of other amyloid prions. Indeed, when htt is induced to aggregate in the absence of this prion ([rnq-] state), it forms non-toxic amyloid aggregates exclusively. These results showcase the potential of MIP for unveiling detailed and subtle structural information on protein systems in live cells.SignificanceProtein aggregation is a hallmark of neurodegenerative diseases, such as Huntington’s Disease. Understanding the nature of neurotoxic aggregates could lead to better therapeutic approaches. The limited progress in this direction is partly due to the lack of tools for extracting structural information in the physiological context of the aggregates. Here, we report a photothermally detected mid-infrared micro-spectroscopy technique able to dissect the secondary structure of aggregates of the huntingtin protein in live cells. We describe for the first time a nanoscale partition of secondary structures between β-rich core and ɑ-rich shell of the aggregates. This work demonstrates the potential of mid-infrared photothermal microscopy for structural and functional mapping of proteins in live cells.
A robust life-or-death selection platform for enzyme evolution
Authors: Jansen Suzanne C. , Mayer Clemens 
Published: October 2023

AbstractLife-or-death selections evaluate the fitness of individual organisms on a population level. In enzyme engineering, such growth selections allow the rapid and straightforward identification of highly efficient biocatalysts from extensive libraries. However, selection-based improvement of (industrially-relevant) biocatalysts is challenging, as they require highly dependable strategies that artificially link their activities to host survival. Here, we showcase a robust and scalable life-or-death selection platform centered around the complementation of non-canonical amino acid-dependent bacteria. Specifically, we demonstrate how serial passaging of populations featuring millions of carbamoylase variants autonomously selects biocatalysts with up to 90,000-fold higher initial rates. Notably, selection of replicate populations enriched diverse biocatalysts, which feature distinct amino-acid motifs that drastically boost carbamoylase activity. As beneficial substitutions also originated from unintended copying errors during library preparation or cell division, we anticipate that our life-or-death selection platform will be applicable to the continuous, autonomous evolution of diverse biocatalysts in the future.