bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivalent coiled-coil interactions enable full-scale centrosome assembly and strength
Authors: Rios Manolo U. , Bagnucka Małgorzata A. , Ryder Bryan D. , Gomes Beatriz Ferreira , Familiari Nicole , Yaguchi Kan , Amato Matthew , Joachimiak Łukasz A. , Woodruff Jeffrey B. 
Published: May 2023

ABSTRACTDuring mitotic spindle assembly, microtubules generate tensile stresses on pericentriolar material (PCM), the outermost layer of centrosomes. The molecular interactions that enable PCM to assemble rapidly and resist external forces are unknown. Here we use cross-linking mass spectrometry to identify interactions underlying supramolecular assembly of SPD-5, the main PCM scaffold protein inC. elegans. Crosslinks map primarily to alpha helices within the phospho-regulated region (PReM), a long C-terminal coiled-coil, and a series of four N-terminal coiled-coils. PLK-1 phosphorylation of SPD-5 creates new homotypic contacts, including two between PReM and the CM2-like domain, and eliminates numerous contacts in disordered linker regions, thus favoring coiled-coil-specific interactions. Mutations within these interacting regions cause PCM assembly defects that are partly rescued by eliminating microtubule-mediated forces. Thus, PCM assembly and strength are interdependent.In vitro, self-assembly of SPD-5 scales with coiled-coil content, although there is a defined hierarchy of association. We propose that multivalent interactions among coiled-coil regions of SPD-5 build the PCM scaffold and contribute sufficient strength to resist microtubule-mediated forces.
FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe
Authors: Jennings Lucy , Walters Heather Andrews , Mason Jennifer M. 
Published: May 2023

ABSTRACTWEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.
Lethal thermal limits in embryos of two intertidally brooding nassariid species, and evolution of a protective developmental mechanism conditioned by maternal experience
Authors: Goulding Morgan Q 
Published: May 2023

SummaryTritia obsoletaandPhrontis vibexare distant relatives in the neogastropod clade Nassariidae (1). Both species are common along coastline from Maine to the Caribbean; females deposit clutches of zygotes in capsules cemented to solid surfaces in intertidal flats (2), with swimming veliger larvae emerging after about a week of development. In this study, embryos ofT. obsoleta(from Massachusetts and Florida) andP. vibex(from Florida) were exposed to temperatures ranging from 33° to 37°C. In both species, very young embryos are especially sensitive to thermal stress. Brief early heat shock did not disturb spiral cleavage geometry but led to variable, typically severe defects in larval morphogenesis and tissue differentiation. InT. obsoletabut notP. vibex, early heat shock resulted in immediate slowing or arrest of interphase progression. This reversible arrest is correlated with improved prognosis for larval development, and (in Massachusetts snails) depends on parental exposure to warm temperature. Embryos from Massachusetts snails housed at lower temperature exhibited cytokinesis defects in response to even mild warming. Thus, parents informed by experience may or may not endow their young with a developmental braking mechanism that lets them withstand occasional perilous conditions during the most vulnerable stage of life.
Cisplatin Induces BDNF Downregulation in Middle-Aged Female Rat Model while BDNF Enhancement Attenuates Cisplatin Neurotoxicity
Authors: Lomeli Naomi , Pearre Diana C. , Cruz Maureen , Di Kaijun , Bota Daniela A. 
Published: May 2023

AbstractCancer-related cognitive impairments (CRCI) are debilitating consequences of cancer treatment with platinum agents (e.g., cisplatin) that greatly alter cancer survivors’ health-related quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning, and memory, and the reduction of BDNF is associated with the development of cognitive impairment in various neurological disorders, including CRCI. Our previous CRCI rodent studies have shown that cisplatin reduces hippocampal neurogenesis and BDNF expression and increases hippocampal apoptosis, which is associated with cognitive impairments. Few studies have reported on the effects of chemotherapy and medical stress on serum BDNF levels and cognition in middle-aged female rat models. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive performance in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected ten weeks after cisplatin completion. We also screened three BDNF-augmenting compounds, riluzole, ampakine CX546, and CX1739, for their neuroprotective effects on hippocampal neurons,in vitro. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD95. Ampakines (CX546 and CX1739) but not riluzole altered the antitumor efficacy of cisplatin in two human ovarian cancer cell lines, OVCAR8 and SKOV3.ip1,in vitro.In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels with cognitive function. We conducted anin vitroscreening of BDNF-enhancing agents to evaluate their potential neuroprotective effects against cisplatin-induced neurotoxicity and their effect on ovarian cancer cell viability.
The cellular basis of feeding-dependent body size plasticity in sea anemones
Authors: Garschall Kathrin , Pascal-Carreras Eudald , Garcia-Pascual Belén , Filimonova Daria , Guse Annika , Johnston Iain G. , Steinmetz Patrick R.H 
Published: May 2023

AbstractAnimals with indeterminate growth can adapt their growth rate and body size to changing food availability throughout their lifetime. As the cellular basis underlying food-dependent growth plasticity is poorly understood, we quantified how the sea anemonesNematostella vectensisandExaiptasia diaphana(Aiptasia) respond to feeding and starvation on organismal and cellular levels. Using mathematical modelling to analyse growth phases, we found that growth and shrinkage rates inNematostellaare exponential, stereotypic and accompanied by high levels of cell gain or loss, respectively. During starvation and re-feeding, a considerable proportion of juvenile polyp cells (>7%) reversibly shift between S/G2/M and G1/G0cell cycle phases, suggesting a tight nutritional control of quiescence and cell cycle re-entry. In the facultative symbiotic sea anemone Aiptasia, we found that growth and cell proliferation rates are dependent on the symbiotic state and, in comparison toNematostella, respond less strongly to changes in food supply. Altogether, we provide a benchmark and resource to study the nutritional regulation of body plasticity on molecular, cellular and genomic levels using the rich functional toolkit available forNematostella.Summary statementFeeding and starvation in sea anemones induce growth and shrinkage, cell size changes and dynamic cell proliferation changes that support a nutritional control of quiescence and cell cycle re-entry.
Indirect Correlative Light and Electron Microscopy (iCLEM): A Novel Pipeline for Multiscale Quantification of Structure from Molecules to Organs
Authors: Struckman Heather L. , Moise Nicolae , Vanslembrouck Bieke , Rothacker Nathan , Chen Zhenhui , van Hengel Jolanda , Weinberg Seth H. , Veeraraghavan Rengasayee 
Published: May 2023

AbstractCorrelative light and electron microscopy (CLEM) methods are powerful methods which combine molecular organization (from light microscopy) with ultrastructure (from electron microscopy). However, CLEM methods pose high cost/difficulty barriers to entry and have very low experimental throughput. Therefore, we have developed anindirectcorrelative light and electron microscopy (iCLEM) pipeline to sidestep the rate limiting steps of CLEM (i.e., preparing and imaging the same samples on multiple microscopes) and correlate multiscale structural data gleaned from separate samples imaged using different modalities by exploiting biological structures identifiable by both light and electron microscopy as intrinsic fiducials.We demonstrate here an application ofiCLEM, where we utilized gap junctions and mechanical junctions between muscle cells in the heart as intrinsic fiducials to correlate ultrastructural measurements from transmission electron microscopy (TEM), and focused ion beam scanning electron microscopy (FIB-SEM) with molecular organization from confocal microscopy and single molecule localization microscopy (SMLM). We further demonstrate howiCLEMcan be integrated with computational modeling to discover structure-function relationships. Thus, we presentiCLEMas a novel approach that complements existing CLEM methods and provides a generalizable framework that can be applied to any set of imaging modalities, provided suitable intrinsic fiducials can be identified.
Adaptive RAxML-NG: Accelerating Phylogenetic inference under Maximum Likelihood using dataset difficulty
Authors: Togkousidis Anastasis , Kozlov Alexey M. , Haag Julia , Höhler Dimitri , Stamatakis Alexandros 
Published: May 2023

ABSTRACTMotivationPhylogenetic inferences under the Maximum-Likelihood (ML) criterion deploy heuristic tree search strategies to explore the vast search space. Depending on the input dataset, searches from different starting trees might all converge to a single tree topology. Often, though, distinct searches infer multiple topologies with large log-likelihood score differences or yield topologically highly distinct, yet almost equally likely, trees. Recently, Haaget al. introduced an approach to quantify, and implemented machine learning methods to predict, the difficulty of an MSA with respect to phylogenetic inference. Easy MSAs exhibit a single likelihood peak on their likelihood surface, associated with a single tree topology to which most, if not all, independent searches rapidly converge. However, as difficulty increases, multiple locally optimal likelihood peaks emerge, yet from highly distinct topologies.ResultsTo this end, we introduce and implement an adaptive tree search heuristic in RAxML-NG, which modifies the thoroughness of the tree search strategy as a function of the predicted difficulty. Our adaptive strategy is based upon three observations. First, on easy datasets, searches converge rapidly and can hence be terminated at an earlier stage. Second, over-analyzing difficult datasets is hopeless and, thus, it suffices to quickly infer only one of the numerous almost equally likely topologies, to reduce overall execution time. Third, more extensive searches are justified and required on datasets with intermediate difficulty. While the likelihood surface exhibits multiple locally optimal peaks in this case, a small proportion of them is significantly better. Our experimental results for the adaptive heuristic on 9, 515 empirical and 5, 000 simulated datasets with varying difficulty exhibit substantial speedups, especially on easy and difficult datasets (53% of total MSAs), where we observe average speedups of more than 10x. Further, approximately 94% of the inferred trees using the adaptive strategy are statistically indistinguishable from the trees inferred under the standard strategy (RAxML-NG).AvailabilityGNU GPL athttps://github.com/togkousa/raxml-ng/tree/adaptive.ContactAnastasis.Togkousidis@h-its.orgSupplementary MaterialAvailable
Extrastriate activity reflects the absence of local retinal input
Authors: Urale Poutasi W. B. , Zhu Lydia , Gough Roberta , Arnold Derek , Schwarzkopf Dietrich Samuel 
Published: May 2023

AbstractThe physiological blind spot corresponds to the optic disc where the retina contains no light-detecting photoreceptor cells. Our perception seemingly fills in this gap in input. Here we suggest that rather than an active process, such perceptual filling-in could instead be a consequence of the integration of visual inputs at higher stages of processing discounting the local absence of retinal input. Using functional brain imaging, we resolved the retinotopic representation of the physiological blind spot in early human visual cortex and measured responses while participants perceived filling-in. Responses in early visual areas simply reflected the absence of visual input. In contrast, higher extrastriate regions responded more to stimuli in the eye containing the blind spot than the fellow eye. However, this signature was independent of filling-in. We argue that these findings agree with philosophical accounts that posit that the concept of filling-in of absent retinal input is unnecessary.
Toward Understanding Genetic Risk of Burnout through Genome-wide Associations of Cynicism and Cynical Distrust
Authors: Chapleau Richard R 
Published: May 2023

AbstractCynicism is an attitude that people are motivated primarily by self-interest, and often manifests alongside emotions like contempt, anger, and hostility. Cynicism can impact all aspects of an individual’s life: in the workplace it is a critical component of burnout, while at home it often leads to marital dissatisfaction and increased family conflicts. Using data from 2,317 participants in the CARDIA Cohort study, we performed a genome-wide association study (GWAS) to identify genetic variants related to cynicism and the cynical distrust sub-trait. We performed two GWAS tests for each trait, one without controlling for population stratification and a second where we considered possible ancestry-related stratification using principal component analysis within plink 1.9. We also tested multiple genetic inheritance models. Finally, we performed pathway analysis using the STRINGdb web resource to identify meaningful relationships. From our various approaches, we identified 12 variants associated with high cynicism in an additive model and 258 in a genotypic model. We also identified 24 and 275 variants associated with cynical distrust using the respective models. Our network analysis revealed clear pathways for how cynicism can lead to health outcomes like cardiovascular disease, adrenal disorders, neurological disorders, and even addiction. Specifically, genes involved in 30 distinct KEGG pathways were related to cynicism and clear connections can be made between cynicism and cardiomyopathies, Cushing syndrome, Alzheimer’s disease, and amphetamine addiction. Each of the outcomes are supported by gene association with at least 3 intermediate pathways. Our results provide the first objective evidence supporting the observational literature connections to cardiovascular disease, Alzheimer’s disease, and addiction. To the best of our knowledge, this is the first evidence presenting a relationship between cynicism and Cushing’s syndrome, demonstrating the power of population and statistical genetics.
Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis
Authors: Cornish Naomi , Haycock Philip , Brenner Hermann , Figueiredo Jane C. , Galesloot Tessel , Grant Robert C ,   InterLymph consortium,   INVENT-MVP consortium, Johansson Mattias , Mariosa Daniela , McKay James , Pai Rish , Pellatt Andrew J , Samadder N. Jewel , Shi Jianxin , Thibord Florian , Trégouët David-Alexandre , Voegele Catherine , Thirlwell Chrissie , Mumford Andrew , Langdon Ryan 
Published: May 2023

AbstractBackground:People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer.Methods:We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers.Results:We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE,P =0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship.Conclusions:These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.Key messages1) There is strong observational evidence that active cancer is associated with venous thromboembolism.2) It is currently unknown whether venous thromboembolism is a risk factor for cancer.3) We applied a bi-directional Mendelian randomisation framework to appraise the causal relationships between genetically-proxied risk of venous thromboembolism and 18 different cancers.4) Overall, there was no clear evidence from Mendelian randomisation that lifetime-elevated risk of venous thromboembolism is causally associated with an increased risk of cancer, or visa versa.
The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria
Authors: Ojewunmi Oyesola O. , Adeyemo Titilope A. , Oyetunji Ajoke I. , Inyang Bassey , Akinrindoye Afolashade , Mkumbe Baraka S. , Gardner Kate , Rooks Helen , Brewin John , Patel Hamel , Lee Sang-Hyuck , Chung Raymond , Rashkin Sara , Kang Guolian , Chianumba Reuben , Sangeda Raphael , Mwita Liberata , Isa Hezekiah , Agumadu Uche-Nnebe , Ekong Rosemary , Faruk Jamilu A. , Jamoh Bello Y. , Adebiyi Niyi M. , Umar Ismail A. , Hassan Abdulaziz , Grace Christopher , Goel Anuj , Inusa Baba P.D. , Falchi Mario , Nkya Siana , Makani Julie , Ahmad Hafsat R. , Nnodu Obiageli , Strouboulis John , Menzel Stephan 
Published: May 2023

AbstractBackgroundThe clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A,HBS1L-MYB, andXmn1-HBG2) have been reported, but a considerable hidden heritability remains.AimBuilding on the power of a large and genetically diverse patient pool present in Nigeria, we conducted a genome-wide association study for HbF levels in patients from three regions of the country with a diverse ethnic make-up.MethodsWe analysed genome-wide trait association in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional analysis, haplotype association analysis and included public functional annotation data (fGCTA).ResultsAssociation signals were detected forBCL11A(lead SNP rs6706648, β=- 0.39,P=4.96 x 10-34) andHBS1L-MYB(lead SNP rs61028892, β=0.73,P=1.18 x 10-9), whereas the variant allele forXmn1-HBG2was found to be very rare. Genetically dissecting the two major loci, we defined trait-boosting haplotypes containing suspected or so-far unidentified causal variants. AtBCL11A, one such haplotype (trait increaseP< 0.0001) contains the putative functional variant rs1427407-‘T’ and a second haplotype (P< 0.0001) is tagged by the rs7565301-‘A’ allele, with no obvious candidate causal variant. AtHBS1L- MYB, one haplotype (trait increaseP< 0.0001) contains the likely functional rs66650371 (Δ3-bp), and a second (P< 0.0001) is tagged by the ‘C’ allele of rs6102889. Together, variants atBCL11AandHBS1L-MYBSNPs explained 24.1% of the trait variance.We detected three novel association signals:SLC28A3on chromosome 9 (rs115555854: β=- 0.73,P=2.52 x 10-8),TICRRon chromosome 15 (rs140496989: β=-0.43,P=3.34 x 10-8), andPIEZO2on chromosome 18 (rs58817161: β= −0.63,P= 8.04 x 10-8). These appeared to be restricted to the Nigerian patient cohort and were not confirmed in the replication cohorts.ConclusionsStudying a diverse cohort of Nigerian patients with sickle cell disease, we genetically dissected the known fetal-haemoglobin lociBCL11AandHBS1L-MYBand detected putative new trait-associated regions.
A common gene signature of the right ventricle in failing rat and human hearts
Authors: Jurida Liane , Werner Sebastian , Knapp Fabienne , Niemann Bernd , Li Ling , Grün Dimitri , Wirth Stefanie , Weber Axel , Beuerlein Knut , Liebetrau Christoph , Wiedenroth Christoph B. , Guth Stefan , Kojonazarov Baktybek , Jafari Leili , Weissmann Norbert , Günther Stefan , Braun Thomas , Rohrbach Susanne , Kracht Michael 
Published: May 2023

SummaryThe molecular mechanisms of progressive right heart failure are incompletely understood. We systematically compared rat models of pulmonary artery or aortic banding to identify the transcriptomic changes that occur over months in the failing right versus left ventricle. Detailed bioinformatics analyses of 181 RNAseq datasets from cardiomyocytes or whole heart samples from these models, led to the identification of gene signatures, protein, and transcription factor networks specific to ventricles, compensated or decompensated disease states and type of heart failure. RNA-FISH approaches confirmed PAB-mediated regulation of key genes and revealed striking, spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with 95 transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension led to the identification of more than 50 genes whose expression levels strongly correlated with the severity of right heart disease. Together, these data define a conserved, differentially regulated genetic network that coordinates progressive right heart failure in rats and humans.HighlightsSide-by-side comparisons of RV or LV transcriptomes in the slowly failing rat heartIdentification of RV-specific gene sets in heart hypertrophy versus heart failureIdentification of RV gene sets correlating with severity of human CTEPHDevelopment of a core gene signature characteristic for RV failure