bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of longitudinal diet and waist-to-hip ratio from midlife to old age with hippocampus connectivity and memory in old age: a cohort study
Authors: Jensen Daria EA , Ebmeier Klaus P. , Akbaraly Tasnime , Jansen Michelle G , Singh-Manoux Archana , Kivimäki Mika , Zsoldos Enikő , Klein-Flügge Miriam C , Suri Sana 
Published: December 2023

ABSTRACTEpidemiological studies suggest lifestyle factors may reduce the risk of dementia. However, few studies have examined the association of diet and waist-to-hip ratio with hippocampus connectivity. In the Whitehall II Imaging Sub-study, we examined longitudinal changes in diet quality in 512 participants and waist-to-hip ratio in 665 participants. Diet quality was measured using the Alternative Health Eating Index-2010 assessed three times across 11 years between ages 48 and 60 years, and waist-to-hip ratio five times over 21 years between ages 48 and 68 years. Brain imaging and cognitive tests were performed at age 70±5 years. We measured white matter using diffusion tensor imaging and hippocampal functional connectivity using resting-state functional magnetic resonance imaging. In addition to associations of diet and waist-to-hip ratio with brain imaging measures, we tested whether associations between diet, waist-to-hip ratio and cognitive performance were mediated by brain connectivity. We found better diet quality in midlife and improvements in diet over mid-to-late life were associated with higher hippocampal functional connectivity to the occipital lobe and cerebellum, and better white matter integrity as measured by higher fractional anisotropy and lower diffusivity. Higher waist-to-hip ratio in midlife was associated with higher mean and radial diffusivity and lower fractional anisotropy in several tracts including the inferior longitudinal fasciculus and cingulum. Associations between midlife waist-to-hip ratio, working memory and executive function were partially mediated by radial diffusivity. All associations were independent of age, sex, education, and physical activity. Our findings highlight the importance of maintaining a good diet and a healthy waist-to-hip ratio in midlife to maintain brain health in later life. Future interventional studies for the improvement of dietary and metabolic health should target midlife for the prevention of cognitive decline in old age.
Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis
Authors: Pacyna Clarissa N. , Anandapadamanaban Madhanagopal , Loudon Kevin W. , Hay Iain M. , Perisic Olga , Li Ruoyan , Byrne Matthew , Allen Laura , Roberts Kirsty , Hooks Yvette , Warren Anne Y. , Stewart Grant D. , Clatworthy Menna R. , Teichmann Sarah A. , Behjati Sam , Campbell Peter J. , Williams Roger L. , Mitchell Thomas J. 
Published: December 2023

AbstractEmbryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl, timing their shared origin to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Their sharedMTORmutation, absent from normal tissues, enhances protein flexibility, which enables a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.
Genome-wide association study of delay discounting in Heterogenous Stock rats
Authors: Lara Montana Kay , Chitre Apurva S. , Chen Denghui , Johnson Benjamin B. , Nguyen Khai-Minh , Cohen Katarina A. , Muckadam Sakina A. , Lin Bonnie , Ziegler Shae , Beeson Angela , Sanches Thiago , Solberg Woods Leah C. , Polesskaya Oksana , Palmer Abraham A. , Mitchell Suzanne H. 
Published: December 2023

AbstractDelay discounting refers to the behavioral tendency to devalue rewards as a function of their delay in receipt. Heightened delay discounting has been associated with substance use disorders, as well as multiple co-occurring psychopathologies. Genetic studies in humans and animal models have established that delay discounting is a heritable trait, but only a few specific genes have been associated with delay discounting. Here, we aimed to identify novel genetic loci associated with delay discounting through a genome-wide association study (GWAS) using Heterogenous Stock rats, a genetically diverse outbred population derived from eight inbred founder strains. We assessed delay discounting in 650 male and female rats using an adjusting amount procedure in which rats chose between smaller immediate sucrose rewards or a larger reward at variable delays. Preference switch points were calculated for each rat and both exponential and hyperbolic functions were fitted to these indifference points. Area under the curve (AUC) and the discounting parameterkof both functions were used as delay discounting measures. GWAS for AUC, exponentialk, and indifference points for a short delay identified significant loci on chromosomes 20 and 14. The geneSlc35f1,which encodes a member of the solute carrier family of nucleoside sugar transporters, was the only gene within the chromosome 20 locus. That locus also contained an eQTL forSlc35f1, suggesting that heritable differences in the expression of that gene might be responsible for the association with behavior. The geneAdgrl3, which encodes a member of the latrophilin family of G-protein coupled receptors, was the only gene within the chromosome 14 locus. These findings implicate novel genes in delay discounting and highlight the need for further exploration.
Organelle phenotyping and multi-dimensional microscopy identify C1q as a novel regulator of microglial function
Authors: Sakthivel Pooja S. , Scipioni Lorenzo , Karam Josh , Keulen Zahara , Blurton-Jones Mathew , Gratton Enrico , Anderson Aileen J. 
Published: December 2023

AbstractMicroglia, the immune cells of the central nervous system (CNS), are incredibly dynamic and heterogenous cells. While single cell RNA sequencing has become the conventional methodology for evaluating microglial state, transcriptomics do not provide insight into functional changes. Here, we propose a novel organelle phenotyping approach where we treat live human induced pluripotent stem cell-derived microglia (iMGL) with organelle dyes (mitochondria, lipids, lysosomes) and acquire data by live-cell spectral microscopy. Dimensionality reduction techniques and unbiased cluster identification allow for recognition of microglial subpopulations based in organelle function. We validate this methodology using lipopolysaccharide (LPS) and IL-10 treatment to polarize iMGL to an inflammatory” and “anti-inflammatory state, respectively, and then apply it to identify a novel regulator of iMGL function, complement protein C1q. C1q is traditionally known as the initiator of the complement cascade, but here we use organelle phenotyping to identify a role for C1q in regulating iMGL fatty acid storage and mitochondria membrane potential. Follow up evaluation of microglia with more traditional read outs of activation state confirm that C1q drives an increase in microglia pro-inflammatory cytokine production and migration, while suppressing microglial proliferation. These data together validate the use of a novel organelle phenotyping approach and enable better mechanism investigation of molecular regulators of microglial state, such as C1q.
Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies
Authors: De Carli Alice , Kapelyukh Yury , Kursawe Jochen , Chaplain Mark A.J. , Wolf C. Roland , Hamis Sara 
Published: December 2023

AbstractIn vertical inhibition treatment strategies, multiple components of an intracellular pathway are simulta-neously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK-inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings.To quantitatively address this challenge, we develop a mathematical model of BRAFV600E-MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK-inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E-MEK-ERK pathway, and a set of molecular-level drug-protein interactions, we extract a system of chemical reactions that is parameterized by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies,i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E-MEK-ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF-TMT-SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
ARID1AMutations Protect Follicular Lymphoma from FAS-dependent Immune Surveillance by Reducing RUNX3/ETS1-Driven FAS-Expression
Authors: Antoniolli Martina , Solovey Maria , Strobl Carolin Dorothea , Bararia Deepak , Keay William David , Hildebrand Johannes Adrian , Adolph Louisa , Heide Michael , Passerini Verena , Freyholdt Tabea , Wange Lucas , Enard Wolfgang , Thieme Susanne , Blum Helmut , Rudelius Martina , Mergner Julia , Ludwig Christina , Bultmann Sebastian , Schmidt-Supprian Marc , Leonhardt Heinrich , Subklewe Marion , von Bergwelt-Baildon Michael , Colomé-Tatché Maria , Weigert Oliver 
Published: December 2023

ABSTRACTThe cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18) (q32;q21)IGH::BCL2translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations inARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility (“openness”). However, the mechanism howARID1Amutations contribute to FL pathogenesis remains unclear.We analyzed 151 FL biopsies of patients with advanced stage disease at initial diagnosis and found thatARID1Amutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed thatARID1Amutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affectFASpromotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulatesFASexpression, and ARID1A loss leads to reducedRUNX3promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis.In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including bispecific antibodies and CAR T cells.
Dynamic evolution of infarct volumes at MRI in ischemic stroke due to large vessel occlusion
Authors: Munsch Fanny , Planes David , Fukutomi Hikaru , Marnat Gaultier , Courret Thomas , Micard Emilien , Chen Bailiang , Seners Pierre , Dubos Johanna , Planche Vincent , Coupé Pierrick , Dousset Vincent , Lapergue Bertrand , Olivot Jean-Marc , Sibon Igor , Thiebaut de Schotten Michel , Tourdias Thomas 
Published: December 2023

AbstractBackground and ObjectivesThe typical infarct volume trajectories in stroke patients, categorized as slow or fast progressors, remain largely unknown. This study aimed to reveal the characteristic spatiotemporal evolutions of infarct volumes caused by large vessel occlusion (LVO) and show that such growth charts help anticipate clinical outcomes.MethodsWe conducted a secondary analysis from prospectively collected databases (FRAME, 2017– 2019; ETIS, 2015–2022). We selected acute MRI data from anterior LVO stroke patients with witnessed onset which were divided into training- and independent validation-datasets. In the training-dataset, using Gaussian mixture analysis, we classified the patients into three growth groups based on their rate of infarct growth (diffusion volume / time-to-imaging). Subsequently, we extrapolated pseudo-longitudinal models of infarct growth for each group and generated sequential frequency maps to highlight the spatial distribution of infarct growth. We used these charts to attribute a growth group to the independent patients from the validation-dataset. We compared their 3-month modified Rankin scale (mRS) with the predicted values based on a multivariable regression model from the training-dataset that used growth group as independent variable.ResultsWe included 804 patients (median age, 73.0 years [IQR, 61.2-82.0 years]; 409 men). The training-dataset revealed non-supervised clustering into 11% (74/703) slow, 62% (437/703) intermediate, and 27% (192/703) fast progressors. Infarct volume evolutions were best fitted with a linear (r=0.809;P<.001), cubic (r=0.471;P<.001), and power (r=0.63;P<.001) functions for the slow, intermediate and fast progressors, respectively. Notably, the deep nuclei and insular cortex were rapidly affected in the intermediate and fast groups with further cortical involvement in the fast group. The variable “growth group” significantly predicted 3-month mRS (multivariate OR, 0.51; 95% CI: 0.37-0.72,P<.0001) in the training-dataset, yielding a mean AUC of 0.78 (95% CI: 0.66-0.88) in the independent validation-dataset.ConclusionsWe revealed spatiotemporal archetype dynamic evolutions following large vessel occlusion stroke according to three growth phenotypes called slow, intermediate and fast progressors, providing insight into anticipating clinical outcome. We expect this could help in designing neuroprotective trials aiming at modulating infarct growth prior EVT.
Hop stunt viroid infection alters host heterochromatin
Authors: Marquez-Molins Joan , Cheng Jinping , Corell-Sierra Julia , Juarez-Gonzalez Vasti Thamara , Villalba-Bermell Pascual , Annacondia Maria Luz , Gomez Gustavo , Martinez German 
Published: December 2023

ABSTRACTViroids are pathogenic non-coding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including an interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response. Here we have analyzed the changes taking place inCucumis sativusfacultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3. We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks. Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants.
The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging
Authors: Hunt Liam C. , Nyamkondiwa Kudzai , Stephan Anna , Jiao Jianqin , Kavdia Kanisha , Pagala Vishwajeeth , Peng Junmin , Demontis Fabio 
Published: December 2023

SUMMARYUbiquitin-conjugating enzymes (E2s) are key for regulating protein function and turnover via ubiquitination but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in theDrosophilaretina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Transgenic expression of human UBE2D2, homologous to eff, partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAiby re-establishing the physiological levels of effRNAi-regulated proteins, which include several regulators of proteostasis. Interestingly, UBE2D/eff knockdown in young age reproduces part of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme that ensures protein quality control and helps maintain a youthful proteome composition during aging.
Herpes Simplex Virus 1 (HSV-1) Uses the Rab6 Post-Golgi Secretory Pathway For Viral Egress
Authors: Bergeman Melissa H. , Velarde Kimberly , Glenn Honor L. , Hogue Ian B. 
Published: December 2023

ABSTRACTHerpes Simplex Virus 1 (HSV-1) is an alpha herpesvirus that infects a majority of the world population. The mechanisms and cellular host factors involved in the intracellular transport and exocytosis of HSV-1 particles are not fully understood. To elucidate these late steps in the replication cycle, we developed a live-cell fluorescence microscopy assay of HSV-1 virion intracellular trafficking and exocytosis. This method allows us to track individual virus particles, and identify the precise moment and location of particle exocytosis using a pH-sensitive reporter. We show that HSV-1 uses the host Rab6 post-Golgi secretory pathway during egress. The small GTPase, Rab6, binds to nascent secretory vesicles at thetrans-Golgi network and regulates vesicle trafficking and exocytosis at the plasma membrane. HSV-1 particles colocalize with Rab6a in the region of the Golgi, cotraffic with Rab6a to the cell periphery, and undergo exocytosis from Rab6a vesicles. Consistent with previous reports, we find that HSV-1 particles accumulate at preferential egress sites in infected cells. The Rab6a secretory pathway mediates this preferential/polarized egress, since Rab6a vesicles accumulate near the plasma membrane similarly in uninfected cells. These data suggest that, following particle envelopment, HSV-1 egress follows a pre-existing cellular secretory pathway to exit infected cells rather than novel, virus-induced mechanisms.IMPORTANCEHSV-1 infects a majority of people. It establishes a life-long latent infection, and occasionally reactivates, typically causing characteristic oral or genital lesions. Rarely in healthy natural hosts, but more commonly in zoonotic infections and in elderly, newborn, or immunocompromised patients, HSV-1 can cause severe herpes encephalitis. The precise cellular mechanisms used by HSV-1 remain an important area of research. In particular, the egress pathways that newly-assembled virus particles use to exit from infected cells are unclear. In this study, we used fluorescence microscopy to visualize individual virus particles exiting from cells, and found that HSV-1 particles use the pre-existing cellular secretory pathway, regulated by the cellular protein, Rab6.
How does intellectual capital drive firm performance via dynamic capabilities: evidence from India
Authors: Singh Bindu , Verma Pratibha 
Published: December 2023

PurposeThis study examines how intellectual capital (IC) drives firm performance via the lens of dynamic capabilities (DCs). Drawing on resource-based view (RBV) and dynamic capability view (DCV), the authors elaborate the mediating role of learning, integration and reconfiguration DC in the Indian banking context.Design/methodology/approachA sample of 358 top- and middle-level managers from the Indian banking sector was administered with structured questionnaires for data collection. Structural equation modeling (SEM) and Sobel test were used to analyze the data and test the hypothesized mediating effect.FindingsThe findings reveal that learning and integration DCs are key mediators in IC and banks' performance relationships in an emerging economy context. In contrast, the analysis revealed partial mediating role of reconfiguration DC. Furthermore, the learning DC has been identified as the primary mediating mechanism for transforming bank's IC into performance benefits.Practical implicationsThis study provides an important implication for the IC and DC link by empirically developing and validating a model in the Indian banking sector and making a several contributions to the related literature. This sector needs to incorporate and strengthen their IC and DCs to attain enhanced performance in today's dynamic environment. Bank managers can use these findings to bring their knowledge-related activities to channelize specific DCs to transform banks' IC when seeking to improve overall performance. Theoretically, this study extends previous research by outlining a set of organizational elements that tend to influence firm performances with the help of IC, learning, integration and reconfigurations DCs.Originality/valueAlthough several studies have investigated the links between IC, DC and firm performance, studies on emerging economies are scarce. This study is one of the most in-depth investigations of the relationship between IC, learning, integration and reconfiguration DCs and firm performance in an integrated framework, with a particular focus on the banking sector of an emerging economy.