bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide case-only analysis of gene-gene interactions with known Parkinson’s disease risk variants reveals link between LRRK2 and SYT10
Authors: Aleknonytė-Resch Milda , Trinh Joanne , Leonard Hampton , Delcambre Sylvie , Leitão Elsa , Lai Dongbing , Smajić Semra , Orr-Urtreger Avi , Thaler Avner , Blauwendraat Cornelis , Sharma Arunabh , Makarious Mary B. , Kim Jonggeol Jeff , Lake Julie , Rahmati Pegah , Freitag-Wolf Sandra , Seibler Philip , Foroud Tatiana , Singleton Andrew B. ,   The International Parkinson Disease Genomics Consortium, Grünewald Anne , Kaiser Frank , Klein Christine , Krawczak Michael , Dempfle Astrid 
Published: June 2023

AbstractThe effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p = 2.7 × 10−43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.
Multicomponent intranasal adjuvant for mucosal and durable systemic SARS-CoV-2 immunity in young and aged mice
Authors: Jangra Sonia , Landers Jeffrey J. , Laghlali Gabriel , Rathnasinghe Raveen , Warang Prajakta , Park Seok-Chan , O’Konek Jessica. J. , Singh Gagandeep , Janczak Katarzyna W. , García-Sastre Adolfo , Arya Nandini , Karadag Dilara , Baker James R. , Schotsaert Michael , Wong Pamela T. 
Published: June 2023

AbstractMultiple FDA-approved SARS-CoV-2 vaccines currently provide excellent protection against severe disease. Despite this, immunity can wane relatively fast, particularly in the elderly and novel viral variants capable of evading infection- and vaccination-induced immunity continue to emerge. Intranasal (IN) vaccination more effectively induces mucosal immune responses than parenteral vaccines, which would improve protection and reduce viral transmission. Here, we developed a rationally designed IN adjuvant consisting of a combined nanoemulsion (NE)-based adjuvant and an RNA-based RIG-I agonist (IVT DI) to drive more robust, broadly protective antibody and T cell responses. We previously demonstrated this combination adjuvant (NE/IVT) potently induces protective immunity through synergistic activation of an array of innate receptors. We now demonstrate that NE/IVT with the SARS-CoV-2 receptor binding domain (RBD), induces robust and durable humoral, mucosal, and cellular immune responses of equivalent magnitude and quality in young and aged mice. This contrasted with the MF59-like intramuscular adjuvant, Addavax, which showed a decrease in immunogenicity with age. Robust antigen-specific IFN-γ/IL-2/TNF-α was induced in both young and aged NE/IVT-immunized animals, which is significant as their reduced production is associated with suboptimal protective immunity in the elderly. These findings highlight the potential of adjuvanted mucosal vaccines for improving protection against COVID-19.
mTORC2–NDRG1–CDC42 axis couples fasting to mitochondrial fission
Authors: Martinez-Lopez Nuria , Mattar Pamela , Toledo Miriam , Bains Henrietta , Kalyani Manu , Aoun Marie Louise , Sharma Mridul , McIntire Laura Beth J. , Gunther-Cummins Leslie , Macaluso Frank P. , Aguilan Jennifer T. , Sidoli Simone , Bourdenx Mathieu , Singh Rajat 
Published: June 2023

AbstractFasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Alamutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly,RictorKO, NDRG1Ser336Alamutants andCdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.
Material category of visual objects computed from specular image structure
Authors: Schmid Alexandra C. , Barla Pascal , Doerschner Katja 
Published: June 2023

AbstractRecognizing materials and their properties visually is vital for successful interactions with our environment, from avoiding slippery floors to handling fragile objects. Yet there is no simple mapping of retinal image intensities to physical properties. Here, we investigated what image information drives material perception by collecting human psychophysical judgements about complex glossy objects. Variations in specular image structure—produced either by manipulating reflectance properties or visual features directly—caused categorical shifts in material appearance, suggesting that specular reflections provide diagnostic information about a wide range of material classes. Perceived material category appeared to mediate cues for surface gloss, providing evidence against a purely feedforward view of neural processing. Our results suggest that the image structure that triggers our perception of surface gloss plays a direct role in visual categorization, and that the perception and neural processing of stimulus properties should be studied in the context of recognition, not in isolation.
Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci
Authors: Mignogna Gianmarco , Carey Caitlin E. , Wedow Robbee , Baya Nikolas , Cordioli Mattia , Pirastu Nicola , Bellocco Rino , Malerbi Kathryn Fiuza , Nivard Michel G. , Neale Benjamin M. , Walters Raymond K. , Ganna Andrea 
Published: June 2023

AbstractResponse to survey questionnaires is vital for social and behavioural research, and most analyses assume full and accurate response by participants. However, nonresponse is common and impedes proper interpretation and generalizability of results. We examined item nonresponse behaviour across 109 questionnaire items in the UK Biobank (N = 360,628). Phenotypic factor scores for two participant-selected nonresponse answers, ‘Prefer not to answer’ (PNA) and ‘I don’t know’ (IDK), each predicted participant nonresponse in follow-up surveys (incremental pseudo-R2 = 0.056), even when controlling for education and self-reported health (incremental pseudo-R2 = 0.046). After performing genome-wide association studies of our factors, PNA and IDK were highly genetically correlated with one another (rg = 0.73 (s.e. = 0.03)) and with education (rg,PNA = −0.51 (s.e. = 0.03); rg,IDK = −0.38 (s.e. = 0.02)), health (rg,PNA = 0.51 (s.e. = 0.03); rg,IDK = 0.49 (s.e. = 0.02)) and income (rg,PNA = –0.57 (s.e. = 0.04); rg,IDK = −0.46 (s.e. = 0.02)), with additional unique genetic associations observed for both PNA and IDK (P < 5 × 10−8). We discuss how these associations may bias studies of traits correlated with item nonresponse and demonstrate how this bias may substantially affect genome-wide association studies. While the UK Biobank data are deidentified, we further protected participant privacy by avoiding exploring non-response behaviour to single questions, assuring that no information can be used to associate results with any particular respondents.
Elimination of charge-carrier trapping by molecular design
Authors: Sachnik Oskar , Tan Xiao , Dou Dehai , Haese Constantin , Kinaret Naomi , Lin Kun-Han , Andrienko Denis , Baumgarten Martin , Graf Robert , Wetzelaer Gert-Jan A. H. , Michels Jasper J. , Blom Paul W. M. 
Published: June 2023

AbstractA common obstacle of many organic semiconductors is that they show highly unipolar charge transport. This unipolarity is caused by trapping of either electrons or holes by extrinsic impurities, such as water or oxygen. For devices that benefit from balanced transport, such as organic light-emitting diodes, organic solar cells and organic ambipolar transistors, the energy levels of the organic semiconductors are ideally situated within an energetic window with a width of 2.5 eV where charge trapping is strongly suppressed. However, for semiconductors with a band gap larger than this window, as used in blue-emitting organic light-emitting diodes, the removal or disabling of charge traps poses a longstanding challenge. Here we demonstrate a molecular strategy where the highest occupied molecular orbital and lowest unoccupied molecular orbital are spatially separated on different parts of the molecules. By tuning their stacking by modification of the chemical structure, the lowest unoccupied molecular orbitals can be spatially protected from impurities that cause electron trapping, increasing the electron current by orders of magnitude. In this way, the trap-free window can be substantially broadened, opening a path towards large band gap organic semiconductors with balanced and trap-free transport.
Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci
Authors: Han Xikun , Gharahkhani Puya , Hamel Andrew R. , Ong Jue Sheng , Rentería Miguel E. , Mehta Puja , Dong Xianjun , Pasutto Francesca , Hammond Christopher , Young Terri L. , Hysi Pirro , Lotery Andrew J. , Jorgenson Eric , Choquet Hélène , Hauser Michael , Cooke Bailey Jessica N. , Nakazawa Toru , Akiyama Masato , Shiga Yukihiro , Fuller Zachary L. , Wang Xin , Hewitt Alex W. , Craig Jamie E. , Pasquale Louis R. , Mackey David A. , Wiggs Janey L. , Khawaja Anthony P. , Segrè Ayellet V. ,   23andMe Research Team,   International Glaucoma Genetics Consortium, MacGregor Stuart 
Published: June 2023

AbstractGlaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated atP < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.
Immunomodulatory response in an experimental model of brain death
Authors: Santana Alexandre Chagas , Andraus Wellington , Zimelewicz Oberman Dan , Rabelo Nícollas Nunes , Silva Filipe Miranda Oliveira , Dellê Humberto , Pepineli Rafael , de Moraes Edvaldo Leal , Scavone Cristoforo , de Sá Lima Larissa , Degaspari Sabrina , Brasil Sérgio , Solla Davi Jorge Fontoura , Ruiz Liliane Moreira , de Oliveira-Braga Karina Andrighetti , Nepomuceno Natalia Aparecida , Pêgo-Fernandes Paulo Manuel , Tullius Stefan Gunther , Figueiredo Eberval Gadelha 
Published: June 2023

AbstractLiver transplantation has come a long way and is now regarded as the gold standard treatment for end-stage liver failure. The great majority of livers utilized in transplantation come from brain-dead donors. A broad inflammatory response characterizes BD, resulting in multiorgan damage. This process is primarily mediated by cytokines, which increase the immunogenicity of the graft. In male Lewis rats, we evaluated the immune response in a BD liver donor and compared it to that of a control group. We studied two groups: Control and BD (rats subjected to BD by increasing intracranial pressure). After the induction of BD, there was an intense rise in blood pressure followed by a fall. There were no significant differences observed between the groups. Blood tissue and hepatic tissue analyzes showed an increase in plasma concentrations of liver enzymes (AST, ALT, LDH and ALP), in addition to pro-inflammatory cytokines and macrophages in liver tissue in animals submitted to BD. The current study found that BD is a multifaceted process that elicits both a systemic immune response and a local inflammatory response in liver tissue. Our findings strongly suggested that the immunogenicity of plasma and liver increased with time following BD.
Non-contrast CT synthesis using patch-based cycle-consistent generative adversarial network (Cycle-GAN) for radiomics and deep learning in the era of COVID-19
Authors: Kalantar Reza , Hindocha Sumeet , Hunter Benjamin , Sharma Bhupinder , Khan Nasir , Koh Dow-Mu , Ahmed Merina , Aboagye Eric O. , Lee Richard W. , Blackledge Matthew D. 
Published: June 2023

AbstractHandcrafted and deep learning (DL) radiomics are popular techniques used to develop computed tomography (CT) imaging-based artificial intelligence models for COVID-19 research. However, contrast heterogeneity from real-world datasets may impair model performance. Contrast-homogenous datasets present a potential solution. We developed a 3D patch-based cycle-consistent generative adversarial network (cycle-GAN) to synthesize non-contrast images from contrast CTs, as a data homogenization tool. We used a multi-centre dataset of 2078 scans from 1,650 patients with COVID-19. Few studies have previously evaluated GAN-generated images with handcrafted radiomics, DL and human assessment tasks. We evaluated the performance of our cycle-GAN with these three approaches. In a modified Turing-test, human experts identified synthetic vs acquired images, with a false positive rate of 67% and Fleiss’ Kappa 0.06, attesting to the photorealism of the synthetic images. However, on testing performance of machine learning classifiers with radiomic features, performance decreased with use of synthetic images. Marked percentage difference was noted in feature values between pre- and post-GAN non-contrast images. With DL classification, deterioration in performance was observed with synthetic images. Our results show that whilst GANs can produce images sufficient to pass human assessment, caution is advised before GAN-synthesized images are used in medical imaging applications.
Performance optimization of efficient PbS quantum dots solar cells through numerical simulation
Authors: Kumar Sandeep , Bharti Pragya , Pradhan Basudev 
Published: June 2023

AbstractColloidal quantum dots (CQDs) solar cells are less efficient because of the carrier recombination within the material. The electron and hole transport layers have high impact on the performance of CQDs based solar cells which makes its investigation a very important component of the development of the more efficient devices. In this work, we have tried performance optimization in tetrabutyl ammonium iodide capped lead sulfide (PbS) CQDs (PbS-TBAI) as absorber layers based solar cells by incorporating different hole transport layers (HTLs) to achieve better power conversion efficiency (PCE) in different device architectures by SCAPS—1D numerical simulation software. It was observed from the simulation that the ITO/TiO2/PbS-TBAI/HTL/Au device architecture shows higher power conversion efficiency as compared to the conventional experimentally realized device architecture of ITO/TiO2/PbS-TBAI/PbS-EDT/HTL/Au. The influence of interface defect density (IDD) at the interface TiO2/PbS-TBAI has also been studied where IDD is varied from 1 × 1013 cm−2 to 1 × 1018 cm−2 while keeping the rest of the device parameters intact. The result shows a noteworthy reduction in the PV performance of the device at higher IDD. This modelled device structure provides a new direction toward the experimental realization in high efficiency PbS QDs solar cells.
Mechanism of TNFα-induced downregulation of salt-inducible kinase 2 in adipocytes
Authors: Vaváková Magdaléna , Hofwimmer Kaisa , Laurencikiene Jurga , Göransson Olga 
Published: June 2023

AbstractSalt-inducible kinase 2 (SIK2) is highly expressed in white adipocytes, but downregulated in individuals with obesity and insulin resistance. These conditions are often associated with a low-grade inflammation in adipose tissue. We and others have previously shown that SIK2 is downregulated by tumor necrosis factor α (TNFα), however, involvement of other pro-inflammatory cytokines, or the mechanisms underlying TNFα-induced SIK2 downregulation, remain to be elucidated. In this study we have shown that TNFα downregulates SIK2 protein expression not only in 3T3L1- but also in human in vitro differentiated adipocytes. Furthermore, monocyte chemoattractant protein-1 and interleukin (IL)-1β, but not IL-6, might also contribute to SIK2 downregulation during inflammation. We observed that TNFα-induced SIK2 downregulation occurred also in the presence of pharmacological inhibitors against several kinases involved in inflammation, namely c-Jun N-terminal kinase, mitogen activated protein kinase kinase 1, p38 mitogen activated protein kinase or inhibitor of nuclear factor kappa-B kinase (IKK). However, IKK may be involved in SIK2 regulation as we detected an increase of SIK2 when inhibiting IKK in the absence of TNFα. Increased knowledge about inflammation-induced downregulation of SIK2 could ultimately be used to develop strategies for the reinstalment of SIK2 expression in insulin resistance.
Image quality assessment using deep learning in high b-value diffusion-weighted breast MRI
Authors: Kapsner Lorenz A. , Balbach Eva L. , Folle Lukas , Laun Frederik B. , Nagel Armin M. , Liebert Andrzej , Emons Julius , Ohlmeyer Sabine , Uder Michael , Wenkel Evelyn , Bickelhaupt Sebastian 
Published: June 2023

AbstractThe objective of this IRB approved retrospective study was to apply deep learning to identify magnetic resonance imaging (MRI) artifacts on maximum intensity projections (MIP) of the breast, which were derived from diffusion weighted imaging (DWI) protocols. The dataset consisted of 1309 clinically indicated breast MRI examinations of 1158 individuals (median age [IQR]: 50 years [16.75 years]) acquired between March 2017 and June 2020, in which a DWI sequence with a high b-value equal to 1500 s/mm2 was acquired. From these, 2D MIP images were computed and the left and right breast were cropped out as regions of interest (ROI). The presence of MRI image artifacts on the ROIs was rated by three independent observers. Artifact prevalence in the dataset was 37% (961 out of 2618 images). A DenseNet was trained with a fivefold cross-validation to identify artifacts on these images. In an independent holdout test dataset (n = 350 images) artifacts were detected by the neural network with an area under the precision-recall curve of 0.921 and a positive predictive value of 0.981. Our results show that a deep learning algorithm is capable to identify MRI artifacts in breast DWI-derived MIPs, which could help to improve quality assurance approaches for DWI sequences of breast examinations in the future.
Reduction in disialyl-T antigen levels in mice deficient for both St6galnac3 and St6galnac4 results in blood filling of lymph nodes
Authors: Fuseya Sayaka , Izumi Hiroyuki , Hamano Ayane , Murakami Yuka , Suzuki Riku , Koiwai Rikako , Hayashi Takuto , Kuno Atsushi , Takahashi Satoru , Kudo Takashi 
Published: June 2023

AbstractSialic acid (SA) is present at the terminal ends of carbohydrate chains in glycoproteins and glycolipids and is involved in various biological phenomena. The biological function of the disialyl-T (SAα2-3Galβ1-3(SAα2-6)GalNAcα1-O-Ser/Thr) structure is largely unknown. To elucidate the role of disialyl-T structure and determine the key enzyme from the N-acetylgalactosaminide α2,6-sialyltransferase (St6galnac) family involved in its in vivo synthesis, we generated St6galnac3- and St6galnac4-deficient mice. Both single-knockout mice developed normally without any prominent phenotypic abnormalities. However, the St6galnac3::St6galnact4 double knockout (DKO) mice showed spontaneous hemorrhage of the lymph nodes (LN). To identify the cause of bleeding in the LN, we examined podoplanin, which modifies the disialyl-T structures. The protein expression of podoplanin in the LN of DKO mice was similar to that in wild-type mice. However, the reactivity of MALII lectin, which recognizes disialyl-T, in podoplanin immunoprecipitated from DKO LN was completely abolished. Moreover, the expression of vascular endothelial cadherin was reduced on the cell surface of high endothelial venule (HEV) in the LN, suggesting that hemorrhage was caused by the structural disruption of HEV. These results suggest that podoplanin possesses disialyl-T structure in mice LN and that both St6galnac3 and St6galnac4 are required for disialyl-T synthesis.