bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank
Authors: Wuttke Matthias , König Eva , Katsara Maria-Alexandra , Kirsten Holger , Farahani Saeed Khomeijani , Teumer Alexander , Li Yong , Lang Martin , Göcmen Burulca , Pattaro Cristian , Günzel Dorothee , Köttgen Anna , Fuchsberger Christian 
Published: March 2023

AbstractGenome-wide association studies have discovered hundreds of associations between common genotypes and kidney function but cannot comprehensively investigate rare coding variants. Here, we apply a genotype imputation approach to whole exome sequencing data from the UK Biobank to increase sample size from 166,891 to 408,511. We detect 158 rare variants and 105 genes significantly associated with one or more of five kidney function traits, including genes not previously linked to kidney disease in humans. The imputation-powered findings derive support from clinical record-based kidney disease information, such as for a previously unreported splice allele in PKD2, and from functional studies of a previously unreported frameshift allele in CLDN10. This cost-efficient approach boosts statistical power to detect and characterize both known and novel disease susceptibility variants and genes, can be generalized to larger future studies, and generates a comprehensive resource (https://ckdgen-ukbb.gm.eurac.edu/) to direct experimental and clinical studies of kidney disease.
Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors
Authors: Zapata Luis , Caravagna Giulio , Williams Marc J. , Lakatos Eszter , AbdulJabbar Khalid , Werner Benjamin , Chowell Diego , James Chela , Gourmet Lucie , Milite Salvatore , Acar Ahmet , Riaz Nadeem , Chan Timothy A. , Graham Trevor A. , Sottoriva Andrea 
Published: March 2023

AbstractIn cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.
Bioactivity of brassica seed meals and its compounds as ecofriendly larvicides against mosquitoes
Authors: Flor-Weiler Lina B. , Behle Robert W. , Berhow Mark A. , McCormick Susan P. , Vaughn Steven F. , Muturi Ephantus J. , Hay William T. 
Published: March 2023

AbstractStrategic, sustainable, and ecofriendly alternatives to chemical pesticides are needed to effectively control mosquitoes and reduce the incidence of their vectored diseases. We evaluated several Brassicaceae (mustard family) seed meals as sources of plant derived isothiocyanates produced from the enzymatic hydrolysis of biologically inactive glucosinolates for the control of Aedesaegypti (L., 1762). Five defatted seed meals (Brassicajuncea (L) Czern., 1859, Lepidiumsativum L., 1753, Sinapisalba L., 1753, Thlaspiarvense L., 1753, and Thlaspiarvense—heat inactivated and three major chemical products of enzymatic degradation (allyl isothiocyanate, benzyl isothiocyanate and 4-hydroxybenzyl isothiocyanate) were assayed to determine toxicity (LC50) to Ae.aegypti larvae. All seed meals except the heat inactivated T.arvense were toxic to mosquito larvae. L.sativum seed meal was the most toxic treatment to larvae (LC50 = 0.04 g/120 mL dH2O) at the 24-h exposure. At the 72-h evaluation, the LC50 values for B.juncea,S.alba and T.arvense seed meals were 0.05, 0.08 and 0.1 g/120 mL dH2O, respectively. Synthetic benzyl isothiocyanate was more toxic to larvae 24-h post treatment (LC50 = 5.29 ppm) compared with allyl isothiocyanate (LC50 = 19.35 ppm) and 4-hydroxybenzyl isothiocyanate (LC50 = 55.41 ppm). These results were consistent with the higher performance of the benzyl isothiocyanate producing L.sativum seed meal. Isothiocyanates produced from seed meals were more effective than the pure chemical compounds, based on calculated LC50 rates. Using seed meal may provide an effective method of delivery for mosquito control. This is the first report evaluating the efficacy of five Brassicaceae seed meals and their major chemical constituent against mosquito larvae and demonstrates how natural compounds from Brassicaceae seed meals can serve as a promising ecofriendly larvicides to control mosquitoes.
Environmental effects on brain functional networks in a juvenile twin population
Authors: Tassi Emma , Maggioni Eleonora , Mauri Maddalena , Fagnani Corrado , Agarwal Nivedita , Bianchi Anna Maria , Stazi Maria A. , Nobile Maria , Brambilla Paolo 
Published: March 2023

AbstractThe brain’s intrinsic organization into large-scale functional networks, the resting state networks (RSN), shows complex inter-individual variability, consolidated during development. Nevertheless, the role of gene and environment on developmental brain functional connectivity (FC) remains largely unknown. Twin design represents an optimal platform to shed light on these effects acting on RSN characteristics. In this study, we applied statistical twin methods to resting-state functional magnetic resonance imaging (rs-fMRI) scans from 50 young twin pairs (aged 10–30 years) to preliminarily explore developmental determinants of brain FC. Multi-scale FC features were extracted and tested for applicability of classical ACE and ADE twin designs. Epistatic genetic effects were also assessed. In our sample, genetic and environmental effects on the brain functional connections largely varied between brain regions and FC features, showing good consistency at multiple spatial scales. Although we found selective contributions of common environment on temporo-occipital connections and of genetics on frontotemporal connections, the unique environment showed a predominant effect on FC link- and node-level features. Despite the lack of accurate genetic modeling, our preliminary results showed complex relationships between genes, environment, and functional brain connections during development. A predominant role of the unique environment on multi-scale RSN characteristics was suggested, which needs replications on independent samples. Future investigations should especially focus on nonadditive genetic effects, which remain largely unexplored.
In a secondary analysis from a randomised, double-blind placebo-controlled trial Dexmedetomidine blocks cholinergic dysregulation in delirium pathogenesis in patients with major surgery
Authors: Jacob Yanite , Schneider Bill , Spies Claudia , Heinrich Maria , von Haefen Clarissa , Kho Widuri , Pohrt Anne , Müller Anika 
Published: March 2023

AbstractDexmedetomidine is an alpha-2 adrenoreceptor agonist with anti-inflammatory and anti-delirogenic properties. Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are discussed as biomarkers for both POD and severity in acute inflammation. To show whether there is a link between blood cholinesterase activities and dexmedetomidine, we performed a secondary analysis of a randomised, double-blind, placebo-controlled trial that recently showed a lower incidence of POD in the dexmedetomidine group. Abdominal or cardiac surgical patients aged ≥ 60 years were randomised to receive dexmedetomidine or placebo intra- and postoperatively in addition to standard general anaesthesia. We analysed the course of perioperative cholinesterase activities of 56 patients, measured preoperatively and twice postoperatively. Dexmedetomidine resulted in no change in AChE activity and caused a rapid recovery of BChE activity after an initial decrease, while placebo showed a significant decrease in both cholinesterase activities. There were no significant between-group differences at any point in time. From these data it can be assumed that dexmedetomidine could alleviate POD via altering the cholinergic anti-inflammatory pathway (CAIP). We advocate for further investigations to show the direct connection between dexmedetomidine and cholinesterase activity.
Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR−/− mice
Authors: Thompson Dawn , Mahmood Shehroz , Morrice Nicola , Kamli-Salino Sarah , Dekeryte Ruta , Hoffmann Philip A. , Doherty Mary K. , Whitfield Philip D. , Delibegović Mirela , Mody Nimesh 
Published: March 2023

AbstractFenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR−/− mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR−/− mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.
A pilot study on lengthening potentials and biomechanical effects of double and triple hemisection on tendon with slide lengthening
Authors: Wang T. , Yu H. , Tian Guo-fu , Zhao Rui-xiang 
Published: March 2023

AbstractThe current study explored the slide-lengthening potentials of double and triple hemisections and the biomechanical effects of different inter-hemisection distances. Forty-eight porcine flexor digitorum profundus tendons were divided into double- and triple-hemisection groups (Groups A and B) and a control group (Group C). Group A was divided into Group A1 (distance between hemisections were the same as Group B) and Group A2 (distance between hemisections corresponded to the greatest distance between hemisections in Group B). Biomechanical evaluation, motion analysis, and finite element analysis (FEA) were performed. Failure load of intact tendon was significantly highest among groups. When the distance was 4 cm, the failure load of Group A increased significantly. When the distance between the hemisections was 0.5 or 1 cm, the failure load of Group B was significantly lower than Group A. Tendon elongation and failure load of Group B were significantly lower than those in Group A when the greatest distance between hemisections was the same. Consequently, Double hemisections had a similar lengthening ability to that of triple hemisections with the same distance, but better when the distances between extreme hemisections matched. However, the driving force for the initiation of lengthening may be greater.
The electronic medical record management systems may improve monitoring and control of disease activity in patients with ankylosing spondylitis
Authors: Huang Pei-Ju , Chen Yi-Hsing , Huang Wen-Nan , Chen Yi-Ming , Lai Kuo-Lung , Hsieh Tsu-Yi , Hung Wei-Ting , Lin Ching-Tsai , Tseng Chih-Wei , Tang Kuo-Tung , Chou Yin-Yi , Wu Yi-Da , Huang Chin-Yin , Hsieh Chia-Wei , Chen Yen-Ju , Liao Yu-Wan , Liu Yen-Tze , Chen Hsin-Hua 
Published: March 2023

AbstractTo investigate the impact of an electronic medical record management system (EMRMS) on disease activity and the frequency of outpatient visits among patients with ankylosing spondylitis (AS). We identified 652 patients with AS who were followed up for at least 1 year before and after the first Ankylosing Spondylitis Disease Activity Score (ASDAS) assessment and compared the number of outpatient visits and average visit time within 1 year before and after the initial ASDAS assessment. Finally, we analyzed 201 patients with AS who had complete data and received ≥ 3 continuous ASDAS assessments at an interval of 3 months, and we compared the results of the second and third ASDAS assessments with those of the first. The number of annual outpatient visits increased after ASDAS assessment (4.0 (4.0, 7.0) vs. 4.0 (4.0, 8.0), p < 0.001), particularly among those with a high initial disease activity. The average visit time was reduced within 1 year after ASDAS assessment (6.4 (8.5, 11.2) vs. 6.3 (8.3, 10.8) min, p = 0.073), especially among patients whose with an inactive disease activity was < 1.3 (ASDAS C-reactive protein (CRP) 6.7 (8.8, 11.1) vs. 6.1 (8.0, 10.3) min, p = 0.033; ASDAS erythrocyte sedimentation rate (ESR) 6.4 (8.7, 11.1) vs. 6.1 (8.1, 10.0) min, p = 0.027). Among patients who received at least three ASDAS assessments, the third ASDAS-CRP tended to be lower than the first (1.5 (0.9, 2.1) vs. 1.4 (0.8, 1.9), p = 0.058). The use of an EMRMS increased the frequency of ambulatory visits among AS patients with high and very high disease activity and reduced the visit time among those with an inactive disease. Continual ASDAS assessments may help control the disease activity of patients with AS.
ECG-guided non-invasive estimation of pulmonary congestion in patients with heart failure
Authors: Raghu Aniruddh , Schlesinger Daphne , Pomerantsev Eugene , Devireddy Srikanth , Shah Pinak , Garasic Joseph , Guttag John , Stultz Collin M. 
Published: March 2023

AbstractQuantifying hemodynamic severity in patients with heart failure (HF) is an integral part of clinical care. A key indicator of hemodynamic severity is the mean Pulmonary Capillary Wedge Pressure (mPCWP), which is ideally measured invasively. Accurate non-invasive estimates of the mPCWP in patients with heart failure would help identify individuals at the greatest risk of a HF exacerbation. We developed a deep learning model, HFNet, that uses the 12-lead electrocardiogram (ECG) together with age and sex to identify when the mPCWP > 18 mmHg in patients who have a prior diagnosis of HF. The model was developed using retrospective data from the Massachusetts General Hospital and evaluated on both an internal test set and an independent external validation set, from another institution. We developed an uncertainty score that identifies when model performance is likely to be poor, thereby helping clinicians gauge when to trust a given model prediction. HFNet AUROC for the task of estimating mPCWP > 18 mmHg was 0.8 $$2\pm$$

2
±

0.01 and 0.$$81\pm$$

81
±

0.01 on the internal and external datasets, respectively. The AUROC on predictions with the highest uncertainty are 0.50 $$\pm$$
±
0.02 (internal) and 0.$$56\pm$$

56
±

0.04 (external), while the AUROC on predictions with the lowest uncertainty were 0.86 ± 0.01 (internal) and 0.82 ± 0.01 (external). Using estimates of the prevalence of mPCWP > 18 mmHg in patients with reduced ventricular function, and a decision threshold corresponding to an 80% sensitivity, the calculated positive predictive value (PPV) is 0.$$89\pm$$

89
±

0.01when the corresponding chest x-ray (CXR) is consistent with interstitial edema HF. When the CXR is not consistent with interstitial edema, the estimated PPV is 0.$$78\pm$$

78
±

0.02, again at an 80% sensitivity threshold. HFNet can accurately predict elevated mPCWP in patients with HF using the 12-lead ECG and age/sex. The method also identifies cohorts in which the model is more/less likely to produce accurate outputs.
Cre-dependent ACR2-expressing reporter mouse strain for efficient long-lasting inhibition of neuronal activity
Authors: Mukai Yasutaka , Li Yan , Nakamura Akiyo , Fukatsu Noriaki , Iijima Daisuke , Abe Manabu , Sakimura Kenji , Itoi Keiichi , Yamanaka Akihiro 
Published: March 2023

AbstractOptogenetics is a powerful tool for manipulating neuronal activity by light illumination with high temporal and spatial resolution. Anion-channelrhodopsins (ACRs) are light-gated anion channels that allow researchers to efficiently inhibit neuronal activity. A blue light-sensitive ACR2 has recently been used in several in vivo studies; however, the reporter mouse strain expressing ACR2 has not yet been reported. Here, we generated a new reporter mouse strain, LSL-ACR2, in which ACR2 is expressed under the control of Cre recombinase. We crossed this strain with a noradrenergic neuron-specific driver mouse (NAT-Cre) to generate NAT-ACR2 mice. We confirmed Cre-dependent expression and function of ACR2 in the targeted neurons by immunohistochemistry and electrophysiological recordings in vitro, and confirmed physiological function using an in vivo behavioral experiment. Our results show that the LSL-ACR2 mouse strain can be applied for optogenetic inhibition of targeted neurons, particularly for long-lasting continuous inhibition, upon crossing with Cre-driver mouse strains. The LSL-ACR2 strain can be used to prepare transgenic mice with homogenous expression of ACR2 in targeted neurons with a high penetration ratio, good reproducibility, and no tissue invasion.
A comparative analysis of clinicopathological features and survival between pre and postmenopausal breast cancer from an Indian cohort
Authors: Nimbalkar Vidya P. , Rajarajan Savitha , V P Snijesh , Alexander Annie , Kaluve Rohini , Selvam Sumithra , Ramesh Rakesh , B S Srinath , Prabhu Jyothi S. 
Published: March 2023

AbstractBreast cancer (BC) among premenopausal women is an aggressive disease associated with poor outcome despite intensive treatment. Higher burden is observed in southeast Asian countries attributed to younger population structure. We compared the reproductive and clinicopathological characteristics, distribution of subtypes and survival between pre and postmenopausal women from a retrospective cohort of BC patients with median follow up over 6 years to examine the differences. In our cohort of 446 BC patients, 162/446 (36.3%) were premenopausal. Parity and age at last childbirth were significantly different between pre and postmenopausal women. Premenopausal BC had a higher proportion of HER2 amplified and triple negative breast cancer (TNBC) tumors (p = 0.012). Stratified analysis by molecular subtypes showed TNBC had significantly better disease free (DFS) and overall survival (OS) among premenopausal group (mean survival, pre vs. post, DFS = 79.2 vs. 54.0 months, OS = 72.5 vs. 49.5 months, p = 0.002 for both). Analysis on external datasets (SCAN-B, METABRIC) confirmed this finding for overall survival. Our data confirmed the previously observed association of clinical and pathological features between pre and postmenopausal BC. Exploration of better survival among premenopausal TNBC tumors is warranted in larger cohorts with long term follow up.
Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes
Authors: Leblanc Francis J. A. , Lettre Guillaume 
Published: March 2023

AbstractEpigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities. Current best practices to infer the regulatory effect of candidate cis-regulatory elements (cCREs) in multiomic data involve removing biases associated with GC content by generating null distributions of matched ATACseq peaks drawn from different chromosomes. This strategy has been broadly adopted by popular single-nucleus multiomic workflows such as Signac. Here, we uncovered limitations and confounders of this approach. We found a strong loss of power to detect a regulatory effect for cCREs with high read counts in the dominant cell-type. We showed that this is largely due to cell-type-specific trans-ATACseq peak correlations creating bimodal null distributions. We tested alternative models and concluded that physical distance and/or the raw Pearson correlation coefficients are the best predictors for peak-gene links when compared to predictions from Epimap (e.g. CD14 area under the curve [AUC] = 0.51 with the method implemented in Signac vs. 0.71 with the Pearson correlation coefficients) or validation by CRISPR perturbations (AUC = 0.63 vs. 0.73).
The acute effects of stress on dishonesty are moderated by individual differences in moral default
Authors: Speer Sebastian P. H. , Martinovici Ana , Smidts Ale , Boksem Maarten A. S. 
Published: March 2023

AbstractIn daily life we regularly must decide whether to act dishonestly for personal gain or to be honest and maintain a positive image of ourselves. While evidence suggests that acute stress influences moral decisions, it is unclear whether stress increases or decreases immoral behavior. Here, we hypothesize that stress, through its effects on cognitive control, has different effects on moral decision making for different individuals, depending on their moral default. We test this hypothesis by combining a task which allows for inconspicuously measuring spontaneous cheating with a well-established stress induction task. Our findings confirm our hypothesis, revealing that effects of stress on dishonesty are not uniform, but instead depend on the individual: for those who are relatively dishonest, stress increases dishonesty, whereas for participants who are relatively honest stress makes them more honest. These findings go a long way in resolving the conflicting findings in the literature on the effects of stress on moral decisions, suggesting that stress affects dishonesty differently for different individuals, depending on their moral default.