bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RING-finger domain ofArabidopsisRMR functions as an E3 ligase essential for post-Golgi trafficking
Authors: Chen Shuai , Zeng Yonglun , Wong Hiu Yan , Chen Yihong , Yang Lei , Luo Fang , Gao Caiji , Jiang Liwen , Wong Kam-Bo 
Published: January 2025

AbstractReceptor-homology-transmembrane-RING-H2 (RMR) sorting receptors are essential for directing soluble cargo proteins to protein storage vacuoles in plants. These type I integral membrane proteins comprise a single transmembrane domain, an N-terminal lumenal region containing a protease-associated domain for cargo recognition, and a C-terminal cytoplasmic region (CT) with a Really-Interesting-New-Gene-H2 (RING-H2) domain. Here, we determined the crystal structure of the RING-H2 domain ofArabidopsisRMR isoform-1 (AtRMR1-RING), where the conserved C3H2C3 motif coordinates two Zn ions, a feature typical of RING-type E3 ligases. AtRMR1-RING was shown to interact withArabidopsisE2 ubiquitin-conjugating enzyme, and exhibits E3 ligase activity in an in vitro ubiquitination assay. Biochemical analysis reveals that I234Y substitution disrupted the E2/E3 interaction and greatly reduced E3 ligase activity. Furthermore, we showed that the conserved RING-H2 domains of AtRMR isoform 2, 3 and 4 are also E3 ligases. Inactivation of E3 ligase activity by the I234Y mutation resulted in Golgi retention of AtRMR1-CT and AtRMR2. These findings suggest that the E3 ligase activity is essential for post-Golgi trafficking of RMR receptors, providing new insights into receptor-mediated protein sorting in plants.
Structural and Mechanistic Insights into Symmetry Conversion in Plant GORK K+Channel Regulation
Authors: Li Qi-yu , Qin Li , Tang Ling-hui , Zhang Chun-rui , Huang Shouguang , Wang Ke , Zhang Gao-hua , Hao Ning-jie , Su Min , Hedrich Rainer , Chen Yu-hang 
Published: January 2025

AbstractGORK is a shaker-like potassium channel in plants that contains ankyrin (ANK) repeats. In guard cells, activation of GORK causes K+efflux, reducing turgor pressure and closing stomata. However, how GORK is regulated remains largely elusive. Here, we solved the cryo-EM structure ofArabidopsisGORK, revealing an unusual symmetry reduction (from C4 to C2) feature within its tetrameric assembly. This symmetry reduction in GORK channel is driven by ANK dimerization, which disrupts the coupling between transmembrane helices and cytoplasmic domains, thus maintaining GORK in an autoinhibited state. Electrophysiological and structural analyses further confirmed that ANK dimerization inhibits GORK, and its removal restores C4 symmetry, converting GORK to an activatable state. This dynamic switching between C2 and C4 symmetry, mediated by ANK dimerization, presents a GORK target site that guard cells regulate to switch the plant K+channel between inhibited and activatable states, thus controlling stomatal movement in response to environmental stimuli.
On the evolution of dispersal strategies under the costs of acquisition of private and social information
Authors: Sion Antoine , Marcantonio Matteo , Masier Stefano , Tuci Elio 
Published: January 2025

AbstractDispersal between patches of suitable habitat is a key behaviour for the survival of animal populations and is impacted by rapid environmental changes. Animals must cope with several costs related to the dispersal process, such as expenses in energy for acquiring information or increased mortality risks. There is a growing interest in studying how the costs of acquisition of information influence the dispersal be- haviour of species, and particularly how the use of social and private information can shape this behaviour over multiple generations. Current models of dispersal rarely incorporate both sources of information, and there is specifically a lack of modelling studies taking into account costs of acquisition for private and social information. We develop an agent-based model simulating a population of butterflies with genetic factors linked to the acquisition of both types of information and their associated reproductive costs. We show that different costs, environmental variability conditions and sensory abilities result in various dispersal behaviours and have an impact on the fitness of the population. In stable environments, low-cost information is used by a varying proportion of agents to disperse, but when the cost rises lightly, all agents stay uninformed. In highly variable environments, the same trend is observed, but agents rely on information even if the cost of acquisition increases up to twice compared to stable environments as it provides an evolutionary advantage. Agents with a limited perceptual range use both information sources equally in variable environments, and those with a bigger perceptual range rely exclusively on private information to take dispersal decisions, except at free cost of acquisition. Globally, the use of information induces a higher fitness for the population in stable environments if costs of acquisition are free or very low. In variable environmental conditions, the highest fitness is maintained with a limited perceptual range when the total cost rises up to twice the value found for stable environments. With a bigger perceptual range, the highest fitness is maintained for the whole range of total costs studied.
CDNF rescues human iPSCs-derived dopamine neurons through direct binding to unfolded protein response sensors PERK and IRE1α
Authors: Kovaleva Vera , Shpironok Olesya , Yu Li-Ying , Ivanova Larisa , Fudo Satoshi , Happonen Lotta J. , Toots Urve , Ustav Mart , Kajander Tommi , Karelson Mati , Saarma Mart 
Published: January 2025

SUMMARYCerebral dopamine neurotrophic factor (CDNF) is an unconventional trophic factor that protects dopamine neurons in cellular and animal models of Parkinson’s disease (PD). CDNF was safe and well tolerated in phase 1 clinical trials for PD treatment, and currently, its peptide analogue is under investigation in phase 1 clinical trials for PD. Despite prominent neuroprotective and neurorestorative activity, the receptors and exact mechanism of CDNF functioning have been obscure. Intracellularly acting CDNF exerts cytoprotection by attenuating endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We demonstrated that this activity occurs through the direct binding of CDNF to ER transmembrane UPR sensors PERK and IRE1α for purified proteins and in cells. We identified CDNF mutants deficient for binding to UPR sensors. CDNF binding to PERK and IRE1α appeared to be crucial for the survival of mouse dopamine neurons in culture. Importantly for clinical translation, CDNF rescues human induced pluripotent stem cell-derived dopamine neurons and promotes their regeneration. CDNF binding to UPR sensors alleviated terminal UPR and promoted neurite outgrowth of human dopamine neurons through direct binding to PERK and IRE1α. CDNF binding to BiP was dispensable for the neuroprotective and neurorestorative activity of CDNF. Therefore, CDNF, or small molecules mimicking its binding to UPR sensors and acting selectively on dopamine neurons with activated UPR, are promising drug candidates for PD treatment.
Optimization-based dietary recommendations for healthy eating
Authors: Wang Xu-Wen , Weiss Scott T. , Hu Frank B. , Liu Yang-Yu 
Published: January 2025

ABSTRACTVarious diet scores have been developed to assess compliance with dietary guidelines. Yet, enhancing those diet scores is very challenging. Here, we tackle this issue by formalizing an optimization problem and solving it with simulated annealing. Our optimization-based dietary recommendation (ODR) approach, evaluated using Diet-Microbiome Association study data, provides efficient and reasonable recommendations for different diet scores. ODR has the potential to enhance nutritional counseling and promote dietary adherence for healthy eating.
Evidence for systematic - yet task- and motor-contingent - rhythmicity of auditory perceptual judgements
Authors: Fabio Cécile , Kayser Christoph 
Published: January 2025

AbstractNumerous studies advocate for a rhythmic mode of perception; however, the evidence in the context of auditory perception remains inconsistent. We propose that the divergent conclusions drawn from previous work stem from conceptual and methodological issues. These include ambiguous assumptions regarding the origin of perceptual rhythmicity, variations in listening tasks and attentional demands, differing analytical approaches, and the reliance on fixed participant samples for statistical testing. To systematically address these points, we conducted a series of experiments in which human participants performed auditory tasks involving monaural target sounds presented against binaural white noise backgrounds, while also recording eye movements. These experiments varied in whether stimuli were presented randomly or required motor initialization by the participant, the necessity of memory across trials and the manipulation of attentional demands across modalities. Our findings challenge the notion of universal rhythmicity in hearing, but support the existence of paradigm- and ear-specific fluctuations in perceptual sensitivity and response bias that emerge at multiple frequencies. Notably, the rhythmicity for sounds in the left and right ears appears to be largely independent among participants, and the strength of rhythmicity in behavioural data is linked to oculomotor activity and attentional requirements of the task. Overall, these results resolve conflicting conclusions drawn in previous work and provide specific avenues for further studies into the rhythmicity of auditory perception.
In vitrodisintegration of lozenge in oral cavity
Authors: Pham Quoc Dat , Edman Martin , Lindell Katarina , Wahlgren Marie 
Published: January 2025

AbstractThe aim of this study is to develop a newin vitrodisintegration method for lozenges in the oral cavity (OC) by mimicking physiologically relevant conditions in the OC including saliva flow rate and suction. Disintegration of solid-state dosage forms in the OC can be employed for local absorption in the OC or for delivering to the succeeding parts of the gastrointestinal tract. Understanding the disintegration is important before gaining insight into dissolution and absorption. Here abrasion force and rate exerted on the lozenge during the disintegration are controlled by a texture analyser. We showed that a higher flow rate and more frequent abrasion can lead to a faster disintegration, while variation of the compression force within a range in this study does not affect the disintegration statistically. The results are relevant to different types of consumers with variation in saliva production, for example, people with salivary dysfunction including elderly people. It is also important to consider these effects when formulating flavor and taste of lozenge that can affect consumer perception and consequently suction force and rate or saliva production. We could also observe disintegrated but not dissolved parts of the lozenge by using this apparatus, demonstrating the importance of the correlation between disintegration and dissolution when considering drug absorption in the OC to overcome the challenges of drug clearance from the OC by swallowing.
Instantaneous Frequency: A New Functional Biomarker for Dynamic Brain Causal Networks
Authors: Tang Haoteng , Dai Siyuan , Guo Lei , Gu Pengfei , Liu Guodong , Leow Alex D. , Thompson Paul M. , Huang Heng , Zhan Liang ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractThis study introduces instantaneous frequency (IF) analysis as a novel method for characterizing dynamic brain causal networks from fMRI blood-oxygen-level-dependent (BOLD) signals. Effective connectivity, estimated using dynamic causal modeling (DCM), is analyzed to derive IF sequences, with the average IF across brain regions serving as a potential biomarker for global network oscillatory behavior. Analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Open Access Series of Imaging Studies (OASIS), and Human Connectome Project (HCP) demonstrates the method’s efficacy in distinguishing between clinical and demographic groups, such as cognitive decline stages, sex differences, and sleep quality levels. Statistical analyses reveal significant group differences in IF metrics, highlighting its potential as a sensitive indicator for early diagnosis and monitoring of neurodegenerative and cognitive conditions.Graphical AbstractHighlightsThe study introduces instantaneous frequency (IF) as a novel biomarker derived from dynamic brain effective connectivity, capturing temporal fluctuations in brain networks.The proposed IF biomarker effectively differentiates between various clinical stages, such as Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD), and demographic factors, including sex and sleep quality.The robustness and clinical relevance of the IF biomarker are validated using three independent datasets: ADNI, OASIS, and HCP, demonstrating its potential in cognitive and neurological research.
Accurate calling of low-frequency somatic mutations by sample-specific modeling of error rates
Authors: Lin Yixin , Oroperv Carmen , Porsgård Peter Sørud , Frydendahl Boll Johansen Amanda , Rasmussen Mads Heilskov , Bataillon Thomas , Schierup Mikkel Heide , Andersen Claus Lindbjerg , Almstrup Kristian , Besenbacher Søren 
Published: January 2025

AbstractCalling rare somatic variants from NGS data is more challenging than calling inherited variants, especially if the somatic variant is only present in a small fraction of the cells in the sequenced biopsy. In this case, having a good estimate of the error rate of a specific base in a particular read becomes essential. In paired-end sequencing, where some DNA fragments are shorter than twice the read length, the overlapping regions of the read pairs are an ideal resource for training models to discern context-dependent base error rates, as any discordant bases in the overlaps must be caused by a sequencing error or an alignment error. We have created a new tool named BBQ (an acronym for Better Base Quality) that uses overlapping reads to estimate the error rate conditional on the mutation type, sequence context, and base quality. We also estimate how much the error rate of concordant bases in overlapping reads is decreased compared to bases in non-overlapping reads. Results show that overlapping reads can remove sequencing errors induced by DNA damage and that the increased quality of overlapping reads differs between samples and mutation types, reflecting different damage patterns between samples. We use the error models to call rare somatic variants. Sequencing data from a testis biopsy and a cell-free DNA sample serve as a proof-of-concept for rare germ cell mutation calling and for detecting rare cancer mutations. We find that using the sample-specific error models of BBQ allows us to call rare somatic variants with fewer false positives than existing tools such as Mutect2 and Strelka2.
CSF1R-CAR T cells induce CSF1R signalling and promote cancer cell growth
Authors: Callahan Aurora , Zhang Xinyan , Wang Amber , Mojumdar Aisharja , Zeng Longhui , Su Xiaolei , Salomon Arthur R. 
Published: January 2025

AbstractChimeric antigen receptor (CAR) T cells have transformed the landscape of cancer therapy and demonstrate unprecedented success in treating relapsed/refractory blood cancers. The mechanism underlaying the interactions and responses of CAR T cells and their targets remain incompletely understood. Previous studies focus on the activation of CAR T cells and attempt to optimise CAR design to increase efficacy, meanwhile ignoring tumours and their responses to CAR ligation. Here, we evaluate the signalling capacity of a second generation CSF1-tageted CSF1R CAR compared with a scFv-targeted CD19-CAR using a SILAC co- culture approach coupled with phosphotyrosine (pY) enrichment and LC-MS/MS. We show that ligation of CSF1R-expressing THP1 cells with CSF1R-CAR T cells induces CSF1R-like signalling in THP1 cells, whereas no target cell signalling response is observed after CD19- CAR/Raji B cell ligation. Using small molecule inhibitors of Lck, actin polymerisation, and CSF1R, we find that CAR-induced CSF1R signalling in THP1 cells depends exclusively on CSF1R kinase activity with no participation from T cell activation. Consistently, CSF1R- CAR T cells promote THP1 growth at low effector-to-target (E:T) ratios but prevent THP1 growth at high E:T ratios. Our data provide evidence for an unintended consequence of CARs; CAR-induced signalling in cancer cells. These data may have broad implications for the choice of CAR antigen for optimal clinical efficacy.One Sentence Summary:CSF1R-CAR activates intracellular signalling cascades in THP1 cells, which promote THP1 cell growth.
Cardiovascular autonomic dysfunction precedes cardiovascular disease and all-cause mortality: 11-year follow-up of the ADDITION-PRO study
Authors: Schaarup Jonas R. , Bjerg Lasse , Hansen Christian S. , Grove Erik L. , Andersen Signe T. , Vistisen Dorte , Brage Søren , Sandbæk Annelli , Witte Daniel R. 
Published: January 2025

AbstractBackgroundCardiovascular autonomic dysfunction remains a silent complication in people at high risk of diabetes. We aim to determine the impact of week-long heart rate variability (HRV) on the risk of cardiovascular events and mortality in this population.MethodsWeek-long HRV and mean heart rate (mHR) were measured in 1,627 participants from the ADDITION-PRO study between 2009-2011. As measurement for HRV, we calculated a proxy for standard deviation of normal heartbeat (SDNN) both weekly, daily and hourly. Data on cardiovascular events (CVD) and all-cause mortality were obtained from Danish patient registers until 2021. We fitted poisson regression to determine incidence rate ratios (IRR) for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, cardiovascular death), heart failure, and all-cause mortality.ResultsMean (SD) age was 66 years (7), and 47 % were women. The population had a mean (SD) week-long SDNN of 139.0 (32.3) ms. Week-long HRV index SDNN showed an IRR of 0.82 (CI: 0.69; 0.97), 0.76 (CI: 0.58; 0.99), and 0.79 (CI: 0.66; 0.94) per SD for MACE, heart failure, and all-cause mortality, respectively. The risk for MACE, heart failure, and all-cause mortality was higher at SDNN values below 120ms. SDNN measurements taken from 6:00-7:00 AM showed the strongest association with the risk of MACE. Lower SDNN was consistently associated with higher all-cause mortality risk across all hours of the day. Adjustment for concurrent physical acceleration and heart rate did not materially change the magnitude of these associations. Night-time heart rate was associated with a higher risk of MACE, heart failure and all-cause mortality.ConclusionCardiovascular autonomic dysfunction, measured by week-long HRV, is associated with higher risk of CVD, heart failure and all-cause mortality. Certain time frames of the day for HRV and heart rate under free-living conditions showed higher risk of CVD. Hence, long-term HRV and the diurnal response are linked with CVD risk among people with high risk of diabetes. Studies exploring the benefit of HRV modifications in CVD prevention are warranted.
Associations between the mid-adolescent external exposome and proteomic biomarkers of mental health
Authors: Wang Zhiyang , Drouard Gabin , Afonin Aleksei , Botella Núria , Peuters Carmen , Piironen Aino-Kaisa , Whipp Alyce. M. , Cheval Boris , Šulc Libor , Heinonen-Guzejev Marja , Foraster Maria , Gulliver John , Selander Jenny , Dadvand Payam , Júlvez Jordi , van Kamp Irene , Kanninen Katja M. , Kaprio Jaakko ,   Equal-Life Scientific Team
Published: January 2025

AbstractThe exposome, encompassing all external and internal environmental factors, provides a comprehensive understanding of the complex etiology of mental health. This study investigated the relationship between the external exposome during mid-adolescence and plasma proteomic biomarkers of mental health in 935 participants from the FinnTwin12 (Finland) and WALNUTs (Spain) cohorts. The mid-adolescent external exposome included 60 exposures. Biomarkers included 26 plasma proteins (mean age 22) for FinnTwin12 and 31 (mean age 13) for WALNUTs. The exposome-wide proteome-wide analysis revealed seven exposures (related to lifestyle, indoor environmental quality, natural environment, and family environment) linked to six proteins. Greenspace-related exposures were associated with proteins in both cohorts. However, these exposures showed no direct association with concurrent measures: the psychopathology factor or depressive symptoms. Twin analyses indicated genetic influences in some covariations between exposures and proteins. These findings provide evidence for mid-adolescents about the association between external environments and proteomic biomarkers of mental health.
Prevalence and factors associated with undernutrition among under-five children with sickle cell disease at Mulago National Referral Hospital, Uganda: A facility-based cross-sectional study
Authors: Namubamba Annet , Wamani Henry , Namaganda Agnes , Namagala Umusalima , Cheputyo Priscilla , Muramuzi Dan , Kamukama Saul 
Published: January 2025

AbstractBackgroundSickle cell disease (SCD) significantly contributes to under-five morbidity and mortality in sub-Saharan Africa and increases vulnerability to undernutrition. However, limited studies exist on the prevalence of undernutrition and its associated factors among children under five years with SCD in Uganda. We assessed the prevalence of undernutrition and its associated factors among children with SCD aged 6-59 months attending the sickle cell clinic at Mulago National Referral Hospital in Kampala, Uganda.MethodsA facility-based cross-sectional study was conducted among 329 children aged 6-59 months. Data was collected in August 2022 using a structured questionnaire and analyzed using STATA version 14.0. Modified Poisson regression was used to identify the factors associated with undernutrition.ResultsThe prevalence of undernutrition among children with SCD aged 6-59 months was 31.3% (n=103) 95% CI 26.5, 36.5; 27.4% (n=90) 95% CI 22.8, 32.5 were stunted, and 14.3% (n=47) 95% CI 10.8, 18.5 were underweight. Undernutrition among children with SCD was statistically significantly associated with children below 24 months but not breastfeeding (aPR=1.27; 95% CI: 1.09-1.48; P-0.002), not immunized against measles (aPR=1.31; 95% CI: 1.02-1.68; P-0.03), and child not taking hydroxyurea drug (aPR=1.5; 95% CI: 1.07-2.08; P-0.017).ConclusionEarly weaning of children, not being immunized against measles, and the child not taking hydroxyurea drug were great contributors to undernutrition. There is a need for sensitization of the caretakers about these predictors, and integrating hydroxyurea treatment in the standard care package of management of SCD in Uganda.
Correlation study of serum 25 hydroxyvitamin D with peripheral neuropathy in type 2 diabetes
Authors: Chen Senzhen , Chen Jinfeng , Huang Mengting , Yan Yiling , Zheng Shujing , Chen Nuoqi 
Published: January 2025

ObjectiveTo investigate the correlation between serum 25 hydroxyvitamin D (25 (OH) D) and peripheral neuropathy of type 2 diabetes (Diabetic Peripheral N europathy, DPN) and its predictive value for DPN.MethodsThe subjects were divided into deficient group, insufficient group and normal group, and the relationship between 25(OH)D and DPN and the correlation of 25(OH)D and DPN with various indicators were analyzed.ResultsComparing the DPN group with the NDPN group, 25(OH)D3(22.10±0.77ng/ml vs 24.45±0.66ng/ml), 25(OH)D total (23.12±0.74ng/ml vs 25.68±0.67ng/ml), BMI, RHR, TG, FT3, BUN between the two groups (P <0.05), 25(OH)D3,25(OH)D total, FT3, BMI, and RHR are risk factors for DPN. The ROC curve showed that the optimal cutoff for 25(OH)D3 predicting DPN in T2DM was 18.85ng/ml (AUC 0.76,95% CI 0.697-8.823) and the optimal cutoff for 25(OH)D predicting T2DM was 19.94ng/ml (AUC 0.765,95% CI 0.703-0.828).Conclusion25(OH)D can be used as a simple and effective screening method to predict the occurrence of DPN for total 25(OH)D<19.94ng/ml or 25(OH)D3<18.85ng/ml.