bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Insights into Dopamine Receptor-Ligand Interactions: From Agonists to Antagonists
Authors: Barbosa Emmanuel , Clift Heather , Olson Linda , Zhu Lan , Liu Wei 
Published: November 2023

ABSTRACTThis study explores the intricacies of dopamine receptor-ligand interactions, focusing on the D1R and D5R subtypes. Using molecular modeling techniques, we investigate the binding of the pan-agonist rotigotine, revealing a universal binding mode at the orthosteric binding pocket (OBP). Additionally, we analyze the stability of antagonist-receptor complexes with SKF83566 and SCH23390. By examining the impact of specific mutations on ligand-receptor interactions through computational simulations and thermostability assays, we gain insights into binding stability. Our research also delves into the structural and energetic aspects of antagonist binding to D1R and D5R in their inactive states. These findings enhance our understanding of dopamine receptor pharmacology and hold promise for drug development in central nervous system disorders, opening doors to future research and innovation in this field.
Height loss in adulthood is associated with health outcomes in later life in men and women enrolled in the 1946 UK Birth Cohort (NSHD)
Authors: Matthes Katarina L. , Staub Kaspar 
Published: November 2023

AbstractObjectiveTo investigate the relationship between height in childhood and relative height loss in adult-hood, and to examine the association between height loss and health at age 69.DesignCohort study.SettingData from one of the oldest ongoing cohort studies, the National Survey of Health and Development (NSHD, 1946 UK birth cohort)Participants2,119 study participants who completed the nurse home visit during the 24thand most recent available follow-up examination at age 69.Main outcome measuresLinear regression models to estimate the association between measured height in childhood years relative height loss between ages 36 and 69. Logistic regression models using generalized additive models to estimate the probability of worse health at age 69 (chronic disease score, general health status, osteoarthritis, and pain while walking) in association with height loss.ResultsBetween the ages of 36 and 69, men lost an average of 2.03 cm and women 2.44 cm. Women lost significantly more height than men (p<0.001). The taller the participants were at a young age, the more height they lost in adulthood. There was a significant association between height loss in adulthood on the one hand and general health, chronic disease score (in men), osteoarthritis (in men), and walking pain at age 69. These findings largely persisted after adjusting the models for overweight, sociodemo-graphic information, and lifestyle factors earlier in life.ConclusionsHeight loss seems to mirror deteriorating health as people age. Height measurement and assessment of height loss should be part of regular examinations after the age of 40 to monitor general health status, especially in the case of severe height loss.
TMS-induced plasticity improving cognitive control in OCD I: Clinical and neuroimaging outcomes from a randomised trial of rTMS for OCD
Authors: Fitzsimmons Sophie M.D.D. , Postma Tjardo , van Campen A. Dilene , Vriend Chris , Batelaan Neeltje M. , van Oppen Patricia , Hoogendoorn Adriaan W. , van der Werf Ysbrand D. , van den Heuvel Odile A. 
Published: November 2023

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS) is an emerging treatment option for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have, however, been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP).MethodsIn this three-arm proof-of-concept randomized controlled clinical trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19 (6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA) (n=23 (10M/13F)); or control rTMS to the vertex (n=19 (6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach.ResultsMean OCD symptom severity decreased significantly in all treatment groups (delta=- 10.836, p<0.001, 95% CI [-12.504, -9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. Groups receiving DLPFC or preSMA rTMS showed, respectively, a decrease in planning and error processing task-related activation after treatment that was associated with symptom improvement, while individuals in the vertex rTMS group with greater symptom improvement showed an increase in inhibition-related activation.ConclusionsPreSMA and DLPFC rTMS combined with ERP led to significant symptom improvement related to activation decreases in targeted task networks, although we observed no differences in symptom reduction between groups.This trial was registered at clinicaltrials.gov (NCT03667807)
Whole genome sequencing analysis identifies rare, large-effect non-coding variants and regions associated with circulating protein levels
Authors: Hawkes Gareth , Chundru Kartik , Jackson Leigh , Patel Kashyap A. , Murray Anna , Wood Andrew R , Wright Caroline F , Weedon Michael N , Frayling Timothy M , Beaumont Robin N 
Published: November 2023

AbstractThe role of non-coding rare variation in common phenotypes is largely unknown, due to a lack of whole-genome sequence data, and the difficulty of categorising non-coding variants into biologically meaningful regulatory units. To begin addressing these challenges, we performed acisassociation analysis using whole-genome sequence data, consisting of 391 million variants and 1,450 circulating protein levels in ∼20,000 UK Biobank participants. We identified 777 independent rare non-coding single variants associated with circulating protein levels (P<1×10-9), after conditioning on protein-coding and common associated variants. Rare non-coding aggregate testing identified 108 conditionally independent regulatory regions. Unlike protein-coding variation, rare non-coding genetic variation was almost as likely to increase as decrease protein levels. The regions we identified overlapped predicted tissue-specific enhancers more than promoters, suggesting they represent tissue-specific regulatory regions. Our results have important implications for the identification, and role, of rare non-coding variation associated with common human phenotypes.
A Cellular Basis for Mapping Behavioural Structure
Authors: El-Gaby Mohamady , Harris Adam Loyd , Whittington James C. R. , Dorrell William , Bhomick Arya , Walton Mark E. , Akam Thomas , Behrens Tim E. J. 
Published: November 2023

ABSTRACTTo flexibly adapt to new situations, our brains must understand the regularities in the world, but also in our own patterns of behaviour. A wealth of findings is beginning to reveal the algorithms we use to map the outside world1–6. In contrast, the biological algorithms that map the complex structured behaviours we compose to reach our goals remain enigmatic. Here we reveal a neuronal implementation of an algorithm for mapping abstract behavioural structure and transferring it to new scenarios. We trained mice on many tasks which shared a common structure organising a sequence of goals, but differed in the specific goal locations. Animals discovered the underlying task structure, enabling zero-shot inferences on the first trial of new tasks. The activity of most neurons in the medial Frontal cortex tiled progress-to-goal, akin to how place cells map physical space. These “goal-progress cells” generalised, stretching and compressing their tiling to accommodate different goal distances. In contrast, progress along the overall sequence of goals was not encoded explicitly. Instead a subset of goal-progress cells was further tuned such that individual neurons fired with a fixed task-lag from a particular behavioural step. Together these cells implemented an algorithm that instantaneously encoded the entire sequence of future behavioural steps, and whose dynamics automatically retrieved the appropriate action at each step. These dynamics mirrored the abstract task structure both on-task and during offline sleep. Our findings suggest that goal-progress cells in the medial frontal cortex may be elemental building blocks of schemata that can be sculpted to represent complex behavioural structures.
RudLOV—a new optically synchronized cargo transport method reveals unexpected effect of dynasore
Authors: Tago Tatsuya , Ogawa Takumi , Goto Yumi , Toyooka Kiminori , Tojima Takuro , Nakano Akihiko , Satoh Takunori , Satoh Akiko K. 
Published: November 2023

AbstractLive imaging of secretory cargoes is a powerful method for understanding the mechanisms of membrane trafficking. Inducing the synchronous release of cargoes from an organelle is a key for enhancing microscopic observation. We developed an optical cargo-releasing method named as retention using dark state of LOV2 (RudLOV), which enables exceptional spatial, temporal, and quantity control during cargo release. A limited amount of cargo-release using RudLOV successfully visualized cargo cisternal-movement and cargo-specific exit sites on the Golgi/trans-Golgi network. Moreover, by controlling the timing of cargo-release using RudLOV, we revealed the canonical and non-canonical effects of the well-known dynamin inhibitor dynasore, which inhibits early-Golgi but not late-Golgi transport and exit from thetrans-Golgi network where dynamin-2 is active. Accumulation of COPI vesicles at thecis-side of the Golgi stacks in dynasore-treated cells suggests that dynasore targets COPI-uncoating/tethering/fusion machinery in the early-Golgi cisternae or endoplasmic reticulum but not in the late-Golgi cisternae. These results provide insight into the cisternal maturation of Golgi stacks.
Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice
Authors: Zhong Rui , Xu Yingzheng , Williams Jesse W. , Li Ling 
Published: November 2023

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-β (Aβ) plaques, have been investigated by introducingTrem2deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features Aβ deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall Aβ load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence ofTrem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways inTrem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses toTrem2deficiency, contributing to the pathological changes in the brain ofTrem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular Aβ pathologies, which may have significant implications for both TREM2- and Aβ-targeting therapies for AD.
Protein Engineering with Lightweight Graph Denoising Neural Networks
Authors: Zhou Bingxin , Zheng Lirong , Wu Banghao , Tan Yang , Lv Outongyi , Yi Kai , Fan Guisheng , Hong Liang 
Published: November 2023

AbstractProtein engineering faces challenges in finding optimal mutants from the massive pool of candidate mutants. In this study, we introduce a deep learning-based data-efficient fitness prediction tool to steer protein engineering. Our methodology establishes a lightweight graph neural network scheme for protein structures, which efficiently analyzes the microenvironment of amino acids in wild-type proteins and reconstructs the distribution of the amino acid sequences that are more likely to pass natural selection. This distribution serves as a general guidance for scoring proteins toward arbitrary properties on any order of mutations. Our proposed solution undergoes extensive wet-lab experimental validation spanning diverse physicochemical properties of various proteins, including fluorescence intensity, antigen-antibody affinity, thermostability, and DNA cleavage activity. More than40%of ProtLGN-designed single-site mutants outperform their wild-type counterparts across all studied proteins and targeted properties. More importantly, our model can bypass the negative epistatic effect to combine single mutation sites and form deep mutants with up to 7 mutation sites in a single round, whose physicochemical properties are significantly improved. This observation provides compelling evidence of the structure-based model’s potential to guide deep mutations in protein engineering. Overall, our approach emerges as a versatile tool for protein engineering, benefiting both the computational and bioengineering communities.
TIM‐3 expression induces resistance to PD‐1 inhibitor in G‐CSF‐producing lung spindle cell carcinoma: A case report
Authors: Hayashi Fumiko , Akagi Kazumasa , Taniguchi Hirokazu , Matsutake Toyoshi , Kawahara Hiromi , Sekine Ichiro , Gyotoku Hiroshi , Takemoto Shinnosuke , Soda Hiroshi , Ashizawa Kazuto , Mukae Hiroshi 
Published: November 2023

AbstractLung spindle cell carcinoma is an aggressive subtype of pleomorphic lung cancer resistant to cytotoxic chemotherapy. Programmed cell death‐1 (PD‐1) inhibitors have been reported to have clinical effects in patients with spindle cell carcinoma; however, the resistance mechanism to PD‐1 inhibitors is yet to be fully elucidated. Herein, we report the case of an 88‐year‐old man with G‐CSF‐producing spindle cell carcinoma who acquired resistance to PD‐1/PD‐ligand 1 (L1) inhibitor in an early setting after a remarkable response. A histopathological review of the resistant specimen revealed a low count of CD8+ T cells and a predominant presence of M2 and TIM‐3+ macrophages, indicating the presence of an immunosuppressive microenvironment. Our findings suggest a novel resistance mechanism to PD‐1/PD‐L1 inhibitors in G‐CSF‐producing spindle cell carcinoma.
Identification of ancestral gnathostome Gli3 enhancers with activity in mammals
Authors: Ali Shahid , Abrar Muhammad , Hussain Irfan , Batool Fatima , Raza Rabail Zehra , Khatoon Hizran , Zoia Matteo , Visel Axel , Shubin Neil H. , Osterwalder Marco , Abbasi Amir Ali 
Published: November 2023

AbstractAbnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis‐regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15–21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage‐specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co‐option of limb specificity from other tissues prior to the divergence of amniotes and lobe‐finned fish. These results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.
Reliability and validity of a parent‐reported screening tool for disordered eating in children and young people with type 1 diabetes
Authors: Harrington Megan P. , Satherley Rose‐Marie , John Mary , O'Donnell Nicola , Read Rebecca , Wakelin Katherine , Jones Christina J. 
Published: November 2023

AbstractBackgroundThere is a high prevalence and complex overlap between type 1 diabetes (T1D) and disordered eating. However, screening for disordered eating in children and young people (CYP) with T1D is not routinely conducted, with reluctance reported by both professionals and parents. This study aimed to validate a parent‐reported version of a validated disordered eating screening tool for CYP with T1D (the Diabetes Eating Problems Survey‐Revised; DEPS‐R).MethodsThe existing DEPS‐R was adapted for parental use. Eighty‐nine parents of CYP with T1D aged 11–14 years completed the parent‐reported DEPS‐R and other questionnaires related to demographics, child eating behaviours and parental well‐being. CYP of parents were invited to participate, with 51 CYP completing the validated CYP‐reported DEPS‐R for comparison.ResultsThe parent‐reported DEPS‐R demonstrated good internal consistency (Cronbach's α = 0.89). Moderate to good inter‐rater reliability was found between the parent‐reported DEPS‐R and CYP‐reported DEPS‐R (ICC 0.746, 95% CI = 0.554–0.855, p < 0.001), indicating good convergent validity. Construct validity with hypothesised variables, including specific eating behaviours, diabetes‐related distress, well‐being, CYP BMI, gender and parental worry about CYP disordered eating, suggested validity of the measure. However, some hypothesised variables did not significantly correlate with the parent‐reported DEPS‐R as expected.ConclusionsThe parent‐reported DEPS‐R has demonstrated good reliability and validity, and it may provide clinical benefit by increasing screening and early detection of disordered eating in CYP with T1D. Whilst novel and providing stepped increase in our knowledge, these findings would benefit from further validation (e.g. in a larger sample and responsiveness).
Actualization of interdisciplinary integration at mathematics lessons
Authors: Zhexembinova Aizhan , Kokazhayeva Amangul , Babaev Doolotbai , Shiyapov Kadrzhan , Sekenova Aizhan 
Published: November 2023

AbstractThe relevance of the published research on the actualization of interdisciplinary integration at mathematics lessons is due to the need for conceptual clarification of what is included in the concept of an academic discipline, and, consequently, interdisciplinary integration. Currently, there is no uniformly consistent interdisciplinary terminology, moreover, interdisciplinary boundaries are often difficult to overcome. In pedagogical practice, intersubject is only rhetorically praised, but its practical implementation is often very difficult. This publication aims at studying the role and potential of the actualization of interdisciplinary integration at mathematics lessons. Mathematics is widely recognized as central to human development. However, there are not enough research concerning teaching mathematics in various contexts of educational systems. The object of the study is interdisciplinary integration at mathematics lessons within the framework of holistic learning concepts. Consideration of interdisciplinary integration at mathematics lessons gives researchers the key to education of the XXI century. Nevertheless, few studies are published concerning the proposed object that can serve as a basis for practice in the actualization of interdisciplinary integration at mathematics lessons. Qualitative critical phenomenology was used as a research methodology, since the logic of the actualization of interdisciplinary integration at mathematics lessons reflects a system of historically determined values transmitted by institutionalized models of behaviour, thinking and speech. The application of critical phenomenology allowed us to come to an understanding of how the social and pedagogical aspects of the actualization of interdisciplinary integration at mathematics lessons affect the ways in which students construct reality. Critical phenomenology has made it possible to identify various approaches to the study of the actualization of interdisciplinary integration at mathematics lessons, to study the impact of social interactions in the construction of interdisciplinary discourse by students, the possible impact that interdisciplinary discourse can have on learning. Since the research was of a qualitative nature, it was inevitably influenced by the interpretative methodological paradigm, which recognizes that individual life experience is formed by context, and ideas about knowledge are socially constructed.
Risk management committee and bank performance: Evidence from the adoption of the Dodd–Frank Act
Authors: Jiang Liangliang , Ji Mingming 
Published: November 2023

AbstractWe test the effect of the establishment of a risk management committee on bank risk, bank loan performance and bank profitability. The Dodd–Frank Act of 2010 provides us with quasi‐experimental variation on risk management committee establishment that facilitates identification. We identify the risk management committee effect using an instrumental variable model based on the difference‐in‐differences design. We find that the establishment of a risk committee has effectively reduced bank risks. In addition, risk committee member independence, more risk committee meetings and more risk committee members are all instrumental to bank risk reduction. We also find evidence that the risk reduction effect from the risk management committee is more pronounced among asset‐diversified banks. Finally, the establishment of a risk committee helps with loan quality improvement and firm profitability increment, which sheds light on the bright side of stringent bank regulation.