bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Polymorphisms Play an Important Role in the Drug Interaction Between Posaconazole and Tacrolimus in Renal Transplant Patients
Authors: Hu Nan , Guan Mengmeng , Gu Bin , Yang Xuping , Qian Qing , Zhao Di , Xue Hui , Jiang Jingting 
Published: November 2024

Background:
Posaconazole (POSA), a second-generation triazole antifungal drug, inhibits CYP3A and P-glycoprotein. Here, the interaction between POSA and tacrolimus (TAC) in patients undergoing early renal transplantation was studied.

Methods:
Twenty-two renal transplant recipients who received POSA as antifungal therapy were studied. The following indicators were analyzed statistically: the blood concentration (C), dose (D), and concentration–dose ratio (C/D) of TAC before and after introducing POSA; the change of C/D (ΔC/D) after starting POSA; the genotypes of CYP3A5*3, ABCB1 3435, ABCB1 1236, and POR*28; other routine clinical indicators.

Results:
After starting POSA, the C, D, and C/D values of TAC were 1.29, 0.57, and 2.74 times the original values, respectively. A linear correlation was observed between the plasma levels of POSA and ΔC/D. The CYP3A5*3 gene polymorphism showed a significant impact on C, D, and C/D of TAC; however, it did not affect the ΔC/D. Polymorphism of the ABCB1 3435 gene had a significant effect on ΔC/D, and patients with the CC genotype in ABCB1 3435 had significantly lower ΔC/D than the CT/TT patients.

Conclusions:
In renal transplant patients, considerable interindividual variability was observed in the drug interactions between POSA and TAC. The genotypes of CYP3A5*3 and ABCB1 3435 and the plasma level of POSA had strong impact on the interaction between POSA and TAC.
Lacosamide Pharmacokinetics and Retention in Japanese Patients With Epilepsy: A Retrospective Study on the Influence of Age, Comedications, and Cytochrome P450 2C19 Polymorphism
Authors: Yamamoto Yoshiaki , Shiratani Yuka , Nishida Takuji , Usui Naotaka , Kagawa Yoshiyuki , Takahashi Yukitoshi , Imai Katsumi 
Published: November 2024

Background:
This retrospective study aimed to identify the genetic and nongenetic factors that influence serum lacosamide (LCM) concentrations and evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on the long-term retention rate of LCM.

Methods:
We analyzed serum samples from 1901 Japanese patients with epilepsy and compared the concentration-to-dose (CD) ratio of LCM among 4 age groups (preschool children, 1–5 years; primary school children, 6–11 years; adolescents, 12–17 years; and adults, ≥18 years). In addition, we performed CYP2C19 genotyping using real-time polymerase chain reaction in 302 patients and classified them into 3 groups: extensive metabolizers (EM: CYP2C19*1/*1), intermediate metabolizers (IM: CYP2C19*1/*2 or *1/*3), and poor metabolizers (PM: CYP2C19*2/*2, *3/*3, or *2/*3). We compared the LCM retention rates between the non-PM (EM and IM) and PM groups using the Kaplan–Meier method.

Results:
The adult group had the highest mean CD ratio, which was 33.7%, 21.9%, and 7.3% higher than that of preschool children, school children, and adolescents, respectively. The use of enzyme-inducing antiseizure medications (ASMs; ie, phenytoin, phenobarbital, or carbamazepine) reduced the CD ratio by 34.0% in preschool children, 27.3% in primary school children, 24.3% in adolescents, and 27.4% in adults. In adults, the mean CD ratios were 17.7% and 49.0% higher in the IM and PM groups, respectively, than in the EM group. The 3-year retention rate of LCM was higher in the non-PM group than in the PM group (881 vs. 728 days; log-rank test, P < 0.05).

Conclusions:
Age and the concomitant use of enzyme-inducing ASMs influence LCM pharmacokinetics. In addition, patients with the PM phenotype have a high LCM CD ratio, which may decrease treatment retention. Therapeutic drug monitoring for LCM is a clinically useful method for evaluating pharmacokinetics in individual patients and optimizing the dose of LCM.
Utilization of Recipient Veins with Reflux During Supermicrosurgical Lymphaticovenous Anastomosis for Lower Limb Lymphedema
Authors: Patanè Luca , Kuo Pao-Jen , Ou Yu-Che , Chang Chad , Wu Shao-Chun , Lin Wei-Che , Chien Peng-Chen , Hsieh Ching-Hua , Yang Johnson Chia-Shen 
Published: November 2024

Background:
The use of recipient veins with venous reflux for lymphaticovenous anastomosis (LVA) is discouraged because it is commonly believed that it may lead to venous-lymphatic reflux (VLR). VLR is a phenomenon in which venous blood is refluxed into the lymphatic lumen after anastomosis, potentially lowering the long-term patency rate. However, this concept is yet to be validated. This study aimed to determine the impact on outcomes when recipient veins with reflux were used for LVA in treating unilateral lower limb lymphedema.

Study design:
Seventy-nine patients who underwent LVA as the primary treatment were enrolled. The study group included 31 patients who used only recipient veins with reflux. An additional 48 patients (control group) utilized only reflux-free veins. Patients with a history of previous LVA, liposuction, or excisional therapy were excluded. Patient characteristics, intraoperative findings, functional parameters, and pre-and post-LVA volume changes were recorded and matched using propensity score matching. The primary endpoint was the volume change at 6 and 12 months after LVA.

Results:
After matching, 28 patients were included in each group. All parameters were matched except the study variables, where the study group demonstrated significantly higher venous reflux (p < 0.001) and VLR ratio (p < 0.001). However, at the 6- and 12-month follow-up, the postoperative percentage volume reduction was comparable between the groups (p = 0.385 and 0.391, respectively).

Conclusion:
When reflux-free veins are unavailable, using recipient veins with reflux for LVA is recommended.
Animal-encoded nonribosomal pathway to bursatellin analogs
Authors: Venugopalan Aarthi , Schmidt Eric W. 
Published: November 2024

ABSTRACTThe bursatellin-oxazinin family is a series of tyrosine-derived, nitrile-containing marine natural products from gastro-pod and bivalve molluscs. Although the first analogs were identified and associated with toxicity forty years ago, their biosynthetic origins were unknown. During an investigation of published mollusc genomes and transcriptomes, we serendipitously identified a putative bursatellin biosynthetic gene cluster (referred hereafter as thebur-oxpathway). Through biochemical characterization of somebur-oxgenes, we provide evidence suggesting that bursatellin-type metabolites are produced by molluscs themselves rather than by their microbial symbionts. We show that the reductive domain from a monomodular nonribosomal peptide synthetase (NRPS) protein FmtATR performs a four-electron reduction to produce tyrosinols from tyrosine derivatives. Moreover, an aminocarboxypro-pyltransferase enzyme, ACT, usesS-adenosylmethionine (SAM) to transform tyrosinols into their phenolic homoserine ethers, which in bursatellin is further modified to the nitrile. Widespread occurrence ofbur-oxin molluscs suggests a common biosynthetic origin for bursatellins and oxazinins as well as an important but currently unidentified physiological role for this metabolite family in molluscs inhabiting diverse ecological niches. Further, the presence ofbur-oxpathway homologs in many culinary bivalves such as mussels and geoducks suggests that possible impacts on human consumers should be investigated. As one of the few NRPS pathways of animal origin to be characterized,bur-oxsheds light on underappreciated chemical and biochemical diversity in animals.
Impact of astrocytic C3-production on neuronal mitochondrial dysfunction in tauopathy mouse models
Authors: Lei Chenxu , Zhang Bocheng , Yamaguchi Junji , Tamura Risako , Cao Xingyu , Liu Yunhui , Seki Masahide , Suzuki Yutaka , Suzuki Kuninori , Tanida Isei , Uchiyama Yasuo , Hisatsune Tatsuhiro 
Published: November 2024

AbstractNeuronal mitochondrial dysfunction is associated with cognitive decline in neurodegenerative disorders such as Alzheimer’s Disease (AD). In this study, multiple pieces of evidence proved that phosphorylated tau (p-Tau) caused mitochondrial swelling and dysfunction in neurons. In a novelin vitronewborn neurons culture system, we discovered mitochondrial swelling and dysfunction were associated with increased p-Tau, leading to necroptosis activation, which was induced by Complement C3 (C3) produced from activated astrocytes. In thein vivotauopathy mouse models, the effects of astrocytic C3 on tau-associated mitochondrial dysfunction and necroptosis were also discovered in hippocampal newborn neurons, and we directly showed that p-Tau aggregation was associated with mitochondria swelling in the hippocampal neurons by electron microscopy analysis. In addition, we proved the ability of compound anserine, which can block Tak1-Ikk dependent NF-κB activation, to further down-regulate astrocytic C3 production and alleviate neuronal mitochondrial dysfunctionin vitroandin vivo, respectively. Down-regulation of astrocyte C3-production by anserine could also rescue mortality as well as cognitive and motor functions. Our findings first reported the contribution of p-Tau on neuronal mitochondrial dysfunction and proposed the therapies that down-regulate astrocytic C3 production have a potential role in alleviating this neurotoxic effect.
The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion
Authors: Harris Chris R. , Wang Lan , Dudgeon Crissy , Prela Orjola , Cazarin de Menezes Juliana , Shih Ching-Hua , Davidson Christina , Casabianca Anthony , De Subhajyoti , Narrow Wade , Becker Jennifer , Balachandran Vinod P. , Grandgenett Paul M , Hollingsworth Michael A. , Grem Jean L. , Kim Minsoo , Hong Yeonsun , Gerber Scott , Vertino Paula M. , Gao Chongfeng , Repesh Anna , Klamer Zachary , Hao Yansheng , Altman Brian , Haab Brian , Carpizo Darren R. 
Published: November 2024

SummaryThe mechanisms that regulate cancer dormancy remain poorly understood. Using a mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified Dec2 as a gene that was upregulated in metastatic dormant tumor cells. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism as the survival benefit was abrogated in immunodeficient conditions. Dec2 promoted immune evasion by repressing multiple components of the MHC-I dependent antigen presentation pathway in tumor cells. Dec2 is a regulator of circadian rhythms, and we found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock, which is exploited by Dec2-overexpressing pancreatic tumors to evade the immune system.
Functional Connectivity Alterations in Cocaine Use Disorder: Insights from the Triple Network Model and the Addictions Neuroclinical Assessment Framework
Authors: Xu Ziyang , Li Lie , Liu Ruobing , Azzam Mohamed , Wan Shibiao , Wang Jieqiong 
Published: November 2024

AbstractCocaine use disorder (CUD) disrupts functional connectivity within key brain networks, specifically the default mode network (DMN), salience network (SN), and central executive network (CEN). While the triple network model has been proposed to explain various psychiatric disorders, its applicability to CUD requires further exploration. In the present study, we built machine learning classifiers based on different combinations of DMN/SN/CEN to distinguish cocaine-use disorder (CUD) subjects from healthy control (HC) subjects. Among them, the combination of the SN and the CEN results in a remarkably high accuracy of 73.4% (sensitivity/specificity: 69.6%/78.6%, AUC: 0.78), outperforming the model based on the full triple network. This supports the hypothesis that during the binge/intoxication stage of addiction, the SN and the CEN play a more critical role than the DMN, consistent with the Addictions Neuroclinical Assessment (ANA) framework. Functional connectivity analysis revealed decreased connectivity within the DMN and the SN and increased connectivity within the CEN in CUD patients, suggesting that alterations in these networks could serve as biomarkers for addiction severity.
Morphological brain alterations and morphological brain network disorganizations in heroin and methamphetamine abstinent patients
Authors: Zhou Xiaoliang , Zhang Zhifu , Yuan Haitao , Wang Yuzhou , Xu Ziyu , Liang Wenbin , Lou Mingwu 
Published: November 2024

AbstractHeroin and methamphetamine are the two common types of drugs abused, which poses significant health risks. However, the neural mechanisms underlying the effects of drug addiction on human brain are unclear. In this study, we collected T1-weighted magnetic resonance imaging data from 26 heroin abstinent (HA) patients, 24 methamphetamine abstinent (MA) patients and 32 healthy controls. Four surface-based morphological features including cortical thickness (CT), fractal dimension (FD), gyrification index (GI), and sulcal depth (SD) were calculated, and further used to construct the morphological brain networks. We observed the common CT reductions of the right TE 1.0 and TE 1.2 and SD reductions of the right intermediate lateral area 20 for HA and MA patients, HA-specific CT reductions in the left area 2, and the MA-specific GI reductions in the left medial area 6 and right dorsomedial parietooccipital sulcus. For the morphological brain networks, HA patients exhibited the global disorganizations (higher shortest path length) in CT-based networks, whereas MA patients showed the disrupted nodal efficiency of the left medial area 38 in CT-based networks, the right caudal area 7 in GI-based networks, and the right inferior occipital gyrus in SD-based networks. Furthermore, the altered SD of HA patients and disrupted nodal efficiency of MA patients were associated with drug abuse-related clinical variables. Our findings suggest the morphological index-dependent effects of drug addiction on human brain morphology, and indicate the differential neural mechanism underlying heroin and methamphetamine abuses which attack the global and local information transfer of morphological brain networks, respectively.
Bridging Genomic Gaps: The Pan-Grass Syntenic Gene Set in Grass Crop Evolution
Authors: Dias Henrique M , Sagawa Guilherme YA , Torres-Rodriguez Vladimir J , Mural Ravi V , Schnable James C , Van Sluys Marie-Anne 
Published: November 2024

ABSTRACTUnderstanding orthologous and homeologous relationships among genes can inform our understanding of how evolution and artificial selection have shaped the genomes of related species to adapt to different niches and produce different phenotypes. High-confidence information on orthologous relationships can also increase the impact of the functional characterization in one species by ensuring this information is available to researchers studying orthologs in other species. The grasses are ecologically and economically critical plants, and many genes are conserved in syntenic blocks between species. Here we leverage that conserved gene order to create and describe the Pan-Grass Syntenic Gene Set (PGSGS), a curated database of orthologous and homeologous relationships among the genes of 17 grass species, including both major and orphan crops as well as wild grasses. As a demonstration of the utility of the PGSGS, the dynamics of chromosome structure and gene content changes after polypoidy in several grass lineages are analyzed. This dataset serves as a seminal foundation for improving our understanding of genome evolution subsequent to polyploidy, as well as encouraging and enabling integration of functional genetic and functional genomic information across the grasses, the original promise of the “grasses as a single genetic system” model.SIGNIFICANCE STATEMENTThe Pan-Grass Syntenic Gene Set (PGSGS) leverages our understanding of the genomic background of major grass species, including rice, maize, sorghum, wheat, barley, millet, and sugarcane. It represents a milestone for deciphering the genetic foundations of essential traits such as yield, disease resistance, and environmental adaptability - key factors contributing to agriculture and food security. Scrutinizing pan-syntenic genes unveils the intricate interplay of diverse gene acquisition and loss mechanisms, potentially speeding molecular breeding knowledge transference. The PGSGS emerges as a valuable resource for gene annotation, with implications for improving grass crops.
AlphaRING: Missense Variant Classification via Protein Modelling and Residue Interaction Network Analysis
Authors: Logsdon Aaron , Safari Roghaiyeh , Barnard Anna , Maertens Goedele , Bellos Evangelos 
Published: November 2024

AbstractRecent advancements in protein modelling, particularly with AlphaFold, have opened new avenues for assessing the structural impacts of missense variants on protein function. Tools like AlphaMissense leverage AlphaFold2 to predict missense variant pathogenicity with state-of-the-art performance. However, AlphaMissense is deep learning-based, and its process to predict pathogenicity is opaque and does not explicitly predict the impact of missense variants based on additional biophysical properties. Additionally, AlphaMissense is not publicly available, limiting accessibility. Here, we present AlphaRING, a publicly available tool that leverages AlphaFold2 and captures real physico-chemical properties of variant residues to predict the pathogenicity of both characterised and uncharacterised missense variants. AlphaRING models wild-type and variant proteins using AlphaFold2 and identifies atomic-level non-covalent interactions via residue interaction network analysis using RING4. Unlike deep learning models, our scoring captures real physico-chemical properties of mutated residues, providing interpretable insights into mutation effects. We developed novel formulas for each non-covalent bond type (hydrogen, ionic, π-cation, π-π stacking, and π-hydrogen), incorporating bond-specific energy and geometry values to calculate unique weighting scores per residue. The absolute log2fold change between wild-type and variant residue scores yields a non-negative AlphaRING score—the higher the score, the greater the predicted pathogenicity. Evaluating AlphaRING on over 1,300 human gold-standard missense variants curated by ClinVar expert panels, our results show effective distinction between benign and pathogenic variants, with a receiver operating characteristic area under the curve of 0.79. This strong performance suggests that AlphaRING is a reliable, open-source tool suitable for high-throughput structural predictions and large-scale variant characterisation, accessible to non-experts. By enabling detailed exploration of the relationship between genetic variation and protein structure, AlphaRING addresses key limitations of previous models and paves the way for broader applications in genetic research and precision medicine.
Chemogenetic Breakdown of the Dentate Gate Causes Seizures and Spatial Memory Deficits
Authors: Adam Christopher D. , Schellinger Emily D. , White Alicia , Joksimovic Srdjan M. , Takano Hajime , Coulter Douglas A. 
Published: November 2024

SUMMARYThe dentate gyrus has often been posited to act as a gate that dampens highly active afferent input into the hippocampus. Effective gating is thought to prevent seizure initiation and propagation in the hippocampus and support learning and memory processes. Pathological changes to DG circuitry that occur in temporal lobe epilepsy (TLE) can increase DG excitability and impair its gating ability which can contribute to seizures and cognitive deficits. There is evidence that TLE pathologies and seizures may independently contribute to learning and memory deficits in TLE through distinct mechanisms. These two factors are difficult to untangle since TLE pathologies can drive seizures, and seizures can worsen TLE pathologies. Here we assessed whether chemogenetically increasing dentate granule cell (DGC) excitability was enough to break down the dentate gate in the absence of TLE pathologies. We found that increasing excitability specifically in DGCs caused seizures in non-epileptic mice. Importantly, due to the modulatory nature of DREADD effects, seizures were driven by intrinsic circuit activity rather than direct activation of DGCs. These seizures resulted in a spatial memory deficit when induced after training in the spatial object recognition task and showed stereotypical patterns of activity in miniscope calcium recordings. Our results provide direct support for the dentate gate hypothesis since seizures could be induced in non-epileptic animals by artificially degrading the dentate gate with chemogenetics in the absence of epilepsy pathologies.
DreaM: A Computational Pipeline for Enhanced Short-Read Sequence Analysis in Repetitive Genomic Regions
Authors: Kumar Santosh , Esashi Fumiko 
Published: November 2024

AbstractMapping short sequencing reads to repetitive genomic regions, such as centromeres, presents significant challenges, primarily due to PCR duplicates, which can be erroneously mapped multiple times within these regions. Conventional bioinformatics pipelines often overlook this issue, potentially leading to misinterpretation as signal enrichment. To address this, we developedDreaM(Deduplication of Reads for Enhanced and Accurate Mapping), a computational pipeline that prioritises the preprocessing of raw sequencing data. DreaM firstly identifies and removes PCR duplicates, which is followed by read trimming to reduce noise from multiply mapped reads. When applied to ChIP-Seq and CUT&RUN datasets targeting CENP-A, a key marker of centromeres, DreaM demonstrated improved peak detection within centromeres. Overall, DreaM provides a robust solution for enhancing the analysis of DNA-protein binding sites in repetitive genomic regions using short-read sequencing.
Sox9 and Nfi transcription factors regulate the timing of neurogenesis and ependymal maturation in dopamine progenitors
Authors: Lahti Laura , Volakakis Nikolaos , Gillberg Linda , Salmani Behzad Yaghmaeian , Tiklová Katarína , Kee Nigel , Lundén-Miguel Hilda , Piper Michael , Gronostajski Richard , Perlmann Thomas 
Published: November 2024

AbstractCorrect timing of neurogenesis is critical for both generating the correct number and subtypes of glia and neurons in the embryo, as well as preventing tumours and the depletion of stem cell pools in the adults. Here we analyse how the midbrain dopamine neuron (mDA) progenitors transition into cell cycle arrest (G0) and begin to mature into ependymal cells. The comparison of mDA progenitors from different embryonic stages revealed the upregulation ofNfiandSox9transcription factors during development. Their conditional inactivation in the early embryonic midbrain leads to delayed G0 entry and ependymal maturation, reduced gliogenesis, and increased generation of neurons, including mDA neurons. In contrast, their inactivation in late embryogenesis does not result in mitotic re-entry, suggesting that these factors are necessary for the G0 induction, but not for its maintenance. Our characterisation of mDA-progenitor-derived adult ependymal cells by single-cell RNA sequencing and histology show that they both retain several progenitor features but also secrete neuropeptides and contact neighbouring cells and blood vessels, indicating that these cells may form a novel part of the circumventricular organ system.