bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward Modeling Continental‐Scale Inland Water Carbon Dioxide Emissions
Authors: Saccardi Brian , Brinkerhoff Craig B. , Gleason Colin J. , Winnick Matthew J. 
Published: November 2024

AbstractInland waters emit significant amounts of carbon dioxide (CO2) to the atmosphere; however, the global magnitude and source distribution of inland water CO2 emissions remain uncertain. These fluxes have previously been “statistically upscaled” by independently estimating dissolved CO2 concentrations and gas exchange velocities to calculate fluxes. This scaling, while robust and defensible, has known limitations in representing carbon source limitations and spatial variability. Here, we develop and calibrate a CO2 transport model for the continental United States, simulating carbon transport and transformation in >22 million hydraulically connected rivers, lakes, and reservoirs. We estimate 25% lower CO2 fluxes compared to upscaling estimates forced by the same observational calibration data. While precise CO2 source distribution estimates are limited by the resolution of model parameterizations, our model suggests that stream corridor CO2 production dominates over groundwater inputs at the continental scale. Our results further suggest that the lack of observational networks for groundwater CO2 and scalable metabolic models of aquatic CO2 production remain the most salient barriers to further coupling of our model with other Earth system components.
210Po and 210Pb Distributions Along the GEOTRACES Pacific Meridional Transect (GP15): Tracers of Scavenging and Particulate Organic Carbon (POC) Export
Authors: Cochran J. Kirk , Wei Ziran , Horowitz Evan , Fitzgerald Patrick , Heilbrun Christina , Stephens Mark , Lam Phoebe J. , Le Roy Emilie , Charette Matthew 
Published: November 2024

AbstractDistributions of the natural radionuclide 210Po and its grandparent 210Pb along the GP15 Pacific Meridional Transect provide information on scavenging rates of reactive chemical species throughout the water column and fluxes of particulate organic carbon (POC) from the primary production zone (PPZ). 210Pb is in excess of its grandparent 226Ra in the upper 400–700 m due to the atmospheric flux of 210Pb. Mid‐water 210Pb/226Ra activity ratios are close to radioactive equilibrium (1.0) north of ∼20°N, indicating slow scavenging, but deficiencies at stations near and south of the equator suggest more rapid scavenging associated with a “particle veil” located at the equator and hydrothermal processes at the East Pacific Rise. Scavenging of 210Pb and 210Po is evident in the bottom 500–1,000 m at most stations due to enhanced removal in the nepheloid layer. Deficits in the PPZ of 210Po (relative to 210Pb) and 210Pb (relative to 226Ra decay and the 210Pb atmospheric flux), together with POC concentrations and particulate 210Po and 210Pb activities, are used to calculate export fluxes of POC from the PPZ. 210Po‐derived POC fluxes on large (>51 μm) particles range from 15.5 ± 1.3 mmol C/m2/d to 1.5 ± 0.2 mmol C/m2/d and are highest in the Subarctic North Pacific; 210Pb‐derived fluxes range from 6.7 ± 1.8 mmol C/m2/d to 0.2 ± 0.1 mmol C/m2/d. Both 210Po‐ and 210Pb‐derived POC fluxes are greater than those calculated using the 234Th proxy, possibly due to different integration times of the radionuclides, considering their different radioactive mean‐lives and scavenging mean residence times.
First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors
Authors: Li Wei , Wang Yongsheng , Xiong Anwen , Gao Ge , Song Zhengbo , Zhang Yiping , Huang Dingzhi , Ye Feng , Wang Qiming , Li Zhihui , Liu Jiaye , Xu Chunwei , Sun Yinghui , Liu Xijie , Zhou Fei , Zhou Caicun 
Published: November 2024

AbstractOncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).
Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis
Authors: Hagihara Hideo , Miyakawa Tsuyoshi 
Published: November 2024

Abstract
Introduction
Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has been consistently observed in schizophrenia and bipolar disorder. We recently demonstrated similar brain alterations in various animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited.

Methods
We conducted meta-analyses to assess postmortem brain pH in patients with MDD compared to control subjects, examining its relationships with recurrence of depressive episodes and illness duration, utilizing publicly available demographic data. Studies reporting individual raw pH data were identified through searches in the Stanley Medical Research Institute database, NCBI GEO database, PubMed, and Google Scholar. The data were analyzed using the random effects model, ANOVA, and ANCOVA.

Results
The random effects model, using 39 curated datasets (790 patients and 957 controls), indicated a significant decrease in brain pH in patients with MDD (Hedges’ g = −0.23, p = 0.0056). A two-way ANCOVA revealed that the effect of diagnosis on pH remained significant when considering covariates, including postmortem interval, age at death, and sex. Patients with recurrent episodes, but not a single episode, showed significantly lower pH than controls in both females and males (256 patients and 279 controls from seven datasets). Furthermore, a significant negative correlation was observed between brain pH and illness duration (115 patients from five datasets). Female preponderance of decreased pH was also found, possibly due to a longer illness duration and a higher tendency of recurrent episodes in females.

Conclusion
This study suggests a decrease in brain pH in patients with MDD, potentially associated with recurrent episodes and longer illness duration. As suggested from previous animal model studies, altered brain energy metabolism, leading to decreased pH, may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.
Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice
Authors: Wang Yao-geng , Gan Chang-pei , Beukers-Korver Joke , Rosing Hilde , Li Wen-long , Wagenaar Els , Lebre Maria C. , Song Ji-ying , Pritchard Colin , Bin Ali Rahmen , Huijbers Ivo , Beijnen Jos H. , Schinkel Alfred H. 
Published: November 2024

Abstract
Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2

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strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2

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background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2

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mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2

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mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2

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mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a “healthy” obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.
Outcomes in hematopoetic cell transplantation in the setting of mold infections in patients with chronic granulomatous disease
Authors: Kline Ahnika , Parta Mark , Cuellar-Rodriguez Jennifer , Gea-Banacloche Juan , Kelly Corin , Pittaluga Stefania , Zerbe Christa S. , Holland Steven M. , Malech Harry L. , Kang Elizabeth M. 
Published: November 2024

Abstract
Chronic granulomatous disease (CGD) is a disorder of immunity characterized by phagocyte dysfunction. Mold infections in patients with CGD are often severe and disseminated. We present patient characteristics, microbiological data, and outcomes for 26 patients with CGD who received hematopoietic cell transplantation (HCT) or gene therapy-modified cells (GT) between 2008 and 2019, with proven fungal infection either before or during their transplant. All patients engrafted, and all but one GT recipient had neutrophil recovery and evidence of functional correction. Eighteen patients (69%) are currently alive and 19 patients (73% of total, 90% of patients with repeat imaging performed) had evidence of radiographic improvement. With 3 exceptions, deaths were not principally related to the fungal infection and duration of antecedent infection did not correlate with death. Aspergillus species accounted for the majority of disease (50%), followed by Phellinus species (18%). Osteomyelitis and disseminated disease were common, as only 11 patients (42%) had disease restricted to pneumonia. Triazole therapy was used in all 26 patients, with combination therapy used in 25 (96%). HCT or gene therapy, with appropriate antifungal therapy, are viable therapies for refractory fungal infections in patients with CGD.
Differentiation of adsorption and degradation in steroid hormone micropollutants removal using electrochemical carbon nanotube membrane
Authors: Liu Siqi , Jassby David , Mandler Daniel , Schäfer Andrea I. 
Published: November 2024

AbstractThe growing concern over micropollutants in aquatic ecosystems motivates the development of electrochemical membrane reactors (EMRs) as a sustainable water treatment solution. Nevertheless, the intricate interplay among adsorption/desorption, electrochemical reactions, and byproduct formation within EMR complicates the understanding of their mechanisms. Herein, the degradation of micropollutants using an EMR equipped with carbon nanotube membrane are investigated, employing isotope-labeled steroid hormone micropollutant. The integration of high-performance liquid chromatography with a flow scintillator analyzer and liquid scintillation counting techniques allows to differentiate hormone removal by concurrent adsorption and degradation. Pre-adsorption of hormone is found not to limit its subsequent degradation, attributed to the rapid adsorption kinetics and effective mass transfer of EMR. This analytical approach facilitates determining the limiting factors affecting the hormone degradation under variable conditions. Increasing the voltage from 0.6 to 1.2 V causes the degradation dynamics to transition from being controlled by electron transfer rates to an adsorption-rate-limited regime. These findings unravels some underlying mechanisms of EMR, providing valuable insights for designing electrochemical strategies for micropollutant control.
Multiscale, mechanistic model of Rheumatoid Arthritis to enable decision making in late stage drug development
Authors: Bedathuru Dinesh , Rengaswamy Maithreye , Channavazzala Madhav , Ray Tamara , Packrisamy Prakash , Kumar Rukmini 
Published: November 2024

AbstractRheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects about 0.1% to 2% of the population worldwide. Despite the development of several novel therapies, there is only limited benefit for many patients. Thus, there is room for new approaches to improve response to therapy, including designing better trials e.g., by identifying subpopulations that can benefit from specific classes of therapy and enabling reverse translation by analyzing completed clinical trials. We have developed an open-source, mechanistic multi-scale model of RA, which captures the interactions of key immune cells and mediators in an inflamed joint. The model consists of a treatment-naive Virtual Population (Vpop) that responds appropriately (i.e. as reported in clinical trials) to standard-of-care treatment options—Methotrexate (MTX) and Adalimumab (ADA, anti-TNF-α) and an MTX inadequate responder sub-population that responds appropriately to Tocilizumab (TCZ, anti-IL-6R) therapy. The clinical read-outs of interest are the American College of Rheumatology score (ACR score) and Disease Activity Score (DAS28-CRP), which is modeled to be dependent on the physiological variables in the model. Further, we have validated the Vpop by predicting the therapy response of TCZ on ADA Non-responders. This paper aims to share our approach, equations, and code to enable community evaluation and greater adoption of mechanistic models in drug development for autoimmune diseases.
Multi-bioinformatics revealed potential biomarkers and repurposed drugs for gastric adenocarcinoma-related gastric intestinal metaplasia
Authors: Andersen Gøran Troseth , Ianevski Aleksandr , Resell Mathilde , Pojskic Naris , Rabben Hanne-Line , Geithus Synne , Kodama Yosuke , Hiroyuki Tomita , Kainov Denis , Grønbech Jon Erik , Hayakawa Yoku , Wang Timothy C. , Zhao Chun-Mei , Chen Duan 
Published: November 2024

AbstractBiomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44.
Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation
Authors: Yu Huasheng , Nagi Saad S. , Usoskin Dmitry , Hu Yizhou , Kupari Jussi , Bouchatta Otmane , Yan Hanying , Cranfill Suna Li , Gautam Mayank , Su Yijing , Lu You , Wymer James , Glanz Max , Albrecht Phillip , Song Hongjun , Ming Guo-Li , Prouty Stephen , Seykora John , Wu Hao , Ma Minghong , Marshall Andrew , Rice Frank L. , Li Mingyao , Olausson Håkan , Ernfors Patrik , Luo Wenqin 
Published: November 2024

AbstractThe versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human (h)DRG neurons—critical information to decipher their functions—are lacking due to technical difficulties. In this study, we isolated somata from individual hDRG neurons and conducted deep RNA sequencing (RNA-seq) to detect, on average, over 9,000 unique genes per neuron, and we identified 16 neuronal types. These results were corroborated and validated by spatial transcriptomics and RNAscope in situ hybridization. Cross-species analyses revealed divergence among potential pain-sensing neurons and the likely existence of human-specific neuronal types. Molecular-profile-informed microneurography recordings revealed temperature-sensing properties across human sensory afferent types. In summary, by employing single-soma deep RNA-seq and spatial transcriptomics, we generated an hDRG neuron atlas, which provides insights into human somatosensory physiology and serves as a foundation for translational work.
Fully phased genome assemblies and graph-based genetic variants of the olive flounder, Paralichthys olivaceus
Authors: Kim Julan , Kim Yoonsik , Shin Jeongwoen , Kim Yeong-Kuk , Lee Doo Ho , Park Jong-Won , Lee Dain , Kim Hyun-Chul , Lee Jeong-Ho , Lee Seung Hwan , Kim Jun 
Published: November 2024

AbstractThe olive flounder, Paralichthys olivaceus, also known as the Korean halibut, is an economically important flatfish in East Asian countries. Here, we provided four fully phased genome assemblies of two different olive flounder individuals using high-fidelity long-read sequencing and their parental short-read sequencing data. We obtained 42–44 Gb of ~15-kb and ~Q30 high-fidelity long reads, and their assembly quality values were ~53. We annotated ~30 K genes, ~170-Mb repetitive sequences, and ~3 M 5-methylcytosine positions for each genome assembly, and established a graph-based draft pan-genome of the olive flounder. We identified 5 M single-nucleotide variants and 100 K structural variants with their genotype information, where ~13% of the variants were possibly fixed in the two Korean individuals. Based on our chromosome-level genome assembly, we also explored chromosome evolution in the Pleuronectiformes family, as reported earlier. Our high-quality genomic resources will contribute to future genomic selection for accelerating the breeding process of the olive flounder.
Trends in the use of thyroid diagnostics and treatments between 2008 and 2019 in Germany
Authors: Thiyagarajan Arulmani , Koenen Niklas , Ittermann Till , Völzke Henry , Haug Ulrike 
Published: November 2024

AbstractFollowing implementation of a national prevention program against iodine deficiency-related disorders in 1993 in Germany, the prevalence of thyroid disorders declined, but aggregated drug dispensation data suggested a recent increase in thyroid hormone use. We aimed to systematically investigate trends in the use of thyroid diagnostic and treatment measures between 2008 and 2019 in Germany. Using the GePaRD database (claims data from ~ 20% of the German population), we determined the annual age-specific and age-standardized prevalence of the use of thyroid diagnostics (thyroid-stimulating hormone (TSH) measurement, thyroid ultrasound, scintiscan, biopsy) and treatment (medication, surgery, radioiodine therapy) from 2008 to 2019 stratified by sex. Between 2008 and 2019, the age-standardized prevalence of TSH measurement increased by 44% in males (from 165 to 238 per 1,000 persons) and by 31% in females (from 134 to 176 per 1,000). The prevalence of thyroid ultrasound use showed no clear time trend, while there was a decrease in the prevalence of scintiscan use (males/females: decrease by 42/43%) and biopsy (males/females: decrease by 42/34%). The prevalence of levothyroxine use increased by ~ 31% both in males (from 36 to 47 per 1,000) and females (from 134 to 175 per 1,000), while the prevalence of thionamide use, iodine use, thyroidectomy, and radioiodine therapy decreased. Our study suggests a continued decline in the prevalence of clinically significant thyroid disorders between 2008 and 2019. The substantial increase in the prevalence of TSH measurement and levothyroxine use during this time period might indicate overuse of diagnostics and overtreatment, warranting further investigation.
Vegetation traits and biogeomorphic complexity shape the resilience of salt marshes to sea-level rise
Authors: Cornacchia Loreta , van de Vijsel Roeland C. , van der Wal Daphne , Ysebaert Tom , Sun Jianwei , van Prooijen Bram , de Vet Paul Lodewijk Maria , Liu Quan-Xing , van de Koppel Johan 
Published: November 2024

AbstractThe adaptive capacity of ecosystems, or their ability to function despite altered environmental conditions, is crucial for resilience to climate change. However, the role of landscape complexity or species traits on adaptive capacity remains unclear. Here, we combine field experiments and morphodynamic modelling to investigate how ecosystem complexity shapes the adaptive capacity of intertidal salt marshes. We focus on the importance of tidal channel network complexity for sediment accumulation, allowing vertical accretion to keep pace with sea-level rise. The model showed that landscape-scale ecosystem complexity, more than species traits, explained higher sediment accumulation rates, despite complexity arising from these traits. Landscape complexity, reflected in creek network morphology, also improved resilience to rising water levels. Comparing model outcomes with real-world tidal networks confirmed that flow concentration, sediment transport and deposition increase with drainage complexity. These findings emphasize that natural pattern development and persistence are crucial to preserve resilience to climate change.