bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social and Polygenic Risk Factors for Time to Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis
Authors: Barr Peter B. , Neale Zoe E. , Bigdeli Tim B. , Chatzinakos Chris , Harvey Philip D. , Peterson Roseann E. , Meyers Jacquelyn L. 
Published: December 2024

ABSTRACTImportancePersons with substance use disorders (SUD) often suffer from additional comorbidities, including psychiatric conditions and physical health problems. Researchers have explored this overlap in electronic health records (EHR) using phenome wide association studies (PheWAS) to characterize how different indicators are related to all conditions in an individual’s EHR. However, analyses have been largely cross-sectional in nature.ObjectiveTo characterize whether various social and genetic risk factors are associated with time to comorbid diagnoses in electronic health records (EHR) after the first diagnosis of SUD.DesignLeveraging those with EHR and whole-genome sequencing data in All of Us (N = 287,012), we explored whether social determinants of health are associated with lifetime risk of SUD. Next, within those with a diagnosed SUD (N = 17,460), we examined whether polygenic scores (PGS) were associated with time to comorbid diagnoses performing a phenome-wide survival analysis.SettingParticipating health care organizations across the United States.ParticipantsParticipants in the All of Us Research Program with available EHR and genomic data,ExposuresSocial determinants of health and polygenic scores (PGS) for psychiatric and substance use disorders,Main Outcomes and MeasuresPhecodes for diagnoses derived from International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from EHR.ResultsMultiple social and demographic risk factors were associated with lifetime SUD diagnosis. Most strikingly, those reporting an annual income <$10K had 4.5 times the odds of having an SUD diagnosis compared to those reporting $100-$150K annually (OR = 4.48, 95% CI = 4.01, 5.01). PGSs for alcohol use disorders, schizophrenia, and post-traumatic stress disorder were associated with time to their respective diagnoses (HRAUD= 1.10, 95% CI = 1.06, 1.14; HRSCZ= 1.13, 95% CI = 1.06, 1.20; HRPTSD= 1.15, 95% CI = 1.08, 1.22). A PGS for ever-smoking was associated with time to subsequent smoking related comorbidities and additional SUD diagnoses HRSMOK= 1.6 to 1.16).Conclusions and RelevanceSocial determinants, especially those related to income have profound associations with lifetime SUD risk. Additionally, PGS may include information related to outcomes above and beyond lifetime risk, including timing and severity.
Impact of race, sex and age on the probability of pancreatic cancer among patients with newly diagnosed diabetes
Authors: Afghani Elham , Lau Bryan , Becker Laura , Goggins Michael G , Klein Alison P. 
Published: December 2024

ABSTRACTBackgroundPancreatic cancer diagnoses are frequently preceded by a new diabetes diagnosis. Screening individuals newly diagnosed with diabetes could enable earlier pancreatic cancer detection. We sought to estimate the risk of pancreatic cancer by age, sex, race and time since diabetes diagnosis.MethodsJohns Hopkins Medicine conducted this de-identified claims-based cohort study using the Optum Labs Data Warehouse (OLDW). Enrollees from 1/2008–9/2018 were identified as non-diabetic or newly diagnosed diabetics and time to pancreatic cancer analysis was conducted using a flexible Weibull model. Diabetes and cancer were defined using ICD-9/10 codes.ResultsOur risk set included 4,732,313 individuals (424,129 newly diabetic) in 5,844,934 enrollment periods. Individuals with newly diagnosed diabetes were at an increased hazard ratio (HR) of pancreatic cancer but this effect waned over time. The HR of pancreatic cancer following a diabetes diagnosis was higher in younger individuals and varied by race (lower HR in non-White individuals) (p<0.01, main effects and interactions). Thus, the probability of pancreatic cancer following a diabetes diagnosis was dependent on age, race, and sex. For example: the 1-year probability of pancreatic cancer in a white male aged 75 was 0.45% (95%CI 0.41%-0.49%) if they were newly diagnosed with diabetes and 0.090% (95%CI 0.084%-0.096%) fi they were free of diabetes. In contrast, risk was lower if they were age 55 at 0.15% (new-diabetic, 95%CI 0.13%-0.16) and 0.022% (diabetes free, 95%CI 0.020%-0.023%). The HR of pancreatic cancer for individuals with newly diagnosed diabetes compared to those free of diabetes was highest 1 month after diagnosis (HR=9.6 and 14.7 for a 75 and 55 year old while male, respectively) but decreased in the following months, with a ∼39% reduction in HR from 1- to-3 months, ∼17% from 3 -to-6 months, and ∼14% from 6 month-to -1 year (p<0.01).ConclusionsConsideration of the age-race-sex specific probability of pancreatic cancer and time since diabetes diagnosis is necessary to when evaluating the risk of pancreatic cancer following a diabetes diagnosis.
Assessing the impact of variation in diagnostic coding among the three countries in the UK Biobank
Authors: Clifton Lei , Liu Wenyu , Collister Jennifer A , Littlejohns Thomas J , Goldacre Raphael R , Allen Naomi , Hunter David J 
Published: December 2024

1.AbstractBackgroundThe UK Biobank (UKB) study has linked hospital inpatient data collected from England, Scotland, and Wales, which use different clinical coding systems to record health outcomes. Scotland records up to 6 different diagnostic codes for one inpatient episode, compared with up to 20 in England, and 14 in Wales. We assessed the impact of the variations in diagnostic coding among countries on observed disease incidence rates.MethodsWe examined the number of diagnoses coded by each country, and then compared the incidence of three diseases between countries: Parkinson’s disease (PD), type 2 diabetes (T2D), and dementia. We constructed Cox models for each disease, adjusting for “country”.ResultsEngland appears to have the highest risk (hazard ratio, HR) for all three diseases, while Scotland appears to have the lowest risk: HR [95% CI] = 0.62 [0.54, 0.72] for PD, 0.49 [0.45, 0.54] for T2D, and 0.88 [0.78, 0.99] for dementia.ConclusionsThe observed incidence of these diseases and the estimated effect of “country” in Cox models are likely influenced by the clinical coding variations among countries. Researchers need to be aware of this and account for these variations in their analyses.2.Key messages in a boxWhat is already known on this topic:There are variations in the clinical coding systems in hospitals among the three countries in UKB.These variations could impact research investigating geographic differences in disease incidence. What this study adds:We assessed the impact of the variations in diagnostic coding among the three countries in UKB.We showed that the observed disease incidence and the estimated effect of “country” are likely influenced by these variations.How this study might affect research, practice or policy:Researchers need to understand the provenance of data and account for the different diagnostic coding and other geographic variation specific to each of three countries, in order to reach robust conclusions that are not influenced by artefacts.
In silicocomparison of novel proteins from Plasmodium Falciparum as candidate drug targets against malaria
Authors: Giannetta Surya Angela Merici , Austin Felicia , Parikesit Arli Aditya 
Published: December 2024

AbstractMalaria is a parasitic disease with a persistent prevalence in multiple parts of the world.Plasmodium falciparum, the deadliest human-infecting strain, has been a rising concern as the multi-faceted life-cycle poses a challenge in developing anti-malarial treatments while the effectiveness of present drugs begins to decline. As such, various research has been done to identify new drug targets leveraging modern computational biology techniques, such as proteomics. The objective of this study is to evaluate potential drug targets by comparing novel proteins inP. falciparumas reported in recent literature (2018-2022) based on their structural analysis of their 3D models along with the druggability properties and protein-protein interactions. A list of 22 proteins were acquired from 48 literature, in which only 7 can be considered as a favorable candidate protein drug target due to their non-human homologous nature, ERRAT score, residues percentage in favourable spot in Ramachandran plot, and high druggability score. Following an examination of protein-protein interactions, it is found that among the evaluated proteins only PF3D7_1438600 exhibits a sufficiently robust network, highlighting it to be the most promising candidate for drug targeting. This study demonstrates the valuable role of proteomics in uncovering potential drug targets and highlights its significance in driving emerging research efforts.
PhyloCNN: Improving tree representation and neural network architecture for deep learning from trees in phylodynamics and diversification studies
Authors: Perez Manolo Fernandez , Gascuel Olivier 
Published: December 2024

AbstractPhylodynamics and diversification studies using complex evolutionary models can be challenging, especially with traditional likelihood-based approaches. As an alternative, likelihood-free simulation-based approaches have been proposed due to their ability to incorporate complex models and scenarios. Here, we propose a new simulation-based deep learning (DL) method capable of analyzing large datasets and accurately estimating parameter values for birth-death models in both phylodynamics and diversification studies. Our approach involves encoding trees by extracting a vector of local features for all nodes of the input phylogeny. We also developed a dedicated convolutional neural network architecture called PhyloCNN. Using simulations, we compared the accuracy of PhyloCNN when using feature vectors with a variable number of generations to describe the local context of nodes and leaves. The number of generations had a greater impact when considering smaller training sets, with a broader context showing higher accuracy, especially for complex evolutionary models. Compared to other recently developed DL approaches, PhyloCNN showed higher or similar accuracies for all parameters when used with training sets one or two orders of magnitude smaller (10,000 to 100,000 simulated training trees, instead of millions). We applied PhyloCNN with compelling results to two real-world phylodynamics and diversification datasets, related to HIV superspreaders in Zurich and to primates and their ecological role as seed dispersers. The high accuracy and computational efficiency of our method opens new possibilities for phylodynamics and diversification studies that need to account for idiosyncratic phylogenetic histories with specific parameter spaces and sampling scenarios not considered in more general approaches.
Genome-enabled stilbenoid gene cluster discovery inPleuropterus multiflorus
Authors: Jiang Jinzhu , Liu Xianju , Wang Yi , Liang Zhenchang , Liu An 
Published: December 2024

AbstractStilbenoids, a class of compounds with the stilbene skeleton as part of plant secondary metabolism, are renowned for their diverse health benefits. Among them, 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), specifically abundant in the famous medicinal plantPleuropterus multiflorus, exhibits significant pharmacological properties. A selfing progeny ofP. multifloruscommercial variety ‘Jinwufugui No.1’, which contains high THSG content, was used for genome sequencing. Through the combination of weighted correlation network analysis, genome mining, and enzymatic characterization studies, we identified an unpredicted biosynthetic gene cluster responsible for THSG biosynthesis. This cluster includes a stilbene synthase (PmSTS1), a flavin-containing monooxygenase (PmFMO3), and a UDP-glycosyltransferase (UGT72B90). Our findings suggest this stilbenoid gene cluster is formed by transposable element-mediated gene duplications and neofunctionalization, and regulated by MYB and NAC type transcription factors. Notably, PmFMO3, as the first identified stilbenoid-2-hydroxylase, was confirmed that it can modify the other stilbenoids without the A ring modifications. The novel type of gene cluster, in which FMO serves as the key decorating enzyme, will guide the identification of more biosynthetic gene clusters in plants. In addition, the characterization of PmFMO3 extends our understanding of the FMO gene function in plants, and provides an important catalytic bioparts for the heterologous synthesis of polyhydroxylated stilbenoids.
GABA, Glutamate dynamics and BOLD observed during cognitive processing in psychosis patients with hallucinatory traits
Authors: Craven Alexander R. , Dwyer Gerard , Ersland Lars , Kazimierczak Katarzyna , Lilleskare Lin , Noeske Ralph , Sandøy Lydia Brunvoll , Johnsen Erik , Hugdahl Kenneth 
Published: December 2024

AbstractThe perception of a voice in the absence of an external auditory source – an auditory verbal hallucination – is a characteristic symptom of schizophrenia. To better understand this phenomenon requires integration of findings across behavioural, functional, and neurochemical levels. We address this with a locally adapted MEGA-PRESS sequence incorporating interleaved unsuppressed water acquisitions, allowing concurrent assessment of behaviour, blood-oxygenation-level-dependent (BOLD) functional changes, Glutamate+Glutamine (Glx), and GABA, synchronised with a cognitive (flanker) task. We acquired data from the anterior cingulate cortex (ACC) of 51 patients with psychosis (predominantly schizophrenia spectrum disorder) and hallucinations, matched to healthy controls. Consistent with the notion of an excitatory/inhibitory imbalance, we hypothesized differential effects for Glx and GABA between groups, and aberrant dynamics in response to task. Results showed impaired task performance, lower baseline Glx and positive association between Glx and BOLD in patients, contrasting a negative correlation in healthy controls. Task-related increases in Glx were observed in both groups, with no significant difference between groups. No significant effects were observed for GABA. These findings suggest that a putative excitatory/inhibitory imbalance affecting inhibitory control in the ACC is primarily observed as tonic, baseline glutamate differences, rather than GABAergic effects or aberrant dynamics in relation to a task.HighlightsIn-vivo, GABA-edited functional1H-MRS data were collected from 51 patients with hallucinations and a similar number of matched healthy controlsReduced Glutamate+Glutamine (Glx) levels were observed in the patient group.BOLD association to baseline Glutamate+Glutamine (Glx) differed between patients and controlsRobust task-related increases in measured Glx were observed in the Anterior Cingulate Cortex (ACC)Task-related changes in measured Glx did not differ between patients and controls
Enzymatic epimerization of monoterpene indole alkaloids in Kratom
Authors: McDonald Allwin , Nakamura Yoko , Schotte Carsten , Lau Kin , Alam Ryan , Lopes Adriana A. , Buell C. Robin , O’Connor Sarah 
Published: December 2024

AbstractMonoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-β-carboline scaffold characterized by a 3Sstereocenter. However, a subset of MIAs contain a non-canonical 3Rstereocenter. Herein, we report the basis for 3R-MIA biosynthesis inMitragyna speciosa(Kratom). We discover the presence of the iminium species, 20S-3-dehydrocorynantheidine, which led us to hypothesize that isomerization of 3Sto 3Roccurs by oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments implicated young leaves and stems as the sites for pathway biosynthesis, facilitating the identification of an oxidase/reductase pair that catalyzes this epimerization. This enzyme pair has broad substrate specificity, suggesting that the oxidase and reductase may be responsible for the formation of many 3R-MIAs and downstream spirooxindole alkaloids in Kratom. These enzymes allow biocatalytic access to a range of previously inaccessible pharmacologically active compounds.
RNA virus discovery sheds light on the virome of a major vineyard pest, the European grapevine moth (Lobesia botrana)
Authors: Debat Humberto , Gomez-Talquenca Sebastian , Bejerman Nicolas 
Published: December 2024

AbstractThe European grapevine moth (Lobesia botrana) poses a significant threat to vineyards worldwide, causing extensive economic losses. While its ecological interactions and control strategies are well-studied, its associated viral diversity remains unexplored. Here, we employ high-throughput sequencing data mining to comprehensively characterize theL. botranavirome, revealing novel and diverse RNA viruses. We characterized four new viral members belonging to distinct families, with evolutionary cues of cypoviruses (Reoviridae), sobemo-like viruses (Solemoviridae), phasmaviruses (Phasmaviridae), and carmotetraviruses (Carmotetraviridae). Phylogenetic analysis of the cypoviruses places them within the genus in affinity with other moth viruses, suggesting a potential ecological roles and host range within Lepidoptera. The bi-segmented and highly divergent sobemo-like virus showed a distinctive evolutionary trajectory of its encoding proteins at the periphery of recently reported invertebrate Sobelivirales. Notably, the presence of a novel phasmavirus, typically associated with mosquitoes, expands the known host range and diversity of this family to moths. Furthermore, the identification of a carmotetravirus branching in the same cluster of providence virus, a lepidopteran virus which replicates in plants, raises questions regarding the biological significance of this moth virus and grapevine. We further explored viral sequences in several publicly available transcriptomic datasets of the moth, indicating potential prevalence across distinct conditions. These results underscore the existence of a complex virome withinL. botranaand lays the foundation for future studies investigating the ecological roles, evolutionary dynamics, and potential biocontrol applications of these viruses on theL. botrana—vineyard ecosystem.
A cysteine-rich domain of the Cuf1 transcription factor is required for high copper stress sensing and fungal virulence
Authors: Probst Corinna , Denning-Jannace Catherine A. , du Plooy Lukas M. , Giamberardino Charles , Asfaw Yohannes , Franz Katherine J. , Alspaugh J. Andrew 
Published: December 2024

AbstractThe ability to sense, import but also detoxify copper (Cu) has been shown to be crucial for microbial pathogens to survive within the host. Previous studies conducted with the opportunistic human fungal pathogenCryptococcus neoformans(Cn) have revealed two extreme Cu environments encountered during infection: A high Cu environment within the lung and a low Cu environment within the brain. However, howCnsenses these different host Cu microenvironments, and the consequences of a blunted Cu stress adaption for pathogenesis, are not well understood.In contrast to other fungi,Cnhas a single transcription factor, Cuf1, to regulate adaptive responses to both high- and low-Cu stress. Sequence analysis ofCnCuf1 identified three conserved cysteine (Cys)-rich regions that may play a role in Cu sensing. We mutated the 1stCys-rich region within theCUF1gene to investigate its role forCnhigh Cu stress sensing. Subsequent analysis of Cuf1 transcriptional activity and target gene promoter binding demonstrated that the 1stCys-rich region is required for Cuf1 transcriptional activity in high Cu stress. We performed an inhalational murine infection to analyze the effects of a blunted high Cu stress response on pathogenesis. No significant differences in lung fungal burden were observed based on variable Cuf1 activity. However, strains with defective high Cu stress regulation induced a markedly altered immune response in mice. Based on these findings, we hypothesize that Cuf1-driven high Cu responses are not required for initial survival but instead modulate immune recognition and inflammation within the mouse lung.ImportanceCopper is an essential micronutrient required for survival in all kingdoms of life as it is used as a catalytic cofactor for many essential processes in the cell. In turn, this reactivity of copper ions makes elevated levels of free copper toxic for the cell. This dual nature of copper-essential for life but toxic at elevated levels- is used by our innate immune system in a process called nutritional immunity to combat and kill invading pathogens. In this work we explore how the fungal human pathogenCryptococcus neoformanssenses high copper stress, a copper microenvironment encountered within the host lung. We identified a specific cysteine-rich region within the copper responsive transcription factor Cuf1 to be essential for high copper stress sensing. Mutation of this region led to an impaired high copper stress adaptation, which did not affect fitness of the yeast but did impact immune recognition and inflammation inside the host lung.
ηc2(D21)
and its electromagnetic decays
Authors: Du Xin-Yao , Pei Su-Yan , Li Wei , Jia Man , Li Qiang , Wang Tianhong , Wang Bo , Wang Guo-Li 
Published: December 2024

The spin-singlet state ηc2(D21) has not been discovered in experiment and it is the only missing low-excited D-wave charmonium, so in this paper, we like to study its properties. Using the Bethe-Salpeter equation method, we obtain its mass as 3828.2 MeV and its electromagnetic decay widths as Γ[ηc2(1D)→hc(1P)γ]=284  keV, Γ[ηc2(1D)→J/ψγ]=1.04  keV, Γ[ηc2(1D)→ψ(2S)γ]=3.08  eV, and Γ[ηc2(1D)→ψ(3770)γ]=0.143  keV. Considering the strong decay widths are estimated to be Γ(ηc2(1D)→ηcππ)=144  keV and Γ(ηc2(1D)→gg)=46.1  keV, we obtain the total decay width of 475 keV for ηc2(1D), and point out that the full width is very sensitive to the mass Mηc2. In our calculation, the emphasis is put on the relativistic corrections. Our results show that ηc2→hcγ is the nonrelativistic E1 transition dominated E1+M2+E3 decay, and ηc2→ψγ is the M1+E2+M3+E4 decay but the relativistic E2 transition contributes the most.

Published by the American Physical Society
2024
Cyclic EIS investigation on corrosion evolution of 304 SS in simulated secondary circuit water of PWR system
Authors: Ji Yuefei , Hao Long , Wang Jianqiu , Ke Wei 
Published: December 2024

Purpose
The purpose of this paper is to introduce cyclic electrochemical impedance spectroscopy (EIS) method to understand the corrosion evolution behavior of structural materials in secondary circuit water environments of pressurized water reactor (PWR) system.

Design/methodology/approach
The cyclic EIS has been used to understand the corrosion evolution of 304 stainless steel (SS) in simulated secondary circuit water environment. Scanning electron microscopy and X-ray photoelectron spectroscopy have been used to characterize the microstructure and corrosion morphology of 304 SS sample.

Findings
Cyclic EIS measurement is applicable in gaining information on the corrosion evolution of 304 SS in high-temperature and high-pressure (HTHP) water environments. Based on analyses of the cyclic EIS data, it is considered that the measured EIS response of 304 SS sample under HTHP water environment mainly comes from the compact inner part of the newly formed oxide layer, which gradually inhibits the progress of electrochemical reactions at the oxide layer/substrate interface.

Originality/value
The cyclic EIS has been introduced into HTHP water environment, and its reliability has been evaluated. It may find a wide application in corrosion studies of materials under HTHP water environments, which is critical for a safe operation in nuclear power plants and beneficial for the development of corrosion-resistant materials in PWR system.