Antinociceptive effect of gelsenicine, principal toxic alkaloids of gelsemium, on prostaglandin E2-induced hyperalgesia in mice: Comparison with gelsemine and koumine.

Gelsemium elegans (G.elegans) is a plant of the Loganiaceae family, known for its indole alkaloids, including gelsemine, koumine, and gelsenicine. Gelsemine and koumine are well-studied active alkaloids with low toxicity, valued for their anti-anxiety and analgesic properties. However, gelsenicine, another important alkaloid, remains underexplored due to its high toxicity. This study focuses on evaluating the analgesic properties of gelsenicine and comparing them with gelsemine and koumine. The results indicate that all three alkaloids exhibit robust analgesic properties, with gelsemine, koumine, and gelsenicine showing ED50 values of 0.82 mg/kg, 0.60 mg/kg, and 8.43 µg/kg, respectively, as assessed by the hot plate method. Notably, the therapeutic dose of gelsenicine was significantly lower than its toxic dose (LD50 = 0.185 mg/kg). The study also investigated the mechanism of action by analyzing the expression levels of GlyRα3 and Gephyrin. The PGE2 model group showed decreased expression levels of GlyRα3 and Gephyrin, while groups treated with gelsemine, koumine, and gelsenicine were able to reverse this decrease. These results suggest that gelsenicine effectively alleviates PGE2-induced hyperalgesia by upregulating the expression of GlyRα3 and Gephyrin, which are key targets of the Gly receptor pathway.

The U.S. National Library of Medicine's impact on precision and genomic medicine.

Precision medicine offers the potential to improve health through deeper understandings of the lifestyle, biological, and environmental influences on health. Under Dr. Donald A. B. Lindberg's leadership, the U.S. National Library of Medicine (NLM) has developed the central reference resources for biomedical research and molecular laboratory medicine that enable precision medicine. The hosting and curation of biomedical knowledge repositories and data by NLM enable quality information reachable for providers and researchers throughout the world. NLM has been supporting the innovation of electronic health record systems to implement computability and secondary use for biomedical research, producing the scale of linked health and molecular datasets necessary for precision medicine discovery.

EZH2 expression is associated with inferior overall survival in mantle cell lymphoma.

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

Population genetic analysis of the Plasmodium falciparum erythrocyte binding antigen-175 (EBA-175) gene in Equatorial Guinea.

BACKGROUND: Plasmodium falciparum erythrocyte binding antigen-175 (PfEBA-175) is a candidate antigen for a blood-stage malaria vaccine, while various polymorphisms and dimorphism have prevented to development of effective vaccines based on this gene. This study aimed to investigate the dimorphism of PfEBA-175 on both the Bioko Island and continent of Equatorial Guinea, as well as the genetic polymorphism and natural selection of global PfEBA-175. METHODS: The allelic dimorphism of PfEBA-175 region II of 297 bloods samples from Equatorial Guinea in 2018 and 2019 were investigated by nested polymerase chain reaction and sequencing. Polymorphic characteristics and the effect of natural selection were analyzed using MEGA 7.0, DnaSP 6.0 and PopART programs. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 and Foldx program. RESULTS: Both Bioko Island and Bata district populations, the frequency of the F-fragment was higher than that of the C-fragment of PfEBA-175 gene. The PfEBA-175 of Bioko Island and Bata district isolates showed a high degree of genetic variability and heterogeneity, with π values of 0.00407 & 0.00411 and Hd values of 0.958 & 0.976 for nucleotide diversity, respectively. The values of Tajima's D of PfEBA-175 on Bata district and Bioko Island were 0.56395 and - 0.27018, respectively. Globally, PfEBA-175 isolates from Asia were more diverse than those from Africa and South America, and genetic differentiation quantified by the fixation index between Asian and South American countries populations was significant (FST > 0.15, P < 0.05). A total of 310 global isolates clustered in 92 haplotypes, and only one cluster contained isolates from three continents. The mutations A34T, K109E, D278Y, K301N, L305V and D329N were predicted as probably damaging. CONCLUSIONS: This study demonstrated that the dimorphism of F-fragment PfEBA-175 was remarkably predominant in the study area. The distribution patterns and genetic diversity of PfEBA-175 in Equatorial Guinea isolates were similar another region isolates. And the levels of recombination events suggested that natural selection and intragenic recombination might be the main drivers of genetic diversity in global PfEBA-175. These results have important reference value for the development of blood-stage malaria vaccine based on this antigen.

Genetic diversity and natural selection on the thrombospondin-related adhesive protein (TRAP) gene of Plasmodium falciparum on Bioko Island, Equatorial Guinea and global comparative analysis.

BACKGROUND: Thrombospondin-related adhesive protein (TRAP) is a transmembrane protein that plays a crucial role during the invasion of Plasmodium falciparum into liver cells. As a potential malaria vaccine candidate, the genetic diversity and natural selection of PfTRAP was assessed and the global PfTRAP polymorphism pattern was described. METHODS: 153 blood spot samples from Bioko malaria patients were collected during 2016-2018 and the target TRAP gene was amplified. Together with the sequences from database, nucleotide diversity and natural selection analysis, and the structural prediction were preformed using bioinformatical tools. RESULTS: A total of 119 Bioko PfTRAP sequences were amplified successfully. On Bioko Island, PfTRAP shows its high degree of genetic diversity and heterogeneity, with π value for 0.01046 and Hd for 0.99. The value of dN-dS (6.2231, p < 0.05) hinted at natural selection of PfTRAP on Bioko Island. Globally, the African PfTRAPs showed more diverse than the Asian ones, and significant genetic differentiation was discovered by the fixation index between African and Asian countries (Fst > 0.15, p < 0.05). 667 Asian isolates clustered in 136 haplotypes and 739 African isolates clustered in 528 haplotypes by network analysis. The mutations I116T, L221I, Y128F, G228V and P299S were predicted as probably damaging by PolyPhen online service, while mutations L49V, R285G, R285S, P299S and K421N would lead to a significant increase of free energy difference (ΔΔG > 1) indicated a destabilization of protein structure. CONCLUSIONS: Evidences in the present investigation supported that PfTRAP gene from Bioko Island and other malaria endemic countries is highly polymorphic (especially at T cell epitopes), which provided the genetic information background for developing an PfTRAP-based universal effective vaccine. Moreover, some mutations have been shown to be detrimental to the protein structure or function and deserve further study and continuous monitoring.

Genetic polymorphism of Plasmodium falciparum circumsporozoite protein on Bioko Island, Equatorial Guinea and global comparative analysis.

BACKGROUND: Plasmodium falciparum circumsporozoite protein (PfCSP) is a potential malaria vaccine candidate, but various polymorphisms of the pfcsp gene among global P. falciparum population become the major barrier to the effectiveness of vaccines. This study aimed to investigate the genetic polymorphisms and natural selection of pfcsp in Bioko and the comparison among global P. falciparum population. METHODS: From January 2011 to December 2018, 148 blood samples were collected from P. falciparum infected Bioko patients and 96 monoclonal sequences of them were successfully acquired and analysed with 2200 global pfcsp sequences mined from MalariaGEN Pf3k Database and NCBI. RESULTS: In Bioko, the N-terminus of pfcsp showed limited genetic variations and the numbers of repetitive sequences (NANP/NVDP) were mainly found as 40 (35%) and 41 (34%) in central region. Most polymorphic characters were found in Th2R/Th3R region, where natural selection (p > 0.05) and recombination occurred. The overall pattern of Bioko pfcsp gene had no obvious deviation from African mainland pfcsp (Fst = 0.00878, p < 0.05). The comparative analysis of Bioko and global pfcsp displayed the various mutation patterns and obvious geographic differentiation among populations from four continents (p < 0.05). The global pfcsp C-terminal sequences were clustered into 138 different haplotypes (H_1 to H_138). Only 3.35% of sequences matched 3D7 strain haplotype (H_1). CONCLUSIONS: The genetic polymorphism phenomena of pfcsp were found universal in Bioko and global isolates and the majority mutations located at T cell epitopes. Global genetic polymorphism and geographical characteristics were recommended to be considered for future improvement of malaria vaccine design.

Genetic diversity and allele frequencies of Plasmodium falciparum msp1 and msp2 in parasite isolates from Bioko Island, Equatorial Guinea.

BACKGROUND: Malaria is still a serious public health problem on Bioko Island (Equatorial Guinea), although the number of annual cases has been greatly reduced since 2004 through the Bioko Island Malaria Control Project (BIMCP). A better understanding of malaria parasite population diversity and transmission dynamics is critical for assessing the effectiveness of malaria control measures. The objective of this study is to investigate the genetic diversity of Plasmodium falciparum populations and multiplicity of infection (MOI) on Bioko Island 7 years after BIMCP. METHODS: A total of 181 patients with uncomplicated P. falciparum malaria diagnosed with microscopy were collected from Bioko Island from January 2011 to December 2014. Parasite DNA was extracted using chelex-100 and species were identified using a real-time PCR followed by high-resolution melting. Plasmodium falciparum msp1 and msp2 allelic families were determined using nested PCR. RESULTS: Three msp1 alleles (K1, MAD20, and RO33) and two msp2 alleles (FC27 and 3D7) were analysed in all samples. In msp1, the MAD20 allelic family was predominant with 96.69% (175/178) followed respectively by the K1 allelic family with 96.07% (171/178) and R033 allelic family with 70.78% (126/178). In msp2, the FC27 allelic family was the most frequently detected with 97.69% (169/173) compared to 3D7 with 72.25% (125/173). Twenty-six different alleles were observed in msp1 with 9 alleles for K1, 9 alleles for MAD20 and 8 alleles for R033. In msp2, 25 individual alleles were detected with 5 alleles for FC27 and 20 alleles for 3D7. The overall MOI was 5.51 with respectively 3.5 and 2.01 for msp1 and msp2. A significant increase in overall MOI was correlated with the age group of the patients (P = 0.026) or parasite densities (P = 0.04). CONCLUSIONS: The present data showed high genetic diversity and MOI values among the P. falciparum population in the study, reflecting both the high endemic level and malaria transmission on Bioko Island. These data provide valuable information for surveillance of P. falciparum infection and for assessing the appropriateness of the current malarial control strategies in the endemic area.

Developing a data element repository to support EHR-driven phenotype algorithm authoring and execution.

The Quality Data Model (QDM) is an information model developed by the National Quality Forum for representing electronic health record (EHR)-based electronic clinical quality measures (eCQMs). In conjunction with the HL7 Health Quality Measures Format (HQMF), QDM contains core elements that make it a promising model for representing EHR-driven phenotype algorithms for clinical research. However, the current QDM specification is available only as descriptive documents suitable for human readability and interpretation, but not for machine consumption. The objective of the present study is to develop and evaluate a data element repository (DER) for providing machine-readable QDM data element service APIs to support phenotype algorithm authoring and execution. We used the ISO/IEC 11179 metadata standard to capture the structure for each data element, and leverage Semantic Web technologies to facilitate semantic representation of these metadata. We observed there are a number of underspecified areas in the QDM, including the lack of model constraints and pre-defined value sets. We propose a harmonization with the models developed in HL7 Fast Healthcare Interoperability Resources (FHIR) and Clinical Information Modeling Initiatives (CIMI) to enhance the QDM specification and enable the extensibility and better coverage of the DER. We also compared the DER with the existing QDM implementation utilized within the Measure Authoring Tool (MAT) to demonstrate the scalability and extensibility of our DER-based approach.

PheWAS analysis on large-scale biobank data with PheTK.

Summary: With the rapid growth of genetic data linked to electronic health record data in huge cohorts, large-scale phenome-wide association study (PheWAS), have become powerful discovery tools in biomedical research. PheWAS is an analysis method to study phenotype associations utilizing longitudinal electronic health record (EHR) data. Previous PheWAS packages were developed mostly in the days of smaller biobanks and with earlier PheWAS approaches. PheTK was designed to simplify analysis and efficiently handle biobank-scale data. PheTK uses multithreading and supports a full PheWAS workflow including extraction of data from OMOP databases and Hail matrix tables as well as PheWAS analysis for both phecode version 1.2 and phecodeX. Benchmarking results showed PheTK took 64% less time than the R PheWAS package to complete the same workflow. PheTK can be run locally or on cloud platforms such as the All of Us Researcher Workbench ( All of Us ) or the UK Biobank (UKB) Research Analysis Platform (RAP). Availability and implementation: The PheTK package is freely available on the Python Package Index (PyPi) and on GitHub under GNU Public License (GPL-3) at https://github.com/nhgritctran/PheTK . It is implemented in Python and platform independent. The demonstration workspace for All of Us will be made available in the future as a featured workspace. Contact: PheTK@mail.nih.gov.

Racial and Ethnic Disparities in Antihypertensive Medication Prescribing Patterns and Effectiveness.

Variability in drug effectiveness and provider prescribing patterns have been reported in different racial and ethnic populations. We sought to evaluate antihypertensive drug effectiveness and prescribing patterns among self-identified Hispanic/Latino (Hispanic), Non-Hispanic Black (Black), and Non-Hispanic White (White) populations that enrolled in the NIH All of Us Research Program, a US longitudinal cohort. We employed a self-controlled case study method using electronic health record and survey data from 17,718 White, Hispanic, and Black participants who were diagnosed with essential hypertension and prescribed at least one of 19 commonly used antihypertensive medications. Effectiveness was determined by calculating the reduction in systolic blood pressure measurements after 28 or more days of drug exposure. Starting systolic blood pressure and effectiveness for each medication were compared for self-reported Black, Hispanic, and White participants using adjusted linear regressions. Black and Hispanic participants were started on antihypertensive medications at significantly higher SBP than White participants in 13 and 7 out of 19 medications, respectively. More Black participants were prescribed multiple antihypertensive medications (58.46%) than White (52.35%) or Hispanic (49.9%) participants. First-line HTN medications differed by race and ethnicity. Following the 2017 American College of Cardiology and the American Heart Association High Blood Pressure Guideline release, around 64% of Black participants were prescribed a recommended first-line antihypertensive drug compared with 76% of White and 82% of Hispanic participants. Effect sizes suggested that most antihypertensive drugs were less effective in Hispanic and Black, compared with White, participants, and statistical significance was reached in 6 out of 19 drugs. These results indicate that Black and Hispanic populations may benefit from earlier intervention and screening and highlight the potential benefits of personalizing first-line medications.

Automated quantification of measurable residual disease in chronic lymphocytic leukemia using an artificial intelligence-assisted workflow.

Detection of measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is an important prognostic marker. The most common CLL MRD method in current use is multiparameter flow cytometry, but availability is limited by the need for expert manual analysis. Automated analysis has the potential to expand access to CLL MRD testing. We evaluated the performance of an artificial intelligence (AI)-assisted multiparameter flow cytometry (MFC) workflow for CLL MRD. We randomly selected 113 CLL MRD FCS files and divided them into training and validation sets. The training set (n = 41) was gated by expert manual analysis and used to train the AI model. We then compared the validation set (n = 72) MRD results obtained by the AI-assisted analysis versus those by expert manual analysis using the Pearson correlation coefficient and Bland-Altman plot method. In the validation set, the AI-assisted analysis correctly categorized cases as MRD-negative versus MRD-positive in 96% of cases. When comparing the AI-assisted analysis versus the expert manual analysis, the Pearson r was 0.8650, mean bias was 0.2237 log10 units, and the 95% limit of agreement (LOA) was ±1.0282 log10 units. The AI-assisted analysis performed sub-optimally in atypical immunophenotype CLL and in cases lacking residual normal B cells. When excluding these outlier cases, the mean bias improved to 0.0680 log10 units and the 95% LOA to ±0.2926 log10 units. An automated AI-assisted workflow allows for the quantification of MRD in CLL with typical immunophenotype. Further work is required to improve performance in atypical immunophenotype CLL.

Blastoid and Pleomorphic Mantle Cell Lymphoma Demonstrate Distinct Clinicopathologic and Genetic Features.

The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49 µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8 y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity.

Gelsemium is a medicinal plant that has been used to treat various diseases, but it is also well-known for its high toxicity. Complex alkaloids are considered the main poisonous components in Gelsemium. However, the toxic mechanism of Gelsemium remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of Gelsemium toxicity. The alkaloid compounds and candidate targets of Gelsemium, as well as related targets of excitotoxicity, were collected from public databases. The crucial targets were determined by constructing a protein-protein interaction (PPI) network. Subsequently, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the bioprocesses and signaling pathways involved in the excitotoxicity corresponding to alkaloids in Gelsemium. Then, the binding affinity between the main poisonous alkaloids and key targets was verified by molecular docking. Finally, animal experiments were conducted to further evaluate the potential mechanisms of Gelsemium toxicity. A total of 85 alkaloids in Gelsemium associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of Gelsemium was mainly related to the protein phosphorylation reaction and plasma membrane function. There were also 164 pathways involved in the toxic mechanism, such as the calcium signaling pathway and MAPK signaling pathway. Molecular docking showed that alkaloids have high affinity with core targets, including MAPK3, SRC, MAPK1, NMDAR2B and NMDAR2A. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD50 values of female and male mice were 0.071 mg·kg-1 and 0.149 mg·kg-1, respectively. Furthermore, we found that N-methyl-D-aspartic acid (NMDA), a specific NMDA receptor agonist, could significantly increase the survival rate of acute humantenirine-poisoned mice. The results also show that humantenirine could upregulate the phosphorylation level of MAPK3/1 and decrease ATP content and mitochondrial membrane potential in hippocampal tissue, while NMDA could rescue humantenirine-induced excitotoxicity by restoring the function of mitochondria. This study revealed the toxic components and potential toxic mechanism of Gelsemium. These findings provide a theoretical basis for further study of the toxic mechanism of Gelsemium and potential therapeutic strategies for Gelsemium poisoning.

[Source Analysis and Ecological Risk Assessment of Heavy Metals in the Arable Soil at the Geological High Background, Based on the Township Scale].

Due to the extensive development of carbonate rocks in southwest China, heavy metals are naturally occurring elements that have high natural background levels in the environment. Therefore, it is important to conduct ecological risk assessments and identify potential sources of heavy metals in the geological high background area. Based on the township scale, a total of 307 surface soil samples were collected in Qinglong Town, Fengjie County, Chongqing. The concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn and pH were analyzed and determined. The spatial distribution and source of soil heavy metals were discussed using the geostatistical analysis and an absolute principal component score-multiple linear regression (APCS-MLR) model in the studied area. The results showed that the average values of seven heavy metals (As, Cd, Cr, Cu, Hg, Ni, and Zn) in the arable soil exceeded the background values of Chongqing, and the cumulative effect of Cd and As was obvious. The concentrations of Cd significantly exceededthe screening values in The Risk Control Standard for Soil Environmental Quality and Soil Pollution in Agricultural Land (GB 15618-2018), with the over-standard rates of 52.12%. The spatial characteristics of soil heavy metal contents exhibited a pattern of high in the south and low in the north. PCA and APCS-MLR modeling revealed that the contributions of natural sources to Cr, Cu, Ni, and Zn were 86.62%, 64.34%, 76.44%, and 85.46%, respectively. As, Pb, and Hg mainly derived from industrial activities, which accounted for 74.63%, 61.90%, and 73.49%, respectively, and Cd was affected by both natural sources and industrial activities (accounting for 47.74% and 39.56% of the total Cd content, respectively). The evaluation of the soil by the Nemerow comprehensive index (P) showed that Cd pollution was relatively serious, accounting for 27.04% of soil pollution. The potential ecological hazard index showed that Cd and Hg were the main ecological hazard elements, and the distribution range of RI was 51.77 to 2228, indicating mainly mild and moderate risks, and the moderate and above risk areas in the study area were mainly located around the southern industrial source area. Altogether, our results revealed that in the study area, the heavy metal pollution was mainly caused by industrial activities, and the heavy metal pollution caused by geological background was mainly light to moderate. In conclusion, the medium and above risk areas in the study area were mainly caused by mineral and industrial activities, whereas the heavy metal pollution caused by geological background was mainly light to moderate pollution.

Systematic replication of smoking disease associations using survey responses and EHR data in the All of Us Research Program.

OBJECTIVE: The All of Us Research Program (All of Us) aims to recruit over a million participants to further precision medicine. Essential to the verification of biobanks is a replication of known associations to establish validity. Here, we evaluated how well All of Us data replicated known cigarette smoking associations. MATERIALS AND METHODS: We defined smoking exposure as follows: (1) an EHR Smoking exposure that used International Classification of Disease codes; (2) participant provided information (PPI) Ever Smoking; and, (3) PPI Current Smoking, both from the lifestyle survey. We performed a phenome-wide association study (PheWAS) for each smoking exposure measurement type. For each, we compared the effect sizes derived from the PheWAS to published meta-analyses that studied cigarette smoking from PubMed. We defined two levels of replication of meta-analyses: (1) nominally replicated: which required agreement of direction of effect size, and (2) fully replicated: which required overlap of confidence intervals. RESULTS: PheWASes with EHR Smoking, PPI Ever Smoking, and PPI Current Smoking revealed 736, 492, and 639 phenome-wide significant associations, respectively. We identified 165 meta-analyses representing 99 distinct phenotypes that could be matched to EHR phenotypes. At P < .05, 74 were nominally replicated and 55 were fully replicated. At P < 2.68 × 10-5 (Bonferroni threshold), 58 were nominally replicated and 40 were fully replicated. DISCUSSION: Most phenotypes found in published meta-analyses associated with smoking were nominally replicated in All of Us. Both survey and EHR definitions for smoking produced similar results. CONCLUSION: This study demonstrated the feasibility of studying common exposures using All of Us data.

[Accumulation and Pollution Risks of Heavy Metals in Soils and Agricultural Products from a Typical Black Shale Region with High Geological Background].

Soil polluted by heavy metals (HMs) is an important environmental issue in China, and regional geological background is a vital factor that influences the enrichment of HMs in soils. Previous studies have shown that soils derived from black shales are commonly enriched in HMs and present high potential eco-environmental risks. However, few studies have investigated the HMs in different agricultural products, which inhibit the safe use of land and safe production of food crops in black shale regions. This study investigated the concentrations, pollution risks, and speciation of HMs in soils and agricultural products from a typical black shale region in Chongqing. The results showed that the study soils were enriched in Cd, Cr, Cu, Zn, and Se but not in Pb. Approximately 98.7% of total soils exceeded the risk screening values, and 47.3% of total soils exceeded the risk intervention values. Cd had the highest pollution level and potential ecological risks and was the primary pollutant in soils of the study area. Most of the Cd resided in ion-exchangeable fractions (40.6%), followed by residual fractions (19.1%) and weak organic matter combined fractions (16.6%), whereas Cr, Cu, Pb, Se, and Zn were dominated by residual fractions. Additionally, organic combined fractions contributed to Se and Cu, and Fe-Mn oxide combined fractions contributed to Pb. These results indicated that Cd had higher mobility and availability than those of other metals. The agricultural products presented a weak ability to accumulate HMs. Approximately 18.7% of the collected samples with Cd exceeded the safety limit, but the enrichment factor was relatively low, indicating low pollution risks of the heavy metals. The findings of this study could provide guidelines for safe use of land and safe production of food crops in black shale regions with high geological background.

The U.S. National Library of Medicine's Impact on Precision and Genomic Medicine.

Precision medicine offers the potential to improve health through deeper understandings of the lifestyle, biological, and environmental influences on health. Under Dr. Donald A.B. Lindberg's leadership, the U.S. National Library of Medicine (NLM) has developed the central reference resources for biomedical research and molecular laboratory medicine that enable precision medicine. The hosting and curation of biomedical knowledge repositories and data by NLM enable quality information reachable for providers and researchers throughout the world. NLM has been supporting the innovation of electronic health record systems to implement computability and secondary use for biomedical research, producing the scale of linked health and molecular datasets necessary for precision medicine discovery.

Isocitrate Dehydrogenase Mutations Are Associated with Different Expression and DNA Methylation Patterns of OLIG2 in Adult Gliomas.

Isocitrate dehydrogenase (IDH) mutant gliomas are associated with a better prognosis in comparison to adult IDH wild-type glioma and glioma-CpG island methylator phenotypes. Although OLIG2 is mainly expressed in oligodendrocytes in normal adult brain, it is expressed in both astrocytomas and oligodendrogliomas. Utilizing the clinical, DNA methylation, and RNA-sequencing data from the Cancer Genome Atlas (TCGA) for lower-grade glioma and glioblastoma cohorts, we explored the association between IDH mutation status and OLIG2 expression on transcription, DNA methylation, and gene target levels. Compared to IDH wild-type gliomas, IDH mutant gliomas showed consistently higher expression of OLIG2 transcripts. OLIG2 overexpression is a good surrogate marker for IDH mutation with an AUC of 0.90. At the DNA methylation level, IDH-mutant gliomas showed hyper- and hypomethylation foci upstream of the OLIG2 transcription start site. Underexpressed OLIG2 target genes in IDH mutant glioma were enriched in cell cycle-related pathways. Thus, the differential expression of OLIG2 between IDH mutant and wild-type gliomas reflects involvement in multiple pathways in tumorigenesis.

A Proteomics Study of the Subacute Toxicity of Rat Brain after Long- Term Exposure of Gelsemium elegans.

BACKGROUND: Gelsemium elegans (G. elegans) has been shown to have strong pharmacological and pharmacodynamic effects in relevant studies both in China and USA. G. elegans has been used as a traditional medicine to treat a variety of diseases and even has the potential to be an alternative to laboratory synthesized drugs. However, its toxicity severely limited its application and development. At present, there is little attention paid to protein changes in toxicity. AIM: This study investigated the toxicity effects after long-term exposure of G. elegans of the rat brain through proteomic. METHODS: 11 differential abundance proteins were detected, among which 8 proteins were higher in the G. elegans- exposure group than in the control group, including Ig-like domain-containing protein (N/A), receptor-type tyrosine-protein phosphatase C (Ptprc), disheveled segment polarity protein 3 (Dvl3), trafficking protein particle complex 12 (Trappc12), seizure-related 6 homologlike (Sez6l), transmembrane 9 superfamily member 4 (Tm9sf4), DENN domain-containing protein 5A (Dennd5a) and Tle4, whereas the other 3 proteins do the opposite including Golgi to ER traffic protein 4 (Get4), vacuolar protein sorting 4 homolog B (Vps4b) and cadherin-related 23 (CDH23). Furthermore, we performed validation of WB analysis on the key protein CDH23. RESULTS: Finally, only fewer proteins and related metabolic pathways were affected, indicating that there was no accumulative toxicity of G. elegans. G. elegans has the potential to develop and utilize of its pharmacological activity. CHD23, however, is a protein associated with hearing. CONCLUSION: Whether the hearing impairment is a sequela after G. elegans exposure remains to be further studied.