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1.
Plant Cell ; 2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36738093

RESUMO

Long non-coding RNAs (lncRNAs) are a large and diverse class of genes in eukaryotic genomes that contribute to a variety of regulatory processes. Functionally characterized lncRNAs play critical roles in plants, ranging from regulating flowering to controlling lateral root formation. However, findings from the past decade have revealed that thousands of lncRNAs are present in plant transcriptomes, and characterization has lagged far behind identification. In this setting, distinguishing function from noise is challenging. However, the plant community has been at the forefront of discovery in lncRNA biology, providing many functional and mechanistic insights that have increased our understanding of this gene class. In this review, we examine the key discoveries and insights made in plant lncRNA biology over the past two and a half decades. We describe how discoveries made in the pre-genomics era have informed efforts to identify and functionally characterize lncRNAs in the subsequent decades. We provide an overview of the functional archetypes into which characterized plant lncRNAs fit and speculate on new avenues of research that may uncover yet more archetypes. Finally, this review discusses the challenges facing the field and some exciting new molecular and computational approaches that may help inform lncRNA comparative and functional analyses.

2.
Soc Sci Med ; 320: 115681, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36731303

RESUMO

Extreme weather and climate-related disaster events are associated with a range of adverse health outcomes. People are not equally vulnerable to the adversity, experiencing varied patterns of long-term health trajectories in recovery depending on their vulnerabilities, capacities, and resiliencies. This study aims to identify latent mental and physical health trajectories and their associations with person- and place-based pre-disaster predictors. Using an Australian, population-based, longitudinal dataset spanning 2009-19, group-based multi-trajectory modelling was applied to identify the distinct mental, social, emotional, and physical health trajectories of people who had experienced damage to their home following a climate-related disaster event. Multinomial logistic regression was used to assess a series of social vulnerability predictors (demographic, socioeconomic, housing, health, neighbourhood, and geographical) of health patterns. We identified three distinct health trajectories. Most individuals experienced small or minimal health impacts at the time of the disaster year followed by a fast recovery. However, one-fifth of the exposed population were severely affected during and post disaster. This cohort had the worst mental and physical health prior to the disaster and experienced the largest decreases in mental and physical health and the lowest recoveries. Pre-existing mental and physical conditions were the most substantial risk factors, increasing the probability of experiencing high impact and slow recovery by 61% for mental health and 51% for physical health. In addition, vulnerability in the form of housing affordability stress, lower household income, and lack of community attachment, participation and safety were also significant independent risk factors for ongoing post-disaster health problems. Critically, people's mental and physical health recovery is dependent on pre-disaster vulnerabilities in health, resource access, and capacities. These findings could assist policymakers and health practitioners to more effectively target people most at risk and design prevention and response strategies to prevent the exacerbation of poor health and wellbeing.

3.
J Virol ; : e0171922, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688655

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the most severe emerging infectious disease in the current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins in South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs. The virus could infect three mouse models but showed limited pathogenicity, with mild peribronchial and perivascular inflammatory cell infiltration observed in lungs. Our results suggest that this SARSr-CoV-2 virus from pangolins has the potential for interspecies infection, but its pathogenicity is mild in mice. Future surveillance among these wildlife hosts of SARSr-CoV-2 is needed to monitor variants that may have higher pathogenicity and higher spillover risk. IMPORTANCE SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health. Several SARS-CoV-2-related coronaviruses (SARSr-CoV-2) in bats and pangolins have been identified since the SARS-CoV-2 outbreak. It is therefore important to assess their potential of crossing species barriers for better understanding of their risk of future emergence. In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.

4.
Br J Haematol ; 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604838

RESUMO

Selective patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiD) are at high risk for venous thromboembolism (VTE). The SAVED score is a VTE risk prediction model recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines. Using retrospective data from 501 MM patients with new IMiD initiation between 2010 and 2019, we performed the first independent external validation of this model. The cumulative incidence of VTE after IMiD initiation at 6 and 12 months was 32% and 42% in the high-risk group, versus 6% and 9% in the low-risk group respectively. The C-statistic of the SAVED score to predict VTE within 12 months of IMiD-based treatment start was 0.74 [95% confidence interval (CI): 0.69-0.78], which outperformed several other VTE risk models in MM patients. Our findings suggest that the SAVED score is an accurate risk assessment tool for VTE stratification in patients initiating IMiD-containing regimens.

5.
J Hazard Mater ; 448: 130814, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36706485

RESUMO

Effects of microplastics on microalgae have not been compared from different habitat. To answer this question, three marine microalgae species (Chlorella marined, Nannochloropsis oculate, and Phaeodactylum tricornutum) and two freshwater species (Chlorella vulgaris and Tetradesmus obliquus) were selected and exposed to the environment relevant concentrations of polystyrene microplastics. The results indicated that microplastics have a significant concentration effect on the growth of microalgae. The attachment of microalgae to microplastics surface and the aggregation of microalgae with each other were observed. Under exposure of microplastics, the photosynthesis of microalgae was inhibited while the antioxidant system was activated, indicating that microplastics had a negative impact on microalgae. At the end of exposure, the oxidative stress status caused by microplastics in marine microalgae were alleviated, but the antioxidant system of freshwater microalgae was still at high levels, indicating a stress response. In addition, integrated biomarker response (IBR) indicated that the effects of microplastics on freshwater microalgae were severer than marine microalgae, which might relate to their differences in removing reactive oxygen species (ROS) effectively and membrane structure. Our study provides a reliable data for understanding the complex effects of microplastics on microalgae, and especially for comparing the differential effects of microplastics among different microalgae.

6.
J Phys Chem Lett ; 14(1): 302-309, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36602229

RESUMO

Sn-Ge mixed perovskites have been proposed as promising lead-free candidates in the photovoltaics (PV) field. In this work, we discovered a stable P1 phase Sn-Ge mixed structure (CsSn0.5Ge0.5I3) with an appropriate band gap value of 1.19 eV, which manifests its unique structural stability and physics properties. The thermodynamic stability of this mixed structure under different growth conditions and all possible native defects are depicted in detail. The formation energies and dominant native point defects indicate that P1 phase CsSn0.5Ge0.5I3 exhibits unipolar self-doping behavior (p-type conductivity) and good defect tolerance while the growth condition changes. In addition, the calculation of light absorption confirmed that the P1 phase has a higher light absorption coefficient than that of MAPbI3 in the visible light range, showing excellent light absorption. Our work not only provides theoretical guidance for unraveling the unusual structural stability of Sn-Ge mixed perovskites, but also offers a useful scheme to modulate the stability and optoelectronic properties of Ge-based perovskites through alloy engineering.

7.
PNAS Nexus ; 2(1): pgac297, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36712931

RESUMO

Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+  T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1ß, and IFNß expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.

8.
Small ; : e2207167, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703536

RESUMO

Because of its high specific capacity, the silicon-graphite composite (SGC) is regarded as a promising anode for new-generation lithium-ion batteries. However, the frequently employed two-section preparation process, including the modification of silicon seed and followed mixture with graphite, cannot ensure the uniform dispersion of silicon in the graphite matrix, resulting in a stress concentration of aggregated silicon domains and cracks in composite electrodes during cycling. Herein, inspired by powder engineering, the two independent sections are integrated to construct multistage stable silicon-graphite hybrid granules (SGHGs) through wet granulation and carbonization. This method assembles silicon nanoparticles (Si NPs) and graphite and improves compatibility between them, addressing the issue of severe stress concentration caused by uncombined residue of Si NPs. The optimal SGHG prepared with 20% pitch content exhibits a highly reversible specific capacity of 560.0 mAh g-1 at a current density of 200 mA g-1 and a considerable stability retention of 86.1% after 1000 cycles at 1 A g-1 . Moreover, as a practical application, the full cell delivers an outstanding capacity retention of 85.7% after 400 cycles at 2 C. The multistage stable structure constructed by simple wet granulation and carbonization provides theoretical guidance for the preparation of commercial SGC anodes.

9.
Anal Chim Acta ; 1239: 340693, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36628761

RESUMO

A critical challenge in using deep eutectic solvents (DESs) in capillary electrophoresis (CE) is to develop separation systems in which a DES can really work as a single entity. To achieve this, the authors recently demonstrated a novel strategy that takes advantage of the aqueous dispersibility of hydrophobic DESs (or more accurately hydrophobic eutectic solvents (HESs)). However, the previous work was limited only to the separation of achiral analytes, e.g., analogues, homologues, and isomers. The present study was designed as a follow-up study in order to explore the feasibility of employing HES-type pseudo-stationary phases (PSPs) in CE for chiral separations. By using carboxymethyl-ß-cyclodextrin (CM-ß-CD) as a model chiral selector, we provide the first evidence that there is a potential synergistic effect between HESs and traditional chiral selectors. Specifically, the combined use of HES (-)-menthol:octanoic acid and CM-ß-CD allowed excellent enantioseparations of several basic drugs which were not able to be resolved in the single CM-ß-CD system. The enantioresolutions were significantly improved while the migration times of the enantiomers were also shortened due to the hydrophobic mechanism of the HES-type PSP. Critical factors influencing the novel chiral CE system were systematically investigated. Since HESs are considered as "designer" solvents with highly tunable properties, this study demonstrates the potential of employing HESs (or HDES)-type PSPs in CE for chiral separations.


Assuntos
Eletroforese Capilar , Água , Solventes/química , Estudos de Viabilidade , Seguimentos , Eletroforese Capilar/métodos , Estereoisomerismo
10.
Chemosphere ; : 137833, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36693480

RESUMO

Metals inevitably and easily enter into human bodies and can induce a series of pathophysiological changes, such as oxidative stress damage and lipid peroxidation, which then may further induce dyslipidemia. However, the effects of metals and metals mixture on the lipid profiles are still unclear, especially in older adults. A three-visits repeated measurement of 201 older adults in Beijing was conducted from November 2016 to January 2018. Linear Mixed Effects models and Bayesian kernel machine regression models were used to estimate associations of eight blood metals and metals mixture with lipid profiles, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), Castelli risk indexes I (CRI-1), Castelli risk indexes II (CRI-2), atherogenic coefficient (AC), and non-HDL cholesterol (NHC). Cesium (Cs) was positively associated with TG (ßCs = 0.14; 95% CI: 0.02, 0.26) whereas copper (Cu) was inversely related to TG (ßCu = -0.65; 95%CI: 1.14, -0.17) in adjusted models. Manganese (Mn) was mainly related to higher HDL-C (ßMn = 0.14; 95% CI: 0.07, 0.21) whereas molybdenum showed opposite association. Metals mixture was marginally positive associated with HDL-C, among which Mn played a crucial role. Our findings suggest that the effects of single metal on lipid profiles may be counteracted in mixtures in the context of multiple metal exposures; however, future studies with large sample size are still needed to focus on the detrimental effects of single metals on lipid profiles as well as to identify key components.

11.
Biodegradation ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36596915

RESUMO

The mining and leakage of molybdenum (Mo) can cause environmental contamination which has not been realized until recently. Bacteria that can mitigate Mo-contamination was enriched and isolated. The low temperature and different pH conditions were considered to analysis its feasibility in Northern China which suffers from a long time of low temperatures every year. The result showed that the removal rate of MoO42- by Raoultella ornithinolytica A1 reached 30.46% at 25 °C and pH 7.0 in Luria-Bertani medium (LB). Meanwhile, A1 also showed some efficiency in the reduction of MoO42- in low phosphate molybdate medium (LPM), which reached optimum at the MoO42- concentration of 10 mM. The results of FTIR indicated that the cell wall performed an essential role in the MoO42- removal process, which was illustrated by the distribution of Mo in A1 (Mo bound to cell wall accounted for 92.29% of the total MoO42- removed). In addition, low temperature (10 °C) effect the removal rate of MoO42- by - 8.38 to 11.66%, indicating the potential for the in-situ microbial remediation of Mo-contaminated environments in low temperature areas.

12.
Cell Rep ; 42(1): 111986, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640348

RESUMO

Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to stress without first requiring nuclear feedback. In this study, we identify diaphanous-related formin 3 (DIAPH3), an actin nucleator, as a scaffold protein to initiate liquid-liquid phase separation (LLPS) and form abundant cytosolic phase-separated DIAPH3 granules (D-granules) in mammalian cells such as HeLa, HEK293, and fibroblasts under various stress conditions. Neither mRNAs nor known stress-associated condensate markers, such as G3BP1, G3BP2, and TIA1 for SGs and DCP1A for P-bodies, are detected in D-granules. Using overexpression and knockout of DIAPH3, pharmacological interventions, and optogenetics, we further demonstrate that stress-induced D-granules spatially sequester DIAPH3 within the condensation to inhibit the assembly of actin filaments in filopodia. This study reveals that D-granules formed by LLPS act as a regulatory hub for actin cytoskeletal remodeling in response to stress.

13.
Sci Adv ; 9(1): eabo7555, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598999

RESUMO

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.


Assuntos
Glutamina , Folículo Piloso , Animais , Humanos , Camundongos , Glutamina/metabolismo , Queratinócitos , Regeneração , Pele/metabolismo , Cicatrização , Microbiota
15.
Chemosphere ; 316: 137853, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36640974

RESUMO

In shrimp, hemocytes play an important role in detoxification and immune defense, and are where nitrite accumulates during exposure to this toxic environmental pollutant. However, the heterogeneity mechanisms of toxicity have not been reported under nitrite expose in shrimp. Here, we used single-cell RNA-seq to resolve 24,000 cells, which the responses of different cell populations of hemocytes under nitrite exposure in Penaeus vannamei. We identified 394 specific nitrite-responsive genes in 9 clusters of hemocytes, and found heterogeneity in the nitrite response of the three subpopulations of hemocytes (hyaline, semi-granular and granular cells). In hyaline, the response appeared modest, whereas nitrite-related dysregulation of metabolic processes in granular and semi-granular was pronounced. Ammonia nitrogen will rapidly accumulate in hemocytes of shrimp under nitrite stress. In semi-granular, excessive ammonia will interfere with oxidative phosphorylation and antioxidant system, thus inducing the production of reactive oxygen species. In granular, the abnormality of urea cycle caused by ammonia accumulation is the main toxic factor, which by inhibits arginase and arginine kinase. Collectively, our data provide a single-cell atlas for the dissection of shrimp hemocyte complexity, and reveal the toxicity mechanisms associated with nitrite exposure.


Assuntos
Hemócitos , Penaeidae , Animais , Hemócitos/metabolismo , Nitritos/toxicidade , Nitritos/metabolismo , Amônia/metabolismo , Antioxidantes/metabolismo , Penaeidae/genética
16.
J Extracell Vesicles ; 12(1): e12300, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36604402

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies that is usually detected late in the clinic. The currently available diagnostic tools for CRC are either invasive or insensitive to early lesions due to the dearth of reliable biomarkers. In this study, we discovered that the extracellular vesicles (EVs) in the faeces of CRC patients can act as a potent biomarker for the non-invasive diagnosis and prognosis of CRC. This finding is based on the identification of two transmembrane proteins-CD147 and A33-on faeces-derived EVs (fEVs) that are intrinsically associated with CRC. The detection results show that the levels of CD147 and A33 on fEVs were upregulated in the CRC patients (n = 48), dramatically distinguishing them from the healthy donors (n = 16). The CD147/A33-enriched EVs offer a clinical sensitivity of 89%, much higher than that (40%) of carcinoembryonic antigen (CEA), a clinically-established serum biomarker for CRC diagnosis. In addition, the analysis of longitudinal faeces samples (n = 29) demonstrated that the CD147/A33-enriched fEVs can be utilized to track the prognosis of CRC. Due to the high compliance of faeces-based detection, the CD147/A33-enriched fEVs could serve as new-generation CRC biomarkers for large-scale, non-invasive CRC screening as well as real-time monitoring of patient outcomes during clinical interventions.


Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Humanos , Vesículas Extracelulares/patologia , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Fezes
17.
J Clin Oncol ; : JCO2201542, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626707

RESUMO

PURPOSE: Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy. METHODS: Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS). RESULTS: Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set. CONCLUSION: The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months (v 3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.

18.
Infect Drug Resist ; 16: 143-153, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36636369

RESUMO

Objective: To investigate the value of hypernatremia in the intensive care unit (ICU) for the risk prediction of mortality in severe patients. Methods: Clinical data of critically ill patients admitted to the ICU of Beijing Friendship Hospital, were collected for retrospective analysis. Univariate and multivariate logistic regression analyses were employed to analyze the influencing factors. Nomograms predicting the mortality were constructed with R software and validated with repeated sampling. Results: A total of 442 cases were eligible for this study. Hypernatremia within 48 hours of ICU admission, change in sodium concentration (CNa+) within 48 hours, septic shock, APACHE II score, hyperlactatemia within 48 hours, use of continuous renal replacement therapy (CRRT) within 48 hours, and the use of mechanical ventilation (MV) within 48 hours of ICU admission were all identified as independent risk factors for death within 28 days of ICU admission. These predictors were included in a nomogram of 28-day mortality in severe patients, which was constructed using R software. Conclusion: The nomogram could predict the individualized risk of 28-day mortality based on the above factors. The model has better discrimination and accuracy and has high clinical application value.

19.
Ecotoxicol Environ Saf ; 250: 114494, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36608569

RESUMO

Dyslipidemia is a common disease in the older population and represents a considerable disease burden worldwide. Epidemiological and experimental studies have indicated associations between heavy metal exposure and dyslipidemia; few studies have investigated the effects of heavy metal mixture and interactions between metals on dyslipidemia. We recruited 1121 participants living in heavy metal-contaminated and control areas in northeast China from a cross-sectional survey (2017-2019). Urinary metals including chromium (Cr), cadmium (Cd), lead (Pb), and manganese (Mn) and dyslipidemia biomarkers, namely triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, were measured. The generalized linear model (GLM) was used to explore the association of a single metal with dyslipidemia biomarkers. Bayesian kernel machine regression (BKMR) and multivariable linear regression were performed to explore the overall effect of metal mixture and the interaction between metals on dyslipidemia. Heavy metal mixture was positively associated with LDL-C, TC, and TG and negatively with HDL-C. In multivariable linear regression, Pb and Cd exhibited a synergistic association with LDL-C in the participants without hyperlipemia. Mn-Cd and Pb-Cr also showed a synergistic association with increasing the level of LDL-C in subjects without hyperlipemia. Cd-Cr showed an antagonistic association with HDL-C, respectively. Cr-Mn exhibited an antagonistic association with decreased HDL-C and TG levels. No significant interaction was noted among the three metals. Our study indicated that exposure to heavy metals is associated with dyslipidemia biomarkers and the presence of potential synergistic or antagonistic interactions between the heavy metals.


Assuntos
Dislipidemias , Metais Pesados , Humanos , Estudos Transversais , Cádmio/toxicidade , LDL-Colesterol , Teorema de Bayes , Chumbo/toxicidade , Metais Pesados/toxicidade , Manganês , Cromo , Triglicerídeos , HDL-Colesterol , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , China
20.
Am J Hum Genet ; 110(1): 30-43, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608683

RESUMO

Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries and are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects, e.g., when the product of two SNP effects and the linkage disequilibrium (LD) correlation is negative. Here, we introduce "mBAT-combo," a set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,273 gene-trait pairs, indicating that masking effects is common in complex traits. We further validate the improved power of our method in height, body mass index, and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with a 1.7-fold increase in sample sizes. Eleven genes significant only in mBAT-combo for schizophrenia are confirmed by functionally informed fine-mapping or Mendelian randomization integrating gene expression data. The framework of mBAT-combo can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.


Assuntos
Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Desequilíbrio de Ligação , Genômica , Polimorfismo de Nucleotídeo Único/genética
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