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1.
EMBO Mol Med ; : e16235, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36652375

RESUMO

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.

2.
ACS Appl Mater Interfaces ; 15(2): 2552-2563, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36600575

RESUMO

Sonodynamic therapy (SDT) can be described as ultrasonic (US) catalysis. Adequate charge separation is considered as effective means to promote reactive oxygen species (ROS). Here, hollow CoP@N-carbon@PEG (CPCs@PEG) nanospheres (∼60 nm) are prepared as sonosensitizers, showing greater ROS generation than pure CoP@PEG under US irradiation. Both 1O2 and ·O2- are activation species that are determined by O2 and electrons. The great SDT performance of CPCs@PEG is ascribed to the heterostructure which promotes the separation and transfer for US-generated electrons and holes. In addition, holes can be further captured by endogenous glucose that is in favor of electron aggregation and ROS generation. Moreover, the consumption of glucose would decrease intracellular ATP for starvation therapy. Given the higher oxidation ability of Co3+, CPCs@PEG nanospheres possess catalase (CAT) activity to convert H2O2 into O2 for assisting ROS generation. Moreover, they also can oxidize glutathione (GSH) as a mimic GSH oxidase to break intratumor redox balance, facilitating oxidative stress. More importantly, the nanocomposites reveal good degradation ability dominated by the oxidation from insoluble phosphide into soluble phosphate, accelerating elimination via urine and feces within 14 days. CPCs@PEG nanospheres integrate the above effects not only to reveal great tumor inhibition ability but also to excite immune activation for anticancer.


Assuntos
Nanosferas , Neoplasias , Humanos , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Carbono , Linhagem Celular Tumoral
3.
Sci Adv ; 9(1): eabq6978, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598996

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.


Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Doenças Neuroinflamatórias , Antivirais
4.
BMJ ; 380: e071952, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631148

RESUMO

OBJECTIVE: To assess the recent trends in prevalence and management of hypertension in China, nationally and by population subgroups. DESIGN: Six rounds of a national survey, China. SETTING: China Chronic Disease and Risk Factors Surveillance, 2004-18. PARTICIPANTS: 642 523 community dwelling adults aged 18-69 years (30 501 in 2004, 47 353 in 2007, 90 491 in 2010, 156 836 in 2013, 162 293 in 2015, and 155 049 in 2018). MAIN OUTCOME MEASURES: Hypertension was defined as a blood pressure of ≥140/90 mm Hg or taking antihypertensive drugs. The main outcome measures were hypertension prevalence and proportion of people with hypertension who were aware of their hypertension, who were treated for hypertension, and whose blood pressure was controlled below 140/90 mm Hg. RESULTS: The standardised prevalence of hypertension in adults aged 18-69 years in China increased from 20.8% (95% confidence interval 19.0% to 22.5%) in 2004 to 29.6% (27.8% to 31.3%) in 2010, then decreased to 24.7% (23.2% to 26.1%) in 2018. During 2010-18, the absolute annual decline in prevalence of hypertension among women was more than twice that among men (-0.83 percentage points (95% confidence interval -1.13 to -0.52) v -0.40 percentage points (-0.73 to -0.07)). Despite modest improvements in the awareness, treatment, and control of hypertension since 2004, rates remained low in 2018, at 38.3% (36.3% to 40.4%), 34.6% (32.6% to 36.7%), and 12.0% (10.6% to 13.4%). Of 274 million (95% confidence interval 238 to 311 million) adults aged 18-69 years with hypertension in 2018, control was inadequate in an estimated 240 million (215 to 264 million). Across all surveys, women with low educational attainment had higher prevalence of hypertension than those with higher education, but the finding was mixed for men. The gap in hypertension control between urban and rural areas persisted, despite larger improvements in diagnosis and control in rural than in urban areas. CONCLUSIONS: The prevalence of hypertension in China has slightly declined since 2010, but treatment and control remain low. The findings highlight the need for improving detection and treatment of hypertension through the strengthening of primary care in China, especially in rural areas.


Assuntos
Hipertensão , Adulto , Masculino , Humanos , Feminino , Prevalência , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/diagnóstico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , China/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Conscientização
5.
J Colloid Interface Sci ; 636: 450-458, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36641820

RESUMO

Bifunctional oxygen electrocatalysts that hold outstanding activity and stability are highly crucial for the development of efficient rechargeable Zn-air batteries. Herein, cobalt-molybdenum-based bimetallic carbide and cobalt nanoparticles embedded N-doped carbon nanocages are synthesized via the pyrolysis of functionalized zeolitic imidazolate framework precursor originated from zeolitic imidazolate framework sequentially coated with polydopamine and phosphomolybdic acid. Furthermore, we revealed the composition-performance relationship based on the exploration of bifunctional performance on the pyrolysis products. More importantly, the synergy of multiple active sites with hollow structure gives the prepared catalyst a low overpotential (284 mV) for oxygen evolution reaction and high half-wave potential (0.865 V) for oxygen reduction reaction, besides an excellent bifunctional durability. Furthermore, the prepared catalyst as a cathode electrocatalyst grants the assembled rechargeable Zn-air batteries a high open-circuit voltage, power density, specific capacity, and remarkable charge-discharge cycle stability. This work provides a strategy for the integration and active-adjustment of bifunctional catalyst and its potential applications in water splitting and other catalytic reactions.

6.
J Matern Fetal Neonatal Med ; 36(1): 2157257, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36521849

RESUMO

OBJECTIVES: Congenital hemangiomas are rare benign vascular tumors but can lead to serious adverse pregnancy outcomes. Its prenatal diagnosis is a challenge. We explored the clinical applications of prenatal ultrasound for evaluating fetal cutaneous hemangioma and associated complications. METHODS: A retrospective observational study was conducted comprising a population of pregnant women with fetal cutaneous hemangioma, the latter diagnosed by prenatal ultrasound, between January 2016 and December 2020. The clinical characteristics, sonographic images, complications, and pregnancy outcomes were documented and analyzed. RESULTS: We identified 20 cases of fetal cutaneous hemangioma diagnosed by prenatal ultrasound and confirmed by postpartum examinations. Most hemangiomas were in the head and neck (55%), with either solid isoechoicity (25%) or solid mildly hyperechoic (25%), and well-circumscribed (80%) mass. Eight (40%) fetuses experienced complications, which often occurred in fetuses with large hemangiomas (67% with maximum diameter ≥5 cm; 100% with a volume ≥40 cm3). The most common complications were cardiac-related (88%), including elevated cardiothoracic area ratio, atrioventricular valve regurgitation, and fetal hydrops. A large hemangioma was usually associated with advanced gestational age and a fast hemangioma growth rate. In five (25%) cases, the pregnancy was terminated; these involved hemangioma of the head or neck. One newborn developed Kasabach-Merritt phenomenon, pulmonary hemorrhage and respiratory distress, and died 3 days after birth. Among the 14 (70%) fetuses that survived birth, all hemangiomas disappeared or regressed after treatments with propranolol, interventional surgery, or observed routinely. CONCLUSIONS: Prenatal ultrasound examination can accurately diagnose fetal cutaneous hemangioma and related complications to facilitate appropriate management during the pregnancy. RATIONALE: Prenatal diagnosis of cutaneous hemangiomas is a clinical challenge. Prenatal ultrasound examination could be a method to accurately diagnose and monitor these hemangiomas.


Assuntos
Hemangioma , Recém-Nascido , Gravidez , Humanos , Feminino , Hemangioma/diagnóstico por imagem , Hemangioma/patologia , Cuidado Pré-Natal , Diagnóstico Pré-Natal/métodos , Feto/patologia , Ultrassonografia Pré-Natal/métodos
7.
J Am Chem Soc ; 145(1): 12-16, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36544241

RESUMO

Herein we report two reduced rare-earth metal-based superconductors, La26Ge19M5O5 (M = Ag, Cu), that feature an unprecedented [La18O5] cluster composed of five oxygen-centered [La6O] octahedra condensed through shared faces and capped with [Ge4] butterfly rings. The structure, determined by single-crystal X-ray diffraction, crystallizes in a tetragonal space group (P4/nmm), with a = 15.508(2) Å and c = 11.238(2) Å. Resistivity and magnetic susceptibility measurements show onsets of superconductivity at Tc = 5.4 and 6.4 K for the Ag and Cu compounds, respectively. Applying high pressures, up to 1.3 GPa, results in increased superconducting transition temperatures (Tc = 6.8 K for Ag and 7.2 K for Cu compounds), with no sign of saturation.

8.
Lancet Public Health ; 7(12): e1027-e1040, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36462514

RESUMO

BACKGROUND: Temporal trends and geographical variations in cardiovascular disease attributable to high systolic blood pressure in China are not yet fully understood. The aim of this study was to quantify the cardiovascular disease burden attributable to high systolic blood pressure at national and provincial levels in China. METHODS: In this population-based study, we evaluated systolic blood pressure and estimated the number of deaths, age-standardised mortality rates, and years of life lost (YLLs) due to cardiovascular disease and its subcategories (including ischaemic heart disease, ischaemic stroke, haemorrhagic stroke, and other cardiovascular diseases) attributable to high systolic blood pressure, at the national level and by 31 provincial levels, in China, from 2005 to 2018. We pooled blood pressure data of 1·30 million adults aged 25 years and older from the China Chronic Disease and Risk Factor Surveillance project, the China National Nutrition Survey, and the China Hypertension Survey. We applied a temporal-spatial Bayesian hierarchical model to estimate age-specific, sex-specific, province-specific, and year-specific average systolic blood pressure, and a comparative risk assessment method to compute the cardiovascular disease burden attributable to high systolic blood pressure by age, sex, year, and province. FINDINGS: Nationally, age-standardised mean systolic blood pressure was 132·5 mm Hg (95% uncertainty interval [UI] 124·6-140·3) in men and 129·4 mm Hg (121·7 to 137·2) in women. 2·67 million (95% UI 2·61 to 2·72) cardiovascular disease deaths in China were attributable to high systolic blood pressure, including 1·12 million deaths (1·07 to 1·16) due to ischaemic heart disease, 0·63 million deaths (0·60 to 0·65) due to ischaemic stroke, 0·58 million deaths (0·57 to 0·60) due to haemorrhagic stroke, and 0·34 million deaths (0·32 to 0·36) due to other cardiovascular disease. The age-standardised cardiovascular disease mortality rates associated with high systolic blood pressure were 268·99 per 100 000 people (95% UI 264·11 to 273·51) in 2005 and 220·84 per 100 000 people (216·30 to 224·76) in 2018, a percentage change of -17·90%; the rate changed by an average of -1·50% (95% UI -1·55% to -1·45%) per year from 2005 to 2018 nationally. YLL rates for total cardiovascular disease caused by high systolic blood pressure varied substantially across provinces, ranging from 3078·33 (95% UI 2807·40 to 3303·57) per 100 000 people in Beijing to 7189·98 (95% UI 6817·18 to 7507·99) per 100 000 people in Heilongjiang in 2018. Age-standardised YLL rates for ischaemic heart disease and ischaemic stroke attributable to high systolic blood pressure were particularly high in northeastern provinces, including Heilongjiang, Liaoning, and Jilin. INTERPRETATION: The deaths and YLLs for cardiovascular disease attributable to high systolic blood pressure in China increased between 2005 and 2018, and age-standardised cardiovascular disease mortality rates decreased in the same timeframe. Our findings could help policy makers in promoting blood pressure control measures and implementing effective and locally adapted preventive interventions to reduce the prevalence of high systolic blood pressure and reduce the burden of systolic blood pressure-related cardiovascular disease in China. FUNDING: China National Key Research and Development Program, China National Science & Technology Pillar Program, and National Health Commission of the People's Republic of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Isquemia Encefálica , Doenças Cardiovasculares , Acidente Vascular Cerebral Hemorrágico , AVC Isquêmico , Isquemia Miocárdica , Acidente Vascular Cerebral , Adulto , Masculino , Feminino , Humanos , Doenças Cardiovasculares/epidemiologia , Pressão Sanguínea , Teorema de Bayes , Pesquisa , Isquemia Miocárdica/epidemiologia , China/epidemiologia
9.
Biomater Adv ; 144: 213168, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36455499

RESUMO

Intratumoral hypoxia, which is in favour of cancer cell proliferation, invasion and metastasis, also inhibits photodynamic therapy (PDT) badly. Herein, second near-infrared (NIR-II) photocatalytic O2 production is established to realize hypoxia relief. MoS2/Co3S4@PEG (MSCs@PEG) nanoflowers (100-150 nm) are prepared via a two-step hydrothermal method. These samples possess high NIR-II harvest and photothermal conversion (39.8 %, 1064 nm) ability. That not only reveals photothermal therapy (PTT) but also lifts the thermal energy of nanomaterials to replenish extra energy, making sure the co-excitation of MoS2 (1.14 eV) and Co3S4 (1.40 eV) by low-energy NIR-II (1064 nm, 1.16 eV) laser. The investigation of band structure further displays the Z-Scheme characterization of MSCs heterostructure. These photo-excited holes/electrons hold great redox ability to form O2 (water splitting) and reactive oxygen species (ROS), simultaneously. In addition, MSC-2@PEG can be served to mimic catalase, peroxidase, and glutathione (GSH) oxidase to further boost oxidative stress. It is noted that heterostructure discovers the greater nanozyme activity, attributing to the lower resistance for charge transfer. Moreover, MSC-2@PEG displays a novel biodegradation ability to induce the elimination via urine and faeces within 14 days. Given the superparamagnetic and photothermal effect, the nanocomposite can be used as magnetic resonance and photothermal imaging (MRI and PTI) contrast. Associated with dual-imaging, intracellular O2 supplementation, and synergistic chemotherapy (CDT)/PTT/PDT, MSC-2@PEG possess great tumor inhibition that also efficiently motivates immune response for anticancer.

10.
BMC Med ; 20(1): 467, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36451190

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in China. No previous study has reported CVD mortality at county-level, and little was known about the nonmedical ecological factors of CVD mortality at such small scale in mainland China. Understanding the spatiotemporal variations of CVD mortality and examining its nonmedical ecological factors would be of great importance to tailor local public health policies. METHODS: By using national mortality registration data in China, this study used hierarchical spatiotemporal Bayesian model to demonstrate spatiotemporal distribution of CVD mortality in 2844 counties during 2006 to 2020 and investigate how nonmedical ecological determinants have affected CVD mortality inequities from the spatial perspectives. RESULTS: During 2006-2020, the age-standardized mortality rate (ASMR) of CVD decreased from 284.77 per 100,000 in 2006 to 241.34 per 100,000 in 2020. Among 2844 counties, 1144 (40.22%) were hot spots counties with a higher CVD mortality risk compared to the national average and located mostly in northeast, north central, and westernmost regions; on the contrary, 1551 (54.53%) were cold spots counties and located mostly in south and southeast coastal counties. CVD mortality risk decreased from 2006 to 2020 was larger in counties where CVD mortality rate had been higher in 2006 in most of the counties, vice versa. Nationwide, nighttime light intensity (NTL) was the major influencing factor of CVD mortality, a higher NTL appeared to be negatively associated with a lower CVD mortality, with one unit increase in NTL, and the CVD mortality risk will decrease 11% (relative risk of NTL was estimated as 0.89 with 95% confidence interval of 0.83-0.94). CONCLUSIONS: Substantial between-county discrepancies of CVD mortality distribution were observed during past 15 years in mainland China. Nonmedical ecological determinants were estimated to significantly explain the overall and local spatiotemporal patterns of this CVD mortality risk. Targeted considerations are needed to integrate primary care with clinical care through intensifying further strategies to narrow unequally distribution of CVD mortality at local scale. The approach to county-level analysis with small area models has the potential to provide novel insights into Chinese disease-specific mortality burden.


Assuntos
Doenças Cardiovasculares , Humanos , Teorema de Bayes , Sistema de Registros , China/epidemiologia
11.
NPJ Biofilms Microbiomes ; 8(1): 97, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526637

RESUMO

The ubiquitous Wsp (wrinkly spreader phenotype) chemosensory system and DSF (diffusible signal factor) quorum sensing are two important chemically associated signaling systems that mediate bacterial communications between the host and environment. Although these two systems individually control biofilm formation in pathogenic bacteria via the ubiquitous second messenger c-di-GMP, their crosstalk mechanisms remain elusive. Here we present a scenario from the plant-beneficial and antifungal bacterium Lysobacter enzymogenes OH11, where biofilm formation favors the colonization of this bacterium in fungal hyphae. We found that the Wsp system regulated biofilm formation via WspR-mediated c-di-GMP signaling, whereas DSF system did not depend on the enzymatic activity of RpfG to regulate biofilm formation. We further found that WspR, a diguanylate cyclase (DGC) responsible for c-di-GMP synthesis, could directly bind to one of the DSF signaling components, RpfG, an active phosphodiesterase (PDE) responsible for c-di-GMP degradation. Thus, the WspR-RpfG complex represents a previously undiscovered molecular linker connecting the Wsp and DSF systems. Mechanistically, RpfG could function as an adaptor protein to bind and inhibit the DGC activity of unphosphorylated WspR independent of its PDE activity. Phosphorylation of WspR impaired its binding affinity to RpfG and also blocked the ability of RpfG to act as an adaptor protein, which enabled the Wsp system to regulate biofilm formation in a c-di-GMP-dependent manner by dynamically integrating the DSF system. Our findings demonstrated a previously uncharacterized mechanism of crosstalk between Wsp and DSF systems in plant-beneficial and antifungal bacteria.


Assuntos
Lysobacter , Percepção de Quorum , Antifúngicos , Biofilmes
12.
Nurs Open ; 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36490363

RESUMO

AIM: To explore the mediating role of self-esteem in the relationship between perceived organizational support and professional benefits among Registered Nurses in China. DESIGN: This was an online, cross-sectional study involving 1850 nurses from six hospitals in China. METHODS: Data were collected using a 4-part questionnaire including a sociodemographic questionnaire, perceived organizational support scale, self-esteem scale and brief nurses' perceived professional benefits questionnaire from September to November 2021. Structural equation modelling (SEM) was used to explore the associations among them. RESULTS: Perceived organizational support was positively correlated with self-esteem and perceived professional benefits among nurses, whereas self-esteem positively predicted nurses' perceived professional benefits . Self-esteem partially mediated the relationship between the two variables. The ratio of the mediating effect to the total effect was 16.7%.

13.
Gels ; 8(12)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36547321

RESUMO

A stretchable double-network (DN) ionogel composed of a physically crosslinked network of chitosan (CS) and a chemically crosslinked network of polyacrylic acid (PAA) was prepared in an ionic liquid ([EMIM][OAc]) using a one-step polymerization method. In this ionogel (CS/PAA), the CS and the PAA polymer chains served as backbones, which constructed an interpenetrating DN structure via numerous hydrogen bonds formed through the hydroxyl, amino and carboxyl groups on the polymer chains. The DN structure improves the mechanical properties of the ionogel. Therefore, the CS/PAA DN ionogel exhibited outstanding mechanical performance in many ways: tensile strength up to 2.04 MPa, strain range up to 1046% and the value of toughness up to 8.52 MJ/m3. The ionogel also showed good self-recovery performance, fatigue resistance, ability to work in a broad temperature range (-20~80 °C) and adhesion properties. As a flexible sensor, the CS/PAA DN ionogel showed high strain sensitivity (gauge factor = 6.235). It can sensitively detect human motion (such as joint-bending, vocal fold vibration, walking gait and other human body motions), revealing the practical application potential of flexible electronic devices.

14.
Front Plant Sci ; 13: 1044415, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36561460

RESUMO

Flax is a dual-purpose crop that is important for oil and fiber production. The growth habit is one of the crucial targets of selection during flax domestication. Wild hybridization between cultivated flax and wild flax can produce superior germplasms for flax breeding and facilitate the study of the genetic mechanism underlying agronomically important traits. In this study, we used pale flax, Linum grandiflorum, and L. perenne to pollinate Longya-10. Only pale flax interspecific hybrids were obtained, and the trait analysis of the F1 and F2 generations showed that the traits analyzed in this study exhibited disparate genetic characteristics. In the F1 generation, only one trait, i.e., the number of capsules per plant (140) showed significant heterosis, while the characteristics of other traits were closely associated with those of the parents or a decline in hybrid phenotypes. The traits of the F2 generation were widely separated, and the variation coefficient ranged from 9.96% to 146.15%. The quantitative trait locus underlying growth habit was preliminarily found to be situated on chromosome 2 through Bulked-segregant analysis sequencing. Then linkage mapping analysis was performed to fine-map GH2.1 to a 23.5-kb interval containing 4 genes. Among them, L.us.o.m.scaffold22.109 and L.us.o.m.scaffold22.112 contained nonsynonymous SNPs with Δindex=1. Combined with the qRT-PCR results, the two genes might be possible candidate genes for GH2.1. This study will contribute to the development of important germplasms for flax breeding, which would facilitate the elucidation of the genetic mechanisms regulating the growth habit and development of an ideal architecture for the flax plant.

15.
Nat Commun ; 13(1): 7533, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36476645

RESUMO

Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Ecossistema , Microambiente Tumoral/genética , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de Aminoácidos
16.
Front Oncol ; 12: 1036543, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531060

RESUMO

Lactate and tumor cell-derived extracellular vesicles (TEVs) both contribute to tumor progression. However, it is still unclear whether lactate can accelerate tumor development by directly promoting TEV production. Here, we show that lactate decreases intracellular cAMP levels and subsequent PKA activation via GPR81, which inhibits the PKA-induced ubiquitination of HIF-1α that causes degradation. Then, the HIF-1α-mediated transcription of Rab27a is enhanced, leading to increased TEV release. In this way, lactate promotes lung metastasis by murine melanoma. In addition, we show that serum lactate levels are positively correlated with serum EV levels and Rab27a and HIF-1α protein levels in the tumor tissues of lung cancer patients. Thus, our results reveal a novel mechanism underlying lactate-mediated tumor progression induced by TEVs and provide new strategies for tumor therapy.

17.
Genome Biol ; 23(1): 255, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36514120

RESUMO

BACKGROUND: The cancer genome is commonly altered with thousands of structural rearrangements including insertions, deletions, translocation, inversions, duplications, and copy number variations. Thus, structural variant (SV) characterization plays a paramount role in cancer target identification, oncology diagnostics, and personalized medicine. As part of the SEQC2 Consortium effort, the present study established and evaluated a consensus SV call set using a breast cancer reference cell line and matched normal control derived from the same donor, which were used in our companion benchmarking studies as reference samples. RESULTS: We systematically investigated somatic SVs in the reference cancer cell line by comparing to a matched normal cell line using multiple NGS platforms including Illumina short-read, 10X Genomics linked reads, PacBio long reads, Oxford Nanopore long reads, and high-throughput chromosome conformation capture (Hi-C). We established a consensus SV call set of a total of 1788 SVs including 717 deletions, 230 duplications, 551 insertions, 133 inversions, 146 translocations, and 11 breakends for the reference cancer cell line. To independently evaluate and cross-validate the accuracy of our consensus SV call set, we used orthogonal methods including PCR-based validation, Affymetrix arrays, Bionano optical mapping, and identification of fusion genes detected from RNA-seq. We evaluated the strengths and weaknesses of each NGS technology for SV determination, and our findings provide an actionable guide to improve cancer genome SV detection sensitivity and accuracy. CONCLUSIONS: A high-confidence consensus SV call set was established for the reference cancer cell line. A large subset of the variants identified was validated by multiple orthogonal methods.


Assuntos
Variações do Número de Cópias de DNA , Neoplasias , Humanos , Análise de Sequência de DNA/métodos , Variação Estrutural do Genoma , Tecnologia , Linhagem Celular , Sequenciamento de Nucleotídeos em Larga Escala , Genoma Humano , Neoplasias/genética
18.
Angew Chem Int Ed Engl ; : e202216189, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36567260

RESUMO

Electrolyte design has become ever more important to enhance the performance of lithium-ion batteries (LIBs). However, the flammability issue and high reactivity of the conventional electrolytes remain a major problem, especially when the LIBs are operated at high voltage and extreme temperatures. Herein, we design a novel non-flammable fluorinated ester electrolyte that enables high cycling stability in wide-temperature variations (e.g., -50 °C-60 °C) and superior power capability (fast charge rates up to 5.0 C) for the graphite||LiNi0.8 Co0.1 Mn0.1 O2 (NCM811) battery at high voltage (i.e., >4.3 V vs. Li/Li+ ). Moreover, this work sheds new light on the dynamic evolution and interaction among the Li+ , solvent, and anion at the molecular level. By elucidating the fundamental relationship between the Li+ solvation structure and electrochemical performance, we can facilitate the development of high-safety and high-energy-density batteries operating in harsh conditions.

19.
J Chem Phys ; 157(18): 184501, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36379776

RESUMO

We investigated the stretched dynamics of the structural relaxation in molecular glass formers by using dielectric and thermal (or enthalpic) relaxations. The dielectric stretching exponents ßdie are determined by the Havriliak-Negami function, while the enthalpic ßTNMH is quantified by using the Tool-Narayanaswamy-Moynihan-Hodge formalism. We found ßTNMH is anticorrelated with the degree of freedom, a molecule addressed by the concept of beads. Referring to the reported relation of ßdie to the dipole moment µ, we proposed a combined parameter of µ2*beads, which can rationalize the difference in stretching exponents obtained by dielectric and enthalpic relaxations. For the majority of glass-forming molecules, the difference is trivial, but for those molecules with both unusually high dipole moments and flexibility, a large difference is obvious. The interplay of the degree of freedom and dielectric dipole-dipole interaction in molecular dynamics is addressed.

20.
Mol Neurobiol ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36394710

RESUMO

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (αSyn) into Lewy bodies. In addition to motor impairment, PD commonly presents with cognitive impairment, a non-motor symptom with poor outcome. Cortical αSyn pathology correlates closely with vascular risk factors and vascular degeneration in cognitive impairment. However, how the brain microvasculature regulates αSyn pathology and neurodegeneration remains unclear. Here, we constructed a rapidly progressive PD model by injecting alpha-synuclein preformed fibrils (αSyn PFFs) into the cerebral cortex and striatum. Brain capillaries in mice with cognitive impairment showed a reduction in diameter and length after 6 months, along with string vessel formation. The intracellular domain of low-density lipoprotein receptor-related protein-1 (LRP1-ICD) was upregulated in brain microvascular endothelium. LRP1-ICD promoted αSyn PFF uptake and exacerbated endothelial damage and neuronal apoptosis. Then, we overexpressed LRP1-ICD in brain capillaries using an adeno-associated virus carrying an endothelial-specific promoter. Endothelial LRP1-ICD worsened αSyn PFF-induced vascular damage, αSyn pathology, or neuron death in the cortex and hippocampus, resulting in severe motor and cognitive impairment. LRP1-ICD increased the synthesis of poly(adenosine 5'-diphosphate-ribose) (PAR) in the presence of αSyn PFFs. Inhibition of PAR polymerase 1 (PARP1) prevented vascular-derived injury, as did loss of PARP1 in the endothelium, which was further implicated in endothelial cell proliferation and inflammation. Together, we demonstrate a novel vascular mechanism of cognitive impairment in PD. These findings support a role for endothelial LRP1-ICD/PARP1 in αSyn pathology and neurodegeneration, and provide evidence for vascular protection strategies in PD therapy.

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