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Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogen Phytophthora contain tandem repeats of the "(L)WY" motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiple Phytophthora effectors, which efficiently recruits the serine/threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire.
Assuntos
Monoéster Fosfórico Hidrolases , Phytophthora , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas/metabolismo , Phytophthora/química , Phytophthora/metabolismo , Plantas/metabolismo , Processamento de Proteína Pós-Traducional , Proteína Fosfatase 2/metabolismo , Doenças das PlantasRESUMO
In early mammalian embryos, it remains unclear how the first cell fate bias is initially triggered and amplified toward cell fate segregation. Here, we report that a long noncoding RNA, LincGET, is transiently and asymmetrically expressed in the nucleus of two- to four-cell mouse embryos. Overexpression of LincGET in one of the two-cell blastomeres biases its progeny predominantly toward the inner cell mass (ICM) fate. Mechanistically, LincGET physically binds to CARM1 and promotes the nuclear localization of CARM1, which can further increase the level of H3 methylation at Arginine 26 (H3R26me), activate ICM-specific gene expression, upregulate transposons, and increase global chromatin accessibility. Simultaneous overexpression of LincGET and depletion of Carm1 no longer biased embryonic fate, indicating that the effect of LincGET in directing ICM lineage depends on CARM1. Thus, our data identify LincGET as one of the earliest known lineage regulators to bias cell fate in mammalian 2-cell embryos.
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Blastocisto/metabolismo , Blastômeros/metabolismo , Linhagem da Célula/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , RNA Longo não Codificante/biossíntese , Animais , Blastocisto/citologia , Blastômeros/citologia , Feminino , Histonas/metabolismo , Metilação , Camundongos , Camundongos Endogâmicos ICR , Proteína-Arginina N-Metiltransferases/biossíntese , Proteína-Arginina N-Metiltransferases/genética , RNA Longo não Codificante/genéticaRESUMO
Mammalian interspecific hybrids provide unique advantages for mechanistic studies of speciation, gene expression regulation, and X chromosome inactivation (XCI) but are constrained by their limited natural resources. Previous artificially generated mammalian interspecific hybrid cells are usually tetraploids with unstable genomes and limited developmental abilities. Here, we report the generation of mouse-rat allodiploid embryonic stem cells (AdESCs) by fusing haploid ESCs of the two species. The AdESCs have a stable allodiploid genome and are capable of differentiating into all three germ layers and early-stage germ cells. Both the mouse and rat alleles have comparable contributions to the expression of most genes. We have proven AdESCs as a powerful tool to study the mechanisms regulating X chromosome inactivation and to identify X inactivation-escaping genes, as well as to efficiently identify genes regulating phenotypic differences between species. A similar method could be used to create hybrid AdESCs of other distantly related species.
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Fusão Celular/métodos , Quimera/genética , Células-Tronco Embrionárias/citologia , Células Híbridas , Camundongos , Ratos , Animais , Diferenciação Celular , Corpos Embrioides , Células-Tronco Embrionárias/metabolismo , Feminino , Haploidia , Masculino , Camundongos Endogâmicos , Ratos Endogâmicos F344 , Especificidade da Espécie , Inativação do Cromossomo XRESUMO
Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.
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Lesão Pulmonar Aguda , Lipopolissacarídeos , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/farmacologia , ATPase Trocadora de Sódio-Potássio/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Arabidopsis Col-0 RPP2A and RPP2B confer recognition of Arabidopsis downy mildew (Hyaloperonospora arabidopsidis [Hpa]) isolate Cala2, but the identity of the recognized ATR2Cala2 effector was unknown. To reveal ATR2Cala2, an F2 population was generated from a cross between Hpa-Cala2 and Hpa-Noks1. We identified ATR2Cala2 as a non-canonical RxLR-type effector that carries a signal peptide, a dEER motif, and WY domains but no RxLR motif. Recognition of ATR2Cala2 and its effector function were verified by biolistic bombardment, ectopic expression and Hpa infection. ATR2Cala2 is recognized in accession Col-0 but not in Ler-0 in which RPP2A and RPP2B are absent. In ATR2Emoy2 and ATR2Noks1 alleles, a frameshift results in an early stop codon. RPP2A and RPP2B are essential for the recognition of ATR2Cala2. Stable and transient expression of ATR2Cala2 under 35S promoter in Arabidopsis and Nicotiana benthamiana enhances disease susceptibility. Two additional Col-0 TIR-NLR (TNL) genes (RPP2C and RPP2D) adjacent to RPP2A and RPP2B are quantitatively required for full resistance to Hpa-Cala2. We compared RPP2 haplotypes in multiple Arabidopsis accessions and showed that all four genes are present in all ATR2Cala2-recognizing accessions.
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Proteínas de Arabidopsis , Arabidopsis , Oomicetos , Doenças das Plantas , Arabidopsis/genética , Arabidopsis/microbiologia , Arabidopsis/imunologia , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Oomicetos/patogenicidade , Proteínas NLR/metabolismo , Proteínas NLR/genética , Nicotiana/genética , Nicotiana/microbiologia , Nicotiana/imunologia , Sequência de Aminoácidos , AlelosRESUMO
Accumulating evidence has demonstrated that high-risk human papillomaviruses (HR-HPVs) are involved in the etiology of a subset of oropharyngeal squamous cell carcinoma (OPSCC). In this regard, the International Agency for Research on Cancer (IARC) has recommended direct molecular HPV testing. So far, there is no agreement on the most appropriate method for HPV detection on OPSCC formalin-fixed paraffin-embedded (FFPE) materials. In this study, we aimed to evaluate the performance of the high-sensitive SureX HPV assay in OPSCC FFPE tissues compared with LiPA-25 and p16ink4a immunostaining. A retrospective series of FFPE primary OPSCC cases were diagnosed between 2008 and 2019 and provided by the Henan Cancer Hospital, China. The level of agreement of two assays was determined using Cohen's Kappa (κ) statistics. A total of 230 FFPE OPSCC samples from tumor resections (n = 160) and diagnostic biopsies (n = 70) were detected. Sixty-six (28.7%) and 70 (30.4%) samples were identified as HPV-DNA-positive by LiPA-25 and SureX, respectively, of which HPV16 was largely the most common type (95.5% vs 94.3%). We found a perfect concordance between LiPA-25 and SureX for HPV-DNA status (κ = 0.906, 95% CI: 0.875-0.937) and for HPV16 (κ = 0.925, 95% CI: 0.897-0.953). In addition, SureX and p16ink4a immunostaining had a perfect concordance (κ = 0.917, 95% CI: 0.888-0.946). Moreover, the HPV-driven fraction, based on double positivity for HPV-DNA and p16ink4a, was similar between SureX (63 of 230, 27.4%) and LiPA-25 (60 of 230, 26.1%). Similar results were found in samples from resections and biopsies. SureX and LiPA-25 are comparable. SureX could be used for routine HPV-DNA detection and genotyping on archival OPSCC FFPE tissues.
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DNA Viral , Genótipo , Proteínas Oncogênicas Virais , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Inclusão em Parafina , Humanos , Neoplasias Orofaríngeas/virologia , Estudos Retrospectivos , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/diagnóstico , Pessoa de Meia-Idade , Masculino , Feminino , Proteínas Oncogênicas Virais/genética , Idoso , DNA Viral/genética , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/classificação , Reação em Cadeia da Polimerase/métodos , Técnicas de Genotipagem/métodos , China , Adulto , Formaldeído , Papillomavirus HumanoRESUMO
BACKGROUND: The Department of Veterans Affairs (VA) offers a 1-year Post-Baccalaureate-Registered Nurse Residency (PB-RNR) Program. The impact of the PB-RNR program on local RN recruitment was unknown. OBJECTIVES: We aimed to evaluate the effect of the size of the PB-RNR program at a VA facility on its time-to-fill RN vacancies. PROJECT DESIGN: We used an instrumental variable approach with a 2-stage residual inclusion specification. SUBJECTS: We included RN filled vacancies in the VA that were posted nationwide between 2020 and 2021. MEASURES: Our independent variable was the facility-year level number of PB-RNR program allocations. The 3 binary outcomes were whether the RN vacancy was filled within 90, 60, or 30 days. RESULTS: An increase of one training allocation was significantly associated with a 5.60 percentage point (PP) (95% CI: 2.74-8.46) higher likelihood of filling a vacancy within 90 days, 7.34 PP (95% CI: 4.66-10.03) higher likelihood of filling a vacancy within 60 days, and 5.32 PP (95% CI: 3.18-7.46) higher likelihood of filling a vacancy within 30 days. The impact was significant in both 2020 and 2021 positions, and in facilities located in areas with lower social deprivation scores, higher-quality public schools, or with either no or partial primary care physician shortages. CONCLUSIONS: We found favorable impacts of the size of the PB-RNR program at a VA facility on filling RN vacancies.
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United States Department of Veterans Affairs , Humanos , Estados Unidos , United States Department of Veterans Affairs/organização & administração , Fatores de Tempo , Seleção de Pessoal , Internato e Residência/organização & administraçãoRESUMO
BACKGROUND: The Department of Veterans Affairs (VA) provides the largest Graduate Medical Education (GME) training platform for health professionals in the United States. Studies on the impact of VA GME programs on physician recruitment were lacking. OBJECTIVES: To examine the impact of the size of residency training programs at a VA facility on the facility's time-to-fill physician vacancies, and whether the impact differs by the socioeconomic deprivation and public school quality of the geographic area. PROJECT DESIGN: We constructed an instrumental variable for training program size by interacting the facility clinicians share with the total training allocation nationally. SUBJECTS: Our evaluation used national data on filled physician vacancies in the VA that were posted between 2020 and 2021. MEASURES: The outcome evaluated was time-to-fill physician vacancies. Our explanatory variable was the facility-year level number of physician residency slots. RESULTS: For positions posted in 2020, an increase of one training slot was significantly associated with a decrease of 1.33 days to fill physician vacancies (95% CI, 0.38-2.28) in facilities in less deprived areas, a decrease of 1.50 days (95% CI, 0.75-2.25) in facilities with better public schools, a decrease of 3.30 days (95% CI, 0.85-5.76) in facilities in both less deprived areas and better public schools. We found similar results for positions posted in 2020 and 2021 when limiting time-to-fill to <500 days. CONCLUSIONS: We found that increasing the size of the residency program at a VA facility could decrease the facility's time-to-fill vacant physician positions in places with less socioeconomic deprivation or better public schools.
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Internato e Residência , Médicos , Humanos , Estados Unidos , Saúde dos Veteranos , United States Department of Veterans Affairs , Educação de Pós-Graduação em MedicinaRESUMO
We report a giant hysteretic spin Seebeck effect (SSE) anomaly with a sign reversal at magnetic fields much stronger than the coercive field in a (001)-oriented Tb_{3}Fe_{5}O_{12} film. The high-field SSE enhancement reaches 4200% at approximately 105 K over its weak-field value and presents a nonmonotonic dependence on temperature. The unexpected high-field hysteresis of SSE is found to be associated with a magnetic transition of double-umbrella spin texture in TbIG. Nearly parallel dispersion curves of magnons and acoustic phonons around this neoteric transition are supported by theoretical calculations, leading to a high density of field-tuned magnon polarons and consequently an extraordinarily large SSE. Our study provides insight into the evolution of magnon dispersions of double-umbrella TbIG and could potentially boost the efficiency of magnon-polarons SSE devices.
RESUMO
Heterocyclic trifluoromethylation is efficiently initiated through a photochemical reaction utilizing an electron donor-acceptor (EDA) complex, proceeding smoothly without the use of photocatalysts, transition-metal catalysts, or additional oxidants. This method has been optimized through extensive experimentation, demonstrating its versatility and efficacy across various substrates, including quinoxalinones, coumarins, and indolones. Notably, this approach enables the practical synthesis of trifluoromethylated quinoxalinones on a gram scale. Mechanistic investigations that incorporate radical trapping and ultraviolet/visible spectroscopy, confirmed the formation of the an EDA complex and elucidated the reaction pathways. This study highlights the crucial role of EDA photoactivation in trifluoromethylation, significantly expanding the application scope of EDA complexes in chemical synthesis.
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BACKGROUND: The assessment of human papillomavirus (HPV) genotype distribution in terms of age and cervical lesions could contribute to the adoption of more targeted preventive approaches to specific populations against cervical cancer. The current study was conducted in Ordos City, China, with the aim of analyzing the HPV genotypes prevalence and infection patterns within a hospital-based population. METHODS: The analysis included a total of 26,692 women aged 25-64 who underwent cervical cancer screening between January 1st, 2019, and June 30th, 2022, in Ordos City. These women had valid results for both the polymerase chain reaction (PCR)-reverse dot blot (RDB) HPV test and the liquid-based cytology (thinprep cytologic test/TCT). Data were extracted from the database of KingMed Diagnostics laboratories. The prevalence of HPV genotypes within different age groups and cytology diagnoses were calculated. RESULTS: Among 26,692 women, 7136 (26.73%) women were HPV positive, 5696 (21.34%) women were high-risk HPV (HR-HPV) positive, and 2102 (7.88%) women had multiple HPV infections. The most frequently detected HPV genotypes were HPV16 (4.72%) and HPV52 (4.15%), ranking as the first and second most prevalent genotypes, respectively. The prevalence of HR-HPV increased with age groups and severity of cervical lesions. Notably, the positive rate of HR-HPV among women aged 35-64 years showed a decreasing trend over the respective years, ranging from 26.00 to 19.70% (Ptrend < 0.001). CONCLUSION: In conclusion, the epidemiology of HPV genotypes partly reflects the effectiveness of regional cervical cancer prevention and control efforts in the past. These findings can inform future initiatives concerning HPV vaccination and screening in the region.
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Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Masculino , Papillomavirus Humano , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Detecção Precoce de Câncer , Prevalência , China/epidemiologiaRESUMO
BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.
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Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Aldosterona , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Hidrocortisona , Mutação , Complicações Neoplásicas na Gravidez , Humanos , Feminino , Gravidez , Adulto , Hidrocortisona/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/cirurgia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/patologia , Hiperaldosteronismo/genética , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Adenoma/genética , Adenoma/patologia , Adenoma/metabolismoRESUMO
BACKGROUND: Cardiovascular disease continues to be a leading cause of mortality worldwide, highlighting the need to explore innovative approaches to improve cardiovascular health outcomes. Time-restricted fasting (TRF) is a dietary intervention that involves limiting the time window for food consumption. It has gained attention for its potential benefits on metabolic health and weight management. This study aims to investigate the impact of TRF on key risk factors, including body weight, glucose metabolism, blood pressure, and lipid profile. METHODS: We conducted a systematic search in five databases (Scopus, Embase, PubMed, Cochrane, and Web of Science) for relevant studies up to January 2023. After applying inclusion criteria, 12 studies were eligible for analysis. Quality assessment was conducted using the ROB-2.0 tool and ROBINS-I. Risk of bias was mapped using Revman 5.3, and data analysis included Hartung-Knapp adjustment using R 4.2.2. RESULTS: The group that underwent the TRF intervention exhibited a significant decrease in body weight (SMD: -0.22; 95%CI: -0.41, -0.04; P < 0.05) and fat mass (SMD: -0.19; 95%CI: -0.36, -0.02; P < 0.05), while maintaining lean mass (SMD: -0.09; 95%CI: -0.08, 0.26; P > 0.05). CONCLUSION: TRF has shown potential as a treatment strategy for reducing total body weight by targeting adipose tissue, with potential improvements in cardiometabolic function.
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Glicemia , Doenças Cardiovasculares , Jejum , Fatores de Risco de Doenças Cardíacas , Humanos , Jejum/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/diagnóstico , Fatores de Tempo , Masculino , Feminino , Medição de Risco , Glicemia/metabolismo , Resultado do Tratamento , Pessoa de Meia-Idade , Adulto , Pressão Sanguínea , Lipídeos/sangue , Idoso , Redução de Peso , Biomarcadores/sangue , Fatores de Proteção , Comportamento de Redução do Risco , Fatores de RiscoRESUMO
KEY MESSAGE: This study identified 16 pyridoxal phosphate-dependent decarboxylases in olive at the whole-genome level, conducted analyses on their physicochemical properties, evolutionary relationships and characterized their activity. Group II pyridoxal phosphate-dependent decarboxylases (PLP_deC II) mediate the biosynthesis of characteristic olive metabolites, such as oleuropein and hydroxytyrosol. However, there have been no report on the functional differentiation of this gene family at the whole-genome level. This study conducted an exploration of the family members of PLP_deC II at the whole-genome level, identified 16 PLP_deC II genes, and analyzed their gene structure, physicochemical properties, cis-acting elements, phylogenetic evolution, and gene expression patterns. Prokaryotic expression and enzyme activity assays revealed that OeAAD2 and OeAAD4 could catalyze the decarboxylation reaction of tyrosine and dopa, resulting in the formation of their respective amine compounds, but it did not catalyze phenylalanine and tryptophan. Which is an important step in the synthetic pathway of hydroxytyrosol and oleuropein. This finding established the foundational data at the molecular level for studying the functional aspects of the olive PLP_deC II gene family and provided essential gene information for genetic improvement of olive.
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Regulação da Expressão Gênica de Plantas , Olea , Álcool Feniletílico , Álcool Feniletílico/análogos & derivados , Filogenia , Olea/genética , Olea/metabolismo , Álcool Feniletílico/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genoma de Planta , Glucosídeos Iridoides/metabolismo , Carboxiliases/genética , Carboxiliases/metabolismo , Fosfato de Piridoxal/metabolismo , Iridoides/metabolismo , Genes de PlantasRESUMO
INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations. METHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed. RESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease. CONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.
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Albinismo Ocular , Síndrome de Hermanski-Pudlak , Humanos , Albinismo Ocular/diagnóstico , Albinismo Ocular/genética , Estudos Retrospectivos , Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/genética , Fenótipo , Proteínas/genética , Mutação , Linhagem , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
OBJECTIVES: Perioperative coagulation management in liver transplantation recipients is challenging. Viscoelastic testing with rotational thromboelastography (TEG) can help quantify hemostatic profiles. The current work aimed to investigate whether the etiology of end-stage liver disease, pretransplant disease severity, or pretransplant thrombotic or bleeding complications are associated with specific TEG patterns. DESIGN: Retrospective cohort study. SETTING: Single quaternary care hospital. PARTICIPANTS: A total of 1,078 adult liver transplant patients. INTERVENTIONS: The primary exposure was the etiology of end-stage liver disease classified as either intrinsic or nonintrinsic (eg, biliary obstruction or cardiovascular). Secondary exposures were patients' preoperative Model for End-Stage Liver Disease (MELD) score, Child-Pugh class, presence of major preoperative thrombotic complications, and major bleeding complications. MEASUREMENTS AND MAIN RESULTS: Patients with intrinsic liver disease (84%) showed higher odds of hypocoagulable (odds ratio [OR]: 3.70, 95% confidence interval [CI]: 1.94-7.07, p < 0.0001) and mixed TEG patterns (OR: 4.59, 95% CI: 2.07-10.16, p = 0.0002) compared with those with nonintrinsic disease. Increasing MELD scores correlated with higher odds of hypocoagulable (OR: 1.14, 95% CI: 1.08-1.19, p < 0.0001) and mixed TEG patterns (OR: 1.08, 95% CI: 1.03-1.14, p = 0.0036). Child-Pugh class C was associated with higher odds of hypocoagulable (OR: 8.55, 95% CI: 3.26-22.42, p < 0.0001) and mixed patterns (OR: 12.48, 95% CI: 3.89-40.03, p < 0.0001). Major preoperative thrombotic complications were not associated with specific TEG patterns, although an interaction with liver disease severity was observed. CONCLUSIONS: Liver transplantation candidates with intrinsic liver disease tend to exhibit hypocoagulable TEG patterns, while nonintrinsic disease is associated with hypercoagulability. Increasing end-stage liver disease severity, as evidenced by increasing MELD scores and higher Child-Pugh classification, was also associated with hypocoagulable TEG patterns.
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The Meiren yak is an important genetic resource in Gansu Province, China. In this study, we aimed to explore the evolutionary history and population structure of the genetic resource of Meiren yak and to mine the characteristic genes of Meiren yak. We analysed a total of 93 yaks of eight yak breeds based on whole genome resequencing combined with population genomics and used θπ ratio and Fst method to screen the selected sites in the genome region. The results proved that Meiren yak can be used as a potential genetic resource in Gansu Province. The genes in Meiren yak with positive selection in selection signal analysis were subjected to the Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses, which indicated that the genes were related to the adaptability to high altitude and hypoxic environment. By analysing the genetic variation of Meiren yak at the genome-wide level, this study provided a theoretical basis for genetic improvement of Meiren yak and for the development of high-quality yak resources.
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Genoma , Bovinos/genética , Animais , Genoma/genética , Análise de Sequência de DNA , ChinaRESUMO
The prevalence of cadmium (Cd) contamination has emerged as a significant global concern. Exposure to Cd during pregnancy is associated with adverse pregnancy outcomes, including miscarriage. However, there is currently a lack of comprehensive summaries on Cd-induced miscarriage. Therefore, it is imperative to further strengthen research into in vivo studies, clinical status, pathological mechanisms, and pharmacological interventions for Cd-induced miscarriage. This study systematically presents the current knowledge on animal models and clinical trials investigating Cd exposure-induced miscarriage. The underlying mechanisms involving oxidative stress, inflammation, endocrine disruption, and placental dysfunction caused by Cd-induced miscarriage are also extensively discussed. Additionally, potential drug interventions such as melatonin, vitamin C, and vitamin E are highlighted for their pharmacological role in mitigating adverse pregnancy outcomes induced by Cd.
Assuntos
Aborto Espontâneo , Humanos , Animais , Gravidez , Feminino , Aborto Espontâneo/induzido quimicamente , Cádmio/toxicidade , Placenta , Resultado da Gravidez , VitaminasRESUMO
Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.
Assuntos
Metanálise em Rede , Hepatopatia Gordurosa não Alcoólica , Extratos Vegetais , Ensaios Clínicos Controlados Aleatórios como Assunto , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacologia , Aspartato Aminotransferases/sangue , Alanina Transaminase/sangue , Cynara scolymus/química , LDL-Colesterol/sangue , Folhas de Planta/químicaRESUMO
Sluggish desolvation in extremely cold environments caused by strong Li+-dipole interactions is a key inducement for the capacity decline of a battery. Although the Li+-dipole interaction is reduced by increasing the electrolyte concentration, its high viscosity inevitably limits ion transfer at low temperatures. Herein, Li+-dipole interactions were eliminated to accelerate the migration rate of ions in electrolytes and at the electrode interface via designing Li+-anion nanometric aggregates (LA-nAGGs) in low-concentration electrolytes. Li+ coordinated by TFSI- and FSI- anions instead of a donor solvent promotes the formation of an inorganic-rich interfacial layer and facilitates Li+ transfer. Consequently, the LA-nAGG-type electrolyte demonstrated a high ionic conductivity (0.6 mS cm-1) at -70 °C and a low activation energy of charge transfer (38.24 kJ mol-1), enabling Li||NiFe-Prussian blue derivative cells to deliver â¼83.1% of their room-temperature capacity at -60 °C. This work provides an advanced strategy for the development of low-temperature electrolytes.