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1.
Antimicrob Agents Chemother ; : e0139922, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622240

RESUMO

Linezolid (LZD) was the first oxazolidinone approved for treating drug-resistant tuberculosis. A newly approved regimen combining LZD with bedaquiline (BDQ) and pretomanid (PMD) (BPaL regimen) is the first 6-month oral regimen that is effective against multidrug- and extensively drug-resistant tuberculosis. However, LZD toxicity, primarily due to mitochondrial protein synthesis inhibition, may undermine the efficacy of LZD regimens, and oxazolidinones with higher efficacy and lower toxicity during prolonged administration are needed. OTB-658 is an oxazolidinone anti-TB candidate derived from LZD that could replace LZD in TB treatment. We previously found that OTB-658 had better anti-TB activity and safety than LZD in vitro and in vivo. In the present work, two murine TB models were used to evaluate replacing LZD with OTB-658 in LZD-containing regimens. In the C3HeB/FeJ murine model, replacing 100 mg/kg LZD with 50 mg/kg OTB-658 in the BDQ + PMD backbone significantly reduced lung and spleen CFU counts (P < 0.05), and there were few relapses at 8 weeks of treatment. Replacing 100 mg/kg LZD with 50 or 100 mg/kg OTB-658 in the pyrifazimine (previously called TBI-166) + BDQ backbone did not change the anti-TB efficacy and relapse rate. In BALB/c mice, replacing 100 mg/kg LZD with 100 mg/kg OTB-658 in the TBI-166 + BDQ backbone resulted in no culture-positive lungs at 4 and 8 weeks of treatment, and there were no significant differences in relapses rate between the groups. In conclusion, OTB-658 is a promising clinical candidate that could replace LZD in the BPaL or TBI-166 + BDQ + LZD regimens and should be studied further in clinical trials.

2.
J Adv Res ; 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36639024

RESUMO

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) with obesity seriously threats public health. Our previous studies showed that dark tea had more potential on regulating lipid metabolism than other teas, and theabrownin (TB) was considered to be a main contributor to the bioactivity of dark tea. OBJECTIVES: This in vivo study aims to reveal the effects and molecular mechanisms of TB on NAFLD and obesity, and the role of the gut-liver axis is explored. METHODS: The histopathological examinations, biochemical tests, and nuclear magnetic resonance were applied to evaluate the effects of TB on NAFLD and obesity. The untargeted metabolomics was used to find the key molecule for further exploration of molecular mechanisms. The 16S rRNA gene sequencing was used to assess the changes in gut microbiota. The antibiotic cocktail and fecal microbiota transplant were used to clarify the role of gut microbiota. RESULTS: TB markedly reduced body weight gain (67.01%), body fat rate (62.81%), and hepatic TG level (51.35%) in the preventive experiment. Especially, TB decreased body weight (32.16%), body fat rate (42.56%), and hepatic TG level (42.86%) in the therapeutic experiment. The mechanisms of action could be the improvement of fatty acid oxidation, lipolysis, and oxidative stress via the regulation of serotonin-related signaling pathways. Also, TB increased the abundance of serotonin-related gut microbiota, such as Akkermansia, Bacteroides and Parabacteroides. Antibiotics-induced gut bacterial dysbiosis disrupted the regulation of TB on serotonin-related signaling pathways in liver, whereas the beneficial regulation of TB on target proteins was regained with the restoration of gut microbiota. CONCLUSION: We find that TB has markedly preventive and therapeutic effects on NAFLD and obesity by regulating serotonin level and related signaling pathways through gut microbiota. Furthermore, gut microbiota and TB co-contribute to alleviating NAFLD and obesity. TB could be a promising medicine for NAFLD and obesity.

3.
Gut ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690433

RESUMO

BACKGROUND AND AIMS: Current practice on Helicobacter pylori infection mostly focuses on individual-based care in the community, but family-based H. pylori management has recently been suggested as a better strategy for infection control. However, the family-based H. pylori infection status, risk factors and transmission pattern remain to be elucidated. METHODS: From September 2021 to December 2021, 10 735 families (31 098 individuals) were enrolled from 29 of 31 provinces in mainland China to examine family-based H. pylori infection, related factors and transmission pattern. All family members were required to answer questionnaires and test for H. pylori infection. RESULTS: Among all participants, the average individual-based H. pylori infection rate was 40.66%, with 43.45% for adults and 20.55% for children and adolescents. Family-based infection rates ranged from 50.27% to 85.06% among the 29 provinces, with an average rate of 71.21%. In 28.87% (3099/10 735) of enrolled families, there were no infections; the remaining 71.13% (7636/10 735) of families had 1-7 infected members, and in 19.70% (1504/7636), all members were infected. Among 7961 enrolled couples, 33.21% had no infection, but in 22.99%, both were infected. Childhood infection was significantly associated with parental infection. Independent risk factors for household infection were infected family members (eg, five infected members: OR 2.72, 95% CI 1.86 to 4.00), living in highly infected areas (eg, northwest China: OR 1.83, 95% CI 1.57 to 2.13), and large families in a household (eg, family of three: OR 1.97, 95% CI 1.76 to 2.21). However, family members with higher education and income levels (OR 0.85, 95% CI 0.79 to 0.91), using serving spoons or chopsticks, more generations in a household (eg, three generations: OR 0.79, 95% CI 0.68 to 0.92), and who were younger (OR 0.57, 95% CI 0.46 to 0.70) had lower infection rates (p<0.05). CONCLUSION: Familial H. pylori infection rate is high in general household in China. Exposure to infected family members is likely the major source of its spread. These results provide supporting evidence for the strategic changes from H. pylori individual-based treatment to family-based management, and the notion has important clinical and public health implications for infection control and related disease prevention.

4.
JCI Insight ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36692956

RESUMO

Bone metastases are a common complication of breast cancer. We have demonstrated that intermittent administration of parathyroid hormone (PTH [1-34]) reduces the incidence of bone metastases in murine models of breast cancer by acting on osteoblasts to alter the bone microenvironment. Here, we examined the role of PTH receptor (PTH1R)-mediated signaling in both osteoblasts and breast cancer cells in influencing bone metastases. In mice with impaired PTH1R signaling in osteoblasts, intermittent PTH did not reduce bone metastasis. Intermittent PTH also failed to reduce bone metastasis when expression of PTH1R was knocked down in 4T1 murine breast cancer cells by shRNA. In 4T1 breast cancer cells, PTH decreased expression of PTH-related protein (PTHrP), implicated in the vicious cycle of bone metastases. Knockdown of PTHrP in 4T1 cells significantly reduced migration towards MC3T3-E1 osteoblasts, and migration was further inhibited by treatment with intermittent PTH. Conversely, overexpression of PTHrP in 4T1 cells increased migration towards MC3T3-E1 osteoblasts and this was not inhibited by PTH. In conclusion, PTH1R expression is crucial in both osteoblasts and breast cancer cells for PTH to reduce bone metastases and in breast cancer cells this may be mediated in part by suppression of PTHrP.

5.
Artigo em Inglês | MEDLINE | ID: mdl-36673979

RESUMO

Soil erosion is an important global environmental issue that severely affects regional ecological environment and socio-economic development. The Yellow River (YR) is China's second largest river and the fifth largest one worldwide. Its watershed is key to China's economic growth and environmental security. In this study, six impact factors, including rainfall erosivity (R), soil erosivity (K), slope length (L), slope steepness (S), cover management (C), and protective measures (P), were used. Based on the revised universal soil loss equation (RUSLE) model, and combined with a geographic information system (GIS), the temporal and spatial distribution of soil erosion (SE) in the YR from 2000 to 2020 was estimated. The patch-generating land use simulation (PLUS) model was used to simulate the land-use and land-cover change (LUCC) under two scenarios (natural development and ecological protection) in 2040; the RUSLE factor P was found to be associated with LUCC in 2040, and soil erosion in the Yellow River Basin (YRB) in 2040 under the two scenarios were predicted and evaluated. This method has great advantages in land-use simulation, but soil erosion is greatly affected by rainfall and slope, and it only focuses on the link between land-usage alteration and SE. Therefore, this method has certain limitations in assessing soil erosion by simulating and predicting land-use change. We found that there is generally slight soil erosivity in the YRB, with the most serious soil erosion occurring in 2000. Areas with serious SE are predominantly situated in the upper reaches (URs), followed by the middle reaches (MRs), and soil erosion is less severe in the lower reaches. Soil erosion in the YRB decreased 11.92% from 2000 to 2020; thus, soil erosion has gradually reduced in this area over time. Based on the GIS statistics, land-use change strongly influences SE, while an increase in woodland area has an important positive effect in reducing soil erosion. By predicting land-use changes in 2040, compared to the natural development scenario, woodland and grassland under the ecological protection scenario can be increased by 1978 km2 and 2407 km2, respectively. Soil erosion can be decreased by 6.24%, indicating the implementation of woodland and grassland protection will help reduce soil erosion. Policies such as forest protection and grassland restoration should be further developed and implemented on the MRs and URs of the YR. Our research results possess important trend-setting significance for soil erosion control protocols and ecological environmental protection in other large river basins worldwide.


Assuntos
Rios , Solo , Erosão do Solo , Modelos Teóricos , Monitoramento Ambiental/métodos , Conservação dos Recursos Naturais
6.
Artigo em Inglês | MEDLINE | ID: mdl-36606555

RESUMO

A large body of literature has established the benefits of undergraduate research experiences via the traditional apprenticeship model. More recently, several studies have shown that many of these benefits can be recapitulated in course-based undergraduate research experiences (CUREs) that are more scalable and easier for students to participate in, compared to the apprenticeship-based research experiences. Many Biology curricula also incorporate more traditional laboratory courses, where students learn to use common laboratory techniques through guided exercises with known outcomes. Indeed, many programs across the nation provide such programs or courses for students early in their careers, with a view toward increasing student interest and engagement in Biology. While there is general consensus that all lab experiences have some benefits for students, very few studies have examined whether either research experiences or learning biological techniques in more traditional lab courses directly impacts student performance in lecture courses. Here, we show that prior familiarity with laboratory techniques does not improve student performance in a lecture course, even if these techniques are directly related to content being taught in the course. However, having prior research experience improves performance in the course, irrespective of whether the research experience included the use of course-related laboratory techniques.

7.
JAMA Netw Open ; 6(1): e2249710, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36602797

RESUMO

Importance: The Sabin-strain inactivated poliovirus vaccine (IPV) may be a tool for polio outbreak response in certain situations. Objective: To investigate the response to a type 2 vaccine-derived poliovirus (VDPV2) outbreak. Design, Setting, and Participants: This case series was conducted in China after a VDPV2 was detected in stool specimens from a child with acute flaccid paralysis (AFP) in Sichuan Province in 2019, 3 years after the global withdrawal of live, attenuated type 2 oral poliovirus vaccine (OPV). Investigation followed National Health Commission and World Health Organization guidance and included searching hospitals for unreported AFP cases; testing stool specimens from the child, his contacts, and local children; enhanced environmental surveillance for VDPV2s in wastewater; and measuring vaccination coverage. Sabin-strain IPV campaigns were conducted in a wide geographic area. Main Outcomes and Measures: Any VDPV2 detection after completion of the supplementary immunization activities. Results: A 28-nucleotide-change VDPV2 was isolated from a young boy. Three VDPV2s were detected in healthy children; 2 were contacts of the original child, and none had paralysis. A search of 31 million hospital records found 10 unreported AFP cases; none were polio. No type 2 polioviruses were found in wastewater. Prior to the event, polio vaccine coverage was 65% among children younger than 5 years. Sabin-strain IPV campaigns reached more than 97% of targeted children, administering 1.4 million doses. No transmission source was identified. More than 1 year of enhanced poliovirus environmental and AFP surveillance detected no additional VDPVs. Conclusions and Relevance: These findings suggest that the circulating VPDV2 outbreak in 2019 was associated with low vaccine coverage. An investigation discovered 3 infected but otherwise healthy children and no evidence of the virus in wastewater. Following Sabin-strain IPV-only campaigns expanding from county to prefecture, the poliovirus was not detected, and the outbreak response was considered by an expert panel and the World Health Organization to have been successful. This success suggests that the Sabin-strain IPV may be a useful tool for responding to circulating VDPV2 outbreaks when high-quality supplementary immunization activities can be conducted and carefully monitored in settings with good sanitation.


Assuntos
Poliomielite , Poliovirus , Masculino , Criança , Humanos , Vacina Antipólio de Vírus Inativado , alfa-Fetoproteínas , Poliomielite/epidemiologia , Poliomielite/prevenção & controle , China/epidemiologia
8.
Oxid Med Cell Longev ; 2023: 9554457, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644575

RESUMO

Disturbed structure and dysfunction of the retinal pigment epithelium (RPE) lead to degenerative diseases of the retina. Excessive accumulation of reactive oxygen species (ROS) in the RPE is thought to play an important role in RPE dysfunction and degeneration. Autophagy is a generally low-activity degradation process of cellular components that increases significantly when high levels of oxidative stress are present. Agents with antioxidant properties may decrease autophagy and provide protection against RPE dysfunction and damage caused by ROS. Lycium barbarum polysaccharide (LBP) has been widely studied as an antioxidant and cell-protective agent. Therefore, we designed this study to investigate the effects of LBP, which inhibits miR-181, on autophagy in retinal pigment epithelium (RPE) with oxidative stress in vitro and in vivo. In the current study, we found that the highly expressed miR-181 downregulated the expression of Bcl-2 in hydrogen peroxide- (H2O2-) induced ARPE-19 cells, resulting in an increase in ROS, apoptosis, and autophagy flux. LBP inhibited the expression of miR-181, decreased the levels of ROS, apoptosis, and autophagy flux, and increased cell viability in H2O2-induced ARPE-19 cells, suggesting that LBP provides protection against oxidative damage in ARPE-19 cells. We also found that LBP decreased RPE atrophy and autophagy flux in rd10 mice. Taken together, the results showed that LBP has a protective effect for RPE under oxidative stress by inhibiting miR-181 and affecting the Bcl-2/Beclin1 autophagy signaling pathway.


Assuntos
Lycium , MicroRNAs , Animais , Camundongos , Antioxidantes/farmacologia , Apoptose , Autofagia , Peróxido de Hidrogênio/farmacologia , Lycium/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo , Polissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Humanos
9.
Transl Vis Sci Technol ; 12(1): 2, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36595279

RESUMO

Purpose: To establish a Beagle dog model of dry eye disease (DED). Methods: DED models were induced by surgical removal of orbital lacrimal glands and entire resection of third eyelids in the left eyes of six Beagle dogs. Intact right eyes served as self-controls. Non-anaesthetized Schirmer test (STT), tear break-up time (TBUT), and fluorescein staining grading were performed monthly after operation. Interleukin (IL)-1ß, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) levels were detected in tears and conjunctiva tissues. Six months after surgery, conjunctiva and cornea were collected and histopathologically analyzed. Results: Signs of DED appeared within one month after surgery and then remained stable. STT values were significantly reduced by 88% within 3 weeks after operation and remained stable over months with 1.6 ± 0.4 mm. Mean TBUT decreased significantly within two months after operation and maintained 5.2 ± 1.1 seconds. The mean fluorescein staining score was highest at the first month and then was reduced, eventually reaching a balance with 11.0 ± 1.3 points. Elevated levels of IL-1ß, IL-8, IL-10, and TNF-α were detected in tears and conjunctivas of operated eyes. Hematoxylin and eosin staining showed cornea neovascularization in the corneal stroma with thickened stroma layer and disorganized collagen bundles. Periodic acid-Schiff staining revealed a reduced function of conjunctival goblet cells. Conclusions: A combined type of DED model on the Beagle dog was established by removal of the orbital lacrimal gland and resection of the third eyelid. This DED model is easily accessible and is stable at six-month observation. Translational Relevance: The surgery-induced Beagle dog DED model is easily accessible and stable over a relatively long time.


Assuntos
Síndromes do Olho Seco , Interleucina-10 , Cães , Animais , Fator de Necrose Tumoral alfa , Interleucina-8 , Fluoresceína
10.
PeerJ ; 11: e14546, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36650830

RESUMO

Background: Preoperative prediction of cervical lymph node metastasis in papillary thyroid carcinoma provided a basis for tumor staging and treatment decision. This study aimed to investigate the utility of machine learning and develop different models to preoperatively predict cervical lymph node metastasis based on ultrasonic radiomic features and clinical characteristics in papillary thyroid carcinoma nodules. Methods: Data from 400 papillary thyroid carcinoma nodules were included and divided into training and validation group. With the help of machine learning, clinical characteristics and ultrasonic radiomic features were extracted and selected using randomforest and least absolute shrinkage and selection operator regression before classified by five classifiers. Finally, 10 models were built and their area under the receiver operating characteristic curve, accuracy, sensitivity, specificity, positive predictive value and negative predictive value were measured. Results: Among the 10 models, RF-RF model revealed the highest area under curve (0.812) and accuracy (0.7542) in validation group. The top 10 variables of it included age, seven textural features, one shape feature and one first-order feature, in which eight were high-dimensional features. Conclusions: RF-RF model showed the best predictive performance for cervical lymph node metastasis. And the importance features selected by it highlighted the unique role of higher-dimensional statistical methods for radiomics analysis.


Assuntos
Neoplasias da Glândula Tireoide , Ultrassom , Humanos , Estudos Retrospectivos , Câncer Papilífero da Tireoide/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem
11.
Int J Hyperthermia ; 40(1): 2161641, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36586419

RESUMO

OBJECTIVE: To evaluate the clinical efficacy of the combination of high-intensity focused ultrasound (HIFU), mifepristone, and levonorgestrel-releasing intrauterine system (LNG-IUS) in adenomyosis treatment. METHODS: HIFU treatment was performed in 123 patients with symptomatic adenomyosis who had refused treatment with gonadotropin-releasing hormone agonist (GnRH-a) at Anyang Maternal and Child Health Care Hospital. In the control group, 34 patients were treated with HIFU alone, 29 patients with HIFU combined with mifepristone, 10 patients with HIFU combined with LNG-IUS. In the study group, 50 patients were treated with HIFU combined with mifepristone and LNG-IUS. RESULTS: Uterine volume, dysmenorrhea pain score, menstruation volume score, and serum CA125 level were significantly lower after treatment with HIFU combined with mifepristone and LNG-IUS than before treatment (p < .05). Moreover, hemoglobin level was significantly higher than that before treatment (p < .05). After 24 months, the efficacy of HIFU combined with mifepristone and LNG-IUS was significantly higher than that of HIFU alone, HIFU combined with mifepristone or HIFU with LNG-IUS (p < .05). CONCLUSIONS: Combination therapy of HIFU, mifepristone, and LNG-IUS is an effective, safe, and inexpensive treatment for patients with symptomatic adenomyosis. This combination therapy demonstrates superior efficacy to treatment with HIFU alone, HIFU combined with mifepristone, and HIFU combined with LNG-IUS.


Assuntos
Adenomiose , Ablação por Ultrassom Focalizado de Alta Intensidade , Feminino , Criança , Humanos , Levanogestrel/uso terapêutico , Adenomiose/tratamento farmacológico , Adenomiose/cirurgia , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Dismenorreia/induzido quimicamente , Dismenorreia/tratamento farmacológico
12.
Metallomics ; 15(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36583695

RESUMO

The influence of the fermentation process on selenite metabolism by a probiotic Bifidobacterium longum DD98 and its consequent enrichment in selenium (Se) were studied. The effects of sodium selenite (Na2SeO3) concentration (18-400 µg/ml), feeding time (12, 16, and 24 h), and fermentation stage (secondary and tertiary fermentation) were evaluated by measuring (i) the total Se content and its distribution between the water-soluble metabolome fraction and the water-insoluble fraction; (ii) the total concentrations of the two principal Se compounds produced: selenomethionine (SeMet) and γ-glutamyl-selenomethionine (γ-Glu-SeMet), and (iii) the speciation of Se in the metabolite fraction. The results revealed that the fermentation process notably changed the Se incorporation into metabolites (γ-Glu-SeMet and free SeMet) and proteins (bound-SeMet) in B. longum DD98. In particular, the production of SeMet was negatively correlated to that of γ-Glu-SeMet when no red precipitate was seen in the bacteria. The study offers a tool for the control of the optimization of the fermentation process towards the desired molecular speciation of the incorporated Se and hence contributes to the production of Se-enriched probiotics with good qualities and bioactivities.


Assuntos
Bifidobacterium longum , Probióticos , Selênio , Selênio/metabolismo , Selenometionina/metabolismo , Ácido Selenioso , Fermentação , Bifidobacterium longum/metabolismo , Selenito de Sódio/metabolismo , Selenito de Sódio/farmacologia
13.
J Hazard Mater ; 446: 130692, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36586330

RESUMO

Bio-toxic inorganic pollutants, e.g., fluorine (F) and heavy metals (HMs), in wastewaters are the potential threats to nitrate (NO3--N) reduction by microorganisms in constructed wetlands (CWs). Selection of suitable substrate with high F and HMs adsorption efficiency and capacity is a potential alternative for simultaneous removal of these pollutants in CWs. Herein, this study investigated the feasibility of applying hydroxyapatite (HA)-gravel media for F and HMs adsorption and its effect on NO3--N reduction in CWs (HA CWs) by comparing the CWs filled with gravel substrate (CK CWs). The results indicated that the removal efficiency of F, Cr, As, and NO3--N in HA CWs increased by 113.6-, 3.3-, 2.7-, and 0.6-folds, respectively, compared to CK CWs. The NO3--N reduction rate decreased by 11-46% in CK CWs after the presence of F and HMs in influent, while for HA CWs, it was only 13-22%. Excellent F and HMs adsorption capacity of HA substrate availed for wetland plants resisting F/HMs toxicity and making catalase activity lower. The HA substrate in CWs resulted in the certain succession of nitrogen-transforming bacteria, e.g., nitrifiers (Nitrospira) and denitrifiers (Thiobacillus and Desulfobacterium). More importantly, key functional genes, including nirK/nirS, korA/korB, ChrA/ChrD, arsA/arsB, catalyzing the processes of nitrogen biotransformation, energy metabolism, NO3--N and metal ions reduction were also enriched in HA CWs. This study highlights HA substrate reduce the inhibitive effect of F and HMs on NO3--N reduction, and provides new insights into how microbiota structurally and functionally respond to different substrates in CWs.


Assuntos
Poluentes Ambientais , Metais Pesados , Nitratos , Áreas Alagadas , Flúor , Bactérias/metabolismo , Nitrogênio/metabolismo , Hidroxiapatitas , Eliminação de Resíduos Líquidos/métodos
14.
NPJ Sci Food ; 6(1): 55, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470888

RESUMO

Understanding how Baijiu facilitates blood circulation and prevents blood stasis is crucial for revealing the mechanism of Baijiu for cardiovascular disease (CVD) risk reduction. Here we established a zebrafish thrombosis model induced using arachidonic acid (AA) to quantitatively evaluate the antithrombotic effect of Wuliangye Baijiu. The prevention and reduction effects of aspirin, Wuliangye, and ethanol on thrombosis were compared using imaging and molecular characterization. Wuliangye Baijiu reduces thrombotic risks and oxidative stress in the AA-treated zebrafish, while ethanol with the same concentration has no similar effect. The prevention and reduction effects of Wuliangye on thrombosis are attributed to the change in the metabolic and signaling pathways related to platelet aggregation and adhesion, oxidative stress and inflammatory response.

15.
Genet Med ; 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36459106

RESUMO

PURPOSE: Expanded pan-ethnic carrier screening is an effective tool for the management of reproductive risk. However, growth in the number of conditions screened, in combination with increasingly more comprehensive test methodologies, can lead to the detection of genetic findings that may affect the health of the tested individual. The objective of this study was to investigate the frequency of pathogenic genotypes in a presumed healthy carrier screening cohort to facilitate broader discussions regarding disclosure of genetic information from carrier screening. METHODS: A retrospective analysis of 73,755 targeted carrier screens was performed to identify individuals with pathogenic genotypes and heterozygous risk alleles. RESULTS: In this study, we identified 79 individuals (0.11%) with pathogenic genotypes associated with moderate to profound autosomal recessive or X-linked conditions. In addition, 10 cases had chromosome X dosage abnormalities suggestive of a sex chromosome abnormality. Heterozygote risk alleles represented the majority of ancillary findings in this cohort, including 280 female carriers of FMR1 premutation alleles, 15 heterozygous females with pathogenic DMD variants, and 174 heterozygotes with pathogenic variants in genes that may confer increased risk for somatic malignancies in the heterozygous state. CONCLUSION: These data suggest that nearly 1% of individuals undergoing carrier screening will have a finding that may require clinical evaluation or surveillance.

17.
J Integr Plant Biol ; 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36534458

RESUMO

Nodulation Receptor Kinase (NORK) functions as a co-receptor of Nod factor receptors to mediate rhizobial symbiosis in legumes, but its direct phosphorylation substrates that positively mediate root nodulation remain to be fully identified. Here, we identified a GmNORK-Interacting Small Protein (GmNISP1) that functions as a phosphorylation target of GmNORK to promote soybean nodulation. GmNORKα directly interacted with and phosphorylated GmNISP1. Transcription of GmNISP1 was strongly induced after rhizobial infection in soybean roots and nodules. GmNISP1 encodes a peptide containing 90 amino acids with a "DY" consensus motif at its N-terminus. GmNISP1 protein was detected to be present in the apoplastic space. Phosphorylation of GmNISP1 by GmNORKα could enhance its secretion into the apoplast. Pretreatment with either purified GmNISP1 or phosphorylation-mimic GmNISP112D on the roots could significantly increase nodule numbers compared with the treatment with phosphorylation-inactive GmNISP112A . The data suggested a model that soybean GmNORK phosphorylates GmNISP1 to promote its secretion into the apoplast, which might function as a potential peptide hormone to promote root nodulation.

18.
Cells ; 11(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36497110

RESUMO

Esophageal cancer is a lethal disease that frequently occurs in developing countries, the incidence of which could be declined by drinking EGCG-enriched drinks or food. SERPINB2, whose complex functions and regulations are not yet fully understood, are induced by multiple inflammatory molecules and anti-tumor agents. Here, we identify 2444 EGCG-regulated genes in esophageal cancer cells, including SERPINB2. EGCG treatment recruits NF-κB at the promoter and enhancers of SERPINB2 and activates gene transcription, which is repressed by NF-κB knockdown or inhibition. Loss of SERPINB2 leads to a faster migration rate and less expression of Caspase-3 in cancer cells. Our study demonstrates that SERPINB2 is a new tumor-suppressor gene involved in cell movement and apoptosis and could be a therapeutic target for esophageal cancer.


Assuntos
Apoptose , Neoplasias Esofágicas , Peptídeos e Proteínas de Sinalização Intracelular , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , NF-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Genes Supressores de Tumor
19.
ChemistryOpen ; 11(12): e202200240, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36524742

RESUMO

Recently, it was shown that the double Ca-H-Ca-bridged calcium hydride cation dimer [LCaH2 CaL]2+ when stabilized by a larger macrocyclic N,N',N'',N''',N''''-pentadentate ligand showed evidently higher activity than when stabilized by a smaller N,N',N'',N'''-tetradentate ligand in the catalytic hydrogenation of unactivated 1-alkenes. In this DFT-mechanistic work, the origin of the observed ring-size effect is examined in detail using 1-hexene, CH2 =CH2 and H2 as substrates. It is shown that, at room temperature, both the N,N',N'',N''',N''''-stabilized dimer and the monomer are not coordinated by THF in solution, while the corresponding N,N',N'',N'''-stabilized structures are coordinated by one THF molecule mimicking the fifth N-coordination. Catalytic 1-alkene hydrogenation may occur via anti-Markovnikov addition over the terminal Ca-H bonds of transient monomers, followed by faster Ca-C bond hydrogenolysis. The higher catalytic activity of the larger N,N',N'',N''',N''''-stabilized dimer is due to not only easier formation of but also due to the higher reactivity of the catalytic monomeric species. In contrast, despite unfavorable THF-coordination in solution, the smaller N,N',N'',N'''-stabilized dimer shows a 3.2 kcal mol-1 lower barrier via a dinuclear cooperative Ca-H-Ca bridge for H2 isotope exchange than the large N,N',N'',N''',N''''-stabilized dimer, mainly due to less steric hindrance. The observed ring-size effect can be understood mainly by a subtle interplay of solvent, steric and cooperative effects that can be resolved in detail by state-of-the-art quantum chemistry calculations.


Assuntos
Alcenos , Cálcio , Ligantes , Hidrogenação , Alcenos/química , Cátions
20.
J Integr Plant Biol ; 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36515424

RESUMO

Cell wall is the first physical barrier to aluminum (Al) toxicity. Modification of cell wall properties to change its binding capacity to Al is one of the major strategies for plant Al resistance; nevertheless, how it is regulated in rice remains largely unknown. In this study, we show that exogenous application of putrescines (Put) could significantly restore the Al resistance of art1, a rice mutant lacking the central regulator Al RESISTANCE TRANSCRIPTION FACTOR 1 (ART1), and reduce its Al accumulation particularly in the cell wall of root tips. Based on RNA-sequencing, yeast-one-hybrid and electrophoresis mobility shift assays, we identified an R2R3 MYB transcription factor OsMYB30 as the novel target in both ART1-dependent and Put-promoted Al resistance. Furthermore, transient dual-luciferase assay showed that ART1 directly inhibited the expression of OsMYB30, and in turn repressed Os4CL5-dependent 4-coumaric acid accumulation, hence reducing the Al-binding capacity of cell wall and enhancing Al resistance. Additionally, Put repressed OsMYB30 expression by eliminating Al-induced H2 O2 accumulation, while exogenous H2 O2 promoted OsMYB30 expression. We concluded that ART1 confers Put-promoted Al resistance via repression of OsMYB30-regulated modification of cell wall properties in rice.

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