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1.
Nat Commun ; 13(1): 348, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039506

RESUMO

2-(2-Phenylethyl)chromones (PECs) are the principal constituents contributing to the distinctive fragrance of agarwood. How PECs are biosynthesized is currently unknown. In this work, we describe a diarylpentanoid-producing polyketide synthase (PECPS) identified from Aquilaria sinensis. Through biotransformation experiments using fluorine-labeled substrate, transient expression of PECPS in Nicotiana benthamiana, and knockdown of PECPS expression in A. sinensis calli, we demonstrate that the C6-C5-C6 scaffold of diarylpentanoid is the common precursor of PECs, and PECPS plays a crucial role in PECs biosynthesis. Crystal structure (1.98 Å) analyses and site-directed mutagenesis reveal that, due to its small active site cavity (247 Å3), PECPS employs a one-pot formation mechanism including a "diketide-CoA intermediate-released" step for the formation of the C6-C5-C6 scaffold. The identification of PECPS, the pivotal enzyme of PECs biosynthesis, provides insight into not only the feasibility of overproduction of pharmaceutically important PECs using metabolic engineering approaches, but also further exploration of how agarwood is formed.

2.
Emerg Microbes Infect ; : 1-43, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35045787

RESUMO

Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased cases of infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody response achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of an age- and gender-controlled healthy cohort who received inactivated SARS-CoV-2 vaccines, and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.

3.
Bioengineered ; 13(2): 3207-3220, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35045793

RESUMO

Acute pancreatitis (AP) is a common gastrointestinal disease with substantial morbidity and mortality. Pancreatic acinar intracellular trypsinogen activation (PAITA) is an important event in the early stage of AP. The present study aimed to investigate the effects of tRNA-derived fragments (tRFs) and the microRNA regulatory network on pancreatic acinar intracellular trypsinogen activation (PAITA) and identify novel key targets in AP. Taurolithocholic acid 3-sulfate (TLC-S)-treated AR42J cells were used to establish a PAITA model. Twenty differentially expressed tRFs and 35 DE microRNAs were identified in PAITA through gene sequencing. Based on these genes, we established the tRF-mRNA and microRNA-mRNA regulatory networks by using bioinformatics methods. The networks revealed 29 hub microRNAs (e.g., Let-7 family, miR-21-3p.) and 19 hub tRFs (e.g., tRF3-Thr-AGT, i-tRF-Met-CAT) in PAITA. GO analysis showed that the functions of the two networks were similar and mainly enriched in RNA splicing, mRNA processing, and so on. tRF3-Thr-AGT, targeting Btg2, Cd44, Zbp1, etc., was significantly decreased in PAITA. Moreover, the trypsinogen activation level was increased significantly in the tRF3-Thr-AGT deficiency groups, but rescued by tRF3-Thr-AGT mimics. The results revealed that downregulated tRF3-Thr-AGT was involved in PAITA. This study provides potential novel targets for researching the underlying mechanisms of AP.

4.
Respirol Case Rep ; 10(2): e0902, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35059200

RESUMO

Treating advanced lung cancer in patients with pulmonary fibrosis can be challenging due to increased risks of drug-induced and radiation-induced pneumonitis. We present the case of a 78-year-old female with stage IIIB lung adenocarcinoma and idiopathic pulmonary fibrosis (IPF). Following partial response to platinum-based chemotherapy, she was started on maintenance pemetrexed, but this was stopped due to bone marrow suppression and kidney injury. She received no further chemotherapy. Nintedanib was subsequently commenced for treatment of IPF. Remarkably, progress imaging at 2 years showed further regression of her lung adenocarcinoma, with stability of IPF. Nintedanib is a multi-target tyrosine kinase inhibitor with anti-cancer effects due to inhibition of angiogenesis. Nintedanib with chemotherapy has shown improvements in survival in non-small cell lung cancer (NSCLC). This case report and literature review discuss the effectiveness of nintedanib in treating patients with concurrent IPF and NSCLC, in particular for patients poorly tolerant of conventional chemotherapy.

5.
Support Care Cancer ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34981197

RESUMO

PURPOSE: Sarcopenia is an independent risk factor for poor prognosis of cancers. The nutritional risk screening 2002 (NRS2002) and patient-generated subjective global assessment (PG-SGA) tools are widely used tools for nutrition risk screening and assessing. The purpose of this study was to investigate whether NRS2002 and PG-SGA scores are associated with sarcopenia in gastrointestinal cancers. METHODS: A consecutive cohort comprised of 432 gastrointestinal cancer patients was conducted. We used NRS2002 and PG-SGA to assess their nutrition status. Sarcopenia was diagnosed with CT scan at the third lumber vertebra level. The correlations of nutritional scores with SMI, nutritional categories with sarcopenia were assessed by Spearman's correlation test and point biserial correlation. The cut-off value of nutritional scores for identifying sarcopenia was obtained by maximum Youden index. Logistic regression was used to confirm the associations. RESULTS: Sarcopenia patients had higher NRS2002 (2.63 ± 1.16 vs. 2.15 ± 1.20, p < 0.001) and PG-SGA (8.69 ± 1.16 vs. 5.56 ± 3.28, p < 0.001) scores. The NRS2002 (r = -0.198, p < 0.001) and PG-SGA (r = -0.409, p < 0.001) scores were significantly and negatively correlated with skeletal muscle mass index. The cut-off value of PG-SGA score for predicting sarcopenia was 7. In multivariate logistic regression, the PG-SGA exceeded 7 score (OR = 7.489, 95% CI: 4.122-13.608, p < 0.001) was significantly associated with increased risk of sarcopenia, while NRS2002 score showed no significant association with sarcopenia. CONCLUSIONS: PG-SGA ≥ 7 was associated with increased risk of sarcopenia and could serve as a useful criterion for capturing sarcopenia in gastrointestinal cancers. Routine PG-SGA evaluation for patient with gastrointestinal cancers is important.

6.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35012976

RESUMO

COVID-19 remains a stark health threat worldwide, in part because of minimal levels of targeted vaccination outside high-income countries and highly transmissible variants causing infection in vaccinated individuals. Decades of theoretical and experimental data suggest that nonspecific effects of non-COVID-19 vaccines may help bolster population immunological resilience to new pathogens. These routine vaccinations can stimulate heterologous cross-protective effects, which modulate nontargeted infections. For example, immunization with Bacillus Calmette-Guérin, inactivated influenza vaccine, oral polio vaccine, and other vaccines have been associated with some protection from SARS-CoV-2 infection and amelioration of COVID-19 disease. If heterologous vaccine interventions (HVIs) are to be seriously considered by policy makers as bridging or boosting interventions in pandemic settings to augment nonpharmaceutical interventions and specific vaccination efforts, evidence is needed to determine their optimal implementation. Using the COVID-19 International Modeling Consortium mathematical model, we show that logistically realistic HVIs with low (5 to 15%) effectiveness could have reduced COVID-19 cases, hospitalization, and mortality in the United States fall/winter 2020 wave. Similar to other mass drug administration campaigns (e.g., for malaria), HVI impact is highly dependent on both age targeting and intervention timing in relation to incidence, with maximal benefit accruing from implementation across the widest age cohort when the pandemic reproduction number is >1.0. Optimal HVI logistics therefore differ from optimal rollout parameters for specific COVID-19 immunizations. These results may be generalizable beyond COVID-19 and the US to indicate how even minimally effective heterologous immunization campaigns could reduce the burden of future viral pandemics.

7.
iScience ; 25(1): 103575, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-34988409

RESUMO

I-motifs are noncanonical four-stranded DNA structures formed by C-rich sequences at acidic environment with critical biofunctions. The particular pH sensitivity has inspired the development of i-motifs as pH sensors and DNA motors in nanotechnology. However, the folding and regulation mechanisms of i-motifs remain elusive. Here, using single-molecule FRET, we first show that i-motifs are more dynamic than G4s. Impressively, i-motifs display a high diversity of six folding species with slow interconversion. Further results indicate that i-motifs can be linearized by Replication protein A. More importantly, we identified a number of helicases with high specificity to i-motifs at low pH. All these helicases directly act on and efficiently resolve i-motifs into intermediates independent of ATP, although they poorly unwind G4 or duplex at low pH. Owing to the extreme sensitivity to helicases and no need for ATP, i-motif may be applied as a probe for helicase sensing both in vitro and in vivo.

8.
J Biotechnol ; 343: 128-137, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34906603

RESUMO

Methanol is a promising green feedstock for producing fuels and chemicals because it is inexpensive, clean, environmentally friendly, and easily prepared. Thus, many studies have been devoted to engineering non-native methylotrophic platform microorganisms to utilize methanol. This study adopted a series of strategies to develop a synthetic methylotrophic Bacillus subtilis that can use methanol as the carbon source, including the heterologous expression of methanol dehydrogenase (Mdh), enhancement of the expressions of 3-hexulose-6-phosphate synthase (Hps) and 6-phospho-3-hexuloisomerase (Phi), regulation of the expressions of key enzymes at both the translational and transcriptional levels, stabilization of the key enzyme expression through a dual-system for expressing the target genes on both the plasmid and genome, and improvement of the catalytic activity of Mdh with a recycling strategy for NAD+. As a result, the methanol consumption of the synthetic methylotrophic B. subtilis reached 4.09 g/L, with the maximum OD600 showing a 2.21-fold increase compared with the wild-type B. subtilis, which cannot use methanol. We further deleted the phosphoglucose isomerase (Pgi) and added co-substrates to increase the supply of ribulose-5-phosphate (Ru-5-P), and the specific methanol consumption rate increased by an additional 27.54%. Finally, we successfully constructed two strains that cannot grow in M9 medium with xylose or ribose unless methanol is utilized. The strategies used in this study are generally applicable to other studies on synthetic methylotrophy.


Assuntos
Bacillus , Metanol , Bacillus/genética , Bacillus subtilis/genética , Engenharia Metabólica , Plasmídeos
9.
J Clin Neurosci ; 95: 38-43, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34929649

RESUMO

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by headache, seizures, confusion and visual disturbances, as well as potentially reversible neuroimaging findings in most patients after proper treatment. Seizures is one of the most common clinical presentations of PRES. This review summarizes the potential pathophysiology and clinical features of PRES, as well as a multimodal approach to imaging and also briefly discusses the phenomenon of seizures in paediatric population.


Assuntos
Síndrome da Leucoencefalopatia Posterior , Criança , Cefaleia , Humanos , Imageamento por Ressonância Magnética , Neuroimagem , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Convulsões/etiologia
10.
Front Nutr ; 8: 737157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869517

RESUMO

Background/Aim: Essential oils of sunflower receptacles (SEOs) have antibacterial and antioxidant potential. However, the differences of biological activities from the different varieties of sunflowers have not been studied till now. The purpose of this study was to compare the differences of chemical compounds, antioxidant activities, and inhibitory activities against xanthine oxidase (XO) of SEOs from the three varieties of sunflowers including LD5009, SH363, and S606. Methods: SEOs were extracted by using the optimal extraction conditions selected by response surface methodology (RSM). Chemical compounds of SEOs were identified from the three varieties of sunflowers by gas chromatography-mass spectrometry (GC-MS). Antioxidant activities of SEOs were detected by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and iron ion reduction ability. Inhibitory activities of SEOs against XO were measured by using UV spectrophotometer. XO inhibitors were selected from the main chemical compounds of SEOs by the high-throughput selections and molecular simulation docking. Results: The extraction yields of SEOs from LD5009, SH363, and S606 were 0.176, 0.319, and 0.580%, respectively. A total of 101 chemical compounds of SEOs were identified from the three varieties of sunflowers. In addition, the results of inhibitory activities against XO showed that SEOs can reduce uric acid significantly. Eupatoriochromene may be the most important chemical compounds of SEOs for reducing uric acid. The results of antioxidant activities and inhibitory activities against XO showed that SEOs of LD5009 had the strongest antioxidant and XO inhibitory activities. The Pearson correlation coefficient (r > 0.95) showed that γ-terpinene, (E)-citral, and L-Bornyl acetate were highly correlated with the antioxidant activities and XO inhibitory ability. Conclusion: SEOs had antioxidant activities and XO inhibitory ability. It would provide more scientific information for utilization and selection of varieties of sunflowers, which would increase the food quality of sunflowers and incomes of farmers.

11.
Micromachines (Basel) ; 12(12)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34945406

RESUMO

Cobalt-modified 0.40Bi(Sc3/4In1/4)O3-0.58PbTiO3-0.02Pb(Mg1/3Nb2/3)O3 ceramics (abbreviated as BSI-PT-PMN-xCo) were produced by conventional two-step solid-state processing. The phase structure, micro structure morphology, and electrical properties of BSI-PT-PMN-xCo were systematically studied. The introduction of Co ions exerted a significant influence on the structure and electrical properties. The experiment results demonstrated that Co ions entered the B-sites of the lattice, resulting in slight lattice distortion and a smaller lattice constant. The average grain size increased from ~1.94 µm to ~2.68 µm with the increasing Co content. The optimized comprehensive electrical properties were obtained with proper Co-modified content 0.2 wt.%. The Curie temperature (Tc) was 412 °C, the piezoelectric constant (d33) was 370 pC/N, the remnant polarization (Pr) was 29.2 µC/cm2, the relatively dielectric constant (εr) was 1450, the planar electromechanical coupling coefficient (kp) was 46.5, and the dielectric loss (tanδ) was 0.051. Together with the enhanced DC resistivity of 109 Ω cm under 300 °C and good thermal stability, BSI-PT-PMN-0.2Co ceramic is a promising candidate material for high-temperature piezoelectric applications.

12.
Pain Res Manag ; 2021: 6894001, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34966473

RESUMO

Background: Robot-assisted pedicle screw placement is usually performed under general anesthesia to keep the body still. The aim of this study was to compare the accuracy of the robot-assisted technique under regional anesthesia with that of conventional fluoroscopy-guided percutaneous pedicle screw placement under general anesthesia in minimally invasive lumbar fusion surgery. Methods: This study recruited patients who underwent robot-assisted percutaneous endoscopic lumbar interbody fusion (PELIF) or fluoroscopy-guided minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) between December 2017 and February 2020 at a single center. Based on the method of percutaneous pedicle screw placement used, patients were divided into the robot-assisted under regional anesthesia (group RE-RO) and fluoroscopy-guided under general anesthesia (group GE-FLU) groups. The primary outcome measures were screw accuracy and the incidence of facet joint violation (FJV). Secondary outcome measures included X-ray and visual analogue scale (VAS) scores which were used to evaluate the degree of the postoperative pain at 4 hours and on postoperative days 1, 2, and 3. Intraoperative adverse events were also recorded. Results: Eighteen patients were included in group RE-RO, and 23 patients were included in group GE-FLU. The percentages of clinically acceptable screws (Gertzbein and Robbins grades A and B) were 94.4% and 91.5%, respectively. There was no significant difference in the percentages of clinically acceptable screws (p=0.44) or overall Gertzbein and Robbins screw accuracy grades (p=0.35). Only the top screws were included in the analysis of FJVs. The percentages of FJV (Babu grades 1, 2, and 3) were 5.6% and 28.3%, respectively. This difference was statistically significant (p=0.01). Overall, the FJV grades in group RE-RO were significantly better than those in group GE-FLU (p=0.009). The mean fluoroscopy time for each screw in group RE-RO was significantly shorter than that in group GE-FLU (group RE-RO: 5.4 ± 1.9 seconds and group GE-FLU: 6.8 ± 2.0 seconds; p=0.03). The postoperative pain between the RE-RO and GE-FLU groups was not statistically significant. The intraoperative adverse events included 1 case of registration failure and 1 case of guide-wire dislodgment in group RE-RO, as well as 2 cases of screw misplacement in group GE-FLU. No complications related to anesthesia were observed. Conclusion: Robot-assisted pedicle screw placement under regional anesthesia can be performed effectively and safely. The accuracy is comparable to the conventional technique. Moreover, this technique has the advantage of fewer FJVs and a lower radiation time.


Assuntos
Anestesia por Condução , Parafusos Pediculares , Procedimentos Cirúrgicos Robóticos , Robótica , Fusão Vertebral , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos , Estudos Retrospectivos
13.
Sci Total Environ ; 813: 152397, 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34923007

RESUMO

The generation of free radicals is the key to the photocatalytic efficiency. In this study, the degradation mechanism of photoelectrocatalysis (PEC) membrane could be adequately explained by exploring the generation pathway of different free radicals. The PEC membrane was prepared by gas phase polymerization of poly (3, 4-ethylene dioxythiophene) (PEDOT) on non-woven fabric, industrial filter cloth, ceramic membrane and polyvinylidene fluoride (PVDF) membrane, respectively. Three-dimensional fluorescence test showed that the optimal degradation of mixed or monomer contamination (bovine serum protein, sodium humate, and sodium alginate) was achieved by modified ceramic membrane under PEC condition. As for self-cleaning experiment, the membrane resistance decreased 65.7% when the reaction conditions changed from dark to PEC for 30 min. Combined with the characterization results, PEDOT as photocapacitance extended electron lifetime and promoted free radical generation. This system was mainly dependent on superoxide free radicals (0.01 mmol/L) and singlet oxygen (0.10 mmol/L), which came from energy and electron transfer. Oxygen vacancy could adsorb oxygen to produce superoxide radicals, which was further oxidized to singlet oxygen. In addition, the π-electron conjugated system of PEDOT accelerated the hole transfer and the separation of electrons and holes. Also, this study provided a new view of reactive oxygen species generation mechanism from PEDOT modified membrane.

14.
BMC Public Health ; 21(1): 2252, 2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34895198

RESUMO

BACKGROUND: The number of older people living with HIV (PLWH) is increasing. Although there are many studies affecting medication adherence, research on the impact of social capital and mental health on medication adherence in this particular population is limited. METHOD: Data were collected from an ongoing observational prospective cohort study, starting from November 2018, among older PLWH in Sichuan province, China. Five hundred twenty-one participants were interviewed. Social capital consists of the individual and family (IF) scale, and the community and society (CS) scale. The presence of probable depression and probable anxiety were assessed using the CES-D-10 and GAD-7 scales. Adherence was defined as taking ≥80% of prescribed HIV medication in 4 days prior to the interview. Two sets of Firth' penalized regression analyses were used to estimate the association between social capital, mental health, and medication adherence. RESULTS: The prevalence of non-adherence was 18.2% (95/521) among older PLWH in this study. After adjusting for significant factors, the CS social capital (OR: 0.92, 95%CI:0.85-0.99, p < 0.05) and probable anxiety (OR:1.73, 95%CI:1.07-2.80, p < 0.05) were associated with non-adherence. CONCLUSION: This study highlighted that the effects of social capital and mental health on older PLWH's adherence, which implied that the need to develop interventions to concern for mental health and enhance CS social capital to help the older PLWH better manage HIV medication adherence.

15.
J Orthop Surg Res ; 16(1): 721, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34930346

RESUMO

PURPOSE: Hemivertebra is one of the common pathogenesis of congenital scoliosis. The timing of operation is undefined. Our study compared the surgical outcomes in children under age 10 years with scoliosis due to single nonincarcerated thoracolumbar hemivertebra according to the age at surgery. METHODS: From January 2009 to August 2017, we retrospectively investigated 34 consecutive cases of congenital scoliosis treated by posterior hemivertebra resection and fusion with pedicle screw fixation. All cases were divided into two groups according to the age at surgery and followed-up for at least 2 years, group 1 (≤ 5 years old), and group 2 (5 to 10 years old). RESULTS: The mean Cobb angle of the main curve was improved from 48.58° to 15.53° (68.05%) in group 1, and from 43.73° to 11.33° (75.43%) in group 2. The segmental curve was improved from 44.16° to 11.53° (74.64%) in group 1, and the segmental curve was consistent with the main curve in group 2. The mean segmental kyphosis was improved from 27.50° to 8.42° (67.40%) in group 1, and from 29.00° to 5.00° (84.73%) in group 2. Five patients developed distal adding-on, and four patients were found proximal junctional kyphosis during the follow-up. CONCLUSION: Not all the deformities caused by single nonincarcerated thoracolumbar hemivertebra would progress greatly with the spinal growth. No significant statistical differences were found in the coronal and sagittal correction rate between the two groups. A limited delayed surgery after 5 years but before 10 years of age with close follow-up can achieve satisfied results.

16.
Mol Cell Probes ; 61: 101788, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34954062

RESUMO

Ditylenchus destructor is a plant-parasitic nematode that seriously infests sweet potato crop in China. Thus, fast and accurate detection of D. destructor in soil and plant tissue samples is of great significance. In this study, a real-time recombinase polymerase amplification (RPA) assay was developed for the rapid and accurate detection of D. destructor in various samples. The RPA assay could be easily operated and detected as low as 1/500 individual J4 nematode DNA per reaction in 20 min at 39 °C with high specificity. The assay meets the requirements of rapid detection prior to port quarantine as well as on-site real-time detection and can be applied to detect the parasite in soil and plant samples. The modified gDNA extraction method for a single nematode established in this study significantly reduced the time of detection and improved the applicability of the real-time RPA assay for on-site detection in different environments. The real-time RPA assay to detect D. destructor will be useful for epidemiological investigations in the field as well as for quarantine processes in the sweet potato and potato trade.

17.
Med Sci Monit ; 27: e933425, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34928926

RESUMO

BACKGROUND The aim of this study was to identify feature autophagy-related genes (ARGs) in systemic lupus erythematosus (SLE), evaluate their diagnostic value, and further explore DNA methylation and expression levels in the pathogenesis of SLE. MATERIAL AND METHODS WGCNA was used to construct network and selected hub genes based on gene expression dataset GSE81622. ARGS were overlapped with hub genes, and feature ARGs were identified. A diagnostic model was established by these feature ARGs using LASSO. GSE96879 was used to analyze the methylation levels of feature ARGs. The expression and methylation levels of feature ARGs were verified using RT-PCR and methylation-specific PCR. RESULTS We found that 55 hub genes were highly connected to the red module of WGCNA, and ARGs were extracted from the Human Autophagy Database and the GO_AUTOPHAGY gene set. Overlapping of 55 hub gene with ARGs resulted in 18 feature ARGs. S100A8, MyD88, and NCR3 from the 18 feature ARGs showed higher good diagnostic value for SLE. Five differentially methylated positions locating to S100A8, MyD88, and NCR3 genes were identified from GSE96879. After validation tests, RT-PCR showed that gene expressions of MyD88 and S100A8 were increased in the PBMCs samples of SLE patients compared with healthy controls, whereas NCR3 was the opposite. MSP found that cg24898863 (S100A8) was hypomethylated, while cg27490128 (NCR3) was hypermethylated in the SLE group, and S100A8 and NCR3 methylation were positively correlated with their expressions. CONCLUSIONS Our present study identified the potential roles of feature ARGs in SLE diagnosis, and shows correlation among DNA methylation and gene expressions of these feature ARGs in SLE.

18.
Front Cell Dev Biol ; 9: 742714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746137

RESUMO

ATP6V1B2 encodes the V1B2 subunit in V-ATPase, a proton pump responsible for the acidification of lysosomes. Mutations in this gene cause DDOD syndrome, DOORS syndrome, and Zimmermann-Laband syndrome, which share overlapping feature of congenital sensorineural deafness, onychodystrophy, and different extents of intellectual disability without or with epilepsy. However, the underlying mechanisms remain unclear. To investigate the pathological role of mutant ATP6V1B2 in the auditory system, we evaluated auditory brainstem response, distortion product otoacoustic emissions, in a transgenic line of mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2 Arg506*/Arg506* . To explore the pathogenic mechanism of neurodegeneration in the auditory pathway, immunostaining, western blotting, and RNAscope analyses were performed in Atp6v1b2Arg506*/Arg506* mice. The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss. We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice. Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing. Intraperitoneal administration of the apoptosis inhibitor, BIP-V5, improved both phenotypical and pathological outcomes in two live mutant mice. Based on the pathogenesis underlying hearing loss in Atp6v1b2-related syndromes, systemic drug administration to inhibit apoptosis might be an option for restoring the function of spiral ganglion neurons and promoting hearing, which provides a direction for future treatment.

19.
Nat Commun ; 12(1): 6370, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34737262

RESUMO

The high efficacy, low cost, and long shelf-life of the ChAdOx1 nCoV-19 vaccine positions it well for use in in diverse socioeconomic settings. Using data from clinical trials, an individual-based model was constructed to predict its 6-month population-level impact. Probabilistic sensitivity analyses evaluated the importance of epidemiological, demographic and logistical factors on vaccine effectiveness. Rollout at various levels of availability and delivery speed, conditional on vaccine efficacy profiles (efficacy of each dose and interval between doses) were explored in representative countries. We highlight how expedient vaccine delivery to high-risk groups is critical in mitigating COVID-19 disease and mortality. In scenarios where the availability of vaccine is insufficient for high-risk groups to receive two doses, administration of a single dose of is optimal, even when vaccine efficacy after one dose is just 75% of the two doses. These findings can help inform allocation strategies particularly in areas constrained by availability.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/análise , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Humanos , SARS-CoV-2/genética , Reino Unido , Vacinação
20.
J Immunother Cancer ; 9(11)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34782426

RESUMO

BACKGROUND: Patients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers. METHODS: This multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). RESULTS: The objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB. CONCLUSIONS: Ipilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

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