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1.
Brain Connect ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33403904

RESUMO

The default mode network (DMN) is a prominent intrinsic network that is observable in many mammalian brains. However, few studies have investigated the temporal dynamics of this network based on direct physiological recordings. Herein, we addressed this issue by characterizing the dynamics of local field potentials (LFPs) from the rat DMN during wakefulness and sleep with an exploratory analysis. We constructed a novel coactive micropattern (CAMP) algorithm to evaluate the configurations of rat DMN dynamics and further revealed the relationship between DMN dynamics with different wakefulness and alertness levels. From the gamma activity (40-80 Hz) in the DMN across wakefulness and sleep, three spatially stable CAMPs were detected: a common low-activity level micropattern (cDMN), an anterior high-activity level micropattern (aDMN) and a posterior high-activity level micropattern (pDMN). A dynamic balance across CAMPs emerged during wakefulness and was disrupted in sleep stages. In the slow-wave sleep (SWS) stage, cDMN became the primary activity pattern, whereas aDMN and pDMN were the major activity patterns in the rapid eye movement sleep (REM) stage. Additionally, further investigation revealed phasic relationships between CAMPs and the up-down states of the slow DMN activity in the SWS stage. Our study revealed that the dynamic configurations of CAMPs were highly associated with different stages of wakefulness and provided a potential three-state model to describe the DMN dynamics for wakefulness and alertness.

2.
Proc Natl Acad Sci U S A ; 118(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33380454

RESUMO

Electrochemical CO2 or CO reduction to high-value C2+ liquid fuels is desirable, but its practical application is challenged by impurities from cogenerated liquid products and solutes in liquid electrolytes, which necessitates cost- and energy-intensive downstream separation processes. By coupling rational designs in a Cu catalyst and porous solid electrolyte (PSE) reactor, here we demonstrate a direct and continuous generation of pure acetic acid solutions via electrochemical CO reduction. With optimized edge-to-surface ratio, the Cu nanocube catalyst presents an unprecedented acetate performance in neutral pH with other liquid products greatly suppressed, delivering a maximal acetate Faradaic efficiency of 43%, partial current of 200 mA⋅cm-2, ultrahigh relative purity of up to 98 wt%, and excellent stability of over 150 h continuous operation. Density functional theory simulations reveal the role of stepped sites along the cube edge in promoting the acetate pathway. Additionally, a PSE layer, other than a conventional liquid electrolyte, was designed to separate cathode and anode for efficient ion conductions, while not introducing any impurity ions into generated liquid fuels. Pure acetic acid solutions, with concentrations up to 2 wt% (0.33 M), can be continuously produced by employing the acetate-selective Cu catalyst in our PSE reactor.

3.
Environ Int ; 146: 106251, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33248346

RESUMO

BACKGROUND: To date, few studies have focused on the influence of indoor air pollution on cognitive impairment. Thus, we aimed to explore the association of household fuel use, the major cause of household air pollution, with cognitive functioning among a sample of middle-aged and older Chinese individuals. METHODS: A total of 10,372 and 8,397 participants from the China Health and Retirement Longitudinal Study (CHARLS) were enrolled in the cross-sectional and follow-up analyses, respectively. Cognitive functioning was evaluated via a structured questionnaire in three dimensions: orientation and attention, episodic memory, and visuo-construction. The associations between household solid fuel use (for cooking and heating) and cognitive functioning were elucidated by generalized linear models. Furthermore, we explored the combined effect of solid fuel use in cooking and heating and examined the effects of switching cooking fuel types on a 4-year change in cognitive functioning. RESULTS: In the cross-sectional study, solid fuel use for cooking or heating, separately or simultaneously, was positively associated with cognitive impairment, after adjusting for potential confounders. Similarly, in the follow-up study, solid cooking fuel use was associated with a greater decline in cognitive score overall (ß = -0.24, 95% confidence interval [CI]: -0.45, -0.04), mostly in the episodic memory (ß = -0.19, 95% CI: -0.34, -0.03) and visuo-construction (ß = -0.03, 95% CI: -0.05, -0.01) dimensions; solid heating fuel use was associated only with a greater decrease in the orientation and attention dimension (ß = -0.13, 95% CI: -0.25, -0.01). A combined effect of household fuel use was also observed (P < 0.05). Moreover, subjects who switched from solid to cleaner cooking fuel displayed a significantly lower degree of cognitive decline for all dimensions than did persistent solid fuel users over a 4-year period (P < 0.05). CONCLUSION: Our findings show that household solid fuel use is a risk factor for the development of cognitive impairment. Improving the structure of cooking fuel may therefore have great public health value for the prevention of cognitive impairment.

4.
PLoS Genet ; 16(12): e1009286, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33370779

RESUMO

Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

5.
JCI Insight ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351786

RESUMO

Computational models based on recent maps of the red blood cell proteome suggest that mature erythrocytes may harbor targets for common drugs. This prediction is relevant to red blood cell storage in the blood bank, in which the impact of small molecule drugs or other xenometabolites deriving from dietary, iatrogenic or environmental exposures ("exposome") may alter erythrocyte energy and redox metabolism and, in so doing, affect red cell storage quality and post-transfusion efficacy. To test this prediction, here we provide a comprehensive characterization of the blood donor exposome, including the detection of common prescription and over-the-counter drugs in 250 units donated by healthy volunteers from the REDS-III RBC Omics study. Based on high-throughput drug screenings of 1,366 FDA-approved drugs, we report a significant impact of ~65% of the tested drugs on erythrocyte metabolism. Machine learning models built using metabolites as predictors were able to accurately predict drugs for several drug classes/targets (bisphosphonates, anticholinergics, calcium channel blockers, adrenergics, proton-pump inhibitors, antimetabolites, selective serotonin reuptake inhibitors, and mTOR) suggesting that these drugs have a direct, conserved, and significant impact on erythrocyte metabolism. As a proof of principle, here we show that the antiacid ranitidine - though rarely detected in the blood donor population - has a strong effect on RBC markers of storage quality in vitro. We thus show that ranitidine supplementation to blood units could improve erythrocyte metabolism and storage quality when supplemented to blood bags, through mechanisms involving sphingosine 1-phosphate-dependent modulation of erythrocyte glycolysis and/or direct binding to hemoglobin.

6.
Int J Neural Syst ; : 2150002, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33357153

RESUMO

Very fast ripples (VFRs, 500-1000[Formula: see text]Hz) are considered more specific than high-frequency oscillations (80-500[Formula: see text]Hz) as biomarkers of epileptogenic zones. Although VFRs are frequent abnormal phenomena in epileptic seizures, their functional roles remain unclear. Here, we detected the VFRs in the hippocampal network and tracked their roles during status epilepticus (SE) in rats with pilocarpine-induced temporal lobe epilepsy (TLE). All regions in the hippocampal network exhibited VFRs in the baseline, preictal, ictal and postictal states, with the ictal state containing the most VFRs. Moreover, strong phase-locking couplings existed between VFRs and slow oscillations (1-12[Formula: see text]Hz) in the ictal and postictal states for all regions. Further investigation indicated that during VFRs, the build-up of slow oscillations in the ictal state began from the temporal lobe and then spread through the whole hippocampal network via two different pathways, which might be associated with the underlying propagation of epileptiform discharges in the hippocampal network. Overall, we provide a functional description of the emergence of VFRs in the hippocampal network during SE, and we also establish that VFRs may be the physiological representation of the pathological alterations in hippocampal network activity during SE in TLE.

7.
Environ Res ; 193: 110566, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33278475

RESUMO

Indoor air pollution caused by solid fuel use in cooking and heating in China is common. The relationship between household solid fuel use and peak expiratory flow (PEF) in middle-aged and older adults in China has not been clarified. The aim of this study was to assess the relationship between long-term household solid fuel use (clean for both cooking and heating, solid for either cooking or heating, and solid for both cooking and heating) and PEF changes in middle-aged and older adults using a nationally representative prospective cohort. Covariance analysis was used to compare PEF changes in different indoor air pollution exposure groups. Separate analysis of cooking and heating as well as sub-group analyses by age, sex and smoking status were conducted, linear mixed growth model analysis was used to evaluate the association between cooking fuel type and PEF. A total of 6818 participants were enrolled in the cohort analysis. Results revealed that solid fuel use in cooking and heating separately or conjointly were associated with reduced PEF (solid fuel use in cooking: least square mean [LSM] = 19.9, 95% confidence interval [CI]: 11.5-28.2, P = 0.03; solid fuel use in heating: LSM = 19.4, 95% CI:11.2-27.5, P = 0.04; both solid fuel use: LSM = 17.6, 95% CI: 9.3-25.9, P for trend <0.0001), especially in participants aged >65 years (LSM = -9.22, 95% CI: 27.9-69.52, P for trend <0.0001), females (LSM = -6.41, 95% CI: 19.12-6.30, P for trend <0.0001) and current or former smokers (LSM = -21.55, 95% CI: 36.14 to -6.97, P < 0.02). Compared to that of participants using clean fuels for cooking, PEF of participants using solid fuels were decreased by 3.5 l/min per 2 years over a 4-year follow-up. This cohort study highlights the adverse effects of indoor air pollution on lung function in middle aged and older adults in China.

8.
Ecotoxicol Environ Saf ; 209: 111833, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33360785

RESUMO

BACKGROUND: Previous studies found that ambient air pollution was associated with a higher prevalence of depressive symptoms. However, the longitudinal associations between household solid fuel use, which is the main source of household air pollution, and depressive symptoms remain unclear. This cohort study aimed to explore the associations between household solid fuel use and incidence of depressive symptoms in China. METHODS: In total, 8637 participants were enrolled in this prospective cohort study. Depressive symptoms were assessed using the 10-item Center for Epidemiological Studies Depression Scale. The associations between baseline household solid fuel use and the incidence of depressive symptoms were examined using Cox proportional hazards regression models. RESULTS: During the 4-year of follow-up, 2074 of 8637 participants developed depressive symptoms. Compared with participants who used clean fuel for both heating and cooking, the multivariate-adjusted hazard ratio (HR) (95% confidence intervals [95% CI]) for depressive symptoms incidence in participants who used solid fuels for two purposes (cooking and heating) was 1.15 (1.01, 1.31). In the solid fuel use subgroup analysis, use of solid fuels for cooking (HR, 1.12; 95% CI, 1.02-1.24) was associated with a higher incidence of depressive symptoms after adjustments while use for heating (HR, 1.05; 95% CI, 0.93-1.18) was not. Moreover, compared with persistent solid fuel users, switching from solid to clean fuels for cooking resulted in a lower risk of depressive symptoms before adjustments (HR, 0.82; 95% CI, 0.71-0.95) and a non-significant association (HR, 0.90; 95% CI, 0.77-1.04) afterwards. CONCLUSIONS: The results suggest that household solid fuel use for cooking was associated with a higher incidence of depressive symptoms. Preventive strategies based on improving household cooking environment for depressive symptoms should be established.

9.
Clin Nutr ; 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33308841

RESUMO

BACKGROUND & AIMS: Diet may play an important role in the etiology of ovarian cancer (OC). We aimed to evaluate the strength and credibility of evidence pertaining to dietary risk factors for OC. METHODS: We comprehensively searched PubMed, Web of Science, Cochrane, CINAHL, JBI Database of Systematic Reviews and Implementation Reports, PROSPERO and EMBASE databases to identify related systematic reviews and meta-analyses of prospective cohort studies. This study had been registered at PROSPERO. The registration number is CRD42020187651. For each association, we estimated the summary effect size using fixed and random effects models, the 95% confidence interval and the 95% prediction interval. We assessed heterogeneity, evidence of small-study effects, and excess significance bias. RESULTS: A total of 22 systematic reviews and meta-analyses were included in the present study. These previous reports evaluated 184 individual studies, which proposed a total of 36 associations between dietary factors and OC risk. Out of the 36 associations, there were no strong, highly suggestive and suggestive evidence, only four (black tea, skim/low-fat milk, lactose, and calcium) were determined to be supported by weak evidence. OC risk was inversely associated with intake of black tea or calcium, and positively associated with intake of skim/low-fat milk or lactose. CONCLUSIONS: Our studies revealed that four associations between OC risk and dietary factors (black tea, skim/low-fat milk, lactose, and calcium) were supported by weak evidence. The remaining 32 associations were not confirmed. Additional studies are needed to carefully evaluate the relationship between dietary factors and OC risk.

10.
Front Oncol ; 10: 549168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240807

RESUMO

Immune checkpoint inhibitors (ICIs) cause fewer toxicities than conventional chemotherapy. Although most of the immune-related adverse events (irAEs) are mild, reversible, and manageable, potentially severe and rare irAEs remain relevant. We present a 24-year-old man with advanced hereditary renal cancer who developed bilateral posterior uveitis and retinal detachment after systematic treatment of ICI and an anti-angiogenic drug. Axitinib and pembrolizumab were administered with a partial response and following the severe ocular irAE and systemic corticosteroid treatment was initiated. Our case indicates that ocular irAEs may occur rapidly. To the best of our knowledge, this is the first case of posterior uveitis and retinal detachment in hereditary renal cancer patients treated with ICI and anti-angiogenic drugs.

11.
Front Endocrinol (Lausanne) ; 11: 543623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133012

RESUMO

Bone regeneration has become a research hotspot and therapeutic target in the field of bone and joint medicine. Stem cell-based therapy aims to promote endogenous regeneration and improves therapeutic effects and side-effects of traditional reconstruction of significant bone defects and disorders. Human amniotic mesenchymal stem cells (hAMSCs) are seed cells with superior paracrine functions on immune-regulation, anti-inflammation, and vascularized tissue regeneration. The present review summarized the source and characteristics of hAMSCs and analyzed their roles in tissue regeneration. Next, the therapeutic effects and mechanisms of hAMSCs in promoting bone regeneration of joint diseases and bone defects. Finally, the clinical application of hAMSCs from current clinical trials was analyzed. Although more studies are needed to confirm that hAMSC-based therapy to treat bone diseases, the clinical application prospect of the approach is worth investigating.

12.
Front Oncol ; 10: 570733, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194664

RESUMO

Lung adenocarcinoma accounts for half of all lung cancer cases in most countries. Mounting evidence has demonstrated that microRNAs play important roles in cancer progression, and some of them can be identified as potential biomarkers. This study aimed to explore the role of miR-550a-5p, a lung adenocarcinoma-associated mature microRNA screened out from the TCGA database via R-studio and Perl, with abundant expression in samples and with 5-year survival prognosis difference, as well as having not been studied in lung cancer yet. Potential target genes were predicted by the online database. Gene ontology enrichment, pathway enrichment, protein-protein interaction network, and hub genes-microRNA network were constructed by FunRich, STRING database, and Cytoscape. Then, LIMD1, a known tumor suppressor gene reported by multiple articles, was found to have a negative correlation with miR-550a-5p. The expression of miR-550a-5p was up-regulated in tumor samples and tumor-associated cell lines. Its high expression was also correlated with tumor size. Cell line A549 treated with miR-550a-5p overexpression promoted tumor proliferation, while H1299 treated with miR-550a-5p knockdown showed the opposite result. Mechanically, miR-550a-5p negatively regulated LIMD1 by directly binding to its 3'-UTR validated by dual luciferase assay. In summary, a new potential prognostic and therapeutic biomarker, miR-550a-5p, has been identified by bioinformatics analysis and experimental validation in vitro and in vivo, which promotes lung adenocarcinoma by silencing a known suppressor oncogene LIMD1.

13.
Bioorg Med Chem ; : 115851, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33218896

RESUMO

Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 µM, IC50 = 1.21 ± 0.56 µM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.

14.
ACS Appl Mater Interfaces ; 12(49): 54773-54781, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33226768

RESUMO

Potassium-ion capacitors (KICs) have received a surge of interest because of their higher reserves and lower costs of potassium than lithium. However, the cycle performance and capacity of potassium devices have been reported to be unsatisfactory. Herein, a unique crystalline MnCo2O4.5 and amorphous MnCo2S4 core/shell nanoscale flower structure grown on graphene (MCO@MCS@rGO) was synthesized by a two-step hydrothermal process and demonstrated in KICs. The MCO@MCS@rGO exhibits improved electrical conductivity and excellent structural integrity during the charging and discharging process. The reasons could be attributed to the cavity structure of MCO, the mechanical buffer and high electrolyte diffusion rate of MCS, and the auxiliary effect of graphene. The electrical conductivity of MCO@MCS shows a specific capacity of 272.3 mA h g-1 after 400 cycles at 1 A g-1 and a capacity of 125.6 mA h g-1 at 2 A g-1. Besides, the MCO@MCS@rGO and high-surface-area activated carbon in KICs exhibit a relative energy density of 85.3 W h kg-1 and a power density of 9000 W kg-1 and outstanding cycling stability with a capacity retention of 76.6% after 5000 cycles. Moreover, the reaction mechanism of MCO@MCS@rGO in the K-ion cell was investigated systematically using X-ray diffraction and transmission electron microscopy, providing guidance on the further development of pseudocapacitive materials.

15.
Nat Commun ; 11(1): 5800, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199681

RESUMO

Metal-organic framework (MOF) glasses have become a subject of interest as a distinct category of melt quenched glass, and have potential applications in areas such as ion transport and sensing. In this paper we show how MOF glasses can be combined with inorganic glasses in order to fabricate a new family of materials composed of both MOF and inorganic glass domains. We use an array of experimental techniques to propose the bonding between inorganic and MOF domains, and show that the composites produced are more mechanically pliant than the inorganic glass itself.

16.
Pediatr Res ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203966

RESUMO

OBJECTIVE: The aim of the study was to evaluate the effectiveness of an audio and animated cartoon questionnaire (AACQ) at improving consent process in child for biospecimen donation. METHODS: A multi-center randomized and controlled survey was performed at two pediatric hospitals in China from 2019 to 2020. Children aged from 7 to 18 years in the pediatric surgery wards were invited to investigate the participants' willingness and attitudes for donating biospecimens. A total of 264 children, including 119 in the AACQ group and 145 in the TQ group, and 67 parents of children were analyzed. A separate knowledge test was acquired in the questionnaires. RESULTS: Our findings showed that the response rate of the AACQ group (89.85%) was significantly higher than that of the TQ group (68.44%; p < 0.001). AACQ can improve the child's understanding, increase children's engagement in biospecimen donation, reduced the differences in selected characteristics affecting children understanding, and enhanced their risk awareness of donating biospecimens. We also found that increasing pain and privacy disclosure were the most popular concern among children for the refusal to donate biospecimens. CONCLUSIONS: AACQ is an effective and standardized tool of content delivery to children from the surgical wards. Children who fully understood of biospecimen donation are suggested to participate in the consent signing. IMPACT: Using audio and animated cartoon questionnaire is a more effective and standardized tool of content delivery to children. This study expanded the use of an animated cartoon to a children's survey. Audio and animated cartoon questionnaire (AACQ) can improve the child's understanding, increase children's engagement in biospecimen donation compared to text questionnaire (TQ) group, and enhanced their risk awareness of donating biospecimens. More AACQ should be used with children in the future to effectively deliver content to children and improve children's participation in the survey.

17.
Infect Dis Ther ; 9(4): 1003-1015, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33170499

RESUMO

BACKGROUND: Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) has the potential to improve the pathogen identification in severe community-acquired pneumonia (SCAP). METHODS: In this 1.5-year, multicenter, prospective study, we investigated the usefulness of mNGS of BALF for identifying pathogens of SCAP in hospitalized adults, comparing it with other laboratory methods. RESULTS: Of 329 SCAP adults, a microbial etiology was established in 304 cases (92.4%). The overall microbial yield was 90.3% for mNGS versus 39.5% for other methods (P < 0.05). The most frequently detected pathogens in immunocompetent patients were Streptococcus pneumoniae (14.8%), rhinovirus (9.8%), Haemophilus influenzae (9.1%), Staphylococcus aureus (8.7%), and Chlamydia psittaci (8.0%), while in immunocompromised patients they were Pneumocystis jirovecii (44.6%), Klebsiella pneumoniae (18.5%), Streptococcus pneumoniae (15.4%), Haemophilus influenzae (13.8%), and Pseudomonas aeruginosa (13.8%). Notably, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified from two patients solely by mNGS in January 2020; uncommon pathogens including Orientia tsutsugamushi and Nocardia otitidiscaviarum were identified from one patient, respectively. Furthermore, mixed infections were detected in 56.8% of the patients. CONCLUSIONS: A high microbial detection rate was achieved in SCAP adults using mNGS testing of BALF. The most frequently detected pathogens of SCAP differed between immunocompetent and immunocompromised patients. mNGS testing may be an powerful tool for early identification of potential pathogens for SCAP to initiate a precise antimicrobial therapy.

18.
FASEB J ; 34(12): 15771-15787, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33131093

RESUMO

Over 466 million people worldwide are diagnosed with hearing loss (HL). About 90% of HL cases are sensorineural HL (SNHL) with treatments limited to hearing aids and cochlear implants with no FDA-approved drugs. Intriguingly, ADA-deficient patients have been reported to have bilateral SNHL, however, its underlying cellular and molecular basis remain unknown. We report that Ada-/- mice, phenocopying ADA-deficient humans, displayed SNHL. Ada-/- mice cochlea with elevated adenosine caused substantial nerve fiber demyelination and mild hair cell loss. ADA enzyme therapy in these mice normalized cochlear adenosine levels, attenuated SNHL, and prevented demyelination. Additionally, ADA enzyme therapy rescued SNHL by restoring nerve fiber structure in Ada-/- mice post two-week drug withdrawal. Moreover, elevated cochlear adenosine in untreated mice was associated with enhanced Adora2b gene expression. Preclinically, ADORA2B-specific antagonist treatment in Ada-/- mice significantly improved HL, nerve fiber density, and myelin compaction. We also provided genetic evidence that ADORA2B is detrimental for age-related SNHL by impairing cochlear myelination in WT aged mice. Overall, understanding purinergic molecular signaling in SNHL in Ada-/- mice allows us to further discover that ADORA2B is also a pathogenic factor underlying aged-related SNHL by impairing cochlear myelination and lowering cochlear adenosine levels or blocking ADORA2B signaling are effective therapies for SNHL.

19.
Adv Sci (Weinh) ; 7(19): 2001041, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33042742

RESUMO

High-throughput gene sequencing has identified various genetic variants as the culprits for some common hereditary cancers. However, the heritability of a substantial proportion of cancers remains unexplained, which may result from rare deleterious mutations hidden in a myriad of nonsense genetic variations. This poses a great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Here, whole genome sequencing is employed in a representative case in which one monozygotic twin is discordant for lung inflammatory myofibroblastoma to disclose rare tumor-related mutations. A missense single nucleotide variation rs61955126 T>C in the lysine methyltransferase SETD8 (accession: NM_020382, SETD8C302R ) is exposed. It is shown that SETD8 is vital for genomic integrity by promoting faithful DNA replication, and its C302R mutation downregulates the p53/p21 pathway. Importantly, the SETD8C302R mutation significantly increases the sensitivity of cancer cells to WEE1 inhibition. Given that WEE1 inhibitors have shown great promise for clinical approval, these results impart a potential therapeutic approach using WEE1 inhibitor for cancer patients carrying the same mutation, and indicate that genome sequencing and genetic functional studies can be integrated into individualized therapies.

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