A Profile of Drug-Resistant Mutations in Mycobacterium tuberculosis Isolates from Guangdong Province, China.

Guangdong Province, China's largest economy, has a high incidence of tuberculosis (TB). At present, there are few reports on the distribution, transmission and drug resistance of Mycobacterium tuberculosis (Mtb) strains in this region. In this study, we performed minimum inhibitory concentration testing for 14 anti-TB drugs and whole-genome sequencing of 713 clinical Mtb isolates from 20,662 sputum culture-positive tuberculosis patients registered at 31 tuberculosis drug resistance surveillance sites covering 20 cities in Guangdong Province from 2016 to 2018. Moreover, we evaluated genome-wide associations between mutations and drug resistance, and further investigated the differences in the MICs of mutations. The epidemiology, drug-resistant phenotypes and whole genome sequencing data of 713 clinical Mtb isolates were analyzed, revealing the lineage distribution and drug-resistant gene profiles in Guangdong Province. WGS combined with quantitative MIC measurements identified several novel loci associated with resistance, of which 16 loci were found to be related to resistance to more than one drug. This study analyzed the lineage distribution, prevalence characteristics and resistance-corresponding gene profiles of Mtb isolates in Guangdong province, and provided a theoretical basis for the formulation of tuberculosis prevention and control policy in the province. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-024-01236-3.

Engineered Half-Unit-Cell MoS2/ZnIn2S4 Monolayer Photocatalysts and Adsorbed Hydroxyl Radicals-Assisted Activation of Cα-H Bond for Efficient Cß-O Bond Cleavage in Lignin to Aromatic Monomers.

Photocatalysis has high potential in the cleavage of Cß-O bond in lignin into high-value aromatic monomers; however, the inefficient Cα-H bond activation in lignin and a low hydrogen transfer efficiency on the photocatalyst's surfaces have limited its application in photocatalytic lignin conversion. This study indicates that the cleavage of the Cß-O bond can be improved by the generation of the Cα radical intermediate through Cα-H bond activation, and the formation of desirable aromatic products can be significantly improved by the enhanced hydrogen transfer efficiency from photocatalyst surfaces to aromatic monomeric radicals. We elaborately designed the half-unit-cell MoS2/ZnIn2S4 monolayer with a thickness of ∼1.7 nm to promote the hydrogen transfer efficiency on the photocatalyst surfaces. The ultrathin structure can shorten the diffusion distance of charge carriers from the interior to the surfaces and tight interface between MoS2 and ZnIn2S4 to facilitate the migration of photogenerated electrons from ZnIn2S4 to MoS2, therefore improving the selectivity of desirable products. The adsorbed hydroxyl radical (*OH) on the surfaces of MoS2/ZnIn2S4 from water oxidation can significantly reduce the bond dissociation energy (BDE) of Cα-H bond in PP-ol from 2.38 to 1.87 eV, therefore improving the Cα-H bond activation. The isotopic experiments of H2O/D2O indicate that the efficiency of *OH generation is an important step in Cα-H bond activation for PP-ol conversion to aromatic monomers. In summary, PP-ol can completely convert to 86.6% phenol and 82.3% acetophenone after 1 h of visible light irradiation by using 3% MoS2/ZnIn2S4 and the assistance of *OH, which shows the highest conversion rate compared to previous works.

Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice.

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TßMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TßMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TßMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Mycorrhizal status regulates plant phenological mismatch caused by warming.

Mycorrhiza is an important functional feature of plants, which plays a vital role in regulating plant phenology in response to environmental changes. However, the effect of mycorrhiza on plant phenological asymmetry in response to climate changes is still rarely reported. Based on a global database of mycorrhizal statuses (obligately mycorrhizal, OM and facultatively mycorrhizal, FM) and phenology, we demonstrated that mycorrhizas reduce the phenological mismatches between above- and below-ground plant responses to climate warming under OM status. The mismatch of above- and below-ground growing season length of FM plants to warming was as high as 10.65 days, 9.1925 days and 12.36 days in total, herbaceous and woody plants, respectively. The mismatch of growing season length of OM plants was only 2.12 days, -0.61 days and 7.64 days among plant groups, which was much lower than that of FM plants. Correlation analysis indicated that OM plants stabilized plant phenology by regulating the relationship between the start of the growing season and the length of the growing season. Path analysis found that herbaceous plants and woody plants reduced phenological mismatches by stabilizing below-ground and above-ground phenology, respectively. In exploring the effects of mycorrhizal status on early- or late-season phenophases, we found that different mycorrhizal statuses affected the response of early- or late-season phenophase to warming. OM promoted the advance of early-season phenophase, and FM promoted the delay of late-season phenophase among different plant groups. In different regions, OM and FM promoted the advance of early-season phenophase in temperate and boreal regions, respectively. Our results indicate that mycorrhizal status mediates plant phenological response to warming, so the potential effects of mycorrhizal status should be considered when studying plant phenology changes.

Incidence of drug-resistant pathogens in community-acquired pneumonia at a safety net hospital.

The 2019 Infectious Diseases Society of America guideline for the management of community-acquired pneumonia (CAP) emphasizes the need for clinician to understand local epidemiological data to guide selection of appropriate treatment. Currently, the local distribution of causative pathogens and their associated resistance patterns in CAP is unknown. A retrospective observational study was performed of patients admitted to an 870-bed safety net hospital between March 2016 and March 2021 who received a diagnosis of CAP or healthcare-associated pneumonia within the first 48 hours of admission. The primary outcome was the incidence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (PsA) as determined by comparing the number of satisfactory sputum cultures or blood cultures with these drug-resistant organisms to the total number of reviewed patients. Secondary outcomes studied included risk factors associated with CAP caused by drug-resistant organisms, utilization of broad-spectrum antibiotics, appropriate antibiotic de-escalation within 72 hours, and treatment duration. In this 220-patient cohort, MRSA or PsA was isolated from three sputum cultures and no blood cultures. The local incidence of drug-resistant pathogens among the analyzed sample of CAP patients was 1.4% (n = 3/220). The overall incidence of CAP caused by MRSA or PsA among admitted patients is low at our safety-net county hospital. Future research is needed to identify local risk factors associated with the development of CAP caused by drug-resistant pathogens.IMPORTANCEThis study investigates the incidence of drug-resistant pathogens including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa among community-acquired pneumonia (CAP) patients at a safety net hospital. Understanding local bacteria resistance patterns when treating CAP is essential and supported by evidence-based guidelines. Our findings empower other clinicians to investigate resistance patterns at their own institutions and identify methods to improve antibiotic use. This has the potential to reduce the unnecessary use of broad-spectrum antibiotic agents and combat the development of antibiotic resistance.

Unveiling the Influence of Copy Number Variations on Genetic Diversity and Adaptive Evolution in China's Native Pig Breeds via Whole-Genome Resequencing.

Copy number variations (CNVs) critically influence individual genetic diversity and phenotypic traits. In this study, we employed whole-genome resequencing technology to conduct an in-depth analysis of 50 pigs from five local swine populations [Rongchang pig (RC), Wuzhishan pig (WZS), Tibetan pig (T), Yorkshire (YL) and Landrace (LR)], aiming to assess their genetic potential and explore their prospects in the field of animal model applications. We identified a total of 96,466 CNVs, which were subsequently integrated into 7112 non-redundant CNVRs, encompassing 1.3% of the swine genome. Functional enrichment analysis of the genes within these CNVRs revealed significant associations with sensory perception, energy metabolism, and neural-related pathways. Further selective scan analyses of the local pig breeds RC, T, WZS, along with YL and LR, uncovered that for the RC variety, the genes PLA2G10 and ABCA8 were found to be closely related to fat metabolism and cardiovascular health. In the T breed, the genes NCF2 and CSGALNACT1 were associated with immune response and connective tissue characteristics. As for the WZS breed, the genes PLIN4 and CPB2 were primarily linked to fat storage and anti-inflammatory responses. In summary, this research underscores the pivotal role of CNVs in fostering the diversity and adaptive evolution of pig breeds while also offering valuable insights for further exploration of the advantageous genetic traits inherent to China's local pig breeds. This facilitates the creation of experimental animal models tailored to the specific characteristics of these breeds, contributing to the advancement of livestock and biomedical research.

Improved Lignin Conversion to High-Value Aromatic Monomers through Phase Junction CdS with Coexposed Hexagonal (100) and Cubic (220) Facets.

Photocatalysis has the potential for lignin valorization to generate functionalized aromatic monomers, but its application has been limited by the slow conversion rate and the low selectivity to desirable aromatic products. In this work, we designed the phase junction CdS with coexposed hexagonal (100) and cubic (220) facets to improve the photogenerated charge carriers' transfer efficiency from (100) facet to (220) facet and the hydrogen transfer efficiency for an enhanced conversion rate of lignin to aromatic monomers. Water is found as a sufficient external hydrogen supplier to increase the yields of aromatic monomers. These innovative designs in the reaction system promoted complete conversion of PP-ol to around 94% of aromatic monomers after 1 h of visible light irradiation, which shows the highest reaction rate and selectivity of target products in comparison with previous works. PP-one is a byproduct from the overoxidation of PP-ol and is usually difficult to be further cleaved to acetophenone and phenol as the desirable aromatic monomers. TEA was first identified in this study as a sacrificial electron donor, a hydrogen source, and a mediator to enhance the cleavage of the Cß-O bonds in PP-one. With the assistance of TEA, PP-one can be completely cleaved to desirable aromatic monomer products, and the reaction time is reduced from several hours to 10 min of visible light irradiation.

Chrysanthemum morifolium Ramat extract and probiotics combination ameliorates metabolic disorders through regulating gut microbiota and PPARα subcellular localization.

BACKGROUND: Chrysanthemum morifolium Ramat, a traditional Chinese medicine, has the effects on liver clearing, vision improving, and anti-inflammation. C. morifolium and probiotics have been individually studied for their beneficial effects on metabolic diseases. However, the underlying molecular mechanisms were not completely elucidated. This study aims to elucidate the potential molecular mechanisms of C. morifolium and probiotics combination (CP) on alleviating nonalcoholic fatty liver disease (NAFLD) and the dysregulation of glucose metabolism in high-fat diet (HFD)-fed mice. METHODS: The therapeutic effect of CP on metabolism was evaluated by liver histology and serum biochemical analysis, as well as glucose tolerance test. The impact of CP on gut microbiota was analyzed by 16S rRNA sequencing and fecal microbiota transplantation. Hepatic transcriptomic analysis was performed with the key genes and proteins validated by RT-qPCR and western blotting. In addition, whole body Pparα knockout (Pparα-/-) mice were used to confirm the CP-mediated pathway. RESULTS: CP supplementation ameliorated metabolic disorders by reducing body weight and hepatic steatosis, and improving glucose intolerance and insulin resistance in HFD fed mice. CP intervention mitigated the HFD-induced gut microbiota dysbiosis, which contributed at least in part, to the beneficial effect of improving glucose metabolism. In addition, hepatic transcriptomic analysis showed that CP modulated the expression of genes associated with lipid metabolism. CP downregulated the mRNA level of lipid droplet-binding proteins, such as Cidea and Cidec in the liver, leading to more substrates for fatty acid oxidation (FAO). Meanwhile, the expression of CPT1α, the rate-limiting enzyme of FAO, was significantly increased upon CP treatment. Mechanistically, though CP didn't affect the total PPARα level, it promoted the nuclear localization of PPARα, which contributed to the reduced expression of Cidea and Cidec, and increased expression of CPT1α, leading to activated FAO. Moreover, whole body PPARα deficiency abolished the anti-NAFLD effect of CP, suggesting the importance of PPARα in CP-mediated beneficial effect. CONCLUSION: This study revealed the hypoglycemic and hepatoprotective effect of CP by regulating gut microbiota composition and PPARα subcellular localization, highlighting its potential for therapeutic candidate for metabolic disorders.

Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis.

Doxorubicin (DOX) is a potent chemotherapeutic agent known for its multi-organ toxicity, especially in the heart, which limits its clinical application. The toxic side effects of DOX, including DNA damage, oxidative stress, mitochondrial dysfunction and cell apoptosis, are intricately linked to the involvement of nicotinamide adenine dinucleotide (NAD+). To assess the effectiveness of the NAD+ precursor nicotinamide mononucleotide (NMN) in counteracting the multi-organ toxicity of DOX, a mouse model was established through DOX administration, which led to significant reductions in NAD+ in tissues with evident injury, including the heart, liver and lungs. NMN treatment alleviated both multi-organ fibrosis and mortality in mice. Mechanistically, tissue fibrosis, macrophage infiltration and DOX-related cellular damage, which are potentially implicated in the development of multi-organ fibrosis, could be attenuated by NAD+ restoration. Our findings provide compelling evidence for the benefits of NMN supplementation in mitigating the adverse effects of chemotherapeutic drugs on multiple organs.

Isolation of Extracellular Outer Membrane Vesicles (OMVs) from Escherichia coli Using EVscore47 Beads.

Outer membrane vesicles (OMVs) are attractive for biomedical applications based on their intrinsic properties in relation to bacteria and vesicles. However, their widespread use is hampered by low yields and purities. In this study, EVscore47 multifunctional chromatography microspheres were synthesized and used to efficiently isolate functional OMVs from Escherichia coli. Through this technology, OMV loss can be kept to a minimum, and OMVs can be harvested using EVscore47 at 11-fold higher yields and ~13-fold higher purity than those achieved by means of ultracentrifugation. Based on the results presented here, we propose a novel EVscore47-based isolation of OMVs that is fast and scalable.

Current status and influencing factors of family resilience in families of children with epilepsy: a cross-sectional study.

Purpose: The study was designed to describe the level of family resilience and identify the protective factors and vulnerability factors of family resilience in families of children with epilepsy. So as to provide theoretical guidance for implementing intervention programs to promote family resilience. Methods: From November 2020 to July 2021, 258 parents of children with epilepsy were investigated using a convenience sampling method. The questionnaire included demographic data, Chinese-Family Resilience Assessment Scale, Social Support Rating Scale, and the Beck Depression Inventory. SPSS25.0 was used for descriptive statistical analysis, univariate analysis, and multivariate linear regression analysis. Results: In this study, two hundred and fifty-eight primary caregivers completed the paper questionnaires. The total score of family resilience was (134.97 ± 16.57), which was above the medium level. Multiple linear regression analysis revealed that subjective support (ß=0.327, P<0.001), comorbidity (ß=0.181, P<0.05), objective support (ß=0.117, P<0.05), and parental depression (ß=-0.158, P<0.05) were significantly related to family resilience. These variables contribute 31.7% of the variance in family resilience (F=18.07, P< 0.001). Conclusion: The families of children with epilepsy presented appropriate resilience after the children were diagnosed with epilepsy. Family resilience was correlated with multiple factors, subjective and objective support could be protective factors, comorbidity and parental depression could be vulnerability factors of family resilience. Therefore, future psychosocial interventions could focus on enhancing subjective support and objective support, reducing parental depression, and screening for epilepsy comorbidity to promote the family resilience of children with epilepsy.

Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

Astragalus polysaccharides attenuate chemotherapy-induced immune injury by modulating gut microbiota and polyunsaturated fatty acid metabolism.

BACKGROUND: The damage of chemotherapy drugs to immune function and intestinal mucosa is a common side effect during chemotherapy. Astragalus polysaccharides (APS) exhibit immunomodulatory properties and are recognized for preserving the integrity of the human intestinal barrier. Nevertheless, their application and mechanisms of action in chemotherapy-induced immune damage and intestinal barrier disruption remain insufficiently explored. PURPOSE: This study delved into investigating how APS mitigates chemotherapy-induced immune dysfunction and intestinal mucosal injury, while also providing deeper insights into the underlying mechanisms. METHODS: In a chemotherapy mice model induced by 5-fluorouracil (5-Fu), the assessment of APS's efficacy encompassed evaluations of immune organ weight, body weight, colon length, and histopathology. The regulation of different immune cells in spleen was detected by flow cytometry. 16S rRNA gene sequencings, ex vivo microbiome assay, fecal microbiota transplantation (FMT), and targeted metabolomics analysis were applied to explore the mechanisms of APS effected on chemotherapy-induced mice. RESULTS: APS ameliorated chemotherapy-induced damage to immune organs and regulated immune cell differentiation disorders, including CD4+T, CD8+T, CD19+B, F4/80+CD11B+ macrophages. APS also alleviated colon shortening and upregulated the expression of intestinal barrier proteins. Furthermore, APS significantly restored structure of gut microbiota following chemotherapy intervention. Ex vivo microbiome assays further demonstrated the capacity of APS to improve 5-Fu-induced microbiota growth inhibition and compositional change. FMT demonstrated that the regulation of gut microbiota by APS could promote the recovery of immune functions and alleviate shortening of the colon length. Remarkably, APS significantly ameliorated the imbalance of linoleic acid (LA) and α-linolenic acid in polyunsaturated fatty acid (PUFA) metabolism. Further in vitro experiments showed that LA could promote splenic lymphocyte proliferation. In addition, both LA and DGLA down-regulated the secretion of NO and partially up-regulated the percentage of F4/80+CD11B+CD206+ cells. CONCLUSION: APS can effectively ameliorate chemotherapy-induced immune damage and intestinal mucosal disruption by regulating the composition of the gut microbiota and further restoring PUFA metabolism. These findings indicate that APS can serve as an adjuvant to improve the side effects such as intestinal and immune damage caused by chemotherapy.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Combination eravacycline therapy for ventilator-associated pneumonia due to carbapenem-resistant Acinetobacter baumannii in patients with COVID-19: A case series.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia is associated with poor clinical outcomes and increased mortality. Clinical data regarding the optimal treatment of CRAB is limited, and combination therapy is often preferred. Eravacycline has demonstrated in-vitro activity against A. baumannii and has been considered for the treatment of pulmonary infections caused by CRAB. OBJECTIVE: The objective of this case series was to describe clinical outcomes associated with eravacycline when utilized as part of a combination regimen for the treatment of CRAB pneumonia at a county hospital. METHODS: A retrospective chart review was conducted from April 1, 2020, to October 1, 2020, which included hospitalized patients ≥18 years of age, diagnosed with coronavirus disease 2019 (COVID-19), with a sputum culture positive for CRAB, and receipt of at least one dose of eravacycline. The primary outcome studied was clinical resolution of CRAB pneumonia. A key secondary outcome was microbiological resolution. RESULTS: A total of 24 patients received combination eravacycline therapy for a median of 10.5 days. Overall, 17 (71%) patients demonstrated clinical resolution of CRAB pneumonia. Repeat sputum cultures post-treatment were collected in 17 (71%) patients, of which 12 (71%) achieved microbiological resolution. No adverse events attributable to eravacycline were identified. CONCLUSION: With limited viable salvage treatment options, combination eravacycline therapy showed favorable microbiological and clinical outcomes in patients with CRAB pneumonia. In light of this, eravacycline could be considered as a potential treatment option when designing CRAB pneumonia salvage therapy regimens.

Comparison of the MeltPro TB assay and whole-genome sequencing assay for rapid molecular diagnosis of drug resistant tuberculosis in guangdong province.

BACKGROUND: Rifampicin (RIF) and multidrug-resistant tuberculosis (TB) are major public health threats. As conventional phenotypic drug susceptibility testing requires two-eight weeks, molecular diagnostic assays are widely used to determine drug resistance. METHODS: Clinical Mycobacterium tuberculosis isolates with consistent drug susceptibility results, tested using microbroth dilution and proportion methods in Löwenstein-Jensen medium from patients with TB in Guangdong province were utilized to evaluate MeltPro TB and whole-genome sequencing (WGS) assays in detecting resistance to RIF, isoniazid (INH), ethambutol (EMB), fluoroquinolones (FQ), and streptomycin (SM). Solid phenotypic drug susceptibility testing was used as the gold standard to evaluate the detection capacity of MeltPro TB on clinical sputum samples of patients with TB. RESULTS: Similar to WGS, MeltPro TB successfully detected RIF, INH, and SM resistance with sensitivities of 86.3, 84.8, and 86.6 %, respectively. However, the resistant isolate detection rates were only 58.1 and 69.6 % for EMB and FQ-resistant strains. For clinical specimens, MeltPro TB still showed good detectable rates of RIF and INH resistance, with sensitivities of 82.4 % and 95.2 %, respectively. Detectable rates of FQ and EMB resistance were low: 77.8 % and 35.3 %, respectively. CONCLUSIONS: MeltPro TB can detect known DNA mutations associated with drug resistance in Mycobacterium tuberculosis strains with comparable efficacy to WGS. For FQ and EMB resistance testing, MeltPro TB requires optimization and is unsuitable for general use. MeltPro TB can be used for diagnosis of RIF and multidrug-resistant tuberculosis to rapidly initiate appropriate anti-TB drug therapy.

Disrupted topological organization of the default mode network in mild cognitive impairment with subsyndromal depression: A graph theoretical analysis.

AIMS: Subsyndromal depression (SSD) is common in mild cognitive impairment (MCI). However, the neural mechanisms underlying MCI with SSD (MCID) are unclear. The default mode network (DMN) is associated with cognitive processes and depressive symptoms. Therefore, we aimed to explore the topological organization of the DMN in patients with MCID. METHODS: Forty-two MCID patients, 34 MCI patients without SSD (MCIND), and 36 matched healthy controls (HCs) were enrolled. The resting-state functional connectivity of the DMN of the participants was analyzed using a graph theoretical approach. Correlation analyses of network topological metrics, depressive symptoms, and cognitive function were conducted. Moreover, support vector machine (SVM) models were constructed based on topological metrics to distinguish MCID from MCIND. Finally, we used 10 repeats of 5-fold cross-validation for performance verification. RESULTS: We found that the global efficiency and nodal efficiency of the left anterior medial prefrontal cortex (aMPFC) of the MCID group were significantly lower than the MCIND group. Moreover, small-worldness and global efficiency were negatively correlated with depressive symptoms in MCID, and the nodal efficiency of the left lateral temporal cortex and left aMPFC was positively correlated with cognitive function in MCID. In cross-validation, the SVM model had an accuracy of 0.83 [95% CI 0.79-0.87], a sensitivity of 0.88 [95% CI 0.86-0.90], a specificity of 0.75 [95% CI 0.72-0.78] and an area under the curve of 0.88 [95% CI 0.85-0.91]. CONCLUSIONS: The coexistence of MCI and SSD was associated with the greatest disrupted topological organization of the DMN. The network topological metrics could identify MCID and serve as biomarkers of different clinical phenotypic presentations of MCI.

A new variant of the colistin resistance gene MCR-1 with co-resistance to ß-lactam antibiotics reveals a potential novel antimicrobial peptide.

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to ß-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to ß-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.

EspB and HtpG interact with the type III-A CRISPR/Cas system of Mycobacterium tuberculosis.

Introduction: Mycobacterium tuberculosis (MTB) has a type III-A clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas) system consisting of a Csm1-5 and CRISPR RNA (crRNA) complex involved in the defense against invading nucleic acids. However, CRISPR/Cas system in the MTB still is clearly unknown and needs to be further explored. Methods: In our work, two non-Cas system proteins EspB and HtpG protein were found and identified by LC-MS/MS. The effect of EspB and HtpG on Type III-A CRISPR/Cas System of M. tuberculosis was examined by using Plasmid interference assay and Co-immunoprecipitation analyses. We explored that EspB could interact with the crRNA RNP complex, but HtpG could inhibit the accumulation of the MTB Csm proteins and defense the mechanism of CRISPR/Cas system. Results: The proteins ESAT-6 secretion system-1(Esx-1) secreted protein B (EspB) and high-temperature protein G (HtpG), which were not previously associated with CRISPR/Cas systems, are involved in mycobacterial CRISPR/Cas systems with distinct functions. Conclusion: EspB is a novel crRNA-binding protein that interacts directly with the MTB crRNP complex. Meanwhile, HtpG influences the accumulation of MTB Csm proteins and EspB and interferes with the defense mechanism of the crRNP complex against foreign DNA in vivo. Thereby, our study not only leads to developing more precise clinical diagnostic tool to quickly detect for MTB infection, but also knows these proteins merits for TB biomarkers/vaccine candidates.

A study on community older people's willingness to use smart home-an extended technology acceptance model with intergenerational relationships.

Introduction: Despite the potential of smart home technology to promote sustainable lifestyles, the adoption rate among older adults remains relatively low. This study aims to investigate the influence of intergenerational relationships on the acceptance of smart home services among seniors. Methods: A survey was conducted among 298 older adults in China, and data were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). Ten predictor variables were examined to assess their impact on the willingness to use smart home services. Results: Intergenerational relationships significantly influenced the utilization of smart home services among older adults. Specifically, intergenerational instrumental support had a direct positive effect on the behavioral intention to use smart homes. Additionally, intergenerational emotional and financial support affected life satisfaction, which subsequently influenced the behavioral intention to use smart homes. Discussion: The assistance and guidance provided by younger generations play a crucial role in shaping the willingness of older adults to adopt smart home technology. Intergenerational support can contribute positively to enabling aging individuals to age in place through the utilization of technology.