Exploring the impact of gut microbiota on liver health in mice and patients with Wilson disease.

BACKGROUND AND AIMS: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD-related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. METHODS: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early- and late-stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD-afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. RESULTS: Patients with hepatic WD and mice with WD-related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD-related liver injury. CONCLUSIONS: Individuals and mice with pronounced WD-related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD-related liver injury.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Thrombotic antiphospholipid syndrome in a child with human immunodeficiency virus: a rare case report.

BACKGROUND: Antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disorder induced by antiphospholipid antibodies, which occurs exceedingly rarely in pediatric population and even more rarely reported in HIV positive children. A case of 11 years old boy had a sudden onset of swelling in his left lower leg along with pain which were worsening gradually. Initially, topical ointment was applied for 1 month which were ineffective in reducing pain and swelling. Instead, the symptoms were aggravated and suddenly spread to the proximal thigh, accompanied by dyskinesia of left lower leg. Both color doppler ultrasonography and vascular CT scan of left lower leg revealed deep venous thrombosis. His serum anti-phospholipid antibodies (aPLs) were tested positive. He was a known case of HIV virological failure with substantial HIV viral load (VL) despite receiving regular antiretroviral therapy (ART). His symptoms improved after giving aggressive antithrombotic and high dose corticosteroid treatments. CONCLUSION: When pediatric patients develop thrombotic disease, APS also needs to be ruled out. The autoantibodies levels should be routinely tested to look for recurrent thrombosis in children with HIV/AIDS.

AIDS-associated Talaromyces marneffei central nervous system infection in patients of southwestern China.

BACKGROUND: The clinical and laboratory characteristics of AIDS-associated Talaromyces marneffei infection, a rare but a fatal mycosis disease of the central nervous system, remain unclear. CASE PRESENTATION: Herein, we conducted a retrospective study of ten AIDS patients with cerebrospinal fluid culture-confirmed central nervous system infection caused by Talaromyces marneffei. All 10 patients were promptly treated with antifungal treatment for a prolonged duration and early antiviral therapy (ART). Among them, seven patients were farmers. Nine patients were discharged after full recovery, while one patient died during hospitalization, resulting in a mortality rate of 10%. All patients initially presented symptoms and signs of an increase in intracranial pressure, mainly manifesting as headache, dizziness, vomiting, fever, decreased muscle strength, diplopia or even altered consciousness with seizures in severe patients. Nine patients (90%) showed lateral ventricle dilatation or intracranial infectious lesions on brain CT. Cerebrospinal fluid findings included elevated intracranial pressure, increased leukocyte count, low glucose, low chloride and high cerebrospinal fluid protein. The median CD4+ T count of patients was 104 cells/µL (IQR, 36-224 cells/µL) at the onset of the disease. The CD4+ T cell counts of three patients who eventually died were significantly lower (W = 6.00, p = 0.020) than those of the patients who survived. CONCLUSIONS: The common clinical symptoms of T. marneffei central nervous system infection are associated with high intracranial pressure and intracranial infectious lesions. Earlier recognition and diagnosis and a prolonged course of amphotericin B treatment followed by itraconazole combined with early ART might reduce the mortality rate.

[De novo domestication to create new crops].

Crop improvement by domestication and traditional breeding often results in fitness penalties and loss of genetic diversity, which greatly threatens crop production and food security under the challenging global climate. De novo domestication has been proposed as a novel strategy for crop breeding. By combining multi-omics, genome editing and synthetic biology approaches, domestication of wild or semi-wild plant species can be accelerated by rapidly introducing desirable traits without causing an associated drag on their inherent traits. In this review, we summarize the history of crop domestication, emphasize the urgency for breeding strategy innovation, and discuss recent progress of de novo crop domestication.

Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties.

Novel representatives of the important group of biologically-active, dehydroabietic acid-bearing oxazolidinone moiety were synthesized to explore more efficacious and less toxic antitumor agents. Structures of all the newly target molecules were confirmed by IR, ¹H-NMR, 13C-NMR, and HR-MS. The inhibitory activities of these compounds against different human cancer cell lines (MGC-803, CNE-2, SK-OV-3, NCI-H460) and human normal liver cell line LO2 were evaluated and compared with the commercial anticancer drug cisplatin, using standard MTT (methyl thiazolytetrazolium) assay in vitro. The pharmacological screening results revealed that most of the hybrids showed significantly improved antiproliferative activities over dehydroabietic acid and that some displayed better inhibitory activities compared to cisplatin. In particular, compound 4j exhibited promising cytotoxicity with IC50 values ranging from 3.82 to 17.76 µM against all the test cell lines and displayed very weak cytotoxicity (IC50 > 100 µM) on normal cells, showing good selectivity between normal and malignant cells. Furthermore, the action mechanism of the representative compound 4j was preliminarily investigated by Annexin-V/PI dual staining, Hoechst 33258 staining, which indicated that the compound can induce cell apoptosis in MGC-803 cells in a dose-dependent manner and arrest the cell cycle in G1 phase. Therefore, 4j may be further exploited as a novel pharmacophore model for the development of anticancer agents.

Asymptomatic oral yeast carriage and antifungal susceptibility profile of HIV-infected patients in Kunming, Yunnan Province of China.

BACKGROUND: Oral Candida colonization and its relation with predisposing factors in HIV-infected patients have received wide concerns during recent decades. In this study, we investigated asymptomatic oral Candida carriage rate, species distribution and antifungal susceptibility of 604 HIV-infected patients and 851 healthy individuals in Kunming, Yunnan Province of China. METHODS: Mucosal swab sampling was taken from each subject and CHROMagar Candida agar medium and API 20C AUX system were used to identify yeast isolates. In vitro antifungal susceptibility was tested by the broth microdilution method according to the M27-A2 document of the Clinical and Laboratory Standard Institute (CLSI). RESULTS: The oral yeast colonization rate in HIV-infected patients (49.5%) was higher than that of healthy subjects (20.7%). Candida albicans constituted the most frequent species, accounting for 82.2% of yeast isolates. The remaining species were composed of C. glabrata, C. parapsilosis, C. krusei, C. tropicalis, C. rugosa, C. norvegensis, Pichia ohmeri and Saccharomyces cerevisiae. In HIV-infected patients, asymptomatic oral yeast colonization was associated with low CD4 cell count (<200 cells/mm3) and lack of highly active antiretroviral therapy (HAART). Different Candida species isolated from our samples presented different susceptibility to voriconazole, fluconazole and itraconazole. Amphotericin B had the best inhibiting effect for all isolates. CONCLUSION: Oral yeast colonization in Han Chinese patients with HIV from Kunming had common and unique features and was associated with CD4 cell number and HARRT. Amphotericin B should be used with first priority in controlling Candida infection in Han Chinese patients from Kunming. Our results provide first hand information on monitoring oral yeasts colonization in HIV-infected patients from Kunming, China.

[Seasonal variation of distribution and removal of high-risk tetracycline resistance genes in constructed wetland.] / é«˜é£Žé™©å››çŽ¯ç´ æŠ—æ€§åŸºå› åœ¨äººå·¥æ¹¿åœ°ä¸­åˆ†å¸ƒå’ŒåŽ»é™¤çš„å­£èŠ‚å˜åŒ–.

Livestock wastewater is an important reservoir of antibiotic resistance genes (ARGs), with high environmental risks. We investigated the seasonal variations of distribution and removal of swine wastewater originated high-risk tetracycline resistance genes (TRGs) in horizontal subsurface flow constructed wetlands. The effects of exogenous addition of tetracycline (TC) and copper ion (Cu2+) on the abundance of TRGs in effluent with single and combined pollution of antibiotic and heavy metal were studied. The results showed that all the three high-risk TRGs (tetM, tetO and tetW) were detected in swine wastewater. Wetlands could effectively reduce the ARGs, with the absolute abundance of TRGs in effluent being decreased by 1.1-2.4 and 1.7-2.9 orders of magnitude in summer and winter compared with the influent, respectively. The abundance of TRGs in wetland soils showed the characte-ristics that the outflow side was lower than the inflow side, the non-rhizosphere area was lower than the rhizosphere area, and lower in winter than in summer. In summer and winter, single and combined pollution of TC and Cu2+ in swine wastewater would increase the abundance of TRGs in effluent compared with that in the control. The constructed wetland is suitable for controlling the environmental diffusion of ARGs in livestock wastewater.

Prevalent and highly mobile antibiotic resistance genes in commercial organic fertilizers.

Compost-based organic fertilizers made from animal manures may contain high levels of antibiotic resistance genes (ARGs). However, the factors affecting the abundance and profile of ARGs in organic fertilizers remain unclear. We conducted a national-wide survey in China to investigate the effect of material type and composting process on ARG abundance in commercial organic fertilizers and quantified the contributions of bacterial composition and mobile genetic elements (MGEs) to the structuring of ARGs, using quantitative PCR and Illumina sequencing of 16S rRNA gene amplicons. The tetracycline, sulfonamide, aminoglycoside and macrolide resistance genes were present at high levels in all organic fertilizers. Seven ARGs that confer resistance to clinically important antibiotics, including three ß-lactam resistance genes, three quinolone resistance genes and the colistin resistance gene mcr-1, were detected in 8 - 50% the compost samples, whereas the vancomycin resistance gene vanC was not detected. Raw material type had a significant (p < 0.001) effect on the ARG abundance, with composts made from animal feces except some cattle feces generally having higher loads of ARGs than those from non-animal raw materials. Composting process type showed no significant (p > 0.05) effect on ARG abundance in the organic fertilizers. MGEs exerted a greater influence on ARG composition than bacterial community, suggesting a strong mobility of ARGs in the organic fertilizers. Our study highlights the need to manage the risk of ARG dissemination from agricultural wastes.

Spatiotemporal visualization for the global COVID-19 surveillance by balloon chart.

BACKGROUND: Considering the widespread of coronavirus disease 2019 (COVID-19) pandemic in the world, it is important to understand the spatiotemporal development of the pandemic. In this study, we aimed to visualize time-associated alterations of COVID-19 in the context of continents and countries. METHODS: Using COVID-19 case and death data from February to December 2020 offered by Johns Hopkins University, we generated time-associated balloon charts with multiple epidemiological indicators including crude case fatality rate (CFR), morbidity, mortality and the total number of cases, to compare the progression of the pandemic within a specific period across regions and countries, integrating seven related dimensions together. The area chart is used to supplement the display of the balloon chart in daily new COVID-19 case changes in UN geographic regions over time. Javascript and Vega-Lite were chosen for programming and mapping COVID-19 data in browsers for visualization. RESULTS: From February 1st to December 20th 2020, the COVID-19 pandemic spread across UN subregions in the chronological order. It was first reported in East Asia, and then became noticeable in Europe (South, West and North), North America, East Europe and West Asia, Central and South America, Southern Africa, Caribbean, South Asia, North Africa, Southeast Asia and Oceania, causing several waves of epidemics in different regions. Since October, the balloons of Europe, North America and West Asia have been rising rapidly, reaching a dramatically high morbidity level ranging from 200 to 500/10 000 by December, suggesting an emerging winter wave of COVID-19 which was much bigger than the previous ones. By late December 2020, some European and American countries displayed a leading mortality as high as or over 100/100 000, represented by Belgium, Czechia, Spain, France, Italy, UK, Hungary, Bulgaria, Peru, USA, Argentina, Brazil, Chile and Mexico. The mortality of Iran was the highest in Asia (over 60/100 000), and that of South Africa topped in Africa (40/100 000). In the last 15 days, the CFRs of most countries were at low levels of less than 5%, while Mexico had exceptional high CFR close to 10%. CONCLUSIONS: We creatively used visualization integrating 7-dimensional epidemiologic and spatiotemporal indicators to assess the progression of COVID-19 pandemic in terms of transmissibility and severity. Such methodology allows public health workers and policy makers to understand the epidemics comparatively and flexibly.