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The urban environmental effects can have multifaceted impacts on the orchard soil microbial community structure and function. To specifically study these effects, we investigated the soil bacterial and fungal community in the laxly managed citrus orchards using amplicon sequencing. Ascomycota demonstrated significant dominance within the citrus orchard soils. The increased presence of beneficial Trichoderma spp. (0.3%) could help suppress plant pathogens, while the elevated abundance of potential pathogenic fungi, such as Fusarium spp. (0.4%), might raise the likelihood of disorders like root rot, thereby hindering plant growth and resulting in reduced yield. Moreover, we observed significant differences in the alpha and beta diversity of bacterial communities between urban and rural soils (p

Candida parapsilosis is becoming a predominant non-albicans cause of invasive candidiasis (IC). Echinocandins are the preferred choice for IC treatment and prophylaxis. Resistance to echinocandins in C. parapsilosis has emerged in several countries, but little is known about the susceptibility profile in China or about mechanisms of resistance. Here, we investigated the echinocandin susceptibilities of 2523 C. parapsilosis isolates collected from China and further explored the resistance mechanism among echinocandin-resistant isolates. Anidulafungin exhibited the highest MICs (MIC50/90, 1 and 2 µg/mL; GM, 0.948 µg/mL), while caspofungin showed better activity (0.5 and 1 µg/mL; 0.498 µg/mL). Significantly higher echinocandin MICs were observed among blood-derived isolates compared to others, especially for caspofungin (GM, 1.348 µg/mL vs 0.478 µg/mL). Isolates from ICU and surgical wards also showed higher MICs. Twenty isolates showed intermediate phenotypes for at least one echinocandin. One was resistant to all three echinocandins, fluconazole and voriconazole, which caused breakthrough IC during long-term exposure to micafungin. WGS revealed this isolate carried a mutation S656P in hotspot1 region of Fks1. Bioinformatics analyses suggested that this mutation might lead to an altered protein conformation. CRISPR Cas9-mediated introduction of this mutation into a susceptible reference C. parapsilosis strain increased MICs of all echinocandins 64-fold, with similar results found in the subspecies, C. orthopsilosis and C. metapsilosis. This is the first report of a multi-azole resistant and pan-echinocandin resistant C. parapsilosis isolate, and the identification of a FKS1S656P conferring pan-echinocandin resistance. Our study underscores the necessity of rigorous management of antifungal use and of monitoring for antifungal susceptibility.

Abstract Background Pancreatic cancer (PAC), a malignancy that is fatal and commonly diagnosed at a late stage. Despite considerable advancements in cancer treatment, the survival rate of PAC remains largely consistent for the past 60 years. The traditional Chinese medicine formula Pulsatilla Decoction (PD) has been clinically used to treat inflammatory diseases for millennia and recently as a supplementary anti-cancer treatment in China. However, the bioactive ingredients and mechanisms underlying its anti-cancer effect remains unclear. Methods The composition and quality control of PD were verified through analysis by high performance liquid chromatography. Cell viability was determined using Cell Counting Kit-8 assay. The cell cycle distribution was analyzed through PI staining and flow cytometry analysis, while apoptotic cells were measured by double staining with Annexin V-FITC and PI. We used immunoblotting to examine protein expressions. The in vivo effects of β-peltatin and podophyllotoxin were evaluated on a subcutaneously-xenografted BxPC-3 cell nude mice model. Results The current study demonstrated that PD markedly inhibited PAC cell proliferation and triggered their apoptosis. Four herbal PD formula was then disassembled into 15 combinations of herbal ingredients and a cytotoxicity assay showed that the Pulsatillae chinensis exerted the predominant anti-PAC effect. Further investigation indicated that β-peltatin was potently cytotoxic with IC50 of ~ 2 nM. β-peltatin initially arrested PAC cells at G2/M phase, followed by apoptosis induction. Animal study confirmed that β-peltatin significantly suppressed the growth of subcutaneously-implanted BxPC-3 cell xenografts. Importantly, compared to podophyllotoxin that is the parental isomer of β-peltatin but clinically obsoleted due to its severe toxicity, β-peltatin exhibited stronger anti-PAC effect and lower toxicity in mice. Conclusions Our results demonstrate that Pulsatillae chinensis and particularly its bioactive ingredient β-peltatin suppress PAC by triggering cell cycle arrest at G2/M phase and apoptosis.

Abstract Bone metastasis occurs when tumour cells dissociate from primary tumours, enter the circulation (circulating tumour cells, CTCs), and colonize sites in bone (disseminated tumour cells, DTCs). The bone marrow seems to be a particularly dormancy-inducing environment for DTCs, yet the mechanisms of dormancy initiation, reactivation, and interaction within the bone marrow have to be elucidated. Intriguingly, some evidence has suggested that dormancy is a reversible state that is switched ‘on’ or ‘off’ depending on the presence of various bone marrow resident cells, particularly osteoclasts and osteoblasts. It has become clear that these two cells contribute to regulating dormant tumour cells in bone both directly (interaction) and indirectly (secreted factors). The involved mechanisms include TGFβ signalling, the Wnt signalling axis, the Notch2 pathway, etc. There is no detailed review that specifically focuses on ascertaining the dynamic interactions between tumour cell dormancy and bone remodelling. In addition, we highlighted the roles of inflammatory cytokines during this ‘cell-to-cell’ communication. We also discussed the potential clinical relevance of remodelling the bone marrow niche in controlling dormant tumour cells. Understanding the unique role of osteoclasts and osteoblasts in regulating tumour dormancy in bone marrow will provide new insight into preventing and treating tumour bone metastasis.

Background and Objective: The novel coronavirus disease (COVID-19) outbreak is currently ravaging populations worldwide. Many studies were registered and conducted in rapid response to the epidemic, but how to choose the proper design for clinical trials remains the main concern. This study aimed to determine the fundamental characteristics of study design during the COVID-19 pandemic and provide references for other emerging infectious diseases. Methods: We searched the database of ClinicalTrials.gov with the keyword “COVID-19” and compared the results with the design features of other conventional studies except for COVID-19. Results: From January 1, 2020 to September 30, 2021, 55,334 trials were registered at ClinicalTrials.gov. Of all the registered trials, 6,408 were related to COVID-19 (11.58%). There were significant differences in the proportion of observational studies between COVID-19 (43.48%) and others (23.27%). The completion rate of observational trials and interventional trials in COVID-19 was 29.04% and 25.84%, respectively. COVID-19 trials showed a higher rate of completion than others (P

ObjectivesTo evaluate the population structure of environmental bacteria and fungi in three different types of medical institutions and the potential risks due to antibiotic resistance during the coronavirus disease 2019 (COVID-19) pandemic.MethodsOne hundred twenty-six environmental surface samples were collected from three medical institutions during the COVID-19 pandemic. A total of 6,093 and 13,514 representative sequences of 16S and ITS ribosomal RNA (rRNA) were obtained by amplicon sequencing analysis. The functional prediction was performed using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States tool based on the Greengenes database and the FAPROTAX database.ResultsOn environmental surfaces in three medical institutions during the COVID-19 pandemic, Firmicutes (51.6%) and Bacteroidetes (25%) were the dominant bacteria, while Ascomycota (39.4%) and Basidiomycota (14.2%) were the dominant fungi. A number of potential bacterial and fungal pathogens were successfully identified by the metagenomic approach. Furthermore, compared with the bacterial results, the fungi showed a generally closer Bray Curtis distance between samples. The overall ratio of Gram-negative bacteria to Gram-positive bacteria was about 3:7. The proportion of stress-tolerant bacteria in medical institutions A, B and C reached 88.9, 93.0 and 93.8%, respectively. Anaerobic bacteria accounted for 39.6% in outdoor environments, 77.7% in public areas, 87.9% in inpatient areas and 79.6% in restricted areas. Finally, the β-Lactam resistance pathway and polymyxin resistance pathway were revealed through functional prediction.ConclusionWe described the microbial population structure changes in three different types of medical institutions using the metagenomic approach during the COVID-19 pandemic. We found that the disinfection measures performed by three healthcare facilities may be effective on the “ESKAPE” pathogens, but less effective on fungal pathogens. Moreover, emphasis should be given to the prevention and control of β-lactam and polymyxin antibiotics resistance bacteria during the COVID-19 pandemic.

Gastrointestinal cancers refer to a group of deadly malignancies of the gastrointestinal tract and organs of the digestive system. Over the past decades, considerable amounts of medicinal plants have exhibited potent anticancer effects on different types of gastrointestinal cancers. OMICS, systems biology approaches covering genomics, transcriptomics, proteomics and metabolomics, are broadly applied to comprehensively reflect the molecular profiles in mechanistic studies of medicinal plants. Single- and multi-OMICS approaches facilitate the unravelling of signalling interaction networks and key molecular targets of medicinal plants with anti-gastrointestinal cancer potential. Hence, this review summarizes the applications of various OMICS and advanced bioinformatics approaches in examining therapeutic targets, signalling pathways, and the tumour microenvironment in response to anticancer medicinal plants. Advances and prospects in this field are also discussed.

Leflunomide is used for the treatment of rheumatoid arthritis. Here, the authors show that effectiveness is limited in patients with higher levels of serum c-reactive protein (CRP). Using animal models, they show that higher CRP induces HIF1a expression, which in turn interferes with Leflunomide signalling, and that effectiveness of the drug is restored when HIF1a is pharmacologically inhibited.

ObjectivesTo evaluate (1) the relationship between heating, ventilation, and air conditioning (HVAC) systems and bioaerosol concentrations in hospital rooms, and (2) the effectiveness of laminar air flow (LAF) and high efficiency particulate air (HEPA) according to the indoor bioaerosol concentrations.MethodsDatabases of Embase, PubMed, Cochrane Library, MEDLINE, and Web of Science were searched from 1st January 2000 to 31st December 2020. Two reviewers independently extracted data and assessed the quality of the studies. The samples obtained from different areas of hospitals were grouped and described statistically. Furthermore, the meta-analysis of LAF and HEPA were performed using random-effects models. The methodological quality of the studies included in the meta-analysis was assessed using the checklist recommended by the Agency for Healthcare Research and Quality.ResultsThe mean CFU/m3 of the conventional HVAC rooms and enhanced HVAC rooms was lower than that of rooms without HVAC systems. Furthermore, the use of the HEPA filter reduced bacteria by 113.13 (95% CI: -197.89, -28.38) CFU/m3 and fungi by 6.53 (95% CI: -10.50, -2.55) CFU/m3. Meanwhile, the indoor bacterial concentration of LAF systems decreased by 40.05 (95% CI: -55.52, -24.58) CFU/m3 compared to that of conventional HVAC systems.ConclusionsThe HVAC systems in hospitals can effectively remove bioaerosols. Further, the use of HEPA filters is an effective option for areas that are under-ventilated and require additional protection. However, other components of the LAF system other than the HEPA filter are not conducive to removing airborne bacteria and fungi.Limitation of studyAlthough our study analysed the overall trend of indoor bioaerosols, the conclusions cannot be extrapolated to rare, hard-to-culture, and highly pathogenic species, as well as species complexes. These species require specific culture conditions or different sampling requirements. Investigating the effects of HVAC systems on these species via conventional culture counting methods is challenging and further analysis that includes combining molecular identification methods is necessary.Strength of the studyOur study was the first meta-analysis to evaluate the effect of HVAC systems on indoor bioaerosols through microbial incubation count. Our study demonstrated that HVAC systems could effectively reduce overall bioaerosol concentrations to maintain better indoor air quality. Moreover, our study provided further evidence that other components of the LAF system other than the HEPA filter are not conducive to removing airborne bacteria and fungi.Practical implicationOur research showed that HEPA filters are more effective at removing bioaerosols in HVAC systems than the current LAF system. Therefore, instead of opting for the more costly LAF system, a filter with a higher filtration rate would be a better choice for indoor environments that require higher air quality; this is valuable for operating room construction and maintenance budget allocation.

Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.