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Thiamine (vitamin B1) carbene liganded gold(i) chloride efficiently catalyses an aldehyde–alkyne–amine (A3) coupling reaction in open air under solvent-free conditions or in water.

Appendectomy impacts the homeostasis of gut microbiome in patients. We aimed to study the role of appendectomy in colorectal cancer (CRC) risk through causing gut microbial dysbiosis. Population-based longitudinal study (cohort 1, n = 129,155) showed a 73.0% increase in CRC risk among appendectomy cases throughout 20 years follow-up (Adjusted sub-distribution hazard ratio (SHR) 1.73, 95% CI 1.49–2.01, P n = 314). Gut microbial dysbiosis in appendectomy subjects was observed with significant enrichment of 7 CRC-promoting bacteria (Bacteroides vulgatus, Bacteroides fragilis, Veillonella dispar, Prevotella ruminicola, Prevotella fucsa, Prevotella dentalis, Prevotella denticola) and depletion of 5 beneficial commensals (Blautia sp YL58, Enterococcus hirae, Lachnospiraceae bacterium Choco86, Collinsella aerofaciens, Blautia sp SC05B48). Microbial network analysis showed increased correlation strengths among enriched bacteria and their enriched oncogenic pathways in appendectomy subjects compared to controls. Of which, B. fragilis was the centrality in the network of the enriched bacteria. We further confirmed that appendectomy promoted colorectal tumorigenesis in mice by causing gut microbial dysbiosis and impaired intestinal barrier function. Collectively, this study revealed appendectomy-induced microbial dysbiosis characterized by enriched CRC-promoting bacteria and depleted beneficial commensals, signifying that the gut microbiome may play a crucial role in CRC development induced by appendectomy.

Objective: To investigate the source in an outbreak of carbapenem-resistant Acinetobacter baumannii (CRA) in a general hospital due to contamination of a laundry evaporative cooler and the laundry environment using multilocus sequence typing (MLST). Methods: For CRA culture, clinical samples were collected from infected patients and close contacts, and environmental sampling was performed in patient surroundings and laundry facilities. MLST was used for the molecular typing of representative CRA isolates. Bacterial isolates with identical sequence types were considered epidemiologically linked and attributable to the same source. OXA genes in Acinetobacter baumannii were detected using polymerase chain reaction (PCR). Results: In total, 58 patients were affected in this outbreak. The mean patient age was 75.3, and 50% were female. The most common diagnoses at admission were skin and soft-tissue infection (n = 12, 20.7%) and pneumonia (n = 12, 20.7%). OXA-23 was positive in 64.7% of isolates. A CRA isolate from the evaporative cooler in the laundry was identical to that of 11 patients across 3 wards, belonging to ST345. Isolates from 3 laundry linen racks were identical to those of 7 patients from 3 wards, classified as ST1145. Isolates found on another linen rack and a pajama shelf were identical to isolates from 3 other patients from 2 wards, belonging to ST2207. There was no significant difference between sequence type distributions of clinical and environmental isolates (P = .12), indicating high likelihood of CRA originating from the same source. Conclusions: MLST confirmed that contamination of the laundry evaporative cooler and surrounding environment caused a polyclonal CRA hospital outbreak. Hospital laundry is an important area for infection control and outbreak investigations of CRA.

Older adults have been statistically proved to be at a higher risk of getting severely infected by the coronavirus COVID-19, evoking sweeping narratives of compassionate ageism surrounding them in different discourses. By analysing the media content, scholars from different areas have alerted us about the amplified ageism aroused by the pandemic crisis. However, we are still short of empirical evidence to learn how ageism is constructed in diverse sociocultural contexts in the wake of this global pandemic crisis. This study provides the case of Hong Kong to reflect on how ageism, as a set of social inequalities, is constructed. By examining 814 articles collected from the three most popular newspapers with different political orientations in Hong Kong, this study uses quantitative and qualitative content analysis to examine how older people have been generally represented. Then it further compares how these representations have been influenced by the media's liberal or conservative preferences. Third, it examines the relationship between the political orientation of newspapers and how different forms of ageism are constructed. The findings indicate that despite the liberal or conservative inclination of the three newspapers, they portray the older population as frail, dependent and deprived not only at the biomedical level but in all aspects of life. This study also reveals that the newspapers with a populist inclination in both camps have shown more hostile attitudes in representing compassionate ageism. In contrast, liberal and conservative-leaning media affirmed the government's dominant role in taking full responsibility for caring for the older population. The findings indicate that the polarised ageism frame cannot fully explain the underpinnings of ageism and implied policy processing in different contexts.

The consistency of the associations between gastric mucosal microbiome and gastric cancer across studies remained unexamined. We aimed to identify universal microbial signatures in gastric carcinogenesis through a meta-analysis of gastric microbiome from multiple studies. Compositional and ecological profiles of gastric microbes across stages of gastric carcinogenesis were significantly altered. Meta-analysis revealed that opportunistic pathobionts Fusobacterium, Parvimonas, Veillonella, Prevotella and Peptostreptococcus were enriched in GC, while commensals Bifidobacterium, Bacillus and Blautia were depleted in comparison to SG. The co-occurring correlation strengths of GC-enriched bacteria were increased along disease progression while those of GC-depleted bacteria were decreased. Eight bacterial taxa, including Veillonella, Dialister, Granulicatella, Herbaspirillum, Comamonas, Chryseobacterium, Shewanella and Helicobacter, were newly identified by this study as universal biomarkers for robustly discriminating GC from SG, with an area under the curve (AUC) of 0.85. Moreover, H. pylori-positive samples exhibited reduced microbial diversity, altered microbiota community and weaker interactions among gastric microbes. Our meta-analysis demonstrated comprehensive and generalizable gastric mucosa microbial features associated with histological stages of gastric carcinogenesis, including GC associated bacteria, diagnostic biomarkers, bacterial network alteration and H. pylori influence.

As people’s focus broadens from animals on farms to zoos and aquaria, the field of welfare science and the public’s concern for animal welfare continue to grow. In captive animals, stress and its causes are topics of interest in welfare issues, and the identification of an objective method that can be used to assess animals’ stress as a physiological state is essential. Both behavioral and physiological parameters can be used as indicators in order to assess animal stress quantitatively. To validate this approach, acoustic activity and the sloughed scrape skin cortisol concentration were used to evaluate the animal welfare of captive beluga whales (Delphinapterus leucas). The acoustic activity (5 min at 10:00 am) of three captive D. leucas was routinely recorded by a transducer and analyzed using audio editing software. The calls were separated into three main categories: whistles, pulses, and combo calls. The sloughed scrape skin samples were collected non-invasively once a week from all three animals’ fluke and/or flipper. Cortisol was extracted using a modified skin steroid extraction technique, and detected via commercially available enzyme immunoassays. The results showed that the cortisol concentration increased by varying levels when the whales encountered the same event. In addition, the number and distribution of the calls changed along with the events. This indicated that the changes in the cortisol concentration and acoustic behavior may have reflected the fluctuations in the environment and body condition. Therefore, the scrape cortisol measurement and acoustic recordings could be used to monitor stress levels in captive beluga whales. We recommend that aquaria consider incorporating skin scrape cortisol and acoustic activity monitoring into their standards for animal welfare.

Follicular lymphoma (FL) accounts for approximately 20% of all new lymphoma cases. Increases in cytological grade are a feature of the clinical progression of this malignancy, and eventual histologic transformation (HT) to the aggressive diffuse large B-cell lymphoma (DLBCL) occurs in up to 15% of patients. Clinical or genetic features to predict the risk and timing of HT have not been comprehensively described. In this study, we analyzed whole genome sequencing data from 423 patients to compare the protein coding and non-coding mutation landscapes of untransformed FL, transformed FL and de novo DLBCL. This revealed two genetically distinct subgroups of FL which we have named DLBCL-like (dFL) and constrained FL (cFL). Each subgroup has distinguishing mutational patterns, aberrant somatic hypermutation rates, biological, and clinical characteristics. We implemented a machine-learning-derived classification approach to stratify FL patients into cFL and dFL subgroups based on their genomic features. Using separate validation cohorts, we demonstrate that cFL status, whether assigned with this full classifier or a single-gene approximation, is associated with a reduced rate of HT. This implies distinct biological features of cFL that constrain its evolution and we highlight the potential for this classification to predict HT from genetic features present at diagnosis.

Urease is a nickel (Ni) enzyme that is essential for the colonization of Helicobacter pylori in the human stomach. To solve the problem of delivering the toxic Ni ion to the active site without diffusing into the cytoplasm, cells have evolved metal carrier proteins, or metallochaperones, to deliver the toxic ions to specific protein complexes. Ni delivery requires urease to form an activation complex with the urease accessory proteins UreFD and UreG. Here, we determined the cryo–electron microscopy structures of H. pylori UreFD/urease and Klebsiella pneumoniae UreD/urease complexes at 2.3- and 2.7-angstrom resolutions, respectively. Combining structural, mutagenesis, and biochemical studies, we show that the formation of the activation complex opens a 100-angstrom-long tunnel, where the Ni ion is delivered through UreFD to the active site of urease.

Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution

Supplementary Figure from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution

Cancer-related genes have evolved specific genetic and genomic features to favor tumor suppression. Previously we reported that tumor suppressor genes (TSGs) acquired high promoter CpG dinucleotide frequencies during evolution to maintain high expression in normal tissues and resist cancer-specific downregulation. In this study, we investigated whether 3'untranslated regions (3'UTRs) of TSGs have evolved specific features to carry out similar functions. We found that 3'UTRs of TSGs, especially those involved in multiple histological types and pediatric cancers, are longer than those of non-cancer genes. 3'UTRs of TSGs also exhibit higher density of binding sites for RNA-binding proteins (RBPs), particularly those having high affinities to C-rich motifs. Both longer 3'UTR length and RBP binding sites enrichment are correlated with higher gene expression in normal tissues across tissue types. Moreover, both features together with the correlated N

Background: Peritoneal dialysis (PD) patients with impaired hand–eye function require helper assistance. Our centre developed a connection device that assists patients with impaired hand–eye function to perform PD exchange themselves, but the clinical outcomes in these patients have not been investigated. Methods: We retrospectively reviewed patients who had device-assisted continuous ambulatory peritoneal dialysis (CAPD) during 2007–2016 and compared their clinical outcomes with age- and sex-matched patients receiving helper-assisted CAPD. Results: One hundred seventy-two patients (86 each in the device- and helper-assisted CAPD groups) were followed for 29.9 (19.4–43.3) months. The device- and helper-assisted groups had comparable peritonitis rates (0.489 and 0.504 episode per patient-year, respectively, p = 0.814), with no difference in the distribution of causative organisms and the organism-specific peritonitis rates. The device-assisted group showed similar peritonitis-free survival compared with the helper-assisted group (2.58 (1.85–3.31) vs. 1.78 (0.68–2.88) years, p = 0.363) and time-to-PD discontinuation (6.27 (3.65–8.90) vs. 4.35 (3.48–5.22) years, p = 0.677). The median patient survival was similar between the two groups (3.89 (2.22–5.55) vs. 3.81 (3.27–4.36) years in the device- and helper-assisted groups, respectively, p = 0.505). Conclusion: Device-assisted CAPD confers comparable outcomes as helper-assisted CAPD and is a viable option in PD patients with impaired hand–eye function.

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited. Published version This work was supported by The TUYF Charitable Trust and Shenzhen Science and Technology Programme (JCYJ20180508161604382).

Clostridioides difficile infection (CDI) is a common cause of nosocomial diarrhea. TcdB is a major C. difficile exotoxin that activates macrophages to promote inflammation and epithelial damage. Lysosome impairment is a known trigger for inflammation. Herein, we hypothesize that TcdB could impair macrophage lysosomal function to mediate inflammation during CDI. Effects of TcdB on lysosomal function and the downstream pro-inflammatory SQSTM1/p62-NFKB (nuclear factor kappa B) signaling were assessed in cultured macrophages and in a murine CDI model. Protective effects of two lysosome activators (i.e., vitamin D3 and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/β-catenin activity to downregulate MITF (melanocyte inducing transcription factor) and its direct target genes encoding components of lysosomal membrane vacuolar-type ATPase, thereby suppressing lysosome acidification in macrophages. The resulting lysosomal dysfunction then impaired autophagic flux and activated SQSTM1-NFKB signaling to drive the expression of IL1B/IL-1β (interleukin 1 beta), IL8 and CXCL2 (chemokine (C-X-C motif) ligand 2). Restoring MITF function by enforced MITF expression or restoring lysosome acidification with 1α,25-dihydroxyvitamin D3 or carbamazepine suppressed pro-inflammatory cytokine expression in vitro. In mice, gavage with TcdB-hyperproducing C. difficile or injection of TcdB into ligated colon segments caused prominent MITF downregulation in macrophages. Vitamin D3 and carbamazepine lessened TcdB-induced lysosomal dysfunction, inflammation and histological damage. In conclusion, TcdB inhibits the CTNNB1-MITF axis to suppress lysosome acidification and activates the downstream SQSTM1-NFKB signaling in macrophages during CDI. Vitamin D3 and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice. Abbreviations: ATP6V0B: ATPase H+ transporting V0 subunit b; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1H: ATPase H+ transporting V1 subunit H; CBZ: carbamazepine; CDI: C. difficile infection; CXCL: chemokine C-X-X motif ligand; IL: interleukin; LAMP1: lysosomal-associated membrane protein 1; LC3: microtubule-associated protein 1 light chain 3; LEF: lymphoid enhancer binding factor 1; MITF: melanocyte inducing transcription factor; NFKB: nuclear factor kappa B; PMA: phorbol 12-myristate 13-acetate; TcdA: Clostridial toxin A; TcdB: Clostridial toxin B; TFE3: transcription factor E3; TFEB: transcription factor EB. Published version This work was supported by the National Natural Science Foundation of China [82070576] and the Hong Kong Food and Health Bureau (FHB) Commissioned Health and Medical Research Fund [CID-CUHK-C].

Blood is conventionally thought to be sterile. However, emerging evidence on the blood microbiome has started to challenge this notion. Recent reports have revealed the presence of genetic materials of microbes or pathogens in the blood circulation, leading to the conceptualization of a blood microbiome that is vital for physical wellbeing. Dysbiosis of the blood microbial profile has been implicated in a wide range of health conditions. Our review aims to consolidate recent findings about the blood microbiome in human health and to highlight the existing controversies, prospects, and challenges around this topic. Current evidence does not seem to support the presence of a core healthy blood microbiome. Common microbial taxa have been identified in some diseases, for instance, Legionella and Devosia in kidney impairment, Bacteroides in cirrhosis, Escherichia/Shigella and Staphylococcus in inflammatory diseases, and Janthinobacterium in mood disorders. While the presence of culturable blood microbes remains debatable, their genetic materials in the blood could potentially be exploited to improve precision medicine for cancers, pregnancy-related complications, and asthma by augmenting patient stratification. Key controversies in blood microbiome research are the susceptibility of low-biomass samples to exogenous contamination and undetermined microbial viability from NGS-based microbial profiling, however, ongoing initiatives are attempting to mitigate these issues. We also envisage future blood microbiome research to adopt more robust and standardized approaches, to delve into the origins of these multibiome genetic materials and to focus on host-microbe interactions through the elaboration of causative and mechanistic relationships with the aid of more accurate and powerful analytical tools. Published version

BackgroundThe storage miteTyrophagus putrescentiaeis one of the major mites causing allergies in Chinese and Korean populations, but its allergen profile in incomplete when compared with that of house dust mites. Multiple genome-based methods have been introduced into the allergen study of mites and have enabled a better understanding of these medically important organisms.ObjectiveWe sought to reveal a comprehensive allergen profile ofTyrophagus putrescentiaeand advance the allergen study of storage mites.MethodsBased on a high-quality assembled and annotated genome, anin silicoanalysis was performed by searching reference sequences to identify allergens. Immunoassay ELISA assessed the allergenicities of recombinant proteins. MALDI-TOF mass spectrometry identified the IgE-binding proteins. Comparative genomics analysis was employed for the important allergen gene families.ResultsA complete allergen profile ofTyrophagus putrescentiaewas revealed, including thirty-seven allergen groups (up to Tyr p 42). Among them, five novel allergens were verified using the sera of allergy patients. Massive allergen homologs were identified as the result of gene duplications in genome evolution. Proteomic identification again revealed a wide range of allergen homologs. In the NPC2 family and GSTs, comparative analysis shed light on the expansion and diversification of the allergen groups.ConclusionUsing multi-omic approaches, the comprehensive allergen profile including massive homologs was disclosed inTyrophagus putrescentiae, which revealed the allergen complexity of the storage mite and could ultimately facilitate the component-resolved diagnosis.

To (i) compare the acceptance of a newly developed, novel biofeedback device (PelviSense) with that of conventional biofeedback (CB) using an intravaginal probe for the treatment of stress urinary incontinence (SUI) in women, (ii) examine the feasibility and safety of using the PelviSense device as a pelvic floor muscle (PFM) training (PFMT) adjunct, and (iii) compare the PFMT adherence and effectiveness of CB, the PelviSense device, with PFMT alone for women with SUI.An assessor-blinded, three-arm, randomized controlled pilot trial was conducted among 51 women with SUI. Women were randomly allocated to one of three study groups (PelviSense-assisted PFMT, CB-assisted PFMT, or PFMT alone [control]). Outcome measures included the International Consultation on Incontinence Questionnaire-Short Form, the 1-h pad test, and the Modified Oxford Scale.Participants in the PelviSense-assisted PFMT group expressed good device acceptance. PFMT adherence was greater in the PelviSense-assisted PFMT group than in the unassisted or CB-assisted PFMT groups. Between-groups analysis revealed significant effects on improved SUI symptoms, urine loss severity, and PFM strength for the PelviSense-assisted PFMT group compared with the CB-assisted and PFMT alone groups.The pilot trial results demonstrated moderate to high PFMT adherence in the PelviSense-assisted PFMT group and supported the safety of using the PelviSense device. The preliminary results of the pilot trial showed that PelviSense-assisted PFMT was more effective for reducing SUI symptoms among women than unassisted or CB-assisted PFMT.This trial was registered in http://ClinicalTrials.gov (reference number: NCT04638348) before the recruitment of the first participant.