Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus which causes coronavirus disease (COVID-19), has spread rapidly across the globe infecting millions of people and causing ...significant health and economic impacts. Authorities are exploring complimentary approaches to monitor this infectious disease at the community level. Wastewater-based epidemiology (WBE) approaches to detect SARS-CoV-2 RNA in municipal wastewater are being implemented worldwide as an environmental surveillance approach to inform health authority decision-making. Owing to the extended excretion of SARS-CoV-2 RNA in stool, WBE can surveil large populated areas with a longer detection window providing unique information on the presence of pre-symptomatic and asymptomatic cases that are unlikely to be screened by clinical testing. Herein, we analysed SARS-CoV-2 RNA in 24-h composite wastewater samples (n = 63) from three wastewater treatment plants (WWTPs) in Brisbane, Queensland, Australia from 24th of February to 1st of May 2020. A total of 21 samples were positive for SARS-CoV-2, ranging from 135 to 11,992 gene copies (GC)/100 mL of wastewater. Detections were made in a Southern Brisbane WWTP in late February 2020, up to three weeks before the first clininal case was reported there. Wastewater samples were generally positive during the period with highest caseload data. The positive SARS-CoV-2 RNA detection in wastewater while there were limited clinical reported cases demonstrates the potential of WBE as an early warning system to identify hotspots and target localised public health responses, such as increased individual testing and the provision of health warnings.
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•SARS-CoV-2 RNA was detected in wastewater when clinical cases were low.•The decline of the RNA occurrence in wastewater aligned with the tapering of the epidemic.•SARS-CoV-2 RNA in wastewater showed no correlation with daily cases.•Early detection of SARS-CoV-2 in wastewater is useful for COVID-19 management.
LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in ...cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.
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► L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) ► Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling ► L1 mobilization in tumor cells accelerates transformation of the HCC genome ► A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18
L1 retrotransposons, which are widespread in the human genome, can mobilize and activate oncogenes in the livers of individuals infected with the hepatitis B or hepatitis C virus, promoting the development and growth of hepatocellular carcinoma. Genes identified by the L1 insertions present new options for cancer screening and intervention.
The nuclear ribosomal internal transcribed spacer (ITS) region is the formal fungal barcode and in most cases the marker of choice for the exploration of fungal diversity in environmental samples. ...Two problems are particularly acute in the pursuit of satisfactory taxonomic assignment of newly generated ITS sequences: (i) the lack of an inclusive, reliable public reference data set and (ii) the lack of means to refer to fungal species, for which no Latin name is available in a standardized stable way. Here, we report on progress in these regards through further development of the UNITE database (http://unite.ut.ee) for molecular identification of fungi. All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type (e.g. Hymenoscyphus pseudoalbidus|GU586904|SH133781.05FU), and their taxonomic and ecological annotations were corrected as far as possible through a distributed, third‐party annotation effort. We introduce the term ‘species hypothesis’ (SH) for the taxa discovered in clustering on different similarity thresholds (97–99%). An automatically or manually designated sequence is chosen to represent each such SH. These reference sequences are released (http://unite.ut.ee/repository.php) for use by the scientific community in, for example, local sequence similarity searches and in the QIIME pipeline. The system and the data will be updated automatically as the number of public fungal ITS sequences grows. We invite everybody in the position to improve the annotation or metadata associated with their particular fungal lineages of expertise to do so through the new Web‐based sequence management system in UNITE.
Characterizing the density of states (DOS) width accurately is critical in understanding the charge‐transport properties of organic semiconducting materials as broader DOS distributions lead to an ...inferior transport. From a morphological standpoint, the relative densities of ordered and disordered regions are known to affect charge‐transport properties in films; however, a comparison between molecular structures showing quantifiable ordered and disordered regions at an atomic level and its impact on DOS widths and charge‐transport properties has yet to be made. In this work, for the first time, the DOS distribution widths of two model conjugated polymer systems are characterized using three different techniques. A quantitative correlation between energetic disorder from band‐bending measurements and charge transport is established, providing direct experimental evidence that charge‐carrier mobility in disordered materials is compromised due to the relaxation of carriers into the tail states of the DOS. Distinction and quantification of ordered and disordered regions of thin films at an atomic level is achieved using solid‐state NMR spectroscopy. An ability to compare solid‐state film morphologies of organic semiconducting polymers to energetic disorder, and in turn charge transport, can provide useful guidelines for applications of organic conjugated polymers in pertinent devices.
A quantitative correlation between energetic disorder from charge transport and band bending measurements is established for two organic semiconducting polymers providing direct experimental evidence that charge carrier mobility is compromised due to the relaxation of charge carriers into the tail states of the density‐of‐states distribution. Ordered and disordered regions of polymer films were distinguished and quantified at an atomic‐scale.
Carbohydrates are essential moieties of many bioactive molecules in nature. However, efforts to elucidate their modes of action are often impeded by limitations in synthetic access to well‐defined ...oligosaccharides. Most of the current methods rely on the design of specialized coupling partners to control selectivity during the formation of glycosidic bonds. Reported herein is the use of a commercially available phenanthroline to catalyze stereoretentive glycosylation with glycosyl bromides. The method provides efficient access to α‐1,2‐cis glycosides. This protocol has been performed for the large‐scale synthesis of an octasaccharide adjuvant. Density‐functional theory calculations, together with kinetic studies, suggest that the reaction proceeds by a double SN2 mechanism.
No limits: The commercially available phenanthroline serves as an efficient catalyst to promote the stereoselective formation of α‐1,2‐cis glycosides. The selectivity of this newly developed catalyst system is not limited by the nature of the protecting groups on the coupling partners.
The gastrointestinal tract is lined by a single layer of epithelial cells that secrete mucus toward the lumen, which collectively separates the immune sentinels in the underlying lamina propria from ...the intestinal microflora to prevent aberrant immune responses. Inflammatory bowel disease (IBD) describes a group of autoimmune diseases that arise from defects in epithelial barrier function and, as a consequence, aberrant production of inflammatory cytokines. Among these, interleukin (IL)-6, IL-11, and IL-22 are elevated in human IBD patients and corresponding mouse models and, through activation of the JAK/STAT3 pathway, can both propagate and ameliorate disease. In particular, cytokine-mediated activation of STAT3 in the epithelial lining cells affords cellular protection, survival, and proliferation, thereby affording therapeutic opportunities for the prevention and treatment of colitis. In this review, we focus on recent insights gained from therapeutic modulation of the activities of IL-6, IL-11, and IL-22 in models of IBD and advocate a cautionary approach with these cytokines to minimize their tumor-promoting activities on neoplastic epithelium.
Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How ...Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling.
From time‐resolved luminescence measurements it is demonstrated that the background concentration of excitonquenching defects in a range of organic semiconductors is the same as their electron‐trap ...concentration. This observation suggests that the exciton‐quenching defects and the electron traps share the same origin. The typical exciton diffusion length of 5–8 nm for organic semiconductors is therefore governed by the distance between the universal electron traps.
Among the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer “hallmarks” through downstream activation of the gp130/STAT3 signaling pathway. However, we ...show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers.
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•Elevated IL-11 levels in GI tumors correlate with oncogenic STAT3 activation•IL-11 is the dominant IL-6 family cytokine required for GI cancer progression•IL-11/STAT3 signaling promotes tumor cell proliferation and survival•Therapeutic inhibition of IL-11 signaling impedes GI tumorigenesis in vivo
biofilms are poorly responsive to antibiotics. Underlying reasons include a matrix effect preventing drug access to embedded bacteria, or the presence of dormant bacteria with reduced growth rate. ...Using 18 clinical isolates previously characterized for their moxifloxacin-resistant and moxifloxacin-persister character in stationary-phase culture, we studied their biofilm production and matrix composition and the anti-biofilm activity of moxifloxacin. Biofilms were grown in microtiter plates and their abundance quantified by crystal violet staining and colony counting; their content in polysaccharides, extracellular DNA and proteins was measured. Moxifloxacin activity was assessed after 24 h of incubation with a broad range of concentrations to establish full concentration-response curves. All clinical isolates produced more biofilm biomass than the reference strain ATCC 25923, the difference being more important for those with high relative persister fractions to moxifloxacin, most of which being also resistant. High biofilm producers expressed
to higher levels, enriching the matrix in polysaccharides. Moxifloxacin was less potent against biofilms from clinical isolates than from ATCC 25923, especially against moxifloxacin-resistant isolates with high persister fractions, which was ascribed to a lower concentration of moxifloxacin in these biofilms. Time-kill curves in biofilms revealed the presence of a moxifloxacin-tolerant subpopulation, with low multiplication capacity, whatever the persister character of the isolate. Thus, moxifloxacin activity depends on its local concentration in biofilm, which is reduced in most isolates with high-relative persister fractions due to matrix effects, and insufficient to kill resistant isolates due to their high MIC.
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