The Stenotrophomonas maltophilia complex (Smc) comprises opportunistic environmental Gram-negative bacilli responsible for a variety of infections in both humans and animals. Beyond its large genetic diversity, its genetic organization in genogroups was recently confirmed through the whole-genome sequencing of human and environmental strains. As they are poorly represented in these analyses, we sequenced the whole genomes of 93 animal strains to determine their genetic background and characteristics. Combining these data with 81 newly sequenced human strains and the genomes available from RefSeq, we performed a genomic analysis that included 375 nonduplicated genomes with various origins (animal, 104; human, 226; environment, 30; unknown, 15). Phylogenetic analysis and clustering based on genome-wide average nucleotide identity confirmed and specified the genetic organization of Smc in at least 20 genogroups. Two new genogroups were identified, and two previously described groups were further divided into two subgroups each. Comparing the strains isolated from different host types and their genogroup affiliation, we observed a clear disequilibrium in certain groups. Surprisingly, some antimicrobial resistance genes, integrons, and/or clusters of attC sites lacking integron-integrase (CALIN) sequences targeting antimicrobial compounds extensively used in animals were mainly identified in animal strains. We also identified genes commonly found in animal strains coding for efflux systems. The result of a large whole-genome analysis performed by us supports the hypothesis of the putative contribution of animals as a reservoir of Stenotrophomonas maltophilia complex strains and/or resistance genes for strains in humans.

IMPORTANCE Given its naturally large antimicrobial resistance profile, the Stenotrophomonas maltophilia complex (Smc) is a set of emerging pathogens of immunosuppressed and cystic fibrosis patients. As it is group of environmental microorganisms, this adaptation to humans is an opportunity to understand the genetic and metabolic selective mechanisms involved in this process. The previously reported genomic organization was incomplete, as data from animal strains were underrepresented. We added the missing piece of the puzzle with whole-genome sequencing of 93 strains of animal origin. Beyond describing the phylogenetic organization, we confirmed the genetic diversity of the Smc, which could not be estimated through routine phenotype- or matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF)-based laboratory tests. Animals strains seem to play a key role in the diversity of Smc and could act as a reservoir for mobile resistance genes. Some genogroups seem to be associated with particular hosts; the genetic support of this association and the role of the determinants/corresponding genes need to be explored.

Gastrointestinal (GI) or gut microbiotas play essential roles in host development and physiology. These roles are influenced partly by the microbial community composition. During early developmental stages, the ecological processes underlying the assembly and successional changes in host GI community composition are influenced by numerous factors, including dispersal from the surrounding environment, age-dependent changes in the gut environment, and changes in dietary regimes. However, the relative importance of these factors to the gut microbiota is not well understood. We examined the effects of environmental (diet and water sources) and host early ontogenetic development on the diversity of and the compositional changes in the gut microbiota of a primitive teleost fish, the lake sturgeon (Acipenser fulvescens), based on massively parallel sequencing of the 16S rRNA gene. Fish larvae were raised in environments that differed in water source (stream versus filtered groundwater) and diet (supplemented versus nonsupplemented Artemia fish). We quantified the gut microbial community structure at three stages (prefeeding and 1 and 2 weeks after exogenous feeding began). The diversity declined and the community composition differed significantly among stages; however, only modest differences associated with dietary or water source treatments were documented. Many taxa present in the gut were over- or underrepresented relative to neutral expectations in each sampling period. The findings indicate dynamic relationships between the gut microbiota composition and host gastrointestinal physiology, with comparatively smaller influences being associated with the rearing environments. Neutral models of community assembly could not be rejected, but selectivity associated with microbe-host GI tract interactions through early ontogenetic stages was evident. The results have implications for sturgeon conservation and aquaculture production specifically and applications of microbe-based management in teleost fish generally.

IMPORTANCE We quantified the effects of environment (diet and water sources) and host early ontogenetic development on the diversity of and compositional changes in gut microbial communities based on massively parallel sequencing of the 16S rRNA genes from the GI tracts of larval lake sturgeon (Acipenser fulvescens). The gut microbial community diversity declined and the community composition differed significantly among ontogenetic stages; however, only modest differences associated with dietary or water source treatments were documented. Selectivity associated with microbe-host GI tract interactions through early ontogenetic stages was evident. The results have implications for lake sturgeon and early larval ecology and survival in their natural habitat and for conservation and aquaculture production specifically, as well as applications of microbe-based management in teleost fish generally.

In Lysobacter enzymogenes OH11, RpfB1 and RpfB2 were predicted to encode acyl coenzyme A (CoA) ligases. RpfB1 is located in the Rpf gene cluster. Interestingly, we found an RpfB1 homolog (RpfB2) outside this canonical gene cluster, and nothing is known about its functionality or mechanism. Here, we report that rpfB1 and rpfB2 can functionally replace EcFadD in the Escherichia coli fadD mutant JW1794. RpfB activates long-chain fatty acids (n-C_16:0 and n-C_18:0) for the corresponding fatty acyl-CoA ligase (FCL) activity in vitro, and Glu-361 plays critical roles in the catalytic mechanism of RpfB1 and RpfB2. Deletion of rpfB1 and rpfB2 resulted in significantly increased heat-stable antifungal factor (HSAF) production, and overexpression of rpfB1 or rpfB2 completely suppressed HSAF production. Deletion of rpfB1 and rpfB2 resulted in increased L. enzymogenes diffusible signaling factor 3 (LeDSF3) synthesis in L. enzymogenes. Overall, our results showed that changes in intracellular free fatty acid levels significantly altered HSAF production. Our report shows that intracellular free fatty acids are required for HSAF production and that RpfB affects HSAF production via FCL activity. The global transcriptional regulator Clp directly regulated the expression of rpfB1 and rpfB2. In conclusion, these findings reveal new roles of RpfB in antibiotic biosynthesis in L. enzymogenes.

IMPORTANCE Understanding the biosynthetic and regulatory mechanisms of heat-stable antifungal factor (HSAF) could improve the yield in Lysobacter enzymogenes. Here, we report that RpfB1 and RpfB2 encode acyl coenzyme A (CoA) ligases. Our research shows that RpfB1 and RpfB2 affect free fatty acid metabolism via fatty acyl-CoA ligase (FCL) activity to reduce the substrate for HSAF synthesis and, thereby, block HSAF production in L. enzymogenes. Furthermore, these findings reveal new roles for the fatty acyl-CoA ligases RpfB1 and RpfB2 in antibiotic biosynthesis in L. enzymogenes. Importantly, the novelty of this work is the finding that RpfB2 lies outside the Rpf gene cluster and plays a key role in HSAF production, which has not been reported in other diffusible signaling factor (DSF)/Rpf-producing bacteria.

Cushing syndrome results from chronic excessive exposure to glucocorticoids, impacting virtually every organ system with the most dominant effects on fat metabolism, immune function, and musculoskeletal systems. Endogenous Cushing syndrome is rare, most usually due to excess ACTH secretion from pituitary, and less frequently from ectopic tumors. Other cases result from ACTH-independent adrenal overproduction of cortisol.

This interesting case report from South Africa focuses on a difficult diagnostic challenge: apparent Cushing syndrome with inconsistent laboratory findings.

Cushing syndromeExogenousDexamethasoneSkinWhiteningCream

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori. Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori. The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo. During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori. In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC₅₀] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC₅₀ of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C. albicans, a gain-of-function mutation in the transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 and SNQ2. In C. parapsilosis, a mitochondrial deletion activated expression of the major facilitator superfamily transporter gene MDR1.

The poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) impels an improved understanding of disease biology to facilitate the development of better therapies. PDAC typically features a remarkably dense stromal reaction, featuring and established by a prominent population of cancer-associated fibroblasts (CAF). Genetically engineered mouse models and increasingly sophisticated cell culture techniques have demonstrated important roles for fibroblasts in PDAC progression and therapy response, but these roles are complex, with strong evidence for both tumor-supportive and tumor-suppressive or homeostatic functions. Here, we review the recent literature that has improved our understanding of heterogeneity in fibroblast fate and function in this disease including the existence of distinct fibroblast populations, and highlight important avenues for future study.

Unlike replicative senescence, oncogene-induced senescence caused heterochromatin-body formation.

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response.

Background:

Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

Cruciferous vegetables have been of special interest due to the rich presence of bioactive compounds such as sulforaphane which show promising potential on cancer prevention and therapy as an epigenetic dietary strategy. Abnormal epigenetic alteration as one of the primary contributors to tumor development is closely related to breast cancer initiation and progression. In the present study, we investigated the effect of dietary broccoli sprouts (BSp), a common cruciferous vegetable, on prevention of estrogen receptor (ER)-negative mammary tumors at three different temporal exposure windows using a spontaneous breast cancer mouse model. Our findings indicate that maternal BSp treatment exhibited profound inhibitory and preventive effects on mammary cancer formation in the nontreated mouse offspring. The BSp diet administered to adult mice also showed suppressive effects on mammary cancer but was not as profound as the maternal BSp preventive effects. Moreover, such protective effects were linked with differentially expressed tumor- and epigenetic-related genes, as well as altered global histone acetylation, DNA methylation, and DNA hydroxymethylation levels. We also found that the expression changes of tumor-related genes were associated with the levels of histone methylation of H3K4 and H3K9 in the gene promoter regions. In addition, BSp-enriched sulforaphane was shown to increase protein expression of tumor suppressor genes such as p16 and p53 and inhibit the protein levels of Bmi1, DNA methyltransferases, and histone deacetylases in ERα-negative breast cancer cell lines. Collectively, these results suggest that maternal exposure to key phytochemicals may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations.

Every day on Pluto, nitrogen puffs out the icy world’s heart-shaped plain into the atmosphere, and every night it refreezes, creating winds unlike any we’ve seen before

A private satellite that is low on fuel could survive five more years because another satellite has come to its rescue – a technique that could be used by future service spacecraft

The Rosetta spacecraft’s measurements of comet 67P have revealed a hidden source of nitrogen that may help us learn how giant planets – and even life – formed

About 80 per cent of stars in the Milky Way’s central bulge have relatively close encounters with another star, which can fling off any planets orbiting them

A team of researchers at the Massachusetts Institute of Technology (MIT) has demonstrated that single-celled microorganisms such as Escherichia coli and Saccharomyces cerevisiae that normally do not inhabit hydrogen-rich environments can survive and grow in a 100% hydrogen atmosphere. “There’s a diversity of habitable worlds out there, and we have confirmed that Earth-based life can [...]

ROGER FEDERER has explained why he gets injured less than rivals Rafael Nadal and Novak Djokovic..

America's Country Airplay chart with the couple's duet, Nobody But You, three months after its initial release.

Bollywood actors Ayushmann Khurrana, Kriti Sanon and Sara Ali Khan...

The post Virat Kohli, Ayushmann Khurrana, Sara Ali Khan And Kriti Sanon Come Together For A PSA On Fake News appeared first on Man's World India.

Investment mandate of the Clean Energy Financing Corporation will be changed, but no guarantee hydrogen will be produced from renewables

The Morrison government will change the investment mandate of the Clean Energy Finance Corporation, directing it to make up to $300m available for a new Advancing Hydrogen Fund as part of the national hydrogen strategy.

The Coalition’s move to create a dedicated hydrogen financing fund will be confirmed on Monday, and comes ahead of other changes the government intends to make to the CEFC’s investment program, including requiring it to support new investments in grid reliability.

The different hominid species, possibly including the oldest-known Homo erectus, existed in the region's hills and caves

As a biological anthropologist focused on health, diseases are part of Sabrina Sholts' specialty

Hydrogen is a possible next generation energy solution, and it can be produced from sunlight and water using photocatalysts. A research group has now developed a strategy that greatly increases the amount of hydrogen produced using hematite photocatalysts. In addition to boosting the high efficiency of what is thought to be the world's highest performing photoanode, this strategy will be applied to artificial photosynthesis and solar water-splitting technologies via university-industry collaborations.

The U.S. Department of Commerce is close to signing off on a new rule that would allow U.S. companies to work with China's Huawei Technologies on setting standards for next generation 5G networks, people familiar with the matter said.

The Australian government on Monday set aside A$300 million ($191 million) to jumpstart hydrogen projects with the help of low-cost financing as the country aims to build the industry by 2030, the country's energy minister said on Monday.

BP Plc has won Australian government backing for a feasibility study into producing hydrogen using wind and solar power to split water and converting the hydrogen to ammonia in Western Australia.

Hydrogen has long been touted as a clean alternative to fossil fuels. Now, as major economies prepare green investments to kickstart growth, advocates spy a golden chance to drag the niche energy into the mainstream of a post-pandemic world.

Read our live coronavirus updates HERE

Stars including Beyonce, Paul McCartney, The Rolling Stones and Elton John took part in the concert

Little Mix, Michael Buble and Sir Elton John were among the stars playing tribute to the NHS in a special online concert.

Footage of Londoners gathered on Westminster Bridge to applaud the NHS have prompted backlash amid fears lockdown rules have been broken for the second week running.

Design and technology teachers have made more than 200,000 pieces of protective equipment for frontline NHS workers, new figures reveal.

Boris Johnson is set to urge countries to "pull together" in the fight against the global coronavirus pandemic.

A new biography of Harry and Meghan will "go beyond the headlines" and "reveal unknown details" of the couple's life together.

A solar-driven hydrogen-producing machine that makes more copies of itself.

'I am a fan of ETFs, well certainly they have grown a whole lot'

Welcome to Staying Apart, Together, a USA TODAY newsletter that aims to entertain you, distract you and help you cope during the coronavirus pandemic.

Sources say the couple have gone their separate ways

'We've never been apart for sixty plus years, we don't do apart,' says Sidney Moore

Celebrities from across the globe came together Saturday night to lift their fans’ spirits as the world continues to cope with the coronavirus pandemic.

Canadian actors, musicians and public figures came together on Saturday night for a televised special to support frontline and essential workers, and to raise funds for Food Banks Canada.