SARS-CoV-2 Interacts with Mucosal Dysbiosis to Cause the Wide Range of Disease Seen in Covid-19

Hypothesis: SARS-CoV-2 amplifies pre-existing dysbiosis induced mucosal inflammation and this can cause a severe systemic inflammatory disease. The microbial flora perturbation can persist long after the virus has been eliminated leading to a wide range of long Covid symptoms. Evidence: Dysbiosis induced mucosal inflammation increases with age and is strongly associated with the metabolic syndrome (obesity, type 2 diabetes mellitus, ischaemic heart disease, hypertension, and depression). These are risk factors for the conversion of mild to severe Covid-19. Certain common strains of Staphylococcus aureus, which is commonly carried in pharyngeal mucosa, can trigger a cytokine cascade as seen in severe Covid-19. Blood group A and vitamin D deficiency, which are risk factors for hospitalisation in Covid-19 are also associated with increased S. aureus pharyngeal carriage rates. Multi-inflammatory syndrome in children is a post Covid condition which resembles toxic shock syndrome and Kawasaki disease (the former is known to be caused by staphylococcal pyrogenic toxins). A number of studies have shown dysbiosis of the oral mucosa and rectal mucosa in patients who progress to severe Covid-19. The wide range of pathology seen during and following SARS-CoV-2 infection is more in keeping with dysbiosis induced inflammation (multiple pathogenic bacteria at multiple sites) than with an otherwise simple viral induced respiratory tract infection. Implication: Optimization of the microbial flora, prior to encountering the virus, could have reduced the severity of the pandemic. The consumption of fermented foods, especially yoghurt, holds the most promise for reducing dysbiosis induced mucosal inflammation and preventing a wide range of complications. Reduced mucosal inflammation brings not only health but also happiness in which oxytocin has a key role

High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse

Obesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance.Conventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in GF NF-kappaB(EGFP) mice.Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance

Intestinal epithelial Suppressor of Cytokine Signaling (SOCS) 3 enhances microbial induced inflammatory TNFα, contributing to epithelial barrier dysfunction

A single layer of intestinal epithelial cells (IEC) lines the entire GI tract and provides the first line of defence and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer. Our data indicate that SOCS3 can limit microbial-induced epithelial repair, promote TNFα, possibly through limiting TNFR2 expression in intestinal epithelial cells (IEC). Activation of TLR5 signalling pathways, compared with other TLR, increase TNFα mRNA in a dose dependent manner and SOCS3 enhances TLR5-induced TNFα. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 may limit this expression, presenting a mechanism of SOCS3 action. Our data also supports the role of microbial ligands in epithelial wound healing and suggests that a functional consequence of increased TNFα is reduced wound healing. These results provide further evidence to support the regulatory role of epithelial SOCS3 in intestinal health and suggest that the increased expression of SOCS3 observed in IBD may serve to perpetuate 'inflammation' by promoting TNFα production and limiting epithelial repair in response to commensal microflora

Intestinal bacteria are necessary for doxorubicin-induced intestinal damage but not for doxorubicin-induced apoptosis

Doxorubicin (DOXO) induces significant, but transient, increases in apoptosis in the stem cell zone of the jejunum, followed by mucosal damage involving a decrease in crypt proliferation, crypt number, and villus height. The gastrointestinal tract is home to a vast population of commensal bacteria and numerous studies have demonstrated a symbiotic relationship between intestinal bacteria and intestinal epithelial cells (IEC) in maintaining homeostatic functions of the intestine. However, whether enteric bacteria play a role in DOXO-induced damage is not well understood. We hypothesized that enteric bacteria are necessary for induction of apoptosis and damage associated with DOXO treatment. Conventionally raised (CONV) and germ free (GF) mice were given a single injection of DOXO, and intestinal tissue was collected at 6, 72, and 120 h after treatment and from no treatment (0 h) controls. Histology and morphometric analyses quantified apoptosis, mitosis, crypt depth, villus height, and crypt density. Immunostaining for muc2 and lysozyme evaluated Paneth cells, goblet cells or dual stained intermediate cells. DOXO administration induced significant increases in apoptosis in jejunal epithelium regardless of the presence of enteric bacteria; however, the resulting injury, as demonstrated by statistically significant changes in crypt depth, crypt number, and proliferative cell number, was dependent upon the presence of enteric bacteria. Furthermore, we observed expansion of Paneth and goblet cells and presence of intermediate cells only in CONV and not GF mice. These findings provide evidence that manipulation and/or depletion of the enteric microbiota may have clinical significance in limiting chemotherapy-induced mucositis

Star Formation at z = 2.481 in the Lensed Galaxy SDSS J1110+6459: Star Formation Down to 30 pc Scales

We present measurements of the surface density of star formation, the star-forming clump luminosity function, and the clump size distribution function, for the lensed galaxy SGAS J111020.0+645950.8 at a redshift of z =2.481. The physical size scales that we probe, radii r = 30-50 pc, are considerably smaller scales than have yet been studied at these redshifts. The star formation surface density we find within these small clumps is consistent with surface densities measured previously for other lensed galaxies at similar redshift. Twenty-two percent of the rest-frame ultraviolet light in this lensed galaxy arises from small clumps, with r is less than 100 pc. Within the range of overlap, the clump luminosity function measured for this lensed galaxy is remarkably similar to those of z is approximately 0 galaxies. In this galaxy, star-forming regions smaller than 100 pc-physical scales not usually resolved at these redshifts by current telescopes-are important locations of star formation in the distant universe. If this galaxy is representative, this may contradict the theoretical picture in which the critical size scale for star formation in the distant universe is of order 1 kiloparsec. Instead, our results suggest that current telescopes have not yet resolved the critical size scales of star-forming activity in galaxies over most of cosmic time

The Hunt for Red Quasars : Luminous Obscured Black Hole Growth Unveiled in the Stripe 82 X-Ray Survey

We present results of a ground-based near-infrared campaign with Palomar TripleSpec, Keck NIRSPEC, and Gemini GNIRS to target two samples of reddened active galactic nucleus (AGN) candidates from the 31 deg(2) Stripe 82 X-ray survey. One sample, which is similar to 89% complete to K 4, Vega). The fainter sample (K > 17, Vega) represents a pilot program to follow-up four sources from a parent sample of 34 that are not detected in the single-epoch SDSS catalog and have WISE quasar colors. All 12 sources are broad-line AGNs (at least one permitted emission line has an FWHM exceeding 1300 km s(-1)) and span a redshift range 0.59 0.5), and a greater percentage have high X-ray luminosities (L-X,L- full > 10(44) erg s(-1)). Such outflows and high luminosities may be consistent with the paradigm that reddened broad-line AGNs represent a transitory phase in AGN evolution as described by the major merger model for black hole growth. Results from our pilot program demonstrate proof of concept that our selection technique is successful in discovering reddened quasars at z > 1 missed by optical surveys.Peer reviewe

Astro2020 Must Issue Actionable Recommendations Regarding Diversity, Inclusion, and Harassment

The 2010 Decadal survey failed to issue any recommendations on diversity and inclusion.Astro2020 cannot make the same mistake. Findings can be ignored by funding agencies;recommendations cannot. In the past decade, multiple groups have assembled detailed actionplans to fix a broken climate within our profession. Astro2020 should play a key role, bysynthesizing this work to produce actionable recommendations to support diversity andinclusion and stop harassment within our profession

Development, confirmation, and application of a seeded Escherichia coli process control organism to validate Salmonella enterica serovar Typhi environmental surveillance methods

Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of Typhoid fever. Blood culture is the gold standard for clinical diagnosis, but this is often difficult to employ in resource limited settings. Environmental surveillance of waste-impacted waters is a promising supplement to clinical surveillance, however validating methods is challenging in regions where S. Typhi concentrations are low. To evaluate existing S. Typhi environmental surveillance methods, a novel process control organism (PCO) was created as a biosafe surrogate. Using a previous described qPCR assay, a modified PCR amplicon for the staG gene was cloned into E. coli. We developed a target region that was recognized by the Typhoid primers in addition to a non-coding internal probe sequence. A multiplex qPCR reaction was developed that differentiates between the typhoid and control targets, with no cross-reactivity or inhibition of the two probes. The PCO was shown to mimic S. Typhi in lab-based experiments with concentration methods using primary wastewater: filter cartridge, recirculating Moore swabs, membrane filtration, and differential centrifugation. Across all methods, the PCO seeded at 10 CFU/mL and 100 CFU/mL was detected in 100% of replicates. The PCO is detected at similar quantification cycle (Cq) values across all methods at 10 CFU/mL (Average = 32.4, STDEV = 1.62). The PCO was also seeded into wastewater at collection sites in Vellore (India) and Blantyre (Malawi) where S. Typhi is endemic. All methods tested in both countries were positive for the seeded PCO. The PCO is an effective way to validate performance of environmental surveillance methods targeting S. Typhi in surface water