A phospholipid immunomodulator from Akkermansia muciniphila.

A recent paper in Nature (Bae et al., 2022) reports the discovery of a phosphatidylethanolamine from Akkermansia muciniphila that mediates the immunomodulatory function of the bacterium via regulation of the Toll-like receptor 2 (TLR2) or the TLR2-TLR1 signaling complex in immune cells.

Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity.

Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotoxicity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhibited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced conversion of tilimycin to tilivalline, and activation of PXR. IMPORTANCE The human gut harbors a complex community of microbes, including several species and strains that could be commensals or pathogens depending on context. The specific environmental conditions under which a resident microbe changes its relationship with a host and adopts pathogenic behaviors, in many cases, remain poorly understood. Here, we describe a novel communication network involving the regulation of K. grimontii and K. oxytoca enterotoxicity. Bacterial indole was identified as a central modulator of these colitogenic microbes by suppressing bacterial toxin (tilimycin) synthesis and converting tilimycin to tilivalline while simultaneously activating a host receptor, PXR, as a means of mitigating tissue cytotoxicity. On the other hand, fermentable carbohydrates were found to inhibit indole biosynthesis and enhance toxin production. This integrated network involving microbial, host, and metabolic factors provides a contextual framework to better understand K. oxytoca complex pathogenicity.

Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage.

BACKGROUND AND AIMS: Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. METHODS: We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. RESULTS: We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. CONCLUSIONS: Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

Alternative Techniques for Breast Tumour Detection using Ultrasound.

Ultrasound images are potentially invaluable for imaging internal organs and diseases. However, due to noise, they are still difficult to interpret. We apply and compare supervised machine learning approaches to train a model of lesions using features with unsupervised machine learning approaches to segment and detect tumours in breasts. Two synthetic and one real datasets are used in our experiments. The best system performance is achieved by Frost Filter with Quick Shift.

Divergent early mesoderm specification underlies distinct head and trunk muscle programmes in vertebrates.

Head and trunk muscles have discrete embryological origins and are governed by distinct regulatory programmes. Whereas the developmental route of trunk muscles from mesoderm is well studied, that of head muscles is ill defined. Here, we show that, unlike the myogenic trunk paraxial mesoderm, head mesoderm development is independent of the T/Tbx6 network in mouse. We reveal that, in contrast to Wnt and FGF-driven trunk mesoderm, dual inhibition of Wnt/ß-catenin and Nodal specifies head mesoderm. Remarkably, the progenitors derived from embryonic stem cells by dual inhibition efficiently differentiate into cardiac and skeletal muscle cells. This twin potential is the defining feature of cardiopharyngeal mesoderm: the head subtype giving rise to heart and branchiomeric head muscles. Therefore, our findings provide compelling evidence that dual inhibition specifies head mesoderm and unravel the mechanism that diversifies head and trunk muscle programmes during early mesoderm fate commitment. Significantly, this is the first report of directed differentiation of pluripotent stem cells, without transgenes, into progenitors with muscle/heart dual potential. Ability to generate branchiomeric muscle in vitro could catalyse efforts in modelling myopathies that selectively involve head muscles.

Two zinc finger proteins from Mycobacterium smegmatis: DNA binding and activation of transcription.

Single zinc finger domain containing proteins are very few in number. Of numerous zinc finger proteins in eukaryotes, only three of them like GAGA, Superman and DNA binding by one finger (Dof) have single zinc finger domain. Although few zinc finger proteins have been described in eubacteria, no protein with single C4 zinc finger has been described in details in anyone of them. In this article, we are describing two novel C-terminal C4 zinc finger proteins-Msmeg_0118 and Msmeg_3613 from Mycobacterium smegmatis. We have named these proteins as Mszfp1 (Mycobacterial Single Zinc Finger Protein 1) and Mszfp2 (Mycobacterial Single Zinc Finger Protein 2). Both the proteins are expressed constitutively, can bind to DNA and regulate transcription. It appears that Mszfp1 and Mszfp2 may activate transcription by interacting with RNA polymerase.

Mechanism of regulation of phosphorylation-dephosphorylation of Ca2+, Mg2+ and Ca2+ -Atpases by modulator proteins isolated from rat brain cytosol.

Two proteins of molecular mass 13 kDa, a specific inhibitor of Na+, K+ -ATPase and another of 12 kDa, which can distinguish between Ca2, Mg2+ and Ca2+ -ATPase activities have been obtained from the pooled fractions isolated from rat brain, using Sephadex G-100 chromatography. In order to determine the key step(s), which is affected by the modulators, we have designed an in vitro experiment of phosphorylation and dephosphorylation of these ATPases in the absence and presence of the modulators. The results suggest that the phosphorylation step of Mg2+ -independent Ca2+ -ATPase is inhibited, while in Mg2+ -dependent Ca2 -ATPase, the dephosphorylation step is stimulated by the modulators. The findings support our earlier observation that the modulators are able to distinguish between Mg2+ -independent and dependent Ca2+ -ATPases activities.

Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India.

To identify the genetic modifier(s) that might alter the age at onset in Huntington's disease (HD) we have analyzed variations in GluR6 kainate receptor (GluR6), CA150 gene, Delta2642 and polymorphic CCG repeat variation in huntingtin (htt) gene in 77 HD patients and normal individuals. In addition, variation in the RAI1 gene was analyzed in 30 spinocerebellar ataxia (SCA2) patients and normal individuals to show the possible influence on the age at onset. Multiple regression analysis indicated that variation in GluR6 and CCG repeat genotype might explain 6.2% and 3.1%, respectively, of the variability in the age at onset in HD. Similar analysis with SCA2 patients indicated that RAI1 might explain about 13% of the variability in the age at onset. Specific alleles in GluR6 and CA150 locus were only observed in HD patients.