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The [M1.sub.UK] lineage of group A Streptococcus (GAS) is a hypertoxigenic clone within the serotype M1 GAS strain and has been associated with increased scarlet fever and invasive GAS (iGAS) [...]

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3- overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK., Introduction Myelodysplastic syndromes (MDS) refer to a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis and morphological dysplasia (1). Recent studies indicate that up to 14%-25% of patients with [...]

Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated [Na.sup.+] import/[K.sup.+] efflux triggered activation of GPCR/IP3- mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX- 147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1G1 transgenic mice, we showed that IFN-[gamma]- mediated induction of G1 caused [K.sup.+] efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated [Na.sup.+]/[K.sup.+] transport as the proximal driver of APOL1-mediated kidney disease., Introduction Two African apolipoprotein L1 (APOL1) variants, named G1 (p.S342G and p.I384M) and G2 (deletion of p.N388/Y389), appear to have evolved to confer protection against the African sleeping sickness parasite [...]

A piezoelectric immunosensor with a recognition layer based on magnetic carbon nanocomposites is developed for the determination of ciprofloxacin. The receptor coating of the sensor is formed by the action of a magnetic field on magnetic particles located on the surface of carbon nanotubes modified with a ciprofloxacin conjugate. The sizes of magnetic particles in the composition of the nanocomposite are determined by scanning electron microscopy. A dependence of the mass of the recognition coating on the size of magnetic particles on the surface of carbon nanotubes is shown. A detection cell with a sensor located above a neodymium magnet is proposed. The analytical characteristics of the immunosensor are determined, the limit of detection for ciprofloxacin is 2 ng/mL, and the linear range of determined concentrations is 5-400 ng/mL. The use of magnetic carbon nanocomposites in the creation of a recognition layer ensures the reduction of the time of sensor preparation to analysis from 24 to 1.5 h and extends its service life. The sensor is tested in the detection of antibiotics in milk and meat., Author(s): E. V. Bizina [sup.1], O. V. Farafonova [sup.1], N. I. Zolotareva [sup.2], S. S. Grazhulene [sup.2], T. N. Ermolaeva [sup.1] Author Affiliations: (1) grid.459699.e, 0000 0001 0096 2646, Lipetsk [...]

A simple and an available method is proposed for the determination of quinolone antibiotics using solid-phase fluorescence digital colorimetry. The intrinsic fluorescence of 17 quinolones and the quinolone-sensitizedfluorescence of europium on cellulose paper (CP) and a thin silica layer are studied. Upon the irradiation of quinolone solutions applied to a matrix with ultraviolet light (365 nm), blue (CP, high-performance thin-layer chromatography (HPTLC)) and pink (CP-Eu, HPTLC-Eu) fluorescence is observed. Measurement of the fluorescence intensity on the surface of matrices is carried out using a smartphone. The values of colorimetric parameters in the RGB system are used as the analytical signal (A.sub.r): A.sub.r = [Formula omitted] The limits of detection and determination are 0.2-4 and 0.6-12 [micro]g/mL, respectively, for all analyzed analytes. The analytical ranges are 0.6-500 [micro]g/mL. A procedure for the determination of fluoroquinolones in medicinal preparations is proposed. The relative standard deviation of the results of analysis does not exceed 5%., Author(s): V. G. Amelin [sup.1] [sup.2], Z. A. Ch. Shogah [sup.1], D. S. Bol'shakov [sup.2] Author Affiliations: (1) grid.171855.f, 0000 0000 9825 6119, Vladimir State University, , 600000, Vladimir, Russia [...]

Tick-borne relapsing fever (TBRF) is a zoonosis caused by spirochetes of the genus Borrelia. The arthropod vector is a soft tick of the genus Ornithodoros, which is endemic to America, [...]

Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Ang2 expression was induced in CNS autoimmunity, and transgenic mice overexpressing Ang2 specifically in endothelial cells (ECs) developed a significantly more severe EAE. In contrast, treatment with Ang2-blocking Abs ameliorated neuroinflammation and decreased spinal cord demyelination and leukocyte infiltration into the CNS. Similarly, Ang2-binding and Tie2-activating Ab attenuated the development of CNS autoimmune disease. Ang2 blockade inhibited expression of EC adhesion molecules, improved blood-brain barrier integrity, and decreased expression of genes involved in antigen presentation and proinflammatory responses of microglia and macrophages, which was accompanied by inhibition of [[alpha].sub.5][[beta].sub.1] integrin activation in microglia. Taken together, our data suggest that Ang2 provides a target for increasing Tie2 activation in ECs and inhibiting proinflammatory polarization of CNS myeloid cells via [[alpha].sub.5][[beta].sub.1] integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease., Introduction The blood-brain barrier (BBB) is indispensable for the maintenance of CNS homeostasis, acting by restricting molecular and cellular trafficking across the blood vascular endothelium into the CNS (1). Compromised [...]

As incidence of Neisseria gonorrhoeae infection increases worldwide (1-3), sporadic cases of the ceftriaxone-resistant multilocus sequence type (MLST) 1903 (original isolate FC428 identified in Japan) continue to be detected (4). [...]

Campylobacter jejuni and C. coli are the most common causes of bacterial foodborne gastroenteritis in the industrialized world (1). In the United Kingdom alone, Campylobacter is implicated in >500,000 cases, [...]

Yersinia pestis, the causative agent of plague, is a Tier 1 select agent because of the high case-fatality rate associated with pneumonic plague and its potential as a bioterrorism agent [...]