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Mechanisms of disulfide bond formation in the human pathogen Streptococcus pyogenes are currently unknown. To date, no disulfide bond-forming thiol-disulfide oxidoreductase (TDOR) has been described and at least one disulfide bonded protein is known in S. pyogenes. This protein is the superantigen SpeA, which contains 3 cysteine residues (Cys 87, Cys90, and Cys98) and has a disulfide bond formed between Cys87 and Cys98. In this study, candidate TDORs were identified from the genome sequence of S. pyogenes MGAS8232. Using mutational and biochemical approaches, one of the candidate proteins, SpyM18_2037 (named here SdbA), was shown to be the catalyst that introduces the disulfide bond in SpeA. SpeA in the culture supernatant remained reduced when sdbA was inactivated and restored to the oxidized state when a functional copy of sdbA was returned to the sdbA-knockout mutant. SdbA has a typical C46XXC49 active site motif commonly found in TDORs. Site-directed mutagenesis experiments showed that the cysteines in th acids form a disulfide loop that is conserved among many superantigens, including those from Staphylococcus aureus. SpeA and staphylococcal enterotoxins lacking the disulfide bond are biologically inactive. Thus, the discovery of the enzyme that catalyzes the disulfide bond in SpeA is important for understanding the biochemistry of SpeA production and presents a target for mitigating the virulence of S. pyogenes.As ultraprocessed foods (i.e., foods composed of mostly cheap industrial sources of dietary energy and nutrients plus additives) have become more abundant in our food supply, rates of obesity and diet-related disease have increased simultaneously. Food addiction has emerged as a phenotype of significant empirical interest within the past decade, conceptualized most commonly as a substance-based addiction to ultraprocessed foods. We detail (a) how approaches used to understand substance-use disorders may be applicable for operationalizing food addiction, (b) evidence for the reinforcing potential of ingredients in ultraprocessed foods that may drive compulsive consumptions, (c) the utility of conceptualizing food addiction as a substance-use disorder versus a behavioral addiction, and (d) clinical and policy implications that may follow if ultraprocessed foods exhibit an addictive potential. Broadly, the existing literature suggests biological and behavioral parallels between food addiction and substance addictions, with ultraprocessed foods high in both added fat and refined carbohydrates being most implicated in addictive-like eating. Future research priorities are also discussed, including the need for longitudinal studies and the potential negative impact of addictive ultraprocessed foods on children. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http//www.annualreviews.org/page/journal/pubdates for revised estimates.Malaria infects millions of people every year, and despite recent advances in controlling disease spread, such as vaccination, it remains a global health concern. The circumsporozoite protein (CSP) has long been acknowledged as a key target in anti-malarial immunity. Leveraging the DNA vaccine platform against this formidable pathogen, five synthetic DNA vaccines encoding variations of CSP were designed and studied 3D7, GPI1, ΔGPI, TM, and DD2. Among the single CSP antigen constructs a range of immunogenicity was observed with ΔGPI generating the most robust immunity. In an IV sporozoite challenge the best protection among vaccinated mice was achieved by ΔGPI, which performed almost as well as the MAb311 antibody control. Further analyses revealed that ΔGPI develops high molecular weight multimers in addition to monomeric CSP. We then compared the immunity generated by ΔGPI vs synDNA mimics for the anti-malaria vaccines RTS,S and R21. The anti-CSP antibody responses induced were similar among these three immunogens. T cell responses demonstrated that ΔGPI induced a more focused anti-CSP response. click here In an infectious mosquito challenge all three of these constructs generated inhibition of liver stage infection, as well as immunity from blood stage parasitemia. This study demonstrates that synDNA mimics of complex malaria immunogens can provide substantial protection, as can a novel synDNA vaccine ΔGPI.

In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%.

To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial.

Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov NCT03521934).

306 sites in 32 countries.

1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure.

200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo.

The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days).

Other than heart failure, the primary reason for each hospitalization was unspecified.

Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life.

Sanofi at initiation and Lexicon Pharmaceuticals at completion.

Sanofi at initiation and Lexicon Pharmaceuticals at completion.

The Kidney Disease Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.

The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence.