Bisubstrate Analog Inhibitors of DXP Synthase Show Species Specificity.

1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) is a unique thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the formation of DXP, a branchpoint metabolite required for the biosynthesis of vitamins and isoprenoids in bacterial pathogens. DXPS has relaxed substrate specificity and utilizes a gated mechanism, equipping DXPS to sense and respond to diverse substrates. We speculate that pathogens utilize this distinct gated mechanism in different ways to support metabolic adaptation during infection.

The role of estrogen metabolites in human ovarian function.

Estrogens produced by the ovary play diverse roles in controlling physiological changes in the function of the female reproductive system. Although estradiol acts through classical nuclear receptors, its metabolites (EMs) act by alternative pathways. It has been postulated that EMs act through paracrine-autocrine pathways to regulate key processes involved in normal follicular growth, corpus luteum (CL) development, function, and regression.

Toxoplasma ERK7 protects the apical complex from premature degradation.

Accurate cellular replication balances the biogenesis and turnover of complex structures. In the apicomplexan parasite Toxoplasma gondii, daughter cells form within an intact mother cell, creating additional challenges to ensuring fidelity of division. The apical complex is critical to parasite infectivity and consists of apical secretory organelles and specialized cytoskeletal structures.

Vogt-Koyanagi-Harada Disease following Covid-19 Vaccine: A Case Report and Literature Overview.

Purpose: To describe a case of Vogt-Koyanagi-Harada (VKH) disease after a Covid-19 mRNA vaccine (tozinameran) and to present the results of a pharmacovigilance disproportionality study.

Methods: A retrospective chart review and a pharmacovigilance disproportionality study using the WHO global individual case safety reports database (VigiBase).

Results: A 57-year-old female with no medical history developed a VKH disease 3 weeks after Covid-19 mRNA vaccine.

Immunogenicity of BNT162b2 vaccine against the Alpha and Delta variants in immunocompromised patients with systemic inflammatory diseases.

Objectives: The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.

The structural basis of PTEN regulation by multi-site phosphorylation.

Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN.

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Lymphoproliferative syndromes (multiple myeloma, Waldenström's disease, chronic lymphocytic leukemia, lymphomas) may be associated with peripheral neuropathies. The mechanism can be dysimmune, associated or not with monoclonal gammopathies; paraneoplastic; infiltrative; or more commonly, iatrogenic or due to vitamin deficiency. The diagnosis can be complex, especially when the neuropathy is the presenting manifestation, requiring a close cooperation between internists and neurologists.

Discovery of Anti-SS-A Antibodies during Stroke Investigations in Young Adults: What Impact?

Objectives: French national guidelines recommend searching for anti-SS-A antibodies during the second-line assessment of stroke in adults < 55 years of age in the absence of an identified etiology. We aimed to assess the impact of finding anti-SS-A antibodies during the etiological investigations of stroke in young adults.

Methods: Medical files from all patients ≤ 55 years of age admitted to a single stroke unit during a five-year period and for whom anti-SS-A antibodies were positive were retrospectively analyzed.

Impact of Cardiovascular Risk Factors on the Occurrence of Cardiovascular Events in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitides.

Despite improvement in the prognosis of ANCA-associated vasculitides (AAVs), increased mortality, mainly from a cardiovascular origin, persists. We aimed to determine the role of cardiovascular risk factors (CVRFs) on the occurrence of major cardiovascular events (MACEs) in AAVs. Patients with AAVs were successively included in a prospective cohort study, which assessed CVRFs (defined by age >50 years in men and >60 years in women, personal history of cardiovascular disease, smoking status, obesity, diabetes, dyslipidemia, hypertension, and sedentary lifestyle), the use of glucocorticoids and immunosuppressive agents at baseline and during follow-up, and the occurrence of MACEs.

Significance of pro-angiogenic estrogen metabolites in normal follicular development and follicular growth arrest in polycystic ovary syndrome.

Study Question: Do alterations in pro- and anti-angiogenic estrogen metabolites in follicular fluid (FF) contribute to the follicular growth arrest and anovulation associated with polycystic ovary syndrome (PCOS)?

Summary Answer: FF of PCOS women with anovulation have reduced levels of pro-angiogenic estrogen metabolites (EMs) and vascular endothelial growth factor (VEGF) compared to that of fertile women with regular menstrual cycles, but exogenous gonadotropins increase the pro-angiogenic EMs and VEGF levels in PCOS women.

What Is Known Already: PCOS is characterized by the arrest of follicular development that leads to chronic anovulation. Follicular arrest is generally associated with elevated plasma levels of luteinizing hormone (LH), androgens and anti-Mullerian hormone (AMH).

Handgrip strength is a comorbidity marker in systemic necrotizing vasculitides and predicts the risk of fracture and serious adverse events.

Objective: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV.

The proportion of CD57+ cells among effector CD8+ T cells is lower in HIV controllers compared with antiretroviral therapy-treated patients.

Background: HIV infection has often been linked to faster immune ageing. We sought to determine whether or not treatment-naive spontaneous HIV-1 controllers (HICs) and ART-exposed patients differ with regard to the expression of cell senescence markers.

Methods: Eighty-eight chronically infected HICs and ART-exposed patients (median time since infection: 15 years) with an undetectable plasma HIV RNA load (at least for the previous 2 years) were included.

Frontline Science: Exhaustion and senescence marker profiles on human T cells in BRGSF-A2 humanized mice resemble those in human samples.

This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2 IL2rgc Sirpα Flk2 HLA-A2 (BRGSF-A2) mouse reconstituted with human CD34 cord blood cells. With regard to senescence markers, the percentage of CD57 T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1 hCD8 T cells.

Analysis of Site-Specific Phosphorylation of PTEN by Using Enzyme-Catalyzed Expressed Protein Ligation.

The activity and localization of PTEN, a tumor suppressor lipid phosphatase that converts the phospholipid PIP3 to PIP2, is governed in part by phosphorylation on a cluster of four Ser and Thr residues near the C terminus. Prior enzymatic characterization of the four monophosphorylated (1p) PTENs by using classical expressed protein ligation (EPL) was complicated by the inclusion of a non-native Cys at the ligation junction (aa379), which may alter the properties of the semisynthetic protein. Here, we apply subtiligase-mediated EPL to create wt 1p-PTENs.

Abdominal adipose tissue predicts major cardiovascular events in systemic necrotising vasculitides.

Objectives: Cardiovascular (CV) events are highly prevalent in systemic necrotising vasculitides (SNV). Visceral/subcutaneous adipose tissue (VAT/SAT) ratio has been shown to be associated with CV events in various diseases. We aimed to assess the relevance of abdominal adipose tissue measurement to predict major CV events (MCVEs) in SNV.

Molecular modelling predicts that 2-methoxyestradiol disrupts HIF function by binding to the PAS-B domain.

An estradiol metabolite, 2-methoxyestradiol (2ME), has emerged as an important regulator of ovarian physiology. 2ME is recognized as a potent anti-angiogenic agent in clinical trials and laboratory studies. However, little is known about its molecular actions and its endogenous targets.

Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro.

Pathogenic basidiomycetous yeast, Cryptococcus neoformans, causes fatal meningitis in immunocompromised individuals. Fluconazole (FLC) is a fungistatic drug commonly administered to treat cryptococcosis. Unfortunately, FLC-resistant strains characterized by various degree of chromosomal instability were isolated from clinical patients.

Effects of Two Training Modalities on Body Fat and Insulin Resistance in Postmenopausal Women.

Henríquez, S, Monsalves-Alvarez, M, Jimenez, T, Barrera, G, Hirsch, S, de la Maza, MP, Leiva, L, Rodriguez, JM, Silva, C, and Bunout, D. Effects of two training modalities on body fat and insulin resistance in postmenopausal women. J Strength Cond Res 31(11): 2955-2964, 2017-Our objective was to compare the effects of a low-load circuit resistance training protocol and usual aerobic training in postmenopausal women.

In-vitro study of gonadotrophin signaling pathways in human granulosa cells in relation to progesterone receptor expression.

In humans, data on gonadotrophin-activated (LH, HCG and FSH) progesterone receptor expression and signalling pathways involved in matrix metalloproteinases (MMPs) expression presumably linked to the follicle rupture, are limited. Our hypothesis is LH, HCG and FSH increase progesterone receptor expression in granulosa cells through different signalling pathways, leading to an increased expression of ADAMTS-1 and MMP3/10, which may mediate follicular rupture through the transcription factor, HIF1A. Human granulosa cells were isolated from follicular aspirates obtained from 22 healthy women participating in our IVF programme for male-factor infertility.

The significance of estradiol metabolites in human corpus luteum physiology.

The human corpus luteum (CL) is a temporary endocrine gland derived from the ovulated follicle. Its formation and limited lifespan is critical for steroid hormone production required to support menstrual cyclicity, endometrial receptivity for successful implantation, and the maintenance of early pregnancy. Endocrine and paracrine-autocrine molecular mechanisms associated with progesterone production throughout the luteal phase are critical for the development, maintenance, regression, and rescue by hCG which sustains CL function into early pregnancy.

Glucocorticoid resistance in chronic diseases.

Glucocorticoids are involved in several responses triggered by a variety of environmental and physiological stimuli. These hormones have a wide-range of regulatory effects in organisms. Synthetic glucocorticoids are extensively used to suppress allergic, inflammatory, and immune disorders.