Oxidative-Nitrative Stress and Poly (ADP-Ribose) Polymerase Activation 3 Years after Pregnancy

Background: Oxidative-nitrative stress and poly (ADP-ribose) polymerase activation have been previously observed in healthy and gestational diabetic pregnancies, and they were also linked to the development of metabolic diseases. The aim of the present study was to examine these parameters and their correlation to known metabolic risk factors following healthy and gestational diabetic pregnancies. // Methods: Fasting and 2 h postload plasma total peroxide level, protein tyrosine nitration, and poly (ADP-ribose) polymerase activation were measured in circulating leukocytes three years after delivery in women following healthy, “mild” (diet-treated) or “severe” (insulin-treated) gestational diabetic pregnancy during a standard 75 g OGTT. Nulliparous women and men served as control groups. // Results: Fasting plasma total peroxide level was significantly elevated in women with previous pregnancy (B = 0.52 ± 0.13; p < 0 001), with further increase in women with insulin-treated gestational diabetes (B=0 36 ± 0 17; p < 0 05) (R2 = 0 419). Its level was independently related to previous pregnancy (B=0 47 ± 0 14; p < 0 01) and current CRP levels (B=0 06 ± 0 02; p < 0 05) (R2 = 0 306). // Conclusions: Elevated oxidative stress but not nitrative stress or poly (ADP-ribose) polymerase activation can be measured three years after pregnancy. The increased oxidative stress may reflect the cost of reproduction and possibly play a role in the increased metabolic risk observed in women with a history of severe gestational diabetes mellitus

Oxidative-Nitrative Stress and Poly (ADP-Ribose) Polymerase Activation 3 Years after Pregnancy

Background: Oxidative-nitrative stress and poly (ADP-ribose) polymerase activation have been previously observed in healthy and gestational diabetic pregnancies, and they were also linked to the development of metabolic diseases. The aim of the present study was to examine these parameters and their correlation to known metabolic risk factors following healthy and gestational diabetic pregnancies. Methods: Fasting and 2 h postload plasma total peroxide level, protein tyrosine nitration, and poly (ADP-ribose) polymerase activation were measured in circulating leukocytes three years after delivery in women following healthy, "mild" (diet-treated) or "severe" (insulin-treated) gestational diabetic pregnancy during a standard 75 g OGTT. Nulliparous women and men served as control groups. Results: Fasting plasma total peroxide level was significantly elevated in women with previous pregnancy (B = 0.52 +/- 0.13; p < 0.001), with further increase in women with insulin-treated gestational diabetes (B = 0.36 +/- 0.17; p < 0.05) (R(2) = 0.419). Its level was independently related to previous pregnancy (B = 0.47 +/- 0.14; p < 0.01) and current CRP levels (B = 0.06 +/- 0.02; p < 0.05) (R(2) = 0.306). Conclusions: Elevated oxidative stress but not nitrative stress or poly (ADP-ribose) polymerase activation can be measured three years after pregnancy. The increased oxidative stress may reflect the cost of reproduction and possibly play a role in the increased metabolic risk observed in women with a history of severe gestational diabetes mellitus

Osteoid osteoma of the femur in a 7-month-old infant treated with radiofrequency ablation

Osteoid osteoma occurs most commonly in children, adolescents, and young adults between the ages of 5 and 30 years. In the preschool age group, it is quite uncommon, accounting for only 3–8% of all osteoid osteoma cases. We report a case of osteoid osteoma in a 7-month-old infant, who presented with decreased use of the right lower extremity due to pain. Magnetic resonance imaging (MRI) showed an atypical appearance. A biopsy of the lesion, with histopathological examination, confirmed the diagnosis of osteoid osteoma. Radiofrequency ablation (RFA) of the nidus under computed tomography (CT) guidance was performed. The patient developed a recurrence after 3 months, which was treated with a second RFA. On subsequent follow-up, the infant did not show signs of pain after 1 month. In summary, this case report shows that osteoid osteoma can present in early infancy and can be successfully treated with RFA at this age, however, recurrence after the procedure can occur and close follow-up is recommended

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans

This is the final version. Available on open access from the National Academy of Sciences via the DOI in this recordData, Materials, and Software Availability: All study data are included in the article and/or supporting information. The raw RNA sequencing data can be found within the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) under the Sequence Read Archive (SRA) accession PRJNA996496 (93).Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.US Army Research OfficeUnited Mitochondrial Disease FoundationUniversity of ExeterUK Space AgencyBiotechnology and Biological Sciences Research Council (BBSRC)NASAOsteopathic Heritage Foundatio

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

The CIN4 chromosomal instability qPCR classifier defines tumor aneuploidy and stratifies outcome in grade 2 breast cancer.

Purpose: Quantifying chromosomal instability (CIN) has both prognostic and predictive clinical utility in breast cancer. In order to establish a robust and clinically applicable gene expression-based measure of CIN, we assessed the ability of four qPCR quantified genes selected from the 70-gene Chromosomal Instability (CIN70) expression signature to stratify outcome in patients with grade 2 breast cancer. Methods: AURKA, FOXM1, TOP2A and TPX2 (CIN4), were selected from the CIN70 signature due to their high level of correlation with histological grade and mean CIN70 signature expression in silico. We assessed the ability of CIN4 to stratify outcome in an independent cohort of patients diagnosed between 1999 and 2002. 185 formalin-fixed, paraffin-embedded (FFPE) samples were included in the qPCR measurement of CIN4 expression. In parallel, ploidy status of tumors was assessed by flow cytometry. We investigated whether the categorical CIN4 score derived from the CIN4 signature was correlated with recurrence-free survival (RFS) and ploidy status in this cohort. Results: We observed a significant association of tumor proliferation, defined by Ki67 and mitotic index (MI), with both CIN4 expression and aneuploidy. The CIN4 score stratified grade 2 carcinomas into good and poor prognostic cohorts (mean RFS: 83.864.9 and 69.4 +- 8.2 months, respectively, p = 0.016) and its predictive power was confirmed by multivariate analysis outperforming MI and Ki67 expression. Conclusions: The first clinically applicable qPCR derived measure of tumor aneuploidy from FFPE tissue, stratifies grade 2 tumors into good and poor prognosis groups

Amelioration of Experimental Autoimmune Encephalomyelitis by Plumbagin through Down-Regulation of JAK-STAT and NF-κB Signaling Pathways

Plumbagin(PL), a herbal compound derived from roots of the medicinal plant Plumbago zeylanica, has been shown to have immunosuppressive properties. Present report describes that PL is a potent novel agent in control of encephalitogenic T cell responses and amelioration of mouse experimental autoimmune encephalomyelitis (EAE), through down-regulation of JAK-STAT pathway. PL was found to selectively inhibit IFN-γ and IL-17 production by CD4+ T cells, which was mediated through abrogated phosphorylation of JAK1 and JAK2. Consistent with IFN-γ and IL-17 reduction was suppressed STAT1/STAT4/T-bet pathway which is critical for Th1 differentiation, as well as STAT3/ROR pathway which is essential for Th17 differentiation. In addition, PL suppressed pro-inflammatory molecules such as iNOS, IFN-γ and IL-6, accompanied by inhibition of IκB degradation as well as NF-κB phosphorylation. These data give new insight into the novel immune regulatory mechanism of PL and highlight the great value of this kind of herb compounds in probing the complex cytokine signaling network and novel therapeutic targets for autoimmune diseases