Brucella suis histidinol dehydrogenase: synthesis and inhibition studies of substituted N-L-histidinylphenylsulfonyl hydrazide

Histidinol dehydrogenase (HDH, EC EC1.1.1.23) catalyses the final step in the biosynthesis of histidine and constitutes an attractive novel target for the development of new agents against the pathogenous, bacteria Brucella suis. A small library of new HDH inhibitors based on the L-histidinylphenylsulfonyl hydrazide scaffold has been synthesized and their inhibitory activity investigated. The obtained results demonstrate that modification of the group between the histidinyl moiety and the phenyl ring constitutes an important structural factor for the design of effective HDH inhibitors.     

Candidate Luminal B Breast Cancer Genes Identified by Genome,Gene Expression and DNA Methylation Profiling

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.     

The apocytochrome b gene of Chlamydomonas smithii contains a mobile intron related to both Saccharomyces and Neurospora introns.

Summary The mitochondrial DNA of the two interfertile algal species Chlamydomonas smithii and Chlamydomonas reinhardtii are co-linear with the exception of ca. 1 kb insertion (the a insert) present in C. smithii DNA only. In vegetative diploids resulting from interspecific crosses, mitochondrial genomes are transmitted biparentally except for the a insert which is transmitted to all C. reinhardtii molecules in a manner reminiscent of the intron-mediated conversion event that occurs at the omega locus in yeast mitochondria, under the action of the I-SceI endonuclease. Here we report that the insert corresponds to a typical group I intron of 1075 bp, inserted within the gene for apocytochrome b and containing a 237 codon open reading frame (ORF). We also report the complete sequence of the apocytochrome b gene of C. smithii. Comparison with the sequence of the same gene in C. reinhardtii reveals the precise intron insertion site. These data, together with the previous genetic data provide the first example of intron mobility in mitochondria of the plant kingdom. The product of the intronic ORF shows 36% amino acid identity with the I-SceI endonuclease whereas the intron ribozyme shows a 60% identity at the nucleotide level with the Neurospora crassa cob · 1 intron. The possibility of a recent horizontal transfer of introns between fungi and algae is discussed.     

Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis

Objectives

Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients.

Methods

Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs.

Results

Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p<0.001) and, interestingly, in 7 of 14 MPO and PR3 ANCA negative AAV patients. Moreover, by indirect immunofluorescence on fixed neutrophils, anti-PTX3 aAbs gave rise to a specific cytoplasmic fluorescence pattern distinct from the classical cytoplasmic (c-ANCA), perinuclear (p-ANCA), and atypical (a-ANCA) pattern. Anti-PTX3 aAbs levels were higher in patients with active AAV as compared to patients with inactive disease.

Conclusion

Our work suggests that PTX3 is as a novel ANCA antigen. Anti-PTX3 aAbs appear thus as a promising novel biomarker in the diagnosis of AAV, including in patients without detectable MPO and PR3 ANCA.     

Hourly distribution of time of parturition in the domestic goat

Data on 2589 records collected during 12 years in one breed of dairy goats that were maintained in stables were analysed to examine the influence of various factors on the time of parturition. Parturitions were observed from mid-January to the end of April. Hourly frequencies of birth showed an unimodal distribution with maximum births at midday and minimum births around midnight with 90.6% of deliveries occurring between 0600 and 2000 h. The distribution showed a noticeable homogeneity when the following parameters were taken into account: litter-size, litters with live or stillborn kids, time of the year and length of gestation. In two other herds, 117 and 166 records obtained after 4 and 3 years of observation were studied. As in the first herd, births were more frequent between 0700 to 1900 h (day; 72.3 and 70.2 %, respectively) than between 1900 and 0700 h (night; P<0.001). These observations on the time of birth of the domestic goat suggest a regulation of the birth process by circadian events which themselves remain unknown.     

Relationship between bronchial hyperresponsiveness and impaired lung function after infantile asthma

Wheezing during infancy has been linked to early loss of pulmonary function. We prospectively investigated the relation between bronchial hyperresponsiveness (BHR) and progressive impairment of pulmonary function in a cohort of asthmatic infants followed until age 9 years. We studied 129 infants who had had at least three episodes of wheezing. Physical examinations, baseline lung function tests and methacholine challenge tests were scheduled at ages 16 months and 5, 7 and 9 years. Eighty-three children completed follow-up. Twenty-four (29%) infants had wheezing that persisted at 9 years of age. Clinical outcome at age 9 years was significantly predicted by symptoms at 5 years of age and by parental atopy. Specific airway resistance (sRaw) was altered in persistent wheezers as early as 5 years of age, and did not change thereafter. Ninety-five per cent of the children still responded to methacholine at the end of follow-up. The degree of BHR at 9 years was significantly related to current clinical status, baseline lung function, and parental atopy. BHR at 16 months and 5 years of age did not predict persistent wheezing between 5 and 9 years of age, or the final degree of BHR, but it did predict altered lung function. Wheezing that persists from infancy to 9 years of age is associated with BHR and to impaired lung function. BHR itself is predictive of impaired lung function in children, strongly pointing to early airway remodeling in infantile asthma.     

Siberian Miscanthus sacchariflorus accessions surpass the exceptional chilling tolerance of the most widely cultivated clone of Miscanthus x giganteus

Chilling temperatures (0–15°C) inhibit photosynthesis in most C₄ grasses, yet photosynthesis is chilling tolerant in the ‘Illinois’ clone of the C₄ grass Miscanthus x giganteus, a candidate cellulosic bioenergy crop. M. x giganteus is a hybrid between Miscanthus sacchariflorus and Miscanthus sinensis; therefore chilling‐tolerant parent lines might produce hybrids superior to the current clone. Recently a collection of M. sacchariflorus from Siberia, the apparent low temperature limit of natural distribution, became available, which may be a source for chilling tolerance. The collection was screened for chilling tolerance of photosynthesis by measuring dark‐adapted maximum quantum yield of PSII photochemistry (F_v/F_m) on plants in the field in cool weather. Superior accessions were selected for further phenotyping: plants were grown at 25°C, transferred to 10°C (chilling) for 15 days, and returned to 25°C for 7 days (recovery). Two experiments assessed: (a) light‐saturated net photosynthetic rate (A_sat) and operating quantum yield of PSII photochemistry (Φ_PSII), (b) response of net leaf CO₂ uptake (A) to intercellular [CO₂] (c_i). Three accessions showed superior chilling tolerance: RU2012‐069 and RU2012‐114 achieved A_sat up to double that of M. x giganteus prior to and during chilling, due to increased c_i ‐ saturated photosynthesis (V_max). RU2012‐069 and RU2012‐114 also maintained greater levels of Φ_PSII during chilling, indicating reduced photodamage. Additionally, accession RU2012‐112 maintained a stable A_sat throughout the 15‐day chilling period, while A_sat continuously declined in other accessions; this suggests RU2012‐112 could outperform others in lengthy chilling periods. Plants were returned to 25°C after the chilling period; M. x giganteus showed the weakest recovery after 1 day, but a strong recovery after 1 week. This study has therefore identified important genetic resources for the synthesis of improved lines of M. x giganteus, which could facilitate the displacement of fossil fuels by cellulosic bioenergy.     

C-glycosylflavones from roots of glycine max

Chemical investigation of the roots of Glycine max yielded six C-glycosylflavones identified on the basis of spectral data as carlinoside, isocarlinoside, vitexin, vitexin 2″-O-rhamnoside, isoschaftoside and a new compound 6,8-di-C-hexosylgenkwanin.