Goldston syndrome: report of a case.

Cerebrohepatorenal malformation is a rare familial disorder characterized by typical renal lesions combined with Dandy-Walker malformation, and congenital hepatic fibrosis. In this case report, a male premie with the diagnosis of cerebrorenal syndrome or so called Goldston syndrome is presented. Besides the rarity of this syndrome, this case is the second reported patient diagnosed prenatally.     

Mechanisms of abemaciclib,a CDK4/6 inhibitor,induced apoptotic cell death in prostate cancer cells in vitro

The therapeutic effects of abemaciclib (ABE), an inhibitor of cyclin- dependent kinases (CDK) 4/6, on the proliferation of two types of prostate cancer (PC) cells were revealed. In this study, in vitro cytotoxic and apoptotic effects of ABE on metastatic castration-resistant prostate cancer (mCRPC) androgen receptor (AR) negative PC-3 and AR mutant LNCaP PC cells were analyzed with WST-1, Annexin V, cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential, RT-PCR, western blot, and apoptosis protein array. ABE considerably inhibited the growth of PC cells in a dose-dependent manner (p<0.01) and caused significant apoptotic cell death through the suppression of CDK4/6-Cyclin D complex, ROS generation and depolarization of mitochondria membrane potential. However, PC-3 cells were more sensitive to ABE than LNCaP cells. Furthermore, the expression levels of several pro-apoptotic and cell cycle regulatory proteins were upregulated by ABE in especially PC-3 cells with the downregulation of apoptotic inhibitor proteins. Our results suggest that ABE inhibits PC cell growth and promotes apoptosis and thus ABE treatment may be a promising treatment strategy in especially mCRPC. Further preclinical and clinical studies should be performed to clarify the clinical use of ABE for the treatment of PC.     

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.     

Tumour necrosis factor alpha, lipid peroxidation and NO* are increased and associated with decreased free-radical scavenging enzymes in patients with Weill-Marchesani syndrome

AIM: Weill-Marchesani syndrome (WMS) is a rare systemic disorder with both autosomal recessive and dominant inheritances. Accumulation of reactive oxygen species such as O2*-, H2O2 and OH* causes lipid peroxidation (LPO), whereas antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GSHPx)) mediate defence against oxidative stress. Excess tumour necrosis factor (TNF)-alpha and NO* react with O2*- and cause further antioxidant depletion with an increase in mutation frequency by H2O2. This study investigated the levels of SOD, GSHPx, catalase (CAT), TNF-alpha, NO and LPO in patients with WMS. METHODS: A group of 10 WMS patients (four males, six females; age, 26.5+/-19.0 years) and 10 age-matched and sex-matched controls (five males, five females; age, 27.3+/-18.2 years) were included. Serum TNF-alpha levels were determined by a spectrophotometer technique using immulite chemiluminescent immunometric assay. Malondialdehyde (MDA) was determined in plasma; CAT in red blood cells (RBCs), and SOD and GSHPx in both plasma and RBCs. Total serum NO* levels were evaluated by Griess reaction. RESULTS: Mean levels of TNF-alpha (8.3+/-0.6 pg/ml) in WMS patients were significantly (p<0.001) higher than controls (4.3+/-0.2 pg/ml). Plasma MDA levels in patients and controls were 5.4+/-0.8 and 1.8+/-0.6 micromol/l, respectively, and the difference was significant (p=0.0002). SOD and GSHPx activities were significantly lower in both RBCs and plasma of WMS than in controls (RBC-SOD, 3981.9+/-626.6 versus 5261.6+/-523.0 U/g haemoglobin (Hb), p=0.0005; plasma-SOD, 529.4+/-49.3 versus 713.4+/-55.7 U/g protein, p=0.0002; RBC-GSHPx, 682.7+/-42.0 versus 756.5+/-47.6 U/g Hb, p=0.0011; plasma-GSHPx, 107.3+/-15.0 versus 131.4+/-19.7 U/g protein, p=0.0113). In addition, serum NO (NO*-2 + NO*-3) levels were also significantly (p = 0.0002) increased in WMS patients (54.4+/-5.7 versus 26.9+/-6.7 micromol/l). RBC-CAT levels were similar between groups (125.6+/-21.3 versus 131.0+/-21.5 k/g Hb, p = 0.8798). CONCLUSIONS: The elevated LPO, TNF-alpha and NO* with decreased antioxidant enzyme activities indicated impaired antioxidative defence mechanisms with an oxidative injury and cell toxicity in WMS patients. The use of multiple antioxidants and free radical scavengers might be helpful in this genetic disorder.     

A Flexible Docking Scheme Efficiently Captures the Energetics of Glycan-Cyanovirin Binding

Cyanovirin-N (CVN), a cyanobacterial lectin, exemplifies a class of antiviral agents that inhibit HIV by binding to the highly glycosylated envelope protein gp120. Here, we investigate the energetics of glycan recognition using a computationally inexpensive flexible docking approach, backbone perturbation docking (BP-Dock). We benchmarked our method using two mutants of CVN: P51G-m4-CVN, which binds dimannose with high affinity through domain B, and CVN^(mutDB), in which binding to domain B has been abolished through mutation of five polar residues to small nonpolar side chains. We investigated the energetic contribution of these polar residues along with the additional position 53 by docking dimannose to single-point CVN mutant models. Analysis of the docking simulations indicated that the E41A/G and T57A mutations led to a significant decrease in binding energy scores due to rearrangements of the hydrogen-bond network that reverberated throughout the binding cavity. N42A decreased the binding score to a level comparable to that of CVN^(mutDB) by affecting the integrity of the local protein structure. In contrast, N53S resulted in a high binding energy score, similar to P51G-m4-CVN. Experimental characterization of the five mutants by NMR spectroscopy confirmed the binding affinity pattern predicted by BP-Dock. Despite their mostly conserved fold and stability, E41A, E41G, and T57A displayed dissociation constants in the millimolar range. N53S showed a binding constant in the low micromolar range, similar to that observed for P51G-m4-CVN. No binding was observed for N42A. Our results show that BP-Dock is a useful tool for rapidly screening the relative binding affinity pattern of in silico-designed mutants compared with wild-type, supporting its use to design novel mutants with enhanced binding properties.     

Antitumoral and antioxidant effect of essential oils and <Emphasis Type="Italic">in vitro</Emphasis> antioxidant properties of essential oils and aqueous extracts from <Emphasis Type="Italic">Salvia pisidica</Emphasis>

The aim of the work was to investigate antitumoral effect of essential oils on cancer cells and their possible protective (antioxidant) effects against hydrogen peroxide-induced cytotoxicity. Also, in vitro antioxidant properties of essential oils and aqueous extracts from wild form and cultivated form of Salvia pisidica were compared.     

Serum IGF-1, IGFBP-3 and growth hormone levels in children with congenital heart disease: relationship with nutritional status, cyanosis and left ventricular functions

In this study we aimed to evaluate serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) levels in children with congenital heart disease (CHD) and to determine if these parameters have any relationship to the cyanosis, nutritional status and the left ventricular systolic function. This study is prospective-randomized study which conducted in 94 CHD patients (36 girls and 58 boys, aged between one 1-192 months, 19 cyanotic CHD and 75 acyanotic CHD) and age-sex matched 54 children (26 girls and 28 boys) with no CHD. In the study group, 37 out of the 94 CHD patients (39.4%) and 16 out of the 54 controls (29.6%) had malnutrition. The difference between the cyanotic and acyanotic patients in respect to malnutrition was significant (57.9% and 34.6%, p<0.05). Serum IGF-1 levels were lower (41.8+/-3.9 microg/L, 106.9+/-17.9 microg/L respectively, p<0.001) and GH levels were higher (6.43+/-0.9 ng/ml, 3.87+/-0.5 respectively, p<0.05) in CHD patient group than the controls. Serum IGF-1 levels were significantly lower in cyanotic CHD patients than the acyanotic patients (17.2+/-3.2 microg/L, 48.7.0+/-4.6 microg/L respectively, p<0.001) and serum IGF-1 levels were both lower in acyanotic and cyanotic CHD patients than the controls (p<0.001 for both). Serum IGF-1 and GH levels were similar between the well-nourished CHD patients and CHD patients with malnutrition (p>0.05). In total study group, the most effective factors on serum IGF-1 levels was presence of CHD (p<0.001), in CHD patients, the presence of cyanosis is the most effective factor on serum IGF-1 level, the presence of malnutrition is the most effective factor on serum IGFBP-3 levels (p<0.01). In the acyanotic, cyanotic, and the entire CHD patient groups, we find no correlations between the serum IGF-1, IGFBP-3 levels and left ventricular systolic function measurements. But serum GH levels were negatively correlated with diastolic left ventricular interseptum diameter, diastolic left ventricular mass and left ventricular end-diastolic volume measurements in CHD patients. In conclusion, we determined that the most important factor on serum IGF-1 levels is cyanosis. Reduced IGF1 levels and decreased left ventricular mass with an elevated GH levels in CHD patients and these findings are prominent in the cases with cyanosis and malnutrition. For this reason we believe that chronic hypoxia plays a significant role in the pathogenesis of malnutrition and also we believe that IGF-1 deficiency seen in CHD patients may be responsible in the etiology of the decrease in left ventricular mass independently from GH.     

Independent wheat B and G genome origins in outcrossing Aegilops progenitor haplotypes

The origin of modern wheats involved alloploidization among related genomes. To determine if Aegilops speltoides was the donor of the B and G genomes in AABB and AAGG tetraploids, we used a 3-tiered approach. Using 70 amplified fragment length polymorphism (AFLP) loci, we sampled molecular diversity among 480 wheat lines from their natural habitats encompassing all S genome Aegilops, the putative progenitors of wheat B and G genomes. Fifty-nine Aegilops representatives for S genome diversity were compared at 375 AFLP loci with diploid, tetraploid, and 11 nulli-tetrasomic Triticum aestivum wheat lines. B genome-specific markers allowed pinning the origin of the B genome to S chromosomes of A. speltoides, while excluding other lineages. The outbreeding nature of A. speltoides influences its molecular diversity and bears upon inferences of B and G genome origins. Haplotypes at nuclear and chloroplast loci ACC1, G6PDH, GPT, PGK1, Q, VRN1, and ndhF for approximately 70 Aegilops and Triticum lines (0.73 Mb sequenced) reveal both B and G genomes of polyploid wheats as unique samples of A. speltoides haplotype diversity. These have been sequestered by the AABB Triticum dicoccoides and AAGG Triticum araraticum lineages during their independent origins.     

Effects of some boron compounds on peripheral human blood

Peripheral blood cultures were exposed to various doses (5 to 500 mg/L) of boron compounds. Sister-chromatid exchange, micronucleus and chromosomal aberration tests were applied to estimate the DNA damage, and biochemical parameters (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, total glutathione, malondialdehyde and total antioxidant capacity) were examined to determine oxidative stress. According to our findings, various boron compounds at low doses were useful in supporting antioxidant enzyme activities in human blood cultures. It was found that the boron compounds do not have genotoxic effects even in the highest concentrations, though in increasing doses they constitute oxidative stress. It is concluded that the tested boron compounds can be used safely, but it is necessary to consider the tissue damages which are likely to appear depending on the oxidative stress.