Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function,and literature review

Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.     

Fas,FasL, and cleaved caspases 8 and 3 in glioblastomas: A tissue microarray-based study

This investigation analyzed the immunoexpression of FasL, Fas, cleaved caspase-8, and cleaved caspase-3 in glioblastomas. Formalin-fixed and paraffin-embedded glioblastoma tissues and control brain tissues from 97 patients were analyzed by tissue microarrays and immunohistochemistry. Patients with glioblastomas that were negative or weakly stained (<50% of cells positive) for cleaved caspase-8 had worse cancer-specific overall survival (median = 8.5 months) than did patients with tumors that highly expressed cleaved caspase-8 (median = 11.7 months; P = 0.0325), independent of clinical variables. There was no association of other markers with survival, treatment, sex, age, tumor size, and primary site. Among the tumors, there were reasonable to good positive correlations between the expression of FasL and Fas (r = 0.47) and between Fas and cleaved caspase-8 (r = 0.41), and there were poor positive correlations between Fas and cleaved caspase-3 (r = 0.26), FasL and cleaved caspase-8 (r = 0.22), and cleaved caspase-8 and -3 (r = 0.31). Our results suggest that Fas-Fas-ligand signal transduction could be inhibited, especially at the stage of caspase-8 activation, thereby establishing a major mechanism for evasion of apoptosis by these tumors. The absence or low expression of cleaved caspase-8 in the tumors was a negative prognostic indicator for patient survival.     

Synthesis and characterization of thermoresponsive ZIF-8@PNIPAm-co-MAA microgel composites with enhanced performance as an adsorption/release platform

Composite materials featuring a synergic combination of interesting properties such as stimuli responsiveness and tailored porosity are highly appealing due to their multiple possible applications. We hereby present an example which brings together such features by using poly(N-isopropyl-acrylamide)-derived thermo-responsive microgels and Zn-based Metal Organic Framework (MOF) ZIF-8, capable of selective adsorption. Such a composite was obtained by including methacrylic acid as a co-monomer in the microgel, in order to position carboxylic acid moieties within the polymeric matrix, which via preconcentration of MOF precursors would trigger confined heterogeneous nucleation. The highly integrated composite obtained features thermoresponsivity and permanent porosity. Methylene blue adsorption/desorption experiments were performed, revealing a dramatic enhancement of its cargo capacity together with an increased release efficiency.

We hereby present a composite material which combines porosity (ZIF-8 MOF) and stimuli-responsiveness (PNIPAm-co-MAA microgel) in a synergistic way thus opening the path for its use in adsorption and sensing applications.     

Mild Choline Deficiency and MTHFD1 Synthetase Deficiency Interact to Increase Incidence of Developmental Delays and Defects in Mice

Folate and choline are interconnected metabolically. The MTHFD1 R653Q SNP is a risk factor for birth defects and there are concerns that choline deficiency may interact with this SNP and exacerbate health risks. 80–90% of women do not meet the Adequate Intake (AI) for choline. The objective of this study was to assess the effects of choline deficiency on maternal one-carbon metabolism and reproductive outcomes in the MTHFD1-synthetase deficient mouse (Mthfd1S), a model for MTHFD1 R653Q. Mthfd1S^+/+ and Mthfd1S^+/− females were fed control (CD) or choline-deficient diets (ChDD; 1/3 the amount of choline) before mating and during pregnancy. Embryos were evaluated for delays and defects at 10.5 days gestation. Choline metabolites were measured in the maternal liver, and total folate measured in maternal plasma and liver. ChDD significantly decreased choline, betaine, phosphocholine, and dimethylglycine in maternal liver (p < 0.05, ANOVA), and altered phosphatidylcholine metabolism. Maternal and embryonic genotype, and diet-genotype interactions had significant effects on defect incidence. Mild choline deficiency and Mthfd1S^+/− genotype alter maternal one-carbon metabolism and increase incidence of developmental defects. Further study is required to determine if low choline intakes contribute to developmental defects in humans, particularly in 653QQ women.     

Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma.

AIMS: Loss of heterozygosity (LOH) at specific chromosomal regions strongly suggests the existence of tumour suppressor genes at the relevant segment. Frequent LOH on chromosome 5q has been reported in a wide variety of human tumours, including those of the lung. The aim of this study was to screen for LOH and to clarify the location of putative tumour suppressor genes on chromosome 5 implicated in the genesis and/or development of non-small cell lung carcinoma. METHODS: Thirty three patients with advanced non-small cell lung carcinoma were screened for LOH with a panel of 21 microsatellite DNA markers spanning the entire chromosome 5, using semi-automated fluorochrome based methodology. RESULTS: Twenty of the non-small cell lung carcinoma samples displayed LOH for one or more informative locus. LOH involving only 5q was found in 10 of 14 of the informative samples. Deletions involving 5p only were not present in the samples under study. There was no evidence of microsatellite instability in any of the analysed loci. These results indicate the presence of five distinct segments displaying high frequencies of deletion on chromosome 5, namely: 5q11.2-q12.2, 5q15 (D5S644 locus), 5q22.3-q23.1, 5q31.1, and 5q35.3. Eight of 14 samples had simultaneous interstitial deletions in at least two different regions. Moreover, concomitant deletion of three and four distinct regions was displayed in three of 14 and two of 14, respectively, of the informative samples. CONCLUSION: Allelic deletion on chromosome 5 is a frequent event in patients with non-small cell lung carcinoma. These results suggest the involvement of these five regions, either independently or simultaneously, in both lung squamous cell carcinoma and lung adenocarcinoma.     

Nutritional aspects of liver transplantation

Most adult and pediatric liver transplantation candidates present several metabolic disturbances that lead to malnutrition. Because malnutrition may adversely affect morbidity and mortality of orthotopic liver transplantation, it is very important to carefully assess the nutritional status of the waiting list patients. Pretransplant nutritional therapy -- enteral or parenteral -- may positively influence liver metabolism, muscle function, and immune status. Nutrition therapy should continue in the short- and also in the long-term post-transplant periods. For malnourished patients, early post-transplant enteral or parenteral nutrition have been useful in improving nutritional status. Finally, the metabolic and nutritional care of the liver transplant donor must be considered to reduce allograft dysfunction indices.     

Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer

The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the AR(ccr). Our studies provide the first structural explanation for the glucocorticoid activation of AR(ccr), which is important for the development of new therapeutic treatments for androgen-independent prostate cancer.     

Effect of D-2 amino-5-phosphonopentanoate and nifedipine on postsynaptic calcium changes associated with long-term potentiation in hippocampal CA1 area

The induction of long-term potentiation (LTP) in CA1 hippocampal area requires a rise in intracellular postsynaptic calcium. Two major calcium mechanisms may mediate the transmembrane calcium influxes that contribute to this calcium accumulation: the N-methyl-D-aspartate (NMDA) receptor channels, which are voltage dependent and have large calcium permeability and voltage-dependent calcium channels (VDCCs). We have addressed the relative contribution of these routes of calcium entry before and during LTP expression, in synaptically evoked dendritic calcium transients from a population of CA1 pyramidal neurons. Combining the use of the fluorescent calcium indicator Fura-2 with field potential measurements, we observed that the calcium transients evoked by single stimuli, during the maintenance phase of LTP, were enhanced. These transients were not affected by D-2 amino-5-phosphonopentanoate (D-APV) (50 microM), an antagonist of NMDA receptors but were reduced by approximately one-quarter, in the presence of the L-type VDCCs blocker nifedipine (10 microM). During tetanic stimulation (100 Hz, 1 s) the components triggered by the activation of those two calcium mechanisms had comparable magnitudes representing the sum about half of the intracellular calcium accumulation. Thus, following both single and high frequency stimulation, a substantial fraction of calcium entry may occur through other types of VDCCs or be due to calcium release from intracellular stores.