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.     

The human brain processes hierarchical structures of meter and harmony differently: Evidence from musicians and nonmusicians

The processing of temporal structure has been widely investigated, but evidence on how the brain processes temporal and nontemporal structures simultaneously is sparse. Using event-related potentials (ERPs), we examined how the brain responds to temporal (metric) and nontemporal (harmonic) structures in music simultaneously, and whether these processes are impacted by musical expertise. Fifteen musicians and 15 nonmusicians rated the degree of completeness of musical sequences with or without violations in metric or harmonic structures. In the single violation conditions, the ERP results showed that both musicians and nonmusicians exhibited an early right anterior negativity (ERAN) as well as an N5 to temporal violations (“when”), and only an N5-like response to nontemporal violations (“what”), which were consistent with the behavioral results. In the double violation condition, however, only the ERP results, but not the behavioral results, revealed a significant interaction between temporal and nontemporal violations at a later integrative stage, as manifested by an enlarged N5 effect compared to the single violation conditions. These findings provide the first evidence that the human brain uses different neural mechanisms in processing metric and harmonic structures in music, which may shed light on how the brain generates predictions for “what” and “when” events in the natural environment.     

Ecology and evolution in microbial systems: the generation and maintenance of diversity in phage-host interactions

Insights gained from studying the interactions between viruses and bacteria have important implications for the ecology and evolution of virus–host interactions in many environments and for pathogen–host and predator–prey interactions in general. Here, we focus on the generation and maintenance of diversity, highlighting recent laboratory and field experiments with microorganisms.     

Subcellular and regional location of “brain” proteins BASP1 and MARCKS in kidney and testis

Proteins BASP1 and MARCKS are abundant in axonal endings of neurons. Similarly to brain-specific protein GAP-43, BASP1 and MARCKS are reversibly bound to the plasma membrane. These proteins control both actin polymerization and actin cytoskeleton binding to the membrane. Performing these functions, BASP1 and MARCKS take part in growth cone guidance during development and in neurotransmitter secretion in adults. These activities predetermine the pivotal role of BASP1 and MARCKS in learning and memory. BASP1 and MARCKS were also found in non-nerve tissues, in particular, in the kidney and testis. Evidently, the physiological roles of these proteins differ in different tissues. Correspondingly, their intracellular location and activities may not be similar to those in neurons. In this paper, we analyze subcellular fractions (cytoplasm and nuclei) of rat kidney and testis with the purpose of determining the intracellular location of BASP1 and MARCKS. Western blots demonstrated that in these tissues, as in the brain, both proteins are present in the cytoplasm of the cell. According to our immunohistochemical study, BASP1 and MARCKS are specifically distributed in the tissues studied. In kidney, both proteins are present in cells located in glomeruli. In the testicular tubules, BASP1 is mainly expressed at the late stage of spermatogenesis (in spermatids) and is preserved in mature spermatozoa, while MARCKS appears equally during all stages of spermatogenesis. MARCKS is not found in mature spermatozoa. The results indicate that study of functions of BASP1 and MARCKS in the kidney and in the reproduction system holds much promise.     

A 1 Mb-sized microdeletion Xq26.2 encompassing the GPC3 gene in a fetus with Simpson-Golabi-Behmel syndrome Report, antenatal findings and review

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive disorder encompassing pre- and postnatal overgrowth and a variety of additional anomalies including craniofacial dysmorphism, macrocephaly, congenital heart defects and genitourinary anomalies. There is little published information regarding the prenatal presentation of SGBS in pregnancy. In the present report we describe the antenatal features of an affected fetus from 12 gestational weeks onwards, subsequently diagnosed with SGBS by molecular testing positive for GPC3 gene mutation.     

EEC‐ and ADULT‐Associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences

TP63 germ‐line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm‐derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA‐binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild‐type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN‐P63α‐specific REs derived from genes closely related to the clinical manifestations of the TP63‐associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.     

Composition of PLGA and PEI/DNA nanoparticles improves ultrasound-mediated gene delivery in solid tumors in vivo

The goal of this study was to enhance gene delivery and tumor cell transfection in vivo by using a combination of ultrasonication with complex nanoparticles consisting of two types of nanoparticles: PEI/DNA β-gal plasmid with highly positive zeta-potential and air-filled poly (lactic-co-glycolic acid) (PLGA) particles (with negative zeta-potential) manufactured in our laboratory. The PLGA/PEI/DNA nanoparticles were a colloid with positive zeta-potential and injected i.v. in nude mice with DU145 human prostate tumors. We found that the combination of PLGA/PEI/DNA nanoparticles with ultrasonication substantially enhanced tumor cell transfection in vivo. The overexpression of β-gal gene was evaluated histochemically and by Western blot analysis. At least an 8-fold increase of the cell transfection efficacy was obtained in irradiated tumors compared to non-irradiated controls, while little to no cell death was produced by ultrasonication.     

Long-term effects of early kwashiorkor compared with marasmus. II. Intellectual performance

Intellectual performance including IQ (Wechsler Intelligence Scale for Children-Revised) and conservation was measured at ages 11-18 years in a follow-up study of Barbadian girls and boys who had histories of kwashiorkor (n = 53) or marasmus (n = 55) in their first year of life. They were compared with healthy neighborhood children matched by sex and age who had normal patterns of growth in early childhood (n = 58). On both IQ and conservation tests, children with previous kwashiorkor or marasmus had similar scores, which were significantly lower than scores of healthy comparison children. These findings were examined in relationship to current environmental conditions, which were similar in children with histories of kwashiorkor or marasmus and somewhat less advantaged than those of the comparison children. The effect of early malnutrition and related conditions at the time of episode still emerged as significant even when the current environmental factors were controlled for.     

Do blind persons have a better sense of smell than normal sighted people?

Functional disorders of sense organs may intensify the remaining senses. It is presumed that blind persons do not only hear better and have an intensified tactile sense but also have a stronger sense of smell. Better hearing ability was demonstrated by auditory evoked potentials. We investigated the sense of smell of blind persons by subjective tests (Sniffin' sticks: threshold, discrimination and identification) and for the first time also by objective tests (olfactory evoked potentials and trigeminal evoked potentials) and compared the results with the smelling ability of normal sighted persons by pair matching. Moreover, the investigated persons judged their performance via a questionnaire. The subjective test showed neither differences in the peripheral function nor in the central function between both groups. The amplitudes and latencies of the evoked potentials of vanillin, carbon dioxide and hydrogen sulfide were also not different. Blind persons tried unasked to identify the smell given in the discrimination test and thought themselves to be better in smelling. For the first time the smelling ability of blind people was compared with normal sighted people by objective test methods. Neither with subjective nor with objective methods differences were found.