The many substrates of presenilin/γ-secretase

The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins.     

Lost in transition: A review of the unmet need of patients with attention deficit/hyperactivity disorder transitioning to adulthood

This review discusses the unmet needs of patients with attention deficit/hyperactivity disorder (ADHD) who are transitioning into adulthood. Although awareness and recognition of ADHD in children, adolescents, and adults have improved in recent years, there is often an interruption in management of the disorder when adolescent patients transition to adult health care services. This review has the following objectives: (1) to identify key issues patients with ADHD (with or without an early diagnosis) face during transition into adulthood; (2) to review the current clinical practice and country‐specific approaches to the management of the transition into adulthood for patients with ADHD; (3) to discuss challenges facing clinicians and their patients when drug treatment for ADHD is initiated; (4) to review current ADHD guidelines on transition management in Hong Kong, Singapore, South Korea, Turkey, and Africa; and (5) to examine economic consequences associated with ADHD. The review suggests that the transition period to adult ADHD may be an underresearched and underserved area. The transition period plays an important role regarding how ADHD symptoms may be perceived and acted upon by adult psychiatrists. Further studies are needed to explore the characteristics of the transition period. If only a fraction of adolescents go on to have mental disorders during adulthood, especially ADHD, it is crucial to identify their characteristics to target appropriate interventions at the beginning of the course of illness. There continues to be low recognition of adult ADHD and a severe lack of medical services equipped to diagnose and care for patients with ADHD transitioning from child to adult services.     

Gerbich reactivity in 4.1(—) hereditary elliptocytosis and protein 4.1 level in blood group Gerbich deficiency

The membrane polypeptide composition and the blood group Gerbich phenotype of red cells from 4.1 (-) hereditary elliptocytic patients and from Gerbich-negative donors, who display two unrelated genetic abnormalities, were compared. In homozygous 4.1 (-) hereditary elliptocytosis where the primary defect was presumably the absence of the membrane skeletal protein 4.1, there was approximatively a 70% reduction in the minor sialoglycoproteins beta and gamma. This was associated with a severe reduction of blood group Gerbich reactivity as determined with both murine monoclonal and human anti-Gerbich antibodies. In the heterozygous state in the presence of one haploid set of protein 4.1 gene there was only a modest decrease in glycoproteins beta and gamma and the Gerbich serological reactivity was within normal limits. In homozygous Gerbich-negative red cells which lack glycoproteins beta and gamma but do not display elliptocytic red cells, the levels of protein 4.1 was repeatedly found within or just below the lowest values of normal controls. In the heterozygous Gerbich-negative conditions, glycoproteins beta and gamma were present in reduced amounts but the blood group Gerbich reactivity fell within normal limits since the anti-Gerbich reagents used were unable to detect a dosage effect. The amount of protein 4.1 was normal. These results add further support to the view that protein 4.1 and the sialoglycoproteins beta and gamma are physically linked in vivo which in some way serve to maintain red cell shape and integrity. Of interest was the finding that absence of protein 4.1 had a greater influence on the level of membrane glycoproteins beta and gamma than did the absence of beta and gamma glycoproteins on band 4.1.     

The isoflavones mixture from Trifolium pratense L. protects HCN 1-A neurons from oxidative stress

Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases such as Alzheimer's disease and Parkinson's. Using the Alzheimer's disease-associated hydrogen peroxide (H(2)O(2)), we investigated the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Trifolium pratense L. (Red clover) against oxidative stress-induced cell death in human cortical cell line HCN 1-A maintained in culture. Neuronal viability was determined by MTT or trypan blue test and neuronal integrity by morphological analysis.The results obtained indicate that exposure of HCN 1-A cell cultures to hydrogen peroxide resulted in a concentration-dependent decrease in neuron viability. Concentration of H(2)O(2) ranging from 50 to 200 microg/ml were toxic to these cultures. A 24-hour pretreatment with 0.5, 1 and 2 microg/ml isoflavones extract significantly increased cell survival as evidenced by MTT or trypan blue test and significantly prevented the morphological disruption caused by H(2)O(2) as shown by microscopical inspection, indicating that neurons treated with isoflavones were protected from the cell death induced by H(2)O(2) exposure. These findings imply that the neuroprotective effect of isoflavones extract is partly associated with its antioxidant activity. Further, results of these investigations indicate that although isoflavones extract exert a neuroprotective effect, it do not promoted cortical neuron process outgrowth.     

Echocardiographic findings in patients with Williams-Beuren syndrome

BACKGROUND: Williams-Beuren syndrome is a multisystem developmental disorder caused by a microdeletion at chromosome 7q11.23. In its classic form it includes dysmorphic facial features, joint contractures, retardation of growth and mental development, gregarious personality, visuospatial cognitive deficits, hypercalcemia, primary or secondary hypertension and cardiovascular disorders. AIM: Clinical diagnosis of Williams-Beuren syndrome can be a challenge in young patients if none of the characteristic cardiovascular features, i.e. supravalvular aortic stenosis or pulmonary artery stenosis, are present. Our aim was to demonstrate the changes in cardiovascular lesions during the postnatal development of Williams-Beuren patients and to follow all cardiovascular findings beyond the most common ones. METHODS: The cardiovascular status of 29 patients with Williams-Beuren syndrome (mean age 12.8 years) was recorded in correlation with age. RESULTS: Cardiovascular diagnoses changed in the majority (72.4%) of patients. Interestingly, 44.8% of the patients had periods with no reported cardiovascular disease. Furthermore, 65.5% of the patients experienced periods when none of the typical cardiovascular lesions, i.e. diffuse or localized supravalvular aortic stenosis and/or pulmonary artery stenosis, were detected. Spontaneous regression and progression of both supravalvular aortic stenosis and pulmonary artery stenosis were observed. An unexpectedly high frequency (41%) of mitral valve disorders was found. CONCLUSIONS: Our study showed that temporary absence of and changes in cardiovascular findings are frequent in Williams-Beuren syndrome. These results could contribute to the refinement of diagnostic criteria and recommendations for cardiovascular follow-up of patients with this syndrome.     

Effects of neurological damage on production of formulaic language

Early studies reported preserved formulaic language in left hemisphere damaged subjects and reduced incidence of formulaic expressions in the conversational speech of stroke patients with right hemispheric damage. Clinical observations suggest a possible role also of subcortical nuclei. This study examined formulaic language in the spontaneous speech of stroke patients with left, right, or subcortical damage. Four subjects were interviewed and their speech samples compared to normal speakers. Raters classified formulaic expressions as speech formulae, fillers, sentence stems, and proper nouns. Results demonstrated that brain damage affected novel and formulaic language competence differently, with a significantly smaller proportion of formulaic expressions in subjects with right or subcortical damage compared to left hemisphere damaged or healthy speakers. These findings converge with previous studies that support the proposal of a right hemisphere/subcortical circuit in the management of formulaic expressions, based on a dual‐process model of language incorporating novel and formulaic language use.     

Antibody Response to the BNT162b2 mRNA COVID-19 Vaccine in Subjects with Prior SARS-CoV-2 Infection

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.     

Comparison of Benchtop Microplate Beta Counters with the Traditional Gamma Counting Method for Measurement of Chromium-51 Release in Cytotoxic Assays

The most traditional method used to measure the lytic activity of cytotoxic T lymphocytes or natural killer (NK) cells is the chromium release assay (CRA). No study has been reported that systematically compares the traditional gamma counting method with various benchtop microplate scintillation formats to measure chromium release. Here we investigated the utilization of microplate beta counters in comparison with the traditional gamma counting method to quantitate antigen-specific cytolysis, lymphokine-activated killer (LAK) activity, and NK activity in the CRA. Supernatants from standard CRA (n = 7) were directly transferred to a 96-well microplate containing either a solid scintillant (Lumaplate) or a liquid scintillant (flexible beta plate). Samples were quantified by using two benchtop microplate beta counters, Wallac Microbeta Trilux (Lumalux and Trilux methods, respectively) and Packard TopCount instruments (TopCount method). These results were then compared with data from an identical assay run in parallel using the traditional gamma counting method (LKB). The lytic activity for influenza virus-stimulated effectors measured in the benchtop microplate beta counters using Lumalux and Trilux methods exhibited excellent correlations with the one measured in the traditional LKB (r = 0.967 and 0.968, respectively). The TopCount method demonstrated a similar correlation (r = 0.966). Similar findings were observed for LAK and NK activity. The 96-well microplate format, specifically the dry-scintillant Lumaplates, offers several advantages over the traditional gamma counting format. Most notable are the reductions in sample volume needed and in the total sample preparation and counting time. Furthermore, this system reduces the amount of dry and mixed radioactive waste generated while using the same instrument for gamma- and beta-emitting isotopes.