Multifaceted Modulation of K+ Channels by Protein-tyrosine Phosphatase {epsilon} Tunes Neuronal Excitability

Non-receptor-tyrosine kinases (protein-tyrosine kinases) and non-receptor tyrosine phosphatases (PTPs) have been implicated in the regulation of ion channels, neuronal excitability, and synaptic plasticity. We previously showed that protein-tyrosine kinases such as Src kinase and PTPs such as PTPα and PTPε modulate the activity of delayed-rectifier K(+) channels (I(K)). Here we show cultured cortical neurons from PTPε knock-out (EKO) mice to exhibit increased excitability when compared with wild type (WT) mice, with larger spike discharge frequency, enhanced fast after-hyperpolarization, increased after-depolarization, and reduced spike width. A decrease in I(K) and a rise in large-conductance Ca(2+)-activated K(+) currents (mBK) were observed in EKO cortical neurons compared with WT. Parallel studies in transfected CHO cells indicate that Kv1.1, Kv1.2, Kv7.2/7.3, and mBK are plausible molecular correlates of this multifaceted modulation of K(+) channels by PTPε. In CHO cells, Kv1.1, Kv1.2, and Kv7.2/7.3 K(+) currents were up-regulated by PTPε, whereas mBK channel activity was reduced. The levels of tyrosine phosphorylation of Kv1.1, Kv1.2, Kv7.3, and mBK potassium channels were increased in the brain cortices of neonatal and adult EKO mice compared with WT, suggesting that PTPε in the brain modulates these channel proteins. Our data indicate that in EKO mice, the lack of PTPε-mediated dephosphorylation of Kv1.1, Kv1.2, and Kv7.3 leads to decreased I(K) density and enhanced after-depolarization. In addition, the deficient PTPε-mediated dephosphorylation of mBK channels likely contributes to enhanced mBK and fast after-hyperpolarization, spike shortening, and consequent increase in neuronal excitability observed in cortical neurons from EKO mice.     

New Mechanism for Voltage Induced Charge Movement Revealed in GPCRs - Theory and Experiments

Depolarization induced charge movement associated currents, analogous to gating currents in channels, were recently demonstrated in G-protein coupled receptors (GPCRs), and were found to affect the receptor''s Agonist binding Affinity, hence denoted AA-currents. Here we study, employing a combined theoretical-experimental approach, the properties of the AA-currents using the m2-muscarinic receptor (m2R) as a case study. We found that the AA-currents are characterized by a “bump”, a distinct rise followed by a slow decline, which appears both in the On and the Off responses. The cumulative features implied a directional behavior of the AA-currents. This forced us to abandon the classical chemical reaction type of models and develop instead a model that includes anisotropic processes, thus producing directionality. This model fitted well the experimental data. Our main findings are that the AA-currents include two components. One is extremely fast, , at all voltages. The other is slow, at all voltages. Surprisingly, the slow component includes a process which strongly depends on voltage and can be as fast as at . The reason that it does not affect the overall time constant of the slow component is that it carries very little charge. The two fast processes are suitable candidates to link between charge movement and agonist binding affinity under physiological conditions.     

Wall Pellitory as a Glass Cleaning Material in the Land of Israel in the Middle Ages

Wall Pellitory as a Glass Cleaning Material in the Land of Israel in the Middle Ages  This article describes the unique uses of the plant wall pellitory (Parietaria judaica L.), as based on Arabic sources from the Middle Ages. These sources reveal that this plant was used in Israel for producing alkaline substances, in general, and material to clean glass, in particular. Examination of the plant’s composition demonstrates that it contains sodium and potassium in high concentrations, even in comparison with salt flat vegetation (desert and coastal), such as prickly saltworts (Salsola kali L.), which were known in the ancient world as a source of cleaning materials. Thus, corroboration was found for the information obtained from the historical sources.     

Tuberculosis Incidence in HIV/AIDS Patients in Israel, 1983–2010

Objectives

People living with HIV/AIDS (PLWHA) who develop tuberculosis disease are at greater mortality-risk. This study aimed to assess tuberculosis disease incidence among all PLWHA in Israel and identify populations at high-risk for developing tuberculosis.

Design and Methods

Retrospective cohort-study based on the National HIV and Tuberculosis Registries, which were cross-matched and followed for the last 28-years. PLWHA who developed tuberculosis were compared to those who did not by the Cox-proportional analysis to generate hazard-ratios, and survival-analysis was performed by Log-Rank test.

Results

Of all the 6579 PLWHA reported between 1983 and 2010, corresponding to 55737 person-years, 384 (5.8%) developed tuberculosis. Of those, 14 were Israeli-born and 370 were non-Israeli born. The overall tuberculosis incidence-density was 6.9 cases/1000 person-years (95% CI 1.8–12.0). The cumulative tuberculosis-incidence among PLWHA in 2010 was 586 times higher than in HIV-negative individuals (3400 and 5.8 cases per 100000 population, respectively). Higher hazard-ratios to developing tuberculosis were found in migrant citizens PLWHA who were males, non-Israeli born, those who were diagnosed with HIV/AIDS after 1997, those who originated in high-tuberculosis prevalence country and those who acquired HIV by heterosexual or drug-injection transmission. PLWHA who developed tuberculosis had higher odds of dying than other PLWHA (36.5% and 16.6%, respectively, p<0.001, odds ratio = 2.8, 95% confidence-interval 2.3–3.6). In survival-analysis, time to develop tuberculosis was shorter among males than females, in PLWHA who were reported with HIV after 1997, in heterosexual who originated in high-tuberculosis countries, followed by injecting drug-users, heterosexual from low-tuberculosis burden countries and men who have sex with men.

Conclusion

Tuberculosis-incidence is higher among non-Israeli born PLWHA, with decreasing trends from 1991. Despite the moderate TB-rate disease among PLWHA, it remains an important cause for severe morbidity and mortality. Tuberculosis in PLWHA reflects mainly the tuberculosis-burden in the originating country and possibly also the mode of HIV-transmission.     

Chronic B cell deficiency from birth prevents age-related alterations in the B lineage

Aging is accompanied by a decline in B lymphopoiesis in the bone marrow and accumulation of long-lived B cells in the periphery. The mechanisms underlying these changes are unclear. To explore whether aging in the B lineage is subjected to homeostatic regulation, we used mutant mice bearing chronic B cell deficiency from birth. We show that chronic B cell deficiency from birth, resulting from impaired maturation (CD19(-/-) and CD74(-/-)) or reduced survival (baff-r(-/-)), prevents age-related changes in the B lineage. Thus, frequencies of early and late hematopoietic stem cells, B lymphopoiesis, and the rate of B cell production do not substantially change with age in these mice, as opposed to wild-type mice where kinetic experiments indicate that the output from the bone marrow is impaired. Further, we found that long-lived B cells did not accumulate and peripheral repertoire was not altered with age in these mice. Collectively, our results suggest that aging in the B lineage is not autonomously progressing but subjected to homeostatic regulation.     

Argovin,a novel natural product secreted by the fungus Meira argovae,is antagonistic to mites

A metabolite of the fungus Meira argovae Boekhout, Scorzetti, Gerson & Sztejnberg (Exobasidiomycetidae) was assayed as an antagonist of mites. Separation of extracted fungal metabolites by reversed phase liquid chromatography (RPLC), with subsequent testing of the obtained fractions, allowed us to isolate a single mite‐antagonistic fraction (also active against a bacterium) that primarily includes one major component. This active compound (herein termed ‘argovin’) was identified by analyzing its spectral characteristics as 4,5‐dihydroxyindan‐1‐one, which has previously only been described as a product of chemical reactions. The growth rate of the fungus was higher at a neutral pH than at an acidic one. Meira argovae adjusts the pH of its media to values optimal for its colony growth and toxic secretions. RPLC‐cleaned argovin at 0.2 mg ml^?1 killed 100% of a population of the citrus rust mite, Phyllocoptruta oleivora (Ashmead) (Acari: Eriophyidae). This trait may be used to control citrus rust mites in the field, as well as for toxin production for industrial and pharmaceutical uses.