Activity-dependent control of bulk endocytosis by protein dephosphorylation in central nerve terminals

Bulk endocytosis is the process by which nerve terminals retrieve large amounts of synaptic vesicle membrane during periods of strong stimulation intensity. The process is rapidly activated and is most probably calcium dependent in a similar manner to synaptic vesicle exocytosis. This article briefly summarizes the current knowledge of bulk endocytosis with respect to its activation, kinetics and molecular mechanism. It also presents recent data from our laboratory showing that the dephosphorylation of a group of endocytosis proteins called the dephosphins by the Ca²⁺-dependent protein phosphatase calcineurin is key to the activity-dependent stimulation of the process. Possible downstream effectors of calcineurin are discussed such as the large GTPase dynamin I and its phosphorylation-dependent interaction partner syndapin I.     

The relationship of childhood sexual abuse and depression with somatic symptoms and medical utilization

BACKGROUND: Previous research suggests that childhood sexual abuse is associated with high rates of retrospectively reported medical utilization and medical problems as an adult. The goal of this study was to determine if abused females have higher rates of medical utilization using self-report and objective measures, compared with non-abused females. A further goal was to determine whether findings of prior research would be replicated when childhood physical abuse level was controlled. This study also examined the moderating impact of depressed mood on current health measures in this population. METHODS: Six hundred and eight women recruited from a health maintenance organization completed self-report measures of health symptoms for the previous month and doctor visits for the previous year. Objective doctor records over a 2 year period were examined for a subset of 136 of these women. RESULTS: Results showed significantly more self-reported health symptoms and more self-reported doctor visits in abused participants compared with those who reported no childhood history of sexual abuse. Objective doctor visits demonstrated the same pattern with abused participants exhibiting more visits related to out-patient surgery and out-patient internal medicine. In addition, persons who were both sexually abused and depressed tended to visit the emergency room more frequently and to have more in-patient internal medicine and ophthalmology visits than sexually abused participants who reported low depressed mood and non-abused controls. CONCLUSIONS: These results replicate prior studies and suggest that current depression may moderate the relationship between sexual abuse and medical problems in adulthood.     

Messenger RNA processing sites in Trypanosoma brucei

In Kinetoplastids, protein-coding genes are transcribed polycistronically by RNA polymerase II. Individual mature mRNAs are generated from polycistronic precursors by 5' trans splicing of a 39-nt capped leader RNA and 3' polyadenylation. It was previously known that trans splicing generally occurs at an AG dinucleotide downstream of a polypyrimidine tract, and that polyadenylation is coupled to downstream trans splicing. The few polyadenylation sites that had been examined were 100-400 nt upstream of the polypyrimidine tract which marked the adjacent trans splice site. We wished to define the sequence requirements for trypanosome mRNA processing more tightly and to generate a predictive algorithm. By scanning all available Trypanosoma brucei cDNAs for splicing and polyadenylation sites, we found that trans splicing generally occurs at the first AG following a polypyrimidine tract of 8-25 nt, giving rise to 5'-UTRs of a median length of 68 nt. We also found that in general, polyadenylation occurs at a position with one or more A residues located between 80 and 140 nt from the downstream polypyrimidine tract. These data were used to calibrate free parameters in a grammar model with distance constraints, enabling prediction of polyadenylation and trans splice sites for most protein-coding genes in the trypanosome genome. The data from the genome analysis and the program are available from: .     

Ectodermal dysplasias: Classification and organization by phenotype,genotype and molecular pathway

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin”). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT “wingless‐type,” TP63 “tumor protein p63”) or the components of complex molecular structures (e.g., connexins, keratins, cadherins).     

Recruitment and baseline epidemiologic profile of participants in the first phase 3 HIV vaccine efficacy trial

OBJECTIVE: To describe recruitment and baseline epidemiologic characteristics of volunteers in the first phase 3 placebo-controlled trial of a recombinant gp120 HIV vaccine (AIDSVAX B/B). METHODS: Volunteers were gay/bisexual men or women at risk for sexually transmitted HIV infection. Recruitment strategies, demographics, and risk factors were assessed. HIV status was determined by standard HIV-1 antibody assays. Seronegative/viremic HIV infection at enrollment was determined using the HIV-1 nucleic acid test. RESULTS: From June 1998 through October 1999, 5417 of 7185 volunteers screened were enrolled at 61 sites in the United States, Canada, and The Netherlands. Successful recruitment methods included distribution of study information at gay venues, advertising and media coverage, and referrals from volunteers. Most volunteers were altruistically motivated, men (98%), young (median, 36 years), white (83%), well educated (61% college education or more), and at high risk for HIV during the 6 months before enrollment. At baseline, 14 were HIV infected (12 were seronegative but viremic; 2 were seropositive and viremic). CONCLUSION: Men and women at high risk for sexually transmitted HIV infection were successfully recruited for the first phase 3 HIV vaccine efficacy trial. Knowledge of recruitment and baseline epidemiologic characteristics of participants in this trial will provide valuable guidance for designing and conducting future trials.     

Leukotrienes do not contribute to the pathogenesis of indomethacin-induced ulceration of the gastric antrum in the re-fed rat

The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B₄ releaseex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B₄ antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin.Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.     

Occurrence of cancer in Asians and non-Asians.

Cancer registration data for a defined geographical area, covering a seven year period, were modified to include the variable "Asian ethnic origin." The data were then used to test the hypothesis that a difference would be found between Asians and non-Asians in the pattern of cancer by site. Whereas the incidence of cancer of all sites appeared to be significantly lower in Asians (p less than 0.05), after taking account of this, and adjusting for the very different age distributions of the two populations, a highly significant difference (p less than 0.0005) was found between the two groups in the distribution of cancer between sites. Although, given the size and young age structure of the Asian population, absolute numbers of cases were small, a significant excess of Asian cases (compared with the expected) occurred for cancer of the tongue, oral cavity, pharynx, and oesophagus. For most sites there were fewer Asian cases than would be expected, particularly so for the stomach, testis, and skin. The results indicate the need for formal epidemiological study to test specific aetiological hypotheses which may account for these apparent differences.