Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals

TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors

Background: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than "classic" IDHwt GBM. Methods: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. Results: p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1, IDH2, BRAF, or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53, ATRX, RB1, and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53-mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53-mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, P < .002). Conclusions: gcGBMs have molecular features that contrast to "classic" IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine

On the Estimation Stability of Efficiency and Economies of Scale in Microfinance Institutions

This paper uses a panel data set of microfinance institutions (MFI) across the world to compare several identification strategies of cost efficiency and economies of scale. Concretely, we contrast the non-parametric Data Envelopment Analysis (DEA) with the Stochastic Frontier Analysis (SFA) and a distribution-free identification based on time-invariant heterogeneity estimates. Furthermore, we analyze differences of production functions across regions and investigate the relevance of accounting for unobserved heterogeneity across countries. The results suggest that efficiency rankings of MFIs are robust across identification strategies, but highlight the relevance of accounting for unobserved heterogeneity. We further find substantial economies of scale for a pure financial production process. However, accounting for the multi-dimensional production process of MFIs by including a measure of outreach lowers the estimated extent of economies of scale for the parametric estimations, suggesting that producing outreach creates high transaction costs and requires exploitation of local knowledge

Long-Term Effects of Labor Market Conditions on Family Formation for Japanese Youth

This study aims to examine how each cohort's family formation is affected by labor market conditions experienced in youth in Japan. Although deterioration in youth employment opportunities has often been blamed for Japan's declining marriage and fertility rates, the effects of slack labor market conditions on marriage and fertility are theoretically unclear. We estimate the effects of regional labor market conditions on marriage and fertility, controlling for nation-wide year effects and prefecture fixed effects, and find the following. First, the male unemployment rate is negatively correlated with marriage of women in the local labor market, although the correlation is weak and concentrated on the less educated group. Second, high school-educated women who experienced a recession while entering the labor market are less likely to have children and tend to marry later. In contrast, a recession at entry to the labor market rather increases fertility among college-educated women. The overall impact of labor market conditions experienced in youth on family formation is relatively weak, compared to the substantial losses in earnings and employment stability documented by the existing studies

Corporate Governance and Firm Valuation in Colombia

This paper studies the separation of ownership and control of 108 listed companies in Colombia from 1996 to 2002, finding that voting rights are greater than cash flow rights because of indirect ownership across firms. The paper also examines the association of various ownership and control measures and separation ratios with a firms value and performance for the same sample of companies that traded their stock from 1998 to 2002. Large blockholders were found to exert a positive influence upon a firms valuation and performance, which validates the positive monitoring approach of large shareholders, but this relationship is not monotonic. The paper further reports results from a 2004 survey which suggests that Colombian firms have been slow to improve their corporate governance practices.En este trabajo se analiza la separación de la propiedad y el control de 108 empresas inscritas en bolsa en Colombia entre 1996 y 2002, y se descubre que los derechos de voto son mayores que los derechos referentes al flujo de caja debido a la propiedad indirecta entre empresas. También se analiza la relación de varias medidas de propiedad y control y las proporciones de separación con el valor y el desempeño de una empresa para la misma muestra de compañías que cotizaron sus acciones en bolsa entre 1998 y 2002. Se descubre que los tenedores de grandes bloques de acciones ejercen una influencia positiva en la valoración y el desempeño de una empresa. El trabajo además da cuenta de resultados de una encuesta efectuada en 2004 que sugiere que las empresas colombianas han mostrado cierta lentitud en el mejoramiento de sus prácticas de buena gestión empresarial

Can Parents Afford to Work? Childcare Costs, Tax-Benefit Policies and Work Incentives

Childcare policies play a crucial role in helping parents reconcile care and employment-related tasks. This paper quantifies the net cost of purchasing full-time centre-based childcare in OECD countries taking into account a wide range of influences on household budgets, including fees charged by childcare providers as well as childcare-related tax concessions and cash benefits available to parents. Building on these calculations, family resources are evaluated for different employment situations in order to assess the financial trade-offs between work and staying at home. Results are disaggregated to identify the policy features that present barriers to work for parents whose employment decisions are known to be particularly responsive to financial work incentives: lone parents and second earners with young children requiring care. The results indicate that the cost of purchasing childcare services should be analysed in conjunction with other social and fiscal policies that affect family incomes. While childcare fees can be very high, high prices may not impede employment if tax-benefit systems incorporate well-balanced provisions that help parents pay for these services. Conversely, even highly subsidised childcare markets can leave parents with little financial gain from employment if high tax burdens or benefit claw-back rates give rise to adverse work incentives