Fertility is a highly complex and regulated phenomenon essential for the survival of any species. To identify Drosophila fertility-specific neural networks, we used a GAL4/UAS enhancer trap genetic screen that selectively inactivates groups of neurons. We identified a GAL4 line (bwktqs) that has a female sterile phenotype only when it expresses the tetanus toxin light chain (TeTxLC). These flies lack oviduct contraction, lay almost no eggs, sperm accumulate in the oviducts, and fewer than normal are seen in the storage organs. In insects, two neuroactive substances are important for oviduct contraction: octopamine (OA), a monoamine that inhibits oviduct contraction, and glutamate (Glu), a neurotransmitter that induces contraction. It is known that octopaminergic neurons of the thoracic abdominal ganglion (TAG) modulate oviduct contraction, however, the glutamatergic neurons that innervate the oviduct have not been identified yet and the interaction between these two neuroactive substances is not well understood. Immunostaining experiments revealed that the bwktqs line trapped an octopaminergic neural network that innervates the genital tract. We show that wt like oviduct contraction in TeTxLC-inactivated flies can only be rescued by simultaneous application of Glu and OA suggesting that the abdominal bwktqs neurons are both octopaminergic and glutamatergic, the use of an agonist and an antagonist for Glu receptors as well as their direct visualization confirmed its participation in this phenomenon. Our work provides the first evidence that adult abdominal type II visceral innervations co-express Glu and OA and allows us to re-evaluate the previous model of neuronal network controlling insect oviduct contraction.
The control of cell death is a biological process essential for proper development, and for preventing devastating pathologies like cancer and neurodegeneration. On the other hand, autophagy regulation is essential for protein and organelle degradation, and its dysfunction is associated with overlapping pathologies like cancer and neurodegeneration, but also for microbial infection and aging. In the present report we show that two evolutionarily unrelated receptors—Neurokinin 1 Receptor (NK1R,) a G-protein coupled receptor, and Insulin-like Growth Factor 1 Receptor (IGF1R), a tyrosine kinase receptor—both induce non-apoptotic cell death with autophagic features and requiring the activity of the autophagic core machinery proteins PI3K-III, Beclin-1 and Atg7. Remarkably, this form of cell death occurs in apoptosis-competent cells. The signal transduction pathways engaged by these receptors both converged on the activation of the nuclear receptor NR4A1, which has previously been shown to play a critical role in some paradigms of apoptosis and in NK1R-induced cell death. The activity of NR4A1 was necessary for IGF1R-induced cell death, as well as for a canonical model of cell death by autophagy induced by the presence of a pan-caspase inhibitor, suggesting that NR4A1 is a general modulator of this kind of cell death. During cell death by autophagy, NR4A1 was transcriptionally competent, even though a fraction of it was present in the cytoplasm. Interestingly, NR4A1 interacts with the tumor suppressor p53 but not with Beclin-1 complex. Therefore the mechanism to promote cell death by autophagy might involve regulation of gene expression, as well as protein interactions. Understanding the molecular basis of autophagy and cell death mediation by NR4A1, should provide novel insights and targets for therapeutic intervention.
BackgroundFSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Given the paucity of data on the FSHR c.919A > G, c.2039A > G and − 29G > A SNPs in Hispanic population, we here analyzed their frequency distribution in Mexican mestizo women.MethodsSamples from 224 Mexican mestizo women enrolled in an IVF program as well as a genotype database from 8182 Mexican mestizo subjects, were analyzed for FSHR SNPs at positions c.919, c.2039 and − 29G > A. Association between the genetic variants and reproductive outcomes was assessed.ResultsThe c.919 and c.2039 SNPs were in strong linkage disequilibrium and their corresponding genotype frequencies in the IVF group were: AA 46.8%, AG 44.2%, and GG 8.9%, and AA 41.9%, AG 48.2% and GG 9.8%, respectively. For the -29G > A SNP, genotype frequencies were 27% (GG), 50% (GA) and 23% (AA). In normal oocyte donors with the c.2039 GG genotype, the number of oocytes recovered after ovarian stimulation (COS) were significantly (p < 0.01) lower than in those bearing other genotypes in this or the -29G > A SNP. Analysis of the large scale database revealed that both allelic and genotype frequencies for the three SNPs were very similar to those detected in the IVF cohort (p ≥ 0.38) and that female carriers of the c.2039 G allele tended to present lower number of pregnancies than women bearing the AA genotype; this trend was stronger when women with more Native American ancestry was separately analyzed (OR = 2.0, C.I. 95% 1.03–3.90, p = 0.04). There were no differences or trends in the number of pregnancies among the different genotypes of the -29G > A SNP.ConclusionsThe frequency of the GG/GG combination genotype for the c.919 and c.2039 SNPs in Mexican hispanics is among the lowest reported. The GG genotype is associated with decreased number of oocytes recovered in response to COS as well as to lower pregnancy rates in Hispanic women from the general population. The absence of any effect of the -29AA genotype on the response to COS, indicates that there is no need to perform this particular genotype testing in Hispanic women with the purpose of providing an individually-tailored COS protocol.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0420-4) contains supplementary material, which is available to authorized users.
Objective. This study aims to generate evidence on intellectual development disorders (IDD) in Mexico. Materials and methods. IDD disease burden will be estimated with a probabilistic model, using population-based surveys. Direct and indirect costs of catastrophic expenses of families with a member with an IDD will be evaluated. Genomic characterization of IDD will include: sequencing participant exomes and performing bioinformatics analyses to identify de novo or inherited variants through trio analysis; identifying genetic variants associated with IDD, and validating randomly selected variants by polymerase chain reaction (PCR) and sequencing or real-time quantitative PCR (qPCR). Delphi surveys will be done on best practices for IDD diagnosis and management. An external evaluation will employ qualitative case studies of two social and labor inclusion programs for people with IDD. Conclusions. The results will constitute scientific evidence for the design, promotion and evaluation of public policies, which are currently absent on IDD. ResumenObjetivo. Esta investigación busca generar evidencia sobre trastornos del desarrollo intelectual (TDI) en México. Material y métodos. La carga de la enfermedad por TDI se estimará con un modelo probabilístico usando encuestas poblacionales. Se estimarán costos directos e indirectos de gastos catastróficos de familias con un integrante con TDI. La caracterización genómica de TDI incluirá secuenciar exomas, realizar análisis bioinformático para identificar variantes de novo o heredadas a través de análisis de tríos, identificar variantes genéticas asociadas con TDI, y validar variantes aleatoriamente seleccionadas con reacción en cadena de polimerasa y secuenciación o qPCR. Se harán encuestas Delphi sobre mejores prácticas de diagnóstico y manejo de TDI. Una evaluación externa empleará estudios cualitativos de caso de dos programas de inclusión social y laboral para personas con TDI. Conclusiones. Los resultados serán evidencia científica que podrá ser la base para el diseño, promoción y evaluación de políticas públicas, actualmente ausentes para TDI.Palabras clave: trastornos del desarrollo intelectual; TDAH; trastorno autista; gasto; México
We aimed to identify patterns of cognitive differences and characterize subgroups of Mexican children and adolescents with three neurodevelopmental disorders (NDD): intellectual disability (ID), autism spectrum disorders (ASD) and attention deficit/hyperactivity disorder (ADHD). The sample included 74 children and adolescents 6–15 years; 34% had ID, ASD or ADHD, 47% had ID in comorbidity with ASD, ADHD or both, 11% had ASD + ADHD, 8% were children without NDD. We applied WISC-IV, Autism Diagnostic Interview-Revised, Mini-International Neuropsychiatric Structured Interview, Child Behavior Checklist, and UNICEF Child Functioning Module. We evaluated the normality of the WISC-IV sub-scales using the Shapiro-Francia test, then conducted a latent class analysis and assessed inter-class differences in terms of household, parent and child characteristics. The following four-class solution best fit the data: “Lower Cognitive Profile” (LCP), “Lower Working Memory” (LWM), “Higher Working Memory” (HWM), “Higher Cognitive Profile” (HCP). LCP included most of the children with ID, who had a low Working Memory (WM) index score. LWM included mainly children with ASD or ID + ADHD; their Perceptual Reasoning (PR) and Processing Speed (PS) index scores were much higher than those for Verbal Comprehension (VC) and WM. HWM included children with ASD or ADHD; their scores for PR, PS and VC were high with lower WM (although higher than for LWM). HCP included children without NDD and with ASD or ADHD or both and had the highest scores on all indices. Children with NDD show cognitive heterogeneity and thus require individualized treatment plans.
Background Paternalism/overprotection limits communication between healthcare professionals and patients and does not promote shared therapeutic decision-making. In the global north, communication patterns have been regulated to promote autonomy, whereas in the global south, they reflect the physician’s personal choices. The goal of this study was to contribute to knowledge on the communication patterns used in clinical practice in Mexico and to identify the determinants that favour a doctor–patient relationship characterized by low paternalism/autonomy. Methods A self-report study on communication patterns in a sample of 761 mental healthcare professionals in Central and Western Mexico was conducted. Multiple ordinal logistic regression models were used to analyse paternalism and associated factors. Results A high prevalence (68.7% [95% CI 60.0–70.5]) of paternalism was observed among mental health professionals in Mexico. The main determinants of low paternalism/autonomy were medical specialty (OR 1.67 [95% CI 1.16–2.40]) and gender, with female physicians being more likely to explicitly share diagnoses and therapeutic strategies with patients and their families (OR 1.57 [95% CI 1.11–2.22]). A pattern of highly explicit communication was strongly associated with low paternalism/autonomy (OR 12.13 [95% CI 7.71–19.05]). Finally, a modifying effect of age strata on the association between communication pattern or specialty and low paternalism/autonomy was observed. Conclusions Among mental health professionals in Mexico, high paternalism prevailed. Gender, specialty, and a pattern of open communication were closely associated with low paternalism/autonomy. Strengthening health professionals’ competencies and promoting explicit communication could contribute to the transition towards more autonomist communication in clinical practice in Mexico. The ethical implications will need to be resolved in the near future.
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