The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

Evolution of the Human Nervous System Function, Structure, and Development.

The nervous system-in particular, the brain and its cognitive abilities-is among humans' most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.

CCR5 closes the temporal window for memory linking.

Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1-5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1-4. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12-24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)-an immune receptor that is well known as a co-receptor for HIV infection6,7-after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here, we show that FMRP regulates translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca's area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases, but not FMRP-deficient mice. Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.

Regulation of prefrontal patterning and connectivity by retinoic acid.

The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory1 and are thought to be altered in disorders such as autism2,3 and schizophrenia4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents6-9, the mechanisms that underlie the development of PFC-mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function12-15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC-mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.

Restoration of brain circulation and cellular functions hours post-mortem.

The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.

Prediction and biological analysis of yeast VDAC1 phosphorylation.

The mitochondrial outer membrane protein porin 1 (Por1), the yeast orthologue of mammalian voltage-dependent anion channel (VDAC), is the major permeability pathway for the flux of metabolites and ions between cytosol and mitochondria. In yeast, several Por1 phosphorylation sites have been identified. Protein phosphorylation is a major modification regulating a variety of biological activities, but the potential biological roles of Por1 phosphorylation remains unaddressed. In this work, we analysed 10 experimentally observed phosphorylation sites in yeast Por1 using bioinformatics tools. Two of the residues, T100 and S133, predicted to reduce and increase pore permeability, respectively, were validated using biological assays. In accordance, Por1T100D reduced mitochondrial respiration, while Por1S133E phosphomimetic mutant increased it. Por1T100A expression also improved respiratory growth, while Por1S133A caused defects in all growth conditions tested, notably in fermenting media. In conclusion, we found phosphorylation has the potential to modulate Por1, causing a marked effect on mitochondrial function. It can also impact on cell morphology and growth both in respiratory and, unpredictably, also in fermenting conditions, expanding our knowledge on the role of Por1 in cell physiology.

The Effectiveness and Safety of Leadless Pacemakers: An Updated Meta-Analysis.

BACKGROUND: Leadless pacemakers (LPs) are promising alternatives to traditional transvenous pacemakers (TVPs), but their comparative effectiveness and safety in clinical outcomes remain uncertain. METHODS: We systematically searched PubMed, Embase, Scopus, Cochrane, and ClinicalTrials.gov for studies comparing LPs and TVPs. A restricted maximum likelihood random-effects model was used for all outcomes. Heterogeneity was assessed using I2 statistics. We performed a subgroup analysis with studies with multivariate-adjusted data. RESULTS: We included 21 studies involving 47,229 patients, of whom 12,199 (25.8%) underwent LP implantation. Compared with TVPs, LPs were associated with a significantly lower risk of overall complications (OR 0.61; 95% CI 0.45-0.81; p < 0.01), dislodgement (OR 0.34; 95% CI 0.20-0.56; p < 0.01), and pneumothorax (OR 0.27; 95% CI 0.16-0.46; p < 0.01). No significant difference in all-cause mortality was observed in the overall analysis (OR 1.43; 95% CI 0.65-3.15; p = 0.35) and in studies with multivariate-adjusted data (OR 1.34; 95% CI 0.65-2.78; p = 0.43). However, LPs were associated with a higher risk of pericardial effusion (OR 2.47; 95% CI 1.39-4.38; p < 0.01) and cardiac tamponade (OR 3.75; 95% CI 2.41-5.83; p < 0.01). LPs also demonstrated a lower pacing capture threshold (MD -0.19 V; 95% CI [-0.23 V]-[-0.16 V]; p < 0.01), but no significant difference in impedance (MD 32.63 ohms; 95% CI [-22.50 ohms]-[87.76 ohms]; p = 0.25). CONCLUSIONS: These findings suggest that LPs were associated with lower overall complication rates and similar effectiveness to TVPs. However, randomized controlled trials are warranted to validate these results.

Harvesting the Power of Green Synthesis: Gold Nanoparticles Tailored for Prostate Cancer Therapy.

Biosynthetic gold nanoparticles (bAuNPs) present a promising avenue for enhancing bio-compatibility and offering an economically and environmentally responsible alternative to traditional production methods, achieved through a reduction in the use of hazardous chemicals. While the potential of bAuNPs as anticancer agents has been explored, there is a limited body of research focusing on the crucial physicochemical conditions influencing bAuNP production. In this study, we aim to identify the optimal growth phase of Pseudomonas aeruginosa cultures that maximizes the redox potential and coordinates the formation of bAuNPs with increased efficiency. The investigation employs 2,6-dichlorophenolindophenol (DCIP) as a redox indicator. Simultaneously, we explore the impact of temperature, pH, and incubation duration on the biosynthesis of bAuNPs, with a specific emphasis on their potential application as antitumor agents. Characterization of the resulting bAuNPs is conducted using ATR-FT-IR, TEM, and UV-Vis spectroscopy. To gain insights into the anticancer potential of bAuNPs, an experimental model is employed, utilizing both non-neoplastic (HPEpiC) and neoplastic (PC3) epithelial cell lines. Notably, P. aeruginosa cultures at 9 h/OD600 = 1, combined with biosynthesis at pH 9.0 for 24 h at 58 °C, produce bAuNPs that exhibit smaller, more spherical, and less aggregated characteristics. Crucially, these nanoparticles demonstrate negligible effects on HPEpiC cells while significantly impacting PC3 cells, resulting in reduced viability, migration, and lower IL-6 levels. This research lays the groundwork for the development of more specialized, economical, and ecologically friendly treatment modalities.

Respiratory muscle training for obstructive sleep apnea: Systematic review and meta-analysis.

Obstructive sleep apnea is the most common sleep disorder. This review aims to evaluate the effectiveness and safety of respiratory muscle training in the treatment of patients with obstructive sleep apnea. The study protocol was registered in Prospero Platform (CRD42018096980). We performed searches in the main databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) via Pubmed; Excerpta Medica dataBASE (Embase) via Elsevier; Cochrane Central Register of Controlled Trials (CENTRAL) via Cochrane Library; Latin American and Caribbean Literature on Health Sciences (LILACS) through the Portal of the Virtual Health Library and Physiotherapy Evidence Database (PEDro) for all randomised-controlled trials published before July 2022. The randomised-controlled trials were assessed for risk of bias and certainty of evidence. Thirteen randomised-controlled trials were included. All studies had an overall high risk of bias. Inspiratory muscle training probably improves systolic blood pressure and sleepiness when compared with sham. However, inspiratory muscle training probably does not improve diastolic blood pressure and maximum expiratory pressure, and may not be superior to sham for apnea-hypopnea index, forced expiratory volume in 1 s, forced vital capacity, sleep quality and quality of life. In addition, it is uncertain whether there is any effect of inspiratory muscle training on maximum inspiratory pressure and physical capacity. Inspiratory muscle training may also improve maximum inspiratory pressure and maximum expiratory pressure compared with oropharyngeal exercises. However, it may not be superior for apnea-hypopnea index, sleep quality, sleepiness, quality of life and functional capacity. When associated with physical exercise, inspiratory muscle training may not be superior to physical exercise alone for maximum inspiratory pressure, maximum expiratory pressure, systolic and diastolic blood pressure, and functional capacity. At the same time, when associated with cardiac rehabilitation exercises, inspiratory muscle training may reduce apnea-hypopnea index, improve inspiratory muscle strength, sleepiness and sleep quality compared with cardiac rehabilitation alone. However, it may not be superior for improving quality of life. Regarding expiratory muscle training, it may improve expiratory muscle strength and sleep quality, but not sleepiness when compared with sham. The evidence on the effects of expiratory muscle training in apnea-hypopnea index is very uncertain.

Novel Injury Scoring Tool for Assessing Brain Injury following Neonatal Hypoxia-Ischemia in Mice.

The variability of severity in hypoxia-ischemia (HI)-induced brain injury among research subjects is a major challenge in developmental brain injury research. Our laboratory developed a novel injury scoring tool based on our gross pathological observations during hippocampal extraction. The hippocampi received scores of 0-6 with 0 being no injury and 6 being severe injury post-HI. The hippocampi exposed to sham surgery were grouped as having no injury. We have validated the injury scoring tool with T2-weighted MRI analysis of percent hippocampal/hemispheric tissue loss and cell survival/death markers after exposing the neonatal mice to Vannucci's rodent model of neonatal HI. In addition, we have isolated hippocampal nuclei and quantified the percent good quality nuclei to provide an example of utilization of our novel injury scoring tool. Our novel injury scores correlated significantly with percent hippocampal and hemispheric tissue loss, cell survival/death markers, and percent good quality nuclei. Caspase-3 and Poly (ADP-ribose) polymerase-1 (PARP1) have been implicated in different cell death pathways in response to neonatal HI. Another gene, sirtuin1 (SIRT1), has been demonstrated to have neuroprotective and anti-apoptotic properties. To assess the correlation between the severity of injury and genes involved in cell survival/death, we analyzed caspase-3, PARP1, and SIRT1 mRNA expressions in hippocampi 3 days post-HI and sham surgery, using quantitative reverse transcription polymerase chain reaction. The ipsilateral (IL) hippocampal caspase-3 and SIRT1 mRNA expressions post-HI were significantly higher than sham IL hippocampi and positively correlated with the novel injury scores in both males and females. We detected a statistically significant sex difference in IL hippocampal caspase-3 mRNA expression with comparable injury scores between males and females with higher expression in females.

Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.

The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

Product indiscriminate use of vitamin risks: A review.

Most of the population does not seek professional advice before taking vitamin products and their indiscriminate use can lead to serious health risks. This study aims to demonstrate, through bibliographic survey, the risks of indiscriminate use of vitamin products related to hypervitaminosis and major drug interactions which the multivitamins are involved. A bibliographic survey was conducted in the databases LILACS, SciELO, PubMed, Medline, Micromedex, Drugs.com and textbooks on the subject. Vitamins are commonly described as harmless products by the majority of the population, but these trace elements can interact with other substances, causing mild disconforts or treatment failure for the patient, severe consequences to the body and can lead to death. To avoid the indiscriminate use of vitamin products, it is necessary that health professionals know and use specific laboratory tests for the determination of vitamins in the body, preventing these products from being unnecesarily prescribed. Also, the knowledge about what the possible effects of the indiscriminate use of vitamin supplements can lead to the rational use of these products.

Incidence, predictors and prognosis of acute kidney injury in nonagenarians: an in-hospital cohort study.

BACKGROUND: Given the aging of the population, nephrologists are ever more frequently assisting nonagenarians with acute kidney injury (AKI). The management of these patients presents unique characteristics, including bioethical dilemmas, such as the utilization of renal replacement therapy (RRT) at this extreme age. METHODS: We conducted a retrospective cohort study at a tertiary hospital. Over a 10-year period, 832 nonagenarians were hospitalized for two or more days. A random sample of 461 patients was obtained; 25 subjects were excluded due to lack of essential data. AKI was defined and staged according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: We analyzed data from 436 patients, mean age 93.5 ± 3.3 years, 74.3% female; 76.4% required intensive care unit (ICU). The incidence of AKI was 45%. Length of hospital stay, ICU admission, vasopressors, and mechanical ventilation (MV) were independent predictors of AKI. Overall in-hospital mortality was 43.1%. Mortality was higher in the AKI compared to the no AKI group (66.8% vs. 23.8%, p < 0.001). Only 13 patients underwent RRT; all were critically ill, requiring vasopressors and 76.9% in MV. Mortality for this RRT group was 100% but not significantly higher than that observed in 26 non-RRT controls (96.1%, p = 1.0) obtained by proportional random sampling, matched by variables related to illness severity. In multivariable analysis, age, Charlson's score, vasopressors, MV, and AKI - but not RRT - were independent predictors of mortality. CONCLUSIONS: AKI is common in hospitalized nonagenarians and carries a grave prognosis, especially in those who are critically iil. The use of RRT was not able to change the fatal prognosis of this subgroup of patients. Our data may help guide informed decisions about the utility of RRT in this scenario.

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis.

Considered prevalent in many countries on five continents, especially in low-income regions, leishmaniasis is a neglected tropical disease classified by World Health Organization as one of the diseases for which the development of new treatments is a priority. It is an infectious disease caused by protozoa of the genus Leishmania, whose species may cause different clinical manifestations, such as cutaneous and visceral leishmaniasis (VL). Treatment is exclusively by drug therapy, as it has not been possible to develop vaccines yet. Currently available drugs are not fully effective in all cases; they have parenteral administration and exhibit a number of serious and very common adverse effects. The only oral drug available is expensive and it is not available in many endemic countries. Injectable administration is the main problem of treatments, since it requires patients to go to health centers, hospitalization and professional administration, which are conditions that are not adapted to the reality of the poverty conditions of patients with the disease. In this context, the development of an oral medicine has become a focus as it may solve many of these issues. Based on this scenario, this review aimed to investigate which therapeutic alternatives have been studied for the development of oral drugs directed to the treatment of human VL.

Environmental and biological monitoring of benzene, toluene, ethylbenzene and xylene (BTEX) exposure in residents living near gas stations.

The volatile organic compounds benzene, toluene, ethylbenzene, and xylene (BTEX) are emitted into the atmosphere at gas stations (GS) leading to chronic exposure of nearby residents, which raises public health concerns. This study aimes at determining the contribution of GS emissions to BTEX exposure in nearby residents. Three Control and Exposed areas to BTEX emissions from GS were defined in a medium-sized European city (Porto, Portugal). BTEX atmospheric levels were determined in Control and Exposed areas using passive samplers deployed outdoors (n = 48) and indoors (n = 36), and human exposure was estimated for 119 non-smoking residents using the first urine of the day. Results showed that median BTEX outdoor and indoor concentrations were significantly higher for Exposed than Control areas, with exception of ethylbenzene and xylene indoor concentrations, where no marked differences were found. Comparison of urinary concentrations between Exposed and Control residents demonstrated no significant differences for benzene and ethylbenzene, whereas levels of toluene and xylene were significantly higher in Exposed residents. No marked correlation was obtained between atmospheric BTEX concentrations and urinary concentrations. Data indicate the potential impact on air quality of BTEX emissions from GS, which confirms the importance of these findings in urban planning in order to minimize the impact on health and well-being of surrounding populations.

Spatio-temporal transcriptome of the human brain.

Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

Influence of fruit age of the Brazilian Green Dwarf coconut on the relationship between Aceria guerreronis population density and percentage of fruit damage.

The coconut mite, Aceria guerreronis Keifer (Acari: Eriophyidae), is one of the main coconut pests in the American, African and parts of the Asian continents, reaching densities of several thousand mites per fruit. Diagrammatic scales have been developed to standardize the estimation of the population densities of A. guerreronis according to the estimated percentage of damage, but these have not taken into account the possible effect of fruit age, although previous studies have already reported the variation in mite numbers with fruit age. The objective of this study was to re-construct the relation between damage and mite density at different fruit ages collected in an urban coconut plantation containing the green dwarf variety ranging from the beginning to nearly the end of the infestation, as regularly seen under field conditions in northeast Brazil, in order to improve future estimates with diagrammatic scales. The percentage of damage was estimated with two diagrammatic scales on a total of 470 fruits from 1 to 5 months old, from a field at Ilhéus, Bahia, Brazil, determining the respective number of mites on each fruit. The results suggested that in estimates with diagrammatic scales: (1) fruit age has a major effect on the estimation of A. guerreronis densities, (2) fruits of different ages should be analyzed separately, and (3) regular evaluation of infestation levels should be done preferably on fruits of about 3-4 months old, which show the highest densities.