The role of β3 integrin gene variants in Autism Spectrum Disorders — Diagnosis and symptomatology

Autism Spectrum Disorders (ASDs) represent a group of very complex early-onset neurodevelopmental diseases. In this study, we analyzed 5 SNPs (rs2317385, rs5918, rs15908, rs12603582, rs3809865) at the β3 integrin locus (ITGB3), which has been suggested as a possible susceptibility gene, both as single markers and as part of haplotypes in 209 ASD children and their biological parents. We tested for association with the following: a) DSM-IV ASD diagnosis; b) clinical symptoms common in ASD patients (repetitive behaviors, echolalia, seizures and epilepsy, mood instability, aggression, psychomotor agitation, sleep disorders); and c) dimensional scores obtained with the Autism Screening Questionnaire and the Childhood Autism Rating Scale. These hypotheses were investigated using family-based tests, logistic regression models and analysis of covariance. The family-based tests showed an association with the H5 haplotype (composed by GTCGA alleles, the order of SNPs as above), which was transmitted less often than expected by chance (P = 0.006; P_corr = 0.036). The analyses of the clinical symptoms showed a trend for an association with rs12603582 (P = 0.008; P_corr = 0.064) and positive results for the haplotype composed of rs15908 and rs12603582 (P_glcorr = 0.048; P_indcorr = 0.015), both in symptoms of echolalia. Other nominal associations with different variants were found and involved epilepsy/seizures, aggression symptoms and higher ASQ scores. Although our positive results are not definitive, they suggest small effect associations of the ITGB3 gene with both ASD diagnosis and symptoms of echolalia. Other studies are nonetheless needed to fully understand the involvement of this locus on the etiology of ASDs and its different clinical aspects.     

A 1.5 Mb terminal deletion of 12p associated with autism spectrum disorder

We report a patient with a terminal 12p deletion associated with autism spectrum disorder (ASD). This 12p13.33 deletion is 1.5 Mb in size and encompasses 13 genes (B4GALNT3, CCDC77, ERC1, FBXL14, IQSEC3, KDM5A, LINC00942, LOC574538, NINJ2, RAD52, SLC6A12, SLC6A13 and WNK1). All previous cases reported with partial monosomy of 12p13.33 are associated with neurodevelopmental delay, and we suggest that ERC1, which encodes a regulator of neurotransmitter release, is the best gene candidate contributing to this phenotype as well as to the ASD of our patient.     

Quantifying the re-exposure process to an infectious agent. Measles and Varicella as examples

Background and objectives

For viral infections conferring what is usually considered as permanent immunity, re-exposure to the pathogen due to contacts with infectious individuals might be critical for immunity boosting. A major example is represented by the varicella-zoster virus (VZV) where re-exposure is thought to lead to boosting of cell mediated immunity (CMI), which plays a protective role against the development of herpes zoster (HZ). Similar concerns have recently been raised also in relation to measles. However, while the first effective exposure, i.e. infection, has been the object of many studies, both theoretical and epidemiological, there has been no corresponding investigation of the re-exposure process.

Methodology and data

By combining basic concepts from deterministic and stochastic modelling of infection, we develop a basic model for quantifying the timing and number of re-exposures and, consequently, the potential for immune boosting at any given age. The model is then applied to measles, mumps and rubella (MMR) in the UK, and to varicella in Italy, using literature estimates of the pre-vaccination forces of infection.

Results

We supply analytical expressions for the expected number of lifetime re-exposures and for underlying age-patterns, including the average age at which the last re-exposure occurs. Based on updated estimates of the force of VZV infection, we show that the expected number of boosting opportunities of CMI might be in the range 2–3, which is consistent with recent findings about the development of herpes zoster. We also show that the estimate of the age at which the last re-exposure to VZV occurs is highly sensitive to the underlying form of age dependence of the force of infection.

Conclusions

Our results contribute to the study of the potential immunity boosting effect of re-exposures to an infective agent by quantifying the re-exposure process.     

Mojokerto revisited: Evidence for an intermediate pattern of brain growth in Homo erectus

Brain development in Homo erectus is a subject of great interest, and the infant calvaria from Mojokerto, Indonesia, has featured prominently in these debates. Some researchers have suggested that the pattern of brain development in H. erectus resembled that of non-human apes, while others argue for a more human-like growth pattern. In this study, we retested hypotheses regarding brain ontogeny in H. erectus using new methods (resampling), and data from additional H. erectus crania. Our results reveal that humans achieve 62% (±10%) and chimpanzees 80% (±9%) of their adult endocranial volume by 0.5–1.5 years of age. Using brain mass data, humans achieve on average 65% and chimpanzees 81% of adult size by 0.5–1.5 years. When compared with adult H. erectus crania (n = 9) from Indonesian sites greater than 1.2 million years old, Mojokerto had reached ∼70% of its adult cranial capacity. Mojokerto thus falls almost directly between the average growth in humans and chimpanzees, and well within the range of both. We therefore suggest that brain development in H. erectus cannot be dichotomized as either ape-like or human-like; it was H. erectus-like. These data indicate that H. erectus may have had a unique developmental pattern that should be considered as an important step along the continuum of brain ontogeny between apes and humans.     

International trends in the incidence of brain tumours in children and young-adults and their association with indicators of economic development

IntroductionChildhood brain tumours (CBTs) are the second most common type of cancer in individuals aged 0–24 years globally and cause significant morbidity and mortality. CBT aetiology remains poorly understood, however previous studies found higher CBT incidence in high-income countries (HIC) compared to low-middle income countries (LMIC), suggesting a positive relationship between incidence and wealth.Materials & methodsAggregated data from Cancer Incidence in Five Continents (CI5) were used to explore CBT epidemiology. Incidence rate ratios (IRR) compared CBT rates between twenty-five geographically and economically diverse countries. The relationship between incidence and economic development was explored using linear regression models and Spearman’s rank correlation tests. Trends in CBT incidence between 1978 and 2012 were investigated using average annual percentage changes (AAPC).ResultsCBT incidence was highest in North America and lowest in Africa. CBT incidence rates increased significantly with increasing GDP per capita (p = 0.006). Gini index was significantly negatively associated with CBT incidence. Incidence decreased with increasing income inequality within countries, indicated by higher Gini indices (p = 0.040). Increasing and decreasing CBT incidence trends were observed within individual countries, although only Italy (p = 0.02) and New Zealand (p < 0.005) experienced statistically significant changes over time.ConclusionsThe excess disease found in HIC may be explained by environmental risk factor exposure increasing CBT risk in wealthy populations. However, systematic limitations of substandard cancer detection and reporting in LMIC may mean incidence disparities result from misinformation bias rather than genuine differences in risk factor exposure. Further research is required to comprehensively describe CBT epidemiology and explain study findings.     

Nonsocial and social cognition in schizophrenia: current evidence and future directions

Cognitive impairment in schizophrenia involves a broad array of nonsocial and social cognitive domains. It is a core feature of the illness, and one with substantial implications for treatment and prognosis. Our understanding of the causes, consequences and interventions for cognitive impairment in schizophrenia has grown substantially in recent years. Here we review a range of topics, including: a) the types of nonsocial cognitive, social cognitive, and perceptual deficits in schizophrenia; b) how deficits in schizophrenia are similar or different from those in other disorders; c) cognitive impairments in the prodromal period and over the lifespan in schizophrenia; d) neuroimaging of the neural substrates of nonsocial and social cognition, and e) relationships of nonsocial and social cognition to functional outcome. The paper also reviews the considerable efforts that have been directed to improve cognitive impairments in schizophrenia through novel psychopharmacology, cognitive remediation, social cognitive training, and alternative approaches. In the final section, we consider areas that are emerging and have the potential to provide future insights, including the interface of motivation and cognition, the influence of childhood adversity, metacognition, the role of neuroinflammation, computational modelling, the application of remote digital technology, and novel methods to evaluate brain network organization. The study of cognitive impairment has provided a way to approach, examine and comprehend a wide range of features of schizophrenia, and it may ultimately affect how we define and diagnose this complex disorder.     

温度和盐胁迫对草莓开花进程和相关基因表达的影响

为探究草莓花器官对高温、低温、盐胁迫的响应特征,该研究以草莓品种‘甜查理’为试材,设置0℃、4℃、25℃(CK)、37℃、200 mmol/L NaCl、400 mmol/L NaCl等逆境胁迫处理,考察草莓花外观形态、生长发育状态、花器官抗氧化酶活性,以及3个草莓花器官分生组织特异性基因、12个成花途径基因、3个抗氧化酶基因、6个抗逆基因的表达等。结果显示:(1)0℃、4℃、37℃、200 mmol/L NaCl、400 mmol/L NaCl溶液处理均抑制了草莓花的开放,0℃低温显著抑制草莓花器官的开放,并对草莓的花器官造成伤害。(2)当草莓植株受到高温、低温、盐胁迫时,其花器官内抗氧化酶SOD、POD、CAT活性及MDA含量均得到提高,其相关抗氧化酶基因的表达水平也相应提高。(3)0℃、4℃、37℃以及200 mmol/L NaCl、400 mmol/L NaCl溶液处理均显著降低了草莓花器官FaAP1、FaLFY、FaFD、FaSOC1等成花基因的表达量;0℃低温诱导了FaICE、FaRD29A、FaCOR、FaAFP等4个抗寒基因的表达水平;200 mmol/L NaCl、400 mmol/L NaCl的盐胁迫显著提高了FaP5CS基因的表达量。研究表明,0℃、4℃、37℃、200 mmol/L NaCl、400 mmol/L NaCl溶液处理不同程度抑制了草莓的开花进程,对草莓花器官造成伤害;不同逆境胁迫处理显著提高了草莓花器官SOD、POD、CAT活性以及MDA含量,相应的抗氧化酶基因表达得到上调,同时显著降低了草莓成花途径相关基因表达,增强了相关抗逆基因的表达水平。     

The Social Life of Death on Delhi's Streets: Unclaimed Souls,Pollutive Bodies,Dead Kin and the Kinless Dead

ABSTRACT

How does the status of ‘street children’ in life inflect the narrative representation of their deaths? Street-dwelling children's interactions with death in North India reveal much about how their identities are produced in public domains. In this paper, I examine several instances of ‘homeless child’ death to illuminate the place of such subjects in society and urban space, and to interrogate the degree to which they can be rendered ‘recognizable’ or ‘grievable’, in Butler's (2010) terminology. In particular, I explore the presence or absence of kin in the ways that child death is narrated. I also explore the related question of how living ‘vagabond (aawara) children’ situate their status in narratives of death and loss. I conclude with discussions of how children negotiate their orientations towards death through ghost narratives, and of the space-, economy- and age-bound assignment of pollutive tasks once reserved for low castes to street-dwelling children.     

Disruption of Contactin 4 in two subjects with autism in Chinese population

Autism is a heterogeneous childhood neurodevelopmental disorder that is characterised by deficits in verbal communication, impaired social interactions, restricted interests and repetitive behaviours. Using an Illumina HumanCNV370-Quad BeadChip, we identified two Han Chinese individuals with autism and large duplications (~1.6 Mb and ~2.4 Mb) disrupting the same CNTN4 gene. CNTN4 encodes a protein that functions as a cell-adhesion molecule and may play an essential role in the formation of axon connections in the developing nervous system. The disruption of this gene has been reported to be the cause of the 3p deletion syndrome and also a possible susceptibility factor for autism spectrum disorders (ASDs). Our results suggest that rare copy number variations (CNVs) in CNTN4 may also influence autism susceptibility in Asian populations. Interestingly, a comparison of the clinical phenotypes between the two subjects revealed that the subject with the 2.4 Mb CNV (involving several other genes) presented with a more severe phenotype than the subject with the 1.6 Mb CNV (disrupting only CNTN4 and CNTN6). This suggests that other genes in the nearby region may contribute to the pathogenesis.     

Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms

This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. Two broad categories of epigenetically mediated effects are highlighted. The first involves developmentally programmed effects. These can result from the influence of the offspring's early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. The second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. Several factors, such as sex‐specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. The most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. Given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi‐generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.