Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt -Glycosylation and Reduce Protein Stability.

has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown.

Neuronal transcription of autism gene PTCHD1 is regulated by a conserved downstream enhancer sequence.

Patched domain-containing 1 (PTCHD1) is a well-established susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID). Previous studies have suggested that alterations in the dosage of PTCHD1 may contribute to the etiology of both ASD and ID. However, there has not yet been a thorough investigation regarding mechanisms that regulate PTCHD1 expression.

Leaf acclimation to soil flooding and light availability underlies photosynthetic capacity of , an endangered shrub of bottomland forests in the Mississippi Alluvial Valley, USA.

is an endangered shrub indigenous to the broadleaf forest of the Mississippi Alluvial Valley (MAV). In this region, extant colonies of the species are found in periodically ponded habitats where a diversity of broadleaf trees can form well-developed overstory and sub-canopies-these habitat characteristics suggest that soil flooding and light availability are primary drivers of ecophysiology. To understand how these two factors affect its photosynthetic capacity, we quantified leaf characteristics and photosynthetic response of plants grown in a large-scaled, field setting of three distinct soil flooding levels (no flood, 0 day; short-term flood, 45 days; and extended flood, 90 days) each containing three distinct light availability levels (high light, 30% shade cloth; intermediate light, 63% shade cloth; and low light, 95% shade cloth).

: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene.

Over the last one and a half decades, copy number variation and whole-genome sequencing studies have illuminated the considerable genetic heterogeneity that underlies the etiologies of autism spectrum disorder (ASD) and intellectual disability (ID). These investigations support the idea that ASD may result from complex interactions between susceptibility-related genetic variants (single nucleotide variants or copy number variants) and the environment. This review outlines the identification and neurobiological characterization of two such genes located in Xp22.

Intensity and mode of reproduction are affected by flooding and light availability.

We studied the impact of flooding and light availability gradients on sexual and asexual reproduction in (Walt.) Blume, an endangered shrub found in floodplain forests of the Mississippi Alluvial Valley (MAV), USA. A water impoundment facility was used to control the duration of soil flooding (0, 45, or 90 days), and shade houses were used to control light availability (high = 72%, intermediate = 33%, or low = 2% of ambient light) received by established on native soil of the MAV.

Distinct epithelial-to-mesenchymal transitions induced by and .

The most common mutation, producing the H1047R mutant of p110α, arises in myriad malignancies and is typically observed in low-grade breast tumours. In contrast, amplification is observed for wild-type , encoding p110β, and occurs at low frequency but in aggressive, high-grade metastatic tumours. We hypothesized that mutant p110α and wild-type p110β give rise to distinct transformed phenotypes.

The protein-specific activities of the transmembrane modules of Ptch1 and Ptch2 are determined by their adjacent protein domains.

Signaling through the Hedgehog (Hh) pathway is mediated by the Patched (Ptch) family of proteins. Although the vertebrate Ptch proteins Ptch1 and Ptch2 harbor two closely related transmembrane modules related to sterol-sensing domains (SSDs), the role of these closely related receptors in the Hh pathway are not equivalent. Ptch1 is essential for development and appears to be the principal receptor mediating responses to Hh ligands, whereas Ptch2 is nonessential, and its role in Hh-signaling remains ambiguous.

The Voluntariat: A Frieirean framework to understand the nature of undergraduate international (medical) experiences.

Despite literature documenting limited and asymmetrical benefits along with ethical issues, short-term international volunteering is increasingly popular among North American university students as a perceived advantage when applying to professional healthcare schools or the job market. Academic institutions are also encouraging students to pursue international experiences in order to cultivate values as global citizens. These experiences are most typically limited to economically privileged students.

Activities of the Cytoplasmic Domains of Patched-1 Modulate but Are Not Essential for the Regulation of Canonical Hedgehog Signaling.

The Hedgehog (Hh) pathway is a highly conserved signaling cascade crucial for cell fate determination during embryogenesis. Response to the Hh ligands is mediated by the receptor Patched-1 (Ptch1), a 12-pass transmembrane glycoprotein. Despite its essential role in Hh signaling and its activity as a tumor suppressor, Ptch1 remains largely uncharacterized.

Competition and habitat quality influence age and sex distribution in wintering rusty blackbirds.

Bird habitat quality is often inferred from species abundance measures during the breeding and non-breeding season and used for conservation management decisions. However, during the non-breeding season age and sex classes often occupy different habitats which suggest a need for more habitat-specific data. Rusty Blackbird (Euphagus carolinus) is a forested wetland specialist wintering in bottomland hardwood forests in the south-eastern U.

Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland.

Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity.

Distinct effects of the mesenchymal dysplasia gene variant of murine Patched-1 protein on canonical and non-canonical Hedgehog signaling pathways.

Hedgehog (Hh) signaling requires regulation of the receptor Patched-1 (Ptch1), which, in turn, regulates Smoothened activity (canonical Hh signaling) as well as other non-canonical signaling pathways. The mutant Ptch1 allele mesenchymal dysplasia (mes), which truncates the Ptch1 C terminus, produces a limited spectrum of developmental defects in mice as well as deregulation of canonical Hh signaling in some, but not all, affected tissues. Paradoxically, mes suppresses canonical Hh signaling and binds to Hh ligands with an affinity similar to wild-type mouse Ptch1 (mPtch1).

Wnt-signalling in the embryonic mammary gland.

The first member of the Wnt-family ligands was identified 30 years ago as a factor in mouse mammary tumours whose expression was deregulated due to the promoter activity emanating from the proximal integration of the Mouse Mammary Tumour Virus genome (Nusse and Varmus, Embo J 31:2670-84, 2012). The Wnt-ligands invoke a number of molecular-genetic signalling cascades fundamental to the patterning of developing tissues and organs during embryogenesis as well as during postnatal development. The Wnt-signalling cascade that controls the activities of β-catenin and the T-cell Factor (Tcf)/Lympoid enhancer factor (Lef1) plays a fundamental role in control of all stages of embryonic mammary gland development.

Migratory New World blackbirds (icterids) are more neophobic than closely related resident icterids.

Environments undergo short-term and long-term changes due to natural or human-induced events. Animals differ in their ability to cope with such changes which can be related to their ecology. Changes in the environment often elicit avoidance reactions (neophobia) which protect animals from dangerous situations but can also inhibit exploration and familiarization with novel situations and thus, learning about new resources.

Mammary epithelial-restricted expression of activated c-src rescues the block to mammary gland morphogenesis due to the deletion of the C-terminus of Patched-1.

Mesenchymal dysplasia (mes) mice expressing a C-terminally truncated version of the Hedgehog (Hh)-ligand receptor, Patched-1 (Ptch1), exhibit a limited spectrum of developmental defects including blocked ductal morphogenesis of the mammary gland during puberty. Given that the Hh-ligands can stimulate signalling cascades distinct from the canonical pathway involving Smo and the Gli-family proteins and that Ptch1 binds to factors harbouring SH3-domains, we determined whether the mes mammary gland defect could be rescued by activating non-canonical signalling pathways downstream of Ptch1. We demonstrate here that expression of constitutively active c-src (c-src(Act)) in mammary epithelial cells overcomes the block to mammary epithelial morphogenesis in mes mice.

First contact pheromone identified for a longhorned beetle (Coleoptera: Cerambycidae) in the subfamily Prioninae.

Little is known of the reproductive behavior of longhorned beetles (Coleoptera: Cerambycidae) in the subfamily Prioninae. Mallodon dasystomus (Say), the hardwood stump borer, is a widely distributed prionine that is native to the southern U.S.

Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling.

Hedgehog (Hh) signalling is mediated through the Patched-1 (Ptch1) receptor. Hh-binding to Ptch1 blocks the inhibitory effects of Ptch1 on the activity of the transmembrane protein, Smoothened (Smo), resulting induction of target genes by the Gli-family of transcription factors. We demonstrate here that Hh-binding to Ptch1 stimulates activation of Erk1/2.

Lymphoid enhancer factor-1 mediates loading of Pax3 to a promoter harbouring lymphoid enhancer factor-1 binding sites resulting in enhancement of transcription.

The transcription factor, Pax3, alters transcription by binding directly to promoter regions harbouring sequences recognized by either its paired domain or its homeodomain. We demonstrated previously that the promoter regions of many of the genes whose expression was altered during a Pax3-induced mesenchymal-to-epithelial transition harboured sequences recognized by lymphoid enhancer factor-1 (Lef1). Given the apparent lack of DNA-binding consensus sequences for Pax3 in these promoters, it was hypothesized that Pax3 might alter transcriptional activity of promoters harbouring Lef1-binding sites independent of Pax3 binding to DNA.

Ptch1 is required locally for mammary gland morphogenesis and systemically for ductal elongation.

Systemic hormones and local growth factor-mediated tissue interactions are essential for mammary gland development. Using phenotypic and transplantation analyses of mice carrying the mesenchymal dysplasia (mes) allele of patched 1 (Ptch1(mes)), we found that Ptch1(mes) homozygosity led to either complete failure of gland development, failure of post-pubertal ductal elongation, or delayed growth with ductal dysplasia. All ductal phenotypes could be present in the same animal.

Loss of Alx4, a stromally-restricted homeodomain protein, impairs mammary epithelial morphogenesis.

Postnatal development of the mammary gland is determined by reciprocal interactions between the ductal epithelia and adjacent stroma. Alx4 is a mesenchymally restricted homeodomain transcription factor expressed in a number of developing tissues, including skin appendages such as hair follicles, whiskers and teeth. We show here that Alx4 is expressed in a subset of ERalpha-expressing mammary stromal cells adjacent to terminal end buds and alveoli during puberty and pregnancy, respectively.

Genetic interaction between Lef1 and Alx4 is required for early embryonic development.

Lymphoid Enhancer Factor-1 (Lef1) facilitates the assembly of transcriptional regulatory complexes and mediates nuclear responses to Wnt signals. We determined previously that the mesenchymally restricted, paired-like homeodomain protein Aristaless-like 4 (Alx4) interacts with Lef1 and together alters promoter activity of candidate genes. In order to define their overlapping functions, mice deficient for both Lef1 and Alx4 activity (Lef1-/-/Alx4lstD/lstD) were produced.

Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland.

Inductive reciprocal signaling between mesenchymal and adjacent epithelia gives rise to skin appendages such as hair follicles and mammary glands. Lef1-mediated canonical Wnt signaling is required for morphogenesis of these skin appendages during embryogenesis. In order to define the role of canonical Wnt signaling during early embryonic mammary gland development, we determined the temporal and spatial changes in Wnt signaling during embryogenesis in wild-type and Lef1-deficient embryos harboring a Tcf/Lef1-betagal reporter (TOPGAL) transgene.

Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR.

The oncogenic fusion protein, Pax3/FKHR, is a more potent transcription factor relative to its normal counterpart, Pax3. Since Pax3 induced a mesenchymal to epithelial transition (MET) in human SaOS-2 osteosarcomas, we hypothesized that Pax3/FKHR would also induce a morphological change in SaOS-2 cells. We demonstrate here that Pax3/FKHR more potently induces a MET in SaOS-2 cells than Pax3.

Homeless people's trust and interactions with police and paramedics.

Although the health impact of patients' trust in physicians has been well documented, less is known about the possible health effects of trust in police or paramedics. Homeless people frequently interact with police officers and paramedics, and these experiences may affect their health and future willingness to seek emergency assistance. We examined homeless people's self-reported interactions with police and paramedics in Toronto, Canada, and their level of trust in these emergency service providers.

The prevalence of psychological morbidity in West Bank Palestinian children.

Objective: To determine the prevalence of psychological morbidity among Palestinian children living in the southern Bethlehem District of the West Bank during July 2000.

Methods: We undertook a descriptive study using the Rutter A2 (parent) Scale to determine psychological morbidity. This questionnaire comprises 31 questions that were answered by a parent of the 206 subject children (ages 6 to 13 years).