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Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

Epithelial adenocarcinoma of the ovary and colon are associated with the highest rates of cancer-related deaths in women in the U.S. The literature supports the role of HDL-associated apolipoproteins in the treatment of cancer and other pro-inflammatory diseases. Previously, we developed a novel 20-amino acid mimetic peptide, HM-10/10, which potently inhibits tumor development and growth in colon and ovarian cancer. Here, we report the properties of HM-10/10 relative to its stability in vitro. The results demonstrated that HM-10/10 had the highest half-life in human plasma compared to plasma from other species tested. HM-10/10 demonstrated stability in human plasma and simulated gastric environment, increasing its promise as an oral pharmaceutical. However, under conditions modeling the small intestine, HM-10/10 demonstrated significant degradation, likely due to the peptidases encountered therein. Furthermore, HM-10/10 demonstrated no evidence of time-dependent drug-drug interactions, although it demonstrated CYP450 induction slightly above cutoff. As proteolytic degradation is a common limitation of peptide-based therapeutics, we are pursuing strategies to improve the stability properties of HM-10/10 by extending its bioavailability while retaining its low toxicity profile. HM-10/10 holds promise as a new agent to address the international women's health crisis of epithelial carcinomas of the ovary and colon.

Neural stem cells (NSCs) in the developing and postnatal brain have distinct positional identities that dictate the types of neurons they generate. Although morphogens initially establish NSC positional identity in the neural tube, it is unclear how such regional differences are maintained as the forebrain grows much larger and more anatomically complex. We found that the maintenance of NSC positional identity in the murine brain requires a mixed-lineage leukemia 1 (Mll1)-dependent epigenetic memory system. After establishment by sonic hedgehog, ventral NSC identity became independent of this morphogen. Even transient MLL1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Thus, spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain.

While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. Here, we show that conditional deletion of Pnky from the developing cortex regulates the production of projection neurons from neural stem cells (NSCs) in a cell-autonomous manner, altering postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a BAC transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates development in trans.

Autism spectrum disorder (ASD) is a neurological disorder that manifests itself within an individual through cognitive, social, and academic deficits. As is true for all spectrum disorders, each individual may experience a range of deficits with varying severity. Many students with autism spectrum disorder experience difficulty in some area of communication. The Picture Exchange Communication System (PECS) was developed in an effort to remedy the communication difficulties between individuals with severe ASD and their peers. The main goal of PECS is to enable students with communication deficits to spontaneously communicate with their peers. The system is composed of six different phases in which a student may progress with increasing independency. While many individuals with ASD are able to communicate effectively with PECS, such a system is not suitable for all individuals on the spectrum; therefore, it is imperative for professionals, parents, and peers to be knowledgeable of the implementation, utilization, and culmination of the Picture Exchange Communication System.

While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations.

Emerging evidence indicates that there are factors within the blood of young animals that have the ability to restore youthful characteristics to a number of organ systems in older animals. Growth/differentiation factor 11 (GDF11) is the first of such factors to be identified, and two new studies demonstrate that this "factor of youth" rejuvenates stem cells found in the skeletal muscle and brain of aged mice.

Background: Nurses working in detention centers play a pivotal role in inmate healthcare. Yet, they often face areas of tension due to conflicting jail policies and nursing principles, which affects their work and their response to the challenging environment. Objectives: This qualitative study explores nurses' experiences in providing healthcare to inmates, focusing on areas of tension within this context. Method: We conducted a Reflective Lifeworld Research study using semi-structured interviews to explore the phenomenon. Results: Four elements emerged as areas of tension: 1) reconciling meaningful care with the harsh environment; 2) navigating between constraints and opportunities; 3) maintaining trust while avoiding manipulation; and 4) balancing alliances with controversies between nurses and other professionals. Conclusions: This study provides an in-depth understanding of nurses' complex roles in detention centers, highlighting their adept handling of areas of tension in a demanding work environment. Nurses successfully manage workplace challenges by remaining consistently aware of the harsh surroundings without compromising their relationships with inmates or the quality of care provided. [ABSTRACT FROM AUTHOR]

The Humanised Care Assessment Tool (HCAT) was collaboratively developed in the UK with input from theory, patients, relatives, and staff. HCAT contains 109 items providing an in-depth understanding of the values considered when assessing whether care is practiced in a humane manner. This study's objective was to provide a linguistically valid and reliable Danish version of the HCAT suitable for primary healthcare settings. We report on the process of translation and adaptation, resulting in the Danish pilot version with 83 items within the eight original dimensions. The Danish pilot HCAT is the first Danish questionnaire intended to serve as both a reflective tool and a measurement instrument for assessing how workplace culture fosters or impedes humane caregiving behavior. The next step is to investigate the validity, reliability and responsiveness of the instrument as well as its value as a tool for reflection in primary healthcare. [ABSTRACT FROM AUTHOR]

There are quite a few challenges in the development of an automated writing placement model for non-native English learners, among them the fact that exams that encompass the full range of language proficiency exhibited at different stages of learning are hard to design. However, acquisition of appropriate training data that are relevant to the task at hand is essential in the development of the model. Using the Cambridge Learner Corpus writing scores, which have been subsequently benchmarked to Common European Framework of Reference for Languages (CEFR) levels, we conceptualize the task as a supervised machine learning problem, and primarily focus on developing a generic writing model. Such an approach facilitates the modeling of truly consistent, internal marking criteria regardless of the prompt delivered, which has the additional advantage of requiring smaller dataset sizes and not necessarily requiring re-training or tuning for new tasks. The system is developed to predict someone's proficiency level on the CEFR scale, which allows learners to point to a specific standard of achievement. We furthermore integrate our model into Cambridge English Write & Improve™--a freely available, cloud-based tool that automatically provides diagnostic feedback to non-native English language learners at different levels of granularity--and examine its use.

BACKGROUND: Human exposure to inorganic arsenic (iAs), a potent oxidative stressor, causes various dermal disorders, including hyperkeratosis and skin cancer. Nuclear factor-erythroid 2-related factor 1 (NRF1, also called NFE2L1) plays a critical role in regulating the expression of many antioxidant response element (ARE)-dependent genes. OBJECTIVES: We investigated the role of NRF1 in arsenic-induced antioxidant response and cytotoxicity in human keratinocytes. RESULTS: In cultured human keratinocyte HaCaT cells, inorganic arsenite (iAs(3+)) enhanced the protein accumulation of long isoforms (120-140 kDa) of NRF1 in a dose-and time-dependent fashion. These isoforms accumulated mainly in the nuclei of HaCaT cells. Selective deficiency of NRF1 by lentiviral short-hairpin RNAs in HaCaT cells [NRF1-knockdown (KD)] led to decreased expression of gamma-glutamate cysteine ligase catalytic subunit (GCLC) and regulatory subunit (GCLM) and a reduced level of intra-cellular glutathione. In response to acute iAs(3+) exposure, induction of some ARE-dependent genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), GCLC, and GCLM, was significantly attenuated in NRF1-KD cells. However, the iAs(3)-induced expression of heme oxygenase 1 (HMOX-1) was unaltered by silencing NRF1, suggesting that HMOX-1 is not regulated by NRF1. In addition, the lack of NRF1 in HaCaT cells did not disturb iAs(3+)-induced NRF2 accumulation but noticeably decreased Kelch-like ECH-associated protein 1 (KEAP1) levels under basal and iAs(3+)-exposed conditions, suggesting a potential interaction between NRF1 and KEAP1. Consistent with the critical role of NRF1 in the transcriptional regulation of some ARE-bearing genes, knockdown of NRF1 significantly increased iAs(3+)-induced cytotoxicity and apoptosis. CONCLUSIONS: Here, we demonstrate for the first time that long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes and protect the cells from acute arsenic cytotoxicity.