Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice.

Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments-a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD.

Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Advanced Cancer in Young Adults (YAs): Living in a Liminal Space.

Young adults (YAs), defined as individuals between the ages of 18 and 39 years, experience unique challenges when diagnosed with advanced cancer. Using the social constructivist grounded theory approach, we aimed to develop a theoretical understanding of how YAs live day to day with their diagnosis. A sample of 25 YAs (aged 22-39 years) with advanced cancer from across Canada participated in semi-structured interviews. Findings illustrate that the YAs described day-to-day life as an oscillating experience swinging between two opposing disease outcomes: (1) hoping for a cure and (2) facing the possibility of premature death. Oscillating between these potential outcomes was characterized as living in a liminal space wherein participants were unsure how to live from one day to the next. The participants oscillated at various rates, with different factors influencing the rate of oscillation, including inconsistent and poor messaging from their oncologists or treatment team, progression or regression of their cancer, and changes in their physical functioning and mental health. These findings provide a theoretical framework for designing interventions to help YAs adapt to their circumstance.

The Transformation of Adolescent and Young Adult Oncological and Supportive Care in Canada: A Mixed Methods Study.

BACKGROUND: Due to ongoing disparity in the specialized care available to adolescents and young adults (AYAs) with cancer, this study aimed to understand the gaps and barriers to accessing care and preferences on types of solutions at a national Canadian level. METHODS: A mixed-methods study involving an online survey and focus groups (FGs) was conducted among AYAs residing in different regions of Canada. RESULTS: There were a total of 174 survey respondents, of whom the majority were between 30-39 years of age (n = 125, 71.8%). Of the 174 respondents, 36 (20.7%) participated in one of seven FGs. Triangulation of the results illustrated that AYAs are not appropriately informed about the long-term health risks of being treated for cancer and where/how to seek support. These results culminated into three themes: (1) the need for AYA relevant and timely information about health risks; by (a) producing health risk-related content with the AYA life stage in mind; (b) providing a guided "map" to help AYAs anticipate what they may experience, and (c) providing checklists to help AYAs navigate their experience; (2) need for tailored and timely supportive care including (a) establishing ongoing check-ins and (b) receiving navigation support, and (3) need for enhanced connections by creating (a) a space to gather, connect and seek mentorship and (b) a hub to access information. CONCLUSION: AYAs continue to lack sufficient support both during and following cancer and mechanisms are required to ensure longitudinal support is provided across jurisdictions and in all stages of the cancer journey.

Supporting People and Their Caregivers Living with Advanced Cancer: From Individual Experience to a National Interdisciplinary Program.

OBJECTIVES: To discuss the unmet needs of patients living with advanced cancer and their caregivers and to review strategies, including collaborating with community and non-profit organizations, to help improve the experience of living with, and beyond, advanced cancer. DATA SOURCES: Published articles, first person experience (SB), community organization input, and survey data (Canadian Cancer Society). CONCLUSION: People living with advanced cancer face significant challenges, including persistent physical symptoms and psychosocial concerns, difficulties with coordination of care, and possible lack of available resources and supports if the person is no longer being followed by cancer health care professionals. More research is required to better understand the needs of patients and their caregivers living with advanced cancer. Existing resources and supports may be inadequate for this population, and delineation of the unique needs of this population may lead to tailored care plans and, ultimately, an improved experience for patients and caregivers alike. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses are ideally suited to care for this population to help elucidate their unique unmet needs and collaborate with patients and other clinicians to develop interventions to address such unmet needs. Oncology nurses can liaise with community organizations to identify sources of support and resources for patients and their loved ones and advocate for improved care for patients affected by advanced cancer.

Physical Activity and Bone Health in Men: A Systematic Review and Meta-Analysis.

BACKGROUND: Research on osteoporosis and physical activity often focuses on women. We aimed to conduct a systematic review to assess the benefits and harms of physical activity interventions for men's bone health. METHODS: We used standard methods and searched for randomized controlled trials (RCTs) (duration, ≥6 months) published in all languages across multiple databases and trial registries. The last search was conducted on July 22, 2020. RESULTS: We included 11 studies (14 publications), resulting in a sample of N=723 men (range, 17-132 participants). We found low-certainty evidence that physical activity has little influence on the areal bone mineral density (aBMD) at the total hip (5 RCTs, N=324; mean difference [MD], 0.03 [95 confidence interval (CI), 0.01 to 0.05]) and little or no influence on the aBMD at the femoral neck (3 RCTs, N=186; MD, 0.00 [95% CI, -0.04 to 0.04]), lumbar spine (3 RCTs; N=213; MD, 0.05 [95% CI, -0.01 to 0.11]), and whole body (4 RCTs, N=203; MD, -0.00 [95% CI, -0.03 to 0.02]). CONCLUSIONS: We found low-certainty evidence that physical activity (≥6 months) has some effect on the total hip in men, but new evidence may change this finding. This review highlights the gap in the evidence on specific intervention prescriptions that can benefit the bone geometry, structure, microarchitecture, and, ultimately, bone strength in men. Future research should engage in comprehensive reporting of harms, quality of life outcomes, advanced imaging findings, and long-term interventions.

Return to Everyday Activity in the Community and Home: a feasibility study for a lifestyle intervention to sit less, move more, and be strong.

BACKGROUND: Many interventions designed to meet physical activity guideline recommendations focus on a single component (e.g., walking), to the detriment of other elements of a healthy lifestyle, such as reducing prolonged sitting and doing balance and strength exercises (i.e., bundled multiple behaviors). Adopting these multiple health behaviors within daily life routines may facilitate uptake and support longer-term behavior change. We tested feasibility for a three-part lifestyle intervention to support older women to sit less, move more, and complete balance and strength exercises. METHODS: We used a convergent parallel mixed-methods, single-arm study design to test feasibility for a 6-week lifestyle intervention: Return to Everyday Activities in the Community and Home (REACH). We collected information at baseline, 3 and 6 weeks (final), and 6 months (follow-up) using questionnaires, semi-structured interviews, and performance-based measures. We describe three key elements: (1) implementation factors such as recruitment, retention, program delivery, and adherence; (2) participants' acceptability and experience with the program; and (3) health outcomes, including participants' global mobility, activity, and perceptions of their physical activity identity, and habit strength for (i) physical activity, (ii) breaking up sitting time, and (iii) balance and strength exercises. RESULTS: We were able to recruit enough participants in the allotted time to conduct one cycle of the REACH group-based program. There were 10 community-dwelling women, median (p25, p75) age 61 (57.5, 71) years, who completed the study. The program was feasible to deliver, with high attendance (mean 5/6 sessions) and positive overall ratings (8/10). Participants rated session content and length high, and educational materials as highly acceptable and understandable. Although participants were active walkers at baseline, few were breaking up prolonged sitting or participating in any balance and strength exercises. At final and follow-up assessments, participants reported developing habits for all three health behaviors, without diminishing physical activity. CONCLUSION: These results show acceptability of the program and its materials, and feasibility for bundling multiple health behaviors within the REACH program. It also provides confirmation to advance to testing feasibility of this three-part lifestyle intervention with older, less active, adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02786394; May 18, 2016.

Role of JNK, MEK and adenylyl cyclase signalling in speed and directionality of enteric neural crest-derived cells.

BACKGROUND: Cells derived from the neural crest colonize the developing gut and give rise to the enteric nervous system. The rate at which the ENCC population advances along the bowel will be affected by both the speed and directionality of individual ENCCs. The aim of the study was to use time-lapse imaging and pharmacological activators and inhibitors to examine the role of several intracellular signalling pathways in both the speed and the directionality of individual enteric neural crest-derived cells in intact explants of E12.5 mouse gut. Drugs that activate or inhibit intracellular components proposed to be involved in GDNF-RET and EDN3-ETB signalling in ENCCs were used. FINDINGS: Pharmacological inhibition of JNK significantly reduced ENCC speed but did not affect ENCC directionality. MEK inhibition did not affect ENCC speed or directionality. Pharmacological activation of adenylyl cyclase or PKA (a downstream cAMP-dependent kinase) resulted in a significant decrease in ENCC speed and an increase in caudal directionality of ENCCs. In addition, adenylyl cyclase activation also resulted in reduced cell-cell contact between ENCCs, however this was not observed following PKA activation, suggesting that the effects of cAMP on adhesion are not mediated by PKA. CONCLUSIONS: JNK is required for normal ENCC migration speed, but not directionality, while cAMP signalling appears to regulate ENCC migration speed, directionality and adhesion. Collectively, our data demonstrate that intracellular signalling pathways can differentially affect the speed and directionality of migrating ENCCs.

Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon.

Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (nNOS-/-) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS+ neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS-/- colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model.

Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells.

The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms.