Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Yield of diagnostic testing in evaluating etiology and end organ effects of pediatric hypertension.

BACKGROUND: Current recommendations regarding the utility of diagnostic investigations for pediatric hypertension are based on limited evidence, leading to wide practice variation. The objective of this study was to characterize the cohort of children that may benefit from secondary hypertension workup, and determine the diagnostic yield of investigations. METHODS: This was a single-center, retrospective cohort study of 169 children aged 1-18 years referred between 2000 and 2015, to a tertiary pediatric nephrology center in Canada, for evaluation of hypertension. The number of investigations completed, abnormal findings, and diagnostic findings that helped establish hypertension etiology was determined. RESULTS: 56 children were diagnosed with primary and 72 children with secondary hypertension in the outpatient setting. Secondary hypertension was predominant at all ages except for obese adolescents ≥ 12 years. Half of children with traditional risk factors for primary hypertension, including obesity, were diagnosed with secondary hypertension. Kidney ultrasound had the highest yield of diagnostic results (19.8%), with no difference in yield between age groups (P = 0.19). Lipid profile had a high yield of abnormal results (25.4%) as part of cardiovascular risk assessment but was only abnormal in overweight/obese children. Echocardiogram had a high yield for identification of target-organ effects in hypertensive children (33.3%). CONCLUSION: A simplified secondary hypertension workup should be considered for all hypertensive children and adolescents. High yield investigations include a kidney ultrasound, lipid profile for overweight/obese children, and echocardiograms for assessment of target-organ damage. Further testing could be considered based on results of initial investigations for the most cost-effective management. A higher resolution version of the Graphical abstract is available as Supplementary information.

Using wearable technology to prevent pressure injuries: An integrative review.

BACKGROUND: Hospital-acquired pressure injuries (HAPIs) are a significant problem for hospitals worldwide, negatively affecting patients and organizations by decreasing quality of life and increasing organizational cost of care and workload. A common pressure injury prevention intervention is frequent turning, though compliance can be low. As a newer technology, wearable sensors have emerged as an intervention to increase turn compliance. AIMS: The aim of this integrative review was to determine the clinical outcomes of using wearable sensors as a HAPI prevention intervention. METHODS: This integrative review was appraised by two independent reviewers using the Johns Hopkins Nursing Evidence-Based Practice Research Appraisal Tool. RESULTS: Eleven articles were included. The use of wearable sensors increases compliance with frequent turn protocols while decreasing HAPIs and reducing organizational costs. Despite this, the use of such technology was not found to increase the quality of turns. Although staff who used this technology reported positive feedback, technological training is needed to ensure proper use of the sensors. LINKING ACTION TO PRACTICE: This innovation has the potential to transform how nursing staff prevent pressure injuries, but more research is needed to definitively state whether wearable sensors will be efficacious as a pressure injury prevention intervention.

68 Degrees: New York City's Residential Heat and Hot Water Code as an Invisible Energy Policy.

For over a century, New York's Residential Heat and Hot Water Code has controlled the distribution of heat in New York City. Established in 1918 by New York's Department of Health, it mandated that all residential and office spaces in the city be heated to sixty-eight degrees Fahrenheit at all times. Changes to it in the ensuing years sought not only to protect New Yorkers' health but reflected pressures in New York's fuel economy, which experienced periods of shortages and a transition from anthracite coal to oil that started between the two World Wars. Consequently, the standardization of sixty-eight degrees Fahrenheit reflected shifting assumptions about health and the "right to heat" for different communities over time, and the practical need to ensure affordable fuel for the city's population. The Heat Code, accordingly, played a crucial role in shaping energy consumption in New York and helping to formulate an "invisible energy policy"-that is, a policy developed in non-energy fields, such as health and housing, that alters energy usage in important but inconspicuous ways, with important consequences for the environment and for social justice.

Development of a fixative protocol using formaldehyde and gluteraldehyde for preservation of microbial art on agar plates.

AIMS: Agar art bridges the gap between science and art using microbes instead of paint. Afterwards, the art can change in response to microbial fluctuation, meaning preservation of the original art is essential. Here, formaldehyde and glutaraldehyde were investigated as preservatives, involving techniques used in healthcare settings to preserve samples. METHODS AND RESULTS: Formaldehyde was tested at 1.0%, 2.0% and 3.7%, w/v, whereas glutaraldehyde was tested at 1% and 2.5%, w/v. Both compounds and respective concentrations were tested for different time periods. Escherichia coli, Serratia marcescens, Staphlococcus aureus and Micrococcus luteus were used as bacteria for "drawing" the works of art. The effectiveness of fixation was determined using integrated densities and visual assessment. Initially, both compounds showed potential promise, albeit with a loss of bacteria. Ser. marcescens was prone to colour changes and glutaraldehyde caused discolouration of agar and bacteria. These could be caused by a pH decrease in the agar, due to residual free aldehyde groups. Reduction of this was tested using 300 mM sodium metabisulfite to neutralize excess aldehydes. This initially led to reduced bacterial loss and avoided colour changes, however measurements 24 h post-fixation showed colour loss to some bacterial clusters. CONCLUSIONS: Here, at least 2% formaldehyde for a short fixation period, typically 1 min, depending on the species, was most promising for the preservation of art. Given the success of this with different bacteria, it would make a good starting combination for anyone trying to fix agar art, although methodology refinement may be needed for optimisation depending on the bacterial species used. SIGNIFICANCE AND IMPACT OF STUDY: This study shows, for the first time, successful fixation and preservation of different bacterial species on agar. The impact of this is to preserve agar art while making it safe and non-infective to those in contact with the microbial art.

A missed opportunity in the ED: Palliative care consult delays during inpatient admission.

STUDY HYPOTHESIS: Although Emergency Medicine has recognized Palliative Care (PC) as an important aspect of Emergency Medicine, the importance of integrating palliative care into standard practice is underscored by the data that many patients qualify for PC but are not utilizing this part of medicine. We believe Emergency Medicine should integrate Palliative Care as our responsibility and not rely on our colleagues. To support our statement, we undertook an examination of patients who died while inpatient to identify whether they were appropriately receiving palliative care consults. We hypothesized that palliative care is under-utilized for patients during these admissions. DESIGN, SETTING, AND PARTICIPANT: Retrospective chart review from 2015 to 2018 of inpatient deaths using an Emergency Medicine Palliative Care Screening Tool to determine qualification for Palliative Care. Setting is John Hopkins Hospital. Participants were age 18 and over; who died during their inpatient admission. MAIN OUTCOMES AND MEASURES: Percentage of patients who qualified for palliative care via the screening tool versus percentage of patients who had palliative care involvement. RESULTS: The final study sample included 428 patients who died inpatient in the hospital between January 2015 and December 2018. The analysis used a Palliative Care Screening Tool to determine which patients would have qualified for palliative care. Analysis demonstrates that 66% of patients qualified for palliative care, whereas only 27% received it. CONCLUSION AND RELEVANCE: The data reflects the percentage of patients who qualified for Palliative Care compared to the definite number of patients who received palliative care. The discrepancy in the percentages support our statement Emergency Medicine should take the lead on initiating palliative care for qualifying patients.

Compassion fatigue in pediatric hematology, oncology, and bone marrow transplant healthcare providers: An integrative review.

OBJECTIVE: Compassion fatigue (CF), which includes burnout and secondary traumatic stress, is highly prevalent among healthcare providers (HCPs). Ultimately, if left untreated, CF is often associated with absenteeism, decreased work performance, poor job satisfaction, and providers leaving their positions. To identify risk factors for developing CF and interventions to combat it in pediatric hematology, oncology, and bone marrow transplant (PHOB) HCPs. METHODS: An integrative review was conducted. Controlled vocabulary relevant to neoplasms, CF, pediatrics, and HCPs was used to search PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and Web of Science MEDLINE. Inclusion criteria were the following: English language and PHOB population. Exclusion criteria were the following: did not address question, wrong study population, mixed study population where PHOB HCPs were only part of the population, articles about moral distress as this is a similar but not the same topic as CF, conference abstracts, and book chapters. RESULTS: A total of 16 articles were reviewed: 3 qualitative, 6 quantitative, 3 mixed methods, and 4 non research. Three themes were explored: (1) high-risk populations for developing CF, (2) sources of stress in PHOB HCPs, and (3) workplace interventions to decrease CF. SIGNIFICANCE OF RESULTS: PHOB HCPs are at high risk of developing CF due to high morbidity and mortality in their patient population. Various interventions, including the use of a clinical support nurse, debriefing, support groups, respite rooms, and retreats, have varying degrees of efficacy to decrease CF in this population.

Community-dwelling older adults who are low-income and disabled weathering financial challenges.

Despite interventions aiming to improve outcomes among older adults experiencing financial challenges, the challenges and strategies employed to handle them are poorly understood. This study examined the experiences of financial challenges among low-income adults aged ≥65 years. Eleven semi-structured interviews were analyzed using thematic analyses. An overarching theme was "I guess it balances", capturing attempts to maintain hope and proactively address challenges despite stress, uncertainty and limitations. Balancing was demonstrated within four domains, including cognitive bandwidth ("think a lot" versus "I don't dwell on that"), emotional experience ("depressing" versus "be thankful"), learned resilience ("that was a shock" versus "there's always a way"), and meeting daily needs ("we learned to do without" versus "take a dollar and stretch it"). Participants described being weathered by challenges and using predominately high-effort coping strategies to weather the challenges. These findings call for strengthening the safety net for older adults facing financial challenges.

Follow-up Care in Inflammatory Bowel Disease: An Integrative Review.

Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract and is associated with high risks for complications, surgeries, and frequent hospitalizations. Approximately one in four inflammatory bowel disease patients are readmitted to the hospital within 90 days of discharge in the United States. Although existing literature showed a timely clinic appointment with gastroenterologists is a protective factor for disease flare-ups and hospitalizations, the follow-up appointments were found to be either lacking or significantly delayed. Further, evidence-based guidelines in timely inflammatory bowel disease care are lacking. Thus, this integrative review examined current literature to identify effective strategies for achieving timely clinic appointments with gastroenterologists in inflammatory bowel disease. A comprehensive search of three electronic databases (PubMed, Embase, and Cumulative Index of Nursing and Allied Health Literature [CINAHL] Plus) was conducted from January 2009 to September 2019 using the key terms: inflammatory bowel disease, ulcerative colitis, Crohn's disease, appointments, and time to appointment. Nine articles met the inclusion criteria. The main interventions for timely inflammatory bowel disease care included (i) clinic-wide scheduling protocols, (ii) a dedicated healthcare team, (iii) efficient referral process, (iv) appointment management based on disease acuity and severity, and (v) addressing shortage of inflammatory bowel disease clinicians. Further research is needed to quantify the magnitude of timely inflammatory bowel disease care interventions with controls and evaluate the efficacy with a head-to-head trial. Through timely referrals, evaluations, and treatments, these quality improvement endeavors will ultimately improve quality of care and contribute to reduction in preventable hospitalizations and associated healthcare costs from delayed outpatient inflammatory bowel disease care.

Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus.

Status epilepticus is defined as a state of unrelenting seizure activity. Generalized convulsive status epilepticus is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with status epilepticus were unresponsive to benzodiazepine treatment, and critically, that the duration of status epilepticus at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of status epilepticus. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of status epilepticus-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on status epilepticus-like activity, while a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent status epilepticus-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during status epilepticus-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the status epilepticus-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant status epilepticus, with relevance to how this life-threatening condition should be managed in the clinic.

That was a game changer: clinical impact of an emergency department-based palliative care communication skills training workshop.

OBJECTIVE: To explore the impact of an adapted goals-of-care communications skills workshop created for ED physicians from the physicians' perspective. METHODS: Semi-structured, one-on-one audio-recorded interviews lasting 30-60 min were conducted with twelve physicians who had completed the training workshop. Interviews explored the experience of undertaking the workshop, its impact on their clinical practice and their ability to teach new skills to other clinicians using learnt techniques. Descriptive content analysis was performed on interview transcripts. RESULTS: Participants reported positive experiences of the workshop. The analysis identified four main themes and ten subthemes dealing with workshop content and its impact on subsequent ED-based clinical practice. There were: 1) value and future improvements for the course; 2) value of the course to practice; 3) value of the course for teaching residents and 4) barriers to application of learning. Specifically recommended components include the use of mnemonics, mechanisms to introduce difficult conversations and a positive feedback environment. Participant-recommended refinements to the workshop included emphasising urgency, replicating the chaotic ED environment and expanding content to include more ED-focused goals-of-care discussions. CONCLUSION: A short, focused training workshop directed at improving palliative care communication skills among ED clinicians appears to be welcomed and useful.

Social media and drug resistance in nursing training: Using a Twitterchat to develop an international community of practice for antimicrobial resistance.

AIMS AND OBJECTIVES: To assess the impact of a Twitterchat focusing on antimicrobial resistance and it is feasibility for integration within a nursing prelicensure research methods class. BACKGROUND: Antimicrobial resistance is one of the greatest threats to global health and food security. Consequently, developing a global approach with large outreach is critical. Twitter, as a popular social media platform, is useful for creating communities of practice and communities of interest. DESIGN: A case study design using a Twitterchat is a hosted, convened and focussed discussion on a particular topic using a discrete hashtag. METHOD: Using a standardised protocol, a Twitterchat was undertaken over a 24-hr period and digital metrics assessed at 72 hr. A summary of impact was undertaken using an online tool provided by Union Metrics (https://unionmetrics.com/). CONCLUSIONS: At 72 hr, 2,632,762 accounts were reached and over 10 million impressions achieved. Twitterchats can be useful in creating awareness and fostering a community of interest and demonstrating the role of nurses in thought leadership. A formalised research study will draw on this case study to evaluate the impact on the Twitter participants and nursing students. RELEVANCE TO CLINICAL PRACTICE: Social media are an accessible and useful tool to harness focus and attention on clinical issues with global relevance. Demonstrating the utility and leverage to nursing students is important in increasing their understanding of the importance of communication and diffusion of information.

Pain in low-income older women with disabilities: a qualitative descriptive study.

The purpose of this qualitative study was to identify how low-income older women with disabilities perceive pain, pain management, and communication with healthcare providers. We interviewed 26 low-income women (average age 75 years; SD 7.0), eliciting the following overarching themes: "Invisibility of Pain: Unnoticed or Undetected," "Escalating Pain Leads to Help Seeking," "Communication with Healthcare Providers and Outcomes," "Pain Management Facilitates Function and Accomplishment," and "The Intersection of Pain, Disability, and Depressive Symptoms." Study findings support the ways in which behavior changes from pain can impede pain management.

Use of fetal fibronectin testing in women transferred for threatened preterm labour in remote far north Queensland.

BACKGROUND: Threatened preterm labour is a common reason for medical transfer from remote communities; however, many transferred women do not deliver preterm. A tool for prediction of preterm birth such as fetal fibronectin may reduce transfers and related social and economic costs. AIM: To review the use of fetal fibronectin testing in women transferred for threatened preterm labour from Cape York to Cairns Hospital between 2011 and 2015 and determine the role testing could play in reducing transfers and associated costs. MATERIALS/METHODS: Records from the Royal Flying Doctor Service and Cairns Hospital were accessed. Women transferred solely for threatened preterm labour were included in the study. Fetal fibronectin testing, hospital admission, outpatient stays and birth outcome data were collated and analysed. Costs were assigned using the National Hospital Cost Data Collection, round 19. RESULTS: Forty-seven women were included in the study; however, only 20 underwent fetal fibronectin testing. Transfer of 30 women who had either a negative test or were not tested but delivered at term resulted in 41 inpatient nights and 443 excess outpatient nights, costing an estimated AU$57 408. Aeromedical transfers were estimated to cost a further $151 500. CONCLUSION: Adherence to clinical guidelines and greater availability and use of fetal fibronectin testing in Cape York have the potential to reduce aeromedical transfers for threatened preterm labour. Substantial inpatient and excess outpatient stays could be avoided with associated reduction in health system and social costs. Strategies to improve adherence to guidelines and increase access to testing are required.

Neuronal Chloride Regulation via KCC2 Is Modulated through a GABAB Receptor Protein Complex.

GABAB receptors are G-protein-coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signaling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABAA receptor in mature neurons. Using biochemical, molecular, and functional studies in rodent hippocampus, we show that activation of GABAB receptors results in a decrease in KCC2 function, which is associated with a reduction in the protein at the cell surface. These findings reveal a novel "crosstalk" between the GABA receptor systems, which can be recruited under conditions of high GABA release and which could be important for the regulation of inhibitory synaptic transmission.SIGNIFICANCE STATEMENT Synaptic inhibition in the brain is mediated by ionotropic GABAA receptors (GABAARs) and metabotropic GABAB receptors (GABABRs). To fully appreciate the function and regulation of these neurotransmitter receptors, we must understand their interactions with other proteins. We describe a novel association between the GABABR and the potassium-chloride cotransporter protein, KCC2. This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. We demonstrate that GABABR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABAAR. Our data therefore support an additional mechanism by which GABABRs are able to modulate fast synaptic inhibition.

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography.

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC50 2.4-7.0 nM, Emax 43%-73%), displaying binding selectivity for M1 mAChRs (Kd = 1.5 nM) that was conserved across species (native tissue Kd = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a ß-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

Emergency department staff priorities for improving palliative care provision for older people: A qualitative study.

BACKGROUND: Emergency department-based palliative care services are increasing, but research to develop these services rarely includes input from emergency clinicians, jeopardizing the effectiveness of subsequent palliative care interventions. AIM: To collaboratively identify with emergency clinicians' improvement priorities for emergency department-based palliative care for older people. DESIGN: This was one component of an experience-based co-design project, conducted using semi-structured interviews and feedback sessions. SETTING/PARTICIPANTS: In-depth interviews with 15 emergency clinicians (nurses and doctors) at a large teaching hospital emergency department in the United Kingdom exploring experiences of palliative care delivery for older people. A thematic analysis identified core challenges that were presented to 64 clinicians over five feedback sessions, validating interview findings, and identifying shared priorities for improving palliative care delivery. RESULTS: Eight challenges emerged: patient age; access to information; communication with patients, family members, and clinicians; understanding of palliative care; role uncertainty; complex systems and processes; time constraints; and limited training and education. Through feedback sessions, clinicians selected four challenges as improvement priorities: time constraints; communication and information; systems and processes; and understanding of palliative care. As resulting improvement plans evolved, "training and education" replaced "time constraints" as a priority. CONCLUSION: Clinician priorities for improving emergency department-based palliative care were identified through collaborative, iterative processes. Though generally aware of older palliative patients' needs, clinicians struggled to provide high-quality care due to a range of complex factors. Further research should identify whether priorities are shared across other emergency departments, and develop, implement, and evaluate strategies developed by clinicians.

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis.

Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.

An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis.

Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3-20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30-240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists.