The lipid flippase ATP8A1 regulates the recruitment of ARF effectors to the trans-Golgi Network.

Formation of transport vesicles requires the coordinate activity of the coating machinery that selects cargo into the nascent vesicle and the membrane bending machinery that imparts curvature to the forming bud. Vesicle coating at the trans-Golgi Network (TGN) involves AP1, GGA2 and clathrin, which are recruited to membranes by activated ARF GTPases. The ARF activation at the TGN is mediated by the BIG1 and BIG2 guanine nucleotide exchange factors (GEFs). Membrane deformation at the TGN has been shown to be mediated by lipid flippases, including ATP8A1, that moves phospholipids from the inner to the outer leaflet of the TGN membrane. We probed a possible coupling between the coating and deformation machineries by testing for an interaction between BIG1, BIG2 and ATP8A1, and by assessing whether such an interaction may influence coating efficiency. Herein, we document that BIG1 and BIG2 co-localize with ATP8A1 in both, static and highly mobile TGN elements, and that BIG1 and BIG2 bind ATP8A1. We show that the interaction involves the catalytic Sec7 domain of the GEFs and the cytosolic C-terminal tail of ATP8A1. Moreover, we report that the expression of ATP8A1, but not ATP8A1 lacking the GEF-binding cytosolic tail, increases the generation of activated ARFs at the TGN and increases the selective recruitment of AP1, GGA2 and clathrin to TGN membranes. This occurs without increasing BIG1 or BIG2 levels at the TGN, suggesting that the binding of the ATP8A1 flippase tail to the Sec7 domain of BIG1/BIG2 increases their catalytic activity. Our results support a model in which a flippase component of the deformation machinery impacts the activity of the GEF component of the coating machinery.

Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.

The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes. Mouse model with conditional deletion of GluD1 from excitatory neurons in the corticolimbic regions was utilized. GluD1 loss led to overactive Akt-mTOR pathway, higher p62 and a lower LC3-II/LC3-I ratio in the somatosensory cortex suggesting reduced autophagy. Excitatory elements were increased in number but had immature phenotype based on puncta size, lower AMPA subunit GluA1 expression and impaired development switch from predominantly GluN2B to mixed GluN2A/GluN2B subunit expression. Overactive Akt-mTOR signaling and impaired autophagy was also observed in dorsal striatum upon conditional ablation of GluD1 and in the prefrontal cortex and hippocampus in constitutive knockout. Finally, cognitive deficits in novel object recognition test and fear conditioning were observed in mice with conditional ablation of GluD1 from the corticolimbic regions. Together, these results demonstrate a novel function of GluD1 in the regulation of autophagy pathway which may underlie autism phenotypes and is relevant to the genetic association of GluD1 coding, GRID1 gene with autism and other developmental disorders.

The ARF guanine nucleotide exchange factor GBF1 is targeted to Golgi membranes through a PIP-binding domain.

ADP-ribosylation factors (ARF) GTPases are activated by guanine nucleotide exchange factors (GEFs) to support cellular homeostasis. Key to understanding spatio-temporal regulation of ARF signaling is the mechanism of GEF recruitment to membranes. Small GEFs are recruited through phosphoinositide (PIP) binding by a pleckstrin homology (PH) domain downstream from the catalytic Sec7 domain (Sec7d). The large GEFs lack PH domains, and their recruitment mechanisms are poorly understood. We probed Golgi recruitment of GBF1, a GEF catalyzing ARF activation required for Golgi homeostasis. We show that the homology downstream of Sec7d-1 (HDS1) regulates Golgi recruitment of GBF1. We document that GBF1 binds phosphoinositides, preferentially PI3P, PI4P and PI(4,5)P2, and that lipid binding requires the HDS1 domain. Mutations within HDS1 that reduce GBF1 binding to specific PIPs in vitro inhibit GBF1 targeting to Golgi membranes in cells. Our data imply that HDS1 and PH domains are functionally analogous in that each uses lipid-based membrane information to regulate GEF recruitment. Lipid-based recruitment of GBF1 extends the paradigm of lipid regulation to small and large GEFs and suggests that lipid-based mechanisms evolved early during GEF diversification. This article has an associated First Person interview with the first author of the paper.

Mobile Health Application and e-Health Literacy: Opportunities and Concerns for Cancer Patients and Caregivers.

Health literacy is critical for cancer patients as they must understand complex procedures or treatment options. Caregivers' health literacy also plays a crucial role in caring for cancer patients. Low health literacy is associated with low adherence to medications, poor health status, and increased health care costs. There is a growing interest in the use of mobile health applications (apps) to improve health literacy. Mobile health apps can empower underserved cancer patients and their caregivers by providing features or functionalities to enhance interactive patient-provider communication and to understand medical information more readily. Despite the potentiality of improving health literacy through mobile health apps, there exist several related concerns: no equal access to mobile technology, no familiarity or knowledge of using mobile health apps, and privacy and security concerns. These elements should be taken into account for health policy making and mobile apps design and development. Importantly, mobile apps should be developed with the goal of achieving a high range of user access by considering all health literacy level and various cultural and linguistic needs.

Provision of Rehabilitation Services in Residential Care Facilities: Evidence From a National Survey.

OBJECTIVE: To examine the association between organizational factors and provision of rehabilitation services that include physical therapy (PT) and occupational therapy (OT) in residential care facilities (RCFs) in the United States. DESIGN: A cross-sectional, observational study conducted using a national sample from the 2010 National Survey of Residential Care Facilities conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics. SETTINGS: U.S. RCFs. PARTICIPANTS: RCFs (N=2302; weighted sample, 31,134 RCFs). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The association between characteristics of the facilities, director and staff, and residents, and provision of PT and OT services was assessed using multivariate logistic regression analyses. RESULTS: Among all RCFs in the United States, 43.9% provided PT and 40.0% provided OT. Medicaid-certified RCFs, larger-sized RCFs, RCFs with a licensed director, RCFs that used volunteers, and RCFs with higher personal care aide hours per patient per day were more likely to provide both PT and OT, while private, for-profit RCFs were less likely to provide PT and OT. RCFs with a higher percentage of white residents were more likely to provide PT, while RCFs with chain affiliation were more likely to provide OT. CONCLUSIONS: Less than half of the RCFs in the United States provide PT and OT, and this provision of therapy services is associated with organizational characteristics of the facilities. Future research should explore the effectiveness of rehabilitation services in RCFs on residents' health outcomes.

Oligomerization of the Sec7 domain Arf guanine nucleotide exchange factor GBF1 is dispensable for Golgi localization and function but regulates degradation.

Members of the large Sec7 domain-containing Arf guanine nucleotide exchange factor (GEF) family have been shown to dimerize through their NH2-terminal dimerization and cyclophilin binding (DCB) and homology upstream of Sec7 (HUS) domains. However, the importance of dimerization in GEF localization and function has not been assessed. We generated a GBF1 mutant (91/130) in which two residues required for oligomerization (K91 and E130 within the DCB domain) were replaced with A and assessed the effects of these mutations on GBF1 localization and cellular functions. We show that 91/130 is compromised in oligomerization but that it targets to the Golgi in a manner indistinguishable from wild-type GBF1 and that it rapidly exchanges between the cytosolic and membrane-bound pools. The 91/130 mutant appears active as it integrates within the functional network at the Golgi, supports Arf activation and COPI recruitment, and sustains Golgi homeostasis and cargo secretion when provided as a sole copy of functional GBF1 in cells. In addition, like wild-type GBF1, the 91/130 mutant supports poliovirus RNA replication, a process requiring GBF1 but believed to be independent of GBF1 catalytic activity. However, oligomerization appears to stabilize GBF1 in cells, and the 91/130 mutant is degraded faster than the wild-type GBF1. Our data support a model in which oligomerization is not a key regulator of GBF1 activity but impacts its function by regulating the cellular levels of GBF1.

Paid sick leave is associated with fewer ED visits among US private sector working adults.

CONTEXT: The United States (US) is the only developed country that does not guarantee short-term or longer-term paid sick leave. OBJECTIVE: This study used a multiyear nationally representative database to examine the association between availability of paid sick leave and frequency of emergency department (ED) use among US private sector employees. STUDY SAMPLE: We used the National Health Interview Survey data (2012-2014). The final study sample consists of 42,460 US adults between 18 and 64years of age and working in nongovernmental private sector. RESULTS: Our results suggest that availability of paid sick leave is significantly associated with lower likelihood of ED use, for both moderate (1-3 times/year) and repeated users (4 or more times/year). After controlling for confounding factors, respondents with paid sick leave are 14% less likely to be moderate ED users (adjusted odds ratio, 0.86; 95% CI, 0.79-0.93) and 32% less likely to be repeated ED users (adjusted odds ratio, 0.68; 95% CI, 0.50-0.91). DISCUSSION: Although expansion of health insurance coverage under the Affordable Care Act has not been shown to reduce utilization of high cost health care services such as the ED, our study suggests other factors such as the availability of paid sick leave may do so, by allowing patients to seek care through other more cost-effective mechanisms (eg, primary care providers). To reduce ED utilization, health policymakers should consider alternative reforms including paid sick leave.

Assessing Potential Conservation and Restoration Areas of Freshwater Fish Fauna in the Indian River Basins.

Conservation efforts globally are skewed toward terrestrial ecosystems. To date, conservation of aquatic ecosystems, in particular fish fauna, is largely neglected. We provide a country-wide assessment of Indian river ecosystems in order to identify and prioritize areas for protection and restoration of freshwater fish fauna. Using various biodiversity and anthropogenic attributes, coupled with tools of ecological modeling, we delineated areas for fish fauna conservation and restoration in the 20 major river basins of India. To do this, we used prioritization analyses and reserve selection algorithms to derive conservation value index (CVI) and vulnerability index (VI) of the river basins. CVI was estimated using endemicity, rarity, conservation value, and taxonomic singularity, while VI was estimated using a disturbance index derived from percent geographic area of the basin under human settlements, human population density, predominant land use, and total number of exotic fish species in each basin. The two indices, CVI and VI, were converted into geo-referenced maps, and each map was super-imposed onto species richness and forest cover maps, respectively. After superimposition, areas with high CVI and low VI shade intensities were delineated for conservation, while areas with high CVI and high VI shade intensities were demarcated for restoration. In view of the importance of freshwater fish for human livelihoods and consumption, and ecosystems of India's rivers, we call for urgent attention to the conservation of their fish fauna along with restoration of their degraded habitats.

Use of Mobile Health Applications for Health-Seeking Behavior Among US Adults.

This study explores the use of mobile health applications (mHealth apps) on smartphones or tablets for health-seeking behavior among US adults. Data was obtained from cycle 4 of the 4th edition of the Health Information National Trends Survey (HINTS 4). Weighted multivariate logistic regression models examined predictors of 1) having mHealth apps, 2) usefulness of mHealth apps in achieving health behavior goals, 3) helpfulness in medical care decision-making, and 4) asking a physician new questions or seeking a second opinion. Using the Andersen Model of health services utilization, independent variables of interest were grouped under predisposing factors (age, gender, race, ethnicity, and marital status), enabling factors (education, employment, income, regular provider, health insurance, and rural/urban location of residence), and need factors (general health, confidence in their ability to take care of health, Body Mass Index, smoking status, and number of comorbidities). In a national sample of adults who had smartphones or tablets, 36 % had mHealth apps on their devices. Among those with apps, 60 % reported the usefulness of mHealth apps in achieving health behavior goals, 35 % reported their helpfulness for medical care decision-making, and 38 % reported their usefulness in asking their physicians new questions or seeking a second opinion. The multivariate models revealed that respondents were more likely to have mHealth apps if they had more education, health insurance, were confident in their ability to take good care of themselves, or had comorbidities, and were less likely to have them if they were older, had higher income, or lived in rural areas. In terms of usefulness of mHealth apps, those who were older and had higher income were less likely to report their usefulness in achieving health behavior goals. Those who were older, African American, and had confidence in their ability to take care of their health were more likely to respond that the mHealth apps were helpful in making a medical care decision and asking their physicians new questions or for a second opinion. Potentially, mHealth apps may reduce the burden on primary care, reduce costs, and improve the quality of care. However, several personal-level factors were associated with having mHealth apps and their perceived helpfulness among their users, indicating a multidimensional digital divide in the population of US adults.

A bright future: innovation transforming public health in Chicago.

Big cities continue to be centers for innovative solutions and services. Governments are quickly identifying opportunities to take advantage of this energy and revolutionize the means by which they deliver services to the public. The governmental public health sector is rapidly evolving in this respect, and Chicago is an emerging example of some of the changes to come. Governments are gradually adopting innovative informatics and big data tools and strategies, led by pioneering jurisdictions that are piecing together the standards, policy frameworks, and leadership structures fundamental to effective analytics use. They give an enticing glimpse of the technology's potential and a sense of the challenges that stand in the way. This is a rapidly evolving environment, and cities can work with partners to capitalize on the innovative energies of civic tech communities, health care systems, and emerging markets to introduce new methods to solve old problems.

Health department use of social media to identify foodborne illness - Chicago, Illinois, 2013-2014.

An estimated 55 million to 105 million persons in the United States experience acute gastroenteritis caused by foodborne illness each year, resulting in costs of $2-$4 billion annually. Many persons do not seek treatment, resulting in underreporting of the actual number of cases and cost of the illnesses. To prevent foodborne illness, local health departments nationwide license and inspect restaurants and track and respond to foodborne illness complaints. New technology might allow health departments to engage with the public to improve foodborne illness surveillance. For example, the New York City Department of Health and Mental Hygiene examined restaurant reviews from an online review website to identify foodborne illness complaints. On March 23, 2013, the Chicago Department of Public Health (CDPH) and its civic partners launched FoodBorne Chicago, a website (https://www.foodbornechicago.org) aimed at improving food safety in Chicago by identifying and responding to complaints on Twitter about possible foodborne illnesses. In 10 months, project staff members responded to 270 Twitter messages (tweets) and provided links to the FoodBorne Chicago complaint form. A total of 193 complaints of possible foodborne illness were submitted through FoodBorne Chicago, and 133 restaurants in the city were inspected. Inspection reports indicated 21 (15.8%) restaurants failed inspection, and 33 (24.8%) passed with conditions indicating critical or serious violations. Eight tweets and 19 complaint forms to FoodBorne Chicago described seeking medical treatment. Collaboration between public health professionals and the public via social media might improve foodborne illness surveillance and response. CDPH is working to disseminate FoodBorne Chicago via freely available open source software.

Supplemental oxygen requirement after tonsillectomy in children >3 years of age.

INTRODUCTION: The indications for postoperative admission after tonsillectomy in children >3 years of age are less well defined than for children <3 years old, and typically include severe obstructive sleep apnea (OSA), obesity, comorbidities, or behavioral factors. Inpatient care after tonsillectomy typically consists of respiratory monitoring and support, as respiratory compromise is the most common complication after pediatric tonsillectomy. We aim to evaluate risk factors associated with postoperative oxygen supplementation and to identify high risk populations within the admitted population who use additional resources or require additional interventions. METHODS: Retrospective chart review of patients between the ages of 3 and 18 years old who underwent tonsillectomy by four surgeons at a tertiary care children's hospital was performed. Data including demographics, comorbidities, surgical intervention, pre- and postoperative AHI, admission, postoperative oxygen requirement, and postoperative complications was collected and analyzed. RESULTS: There were 401 patients included in the analysis. Of the patients in this study, 65.59% were male, 43.39% were Latino, and 53.87% were ages 3 to 7. Of the 397 patients with a record for supplemental oxygen, 36 (9.07%) received supplemental oxygen. The LASSO regression odds ratios (OR) found to be important for modeling supplemental oxygen use (in decreasing order of magnitude) are BMI ≥35 (OR = 2.30), pre-op AHI >30 (OR = 2.28), gastrointestinal comorbidities (OR = 2.20), musculoskeletal comorbidities (OR = 1.91), cardiac comorbidities (OR = 1.20), pulmonary comorbidities (OR = 1.14), and BMI 30 to <35 (OR = 1.07). Female gender was found to be negatively associated with risk of supplemental oxygen use (OR = 0.84). Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement. CONCLUSION: BMI ≥30, pre-op AHI >30, male gender, and gastrointestinal, musculoskeletal, cardiac, and pulmonary comorbidities are all associated with postoperative supplemental oxygen use. Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement.

Public health and social entrepreneurs as activators of equitable health ecosystems.

OBJECTIVES: To describe approaches that public health and social entrepreneurs take to address health equity, and identify strategies for equitable collaborations with these entrepreneurs. METHODS: We leveraged data from semi-structured interviews, conducted August to October 2022, with 20 public health and social entrepreneurs who focus on drivers of health and health equity. Two researchers employed content analysis, guided by a prior framework. RESULTS: To support health equity, public health and social entrepreneurs: center equity, critique biases, innovate for inclusion, engage translational expertise, catalyze capacity, and activate equitable systems. Equitable collaborations are supported by re-examining roles, de-conflicting organizational barriers, prioritizing representation, mitigating bias in generating evidence, and employing equitable capital. CONCLUSIONS: Public health and social entrepreneurs can uplift equity across health service design and delivery. More equitable collaborations can advance this work.

Effect of ifenprodil on GluN1/GluN2B N-methyl-D-aspartate receptor gating.

Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steady-state currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.

Glutamate delta-1 receptor regulates oligodendrocyte progenitor cell differentiation and myelination in normal and demyelinating conditions.

In this study, we investigated the role of glutamate delta 1 receptor (GluD1) in oligodendrocyte progenitor cell (OPC)-mediated myelination during basal (development) and pathophysiological (cuprizone-induced demyelination) conditions. Initially, we sought to determine the expression pattern of GluD1 in OPCs and found a significant colocalization of GluD1 puncta with neuron-glial antigen 2 (NG2, OPC marker) in the motor cortex and dorsal striatum. Importantly, we found that the ablation of GluD1 led to an increase in the number of myelin-associated glycoprotein (MAG+) cells in the corpus callosum and motor cortex at P40 without affecting the number of NG2+ OPCs, suggesting that GluD1 loss selectively facilitates OPC differentiation rather than proliferation. Further, deletion of GluD1 enhanced myelination in the corpus callosum and motor cortex, as indicated by increased myelin basic protein (MBP) staining at P40, suggesting that GluD1 may play an essential role in the developmental regulation of myelination during the critical window period. In contrast, in cuprizone-induced demyelination, we observed reduced MBP staining in the corpus callosum of GluD1 KO mice. Furthermore, cuprizone-fed GluD1 KO mice showed more robust motor deficits. Collectively, our results demonstrate that GluD1 plays a critical role in OPC regulation and myelination in normal and demyelinating conditions.