A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development.

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, given that EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knock-in mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly and specifically blocked. We found that the tyrosine kinase activity of EphBs was required for axon guidance in vivo. In contrast, EphB-mediated synaptogenesis occurred normally when the kinase activity of EphBs was inhibited, suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, our data indicate that EphBs control axon guidance and synaptogenesis by distinct mechanisms and provide a new mouse model for dissecting EphB function in development and disease

A Chemical Genetic Approach Reveals Distinct Mechanisms of EphB Signaling During Brain Development

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, as EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knockin mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly, and specifically blocked. Using these mice we demonstrate that the tyrosine kinase activity of EphBs is required for axon guidance in vivo. By contrast, EphB-mediated synaptogenesis occurs normally when the kinase activity of EphBs is inhibited suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, these experiments reveal that EphBs control axon guidance and synaptogenesis by distinct mechanisms, and provide a new mouse model for dissecting EphB function in development and disease

Diagnostic and clinical experience of patients with pantothenate kinase-associated neurodegeneration

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). OBJECTIVES: To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. METHODS: Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. RESULTS: The analyses included data from 39 patients. Mean age at PKAN symptom onset (P = 0.0007), initial MRI (P = 0.0150), and genetic testing (P = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7-15.2 years; P = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0-90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems (P-values \u3c 0.0500). Over half (56.8%) of caregivers experienced a change in employment because of caregiving. The percentage of patients requiring full-time caregiving increased across the PKAN severity spectrum (range, 11.1-100%; P = 0.0021). CONCLUSIONS: PKAN diagnosis was often delayed, most probably due to low awareness. Considerable burden of functional impairment and high healthcare utilization were found across the PKAN severity spectrum

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

ABSTRACT Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4 + T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. IMPORTANCE Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses

Diagnosis and management of functional tic-like phenomena

Over the past 3 years, a global phenomenon has emerged characterized by the sudden onset and frequently rapid escalation of tics and tic-like movements and phonations. These symptoms have occurred not only in youth known to have tics or Tourette syndrome (TS), but also, and more notably, in youth with no prior history of tics. The Tourette Association of America (TAA) convened an international, multidisciplinary working group to better understand this apparent presentation of functional neurological disorder (FND) and its relationship to TS. Here, we review and summarize the literature relevant to distinguish the two, with recommendations to clinicians for diagnosis and management. Finally, we highlight areas for future emphasis and research

Racial-Ethnic Disparities in Acute Stroke Care in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study

Background-Racial-ethnic disparities in acute stroke care can contribute to inequality in stroke outcomes. We examined raceethnic disparities in acute stroke performance metrics in a voluntary stroke registry among Florida and Puerto Rico Get With the Guidelines-Stroke hospitals. Methods and Results-Seventy-five sites in the Florida Puerto Rico Stroke Registry (66 Florida and 9 Puerto Rico) recorded 58 864 ischemic stroke cases (2010-2014). Logistic regression models examined racial-ethnic differences in acute stroke performance measures and defect-free care (intravenous tissue plasminogen activator treatment, in-hospital antithrombotic therapy, deep vein thrombosis prophylaxis, discharge antithrombotic therapy, appropriate anticoagulation therapy, statin use, smoking cessation counseling) and temporal trends. Among ischemic stroke cases, 63% were non-Hispanic white (NHW), 18% were non-Hispanic black (NHB), 14% were Hispanic living in Florida, and 6% were Hispanic living in Puerto Rico. NHW patients were the oldest, followed by Hispanics, and NHBs. Defect-free care was greatest among NHBs (81%), followed by NHWs (79%) and Florida Hispanics (79%), then Puerto Rico Hispanics (57%) (P \u3c 0.0001). Puerto Rico Hispanics were less likely than Florida whites to meet any stroke care performance metric other than anticoagulation. Defect-free care improved for all groups during 2010-2014, but the disparity in Puerto Rico persisted (2010: NHWs=63%, NHBs=65%, Florida Hispanics=59%, Puerto Rico Hispanics=31%; 2014: NHWs=93%, NHBs=94%, Florida Hispanics=94%, Puerto Rico Hispanics=63%). Conclusions-Racial-ethnic/geographic disparities were observed for acute stroke care performance metrics. Adoption of a quality improvement program improved stroke care from 2010 to 2014 in Puerto Rico and all Florida racial-ethnic groups. However, stroke care quality delivered in Puerto Rico is lower than in Florida. Sustained support of evidence-based acute stroke quality improvement programs is required to improve stroke care and minimize racial-ethnic disparities, particularly in resource-strained Puerto Rico

SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium

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STX3 coimmunoprecipitates with Rho in vivo.

Co-IP results from (A) Rho-GFP/+ IS-enriched retinal lysates incubated with GFP-Trap agarose beads, (B) Rho-GFP-1D4/+ IS-enriched retinal lysates incubated with GFP-Trap agarose beads, (C) Rho-GFP/+ IS-enriched retinal lysates incubated with anti-1D4 IgG agarose beads, and (D) WT IS-enriched retinal lysates incubated with anti-1D4 IgG agarose beads. In all western blots, input lanes correspond to 2% (% vol/vol) of the starting lysate volume, unbound lanes correspond to 2% (% vol/vol) of lysate volume post bead incubation, and bound lanes correspond to half the total eluate from each co-IP. Antibodies/nanobodies used for immunodetection are listed to the right of each corresponding western blot scan. Molecular weight marker sizes are indicated in kDa. Black arrows mark the correct size bands when other bands are present on the scan. Red asterisks indicate mouse IgG bands. In (B), the red arrow indicates the endogenous Rho band and the green arrow indicates the Rho-GFP-1D4 band. co-IP, coimmunoprecipitation; IgG, immunoglobulin G; Rho, rhodopsin; STX3, syntaxin 3; WT, wild-type.</p

Tables containing numerical values corresponding to all graphical data that are presented in the figures.

Tables containing numerical values corresponding to all graphical data that are presented in the figures.</p