Cadherin superfamily members play a critical role in differential adhesion during neurodevelopment, and their disruption has been linked to several neurodevelopmental disorders. Mutations in ...protocadherin-19 (PCDH19), a member of the δ-protocadherin subfamily of cadherins, cause a unique form of epilepsy called PCDH19 clustering epilepsy. While PCDH19 and other non-clustered δ-protocadherins form multimers with other members of the cadherin superfamily to alter adhesiveness, the specific protein surfaces responsible for these interactions are unknown. Only portions of the PCDH19 extracellular domain structure had been solved previously. Here, we present a structure of the missing segment from zebrafish Protocadherin-19 (Pcdh19) and create a complete ectodomain model. This model shows the structural environment for 97% of disease-causing missense mutations and reveals two potential surfaces for intermolecular interactions that could modify Pcdh19's adhesive strength and specificity.
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•Generated a complete structural model of the Pcdh19 ectodomain•Mapped over 100 epilepsy-causing missense mutations onto the structural model•Identified two potential protein interaction sites•Evaluated regions of structural variation between non-clustered protocadherins
Cooper et al. report a complete model of the Protocadherin-19 ectodomain and provide insights into potential structural effects of over 100 epilepsy-causing mutations in this protein. Further analysis reveals potential regions relevant for protein interactions that may influence selective cell adhesion during neural development.
Non-clustered δ-protocadherins are homophilic cell adhesion molecules essential for the development of the vertebrate nervous system, as several are closely linked to neurodevelopmental disorders. ...Mutations in
(
) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations in
have been identified in patients with PCDH19-FE, about half of which are missense mutations in the adhesive extracellular domain. Neither the mechanism of homophilic adhesion by PCDH19, nor the biochemical effects of missense mutations are understood. Here we present a crystallographic structure of the minimal adhesive fragment of the zebrafish Pcdh19 extracellular domain. This structure reveals the adhesive interface for Pcdh19, which is broadly relevant to both non-clustered δ and clustered protocadherin subfamilies. In addition, we show that several PCDH19-FE missense mutations localize to the adhesive interface and abolish Pcdh19 adhesion in
assays, thus revealing the biochemical basis of their pathogenic effects during brain development.
STEMSEAS Cooper, Sharon K.; Lewis, Jonathan C.
Oceanography,
12/2017, Volume:
30, Issue:
4
Journal Article
Peer reviewed
Open access
The Science, Technology, Engineering, and Math Student Experiences Aboard Ships program began, as many inspiring ideas do, on the back of a napkin. Author Cooper has worked for many years for the ...International Ocean Discovery Program and its School of Rock, which provides teacher professional development workshops on the drillship JOIDES Resolution (JR). Author Lewis, an academic, is fortunate to have sailed twice as a School of Rock instructor on the JR and had been pondering since 2013 how undergraduates might be provided similar opportunities. Over coffee in Pittsburgh one day, they discussed the fact that the 19 ships of the University National Oceanographic Laboratories System often have repositioning transits as well, and these voyages frequently sail out of US ports without full science parties, meaning there are multiple available berths. They are well aware that the geosciences overall, and oceanography in particular, lack diversity, and these transits seemed like a perfect opportunity to address this issue in one small corner of our world.
Cell-cell recognition guides the assembly of the vertebrate brain during development. δ-Protocadherins comprise a family of neural adhesion molecules that are differentially expressed and have been ...implicated in a range of neurodevelopmental disorders. Here we show that the expression of δ-protocadherins partitions the zebrafish optic tectum into radial columns of neurons. Using in vivo two-photon imaging of bacterial artificial chromosome transgenic zebrafish, we show that pcdh19 is expressed in discrete columns of neurons, and that these columnar modules are derived from proliferative pcdh19(+) neuroepithelial precursors. Elimination of pcdh19 results in both a disruption of columnar organization and defects in visually guided behaviors. These results reveal a fundamental mechanism for organizing the developing nervous system: subdivision of the early neuroepithelium into precursors with distinct molecular identities guides the autonomous development of parallel neuronal units, organizing neural circuit formation and behavior.
Hepatocellular carcinoma (HCC) is increasing in the U.S. despite a decline in cancer overall. Latinos have higher rates of HCC than the general population according to the Surveillance, Epidemiology, ...and End Results (SEER) Program. Not included in SEER, Texas Latinos make up one-fifth of the U.S. Latino population. To determine whether HCC incidence differs among U.S. and Texas Latinos, this descriptive study compares HCC incidence from 1995 through 2006 among three Latino populations: U.S. SEER, Texas overall and a South Texas subset. To identify lines of prevention research, we compare prevalence of known HCC risk factors among these Latino groups.
Data were collected from the U.S. SEER Program, Texas Cancer Registry and Texas Department of State Health Services (TDSHS). Annual age-specific and age-adjusted HCC incidence rates, annual percent changes (APCs) and 95% confidence intervals were calculated as well as prevalence of obesity, diabetes, heavy alcohol use and cigarette smoking.
Of the three Latino groups compared, South Texas Latinos had the highest age-adjusted HCC incidence rates and SEER Latinos had the lowest (10.6/100,000 (10.1-11.1) and 7.5/100,000 (7.2-7.7), respectively). HCC incidence significantly increased over time (APCs>0) among Latinos in all three geographic groups. Between 1995 and 2006, there was an increase in obesity among all three populations, and obesity was highest among South Texas Latinos. Diabetes increased among U.S. Latinos, and Latino women in South Texas had significantly higher diabetes prevalence than U.S. Latino women. Cigarette smoking and heavy alcohol use were similar among groups.
The incidence of HCC among Latinos in South Texas is higher than elsewhere in the United States. Higher rates of HCC among Texas and South Texas Latinos may be associated with greater prevalence of obesity and diabetes, risk factors for HCC that are amenable to intervention.
To investigate the pre- to posttreatment changes in both posttraumatic stress disorder (PTSD) and persistent postconcussive symptoms (PPCSs).
We studied 257 active-duty patients with a history of ...mild traumatic brain injury (mTBI) who completed multidisciplinary outpatient treatment at Brooke Army Medical Center TBI Clinic from 2008 to 2013. This treatment program included cognitive rehabilitation; vestibular interventions; headache management; and integrated behavioral healthcare to address co-occurring psychiatric conditions such as PTSD, depression, and sleep disturbance.
A 1-group; preexperimental, pre- to posttreatment study.
The Neurobehavioral Symptom Inventory (NSI) was used to assess PPCSs, and the PTSD Checklist-Military Version (PCL-M) was used to asses PTSD symptoms.
Global PPCS resolution (mean NSI: 35.0 pre vs 23.8 post; P < .0001; d = 0.72) and PTSD symptom resolution (mean PCL-M: 43.2 pre vs 37.7 post; P < .0001; d = 0.34) were statistically significant. Compared with those with only mTBI, patients with mTBI and PTSD reported greater global PPCS impairment both pretreatment (mean NSI: 48.7 vs 27.9; P < .0001) and posttreatment (mean NSI: 36.2 vs 17.4; P < .0001). After adjusting for pretreatment NSI scores, patients with comorbid PTSD reported poorer PPCS resolution than those with mTBI alone (mean NSI: 27.9 pre vs 21.7 post; P = .0009).
We found a reduction in both self-reported PPCSs and PTSD symptoms; however, future studies are needed to identify specific components of care associated with symptom reduction.
Abstract
Quartz nucleation normally requires harsh conditions; for instance, hydrothermal processes at 200–300 °C and 15–100 bar, where the high growth rate precludes selective formation of ...nanometer-sized quartz. Under ambient conditions, even quartz growth is considered to occur exceedingly slowly, requiring yearly timescales. Here we show that nanoquartz of size 1–5 nm can be nucleated from microemulsions under ambient conditions within 2 days. The nanoquartz particles are grown and annealed under mild hydrothermal conditions of 175 °C and autogenic pressure. This enables nanoquartz of size <10 nm and controllable structure to be obtained exclusively. Surface defects play a key role in determining the catalytic properties of the nanoquartz. Consequently, a similar two-stage microemulsion-hydrothermal synthesis strategy could provide significant benefits in optimizing nanocrystal catalysts.
BackgroundAlthough migrant and seasonal farmworkers are highly vulnerable to ambient heat because of their working conditions, heat effects in this population have been rarely studied.ObjectivesWe ...estimated effects of heat on mean daily counts of clinic visits among migrant and seasonal farmworkers by taking advantage of a unique longitudinal medical records database in the USA.MethodsWe compiled a daily weather and clinic visit data set based on data from a health centre in Colorado for the summer of 2013. A total of 14 481 patients were included in our analysis, including 150 migrant farmworkers and 231 seasonal farmworkers with an average of 3 and 4 visits per day. We used Poisson regression to estimate the associations between heat and daily all-cause or cardiovascular-specific clinic visits among migrant or seasonal farmworkers or other stratified patients. We defined heat effects as the percentage difference in average daily counts of clinic visits, comparing 90–50th centiles of daily mean apparent temperature, a composite index accounting for both temperature and humidity. We conducted a sensitivity analysis to evaluate the impact of adjustment for ozone levels and different heat definitions.ResultsEstimates of heat effects on average daily clinic visits among migrant farmworkers were positive (88.0%, 95% CI: 26.2% to 180.0%). We did not observe statistically significant associations between heat and clinic visits among other stratified groups.ConclusionsOur study appears to be the first to link heat effects with clinic data among migrant and seasonal farmworkers. This research suggests possible significant impact of heat on migrant farmworkers and provides justifications for further studies.
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