PTEN Regulation of Local and Long-Range Connections in Mouse Auditory Cortex

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed that local inputs onto PTEN-cko neurons in the auditory cortex were similarly enhanced. The hyperconnectivity caused by PTEN-cko could be blocked by rapamycin, a specific inhibitor of the PTEN downstream molecule mammalian target of rapamycin complex 1. Together, our results suggest that local and long-range hyperconnectivity may constitute a physiological basis for the effects of mutations in PTEN and possibly other ASD candidate genes

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs

Projective Hilbert space structures at exceptional points

A non-Hermitian complex symmetric 2x2 matrix toy model is used to study projective Hilbert space structures in the vicinity of exceptional points (EPs). The bi-orthogonal eigenvectors of a diagonalizable matrix are Puiseux-expanded in terms of the root vectors at the EP. It is shown that the apparent contradiction between the two incompatible normalization conditions with finite and singular behavior in the EP-limit can be resolved by projectively extending the original Hilbert space. The complementary normalization conditions correspond then to two different affine charts of this enlarged projective Hilbert space. Geometric phase and phase jump behavior are analyzed and the usefulness of the phase rigidity as measure for the distance to EP configurations is demonstrated. Finally, EP-related aspects of PT-symmetrically extended Quantum Mechanics are discussed and a conjecture concerning the quantum brachistochrone problem is formulated.Comment: 20 pages; discussion extended, refs added; bug correcte

Early Lung Function Abnormalities in Acromegaly.

BACKGROUND: Acromegaly is an insidious disorder caused by a pituitary growth hormone (GH)-secreting adenoma resulting in high circulating levels of GH and insulin-like growth factor I (IGF-I). Respiratory disorders are common complications in acromegaly, and can severely impact on quality of life, eventually affecting mortality. OBJECTIVES: The present study aimed to explore structural and functional lung alterations of acromegalic subjects. METHODS: We enrolled 10 consecutive patients (M/F: 5/5) affected by acromegaly. In all patients, magnetic resonance imaging (MRI) revealed the presence of pituitary tumor. All patients underwent clinical, lung functional, biological, and radiological assessments. Ten healthy age-matched subjects also served as controls. RESULTS: No statistically significant differences in lung function were detected between acromegalic and healthy subjects (p ≥ 0.05 for all analyses). However, the diffusing capacity for CO (TLCO) was significantly lower in the acromegalic group than in healthy subjects (TLCO% predicted: 78.1 ± 16 vs. 90 ± 6 %, respectively, p = 0.04; KCO% predicted: 77 ± 16 vs. 93 ± 5 %, p = 0.02, respectively). None of the lung function parameters correlated with duration of the disease, or with inflammatory marker of the airways. In acromegalics, biological (exhaled NO concentrations) and imaging (total lung volume, TLV, and mean lung density, MLD) evaluations were within normal values. The TLV measured by HRCT was 3540 ± 1555 ml in acromegalics, and the MLD was -711 ± 73 HU. None of the lung functional, radiological, and biological findings correlated with GH or IGF-I levels, and no correlation was found with duration of disease. CONCLUSIONS: In the current study, lung function evaluation allowed to detect early involvement of lung parenchyma, as assessed by TLCO and KCO, even in the absence of parenchymal density alterations of the lung by HRCT. These findings suggest to routinely include the carbon monoxide diffusing capacity in the lung function assessment for an early intervention in acromegaly

Gestational weight gain and group prenatal care: A systematic review and meta-analysis

Abstract Background Group visits for chronic medical conditions in non-pregnant populations have demonstrated successful outcomes including greater weight loss compared to individual visits for weight management. It is plausible that group prenatal care can similarly assist women in meeting gestational weight gain goals. The purpose of this study was to evaluate the effect of group vs. traditional prenatal care on gestational weight gain. Methods A keyword search of Medline, Embase, Scopus, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and Google Scholar was performed up to April 2017. Studies were included if they compared gestational weight gain in a group prenatal care setting to traditional prenatal care in either randomized controlled trials, cohort, or case-control studies. The primary and secondary outcomes were excessive and adequate gestational weight gain according to the Institute of Medicine guidelines. Heterogeneity was assessed with the Q test and I2 statistic. Pooled relative risks (RRs) and confidence intervals (CI) were reported with random-effects models from the randomized controlled trials (RCT) and cohort studies. Results One RCT, one secondary analysis of an RCT, one study with “random assignment”, and twelve cohort studies met the inclusion criteria for a total of 13,779 subjects. Thirteen studies used the CenteringPregnancy model, defined by 10 sessions that emphasize goal setting and self-monitoring. Studies targeted specific populations such as adolescents, African-Americans, Hispanics, active-duty military or their spouses, and women with obesity or gestational diabetes. There were no significant differences in excessive [7 studies: pooled rates 47% (1806/3582) vs. 43% (3839/8521), RR 1.09, 95% CI 0.97–1.23] or adequate gestational weight gain [6 studies: pooled rates 31% (798/2875) vs. 30% (1410/5187), RR 0.92, 95% CI 0.79–1.08] in group and traditional prenatal care among the nine studies that reported categorical gestational weight gain outcomes in the meta-analysis. Conclusions Group prenatal care was not associated with excessive or adequate gestational weight gain in the meta-analysis. Since outcomes were overall inconsistent, we propose that prenatal care models (e.g., group vs. traditional) should be evaluated in a more rigorous fashion with respect to gestational weight gain

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

State of the climate in 2013

In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earths surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series. © 2014, American Meteorological Society. All rights reserved

Effects of Lip Revision Surgery in Cleft Lip/Palate Patients

The decision for lip revision surgery in patients with repaired cleft lip/palate is based on surgeons’ subjective evaluation of lip disability. An objective evaluation would be highly beneficial for the assessment of surgical outcomes. In this study, the effects of lip revision on circumoral movements were objectively quantified. The hypothesis was that lip revision increases scarring and impairment. The study was a non-randomized clinical trial that included patients with cleft lip who had revision, patients with cleft lip who did not, and non-cleft control individuals. Three-dimensional facial movements were measured. Revision patients were measured before and after surgery. Other individuals were measured at similar intervals. Regression models were fit to summary measurements, and changes were modeled. Patients with repaired cleft lip/palate had fewer mean movements than control individuals. Lip revision did not worsen mean movements; however, individual patients’ movements varied from ‘improvement’ to ‘no change’ to ‘worse’ relative to those of control individuals

The effects of lip revision surgery on nasolabial esthetics in patients with cleft lip

1) To determine the concordance among surgeons on subjective assessments of nasolabial esthetics in children with repaired cleft lip; and 2) to evaluate longitudinal changes in nasolabial esthetics in relation to cleft lip revision surgery.School of Dentistry at University of North Carolina, Chapel Hill. Children with repaired unilateral cleft lip: 32 had lip revision surgery and 27 did not have surgery.Retrospective observational study from a non-randomized clinical trial. Ratings of nasolabial esthetics performed by six surgeons using the Asher-McDade scale at baseline and 12-month follow-up.Concordance among surgeons ranged from poor to acceptable. Nasolabial ratings at follow-up were better in the Revision group than in the Non-Revision group, although differences were small. The most prevalent change in the Revision Group was improvement in one or more units on the scale, while ‘no change’ was most prevalent in the Non-Revision group. Participants in the Revision group were more likely to receive a ‘no’ in relation to the need for lip or nose revision at the follow-up visit.There were mild esthetic improvements observed in relation to lip revision surgery, which should be interpreted with caution given the subjectivity of the rating method used