Is oral sex really a dangerous carcinogen? Let's take a closer look.
Questions have recently arisen in the popular press about the association between specific sexual behaviors, namely, fellatio and cunnilingus, with head and neck cancers. Although there has been an overall decline in the incidence of head and neck cancers over the past 25 years, there has been a shift in the distribution of these cancers toward a particular type known as oral squamous cell carcinomas (OSCCs), and a younger demographic. These particular cancers, OSCCs, have been shown to be associated with the human papillomavirus (HPV). Several researchers have suggested that this shift in the epidemiology of head and neck cancers might be attributable to changing sexual practices. While this speculation has caught on in the popular press, there are several interesting contradictions in the existing evidence that suggest this conclusion might be premature and overreached. The intent of this article is to help clarify the issues so that sexual medicine professionals can give accurate and up-to-date information to their patients. This is a review article; no outcome data are reported. This is a review article; no measures were collected. Pubmed search on HPV, oral sex, oral cancers, and OSCCs. One hundred ninety-six articles on HPV were found; 63 articles on oral sex, 55 on oral cancer, and 5 articles on OSCCs were identified as relevant. HPV infections occur commonly and are usually cleared within 18 months, thus HPV infection should not be a cause for concern among monogamous couples with a rich and varied sex life as long as the sexual system remains closed and other immune compromising factors are not present. HPV becomes a concern in the context of immune system compromise and infection persistence. Factors contributing to immune system compromise, HPV persistence, and oncogenesis are reviewed.


Triton's Plumes: The Dust Devil Hypothesis.
Triton's plumes are narrow columns 10 kilometers in height, with tails extending horizontally for distances over 100 kilometers. This structure suggests that the plumes are an atmospheric rather than a surface phenomenon. The closest terrestrial analogs may be dust devils, which are atmospheric vortices originating in the unstable layer close to the ground. Since Triton has such a low surface pressure, extremely unstable layers could develop during the day. Patches of unfrosted ground near the subsolar point could act as sites for dust devil formation because they heat up relative to the surrounding nitrogen frost. The resulting convection would warm the atmosphere to temperatures of 48 kelvin or higher, as observed by the Voyager radio science team. Assuming that velocity scales as the square root of temperature difference times the height of the mixed layer, a velocity of 20 meters per second is derived for the strongest dust devils on Triton. Winds of this speed could raise particles provided they are a factor of 103 to 104 less cohesive than those on Earth.


Understanding treatment non-adherence in schizophrenia and bipolar disorder: a survey of what service users do and why.
Approximately half of service users with schizophrenia or bipolar disorder do not fully follow treatment recommendations. Studies of adherence have not adequately explored the frequency, consequences and meanings of non-adherence behaviours from service users' perspectives. This study contributes to a more fine-grained understanding of treatment choices and the support service users require in order to maximise benefit from their medications. This was a mixed-methods questionnaire study, employing quantitative and thematic qualitative analyses. Thirty-five individuals with a diagnosis of, and receiving psycho-pharmaceutical treatment for, schizophrenia or bipolar disorder answered online or telephone questions about whether, how, and why they deviated from their treatment recommendations, and what support they currently and would like to receive. Over half of participants identified themselves as being non-adherent, however when asked in detail about intentional and unintentional adherence, 77% reported deviating from treatment recommendations. Critically, 29% were non-adherent and satisfied with being so. Service users' satisfaction with their support was positively correlated with satisfaction with their medication. Participants' made treatment choices in order to live well. Both side-effects and symptoms could be obstacles to adherence, but feeling well also impacted on participants' treatment choices. Treatment choices were often made in the context of living well day-to-day, and did not necessarily take into account longer-term effects of non-adherence. Participants wanted more information about their medications, better emotional support (including better access to psychological therapies) and stability in their relationships with health professionals. This study suggests that non-adherence, both intentional and unintentional, is common amongst individuals with diagnoses of schizophrenia and bipolar disorder, and that this often occurs without health professionals' knowledge or support. Treatment choices reflect a desire to live well, but are often driven by short-term needs. Given access to more information, and importantly to emotional support, service users could be helped to make treatment choices that adequately reflect the long-term risks of non-adherence, as well as allowing them to live well day-to-day. More research is required better to understand the meanings and complexities of service users' treatment choices.


Community treatment orders: clinical and social outcomes, and a subgroup analysis from the OCTET RCT.
Despite widespread use internationally, there is no convincing evidence that community treatment orders (CTO) (legal regimes making out-patient treatment compulsory), reduce readmission rates or have wider patient benefit. The primary and secondary outcomes of the Oxford Community Treatment Order Evaluation Trial (OCTET) (hospitalisation) showed no benefit. This article will, first, test the effect of community compulsion on wider clinical and social outcomes and on patients' experiences of services and the use of treatment pressure and second, explore differential effects in different groups of patients. OCTET is a RCT of CTO effectiveness. Three hundred and thirty-six patients were randomised and data for the 333 eligible patients were collected from interviews and medical records at baseline, 6 and 12 months. There was no significant difference at 12 months between the two arms in any of the reported outcomes, except a small difference in patients' view of the effectiveness of treatment pressure, which is unlikely to be clinically meaningful. Two statistically significant interactions were found in the subgroup analysis: symptoms interacted with age and with education, but no pattern was demonstrated. CTOs do not have benefit on any of the tested outcomes, or for any subgroup of patients. Their continued use should be carefully reconsidered.


trans-dominant defective mutants of simian virus 40 T antigen.
We constructed a collection of linker insertion mutants in the simian virus 40 (SV40) genome and studied several of these with changes limited to a part of the large T antigen gene corresponding to an amino acid sequence shared with other ATPases. Two of these mutants were found to have a novel phenotype in that they could not be complemented for plaque formation by a late-region deletion mutant. These two mutants, in contrast to other mutants in this region, were able to transform rat cells in culture at a frequency close to that of the wild-type gene. The noncomplementing mutants were found to be potent inhibitors of SV40 DNA replication despite the presence of wild-type T antigen in the transfected cells. This inhibition was shown to be the result of the introduced mutations in the large T antigen gene. We conclude that the large T antigens of the noncomplementing mutants can act as inhibitors of SV40 DNA replication.


A histological study of the medial meniscus posterior root tibial insertion.
Purpose/Aim of the study: Posterior root injury of the medial meniscus often leads to articular cartilage degeneration due to altered biomechanics. To avoid dysfunction, the attachment must be repaired using the transtibial pullout technique. To guide appropriate placement of the tibial tunnel, additional details on the normal anatomy of the meniscus insertion are needed. Therefore, we performed a histological analysis of a tibial bone slice with the medial meniscus posterior insertion obtained during total knee arthroplasty surgery. Materials and methods: Horizontal slices of the proximal tibia were obtained from 7 patients with osteoarthritis who underwent total knee arthroplasty. After decalcification, the region of the posterior horn was cut out and segmented into four pieces (2.0 mm thickness; medial to lateral). Sagittal sections were evaluated by safranin O staining or immunohistochemistry with anti-type collagen antibody. Results: Safranin O staining showed that the insertion of the posterior root consisted primarily of fibrocartilaginous layers in segment 2. Anatomically, segment 2 corresponded to the sagittal plane passing through the peak of the medial intercondylar tubercle. In this section, safranin O staining and immunohistochemistry revealed that the anterior one-third of the posterior root insertion was richer in proteoglycans and type II collagen than the central and posterior one-third. Conclusions: Anatomical insertion of the posterior root of the medial meniscus was located at the sagittal plane passing through the peak of the medial intercondylar tubercle. The structure of the medial meniscus posterior insertion was mainly localized in the anterior one-third.


Optimising low molecular weight hydrogels for automated 3D printing.
Hydrogels prepared from low molecular weight gelators (LMWGs) are formed as a result of hierarchical intermolecular interactions between gelators to form fibres, and then further interactions between the self-assembled fibres via physical entanglements, as well as potential branching points. These interactions can allow hydrogels to recover quickly after a high shear rate has been applied. There are currently limited design rules describing which types of morphology or rheological properties are required for a LMWG hydrogel to be used as an effective, printable gel. By preparing hydrogels with different types of fibrous network structures, we have been able to understand in more detail the morphological type which gives rise to a 3D-printable hydrogel using a range of techniques, including rheology, small angle scattering and microscopy.


Development of heart and respiratory rate percentile curves for hospitalized children.
To develop and validate heart and respiratory rate percentile curves for hospitalized children and compare their vital sign distributions to textbook reference ranges and pediatric early warning score (EWS) parameters. For this cross-sectional study, we used 6 months of nurse-documented heart and respiratory rates from the electronic records of 14,014 children on general medical and surgical wards at 2 tertiary-care children's hospitals. We developed percentile curves using generalized additive models for location, scale, and shape with 67% of the patients and validated the curves with the remaining 33%. We then determined the proportion of observations that deviated from textbook reference ranges and EWS parameters. We used 116,383 heart rate and 116,383 respiratory rate values to develop and validate the percentile curves. Up to 54% of heart rate observations and up to 40% of respiratory rate observations in our sample were outside textbook reference ranges. Up to 38% of heart rate observations and up to 30% of respiratory rate observations in our sample would have resulted in increased EWSs. A high proportion of vital signs among hospitalized children would be considered out of range according to existing reference ranges and pediatric EWSs. The percentiles we derived may serve as useful references for clinicians and could be used to inform the development of evidence-based vital sign parameters for physiologic monitor alarms, inpatient electronic health record vital sign alerts, medical emergency team calling criteria, and EWSs.


ACR Appropriateness Criteria® Breast Implant Evaluation.
Breast implant imaging varies depending on patient age, implant type, and symptoms. For asymptomatic patients (any age, any implant), imaging is not recommended. Rupture of saline implants is often clinically evident, as the saline is resorbed and there is a change in breast contour. With saline implants and equivocal clinical findings, ultrasound (US) is the examination of choice for patients less than 30 years of age, either mammography/digital breast tomosynthesis or US may be used for those 30 to 39 years of age, and mammography/digital breast tomosynthesis is used for those 40 years and older. For patients with suspected silicone implant complication, MRI without contrast or US is used for those less than 30 years of age; MRI without contrast, mammography/digital breast tomosynthesis, or US may be used for those 30 to 39 years of age; and MRI without contrast or mammography/digital breast tomosynthesis is used for those 40 years and older. Patients with unexplained axillary adenopathy and silicone implants (current or prior) are evaluated with axillary US. For patients 30 years and older, mammography/digital breast tomosynthesis is performed in conjunction with US. Last, patients with suspected breast implant-associated anaplastic large-cell lymphoma are first evaluated with US, regardless of age or implant type. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches.
Glioblastoma is the most common primary adult brain tumour, and despite optimal treatment, the median survival is 12-15 months. Patients with matched recurrent glioblastomas were investigated to try to find actionable mutations. Tumours were profiled using a validated DNA-based gene panel. Copy number variations (CNVs) and single nucleotide variants (SNVs) were examined, and potentially pathogenic variants and clinically actionable mutations were identified. The results revealed that glioblastomas were IDH-wildtype (IDH WT; n = 38) and IDH-mutant (IDH MUT; n = 3). SNVs in TSC2, MSH6, TP53, CREBBP, and IDH1 were variants of unknown significance (VUS) that were predicted to be pathogenic in both subtypes. IDH WT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, WNT, SHH, NOTCH, Rb, and G-protein pathways. Many tumours had BRCA1/2 (18%) variants, including confirmed somatic mutations in haemangioblastoma. IDH WT recurrent tumours had fewer pathways impacted (RTK/Ras/PI(3)K, p53, WNT, and G-protein) and CNV gains (BRCA2, GNAS, and EGFR) and losses (TERT and SMARCA4). IDH MUT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, and WNT pathways. VUS in KLK1 was possibly pathogenic in IDH MUT. Recurrent tumours also had fewer pathways (p53, WNT, and G-protein) impacted by genetic alterations. Public datasets (TCGA and GDC) confirmed the clinical significance of findings in both subtypes. Overall in this cohort, potentially actionable variation was most often identified in EGFR, PTEN, BRCA1/2, and ATM. This study underlines the need for detailed molecular profiling to identify individual GBM patients who may be eligible for novel treatment approaches. This information is also crucial for patient recruitment to clinical trials.


Differentiation of healthy brain tissue and tumors using surface-enhanced Raman scattering.
Surface-enhanced Raman scattering (SERS) is a powerful technique for characterization of biological samples. SERS spectra from healthy brain tissue and tumors are obtained by sudden freezing of tissue in liquid nitrogen and crashing and mixing it with a concentrated silver colloidal suspension. The acquired spectra from tissues show significant spectral differences that can be used to identify whether it is from a healthy region or tumor. The most significant change on SERS spectra from the healthy/peripheral brain tissue to tumor is the increase of the ratio of the peaks at around 723 to 655 cm(-1). In addition, the spectral changes indicate that the protein content in tumors increases compared to the peripheral/healthy tissue as observed with tumor invasion. The preliminary results show that SERS spectra can be used for a quick diagnosis due to the simplicity of the sample preparation and the speed of the spectral acquisition.


Survival analysis and prognostic factors of timing of first childbirth among women in Nigeria.
First childbirth in a woman's life is one of the most important events in her life. It marks a turnaround when she might have to drop roles of career building and education, for motherhood and parenthood. The timing of the commencement of these roles affects the child bearing behavior of women as they progress in their reproductive ages. Prevalent early first childbirth in Nigeria has been reported as the main cause of high population growth and high fertility, mortality and morbidity among women, but little has been documented on the progression into first birth as well as factors affecting it in Nigeria. This paper modelled timing of first birth among women in Nigeria and determined socio-demographic and other factors affecting its timing. We hypothesized that background characteristics of a woman will influence her progression into having first birth. We developed and fitted a survival analysis model to understand the timing of first birth among women in Nigeria using a national representative 2013 NDHS data. Women with no children were right censored as of the date of the survey. The Kaplan Meier survival function was used to estimate the probabilities of first birth not occurring until certain ages of women while Cox proportional hazard regression was used to model the timing of first births at 5 % significance level. About 75.7 % of the respondents had given birth in the Northern region of Nigerian compared with 63.8 % in the South. Half (50.1 %) of the first childbirth occurred within the 15-19 years age bracket and 38.1 % within 20-29 years. The overall median survival time to first birth was 20 years (North 19, South 22), 27 years among women with higher education and 18 years for those with no formal education. The adjusted hazard of first birth was higher in the Northern region of Nigeria than in the South (aHR = 1.24, 95 % CI: 1.20-1.27), and higher in rural areas than in urban areas (aHR = 1.15, 95 % CI: 1.12-1.19). Also, hazard of earlier first birth tripled among women with no education (aHR = 3.36, 95 % CI: 3.17-3.55) compared to women with higher education. The significant factors affecting age at first birth are education, place and zone of residence, age at first marriage, religion, ethnicity and use of contraceptives. This study showed that progression into early first birth is most affected by the education standing of women as well as age at first marriage. Delay of first childbirths as a strategy for fertility reduction and maternal health improvement can be achieved if women are empowered early in life with quality education. Stakeholders should therefore, give adequate attention to educating the girl child. Adverse socio-cultural norms of betrothing and marrying young girls should be abrogated, while health education and promotion of need to delay child bearing must be intensified especially among rural dwellers and also in Northern Nigeria.


Tobacco use prevalence and correlates among adolescents in a clinician initiated tobacco prevention trial in California, USA.
Baseline data for the clinician initiated, tobacco prevention trial, the first non-school based clinician mediated tobacco prevention study, were used to explore the degree to which young people receiving orthodontic treatment use tobacco and the differences in use rates between national, California, and patient samples. Correlates of tobacco use were identified and these correlates were contrasted with findings from the published reports. A 26 item telephone survey assessed demographic information, tobacco use, selected health related behaviours, and variables based on social learning theory. The study was conducted among 11 to 18 year old orthodontic patients from San Diego, Orange, Riverside, San Bernardino, and Los Angeles Counties, California, USA. Of the 17925 patients who were eligible, 16915 (> 94%) completed the survey. Multivariate analyses were conducted using a logistic mixed effects model. Although the 30 day prevalence rate of tobacco use (6%, n = 1010) proved lower than California and national samples, the rates for the age, gender, and race ethnicity subgroups showed trends similar to those seen in California and national samples. Ten variables were significantly associated with tobacco use (p < 0.05), including 30 day alcohol use (OR = 7.88), age (OR = 1.32), and living with a tobacco user (OR = 1.72). Because 6% of orthodontic patients use tobacco, interventions are warranted to reach the health "Objectives for the Nation". Patterns of correlates of tobacco use were essentially the same for orthodontic patients, California, and national samples, suggesting that these associations are generalisable.


Clustering proteins from interaction networks for the prediction of cellular functions.
Developing reliable and efficient strategies allowing to infer a function to yet uncharacterized proteins based on interaction networks is of crucial interest in the current context of high-throughput data generation. In this paper, we develop a new algorithm for clustering vertices of a protein-protein interaction network using a density function, providing disjoint classes. Applied to the yeast interaction network, the classes obtained appear to be biological significant. The partitions are then used to make functional predictions for uncharacterized yeast proteins, using an annotation procedure that takes into account the binary interactions between proteins inside the classes. We show that this procedure is able to enhance the performances with respect to previous approaches. Finally, we propose a new annotation for 37 previously uncharacterized yeast proteins. We believe that our results represent a significant improvement for the inference of cellular functions, that can be applied to other organism as well as to other type of interaction graph, such as genetic interactions.


Quantitative Proteome Landscape of the NCI-60 Cancer Cell Lines.
Here we describe a proteomic data resource for the NCI-60 cell lines generated by pressure cycling technology and SWATH mass spectrometry. We developed the DIA-expert software to curate and visualize the SWATH data, leading to reproducible detection of over 3,100 SwissProt proteotypic proteins and systematic quantification of pathway activities. Stoichiometric relationships of interacting proteins for DNA replication, repair, the chromatin remodeling NuRD complex, β-catenin, RNA metabolism, and prefoldins are more evident than that at the mRNA level. The data are available in CellMiner (discover.nci.nih.gov/cellminercdb and discover.nci.nih.gov/cellminer), allowing casual users to test hypotheses and perform integrative, cross-database analyses of multi-omic drug response correlations for over 20,000 drugs. We demonstrate the value of proteome data in predicting drug response for over 240 clinically relevant chemotherapeutic and targeted therapies. In summary, we present a novel proteome resource for the NCI-60, together with relevant software tools, and demonstrate the benefit of proteome analyses.


Directed assembly of one-dimensional nanostructures into functional networks.
One-dimensional nanostructures, such as nanowires and nanotubes, represent the smallest dimension for efficient transport of electrons and excitons and thus are ideal building blocks for hierarchical assembly of functional nanoscale electronic and photonic structures. We report an approach for the hierarchical assembly of one-dimensional nanostructures into well-defined functional networks. We show that nanowires can be assembled into parallel arrays with control of the average separation and, by combining fluidic alignment with surface-patterning techniques, that it is also possible to control periodicity. In addition, complex crossed nanowire arrays can be prepared with layer-by-layer assembly with different flow directions for sequential steps. Transport studies show that the crossed nanowire arrays form electrically conducting networks, with individually addressable device function at each cross point.


Survival by stroke volume index in patients with low-gradient normal EF severe aortic stenosis.
Low-gradient (LG) severe aortic stenosis (AS) and preserved EF with reduced stroke volume are associated with an adverse prognosis, but the relationship of stroke volume index (SVI) with mortality among a range of values is unknown. We investigated the prognostic impact of SVI in this population. We examined 405 consecutive patients with preserved EF (≥50%) and severe AS (valve area <1.0 cm(2)) with LG (<40 mm Hg) using echocardiography. Patients were stratified into quartiles based on SVI distribution (group 1: <38 mL/m(2) (n=90), group 2: 38-43 mL/m(2) (n=105), group 3: 43-48 mL/m(2) (n=104) and group 4: >48 mL/m(2) (n=106)). Groups 1 and 2 had poorer survival with medical management compared with 3 and 4 (3-year estimate 46% and 67% vs. 78% and 73%, respectively, p=0.002) although aortic valve replacement referral rate was similar (53%-62%, p=0.57). An inverse relationship was observed between SVI and mortality (HR 1.28 (1.11 to 1.46) per every 5 mL/m(2) decrease in SVI). After multivariable analysis, SVI was the strongest predictor of mortality (HR 0.92 (0.89 to 0.95), p<0.0001). Using different SVI cutpoints, SVI <35 was associated with highest mortality (HR 2.36 (1.49 to 3.73), p<0.001), followed by SVI <38 (HR 2.09 (1.39 to 3.16), p<0.001) and by SVI <43 (HR 2.05 (1.38 to 3.05), p<0.001). Survival with SVI ≥43 was similar to age and sex-matched controls (3-year estimate 84%, p=0.24); survival for SVI <43 was significantly worse (3-year estimate 63%, p<0.001). Lower SVI is incrementally associated with mortality in LG severe AS with preserved EF. These findings have implications for classification of AS severity, identification of high-risk groups and subsequent management.


Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure.
Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206- cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized.


Validation of methods for measurement of insulin secretion in humans in vivo.
To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky)-considered the "gold standard"-and the combined model (by Vølund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity of these mathematical techniques for quantification of insulin secretion have been tested in dogs, but not in humans. In the present studies, we examined the validity of both methods to recover the known infusion rates of insulin and C-peptide mimicking ISR during an oral glucose tolerance test. ISR from both the combined model and the deconvolution method were accurate, i.e., recovery of true ISR was not significantly different from 100%. Furthermore, both maximal and total ISRs from the combined model were strongly correlated to those obtained by the deconvolution method (r = 0.89 and r = 0.82, respectively). These results indicate that both approaches provide accurate assessment of prehepatic ISRs in type 2 diabetic patients and control subjects. A simplified version of the deconvolution method based on standard kinetic parameters for C-peptide (Van Cauter et al.) was compared with the 2-day deconvolution method, and a close agreement was found for the results of an oral glucose tolerance test. We also studied whether C-peptide kinetics are influenced by somatostatin infusion. The decay curves after bolus injection of exogenous biosynthetic human C-peptide, the kinetic parameters, and the metabolic clearance rate were similar whether measured during constant peripheral somatostatin infusion or without somatostatin infusion. Assessment of C-peptide kinetics can be performed without infusion of somatostatin, because the endogenous insulin concentration remains constant. Assessment of C-peptide kinetics with and without infusion of somatostatin results in nearly identical secretion rates for insulin during an oral glucose tolerance test.


Biological, behavioral, and relational levels of resilience in the context of risk for early childhood behavior problems.
Longitudinal growth patterns of internalizing and externalizing behavior problems were examined in a community sample of 441 children across the ages of 2 to 5 using hierarchical linear modeling. Contextual risk was measured using five indicators (socioeconomic status, marital status, number of siblings, parent stress, parent psychopathology), and three levels of child resilience (biological, behavioral, and relational) were also assessed. Results indicate that a general pattern of decline in both types of behavior problems was observed for the entire sample across time, although considerable individual variability in this pattern was observed. Children's externalizing and internalizing behavior at age 5 was predicted by the level of risk at age 2. All three child resilience factors were also predictive of externalizing and internalizing behaviors at age 5. In the prediction of the slope of problem behavior over time, risk status interacted with both temperamental fearlessness and a mutually responsive orientation with the mother to predict the decline in externalizing and internalizing problem behavior. Results underscore the complex interactions of risk and multiple levels of resilience that are implicated in the maintenance of problem behavior over time. They highlight the importance of considering whether expected resilience factors operate similarly across different levels of risk.


Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399.
Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients. Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m(2) and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m(2) every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence). One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP). A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.


ZnO-PCBM bilayers as electron transport layers in low-temperature processed perovskite solar cells.
We investigate an electron transport bilayer fabricated at <110 °C to form all low-temperature processed, thermally stable, efficient perovskite solar cells with negligible hysteresis. The components of the bilayer create a symbiosis that results in improved devices compared with either of the components being used in isolation. A sol-gel derived ZnO layer facilitates improved energy level alignment and enhanced charge carrier extraction and a [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) layer to reduce hysteresis and enhance perovskite thermal stability. The creation of a bilayer structure allows materials that are inherently unsuitable to be in contact with the perovskite active layer to be used in efficient devices through simple surface modification strategies.


Echocardiographic studies of regression of left ventricular hypertrophy in hypertension.
The availability of echocardiography has allowed direct determinations of left ventricular wall thickness and calculation of left ventricular mass. As a result, the past decade has witnessed a remarkable evolution in our understanding of structural changes in the heart. Moreover, cardiac hypertrophy was found to be reversible by some forms of therapy. In general, reduction of left ventricular mass became evident after 8 to 12 weeks of antihypertensive therapy. Sympatholytics (including methyldopa and reserpine), converting enzyme inhibitors (captopril and enalapril), and calcium entry blockers led to significant regression of left ventricular hypertrophy. On the other hand, arteriolar vasodilators (hydralazine, trimazosin, and minoxidil) were not associated with regression of hypertrophy despite adequate blood pressure control. Finally, data regarding diuretics and beta-blockers are controversial. These differences in results among various antihypertensive drugs reflect the multiplicity of factors modulating left ventricular hypertrophy.


A distorted honeycomb motif in divalent transition metal compounds based on 4-phosphonbenzoic acid and exchange coupled Co(II) and Cu(II): synthesis, structural description and magnetic properties.
The first example of a two-dimensional inorganic hybrid material with cobalt as an open-shell transition metal ion and 4-phosphonbenzoic acid as a linker is presented together with its copper analogue. For both metal ions the inorganic part consists of edge-sharing metal-oxygen octahedra leading to a metal honeycomb motif. The magnetic properties of the cobalt compound are reported together with those of the corresponding copper compound based on the remarkably six-coordinated copper(II) ions.


The stroke 'Act FAST' campaign: remembered but not understood?
The stroke awareness raising campaign 'Act FAST' (Face, Arms, Speech: Time to call Emergency Medical Services) has been rolled out in multiple waves in England, but impact on stroke recognition and response remains unclear. The purpose of this study was to test whether providing knowledge of the FAST acronym through a standard Act FAST campaign leaflet increases accurate recognition and response in stroke-based scenario measures. This is a population-based, cross-sectional survey of adults in Newcastle upon Tyne, UK, sampled using the electoral register, with individuals randomized to receive a questionnaire and Act FAST leaflet (n = 2500) or a questionnaire only (n = 2500) in 2012. Campaign message retention, stroke recognition, and response measured through 16 scenario-based vignettes were assessed. Data were analyzed in 2013. Questionnaire return rate was 32.3% (n = 1615). No differences were found between the leaflet and no-leaflet groups in return rate or demographics. Participants who received a leaflet showed better campaign recall (75.7% vs. 68.2%, P = 0.003) and recalled more FAST mnemonic elements (66.1% vs. 45.3% elements named correctly, P < 0.001). However, there were no between-group differences for stroke recognition and response to stroke-based scenarios (P > 0.05). Despite greater levels of recall of specific 'Act FAST' elements among those receiving the Act FAST leaflet, there was no impact on stroke recognition and response measures.


Cranial Bosses of Choerosaurus dejageri (Therapsida, Therocephalia): Earliest Evidence of Cranial Display Structures in Eutheriodonts.
Choerosaurus dejageri, a non-mammalian eutheriodont therapsid from the South African late Permian (~259 Ma), has conspicuous hemispheric cranial bosses on the maxilla and the mandible. These bosses, the earliest of this nature in a eutheriodont, potentially make C. dejageri a key species for understanding the evolutionary origins of sexually selective behaviours (intraspecific competition, ritualized sexual and intimidation displays) associated with cranial outgrowths at the root of the clade that eventually led to extant mammals. Comparison with the tapinocephalid dinocephalian Moschops capensis, a therapsid in which head butting is strongly supported, shows that the delicate structure of the cranial bosses and the gracile structure of the skull of Choerosaurus would be more suitable for display and low energy combat than vigorous head butting. Thus, despite the fact that Choerosaurus is represented by only one skull (which makes it impossible to address the question of sexual dimorphism), its cranial bosses are better interpreted as structures involved in intraspecific selection, i.e. low-energy fighting or display. Display structures, such as enlarged canines and cranial bosses, are widespread among basal therapsid clades and are also present in the putative basal therapsid Tetraceratops insignis. This suggests that sexual selection may have played a more important role in the distant origin and evolution of mammals earlier than previously thought. Sexual selection may explain the subsequent independent evolution of cranial outgrowths and pachyostosis in different therapsid lineages (Biarmosuchia, Dinocephalia, Gorgonopsia and Dicynodontia).


Physiology of Electrolyte Transport in the Gut: Implications for Disease.
We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR-CAS technology, stem cell-derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na+ /K+ ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl- channels and the basolateral Na+ -K+ -2Cl- cotransporter, NKCC1 and K+ channels. Absorption chiefly involves apical membrane Na+ /H+ exchangers and Cl- /HCO3 - exchangers in the small intestine and proximal colon and Na+ channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947-1023, 2019.


An Orthotopic Endometrial Cancer Model with Retroperitoneal Lymphadenopathy Made From In Vivo Propagated and Cultured VX2 Cells.
Endometrial cancer is the most common gynecologic malignancy in North America and the incidence is rising worldwide. Treatment consists of surgery with or without adjuvant therapy depending on lymph node involvement as determined by lymphadenectomy. Lymphadenectomy is a morbid procedure, which has not been shown to have a therapeutic benefit in many patients, and thus a new method to diagnose lymph node metastases is required. To test novel imaging agents, a reliable model of endometrial cancer with retroperitoneal lymph node metastases is needed. The VX2 endometrial cancer model has been described frequently in the literature; however, significant variation exists with respect to the method of model establishment. Furthermore, no studies have reported on the use of cultured VX2 cells to create this model as only cells propagated in vivo have been previously used. Herein, we present a standardized surgical method and post-operative monitoring method for the establishment of the VX2 endometrial cancer model and report on the first use of cultured VX2 cells to create this model.


[Reproducibility of a scale for oral health among children and adolescents HIV+/AIDS].
The aim of this study was to investigate the intraobserver reproducibility of a Portuguese version scale used to evaluate aspects of oral health among children and adolescents HIV+. The scale was proposed by Balbo and a questionnaire was applied in two occasions, within a one week period, to 27 children and adolescents. The reproducibility was estimated by kappa statistics by point (k). With relation to the mother, it was reached a maximum of agreement for items related to the importance of maintaining the oral health, diary tooth brushing and the individual utilization of dental brush; breath and esthetics presented a good agreement. Regarding the children, a regular agreement was observed on the dental floss use. In contrast, the respondents had difficulties in reporting the name and address of the professionals that gave guidance in prevention activities to them. The k-values for perception, care and promotion were 0.48, 0.21 and 0.64 respectively, pointing to reproducibility levels classified as regular, fair and good. Given the different levels of reproducibility offered by the dental scale for HIV+ oral health, we suggest that it could be modified, especially in the domain of care.


Ventilator Liberation in the Pediatric ICU.
Despite the accepted importance of minimizing time on mechanical ventilation, only limited guidance on weaning and extubation is available from the pediatric literature. A significant proportion of patients being evaluated for weaning are actually ready for extubation, suggesting that weaning is often not considered early enough in the course of ventilation. Indications for extubation are often not clear, although a trial of spontaneous breathing on CPAP without pressure support seems an appropriate prerequisite in many cases. Several indexes have been developed to predict weaning and extubation success, but the available literature suggests they offer little or no improvement over clinical judgment. New techniques for assessing readiness for weaning and predicting extubation success are being developed but are far from general acceptance in pediatric practice. While there have been some excellent physiologic, observational, and even randomized controlled trials on aspects of pediatric ventilator liberation, robust research data are lacking. Given the lack of data in many areas, a determined approach that combines systematic review with consensus opinion of international experts could generate high-quality recommendations and terminology definitions to guide clinical practice and highlight important areas for future research in weaning, extubation readiness, and liberation from mechanical ventilation following pediatric respiratory failure.


Molecular architecture of the 40S⋅eIF1⋅eIF3 translation initiation complex.
Eukaryotic translation initiation requires the recruitment of the large, multiprotein eIF3 complex to the 40S ribosomal subunit. We present X-ray structures of all major components of the minimal, six-subunit Saccharomyces cerevisiae eIF3 core. These structures, together with electron microscopy reconstructions, cross-linking coupled to mass spectrometry, and integrative structure modeling, allowed us to position and orient all eIF3 components on the 40S⋅eIF1 complex, revealing an extended, modular arrangement of eIF3 subunits. Yeast eIF3 engages 40S in a clamp-like manner, fully encircling 40S to position key initiation factors on opposite ends of the mRNA channel, providing a platform for the recruitment, assembly, and regulation of the translation initiation machinery. The structures of eIF3 components reported here also have implications for understanding the architecture of the mammalian 43S preinitiation complex and the complex of eIF3, 40S, and the hepatitis C internal ribosomal entry site RNA.


Does Online Comprehension Monitoring Make a Unique Contribution to Reading Comprehension in Beginning Readers? Evidence from Eye Movements.
The goal was to investigate the nature of online comprehension monitoring, its predictors, and its relation to reading comprehension. Questions were concerned with (1) beginning readers' sensitivity to inconsistencies, (2) predictors of online comprehension monitoring, and (3) the relation of online comprehension monitoring to reading comprehension over and above word reading and listening comprehension. Using eye-tracking technology, online comprehension monitoring was measured as the amount of time spent rereading target implausible words and looking back at surrounding contexts. Results from 319 second graders revealed that children spent greater time fixating on inconsistent than consistent words and engaged in more frequent lookbacks. Comprehension monitoring was explained by both word reading and listening comprehension. However, comprehension monitoring did not uniquely predict reading comprehension after accounting for word reading and listening comprehension. These results provide insight into the nature of comprehension monitoring and its role in reading comprehension for beginning readers.


Predicting disability progression in multiple sclerosis: Insights from advanced statistical modeling.
There is an unmet need for precise methods estimating disease prognosis in multiple sclerosis (MS). Using advanced statistical modeling, we assessed the prognostic value of various clinical measures for disability progression. Advanced models to assess baseline prognostic factors for disability progression over 2 years were applied to a pooled sample of patients from placebo arms in four different phase III clinical trials. least absolute shrinkage and selection operator (LASSO) and ridge regression, elastic nets, support vector machines, and unconditional and conditional random forests were applied to model time to clinical disability progression confirmed at 24 weeks. Sensitivity analyses for different definitions of a combined endpoint were carried out, and bootstrap was used to assess prediction model performance. A total of 1582 patients were included, of which 434 (27.4%) had disability progression in a combined endpoint over 2 years. Overall model discrimination performance was relatively poor (all C-indices ⩽ 0.65) across all models and across different definitions of progression. Inconsistency of prognostic factor importance ranking confirmed the relatively poor prediction ability of baseline factors in modeling disease progression in MS. Our findings underline the importance to explore alternative predictors as well as alternative definitions of commonly used endpoints.


Reproducibility of newly developed spinal topography measurements for scoliosis.
In an effort to limit exposure to ionizing radiation and fully characterize three dimensional changes in the spine of patients with scoliosis reliable non-invasive methods of spinal back contour analysis (Milwaukee Topographic Scanner) (MTS) have been developed. The current study compares spinal topography measurements among different subject positions and evaluates the reproducibility of the system for both inter-rater and intra-rater reliability. A dummy cast (plastic cast) of one patient with adolescent idiopathic scoliosis was created in order to test the reliability of the MTS. The dummy cast was positioned and rotated in 3D while scanned by two investigators using the MTS. A total of twelve parameters including Q-angle (an analog to X-ray's Cobb angle) were extracted. All measurements of intra-rater and inter-rater reliability were excellent (Intraclass Correlation Coefficients ranging from 0.89 to 0.99) with the exception of Pelvic Tilt (intra-rater ICC is 0.61) and lordosis angle (inter-rater ICC is 0.82). No significant variability among investigators was observed for all tested metrics. No significant variability due to position was observed for the majority of back contour measurements but there were significant changes in the T1-S1 angle, T1-S1 deviation, T1-NC angle, T1-NC deviation, and Back Height metric (p< 0.05). The MTS is a reliable method of raster stereography in the measurement of the back contour, which will help monitor the progression of children with idiopathic scoliosis and reduce the use of X-rays.


Detection of the toughest: Pedestrian injury risk as a smooth function of age.
Though it is common to refer to age-specific groups (e.g., children, adults, elderly), smooth trends conditional on age are mainly ignored in the literature. The present study examines the pedestrian injury risk in full-frontal pedestrian-to-passenger car accidents and incorporates age-in addition to collision speed and injury severity-as a plug-in parameter. Recent work introduced a model for pedestrian injury risk functions using explicit formulae with easily interpretable model parameters. This model is expanded by pedestrian age as another model parameter. Using the German In-Depth Accident Study (GIDAS) to obtain age-specific risk proportions, the model parameters are fitted to the raw data and then smoothed by broken-line regression. The approach supplies explicit probabilities for pedestrian injury risk conditional on pedestrian age, collision speed, and injury severity under investigation. All results yield consistency to each other in the sense that risks for more severe injuries are less probable than those for less severe injuries. As a side product, the approach indicates specific ages at which the risk behavior fundamentally changes. These threshold values can be interpreted as the most robust ages for pedestrians. The obtained age-wise risk functions can be aggregated and adapted to any population. The presented approach is formulated in such general terms that in can be directly used for other data sets or additional parameters; for example, the pedestrian's sex. Thus far, no other study using age as a plug-in parameter can be found.


Structure and function of cholera toxin and hormone receptors.
The enterotoxin from Vibrio cholerae is a protein of 100,000 mol wt which stimulates adenylate cyclase activity ubiquitously. The binding of biologically active 125I-labeled choleragen to cell membranes is of extraordinary affinity and specificity. The binding may be restricted to membrane-bound ganglioside GM1. This ganglioside can be inserted into membranes from exogenous sources, and the increased toxin binding in such cells can be reflected by an increased sensitivity to the biological effects of the toxin. Features of the toxin-activated adenylate cyclase, including conversion of the enzyne to a GTP-sensitive state, and the increased sensitivity of activation by hormones, suggest analogies between the basic mechanism of action of choleragen and the events following binding of hormones to their receptors. The action of the toxin is probably not mediated through intermediary cytoplasmic events, suggesting that its effects are entirely due to processes involving the plasma membrane. The kinetics of activation of adenylate cyclase in erythrocytes from various species as well as in rat adipocytes suggest a direct interaction between toxin and the cyclase enzyme which is difficult to reconcile with catalytic mechanisms of adenylate cyclase activation. Direct evidence for this can be obtained from the comigration of toxin radioactivity with adenylate cyclase activity when toxin-activated membranes are dissolved in detergents and chromatographed on gel filtration columns. Agarose derivatives containing the "active" subunit of the toxin can specifically absorb adenylate cyclase activity, and specific antibodies against the choleragen can be used for selective immunoprecipitation of adenylate cyclase activity from detergent-solubilized preparations of activated membranes. It is proposed that toxin action involves the initial formation of an inactive toxin-ganglioside complex which subsequently migrates and is somehow transformed into an active species which involves relocation within the two-dimensional structure of the membrane with direct perturbation of adenylate cyclase molecules (virtually irreversibly). These studies suggest new insights into the normal mechanisms by which hormone receptors modify membrane functions.


Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).


Improving CPR Performance.
Cardiac arrest continues to represent a public health burden with most patients having dismal outcomes. CPR is a complex set of interventions requiring leadership, coordination, and best practices. Despite the widespread adoption of new evidence in various guidelines, the provision of CPR remains variable with poor adherence to published recommendations. Key steps health-care systems can take to enhance the quality of CPR and, potentially, to improve outcomes, include optimizing chest compressions, avoiding hyperventilation, encouraging intraosseous access, and monitoring capnography. Feedback devices provide instantaneous guidance to the rescuer, improve rescuer technique, and could impact patient outcomes. New technologies promise to improve the resuscitation process: mechanical devices standardize chest compressions, capnography guides resuscitation efforts and signals the return of spontaneous circulation, and intraosseous devices minimize interruptions to gain vascular access. This review aims at identifying a discreet group of interventions that health-care systems can use to raise their standard of cardiac resuscitation.


Polyphenol interaction with the T47D human breast cancer cell line.
Experimental and epidemiological studies indicate that antioxidant food polyphenols could have antimitotic activities, interfering with cancer initiation, progression or mortality. Circulating polyphenols are far lower than the nominal value in foods. In the rare studies dealing with polyphenol bioavailability, it was noted that their active concentrations in the blood are <1% of their food concentration. In the present study we investigated the effect of four polyphenols (resveratrol, and the flavonoids quercetin, catechin and epicatechin, major constituents of wine) in the hormone-sensitive human cancer cell line T47D, at concentrations compatible with their calculated plasma concentrations after ingestion of a moderate quantity of wine (nM or pM). Our results indicate that cell growth was decreased, with cells being arrested at the S phase of the cycle. In addition, we provide evidence of a bimodal modulation of the NO/NOS system, affecting its activity and transcription. We show that modulation of this system is sufficient to explain polyphenol action on this cell line. This result suggests a potential importance of wine ingestion and possibly the consumption of other polyphenol-rich dietary foods and drinks in the control of breast cancer cell growth.


Hemoglobins A and A2 in New World primates: comparative variation and its evolutionary implications.
Hemoglobin A(2) (alpha(2)delta(2)) in New World primates represents about 1/160 to 1/16 of total hemoglobin and, by virtue of this low proportion, is presumed to be functionally unimportant. Nonetheless, A(2) exhibits genetic polymorphism by electrophoresis in three out of five genera, whereas the major component, hemoglobin A (alpha(2)beta(2)), is electrophoretically invariant. Moreover, in four genera, including man, the evolutionary accumulation of mutations has been greater in delta than in beta Such findings suggest that both polymorphism and evolutionary changes can accrue to an effectively functionless and thus selectively nearly netutral gene.


Williams-Beuren syndrome: determination of deletion size using quantitative real-time PCR.
Williams-Beuren syndrome (WBS) is a rare genetic disorder (1/20,000-50,000) and is usually caused by a 1.5- to 1.8-Mb heterozygous deletion on chromosome 7q11.23. At least 25 genes have been identified in the deletion region in WBS patients, which is flanked by large low-copy-repeat sequences (> 320 kb). By using FISH as well as microsatellite analysis, it is not possible to get a precise identification of the size of the deletion. For determining the deletion size, we developed a reliable quantitative PCR approach. Our assay screens 2.5 Mb of the WBS region in 100- to 300-kb intervals. This methodology has been tested in DNA samples of 65 patients with the clinical suspicion of WBS. In every case we were able to exclude or to identify the presence of a deletion and to determine its size. Deletion size varied from 0.2 Mb to 2.5 Mb. The 2.5-Mb rearrangement represents the largest deletion described at present and it was detected in a severely affected patient. We report the detection efficiency of this new system and the genotype/phenotype correlation.


Fusion Proteins: Aflibercept (VEGF Trap-Eye).
Vascular endothelial growth factor (VEGF) inhibitors currently used to treat eye diseases have included monoclonal antibodies, antibody fragments, and an aptamer. A different method of achieving VEGF blockade in retinal diseases includes the concept of a cytokine trap. Cytokine traps are being evaluated for the treatment of various diseases that are driven by excessive cytokine levels. Traps, such as VEGF Trap, consist of two extracellular cytokine receptor domains fused together to form a human IgG. Aflibercept (VEGF Trap-Eye) is a soluble fusion protein which combines ligand-binding elements taken from the extracellular components of VEGF receptor (VEGFR)-1 and VEGFR-2 fused to the Fc portion of IgG. This protein contains all human amino-acid sequences, which minimizes the potential for immunogenicity in human patients. The chapter will summarize the chemical properties of aflibercept and the various studies that have demonstrated a role of aflibercept in the management of retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, macular edema, and retinal vein occlusion.


A journey into chaos: creativity and the unconscious.
The capacity to be creative, to produce new concepts, ideas, inventions, objects or art, is perhaps the most important attribute of the human brain. We know very little, however, about the nature of creativity or its neural basis. Some important questions include how should we define creativity? How is it related (or unrelated) to high intelligence? What psychological processes or environmental circumstance cause creative insights to occur? How is it related to conscious and unconscious processes? What is happening at the neural level during moments of creativity? How is it related to health or illness, and especially mental illness? This paper will review introspective accounts from highly creative individuals. These accounts suggest that unconscious processes play an important role in achieving creative insights. Neuroimaging studies of the brain during "REST" (random episodic silent thought, also referred to as the default state) suggest that the association cortices are the primary areas that are active during this state and that the brain is spontaneously reorganising and acting as a self-organising system. Neuroimaging studies also suggest that highly creative individuals have more intense activity in association cortices when performing tasks that challenge them to "make associations." Studies of creative individuals also indicate that they have a higher rate of mental illness than a noncreative comparison group, as well as a higher rate of both creativity and mental illness in their first-degree relatives. This raises interesting questions about the relationship between the nature of the unconscious, the unconscious and the predisposition to both creativity and mental illness.


Electrical signs of selective attention in the human brain.
Auditory evoked potentials were recorded from the vertex of subjects who listened selectively to a series of tone pips in one ear and ignored concurrent tone pips in the other ear. The negative component of the evoked potential peaking at 80 to 110 milliseconds was substantially larger for the attended tones. This negative component indexed a stimulus set mode of selective attention toward the tone pips in one ear. A late positive component peaking at 250 to 400 milliseconds reflected the response set established to recognize infrequent, higher pitched tone pips in the attended series.


Liver function test abnormalities in users of aqueous kava extracts.
Hepatic toxicity from manufactured herbal remedies that contain kava lactones has been reported in Europe, North America, and Australia. There is no evidence for serious liver damage in kava-using populations in Pacific Island societies or in Indigenous Australians who have used aqueous kava extracts. This article presents evidence that liver function changes in users of aqueous kava extracts appear to be reversible. Data from one Arnhem Land community [Northern Territory (NT), Australia] with 340 indigenous people older than 15 years of age in 2000 are used. This study was a cross-sectional study with 98 participants, 36 of whom had never used kava. Among 62 kava users, 23 had discontinued kava at least 1 year before the study. Continuing users had not used kava for 1 to 2 months (n = 10) or 1 to 2 weeks previously (n = 15). Some (n = 14) had used kava within the previous 24 hr. Liver function tests were compared across these groups, taking into account differences due to age, sex, alcohol, and other substance use. The average quantity of kava powder consumed was 118 g/week, and median duration of use was 12 years (range, 1-18 years). Kava usage levels were less than one-half of those found in previous studies. More recent kava use was independently associated with higher levels of liver enzymes gamma-glutamyl transferase (GGT) (p < 0.001) and alkaline phosphatase (ALP) (p < 0.001), but not with alanine aminotransferase or bilirubin, which were not elevated. In those who were not heavy alcohol users, only those who used kava within the previous 24 hr showed GGT levels higher than nonusers (p < 0.001), whereas higher ALP levels occurred only in those who last used kava 1 to 2 weeks (p = 0.015) and 24 hr previously (p = 0.005). Liver function changes in users of aqueous kava extracts at these moderate levels of consumption appear to be reversible and begin to return to baseline after 1 to 2 weeks abstinence from kava. No evidence for irreversible liver damage has been found.


Computational Statistical Methods for Social Network Models.
We review the broad range of recent statistical work in social network models, with emphasis on computational aspects of these methods. Particular focus is applied to exponential-family random graph models (ERGM) and latent variable models for data on complete networks observed at a single time point, though we also briefly review many methods for incompletely observed networks and networks observed at multiple time points. Although we mention far more modeling techniques than we can possibly cover in depth, we provide numerous citations to current literature. We illustrate several of the methods on a small, well-known network dataset, Sampson's monks, providing code where possible so that these analyses may be duplicated.


High efficient single-frequency output at 1991 nm from a diode-pumped Tm:YAP coupled cavity.
A coupled resonator was developed for high efficient room-temperature single-frequency laser operating near 2 mum optical spectral region. 721 mW stable single-longitudinal-mode oscillation at 1991 nm was obtained when the absorbed pumping power was 2.4 W. The optical-to-optical efficiency was 30%, and the slope efficiency was 46%. 5 nm of frequency tuning range was obtained with stable output power. The beam propagation factors M2 were 1.43 and 1.42 in x and y directions, respectively.


Recent progress in morphology control of supramolecular fullerene assemblies and its applications.
Self-organisation is an elegant tool for the creation of assemblies controlled in all dimensions with tunable properties in natural as well as artificial supramolecular systems. Especially, the supramolecular organisation of fullerene (C(60)) using π-stacking interaction to form various functional assemblies is of particular importance as it can provide excellent optoelectronic properties. Interestingly, the insufficient solubility of C(60) has been overcome through the noncovalent interaction with other hosts and covalent functionalisation with organic moieties. This has resulted in supramolecular assemblies at the nano/micro/macro scales under different preparation conditions. The developments in the area of fullerene self-assembly during the last few decades have significantly contributed to the sensible design and fabrication of organic electronic devices. A summary of the very recent reports regarding the organisation of pristine C(60), its coassembly with other hosts, unique polymorphs of fullerene derivatives, functional liquid crystalline assemblies, donor/acceptor heterojunctions and its applications will be presented in this tutorial review. Future research directions in which the supramolecular fullerene assembly may achieve more precision and improve the efficiency of the photovoltaic devices are also discussed.


Direct α-heteroarylation of amides (α to nitrogen) and ethers through a benzaldehyde-mediated photoredox reaction.
A photoredox reaction for cross-dehydrogenative coupling (CDC) was developed to Cα-arylate amides (α to nitrogen) and ethers using a variety of five- and six-membered electron-deficient heteroarenes. A unique decomposition mechanism of ammonium persulfate enhanced by photoexcited benzaldehydes was revealed. This benzaldehyde-mediated photoredox reaction proceeded smoothly with household 23 W CFL bulbs as the energy source under metal-free conditions, allowing the construction of new Csp2 -Csp2 and Csp3 -Csp2 bonds and access to important pharmacophores of broad utility using commercially available reagents.


Mass spectrometric study of oligourea macrocycles and their anion binding behavior.
Two series, one of tris-urea macrocycles and another of hexakis-urea macrocycles, are examined by (tandem) Fourier-transform ion cyclotron resonance (FTICR) mass spectrometry with respect to their fragmentation patterns and anion binding properties. All macrocycles are based on two different building blocks, one of which is a very rigid xanthene unit and the other one is a more flexible diphenyl ether. The composition and the sequence of these units thus determine their flexibility. During the fragmentation of deprotonated oligourea macrocycles in the gas phase, one urea N-CO bond is cleaved followed by a scrambling reaction within the macrocycle structure. Consequently, fragments are observed that deviate from those that would be expected from the sequence of the subunits. Interesting anion binding properties involve the simultaneous recognition of two chloride anions by one of the hexakis-urea macrocycles, whose flexibility allows this host to form a double-helical structure. Flexibility also determines which of the hexameric receptors bears a high sulfate affinity. The interaction energy between some of the macrocycles and sulfate is high enough to even stabilize the intrinsically unstable sulfate dianion.


Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury.
Drug-induced liver injury (DILI) is one of the most cited reasons for the high drug attrition rate and drug withdrawal from the market. The accumulated large amount of high throughput transcriptomic profiles and advances in deep learning provide an unprecedented opportunity to improve the suboptimal performance of DILI prediction. In this study, we developed an eight-layer Deep Neural Network (DNN) model for DILI prediction using transcriptomic profiles of human cell lines (LINCS L1000 dataset) with the current largest binary DILI annotation data [i.e., DILI severity and toxicity (DILIst)]. The developed models were evaluated by Monte Carlo cross-validation (MCCV), permutation test, and an independent validation (IV) set. The developed DNN model achieved the area under the receiver operating characteristic curve (AUC) of 0.802 and 0.798, and balanced accuracy of 0.741 and 0.721 for training and an IV set, respectively, outperforming the conventional machine learning algorithms, including K-nearest neighbors (KNN), Support Vector Machine (SVM), and Random Forest (RF). Moreover, the developed DNN model provided a more balanced sensitivity of 0.839 and specificity of 0.603. Besides, we found the developed DNN model had a superior predictive performance for oncology drugs. Also, the functional and network analysis of genes driving the predictions revealed their relevance to the underlying mechanisms of DILI. The proposed DNN model could be a promising tool for early detection of DILI potential in the pre-clinical setting.


User profiles and personas in the design and development of consumer health technologies.
"The graying of the globe" has resulted in exponential rise in health care expenses, over-worked health care professionals and a growing patient base suffering from multiple chronic diseases, one of which is diabetes. Consumer health technologies (CHT) are considered important catalysts for empowering health care consumers to take a proactive role in managing their health and related costs. Adoption rate and usability of such devices among the aging is far from being satisfactory. Past studies noted the motivation for adoption by the aging is dependent on the suitability/relevance, perceived usability and anticipated benefits associated with usage of technological innovation. Traditional information technology (IT) development adopts a systematic approach without necessarily using a specific user model that personalizes the system to the aging user groups. The aging patient population has unique needs arising from progressive deterioration in both physiological and psychological abilities. These needs are often ignored in the design, development, trial and adoption of consumer health products resulting in low adoption and usage. The main objective of this research is to investigate the user-centered design (UCD), specifically user profiles and personas, as methodological tools to inform the design and development of CHT devices for an aging population. The adoption of user profile and persona has not received much attention in health care informatics research and, in particular, research involving CHT. Our work begins to fill this void in three ways. We (1) illuminate the process of developing CHT user profiles and personas for a Chinese elder population with a demanding health care needs, i.e., self-management of chronic diabetes, with the hope that the resulting profiles and personas may be used as foundational material for informing the design, development and evaluation of CHT in other similar contexts; (2) call attention to how to further enhance and complement traditional user profile and persona techniques for CHT design by integrating cognitive structures and present behavior that drive health care thinking, future behavior and demand; (3) show how the profiles and personas can be used to inform requirements, design and implementation decisions for a technology aimed at facilitating CHT adoption and diffusion for the elderly. To exemplify process and application, we use an action-research methodology, where user profiles and personas of an aging patient population were developed. The resultant profiles and personas were leveraged to improve the design, development and implementation plans of a smart phone application to assist chronically ill aging Chinese diabetic population capable of disease self-management. The results from the study show that user profile and persona can be a valuable methodological approach in capturing the conceptual model of the aging and informing the design and development decisions of CHT. The demonstration of techniques used in this study can serve as a guideline to CHT developers in bringing conceptual user modeling into the design of software interfaces targeted for users with specific health care needs. Specifically, the study provides guidance on the creation and use of profiles and personas to tap into the conceptual models of the targeted elderly population reflecting their preferences, capabilities and attitudes towards using technology in self-management care in general and the smart phone diabetes management application in particular. Insight into the mental model of the aging group has been shown to inform later stages of UCD development (e.g., the creation of prototypes and usability testing) as well as implementation and adoption strategies. The World Health Organization (WHO) predicts that by 2025, 80% of all new cases of diabetes are expected to appear in the developing countries. In fact, the number of diabetic patients in China is estimated to rise to 42.3 million in 2030 from 20.8 million in 2000. Thus, we investigate the Chinese aging population in order to demonstrate the process of developing and using user profile and persona. We hope that the resultant conceptual model of the Chinese aging diabetic population can be used in future research to guide CHT designers interested in designing health care devices for this vulnerable user group.


Purification of the simian virus 40 (SV40) T antigen DNA-binding domain and characterization of its interactions with the SV40 origin.
To better define protein-DNA interactions at a eukaryotic origin, the domain of simian virus 40 (SV40) large T antigen that specifically interacts with the SV40 origin has been purified and its binding to DNA has been characterized. Evidence is presented that the affinity of the purified T antigen DNA-binding domain for the SV40 origin is comparable to that of the full-length T antigen. Furthermore, stable binding of the T antigen DNA-binding domain to the SV40 origin requires pairs of pentanucleotide recognition sites separated by approximately one turn of a DNA double helix and positioned in a head-to-head orientation. Although two pairs of pentanucleotides are present in the SV40 origin, footprinting and band shift experiments indicate that binding is limited to dimer formation on a single pair of pentanucleotides. Finally, it is demonstrated that the T antigen DNA-binding domain interacts poorly with single-stranded DNA.


Adherens junction proteins in tumour progression.
The loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumour cells, is often a consequence of reduced intercellular adhesion. The primary cause of the "scattering" of cells in invasive carcinomas appears to be a disturbance of the integrity of intercellular junctions, often involving the cell adhesion molecule E-cadherin. Permanent and transient molecular mechanisms can lead to the impairment of junction integrity of epithelial cells and thus to the progression of carcinomas towards a more invasive state. These include downregulation of E-cadherin expression and interaction between the adherens junction protein beta-catenin and the tumour suppressor gene product APC.


Reducing vector-borne disease by empowering farmers in integrated vector management.
Irrigated agriculture exposes rural people to health risks associated with vector-borne diseases and pesticides used in agriculture and for public health protection. Most developing countries lack collaboration between the agricultural and health sectors to jointly address these problems. We present an evaluation of a project that uses the "farmer field school" method to teach farmers how to manage vector-borne diseases and how to improve rice yields. Teaching farmers about these two concepts together is known as "integrated pest and vector management". An intersectoral project targeting rice irrigation systems in Sri Lanka. Project partners developed a new curriculum for the field school that included a component on vector-borne diseases. Rice farmers in intervention villages who graduated from the field school took vector-control actions as well as improving environmental sanitation and their personal protection measures against disease transmission. They also reduced their use of agricultural pesticides, especially insecticides. The intervention motivated and enabled rural people to take part in vector-management activities and to reduce several environmental health risks. There is scope for expanding the curriculum to include information on the harmful effects of pesticides on human health and to address other public health concerns. Benefits of this approach for community-based health programmes have not yet been optimally assessed. Also, the institutional basis of the integrated management approach needs to be broadened so that people from a wider range of organizations take part. A monitoring and evaluation system needs to be established to measure the performance of integrated management initiatives.


Intraglandular injection of botulinum toxin a reduces tear production in rabbits.
To develop an animal model and investigate the dose-dependent effect of an intraglandular injection of botulinum toxin A (BTX-A) on tear production. In a volume of 0.1-ml, 0.625-, 1.25-, or 2.5-U BTX-A was injected transconjunctivally in the superolateral lobe of the lacrimal gland of adult New Zealand white female rabbits. In the contralateral lacrimal gland, 0.1 ml of 0.9% sodium chloride was injected. Prior to injection and at 1-week postinjection, photographs were taken to evaluate pre- and postoperative eyelid position. Fluorescein and Rose Bengal stain were used to evaluate the corneal surface, and Schirmer test was used to assess tear production. Glands injected with the intermediate (1.25 U) and the highest (2.5 U) doses of BTX-A displayed a statistically significant decrease in tear production (p = 0.002 and 0.007, respectively) compared with the contralateral saline-injected glands at 1 week. No corneal pathologic factors from excessive dryness were observed following the injection. While postinjection ptosis was observed (p = 0.025), no difference was seen between BTX-A and saline-injected eyes. In rabbits, intraglandular injection of BTX-A resulted in decreased tear production at 1 week. No additional reduction in tear production was seen with a BTX-A dose greater than 1.25 U, suggesting glandular receptor saturation at this dose. Despite suppression of tear production, no corneal pathologic factors were observed. Further studies are needed to refine this animal model with the ultimate goal of determining optimum delivery route and concentration to reduction in tear production while minimizing side effects in patients.


Integration of conductive reduced graphene oxide into microstructured optical fibres for optoelectronics applications.
Integration of conductive materials into optical fibres can largely expand functions of fibre devices including surface plasmon resonator/metamaterial, modulators/detectors, or biosensors. Some early attempts have been made to incorporate metals such as tin into fibres during the fibre drawing process. Due to the restricted range of materials that have compatible melting temperatures with that of silica glass, the methods to incorporate metals along the length of the fibres are very challenging. Moreover, metals are nontransparent with strong light absorption, which causes high fibre loss. This article demonstrates a novel but simple method for creating transparent conductive reduced graphene oxide film onto microstructured silica fibres for potential optoelectronic applications. The strongly confined evanescent field of the suspended core fibres with only 2 μW average power was creatively used to transform graphene oxide into reduced graphene oxide with negligible additional loss. Existence of reduced graphene oxide was confirmed by their characteristic Raman signals, shifting of their fluorescence peaks as well as largely decreased resistance of the bulk GO film after laser beam exposure.


Evolution of a new function by degenerative mutation in cephalochordate steroid receptors.
Gene duplication is the predominant mechanism for the evolution of new genes. Major existing models of this process assume that duplicate genes are redundant; degenerative mutations in one copy can therefore accumulate close to neutrally, usually leading to loss from the genome. When gene products dimerize or interact with other molecules for their functions, however, degenerative mutations in one copy may produce repressor alleles that inhibit the function of the other and are therefore exposed to selection. Here, we describe the evolution of a duplicate repressor by simple degenerative mutations in the steroid hormone receptors (SRs), a biologically crucial vertebrate gene family. We isolated and characterized the SRs of the cephalochordate Branchiostoma floridae, which diverged from other chordates just after duplication of the ancestral SR. The B. floridae genome contains two SRs: BfER, an ortholog of the vertebrate estrogen receptors, and BfSR, an ortholog of the vertebrate receptors for androgens, progestins, and corticosteroids. BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR. The two genes are partially coexpressed, particularly in ovary and testis, suggesting an ancient role in germ cell development. These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR. Either of two historical mutations that occurred during BfER evolution is sufficient to generate a competitive repressor. Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models.


Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C.
Using immunohistochemical staining methods with antibodies to amyloid beta protein and human cystatin C, we examined cerebrovascular amyloid protein in the brains from 46 cases with cerebral amyloid angiopathy (seven with Alzheimer's disease, one with Down's syndrome, 18 with intracranial hemorrhage, 10 with cerebral infarction, and 10 elderly patients without any neurologic disorder). All cerebrovascular amyloid deposits in these 46 cases were consistently immunoreactive to anti-beta protein antibody. However, in nine cases some vascular walls with strong beta protein immunoreactivity also reacted less intensely with the anti-cystatin C antiserum. Of these nine cases, seven showed relatively heavy cerebrovascular amyloid deposition, and all seven had suffered a fatal subcortical hemorrhage presumably caused by cerebral amyloid angiopathy. Previous limited studies have suggested that the amyloid protein seen in elderly individuals with cerebral amyloid angiopathy is composed of beta protein. However, subcortical hemorrhage rarely occurs in such individuals. Our study shows that aged patients with different brain disorders commonly suffer from beta protein-type cerebral amyloid angiopathy, and we also suggest that the severity of beta protein-type cerebrovascular amyloid deposition is a fundamental factor in cerebral amyloid angiopathy-induced brain hemorrhage in the elderly. The nature of the cystatin C-immunoreactive substance in some of these vascular lesions is uncertain, but it might conceivably play an additional important role in the pathogenesis of brain hemorrhage in these cases.


Effect of aging alone on mechanical properties of the normal adult human lung.
For plethysmographic studies of respiratory mechanics, we selected, from a general population, 51 subjects, aged 25-75 yr, who had never smoked, had no present or past cardiorespiratory symptoms or disease, were alpha1-antitrypsin MM phenotypes, and were normal by physical examination, vectorcardiography, and chest roentgenography. Approximately equal numbers of men and women were represented in each of three age groups; 25-35, 36-64, and 65-75. Both sexes demonstrated loss of lung elastic recoil with age, most significant at high lung volumes, but the rate of loss was less than previously reported. Males had higher lung recoil than females of comparable age, but if lung size was taken into account, there were no sex differences in bulk elastic properties. Maximum expiratory flow diminished with age only at low volumes, suggesting that equal pressure points are more centrally located at low lung volumes in the elderly.


Proton dynamics in the strong chelate hydrogen bond of crystalline picolinic acid N-oxide. A new computational approach and infrared, raman and INS study.
Infrared, Raman and INS spectra of picolinic acid N-oxide (PANO) were recorded and examined for the location of the hydronic modes, particularly O-H stretching and COH bending. PANO is representative of strong chelate hydrogen bonds (H-bonds) with its short O...O distance (2.425 A). H-bonding is possibly well-characterized by diffraction, NMR and NQR data and calculated potential energy functions. The analysis of the spectra is assisted by DFT frequency calculations both in the gas phase and in the solid state. The Car-Parrinello quantum mechanical solid-state method is also used for the proton dynamics simulation; it shows the hydron to be located about 99% of time in the energy minimum near the carboxylic oxygen; jumps to the N-O acceptor are rare. The infrared spectrum excels by an extended absorption (Zundel's continuum) interrupted by numerous Evans transmissions. The model proton potential functions on which the theories of continuum formation are based do not correspond to the experimental and computed characteristics of the hydrogen bond in PANO, therefore a novel approach has been developed; it is based on crystal dynamics driven hydronium potential fluctuation. The envelope of one hundred 0 --> 1 OH stretching transitions generated by molecular dynamics simulation exhibits a maximum at 1400 cm-1 and a minor hump at approximately 1600 cm-1. These positions square well with ones predicted for the COH bending and OH stretching frequencies derived from various one- and two-dimensional model potentials. The coincidences with experimental features have to be considered with caution because the CPMD transition envelope is based solely on the OH stretching coordinate while the observed infrared bands correspond to heavily mixed modes as was previously shown by the normal coordinate analysis of the IR spectrum of argon matrix isolated PANO, the present CPMD frequency calculation and the empirical analysis of spectra. The experimental infrared spectra show some unusual characteristics such as large temperature effects on the intensity of some bands, thus presenting a challenge for theoretical band shape treatments. Our calculations clearly show that the present system is characterized by an asymmetric single well potential with no large amplitudes in the hydronium motion, which extends the existence of Zundel-type spectra beyond the established set of hydrogen bonds with large hydronic vibrational amplitudes.


Near surface nucleation and particle mediated growth of colloidal Au nanocrystals.
During non-classical growth of nanostructures via assembly of primary nuclei, nucleation and assembly are assumed to be distinct processes: nanoparticles nucleate randomly and aggregate to form extended structures through Brownian motion in the presence of long-range attractive interactions. Here we investigate the relationship between these two processes by using in situ AFM, in situ, ex situ and cryo TEM and UV-Vis spectroscopy to observe growth of colloidal gold and simulations to develop a mechanistic model of the process. Our results reveal an inexorable link between nucleation and assembly with nuclei forming almost exclusively within a ∼1 nm interfacial region of existing particles. The new particles immediately close the gap either through a diffusive jump or via growth of a neck between the seed and new particle, generating aggregates exhibiting features commonly attributed to oriented attachment of independently nucleated particles. The results demonstrate that creation of initial particle interfaces leads to local environments that redirect growth towards non-classical processes.


Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes.
Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca(2+) overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfunction, which is not fully understood. In this study, we analyzed the contribution of ER-Ca(2+) release through ryanodine receptors (RyRs) and inositol triphosphate receptors (IP(3)Rs) to excitotoxicity in oligodendrocytes in vitro. First, we observed that oligodendrocytes express all previously characterized RyRs and IP(3)Rs. Blockade of Ca(2+)-induced Ca(2+) release by TMB-8 following α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated insults attenuated both oligodendrocyte death and cytosolic Ca(2+) overload. In turn, RyR inhibition by ryanodine reduced as well the Ca(2+) overload whereas IP(3)R inhibition was ineffective. Furthermore, AMPA-triggered mitochondrial membrane depolarization, oxidative stress and activation of caspase-3, which in all instances was diminished by RyR inhibition. In addition, we observed that AMPA induced an ER stress response as revealed by α subunit of the eukaryotic initiation factor 2α phosphorylation, overexpression of GRP chaperones and RyR-dependent cleavage of caspase-12. Finally, attenuating ER stress with salubrinal protected oligodendrocytes from AMPA excitotoxicity. Together, these results show that Ca(2+) release through RyRs contributes to cytosolic Ca(2+) overload, mitochondrial dysfunction, ER stress and cell death following AMPA receptor-mediated excitotoxicity in oligodendrocytes.


Factors associated with health-related quality of life among overweight and obese Korean women.
Health-related quality of life (HRQOL) tends to be lower among individuals who are overweight and obese than those of normal weight, and women may be more vulnerable to lower HRQOL associated with obesity than men. Identifying factors associated with HRQOL may be crucial for improving HRQOL for overweight/obese women. We aimed to determine the factors associated with obesity-specific HRQOL among overweight/obese Korean women. A cross-sectional study was conducted with 125 women aged 20-64 years, who comprised a baseline sample in the Community-based Heart and Weight Management Trial. The data were collected from September 2010 to November 2011. The Weight Efficacy Lifestyle, Beck Depression Inventory-II, Interpersonal Social Evaluation List, and Impact of Weight on Quality of Life (IWQOL)-Lite scales were used to measure self-efficacy for weight control, depressive symptoms, social support, and HRQOL, respectively. Increased body mass index, lower self-efficacy for weight control, and higher levels of depressive symptoms were significantly associated with greater impairment in total IWQOL in the regression models. However, social support was not significantly associated with IWQOL. Along with weight loss strategies, other strategies for improving self-efficacy and alleviating depressive symptoms may be essential for improving HRQOL among overweight and obese women.