Selection on X-linked genes during speciation in the Drosophila athabasca complex.
We present the results of a restriction site survey of variation at five loci in Drosophila athabasca, complimenting a previous study of the period locus. There is considerably greater differentiation between the three semispecies of D. athabasca at the period locus and two other X-linked genes (no-on-transient-A and E74A) than at three autosomal genes (Xdh, Adh and RC98). Using a modification of the HKA test, which uses fixed differences between the semispecies and a test based on differences in Fst among loci, we show that the greater differentiation of the X-linked loci compared with the autosomal loci is inconsistent with a neutral model of molecular evolution. We explore several evolutionary scenarios by computer simulation, including differential migration of X and autosomal genes, very low levels of migration among the semispecies, selective-sweeps, and background selection, and conclude that X-linked selective sweeps in at least two of the semispecies are the best explanation for the data. This evidence that natural selection acted on the X-chromosome suggests that another X-linked trait, mating song differences among the semispecies, may have been the target of selection.


Covid-19 related oncologist's concerns about breast cancer treatment delays and physician well-being (the CROWN study).
To examine how treatment delays brought on by the COVID-19 pandemic impacted the physical and emotional well-being of physicians treating these patients. A cross-sectional survey of physician breast specialists was posted from April 23rd to June 11th, 2020 on membership list serves and social media platforms of the National Accreditation Program for Breast Centers and the American Society of Breast Surgeons. Physician well-being was measured using 6 COVID-19 burnout emotions and the 4-item PROMIS short form for anxiety and sleep disturbance. We examined associations between treatment delays and physician well-being, adjusting for demographic factors, COVID-19 testing and ten COVID-19 pandemic concerns. 870 physicians completed the survey, 61% were surgeons. The mean age of physicians was 52 and 548 (63.9%) were female. 669 (79.4%) reported some delay in patient care as a result of the COVID-19 pandemic. 384 (44.1%) and 529 (60.8%) of physicians scored outside normal limits for anxiety and sleep disturbance, respectively. After adjusting for demographic factors and COVID-19 testing, mean anxiety and COVID-19 burnout scores were significantly higher among physicians whose patients experienced either delays in surgery, adjuvant chemotherapy, radiation, breast imaging or specialty consultation. A multivariable model adjusting for ten physician COVID-19 concerns and delays showed that "delays will impact my emotional well-being" was the strongest concern associated with anxiety, sleep disturbance and COVID-19 burnout factors. Breast cancer treatment delays during the initial surge of the COVID-19 pandemic in the United States were associated with a negative impact on physician emotional wellness.


Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice.
Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.


High MMP-9 activity characterises pleural tuberculosis correlating with granuloma formation.
Tuberculosis (TB) pleural disease is complicated by extensive tissue destruction. Matrix metalloproteinase (MMP)-1 and -9 are implicated in immunopathology of pulmonary and central nervous system TB. There are few data on MMP activity in TB pleurisy. The present study investigated MMP-1, -2 and -9 and their specific inhibitors (tissue inhibitor of metalloproteinase (TIMP)-1 and -2) in tuberculous effusions, and correlated these with clinical and histopathological features. Clinical data, routine blood tests, and pleural fluid/biopsy material were obtained from 89 patients presenting with pleural effusions in a TB-endemic area. MMP-1, -2 and -9 were measured by zymography or western blot, and TIMP-1 and -2 by ELISA. Pleural biopsies were examined microscopically, cultured for acid-alcohol fast bacilli and immunostained for MMP-9. Tuberculous pleural effusions contained the highest concentrations of MMP-9 compared with malignant effusions or heart failure transudates. MMP-9 concentrations were highest in effusions from patients with granulomatous biopsies: median (interquartile range) 108 (61-218) pg x mL(-1) versus 43 (12-83) pg x mL(-1) in those with nongranulomatous pleural biopsies. MMP-1 and -2 were not upregulated in tuberculous pleural fluid. The ratio of MMP-9:TIMP-1 was significantly higher in TB effusions. Tuberculous pleurisy is characterised by a specific pattern of matrix metalloproteinase-9 upregulation, correlating with the presence of granulomas and suggesting a specific role for matrix metalloproteinase-9 in inflammatory responses in tuberculous pleural disease.


Parents' experiences with and preferences for immunization reminder/recall technologies.
To describe parents' experiences and preferences regarding the use of different communication modes for immunization reminder/recall messages. A cross-sectional, Internet-based survey of a nationally representative sample of parents of children 0 to 17 years of age was performed. Survey items included questions regarding previous receipt of reminder/recall notices; preferences for how to receive notices in the future; recentness of changes to home address, home telephone, cell phone, and e-mail information; child's usual site for immunization; and willingness to register cell phone numbers with the child's immunization provider to receive future cell phone or text messages about immunization. Overall, 31% of parents had ever received an immunization reminder/recall notice, usually by mail. For future immunization messages, approximately one-third of parents preferred mail or calls to the home telephone, 16% preferred e-mail, and 8% preferred calls to a cell phone. More than one-half of parents had maintained the same home address, home telephone number, cell phone number, or e-mail address for the previous 3 years. More than one-half of parents were willing to register their cell phone numbers with their child's usual immunization provider. Although most parents continue to prefer the traditional modes for immunization reminder/recall messages, 1 in 4 preferred newer technologies, and parents' e-mail and cell phone information was surprisingly stable. More than one-half of the parents were willing to register their cell phone numbers for future immunization messaging via cell phone calls or text messages. Research and implementation efforts might benefit from focusing on this willing population.


The ESCRT-II Subunit EAP20/VPS25 and the Bro1 Domain Proteins HD-PTP and BROX Are Individually Dispensable for Herpes Simplex Virus 1 Replication.
Capsid envelopment during assembly of the neurotropic herpesviruses herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) in the infected cell cytoplasm is thought to involve the late-acting cellular ESCRT (endosomal sorting complex required for transport) components ESCRT-III and VPS4 (vacuolar protein sorting 4). However, HSV-1, unlike members of many other families of enveloped viruses, does not appear to require the ESCRT-I subunit TSG101 or the Bro1 domain-containing protein ALIX (Alg-2-interacting protein X) to recruit and activate ESCRT-III. Alternative cellular factors that are known to be capable of regulating ESCRT-III function include the ESCRT-II complex and other members of the Bro1 family. We therefore used small interfering RNA (siRNA) to knock down the essential ESCRT-II subunit EAP20/VPS25 (ELL-associated protein 20/vacuolar protein sorting 25) and the Bro1 proteins HD-PTP (His domain-containing protein tyrosine phosphatase) and BROX (Bro1 domain and CAAX motif containing). We demonstrated reductions in levels of the targeted proteins by Western blotting and used quantitative microscopic assays to confirm loss of ESCRT-II and HD-PTP function. We found that in single-step replication experiments, the final yields of HSV-1 were unchanged following loss of EAP20, HD-PTP, or BROX.IMPORTANCE HSV-1 is a pathogen of the human nervous system that uses its own virus-encoded proteins and the normal cellular ESCRT machinery to drive the construction of its envelope. How HSV-1 structural proteins interact with ESCRT components and which subsets of cellular ESCRT proteins are utilized by the virus remain largely unknown. Here, we demonstrate that an essential component of the ESCRT-II complex and two ESCRT-associated Bro1 proteins are dispensable for HSV-1 replication.


Reputation Management in Children on the Autism Spectrum.
Being able to manage reputation is an important social skill, but it is unclear whether autistic children can manage reputation. This study investigated whether 33 autistic children matched to 33 typical children could implicitly or explicitly manage reputation. Further, we examined whether cognitive processes-theory of mind, social motivation, inhibitory control and reciprocity-contribute to reputation management. Results showed that neither group implicitly managed reputation, and there was no group difference in explicit reputation management. Results suggested different mechanisms contribute to reputation management in these groups-social motivation in typical children and reciprocity in autistic children. Explicit reputation management is achievable for autistic children, and there are individual differences in its relationship to underlying cognitive processes.


Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.
In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.


Comparison of self-reported health-related quality of life between Taiwan hemodialysis and peritoneal dialysis patients: a multi-center collaborative study.
The maintenance of good health-related quality of life (HRQoL) is an important goal for end-stage renal disease (ESRD) patients. Whether hemodialysis (HD) and peritoneal dialysis (PD) have different impacts on HRQoL is a concern shared by both physicians and patients. A comparison study of HRQoL between Taiwanese HD and PD patients was conducted. ESRD patients at 14 hospitals or dialysis centers in northern Taiwan were recruited in this cross-sectional study. The Chinese-language version of the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) was used to evaluate HRQoL. Ordinal regression analyses were used to explore the independent association between HRQoL scores and dialysis modality. By Bonferroni correction test, a P value of <0.005 was regarded as significant. A total of 866 HD patients and 301 PD patients were included. After adjusting for confounding factors, no difference in HRQoL was found among the entire cohort and the diabetic subgroup. This study demonstrated that Taiwanese HD and PD patients had similar HRQoL. The current survey improves our understanding of the association of HRQoL with dialysis modality in Taiwan ESRD population.


Time Preferences Predict Mortality among HIV-Infected Adults Receiving Antiretroviral Therapy in Kenya.
Identifying characteristics of HIV-infected adults likely to have poor treatment outcomes can be useful for targeting interventions efficiently. Research in economics and psychology suggests that individuals' intertemporal time preferences, which indicate the extent to which they trade-off immediate vs. future cost and benefits, can influence various health behaviors. While there is empirical support for the association between time preferences and various non-HIV health behaviors and outcomes, the extent to which time preferences predict outcomes of those receiving antiretroviral therapy (ART) has not been examined previously. HIV-infected adults initiating ART were enrolled at a health facility in Kenya. Participants' time preferences were measured at enrollment and used to classify them as having either a low or high discount rate for future benefits. At 48 weeks, we assessed mortality and ART adherence, as measured by Medication Event Monitoring System (MEMS). Logistic regression models adjusting for socio-economic characteristics and risk factors were used to determine the association between time preferences and mortality as well as MEMS adherence ≥90%. Overall, 44% (96/220) of participants were classified as having high discount rates. Participants with high discount rates had significantly higher 48-week mortality than participants with low discount rates (9.3% vs. 3.1%; adjusted odds ratio 3.84; 95% CI 1.03, 14.50). MEMS adherence ≥90% was similar for participants with high vs. low discount rates (42.3% vs. 49.6%, AOR 0.70; 95% CI 0.40, 1.25). High discount rates were associated with significantly higher risk of mortality among HIV-infected patients initiating ART. Greater use of time preference measures may improve identification of patients at risk of poor clinical outcomes. More research is needed to further identify mechanisms of action and also to build upon and test the generalizability of this finding.


Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders.
The cellular and molecular mechanisms underlying neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The ability to generate patient-specific induced pluripotent stem cells (iPSCs) now offers a novel strategy for modelling human diseases. Recent studies have reported the derivation of iPSCs from patients with neurological disorders. The key challenge remains the demonstration of disease-related phenotypes and the ability to model the disease. Here we report a case study with signs of neurodevelopmental disorders (NDDs) harbouring chromosomal rearrangements that were sequenced using long-insert DNA paired-end tag (DNA-PET) sequencing approach. We identified the disruption of a specific gene, GTDC1. By deriving iPSCs from this patient and differentiating them into neural progenitor cells (NPCs) and neurons we dissected the disease process at the cellular level and observed defects in both NPCs and neuronal cells. We also showed that disruption of GTDC1 expression in wild type human NPCs and neurons showed a similar phenotype as patient's iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC1 in the development of the central nervous system. Our findings highlight the importance of combining sequencing technologies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.


Enhanced surveillance of HIV-1 drug resistance in recently infected MSM in the UK.
To determine the prevalence of inferred low-frequency HIV-1 transmitted drug resistance (TDR) in MSM in the UK and its predicted effect on first-line therapy. The HIV-1 pol gene was amplified from 442 newly diagnosed MSM identified as likely recently infected by serological avidity testing in 2011-13. The PCR products were sequenced by next-generation sequencing with a mutation frequency threshold of >2% and TDR mutations defined according to the 2009 WHO surveillance drug resistance mutations list. The majority (75.6%) were infected with subtype B and 6.6% with rare complex or unique recombinant forms. At a mutation frequency threshold of >20%, 7.2% (95% CI 5.0%-10.1%) of the sequences had TDR and this doubled to 15.8% (95% CI 12.6%-19.6%) at >2% mutation frequency (P < 0.0001). The majority (26/42, 62%) of low-frequency variants were against PIs. The most common mutations detected at >20% and 2%-20% mutation frequency differed for each drug class, these respectively being: L90M (n = 7) and M46IL (n = 10) for PIs; T215rev (n = 9) and D67GN (n = 4) for NRTIs; and K103N (n = 5) and G190E (n = 2) for NNRTIs. Combined TDR was more frequent in subtype B than non-B (OR = 0.38; 95% CI = 0.17-0.88; P = 0.024) and had minimal predicted effect on recommended first-line therapies. The data suggest differences in the types of low-frequency compared with majority TDR variants that require a better understanding of the origins and clinical significance of low-frequency variants. This will better inform diagnostic and treatment strategies.


The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans.
Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.


Sintering-Resistant Single-Site Nickel Catalyst Supported by Metal-Organic Framework.
Developing supported single-site catalysts is an important goal in heterogeneous catalysis since the well-defined active sites afford opportunities for detailed mechanistic studies, thereby facilitating the design of improved catalysts. We present herein a method for installing Ni ions uniformly and precisely on the node of a Zr-based metal-organic framework (MOF), NU-1000, in high density and large quantity (denoted as Ni-AIM) using atomic layer deposition (ALD) in a MOF (AIM). Ni-AIM is demonstrated to be an efficient gas-phase hydrogenation catalyst upon activation. The structure of the active sites in Ni-AIM is proposed, revealing its single-site nature. More importantly, due to the organic linker used to construct the MOF support, the Ni ions stay isolated throughout the hydrogenation catalysis, in accord with its long-term stability. A quantum chemical characterization of the catalyst and the catalytic process complements the experimental results. With validation of computational modeling protocols, we further targeted ethylene oligomerization catalysis by Ni-AIM guided by theoretical prediction. Given the generality of the AIM methodology, this emerging class of materials should prove ripe for the discovery of new catalysts for the transformation of volatile substrates.


Indirect effects of habitat disturbance on invasion: nutritious litter from a grazing resistant plant favors alien over native Collembola.
Biological invasions are major threats to biodiversity, with impacts that may be compounded by other forms of environmental change. Observations of high density of the invasive springtail (Collembola), Hypogastrura manubrialis in heavily grazed renosterveld vegetation in the Western Cape, South Africa, raised the question of whether the invasion was favored by changes in plant litter quality associated with habitat disturbance in this vegetation type. To examine the likely mechanisms underlying the high abundance of H. manubrialis, cages with three types of naturally occurring litter with different nutrient content were placed out in the area and collected after different periods of time. Hypogastrura manubrialis was mainly found in the nutrient-rich litter of the yellowbush (Galenia africana), which responds positively to disturbance in the form of overgrazing. This suggests that invasion may have been facilitated by a positive interaction with this grazing resistant plant. By contrast, indigenous Collembola were least abundant in yellowbush litter. Negative correlations between high abundance of H. manubrialis and the abundance and diversity of other species suggest that competitive interactions might underlie low abundance of these other species at the patch level. Group behavior enables H. manubrialis to utilize efficiently this ephemeral, high quality resource, and might improve its competitive ability. The results suggest that interactions among environmental change drivers may lead to unforeseen invasion effects. H. manubrialis is not likely to be very successful in un-grazed renosterveld, but in combination with grazing, favoring the nutrient-rich yellowbush, it may become highly invasive. Field manipulations are required to fully verify these conclusions.


Medication optimisation in severe mental illness (MEDIATE): protocol for a realist review.
Severe mental illness (SMI) is associated with significant morbidity and mortality. People living with SMI often receive complex medication regimens. Optimising these regimens can be challenging. Non-adherence is common and addressing it requires a collaborative approach to decision making. MEDIATE uses a realist approach with extensive engagement with experts-by-experience to make sense of the complexities and identify potential solutions.Realist research is used to unpack and explain complexity using programme theory/theories that contain causal explanations of outcomes, expressed as context-mechanism-outcome-configurations. The programme theory/theories will enable MEDIATE to address its aim of understanding what works, for whom, in what circumstances, to optimise medication use with people living with SMI. MEDIATE will be conducted over six stages. In stage 1, we will collaborate with our service user/family carer lived experience group (LEG) and practitioner stakeholder group (SG), to determine the focus. In stage 2, we will develop initial programme theories for what needs to be done, by whom, how and why, and in what contexts to optimise medication use. In stage 3, we will develop and run searches to identify secondary data to refine our initial programme theories.Stage 4 involves selection and appraisal: documents will be screened by title, abstract/keywords and full text against inclusion and exclusion criteria. In stage 5, relevant data will extracted, recorded and coded. Data will be analysed using a realist logic with input from the LEG and SG. Finally, in stage 6, refined programme theories will be developed, identifying causal explanations for key outcomes and the strategies required to change contexts to trigger the key mechanisms that produce these outcomes. Primary data will not be collected, and therefore, ethical approval is not required. MEDIATE will be disseminated via publications, conferences and form the basis for future grant applications. CRD42021280980.


Phylogenetic characterization of the epibiotic bacteria associated with the hydrothermal vent polychaete Alvinella pompejana.
Alvinella pompejana is a polychaetous annelid that inhabits active deep-sea hydrothermal vent sites along the East Pacific Rise, where it colonizes the walls of actively venting high-temperature chimneys. An abundant, morphologically diverse epibiotic microflora is associated with the worm's dorsal integument, with a highly integrated filamentous morphotype clearly dominating the microbial biomass. It has been suggested that this bacterial population participates in either the nutrition of the worm or in detoxification of the worm's immediate environment. The primary goal of this study was to phylogenetically characterize selected epibionts through the analysis of 16S rRNA gene sequences. Nucleic acids were extracted from bacteria collected from the dorsal surface of A. pompejana. 16S rRNA genes were amplified with universal bacterial primers by the PCR. These genes were subsequently cloned, and the resulting clone library was screened by restriction fragment length polymorphism analysis to identify distinct clone types. The restriction fragment length polymorphism analysis identified 32 different clone families in the library. Four of these families were clearly dominant, representing more than 65% of the library. Representatives from the four most abundant clone families were chosen for complete 16S rRNA gene sequencing and phylogenetic analysis. These gene sequences were analyzed by a variety of phylogenetic inference methods and found to be related to the newly established epsilon subdivision of the division Proteobacteria. Secondary structural model comparisons and comparisons of established signature base positions in the 16S rRNA confirmed the placement of the Alvinella clones in the epsilon subdivision of the Proteobacteria.


New approach to technical and clinical evaluation of devices for self-monitoring of blood glucose.
Despite the wide distribution of devices for self-monitoring of blood glucose (SMBG), there is no internationally accepted agreement on a standardized procedure for their evaluation. This is due to incomplete or even inappropriate technical evaluation and to inadequate evaluation criteria for their clinical acceptability. To provide adequate information on the performance of these devices over the whole clinically relevant range for SMBG (30-350 mg/dl), a standardized test procedure has been established for technical (accuracy, precision, and total deviation) and clinical (acceptance analysis) evaluation. To demonstrate the potency of this new approach, the following SMBG devices and test strips were evaluated: Chemstrip bG batch (n = 10), Glucostix batch (n = 2), Accu-Check II (n = 5), Diascan (n = 5), Diascan strip batch (n = 4), Glucocheck SC (n = 4), and Glucometer II (n = 4). The devices and test strips were examined by trained technicians, and in addition, 1 Chemstrip bG batch and 2 Accu-Check II meters were examined by 10 and 5 trained diabetic patients, respectively. Even the best-performing device did not achieve the American Diabetes Association's goal that SMBG measurements should be within 15% of the reference value. Instead, the maximal total deviation within the clinically relevant blood glucose range reached values that equalled deviations from the reference value between 16 and 108%. Three of 36 devices were classified as good, 29 as acceptable, and 4 as unacceptable for clinical use. In conclusion, this new approach to the technical and clinical evaluation of devices for SMBG is easy to perform and provides more realistic and comparable information for clinical use and approval than commonly used methods.


A human antibody against anthrax protective antigen protects rabbits from lethal infection with aerosolized spores.
ALXN4100, a fully human antibody that binds to the protective antigen of anthrax toxin, was generated from a Fab isolated from a phage display library and was analyzed for its pharmacokinetic properties in rabbits and then used to protect rabbits from challenge with a lethal aerosol dose of Bacillus anthracis spores (approximately 322X LD(50)). All rabbits receiving 15 or 40 mg/kg of antibody 24 hours before challenge survived; survival of rabbits receiving 4 mg/kg either subcutaneously or intravenously was 80 or 90%, respectively. Susceptibility to anthrax disease appeared to be correlated with serum antibody concentration. This study indicates that ALXN4100 has the potential to be useful for prophylaxis of anthrax disease in humans.


Impact of superior ophthalmic vein thrombosis: a case series and literature review.
Purpose: To present nine new cases of superior ophthalmic vein thrombosis (SOVT) and compare these with the literature, and to assess the impact of SOVT for the clinician. Methods: Using the data bases of the Department of Ophthalmology of the AMC, we searched for patients with radiologically evidenced SOVT between January 2006 and December 2014. In addition, a PubMed search, using the mesh term 'superior ophthalmic vein thrombosis', was done. Results: We found nine patients with SOVT. In three patients, SOVT was related to dural arteriovenous fistulae. In one patient, it was caused by the acute reversal of warfarin by vitamin K. In two patients, an infectious cause was found. In three patients, the cause of SOVT was not found despite screening for coagulation and other disorders. All patients presented with eyelid swelling, proptosis, and/or motility impairment. We found complete recovery in four patients. Three patients had mild sequelae and two patients had severe visual impairment. In the literature, we found 60 cases reporting on SOVT with various aetiologies. Clinical presentation, treatment modalities, and outcomes were comparable to our findings. Conclusion: Our case series and literature review show that SOVT can occur simultaneously with cavernous sinus thrombosis (CST) but can also be a separate entity. Clinical presentation can mimic orbital cellulitis (OC) or CST and when no signs of OC can be found, an alternative cause for SOVT should be sought. When timely and adequate treatment is conducted, the prognosis is predominantly favourable.


Identification of genes associated with bud dormancy release in Prunus persica by suppression subtractive hybridization.
To better understand the molecular and physiological mechanisms underlying maintenance and release of seasonal bud dormancy in perennial trees, we identified differentially expressed genes during dormancy progression in reproductive buds from peach (Prunus persica [L.] Batsch) by suppression subtractive hybridization (SSH) and microarray hybridization. Four SSH libraries were constructed, which were respectively enriched in cDNA highly expressed in dormant buds (named DR), in dormancy-released buds (RD) and in the cultivars with different chilling requirement, 'Zincal 5' (ZS) and 'Springlady' (SZ), sampled after dormancy release. About 2500 clones picked from the four libraries were loaded on a glass microarray. Hybridization of microarrays with the final products of SSH procedure was performed in order to validate the selected clones that were effectively enriched in their respective sample. Nearly 400 positive clones were sequenced, which corresponded to 101 different unigenes with diverse functional annotation. We obtained DAM4, 5 and 6 genes coding for MADS-box transcription factors previously related to growth cessation and terminal bud formation in the evergrowing mutant of peach. Several other cDNAs are similar to dormancy factors described in other species, and others have been related to bud dormancy for the first time in this study. Quantitative reverse transcription polymerase chain reaction analysis confirmed differential expression of cDNAs coding for a Zn-finger transcription factor, a GRAS-like regulator, a DNA-binding protein and proteins similar to forisome subunits involved in the reversible occlusion of sieve elements in Fabaceae, among others.


Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6,244 Japanese individuals.
Additional susceptibility loci for type 2 diabetes have been identified by a meta-analysis of genome-wide association studies (GWASs) in European populations. To examine further the roles of these new loci, we performed a replication study for the association of these single-nucleotide polymorphism (SNP) loci with the disease in three independent Japanese populations. We genotyped seven of the 11 SNPs that emerged in stage 2 of the meta-analysis for European GWASs (rs864745 in JAZF1, rs12779790 near CDC123/CAMK1D, rs7961581 near TSPAN8/LGR5, rs4607103 near ADAMTS9, rs10923931 in NOTCH2, rs1153188 near DCD and rs9472138 near VEGFA) for three independent Japanese populations (first set, 1,630 type 2 diabetes patients vs 1,064 controls; second set, 1,272 type 2 diabetes patients vs 856 controls; third set, 486 type 2 diabetes patients vs 936 controls) using a TaqMan assay. The association of the SNP loci in each population was analysed using a logistic regression analysis, adjusting for age, sex and BMI, and the data were evaluated by a meta-analysis. A meta-analysis for the three case-control studies identified a nominal association of rs864745 in JAZF1 with type 2 diabetes (OR 1.148, 95% CI 1.034-1.275, p = 0.0098, corrected p = 0.069). The association of other loci did not reach statistically significant levels (nominal p > 0.05). From these results the contribution of these seven loci in conferring susceptibility to type 2 diabetes is considered minor in the Japanese population, if they are present.


18F-Fluoroestradiol.
Estrogen receptor (ER) expression is an important determinant of breast cancer behavior and is critical for response to endocrine therapies such as tamoxifen and aromatase inhibitors. In current practice, ER expression is determined by assay of biopsy material. In more advanced disease, tissue assay may present practical difficulties and be associated with significant sampling error. This and other considerations motivated the development of ER imaging agents for positron emission tomography (PET), of which the most successful has been (18)F-16alpha-17beta-fluoroestradiol (FES). In this review, we highlight aspects of ER biology and the importance of the ER in breast cancer therapy; review the structure and synthesis of FES; describe its kinetics and safety/dosimetry data; and highlight validation studies. Also discussed are early results in patients using FES-PET to localize ER-expressing tumors and associated data pointing toward its accuracy as a predictive assay for breast cancer endocrine therapy. Finally, early data for tumors and sites other than breast cancer are mentioned. Preliminary data strongly point toward potential clinical utility for FES-PET, motivating further validation and future clinical trials with prospective endpoints tested under appropriate regulatory oversight.


Erythrocyte entry by malarial parasites. A moving junction between erythrocyte and parasite.
Invasion of erythrocytes by merozoites of the monkey malaria, Plasmodium knowlesi, was investigated by electron microscopy. The apical end of the merozoite makes initial contact with the erythrocyte, creating a small depression in the erythrocyte membrane. The area of the erythrocyte membrane to which the merozoite is attached becomes thickened and forms a junction with the plasma membrane of the merozoite. As the merozoite enters the invagination in the erythrocyte surface, the junction, which is in the form of a circumferential zone of attachment between the erythrocyte and merozoite, moves along the confronted membranes to maintain its position at the orifice of the invagination. When entry is completed, the orifice closes behind the parasite in the fashion of an iris diaphragm, and the junction becomes a part of the parasitophorous vacuole. The movement of the junction during invasion is an important component of the mechanism by which the merozoite enters the erythrocyte. The extracellular merozoite is covered with a prominent surface coat. During invasion, this coat appears to be absent from the portion of the merozoite within the erythrocyte invagination, but the density of the surface coat outside the invagination (beyond the junction) is unaltered.


Cathinone, a natural amphetamine.
Cathinone is an alkaloid that has been discovered some fifteen years ago in the leaves of the khat bush. This plant grows in East Africa and in southern Arabia, and the inhabitants of these regions frequently chew khat because of its stimulating properties. Cathinone, which is S(-)-alpha-aminopropiophenone, was soon found to have a pharmacological profile closely resembling that of amphetamine; indeed, in a wide variety of in vitro and in vivo experiments it was demonstrated that cathinone shares the action of amphetamine on CNS as well as its sympathomimetic effects; thus, for example, drug-conditioned animals will not distinguish between cathinone and amphetamine. These various observations were confirmed by a clinical experiment showing that cathinone also in humans produces amphetamine-like objective and subjective effects. Finally, it was demonstrated that cathinone operates through the same mechanism as amphetamine, i.e. it acts by releasing catecholamines from presynaptic storage sites. Thus, much experimental evidence indicates that cathinone is the main psychoactive constituent of the khat leaf and that, in fact, this alkaloid is a natural amphetamine.


Cognitive-behavioural theories and adherence: Application and relevance in antiretroviral therapy.
Adherence in chronic disease conditions is described as the extent to which a person's behaviour corresponds to the prescribed medical advice of the healthcare provider. This is not limited to medication intake only but also includes acts such as following instructions regarding dietary or fluid restrictions and taking medicines at the prescribed times and intervals. Although adherence to antiretroviral therapy (ART) is a predictor of good clinical outcome among HIV-infected persons on ART, it is a major challenge and strict adherence is not very common. This article aims to examine the application and relevance of some cognitive-behavioural theories in antiretroviral therapy adherence. After doing a thorough literature review, contemporary theories of health behaviour at the individual and interpersonal levels referred to as cognitive-behavioural theories were explored. This review highlights some aspects of the cognitive perspective of health behaviour theories as a good theoretical framework that could be used for organising thoughts about adherence and other health behaviours among patients on lifelong treatment such as ART. Key concepts of these theories stipulate that behaviour is mediated by cognition i.e. knowledge and attitude affect the person's action. In addition, cognitive-behavioural theories recognise knowledge alone as being insufficient to produce behavioural change; a person's perception, motivation, skills and social environment are all influential in the process of behavioural change. Prediction of medication adherence is complex, and health-related knowledge and beliefs alone are insufficient to achieve behaviour change, especially in chronic conditions such as HIV/AIDS. However, people can control or influence the events affecting their lives by integrating cognitive, social, and behavioural sub-skills related to beliefs of personal efficacy in performing these skills.


Fabrication and characterization of monolithically integrated microchannel plates based on amorphous silicon.
Microchannel plates are vacuum-based electron multipliers for particle--in particular, photon--detection, with applications ranging from image intensifiers to single-photon detectors. Their key strengths are large signal amplification, large active area, micrometric spatial resolution and picosecond temporal resolution. Here, we present the first microchannel plate made of hydrogenated amorphous silicon (a-Si:H) instead of lead glass. The breakthrough lies in the possibility of realizing amorphous silicon-based microchannel plates (AMCPs) on any kind of substrate. This achievement is based on mastering the deposition of an ultra-thick (80-120 μm) stress-controlled a-Si:H layer from the gas phase at temperatures of about 200 °C and micromachining the channels by dry etching. We fabricated AMCPs that are vertically integrated on metallic anodes of test structures, proving the feasibility of monolithic integration of, for instance, AMCPs on application-specific integrated circuits for signal processing. We show an electron multiplication factor exceeding 30 for an aspect ratio, namely channel length over aperture, of 12.5:1. This result was achieved for input photoelectron currents up to 100 pA, in the continuous illumination regime, which provides a first evidence of the a-Si:H effectiveness in replenishing the electrons dispensed in the multiplication process.


Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.
Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. Treatment with either methylphenidate or a matched placebo for 16 weeks. Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up. identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.


Reducing rural maternal mortality and the equity gap in northern Nigeria: the public health evidence for the Community Communication Emergency Referral strategy.
The Sustainable Development Goal (SDG) maternal mortality target risks being underachieved like its Millennium Development Goal (MDG) predecessor. The MDG skilled birth attendant (SBA) strategy proved inadequate to end preventable maternal deaths for the millions of rural women living in resource-constrained settings. This equity gap has been successfully addressed by integrating a community-based emergency obstetric care strategy into the intrapartum care SBA delivery strategy in a large scale, northern Nigerian health systems strengthening project. The Community Communication Emergency Referral (CCER) strategy catalyzes community capacity for timely evacuations to emergency obstetric care facilities instead of promoting SBA deliveries in environments where SBA availability and accessibility will remain inadequate for the near and medium term. Community Communication is an innovative, efficient, equitable, and culturally appropriate community mobilization approach that empowers low- and nonliterate community members to become the communicators. For the CCER strategy, this community mobilization approach was used to establish and maintain emergency maternal care support structures. Public health evidence demonstrates the success of integrating the CCER strategy into the SBA strategy and the practicability of this combined strategy at scale. In intervention sites, the maternal mortality ratio reduced by 16.8% from extremely high levels within 4 years. Significantly, the CCER strategy contributed to saving one-third of the lives saved in the project sites, thereby maximizing the effectiveness of the SBAs and upgraded emergency obstetric care facilities. Pre- and postimplementation Knowledge, Attitude, and Practice Survey results and qualitative assessments support the CCER theory of change. This theory of change rests on a set of implementation steps that rely on three innovative components: Community Communication, Rapid Imitation Practice, and CCER support structures. Innovative communication body tools and the rote learning Rapid Imitation Practice training methodology enabled low-literate volunteers to saturate their communities with informed group discussions transferring communication capacity and ownership to the discussion participants. CCER is especially efficient because virtually every timely, community referral for emergency maternal care results in a saved life, whereas on average, only one in every eight births delivered by an SBA (12%) is expected to be a delivery-associated complication requiring lifesaving care.


Repair of Critical-Sized Long Bone Defects Using Dipyridamole-Augmented 3D-Printed Bioactive Ceramic Scaffolds.
There are over two million long bone defects treated in the United States annually, of which ~5% will not heal without significant surgical intervention. While autogenous grafting is the standard of care in simple defects, a customized scaffold for large defects in unlimited quantities is not available. Recently, a three-dimensionally (3D)-printed bioactive ceramic (3DPBC) scaffold has been successfully utilized in the of repair critical-sized (CSD) long bone defects in vivo. In this study, 3DPBC scaffolds were augmented with dipyridamole (DIPY), an adenosine A2A receptor (A2A R) indirect agonist, because of its known effect to enhance bone formation. CSD full thickness segmental defects (~11 mm × full thickness) defects were created in the radial diaphysis in New Zealand white rabbits (n = 24). A customized 3DPBC scaffold composed of β-tricalcium phosphate was placed into the defect site. Groups included scaffolds that were collagen-coated (COLL), or immersed in 10, 100, or 1,000 μM DIPY solution. Animals were euthanized 8 weeks post-operatively and the radii/ulna-scaffold complex retrieved en bloc, for micro-CT, histological, and mechanical analysis. Bone growth was assessed exclusively within scaffold pores and evaluated by microCT and advanced reconstruction software. Biomechanical properties were evaluated utilizing nanoindentation to assess the newly regenerated bone for elastic modulus (E) and hardness (H). MicroCT reconstructions illustrated bone in-growth throughout the scaffold, with an increase in bone volume dependent on the DIPY dosage. The histological evaluation did not indicate any adverse immune response while revealing progressive remodeling of bone. These customized biologic 3DPBC scaffolds have the potential of repairing and regenerating bone. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2499-2507, 2019.


Genetic predisposition to ductal carcinoma in situ of the breast.
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.


Ecological traits and environmental affinity explain Red Sea fish introduction into the Mediterranean.
Alien species are considered one of the prime threats to biodiversity, driving major changes in ecosystem structure and function. Identifying the traits associated with alien introduction has been largely restricted to comparing indigenous and alien species or comparing alien species that differ in abundance or impact. However, a more complete understanding may emerge when the entire pool of potential alien species is used as a control, information that is rarely available. In the eastern Mediterranean, the marine environment is undergoing an unparalleled species composition transformation, as a flood of aliens have entered from the Red Sea following the opening of the Suez Canal in 1869. In this study, we compile data on species traits, geographical distribution, and environmental affinity of the entire pool of reef-associated fish species in the Red Sea and more generally across the Indo-Pacific. We use this extensive data to identify the prime characteristics separating Red Sea species that have become alien in the Mediterranean from those that have not. We find that alien species occupy a larger range of environments in their native ranges, explaining their ability to colonize the seasonal Mediterranean. Red Sea species that naturally experience high maximum temperatures in their native range have a high probability of becoming alien. Thus, contrary to predictions of an accelerating number of aliens following increased water temperatures, hotter summers in this region may prevent the establishment of many alien species. We further find that ecological trait diversity of alien species is substantially more evenly spaced and more divergent than random samples from the pool of Red Sea species, pointing at additional processes, such as competition, promoting ecological diversity among alien species. We use these results to provide a first quantitative ranking of the potential of Red Sea species to become established in the eastern Mediterranean.


Identifying malaria control issues: a district hospital-based evaluation.
Chuk district hospital is centrally located in a rural malarious region in southern Cambodia. It was the site of a hospital-based evaluation (KAP assessment and in vivo i.v. quinine/oral tetracycline drug study) done to identify relevant issues for establishing a rational malaria control strategy. The KAP assessment identified the young, male forest worker as the highest risk group. Of 112 study patients, 73% were male and 82% reported various forest activities. The primary reason found for patient delay (8.9 days) in seeking hospital care was self-treatment at home (N = 102, 91%) with drugs purchased through private sellers (104/105). Using the 7-day WHO field test methodology, resistance rates were calculated (N = 22); S1/R1, 73%; R1, 9%; R2, 0%; R3, 18%. A modified version of the 7-day test was used to calculate its utility in this particular rural setting. It showed a negative predictive value of 93% and a positive predictive value of 71%. The case fatality rate for the study period was 2.7%. Information from this study, which correlates a confirmed malaria diagnosis with prior patient behavior and response to anti-malarial therapy, is intended for realizing the goals set forth by the national malaria control program.


Investigating a space-variant weighted salience account of visual selection.
Weighted salience models are a popular framework for image-driven visual attentional processes. These models operate by: sampling the visual environment; calculating feature maps; combining them in a weighted sum and using this to determine where the eye will fixate next. We examine these stages in turn. We find that a biologically plausible non-uniform retinal sampling causes feature coding unreliability. The linear weighted sum operation seems an adequate model if statistical feature dimension dependencies are considered. Using signal detection theory we find good discrimination between targets and non-targets in the weighted sum, but the fixation criterion of 'peak salience' is suboptimal.


Relativistic statistical arbitrage.
Recent advances in high-frequency financial trading have made light propagation delays between geographically separated exchanges relevant. Here we show that there exist optimal locations from which to coordinate the statistical arbitrage of pairs of spacelike separated securities, and calculate a representative map of such locations on Earth. Furthermore, trading local securities along chains of such intermediate locations results in a novel econophysical effect, in which the relativistic propagation of tradable information is effectively slowed or stopped by arbitrage.


Rivet Graphene.
Large-area graphene has emerged as a promising material for use in flexible and transparent electronics due to its flexibility and optical and electronic properties. The anchoring of transition metal nanoparticles on large-area single-layer graphene is still a challenge. Here, we report an in situ preparation of carbon nano-onion-encapsulated Fe nanoparticles on rebar graphene, which we term rivet graphene. The hybrid film, which allows for polymer-free transfer and is strong enough to float on water with no added supports, exhibits high optical transparency, excellent electric conductivity, and good hole/electron mobility under certain tensile/compressive strains. The results of contact resistance and transfer length indicate that the current in the rivet graphene transistor does not just flow at the contact edge. Carbon nano-onions encapsulating Fe nanoparticles on the surface enhance the injection of charge between rivet graphene and the metal electrode. The anchoring of Fe nanoparticles encapsulated by carbon nano-onions on rebar graphene will provide additional avenues for applications of nanocarbon-based films in transparent and flexible electronics.


Sympathoinhibitory responses to 2-methylserotonin during changes in sodium intake.
The vagal-mediated reflex responses elicited by the selective serotonin type 3 receptor agonist 2-methyl-serotonin were examined by administration (6.25, 12.5, 25, and 50 micrograms/kg i.v.) of 2-methylserotonin to sinoaortic-denervated rats with either intact or sectioned vagi. To study the influence of dietary sodium intake on 2-methylserotonin-induced vagal reflex responses, we performed experiments in rats fed either a high or low sodium diet. Left ventricular end-diastolic pressure was significantly higher in animals on high than low salt diet. However, mean arterial pressure and heart rate were similar in high and low salt groups. In rats with intact vagi, 2-methylserotonin produced a dose-dependent increase in afferent vagal nerve activity and a dose-dependent decrease in efferent renal sympathetic nerve activity, mean arterial pressure, and heart rate. The sympathoinhibitory responses of decreased efferent renal sympathetic nerve activity, mean arterial pressure, and heart rate were abolished by vagotomy and were not affected by changes in dietary sodium intake. We conclude that the sympathoinhibitory effect of 2-methylserotonin is due to stimulation of vagal afferents with inhibitory action on peripheral sympathetic nerve activity and that the sympathoinhibitory responses are unaffected by changes in dietary sodium intake.


Progenetix: 12 years of oncogenomic data curation.
DNA copy number aberrations (CNAs) can be found in the majority of cancer genomes and are crucial for understanding the potential mechanisms underlying tumor initiation and progression. Since the first release in 2001, the Progenetix project (http://www.progenetix.org) has provided a reference resource dedicated to provide the most comprehensive collection of genome-wide CNA profiles. Reflecting the application of comparative genomic hybridization techniques to tens of thousands of cancer genomes, over the past 12 years our data curation efforts have resulted in a more than 60-fold increase in the number of cancer samples presented through Progenetix. In addition, new data exploration tools and visualization options have been added. In particular, the gene-specific CNA frequency analysis should facilitate the assignment of cancer genes to related cancer types. In addition, the new user file processing interface allows users to take advantage of the online tools, including various data representation options for proprietary data pre-publication. In this update article, we report recent improvements of the database in terms of content, user interface and online tools.


Ancestral hierarchy and conflict.
Ancestral Pan, the shared predecessor of humans, bonobos, and chimpanzees, lived in social dominance hierarchies that created conflict through individual and coalitional competition. This ancestor had male and female mediators, but individuals often reconciled independently. An evolutionary trajectory is traced from this ancestor to extant hunter-gatherers, whose coalitional behavior results in suppressed dominance and competition, except in mate competition. A territorial ancestral Pan would not have engaged in intensive warfare if we consider bonobo behavior, but modern human foragers have the potential for full-scale war. Although hunter-gatherers are able to resolve conflicts preemptively, they also use mechanisms, such as truces and peace pacts, to mitigate conflict when the costs become too high. Today, humans retain the genetic underpinnings of both conflict and conflict management; thus, we retain the potential for both war and peace.


Genome-wide association study of cognitive function in diverse Hispanics/Latinos: results from the Hispanic Community Health Study/Study of Latinos.
Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.


Soliton self-frequency shift cancellation in photonic crystal fibers.
We report the cancellation of the soliton self-frequency shift in a silica-core photonic crystal fiber with a negative dispersion slope. Numerical and experimental results show that stabilization of the soliton wavelength is accompanied by exponential amplification of the red-shifted Cherenkov radiation emitted by the soliton. The spectral recoil from the radiation acts on the soliton to compensate for the Raman frequency shift. This phenomenon may find applications in the development of a family of optical parametric amplifiers.


Diels-Alder exo selectivity in terminal-substituted dienes and dienophiles: experimental discoveries and computational explanations.
The Diels-Alder reactions of a series of silyloxydienes and silylated dienes with acyclic alpha,beta-unsaturated ketones and N-acyloxazolidinones have been investigated. The endo/exo stereochemical outcome is strongly influenced by the substitution pattern of the reactants. High exo selectivity was observed when the termini of the diene and the dienophile involved in the shorter of the forming bonds were both substituted, while the normal endo preference was found otherwise. The exo-selective asymmetric Diels-Alder reactions using Evans' oxazolidinone chiral auxiliary furnished a high level of pi-facial selectivity in the same sense as their well-documented endo-selective counterparts. Computational results for these Diels-Alder reactions were consistent with the experimental endo/exo selectivity in most cases. A twist-asynchronous model accounts for the geometries and energies of the computed transition structures.


Helping Parents Understand Applied Behavior Analysis: Creating a Parent Guide in 10 Steps.
Interventions based on applied behavior analysis (ABA) have been shown to be effective for children with a wide range of cognitive, adaptive, and functional abilities. Many special education teachers understand the principles of ABA and are adept at implementing ABA interventions for students. However, as the principles of ABA can be complex, communicating with parents about ABA interventions can be challenging. Providing parents with clear and succinct information in the form of a brief customized reference guide can be instrumental for facilitating and extending communication about their child's behavioral interventions. This article provides school personnel with guidelines and resources for helping parents understand and use interventions that are based on ABA. Specifically, this article presents 10 steps for creating an information guide for parents and provides recommendations for explaining the guide to parents.


Effect of Conditioner Type and Downforce, and Pad Surface Micro-Texture on SiO2 Chemical Mechanical Planarization Performance.
Based on a previous work where we investigated the effect of conditioner type and downforce on the evolution of pad surface micro-texture during break-in, we have chosen certain break-in conditions to carry out subsequent blanket SiO2 wafer polishing studies. Two different conditioner discs were used in conjunction with up to two different conditioning downforces. For each disc-downforce combination, mini-marathons were run using SiO2 wafers. Prior to polishing, each pad was broken-in for 30 min with one of the conditioner-downforce combinations. The goal of this study was to polish wafers after this break-in to see how the polishing process behaved immediately after break-in. One of the discs used in this study produced similar micro-texture results at both downforces, which echoed the results seen in the mini-marathon. When comparing the different polishing results obtained from breaking-in the pad with the different discs used in this study, the coefficient of friction (COF) and SiO2 removal rate (RR) were uncorrelated in all cases. However, the use of different discs resulted in different COF and RR trends. The uncorrelated COF and RR, as well as the differing trends, were explained by pad micro-texture results (i.e. the differing amount of fractured, poorly supported pad asperity summits).


Evaluation of ligament fibroblast viability in ruptured cranial cruciate ligament of dogs.
To determine fibroblast viability, assess development of apoptosis, and evaluate tissue hypoxia via histochemical, in-situ hybridization, or immunohistochemical staining in ruptured and intact cranial cruciate ligaments (CCLs) of dogs. 32 dogs with ruptured CCLs, and 8 aged and 19 young dogs with intact CCLs. Markers of cell viability (lactate dehydrogenase [LDH]), apoptosis (terminal deoxynucleatidyl transferase-mediated deoxyuridine triphosphate-nick end labeling [TUNEL] method), and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha] monoclonal antibody) were applied to CCL specimens; positive cells were assessed objectively (LDH) and subjectively (TUNEL and HIF-1alpha) in the main axial tissue component (core) and synovial intima and subintima (epiligamentous tissue). Viable fibroblasts were seen in all intact and ruptured CCLs. More nonviable cells were found in the core regions of ruptured CCLs and intact CCLs of young dogs than in the epiligamentous regions. Number of nonviable cells in the core region of ruptured CCLs was greater than that in intact CCLs of young and aged dogs, whereas the number in the epiligamentous region was similar in all specimens. The TUNEL and HIF-1alpha staining was only found in the epiligamentous region of ruptured CCLs. Ruptured CCLs contained a high number of nonviable cells but not a great number of apoptotic cells. Repair processes in the epiligamentous region of the CCL include a metabolic response to hypoxia, suggesting that necrosis of ligament fibroblasts and transformation of surviving cells to a spheroid phenotype may be a response to hypoxia cause by microinjury or inadequate blood flow.


Mass-mediated information effects on testicular self-examination among college students.
The author assessed the effects of a youth-targeted national cable broadcast that promoted testicular self-examination (TSE). A telephone survey of 524 college men included variables from the theory of reasoned action, as well as measures of self-exam compliance, message exposure, knowledge, attention, and the effects of humor and fear. Exposure to the show, with attitudes and norms controlled for, demonstrated a statistically significant but very weak effect on viewers' behavioral intentions. Although also statistically significant, the effect of the show on awareness, knowledge, and facilitating interpersonal communication was as weak or weaker than its effect on intention. Furthermore, dose measures failed to demonstrate any significant effect among those who saw the show. It is conceivable that the show might be integrated into a broader effort toward TSE education, but the results of this study do not argue that it could be effectively used as a media-only TSE promotion.


Prenatal features of isolated subependymal pseudocysts associated with adverse pregnancy outcome.
To identify at prenatal ultrasound (US) the features of apparently isolated subependymal pseudocysts (SEPC) that may indicate underlying pathology and should lead to further investigations. This was a retrospective study of cases with SEPC detected on prenatal US and/or magnetic resonance imaging (MRI). Those with apparently isolated SEPC at US were classified into two groups as follows: Group 1 (n = 29): normal prenatal US and MRI (except for SEPC) and normal outcome; Group 2 (n = 12): normal prenatal cerebral US (except for SEPC) and abnormal prenatal cerebral MRI with or without abnormal outcome. A third group (n = 9) included cases with abnormal prenatal US and MRI. The latter cases with obvious cerebral abnormalities at US were excluded from the statistical analysis as they do not represent a diagnostic dilemma for clinicians. Groups 1 and 2 were analyzed, comparing them with respect to their SEPC characteristics (size, number, location in relation to the caudothalamic notch and the ventricular horns and morphology) and extracerebral abnormalities. The mean ± SD SEPC great axis was longer in Group 2 (11.67 ± 5.82 mm) than it was in Group 1 (8.00 ± 5.64 mm) (P = 0.021), suggesting an optimal cut-off for size of SEPC of ≥ 9 mm (sensitivity = 75%, specificity = 62%) to maximize sensitivity for predicting pathological outcome. SEPC adjacent to the temporal horns and SEPC located posterior to the caudothalamic notch were observed more frequently in Group 2, indicating their association with poor outcome (P = 0.003 and P = 0.003, respectively). Atypical morphology and extracerebral abnormalities were observed more frequently in Group 2 (P = 0.013 and P = 0.044, respectively). There was no statistically significant difference between groups for either number or location of cysts along the inferior wall or adjacent to the lateral wall of the frontal horns (P = 0.591 and P = 0.156, respectively). When apparently isolated SEPC are observed at prenatal US, further investigations should be performed under the following circumstances: (1) SEPC great axis ≥ 9 mm; (2) SEPC adjacent to the occipital and temporal horns; (3) SEPC located posterior to the caudothalamic notch; (4) SEPC with atypical morphology.


Correlation-based linear discriminant classification for gene expression data.
Microarray gene expression technology provides a systematic approach to patient classification. However, microarray data pose a great computational challenge owing to their large dimensionality, small sample sizes, and potential correlations among genes. A recent study has shown that gene-gene correlations have a positive effect on the accuracy of classification models, in contrast to some previous results. In this study, a recently developed correlation-based classifier, the ensemble of random subspace (RS) Fisher linear discriminants (FLDs), was utilized. The impact of gene-gene correlations on the performance of this classifier and other classifiers was studied using simulated datasets and real datasets. A cross-validation framework was used to evaluate the performance of each classifier using the simulated datasets or real datasets, and misclassification rates (MRs) were computed. Using the simulated data, the average MRs of the correlation-based classifiers decreased as the correlations increased when there were more correlated genes. Using real data, the correlation-based classifiers outperformed the non-correlation-based classifiers, especially when the gene-gene correlations were high. The ensemble RS-FLD classifier is a potential state-of-the-art computational method. The correlation-based ensemble RS-FLD classifier was effective and benefited from gene-gene correlations, particularly when the correlations were high.


Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin.
EphA2 receptor tyrosine kinase is frequently overexpressed in different human cancers, suggesting that it may promote tumor development and progression. However, evidence also exists that EphA2 may possess antitumorigenic properties, raising a critical question on the role of EphA2 kinase in tumorigenesis in vivo. We report here that deletion of EphA2 in mouse led to markedly enhanced susceptibility to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. EphA2-null mice developed skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grew faster and were twice as likely to show invasive malignant progression. Haploinsufficiency of EphA2 caused an intermediate phenotype in tumor development but had little effects on invasive progression. EphA2 and ephrin-A1 exhibited compartmentalized expression pattern in mouse skin that localized EphA2/ephrin-A1 interactions to the basal layer of epidermis, which was disrupted in tumors. Loss of EphA2 increased tumor cell proliferation, whereas apoptosis was not affected. In vitro, treatment of primary keratinocytes from wild-type mice with ephrin-A1 suppressed cell proliferation and inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activities. Both effects were abolished in EphA2-null keratinocytes, suggesting that loss of ERK inhibition by EphA2 may be one of the contributing mechanisms for increased tumor susceptibility. Interestingly, despite its tumor suppressive function, EphA2 was overexpressed in skin tumors compared with surrounding normal skin in wild-type mice, similar to the observations in human cancers. EphA2 overexpression may represent a compensatory feedback mechanism during tumorigenesis. Together, these results show that EphA2 is a novel tumor suppressor gene in mammalian skin.


Biological and structural characterization of crotoxin and new isoform of crotoxin B PLA(2) (F6a) from Crotalus durissus collilineatus snake venom.
A new crotoxin B isoform PLA(2) (F6a), from Crotalus durissus collilineatus was purified from by one step reverse phase HPLC chromatography using mu-Bondapack C-18 column analytic. The new crotoxin B isoform PLA(2) (F6a), complex crotoxin, the catalytic subunit crotoxin B isoform PLA(2) (F6a) and two crotapotin isoforms (F3 and F4), were isolated from the venom of Crotalus durissus collilineatus. The crotapotins isoforms F3 and F4 had similar chemical properties, the two proteins different in their ability to inhibit of isoforms of PLA(2) (F6 and F6a). The molecular masses estimated by MALDI-TOF mass spectrometry were: crotoxin B: 14,943.14 Da, crotapotin F3: 8,693.24 Da, and crotapotin F4: 9 314.56 Da. The new crotoxin B isoform PLA(2) (F6a) contained 122 amino acid residues and a pI of 8.58. Its amino acid sequence presents high identity with those of other PLA(2)s, particularly in the calcium binding loop and active site helix 3. It also presents similarities in the C-terminal region with other myotoxic PLA(2)s. The new crotoxin B isoform PLA(2) (F6a) contained 122 amino acid residues, with a primary structure of HLLQFNKMIK FETRRNAIPP YAFYGCYCGW GGRGRPKDAT DRCCFVHDCC YGKLAKCNTK WDFYRYSLKS GYITCGKGTW CEEQICECDR VAAECLRRSL STYRYGYMIY PDSRCRGPSE TC. A neuromuscular blocking activity was induced by crotoxin and new crotoxin B isoform PLA(2) (F6a) in the isolated mouse phrenic nerve diaphragm and the biventer cervicis chick nerve-muscle preparation. Whole crotoxin was devoid of cytolytic activity upon myoblasts and myotubes in vitro, whereas new crotoxin B isoform PLA(2) (F6a) was clearly cytotoxic to these cells.


The Emotional and Functional Impact of the Type of Tinnitus Sensation.
One to three percent of individuals with tinnitus experience significant reduction in quality of life. Factors that contribute to distress include personality variables, intolerance to loud noises, external locus of control, and pre-existing anxiety. Characteristics of tinnitus itself, such as perceived loudness, can also cause functional impairment. It is unknown whether different tinnitus sensations have various effects on either emotional or functional impairment, which can reduce quality of life. While audiological tests can determine pitch and loudness of tinnitus, questionnaires also can be easily used to assess subjective characteristics of tinnitus. In this study, 370 participants, recruited via email from a national tinnitus organization, completed online surveys that assessed tinnitus-related distress and provided qualitative descriptions of their tinnitus sensation. Self-reports of tinnitus sensation were rated by five independent coders, with excellent agreement. Individuals who reported a combination of tinnitus sensations were found to experience significantly more functional impairment and avoidant behavior. Future research should utilize more sophisticated approaches to categorize individuals' tinnitus sensation and to examine associated emotional and functional differences. Providers should appropriately refer patients for tinnitus management and empirically-supported therapies aimed at reducing tinnitus related distress and functional impairment.


Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow.
Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor-coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate- and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. This study demonstrates that the FXI-thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal platelet consumption without affecting proximal platelet adhesion.


Serial exercise testing and prognosis in selected patients considered for cardiac transplantation.
This study sought to examine the predictive value of variables obtained from serial maximal exercise testing, echocardiography, and ejection fraction in patients referred as potential heart transplant candidates. Variables such as peak VO2, left ventricular dimensions, ejection fraction, and hemodynamic measurements are known to predict prognosis in heart failure, but there are few data on the impact of serial measurements of these variables on subsequent mortality. Two hundred sixty-three ambulatory patients with severe heart failure referred as potential candidates for heart transplantation who underwent two exercise tests (mean 7.8 months apart) after optimal medical treatment were identified. At the same two time points, echocardiography was performed in 106 (37%) and ejection fraction was measured in 84 (30%). During a mean follow-up period of 3.9+/-0.1 years, 70 (25%) died and 45 (19%) underwent heart transplantation. Exercise capacity, peak exercise heart rate, and peak exercise systolic blood pressure achieved were all significantly higher among survivors compared with nonsurvivors. Among the survivors a slight increase in peak VO2 and ejection fraction were observed, but there were no significant differences in the changes of any of the measured variables between survivors and nonsurvivors. There were no significant differences in survival between patients with increased versus those with decreased peak VO2, left ventricular dimensions, or ejection fraction. Although peak VO2, left ventricular dimensions, and ejection fraction predict survival, changes in these parameters do not add any prognostic information in patients with severe heart failure who have been stabilized with optimal medical treatment. Routine use of these procedures therefore does not seem to be warranted and should be performed only in the context of a specific clinical situation. Serial measurements of these parameters do not appear to be useful in the risk stratification of patients referred for heart transplantation.


Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling.
Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and beta-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. beta-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling. ECE-1 inhibition caused endosomal retention of the SP neurokinin 1 receptor, beta-arrestins, and Src, resulting in markedly sustained ERK2 activation in the cytosol and nucleus, whereas ECE-1 overexpression attenuated ERK2 activation. ECE-1 inhibition also enhanced SP-induced expression and phosphorylation of the nuclear death receptor Nur77, resulting in cell death. Thus, endosomal ECE-1 attenuates ERK2-mediated SP signaling in the nucleus to prevent cell death. We propose that agonist availability in endosomes, here regulated by ECE-1, controls beta-arrestin-dependent signaling of endocytosed GPCRs.


Bias and sensitivity analysis when estimating treatment effects from the cox model with omitted covariates.
Omission of relevant covariates can lead to bias when estimating treatment or exposure effects from survival data in both randomized controlled trials and observational studies. This paper presents a general approach to assessing bias when covariates are omitted from the Cox model. The proposed method is applicable to both randomized and non-randomized studies. We distinguish between the effects of three possible sources of bias: omission of a balanced covariate, data censoring and unmeasured confounding. Asymptotic formulae for determining the bias are derived from the large sample properties of the maximum likelihood estimator. A simulation study is used to demonstrate the validity of the bias formulae and to characterize the influence of the different sources of bias. It is shown that the bias converges to fixed limits as the effect of the omitted covariate increases, irrespective of the degree of confounding. The bias formulae are used as the basis for developing a new method of sensitivity analysis to assess the impact of omitted covariates on estimates of treatment or exposure effects. In simulation studies, the proposed method gave unbiased treatment estimates and confidence intervals with good coverage when the true sensitivity parameters were known. We describe application of the method to a randomized controlled trial and a non-randomized study.


Appearance of peripheral blood plasma cells and memory B cells in a primary and secondary immune response in humans.
In humans, the kinetics of the appearance of memory B cells and plasma cells during primary immunization are not well defined. In this study, we assessed the primary B-cell response of rabies-antigen naive volunteers during a 3-dose course of rabies vaccine compared with the B-cell response to a booster dose of rabies vaccine given to previously immunized volunteers. After a single dose of vaccine, in the naive group plasma and memory B cells appeared later (peak at day 10) than in the primed group (peak at day 7) and were at lower frequency. The most rapid responses (day 4) were detected after a third immunization in the naive group. This is the first study to document the detailed kinetics of the plasma cell and memory B-cell responses to immunization in adult humans and to demonstrate differences in the responses that relate to the preexisting immune status of the persons.


Whole genome sequencing unveils genetic heterogeneity in optic nerve hypoplasia.
Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.


The influence of concentration on the molecular surface structure of simple and mixed aqueous electrolytes.
We investigate various mechanisms contributing to the surface ion distributions in simple and mixed aqueous alkali-halide solutions depending on the total salt concentration, using a combination of photoelectron spectroscopy and molecular dynamics simulations. In simple solutions, the surface enhancement of large polarizable anions is reduced with increasing concentration. In the case of a NaBr/NaCl mixed aqueous solution, with bromide as the minority component, the situation is more complex. While the total anion/cation charge separation is similarly reduced with increasing salt content, this alone does not uniquely determine the ion distribution due to the co-existence of two different anions, Br(-) and Cl(-). We show that bromide is selectively surface enhanced at higher concentrations, despite the fact that the total anion surface enhancement is reduced. This phenomenon, which can be viewed as "salting out" of bromide by NaCl might have consequences for our understanding of the surface structure of mixed aqueous solutions subjected to concentration increase due to dehydration, such as seawater-born aerosols.


Utilization patterns of antidepressants between 1991 and 2011 in a population-based cohort of middle-aged and elderly.
In middle-aged and older patients in whom antidepressant use increased in last decades, patterns of use might be of concern The objective of this study was to investigate the patterns of prevalence, incidence and duration of antidepressant use in an ageing population. All participants (aged>45 years) from the population-based Rotterdam Study were followed from January 1st 1991 until death, loss to follow-up, or end of the study period (December 31st 2011). Antidepressant drug dispensing, based on pharmacy records, were subdivided into Tricyclic Antidepressants (TCAs), Selective Serotonin Reuptake Inhibitors (SSRIs) and other antidepressants. One-year prevalence, 5-year incidence and duration of antidepressant use were calculated. Yearly prevalence of antidepressant use increased from 3.9% in 1991 to 8.3% of the population in 2011. The increase in SSRI use was 5.8-fold, whereas use of other antidepressants doubled and TCA use remained stable over time. Incidence of all antidepressants decreased from 23.9 to 14.2 per 1000 person-years between 1992 and 2011. The duration of a first treatment episode increased over time. Despite the prevalence of antidepressant use increased over time, incidence did not, which is most likely explained by a longer treatment duration and recurrent episodes.


PoPLAR: Portal for Petascale Lifescience Applications and Research.
We are focusing specifically on fast data analysis and retrieval in bioinformatics that will have a direct impact on the quality of human health and the environment. The exponential growth of data generated in biology research, from small atoms to big ecosystems, necessitates an increasingly large computational component to perform analyses. Novel DNA sequencing technologies and complementary high-throughput approaches--such as proteomics, genomics, metabolomics, and meta-genomics--drive data-intensive bioinformatics. While individual research centers or universities could once provide for these applications, this is no longer the case. Today, only specialized national centers can deliver the level of computing resources required to meet the challenges posed by rapid data growth and the resulting computational demand. Consequently, we are developing massively parallel applications to analyze the growing flood of biological data and contribute to the rapid discovery of novel knowledge. The efforts of previous National Science Foundation (NSF) projects provided for the generation of parallel modules for widely used bioinformatics applications on the Kraken supercomputer. We have profiled and optimized the code of some of the scientific community's most widely used desktop and small-cluster-based applications, including BLAST from the National Center for Biotechnology Information (NCBI), HMMER, and MUSCLE; scaled them to tens of thousands of cores on high-performance computing (HPC) architectures; made them robust and portable to next-generation architectures; and incorporated these parallel applications in science gateways with a web-based portal. This paper will discuss the various developmental stages, challenges, and solutions involved in taking bioinformatics applications from the desktop to petascale with a front-end portal for very-large-scale data analysis in the life sciences. This research will help to bridge the gap between the rate of data generation and the speed at which scientists can study this data. The ability to rapidly analyze data at such a large scale is having a significant, direct impact on science achieved by collaborators who are currently using these tools on supercomputers.


Awareness of dying: prevalence, causes and consequences.
Analysis of a subset of data from a survey of 3696 relatives, friends and others who knew a sample of people dying in 1990 who lived in 20 areas of the United Kingdom (the Regional Study of Care for the Dying) is reported. Using the typology of awareness contexts developed by Glaser and Strauss [(1965) Awareness of Dying, Aldine, Chicago], the prevalence of different awareness contexts is described and compared with an earlier survey done in 1969. Open awareness of dying, where both the dying person and the respondent knew that the person was dying, is the most prevalent awareness context. This is particularly so in cancer and represents a change since 1969 when closed awareness (where the respondent knows, but the dying person does not) was more common. The characteristics of those dying in open and closed awareness contexts are then compared, suggesting that having cancer, not being mentally confused, having a respondent who knew for some time that the person was dying, and being of higher social class are independently predictive of full open awareness, a condition marked both by knowledge of dying, and a value commitment towards openness. Compared with people in closed awareness, people dying in full awareness are more able to plan their dying careers, so that they and their respondents are more satisfied with the degree of choice over the place of death, they are less likely to die alone, and are more likely to die in their own homes. Additionally, these individuals are more likely to have spoken of their wishes for euthanasia, another indicator of their desire to control the manner and timing of death. If dying from cancer, people in full open awareness are more likely to have received hospice care. It is suggested that underlying these patterns, and in contrast with some other cultures where awareness of dying is seen as less desirable, people dying in Anglophone countries are particularly concerned to maintain control over projects of self-identity. Their approach to death is a reflection of this individualism.


Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics.
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.