Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging.
The etiology of schizophrenia likely involves genetic interactions. DISC1, a promising candidate susceptibility gene, encodes a protein which interacts with many other proteins, including CIT, NDEL1, NDE1, FEZ1 and PAFAH1B1, some of which also have been associated with psychosis. We tested for epistasis between these genes in a schizophrenia case-control study using machine learning algorithms (MLAs: random forest, generalized boosted regression andMonteCarlo logic regression). Convergence of MLAs revealed a subset of seven SNPs that were subjected to 2-SNP interaction modeling using likelihood ratio tests for nested unconditional logistic regression models. Of the 7C2 = 21 interactions, four were significant at the α = 0.05 level: DISC1 rs1411771-CIT rs10744743 OR = 3.07 (1.37, 6.98) p = 0.007; CIT rs3847960-CIT rs203332 OR = 2.90 (1.45, 5.79) p = 0.003; CIT rs3847960-CIT rs440299 OR = 2.16 (1.04, 4.46) p = 0.038; one survived Bonferroni correction (NDEL1 rs4791707-CIT rs10744743 OR = 4.44 (2.22, 8.88) p = 0.00013). Three of four interactions were validated via functional magnetic resonance imaging (fMRI) in an independent sample of healthy controls; risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during the N-back task, a schizophrenia-linked intermediate biological phenotype: rs3847960-rs440299; rs1411771-rs10744743, rs4791707-rs10744743 (SPM5 p < 0.05, corrected), although we were unable to statistically replicate the interactions in other clinical samples. Interestingly, the CIT SNPs are proximal to exons that encode theDISC1 interaction domain. In addition, the 3' UTR DISC1 rs1411771 is predicted to be an exonic splicing enhancer and the NDEL1 SNP is ~3,000 bp from the exon encoding the region of NDEL1 that interacts with the DISC1 protein, giving a plausible biological basis for epistasis signals validated by fMRI.


Magnetotransport study on as-grown and annealed n- and p-type modulation-doped GaInNAs/GaAs strained quantum well structures.
We report the observation of thermal annealing- and nitrogen-induced effects on electronic transport properties of as-grown and annealed n- and p-type modulation-doped Ga1 - xInxNyAs1 - y (x = 0.32, y = 0, 0.009, and 0.012) strained quantum well (QW) structures using magnetotransport measurements. Strong and well-resolved Shubnikov de Haas (SdH) oscillations are observed at magnetic fields as low as 3 T and persist to temperatures as high as 20 K, which are used to determine effective mass, 2D carrier density, and Fermi energy. The analysis of temperature dependence of SdH oscillations revealed that the electron mass enhances with increasing nitrogen content. Furthermore, even the current theory of dilute nitrides does not predict a change in hole effective mass; nitrogen dependency of hole effective mass is found and attributed to both strain- and confinement-induced effects on the valence band. Both electron and hole effective masses are changed after thermal annealing process. Although all samples were doped with the same density, the presence of nitrogen in n-type material gives rise to an enhancement in the 2D electron density compared to the 2D hole density as a result of enhanced effective mass due to the effect of nitrogen on conduction band. Our results reveal that effective mass and 2D carrier density can be tailored by nitrogen composition and thermal annealing-induced effects. 72.00.00; 72.15.Gd; 72.80.Ey.


Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations.
Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.


Rearrangement and expression of myeov and hst in NIH/3T3 transfectants: a caveat for the interpretation of DNA transfection analyses.
By means of the tumorigenicity assay applying DNA from a patient with a gastric carcinoma (MA) we have already reported the identification of the putative oncogene myeov. In addition we have shown its involvement in t(11;14)-positive multiple myelomas and amplifications of breast tumours and esophageal carcinomas. The failure of myeov cDNA to induce tumour formation in NIH/3T3 cells prompted us to analyze the human sequences present in our MA-T1a1 tertiary transfectants. Sequence analysis revealed the presence of the human oncogene hst (fgf4) at a distance of approximately 9kb from the myeov gene in our MA-T1a1 tertiary transfectants. Both myeov and hst (fgf4) are normally situated approximately 475-kb apart at band 11q13, a region that is frequently amplified and overexpressed in various tumours. Southern and Northern blot analyses confirmed our sequence data and showed rearrangement of hst sequences during the transfection process and its expression in our MA-T1a1 tertiary transfectants.


Outcome of adult acute lymphoblastic leukemia: a single center experience.
To study the outcomes of adult patients with acute lymphoblastic leukemia. Tertiary care hospital. Retrospective analysis. Fifty eight adult patients (age >14 years) diagnosed as cases of acute lymphoblastic leukemia were studied with respect to their clinical, morphological and immunopathological features at presentation and their relationship with treatment outcomes. Forty five (77.5%) of the patients belonged to younger age group with male preponderance. The median age was 20 years and mean age was 25.1 years. Male to female ratio was 3:1. Common presenting signs were lymphadenopathy (17.2%), hepatomegaly (32.7%) and splenomegaly (62%). Laboratory features at presentation revealed: hemoglobin > or = 10 gm/dl in 18 (31%), WBC >50 x 10E9 / L in 18 (31%), LDH more than 1000 IU/L in 44 (75.8%) of patients. Morphology revealed that FAB L1 was seen in 21(37.2%) and L2 in 62 (32.7%). Immunophenotyping showed that 26 (61.9%) were early pre-B ALL, 6 (14.2%) were pre-B ALL and T-ALL were 10 (23.8%). Univariate analysis showed age more than 30 years, male gender, total leucocyte count >50 x 10(9)/L and hemoglobin more than 10 gm/dl to be risk factors for poor outcome. Multivariate analysis revealed age more than 30 years, male sex and total leucocyte count > 50 x 10(9)/L are independent risk factors for poor survival. Patients were treated according to the MRCUKX and XII adult protocols. Thirteen (22.4%) patients died during induction therapy secondary to sepsis and progressive disease whereas 42 (72.4%) patients achieved complete remission. Median survival was 18.6 months and 42% patients were alive at 5-years. Overall survival and disease free survival were comparable to those reported in literature. However, age more than 30 years, male gender and total leucocyte count >50 x 10(9)/L had an adverse impact on overall survival.


Provider perspectives on PrEP for adolescent girls and young women in Tanzania: The role of provider biases and quality of care.
Oral pre-exposure prophylaxis (PrEP) has the potential to reduce HIV acquisition among adolescent girls and young women (AGYW) in sub-Saharan Africa. However, health care providers' (HCPs) perspectives and interactions with potential clients can substantially influence effective provision of quality health services. We examine if HCPs' knowledge, attitude, and skills, as well as their perceptions of facility readiness to provide PrEP are associated with their willingness to provide PrEP to AGYW at high risk of HIV in Tanzania. A self-administered questionnaire was given to 316 HCPs from 74 clinics in two districts and 24 HCPs participated in follow-up in-depth interviews (IDIs). We conducted bivariate and multivariable Poisson regression to assess factors associated with willingness to provide PrEP to AGYW. Thematic content analysis was used to analyze the IDIs, which expanded upon the quantitative results. Few HCPs (3.5%) had prior PrEP knowledge, but once informed, 61.1% were willing to prescribe PrEP to AGYW. Higher negative attitudes toward adolescent sexuality and greater concerns about behavioral disinhibition due to PrEP use were associated with lower willingness to prescribe PrEP. Qualitatively, HCPs acknowledged that biases, rooted in cultural norms, often result in stigmatizing and discriminatory care toward AGYW, a potential barrier for PrEP provision. However, better training to provide HIV services was associated with greater willingness to prescribe PrEP. Conversely, HCPs feared the potential negative impact of PrEP on the provision of existing HIV services (e.g., overburdened staff), and suggested the integration of PrEP into non-HIV services and the use of paramedical professionals to facilitate PrEP provision. Preparing for PrEP introduction requires more than solely training HCPs on the clinical aspects of providing PrEP. It requires a two-pronged strategy: addressing HCPs' biases regarding sexual health services to AGYW; and preparing the health system infrastructure for the introduction of PrEP.


Clinical significance of mucin staining in keratinizing-type squamous cell carcinoma of the uterine cervix.
Tumor tissue from 57 cases of keratinizing-type squamous cell carcinoma of the uterine cervix that had been stored in the archives of Osaka City University Hospital between May 1986 and October 1994 were stained with periodic acid-Schiff (PAS) reagent following amylase and alcian blue to identify the presence of intracellular mucin and to assess the value and significance of demonstrating the presence of mucin. Nineteen specimens (33.3%) stained positive for mucin with alcian blue or PAS following diastase. The results of mucin staining were not significant in terms of survival by Kaplan-Meier's analysis.


Survival strategy of obligately intracellular Ehrlichia chaffeensis: novel modulation of immune response and host cell cycles.
Ehrlichia chaffeensis is an obligatory intracellular bacterium which resides in an early endosome in monocytes. E. chaffeensis infection in a human monocyte cell line (THP1) significantly altered the transcriptional levels of 4.5% of host genes, including those coding for apoptosis inhibitors, proteins regulating cell differentiation, signal transduction, proinflammatory cytokines, biosynthetic and metabolic proteins, and membrane trafficking proteins. The transcriptional profile of the host cell revealed key themes in the pathogenesis of Ehrlichia. First, E. chaffeensis avoided stimulation of or repressed the transcription of cytokines involved in the early innate immune response and cell-mediated immune response to intracellular microbes, such as the interleukin-12 (IL-12), IL-15, and IL-18 genes, which might make Ehrlichia a stealth organism for the macrophage. Second, E. chaffeensis up-regulated NF-kappaB and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third, E. chaffeensis also inhibited the gene transcription of RAB5A, SNAP23, and STX16, which are involved in membrane trafficking. By comparing the transcriptional response of macrophages infected with other bacteria and that of macrophages infected with E. chaffeensis, we have identified few genes that are commonly induced and no commonly repressed genes. These results illustrate the stereotyped macrophage response to other pathogens, in contrast with the novel host response to obligate intracellular Ehrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.


A common bottlenose dolphin (Tursiops truncatus) prey handling technique for marine catfish (Ariidae) in the northern Gulf of Mexico.
Few accounts describe predator-prey interactions between common bottlenose dolphins (Tursiops truncatus Montagu 1821) and marine catfish (Ariopsis felis Linnaeus 1766, Bagre marinus Mitchill 1815). Over the course of 50,167 sightings of bottlenose dolphin groups in Mississippi Sound and along the Florida coast of the Gulf of Mexico, severed catfish heads were found floating and exhibiting movements at the surface in close proximity to 13 dolphin groups that demonstrated feeding behavior. These observations prompted a multi-disciplinary approach to study the predator-prey relationship between bottlenose dolphins and marine catfish. A review was conducted of bottlenose dolphin visual survey data and dorsal fin photographs from sightings where severed catfish heads were observed. Recovered severed catfish heads were preserved and studied, whole marine catfish were collected and examined, and stranding network pathology reports were reviewed for references to injuries related to fish spines. Photographic identification analysis confirms eight dolphins associated with severed catfish heads were present in three such sightings across an approximately 350 km expanse of coast between the Mississippi Sound and Saint Joseph Bay, FL. An examination of the severed catfish heads indicated interaction with dolphins, and fresh-caught whole hardhead catfish (A. felis) were examined to estimate the presumed total length of the catfish before decapitation. Thirty-eight instances of significant trauma or death in dolphins attributed to ingesting whole marine catfish were documented in stranding records collected from the southeastern United States of America. Bottlenose dolphins typically adhere to a ram-feeding strategy for prey capture followed by whole prey ingestion; however, marine catfish skull morphology may pose a consumption hazard due to rigid spines that can puncture and migrate through soft tissue, prompting a prey handling technique for certain dolphins, facilitating consumption of the posterior portion of the fish without the head.


Grand challenges for biological engineering.
Biological engineering will play a significant role in solving many of the world's problems in medicine, agriculture, and the environment. Recently the U.S. National Academy of Engineering (NAE) released a document "Grand Challenges in Engineering," covering broad realms of human concern from sustainability, health, vulnerability and the joy of living. Biological engineers, having tools and techniques at the interface between living and non-living entities, will play a prominent role in forging a better future. The 2010 Institute of Biological Engineering (IBE) conference in Cambridge, MA, USA will address, in part, the roles of biological engineering in solving the challenges presented by the NAE. This letter presents a brief outline of how biological engineers are working to solve these large scale and integrated problems of our society.


Iatrogenic pulmonary lesions.
Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes.


Entrustable professional activities: A useful concept for neurology education.
Medical education is currently undergoing a paradigm shift from process-based to competency-based education, focused on measuring the desired competence of a physician. In an attempt to improve the assessment framework used for medical education, the concept of entrustable professional activities (EPAs) has gained traction. EPAs are defined as professional activities that can be entrusted to an individual in a clinical context. The Association of American Medical Colleges (AAMC) defined a set of 13 such EPAs to define the core of what all students should be able to do on day 1 of residency, regardless of specialty choice. The AAMC is currently piloting these EPAs with 10 medical schools to determine if EPAs can be used as a way to observe, measure, and entrust medical students with core clinical activities by the end of the clinical immersion experiences of the third year. The specialty of pediatrics is piloting the use of specialty-specific EPAs at 5 medical schools to assess readiness for transitions from medical school into pediatric residency training and practice. To date, no neurology-specific EPAs have been published for use in neurology clerkships or neurology residencies. This article introduces the concept of EPAs in the context of competency-based medical education and describes how EPAs might be relevant and applicable in neurologic education across the continuum. The Undergraduate Education Subcommittee of the American Academy of Neurology advocates for a proactive approach to incorporating core EPAs in undergraduate medical education and to considering an EPA-based specialty-specific assessment framework for neurology.


Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells.
Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. 1). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.


Comparative Study on Beneficial Effects of Hydroxytyrosol- and Oleuropein-Rich Olive Leaf Extracts on High-Fat Diet-Induced Lipid Metabolism Disturbance and Liver Injury in Rats.
Oleuropein and hydroxytyrosol, as major compounds of olive leaves, have been reported to exert numerous pharmacological properties, including anticancer, antidiabetic, and anti-inflammatory activities. The purpose of this study is to evaluate and compare the protective effect of oleuropein- and hydroxytyrosol-rich extracts, derived from olive leaves, on high-fat diet-induced lipid metabolism disturbance and liver injury in rats. In this respect, four groups of male rats (8 per group) were used: control group (Control), group treated with high-fat diet (HFD), group treated with HFD and oleuropein (HFD + OLE), and group treated with HFD and hydroxytyrosol (HFD + HYD). The current research showed that the treatment with the HFD increased the body weight and adipose tissue mass in male rats. Moreover, the plasma levels of triglycerides, total cholesterol, LDL-cholesterol, AST, ALT, LDH, and TNF-α were also raised. The hepatic immunohistochemical analysis revealed a significant increase in the expression of inflammatory genes (COX-2, NF-κB, and TNF-α). Equally, it showed a rise of the apoptotic markers (a decrease in the expression of the Bcl-2 and an increase of the P53). In addition, the oral administration of oleuropein- and hydroxytyrosol-rich olive leaf extracts at 16 mg/kg similarly reduced the body weight and adipose tissue mass and improved the lipid profile. Moreover, these extracts, mainly the hydroxytyrosol-rich extract, reduced the elevated liver enzymes, enhanced the antioxidant status, and attenuated the liver inflammation and apoptosis. These findings suggest that the oleuropein- and hydroxytyrosol-rich olive leaf extracts possessed hypolipidemic and hepatoprotective effects against the HFD-induced metabolic disorders by enhancing the antioxidative defense system and blocking the expression of the proteins involved in inflammation and liver damage.


Agonistic behaviour and biogenic amines in shore crabs Carcinus maenas.
To investigate the role of certain neurohormones in agonistic behaviour, fights were staged between pairs of size-matched male shore crabs Carcinus maenas, and blood samples were taken immediately after the contests had been resolved. Samples were also taken from these crabs at rest (before and after fighting) and after walking on a treadmill. A control group of crabs also had samples taken on each experimental day. Concentrations of tyramine, dopamine, octopamine, serotonin (5-HT) and norepinephrine were determined in each blood sample using a gas chromatography/mass spectrometry (GC-MS) system. Norepinephrine was not detectable in any of the samples, but the standards were recovered. Tyramine values were not significantly different between the control group and the fought group, so tyramine does not appear to be important in agonistic behaviour. A comparison between the control and fought groups shows that fighting had an effect on the concentrations of octopamine, dopamine and 5-HT, but exercise only had an effect on octopamine levels, which showed a reduction from resting values in both winners and losers. Resting and post-fight concentrations of octopamine, dopamine and 5-HT were higher in winners than in losers. 5-HT concentration increased in the blood of fought crabs from resting values, whereas dopamine concentration decreased. In winners, octopamine concentrations decreased from resting values, but in losers octopamine levels increased from resting concentrations. The escalatory behaviour or intensity of fighting performed by winners and losers was related to dopamine levels but not to those of octopamine or 5-HT. Therefore, there appears to be a link between relative concentrations of these three amines (dopamine, octopamine and 5-HT) and fighting ability; the effects are not simply a result of activity. The better competitors have higher concentrations of these three amines at rest and after fighting.


Improving Bayesian Reasoning: The Effects of Phrasing, Visualization, and Spatial Ability.
Decades of research have repeatedly shown that people perform poorly at estimating and understanding conditional probabilities that are inherent in Bayesian reasoning problems. Yet in the medical domain, both physicians and patients make daily, life-critical judgments based on conditional probability. Although there have been a number of attempts to develop more effective ways to facilitate Bayesian reasoning, reports of these findings tend to be inconsistent and sometimes even contradictory. For instance, the reported accuracies for individuals being able to correctly estimate conditional probability range from 6% to 62%. In this work, we show that problem representation can significantly affect accuracies. By controlling the amount of information presented to the user, we demonstrate how text and visualization designs can increase overall accuracies to as high as 77%. Additionally, we found that for users with high spatial ability, our designs can further improve their accuracies to as high as 100%. By and large, our findings provide explanations for the inconsistent reports on accuracy in Bayesian reasoning tasks and show a significant improvement over existing methods. We believe that these findings can have immediate impact on risk communication in health-related fields.


Massive hematuria following percutaneous biopsy of renal allograft. Successful control by selective embolization.
We report on a patient who underwent a percutaneous needle biopsy of a renal allograft for evaluation of compromised function. Gross hematuria occurred immediately and persisted for three weeks, interrupted only by long intervals of anuria due to obstruction by a clot. The bleeding was controlled successfully by selective transcatheter embolization with a coli and an absorbable gelatin sponge (Gelfoam). The techniques and complications of allograft biopsy procedures are reviewed, and the management of hematuria occurring after a percutaneous needle biopsy is discussed. A percutaneous needle biopsy is the preferred method of sampling the transplanted kidney, with an adequate specimen obtained in 96% of cases. Hematuria, that has been reported to complicate 7% of percutaneous biopsy procedures, is usually transient, and only rarely is intervention required. Angiographically directed selective embolization is an effective technique for controlling massive or prolonged urinary hemorrhage after renal allograft biopsy.


Diet and environment 1.2 million years ago revealed through analysis of dental calculus from Europe's oldest hominin at Sima del Elefante, Spain.
Sima del Elefante, Atapuerca, Spain contains one of the earliest hominin fragments yet known in Europe, dating to 1.2 Ma. Dental calculus from a hominin molar was removed, degraded and analysed to recover entrapped remains. Evidence for plant use at this time is very limited and this study has revealed the earliest direct evidence for foods consumed in the genus Homo. This comprises starchy carbohydrates from two plants, including a species of grass from the Triticeae or Bromideae tribe, meat and plant fibres. All food was eaten raw, and there is no evidence for processing of the starch granules which are intact and undamaged. Additional biographical detail includes fragments of non-edible wood found adjacent to an interproximal groove suggesting oral hygiene activities, while plant fibres may be linked to raw material processing. Environmental evidence comprises spores, insect fragments and conifer pollen grains which are consistent with a forested environment.


The N-terminal sequence of the extrinsic PsbP protein modulates the redox potential of Cyt b559 in photosystem II.
The PsbP protein, an extrinsic subunit of photosystem II (PSII) in green plants, is known to induce a conformational change around the catalytic Mn4CaO5 cluster securing the binding of Ca(2+) and Cl(-) in PSII. PsbP has multiple interactions with the membrane subunits of PSII, but how these affect the structure and function of PSII requires clarification. Here, we focus on the interactions between the N-terminal residues of PsbP and the α subunit of Cytochrome (Cyt) b559 (PsbE). A key observation was that a peptide fragment formed of the first N-terminal 15 residues of PsbP, 'pN15', was able to convert Cyt b559 into its HP form. Interestingly, addition of pN15 to NaCl-washed PSII membranes decreased PSII's oxygen-evolving activity, even in the presence of saturating Ca(2+) and Cl(-) ions. In fact, pN15 reversibly inhibited the S1 to S2 transition of the OEC in PSII. These data suggest that pN15 can modulate the redox property of Cyt b559 involved in the side-electron pathway in PSII. This potential change of Cyt b559, in the absence of the C-terminal domain of PsbP, however, would interfere with any electron donation from the Mn4CaO5 cluster, leading to the possibility that multiple interactions of PsbP, binding to PSII, have distinct roles in regulating electron transfer within PSII.


Workshop on Emerging Technology and Data Analytics for Behavioral Health.
Wearable and portable digital devices can support self-monitoring for patients with chronic medical conditions, individuals seeking to reduce stress, and people seeking to modify health-related behaviors such as substance use or overeating. The resulting data may be used directly by a consumer, or shared with a clinician for treatment, a caregiver for assistance, or a health coach for support. The data can also be used by researchers to develop and evaluate just-in-time interventions that leverage mobile technology to help individuals manage their symptoms and behavior in real time and as needed. Such wearable systems have huge potential for promoting delivery of anywhere-anytime health care, improving public health, and enhancing the quality of life for many people. The Center for Technology and Behavioral Health at Dartmouth College, a P30 "Center of Excellence" supported by the National Institute on Drug Abuse at the National Institutes of Health, conducted a workshop in February 2017 on innovations in emerging technology, user-centered design, and data analytics for behavioral health, with presentations by a diverse range of experts in the field. The workshop focused on wearable and mobile technologies being used in clinical and research contexts, with an emphasis on applications in mental health, addiction, and health behavior change. In this paper, we summarize the workshop panels on mobile sensing, user experience design, statistics and machine learning, and privacy and security, and conclude with suggested research directions for this important and emerging field of applying digital approaches to behavioral health. Workshop insights yielded four key directions for future research: (1) a need for behavioral health researchers to work iteratively with experts in emerging technology and data analytics, (2) a need for research into optimal user-interface design for behavioral health technologies, (3) a need for privacy-oriented design from the beginning of a novel technology, and (4) the need to develop new analytical methods that can scale to thousands of individuals and billions of data points.


Ethnic disparities in infectious disease hospitalisations in the first year of life in New Zealand.
Infectious disease (ID) hospitalisation rates are increasing in New Zealand (NZ), especially in pre-school children, and Māori and Pacific people. We aimed to identify risk factors for ID hospitalisation in infancy within a birth cohort of NZ children, and to identify differences in risk factors between ethnic groups. We investigated an established cohort of 6846 NZ children, born in 2009-2010, with linkage to a national data set of hospitalisations. We used multivariable logistic regression to obtain odds ratios (OR) for factors associated with ID hospitalisation in the first year of life, firstly for all children, and then separately for Māori or Pacific children. In the whole cohort, factors associated with ID hospitalisation were Māori (OR: 1.49, 95% CI: 1.17-1.89) or Pacific (2.51; 2.00-3.15) versus European maternal ethnicity, male gender (1.32; 1.13-1.55), low birthweight (1.94, 1.39-2.66), exclusive breastfeeding for <4 months (1.22, 1.04-1.43), maternal experience of health-care racism (1.60, 1.19-2.12), household deprivation (most vs. least deprived quintile of households (1.50, 1.12-2.02)), day-care attendance (1.43, 1.12-1.81) and maternal smoking (1.55, 1.26-1.91). Factors associated with ID hospitalisation for Māori infants were high household deprivation (2.16, 1.06-5.02) and maternal smoking (1.48, 1.02-2.14); and for Pacific infants were delayed immunisation (1.72, 1.23-2.38), maternal experience of health-care racism (2.20, 1.29-3.70) and maternal smoking (1.59, 1.10-2.29). Māori and Pacific children in NZ experience a high burden of ID hospitalisation. Some risk factors, for example maternal smoking, are shared, while others are ethnic-specific. Interventions aimed at preventing ID hospitalisations should address both shared and ethnic-specific factors.


Characterization of ZnO Interlayers for Organic Solar Cells: Correlation of Electrochemical Properties with Thin-Film Morphology and Device Performance.
This report focuses on the evaluation of the electrochemical properties of both solution-deposited sol-gel (sg-ZnO) and sputtered (sp-ZnO) zinc oxide thin films, intended for use as electron-collecting interlayers in organic solar cells (OPVs). In the electrochemical studies (voltammetric and impedance studies), we used indium-tin oxide (ITO) over coated with either sg-ZnO or sp-ZnO interlayers, in contact with either plain electrolyte solutions, or solutions with probe redox couples. The electroactive area of exposed ITO under the ZnO interlayer was estimated by characterizing the electrochemical response of just the oxide interlayer and the charge transfer resistance from solutions with the probe redox couples. Compared to bare ITO, the effective electroactive area of ITO under sg-ZnO films was ca. 70%, 10%, and 0.3% for 40, 80, and 120 nm sg-ZnO films. More compact sp-ZnO films required only 30 nm thicknesses to achieve an effective electroactive ITO area of ca. 0.02%. We also examined the electrochemical responses of these same ITO/ZnO heterojunctions overcoated with device thickness pure poly(3-hexylthiophehe) (P3HT), and donor/acceptor blended active layers (P3HT:PCBM). Voltammetric oxidation/reduction of pure P3HT thin films on ZnO/ITO contacts showed that pinhole pathways exist in ZnO films that permit dark oxidation (ITO hole injection into P3HT). In P3HT:PCBM active layers, however, the electrochemical activity for P3HT oxidation is greatly attenuated, suggesting PCBM enrichment near the ZnO interface, effectively blocking P3HT interaction with the ITO contact. The shunt resistance, obtained from dark current-voltage behavior in full P3HT/PCBM OPVs, was dependent on both (i) the porosity of the sg-ZnO or sp-ZnO films (as revealed by probe molecule electrochemistry) and (ii) the apparent enrichment of PCBM at ZnO/P3HT:PCBM interfaces, both effects conveniently revealed by electrochemical characterization. We anticipate that these approaches will be applicable to a wider array of solution-processed interlayers for "printable" solar cells.


Transition to Turbulence Downstream of a Stenosis for Whole Blood and a Newtonian Analog Under Steady Flow Conditions.
Blood, a multiphase fluid comprised of plasma, blood cells, and platelets, is known to exhibit a shear-thinning behavior at low shear rates and near-Newtonian behavior at higher shear rates. However, less is known about the impact of its multiphase nature on the transition to turbulence. In this study, we experimentally determined the critical Reynolds number at which the flow began to transition to turbulence downstream of eccentric stenosis for whole porcine blood and a Newtonian blood analog (water-glycerin mixture). Velocity profiles for both fluids were measured under steady-state flow conditions using an ultrasound Doppler probe placed 12 diameters downstream of eccentric stenosis. Velocity was recorded at 21 locations along the diameter at 11 different flow rates. Normalized turbulent kinetic energy was used to determine the critical Reynolds number for each fluid. Blood rheology was measured before and after each experiment. Tests were conducted on five samples of each fluid inside a temperature-controlled in vitro flow system. The viscosity at a shear rate of 1000 s-1 was used to define the Reynolds number for each fluid. The mean critical Reynolds numbers for blood and water-glycerin were 470 ± 27.5 and 395 ± 10, respectively, indicating a ∼19% delay in transition to turbulence for whole blood compared to the Newtonian fluid. This finding is consistent with a previous report for steady flow in a straight pipe, suggesting some aspect of blood rheology may serve to suppress, or at least delay, the onset of turbulence in vivo.


Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson's Disease.
Diabetes increases the risk of Parkinson's disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs). In total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and p < 0.05 was considered significant. The isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1S312 in blood NDEVs than controls. In addition, the p-IRS-1S312 levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI). PD patients exerted altered p-IRS-1S312 in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.


Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.
We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.


VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.
We have identified an ethylnitrosourea (ENU)-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype that includes cardiac, tracheoesophageal, anorectal, anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, a presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6). Compound mutants (Pcsk5(Vcc/null)) completely recapitulate the Pcsk5(Vcc/Vcc) phenotype, as does an epiblast-specific conditional deletion of Pcsk5. The C470R mutation ablates a disulfide bond in the P domain, and blocks export from the endoplasmic reticulum and proprotein convertase activity. We show that GDF11 is cleaved and activated by PCSK5A, but not by PCSK5A-C470R, and that Gdf11-deficient embryos, in addition to having anteroposterior patterning defects and renal and palatal agenesis, also have a presacral mass, anorectal malformation, and exomphalos. Pcsk5 mutation results in abnormal expression of several paralogous Hox genes (Hoxa, Hoxc, and Hoxd), and of Mnx1 (Hlxb9). These include known Gdf11 targets, and are necessary for caudal embryo development. We identified nonsynonymous mutations in PCSK5 in patients with VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb malformation OMIM 192350) and caudal regression syndrome, the phenotypic features of which resemble the mouse mutation. We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development.


Caveolin-1, a putative tumour suppressor gene.
Caveolae ('little caves') are plasma membrane specializations of 50-100 nm in diameter, and the caveolins are structural proteins used by cells to form caveolae. We and other investigators have discovered that caveolae organelles may be important both in normal signal transduction and in the pathogenesis of a number of human diseases, such as cancer. Here we describe the functional roles of the caveolin gene family and summarize the evidence that supports a role for caveolae as mediators of a number of cellular signalling processes, including apoptosis.


Categorization of vocal and nonvocal stimuli in Guinea baboons (Papio papio).
Categorization of vocal sounds apart from other sounds is one of the key abilities in human voice processing, but whether this ability is present in other animals, particularly nonhuman primates, remains unclear. In the present study, 25 socially housed Guinea baboons (Papio papio) were tested on a vocal/nonvocal categorization task using Go/Nogo paradigm implemented on freely accessible automated learning devices. Three individuals from the group successfully learned to sort Grunt vocalizations from nonvocal sounds, and they generalized to new stimuli from the two categories, indicating that some baboons have the ability to develop open-ended categories in the auditory domain. Contrary to our hypothesis based on the human literature, these monkeys learned the nonvocal category faster than the Grunt category. Moreover, they failed to generalize their classification to new classes of conspecific vocalizations (wahoo, bark, yak, and copulation calls), and they categorized human vocalizations in the nonvocal category, suggesting that they had failed to represent the task as a vocal versus nonvocal categorization problem. Thus, our results do not confirm the existence of a separate perceptual category for conspecific vocalizations in baboons. Interestingly, the three successful baboons are the youngest of the group, with less training in visual tasks, which supports previous reports of age and learning history as crucial factors in auditory laboratory experiments.


Upfront Gamma Knife radiosurgery for Cushing's disease and acromegaly: a multicenter, international study.
Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing's disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas. An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12-40.0 Gy) at a median isodose of 50%. The median endocrine follow-up was 69.5 months (range 9-246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2. Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.


Nursing care of patients undergoing thoracoscopic minimally invasive bypass grafting.
Recent efforts in cardiac surgery to decrease cost, length of hospitalization, and morbidity without compromising care or outcomes include a method of treatment of coronary heart disease called minimally invasive coronary artery bypass grafting. This article describes the use of thoracoscopy without sternotomy, cardiopulmonary bypass, or cardioplegic arrest for grafting of the left anterior descending branch of the coronary artery with the left internal mammary artery. Preliminary information supports the concept that thoracoscopic minimally invasive bypass grafting is a less costly and less invasive procedure for patients with disease of the left anterior descending branch of the coronary artery.


Breast cancer and hormonal contraceptives: further results. Collaborative Group on Hormonal Factors in Breast Cancer.
The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on breast cancer risk and use of hormonal contraceptives. Original data from 54 studies, representing about 90% of the information available on the topic, were collected, checked and analysed centrally. The 54 studies were performed in 26 countries and include a total of 53,297 women with breast cancer and 100,239 women without breast cancer. The studies were varied in their design, setting and timing. Most information came from case-control studies with controls chosen from the general population; most women resided in Europe or North America and most cancers were diagnosed during the 1980s. Overall 41% of the women with breast cancer and 40% of the women without breast cancer had used oral contraceptives at some time; the median age at first use was 26 years, the median duration of use was 3 years, the median year of first use was 1968, the median time since first use was 16 years, and the median time since last use was 9 years. The main findings, summarised elsewhere, are that there is a small increase in the risk of having breast cancer diagnosed in current users of combined oral contraceptives and in women who had stopped use in the past 10 years but that there is no evidence of an increase in the risk more than 10 years after stopping use. In addition, the cancers diagnosed in women who had used oral contraceptives tended to be less advanced clinically than the cancers diagnosed in women who had not used them. Despite the large number of possibilities investigated, few factors appeared to modify the main findings either in recent or in past users. For recent users who began use before age 20 the relative risks are higher than for recent users who began at older ages. For women whose use of oral contraceptives ceased more than 10 years before there was some suggestion of a reduction in breast cancer risk in certain subgroups, with a deficit of tumors that had spread beyond the breast, especially among women who had used preparations containing the highest doses of oestrogen and progestogen. These findings are unexpected and need to be confirmed. Although these data represent most of the epidemiological evidence on the topic to date, there is still insufficient information to comment reliably about the effects of specific types of oestrogen or of progestogen. What evidence there is suggests, however, no major differences in the effects for specific types of oestrogen or of progestogen and that the pattern of risk associated with use of hormonal contraceptives containing progestogens alone may be similar to that observed for preparations containing both oestrogens and progestogens. On the basis of these results, there is little difference between women who have and have not used combined oral contraceptives in terms of the estimated cumulative number of breast cancers diagnosed during the period from starting use up to 20 years after stopping. The cancers diagnosed in women who have used oral contraceptives are, however, less advanced clinically than the cancers diagnosed in never users. Further research is needed to establish whether the associations described here are due to earlier diagnosis of breast cancer in women who have used oral contraceptives, to the biological effects of the hormonal contraceptives or to a combination of both. Little information is as yet available about the effects on breast cancer risk of oral contraceptive use that ceased more than 20 years before and as such data accumulate it will be necessary to re-examine the worldwide evidence.


Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain.
The deposition of amyloid in senile plaques and along the walls of the cerebral vasculature is a characteristic feature of Alzheimer disease. The peptide comprising the carboxyl-terminal 100 amino acids of the beta-amyloid precursor protein (beta APP) has been shown to aggregate into amyloid-like fibrils in vitro and to be neurotoxic, suggesting that this fragment may play a role in the etiology of Alzheimer disease. To address this question, we expressed this carboxyl-terminal 100-amino acid peptide of beta APP in transgenic mice under the control of the brain dystrophin promoter. We used an antibody to the principal component of amyloid, beta/A4, to demonstrate cell-body and neuropil accumulation of beta/A4 immunoreactivity in the brains of 4- and 6-month-old transgenic mice. Only light cytoplasmic staining with this antibody was visible in control mice. In addition, immunocytochemical analysis of the brains with an antibody to the carboxyl terminus of beta APP revealed abnormal aggregation of this epitope of beta APP within vesicular structures in the cytoplasm and in abnormal-appearing neurites in the CA2/3 region of the hippocampus in transgenic mice, similar to its aggregation in the cells of Alzheimer disease brains. Thioflavin S histochemistry suggested accumulations of amyloid in the cerebrovasculature of transgenic mice with the highest expression of the beta APP-C100 transgene. These observations suggest that expression of abnormal carboxyl-terminal subfragments of beta APP in vivo may cause amyloidogenesis and specific neuropathology.


Kinetic metal release from competing processes in aquifers.
Understanding groundwater time scales wherein kinetic metal-desorption and mineral-dissolution are important mechanisms is essential for realistic modeling of metal release. In this study, release rate constants were compiled and the Damköhler number was applied to calculate residence times where kinetic formulations are relevant. Desorption rate constants were compiled for arsenic, barium, cadmium, copper, lead, mercury, nickel, and zinc, and span 6 orders of magnitude, while mineral-dissolution rate constants compiled for calcite, kaolinite, smectite, anorthite, albite, K-feldspar, muscovite, quartz, goethite, and galena ranged over 13 orders of magnitude. This Damköhler analysis demonstrated that metal-desorption kinetics are potentially influential at residence times up to about two years, depending on the metal and groundwater conditions. Kinetic mineral-dissolution should be considered for nearly all residence times relevant to groundwater modeling, provided the rate, solubility, and availability of the mineral generates a non-negligible concentration. Geochemical models of competitive desorption and dissolution for an illustrative metal demonstrate total metal concentrations may be sensitive to dissolution rate variations despite the predominance of release from desorption. Ultimately, this analysis provides constraints on relevant processes for incorporation into transport models.


The organization of dorsal frontal cortex in humans and macaques.
The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for "new" regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed.


Korean Gastric Cancer Association Nationwide Survey on Gastric Cancer in 2014.
The Korean Gastric Cancer Association (KGCA) has conducted nationwide surveys every 5 years, targeting patients who received surgical treatment for gastric cancer. We report the results of the 2014 nationwide survey and compare them to those of the 1995, 1999, 2004, and 2009 surveys. From March 2015 to January 2016, a standardized case report form was sent to every member of the KGCA via e-mail. The survey consisted of 29 questions, regarding patient demographics as well as tumor-, and surgery-related factors. The completed data forms were analyzed by the KGCA information committee. Data on 15,613 patients were collected from 69 institutions. The mean age was 60.9±12.1 years, and the proportion of patients more than 70 years of age increased from 9.1% in 1995 to 25.3% in 2014. Proximal cancer incidence steadily increased from 11.2% in 1995 to 16.0% in 2014. Early gastric cancer incidence consistently increased and accounted for 61.0% of all cases in 2014. The surgical approach was diversified in 2014, and 7,818 cases (50.1%) were treated with a minimally invasive approach. The most common anastomosis was Billroth I (50.2%) after distal gastrectomy, and the proportion of Roux-en-Y anastomoses performed increased to 8.6%. The results of this survey are expected to be important data for future studies and to be useful for generating a national cancer control program.


Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction.
Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1-4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent.


Correlation of neutrophil/lymphocyte and platelet/lymphocyte ratios with the severity of idiopathic carpal tunnel syndrome.
The aim of the present study was to investigate the correlation of the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio with the severity of idiopathic carpal tunnel syndrome (CTS). A total of 407 patients with idiopathic CTS (neurophysiologically 150 mild, 144 moderate, and 113 severe) and 206 subjects without CTS were included (control group). There was a positive correlation between the severity of CTS and NLR (r = 0.224; P < 0.001), age (r = 0.333; P < 0.001), and body mass index (r = 0.251; P < 0.001). A 1-unit increase in NLR level was associated with an approximately 1.7-fold higher incidence of CTS (P = 0.002; odds ratio = 1.668; 95% confidence interval = 1.199-2.319). Our results suggest that neurophysiologically more severe CTS is associated with higher NLR levels. The role of systemic inflammation in CTS should be investigated in further studies.


Natural selection. IV. The Price equation.
The Price equation partitions total evolutionary change into two components. The first component provides an abstract expression of natural selection. The second component subsumes all other evolutionary processes, including changes during transmission. The natural selection component is often used in applications. Those applications attract widespread interest for their simplicity of expression and ease of interpretation. Those same applications attract widespread criticism by dropping the second component of evolutionary change and by leaving unspecified the detailed assumptions needed for a complete study of dynamics. Controversies over approximation and dynamics have nothing to do with the Price equation itself, which is simply a mathematical equivalence relation for total evolutionary change expressed in an alternative form. Disagreements about approach have to do with the tension between the relative valuation of abstract versus concrete analyses. The Price equation's greatest value has been on the abstract side, particularly the invariance relations that illuminate the understanding of natural selection. Those abstract insights lay the foundation for applications in terms of kin selection, information theory interpretations of natural selection and partitions of causes by path analysis. I discuss recent critiques of the Price equation by Nowak and van Veelen.


Competence for transcranial color-coded Duplex sonography is rapidly acquired.
Transcranial color-coded Duplex sonography (TCCD) is a non-invasive bedside tool with broad diagnostic potential in the intensive care setting. Implementation of TCCD requires repeated reliable measurements of flow velocities despite data acquisition by multiple operators with varying experience. Thus the learning curve of TCCD and agreement of measurements between experienced and inexperienced operators is of great interest and unstudied so far. Six untrained ICU-residents and 2 trained operators participated and performed TCCD examinations of the mean cerebral artery (MCA) in 10 volunteers. Measurements of the residents were compared to the according measurements of the trained operators. Operators were either actively supervised during their first five examinations or performed the examinations without supervision. A total of 480 measurements were obtained. Mean flow velocity (MFV) did not differ significantly between trained and untrained operators in the two groups (P=0.78 in not-supervised and P=0.82 in supervised group). We found a favorable learning curve in both groups (ICC 0.8, CI 95% 0.6-0.91- in not supervised and ICC 0.81 CI 95% 0.63-0.92 in supervised group). However, supervision helped trainees to acquire skills more rapidly and to perform more accurate measurements (ICC 0.77 (95% CI 0.39-0.94) to ICC 0.91 (95% CI 0.77-0.98) and ICC 0.66 (95% CI 0.11-0.91) to ICC 0.84 (95% CI 0.58-0.96), respectively. TCCD of the MCA in volunteers is an easy to learn tool with a favorable learning curve. A short-term learning program including initial supervised measurements yields reliable results in the hands of inexperienced operators.


EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine enhance BDNF/TrkB/CREB signaling and inhibit neuronal apoptosis in vitro and in vivo.
Our previous study showed that EPA-enriched ethanolamine plasmalogen (EPA-pPE) exerted more significant effects than EPA-enriched phosphatidylethanolamine (EPA-PE) in improving learning and memory deficit. However, the results of the mechanism study were not consistent with the improved cognitive function, which suggested that other signaling pathways might be involved. In the present study, primary cultured hippocampal neurons and cognitive deficiency rats were used to compare the effects of EPA-pPE and EPA-PE on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis. The in vitro experiment showed that both EPA-pPE and EPA-PE could relieve cell death and improve the cellular morphology of neurons via upregulating anti-apoptotic proteins and downregulating pro-apoptotic proteins. The in vivo experiment showed that EPA-pPE exerted more significant effects than EPA-PE in improving the number of neuronal Nissl bodies, increasing the branching of dendrites and dendritic spine density in cortical neurons, as well as improving the expression of synaptic vesicle-related proteins synaptophysin (SYN) and PSD95 via BDNF/TrkB/CREB signaling. These results indicated that EPA-pPE exerted neuroprotection at least partly through inhibiting neuronal apoptosis and enhancing the BDNF/TrkB/CREB pathway, which suggests that EPA-enriched plasmalogen can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.


Bias-induced photoluminescence quenching of single colloidal quantum dots embedded in organic semiconductors.
We demonstrate reversible quenching of the photoluminescence from single CdSe/ZnS colloidal quantum dots embedded in thin films of the molecular organic semiconductor N,N'-diphenyl-N,N'-bis(3-methylphenyl)-(1,1'-biphenyl)-4,4'-diamine (TPD) in a layered device structure. Our analysis, based on current and charge carrier density, points toward field ionization as the dominant photoluminescence quenching mechanism. Blinking traces from individual quantum dots reveal that the photoluminescence amplitude decreases continuously as a function of increasing forward bias even at the single quantum dot level. In addition, we show that quantum dot photoluminescence is quenched by aluminum tris(8-hydroxyquinoline) (Alq3) in chloroform solutions as well as in thin solid films of Alq3 whereas TPD has little effect. This highlights the importance of chemical compatibility between semiconductor nanocrystals and surrounding organic semiconductors. Our study helps elucidate elementary interactions between quantum dots and organic semiconductors, knowledge needed for designing efficient quantum dot organic optoelectronic devices.


Initial preference for drinking goal in the treatment of alcohol problems: II. Treatment outcomes.
To compare treatment outcomes between clients preferring abstinence and those preferring non-abstinence at the screening stage of a randomized controlled trial of treatment for alcohol problems (the United Kingdom Alcohol Treatment Trial) and to interpret any differential outcome in light of baseline differences between goal preference groups outlined in an accompanying paper. Outcomes at 3 and 12 months' follow-up were recorded both in categorical terms (abstinence/non-problem drinking/much improved/somewhat improved/same/worse) and on continuous measures (percent days abstinent, drinks per drinking day/dependence score). Clients initially stating a preference for abstinence showed a better outcome than those stating a preference for non-abstinence. This superior outcome was clearer at 3 months' follow-up but still evident at 12 months' follow-up. The better outcome consisted almost entirely in a greater frequency of abstinent days, with only a modest benefit in drinking intensity for goal abstainers that disappeared when baseline covariates of goal preference were controlled for. Type of successful outcome (abstinence/non-problem drinking) was related to initial goal preference, with clients preferring abstinence more likely to obtain an abstinent outcome and those preferring non-abstinence a non-problem drinking outcome. The client's personal drinking goals should be discussed in assessment at treatment entry and as a basis for negotiation. Clinicians should be prepared to identify and support goal change as an unexceptional part of the treatment process that need not jeopardize good outcome.


Tasting the fungal cell wall.
The search for common host mechanisms that recognize human fungal pathogens as non-self has led to an increased interest in cell wall polysaccharides since they are absent from mammals and at least for some of them, common to all fungal species. Even though the receptors recognizing mannans and beta-1,3-glucans have been extensively studied to date, the epitope of the polysaccharide ligand is often not well defined. In addition, receptors recognizing other cell wall major components such as chitin, alpha-1,3-glucan or galactose polymers remain to be identified. Moreover, the fungal adhesins playing a role in adhesion to host have been only explored in yeasts. Eventhough progresses have been made in the last 10 years, a comprehensive understanding of the interactions between the host membrane receptors and the fungal cell wall components is still lacking.


Monoclonal antibody-related drugs for cancer therapy.
Much progress has been made during the last few decades in the treatment of malignancies. Many types of cancer cells comprising the tumor mass carry molecular markers that are not expressed or are expressed at much lower levels in normal cells. These findings provide new leads to drug design and development of therapeutic strategies involving monoclonal antibodies (mAbs) or related antibody drugs to treat malignancies. This article reviews recent advances in this targeting approach with a focus on the evolution and current use of prospective antibody drugs as effective ways to treat cancer. Additionally, the development of prospective antibody-drug conjugates will also be briefly described.


First Report of Gray Leaf Spot of Maize Caused by Cercospora zeina in China.
Gray leaf spot of maize (Zea mays L.) is an important foliar disease in many parts of China. The causal organism of gray leaf spot in China is generally regarded as Cercospora zeae-maydis (3). In October 2011, symptoms similar to gray leaf spot were observed on 77% of maize plants in 25 locations (about 3,000 ha.) of Yunnan Province, China, and the disease could cause yield losses of 35 to 50%. The symptoms of leaf spot were different from those caused by C. zeae-maydis. The lesions on leaves were oblong, pale gray to pale brown, 2 to 3 × 5 to 40 mm, and confined by leaf veins that eventually coalesced. To identify the pathogen, 75 leaf samples were collected from 25 fields (three leaf samples for each field) at the kernel maturity stage. Single, well-separated lesions were excised and surface-sterilized by placing them in 75% ethanol for 5 s, then disinfested in 2% sodium hypochlorite for 5 min and rinsed with sterilized water. The lesions were incubated on water agar (WA) at 24°C for 48 to 72 h to allow sporulation. Seventy-five single-conidial isolates were obtained and cultured as described in Crous (1). Morphology of the isolates was determined on plates containing maize leaf powder agar (MLPA). After 5 days, isolates produced pale brown mycelia that consisted of 3- to 4-μm-wide, septate, branched hyphae. Conidiophores were 5 to 7 × 55 to 100 μm, straight to slightly flexuous, and usually 1- to 5-septate. Conidia were average 7.5 × 68 μm, fusiform, apex subobtuse, base subtruncate, and 3- to 6-septate. These characteristics are similar to C. zeina (2). The internal transcribed spacer (ITS) region of rDNA was amplified from each of the 75 isolates using primers ITS1/ITS4 and sequenced. The same sequences were obtained and the sequence of isolate YNGLS was submitted to GenBank (Accession No. KC878692). BLAST analysis of the sequence showed 100% confirmation to C. zeina (DQ185081). Additionally, a PCR-based diagnostic test using species-specific primers (2) confirmed the identification of the 75 isolates as C. zeina. The pathogenicity of the isolates was tested on greenhouse grown maize variety Huidan 4. The test was performed on 40 plants and replicated three times. The plants were inoculated at the 10 leaf stage by injecting 2 ml of conidial suspensions (2,500 conidia ml-1) into leaf whorl using a hypodermic syringe, and control plants were injected with sterile water. Conidia were collected from 5-day-old cultures grown on MLPA and suspended in sterile water. Forty days after inoculation, all inoculated plants showed characteristic lesions on leaves, but control plants remained asymptomatic. C. zeina was reisolated from the lesions, and the identity of the reisolates was confirmed by the morphological and molecular characteristics as stated above. C. zeina was previously reported as the causal agent of maize gray leaf spot (2). To our knowledge, this is the first report of C. zeina causing gray leaf spot of maize in China. References: (1) P. W. Crous. Mycologia Memoir. 21:1, 1998. (2) P. W. Crous et al. Stud. Mycol. 55:189, 2006. (3) C. H. Lu et al. J. Southwest China Normal Univ. 37:51, 2012.


SiO2/Ta2O5 heterojunction ECM memristors: physical nature of their low voltage operation with high stability and uniformity.
Non-uniformity of switching parameters, e.g., switching voltage and resistances of the high resistance state and low resistance state, could obstruct the practical application of electrochemical metallization cells. Higher switching voltages are also undesirable in terms of power consumption. The non-uniformity is usually related to the number of conductive filaments (CFs) and their degree of dissolution during the RESET process. The number of CFs can be ideally reduced to one by decreasing the device area. However, the degree and location of the dissolution of CFs are difficult to control. Here, we introduce a SiO2/Ta2O5 heterojunction to control the dissolution of CFs, in which the growth direction and the shape of CFs are controlled by the SiO2 layer, while the dissolution of CFs is controlled in the ultrathin Ta2O5 layer. Transmission electron microscopy analysis clearly suggested that the formation/dissolution of CFs occurs in the ultrathin Ta2O5 layer, resulting in low voltage operation (<0.3 V) with high stability and uniformity (Vset distributes in the range smaller than 0.1 V and Vreset distributes in the range smaller than 0.08 V).


Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer.
Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease. CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided. Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice. CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.


Combined Red Clover isoflavones and probiotics potently reduce menopausal vasomotor symptoms.
Natural estrogen decline leads to vasomotor symptoms (VMS). Hormone therapy alleviates symptoms but increases cancer risk. Effective treatments against VMS with minimal cancer risks are needed. We investigate the effects of a highly bioavailable aglycone rich Red Clover isoflavone treatment to alleviate existing menopausal VMS, assessed for the first time by 24hour ambulatory skin conductance (SC). We conducted a parallel, double blind, randomised control trial of 62 peri-menopausal women aged 40-65, reporting ≥ 5 hot flushes/day and follicle stimulating hormone ≥35 IU/L. Participants received either twice daily treatment with bioavailable RC extract (RCE), providing 34 mg/d isoflavones and probiotics, or masked placebo formulation for 12 weeks. The primary outcome was change in daily hot flush frequency (HFF) from baseline to 12 weeks using 24hr SC. Secondary outcomes were change in SC determined hot flush intensity (HFI), self-reported HFF (rHFF) and hot flush severity (rHFS), blood pressure and plasma lipids. A significant decrease in 24hr HFF (P < 0.01) and HFI (P<0.05) was found when comparing change from baseline to 12 months of the RCE (-4.3 HF/24hr, CI -6.8 to -2.3; -12956 μS s-1, CI -20175 to -5737) with placebo (0.79 HF/24hr, CI -1.56 to 3.15; 515 μS s-1, CI -5465 to 6496). rHFF was also significantly reduced (P <0.05)in the RCE (-2.97 HFs/d, CI -4.77 to -1.17) group compared to placebo (0.036 HFs/d, CI -2.42 to 2.49). Other parameters were non-significant. RCE was well tolerated. Results suggest that moderate doses of RCE were more effective and superior to placebo in reducing physiological and self-reported VMS. Findings support that objective physiological symptom assessment methods should be used together with self-report measures in future studies on menopausal VMS. ClinicalTrials.gov NCT02028702.


The effects of sympathetic stimulation and adenosine on coronary circulation and heart function in diabetes mellitus.
The aim of the experiment was to clarify whether the altered coronary reactivity in diabetes mellitus might be caused by a general modification of the sympathetic responses. Six of 12 young mongrel dogs of both sexes were made diabetic with alloxan (560 mmol/kg). This amount of alloxan induced a clinically manifest diabetes, however the animals failed to develop ketosis. The remaining six dogs served as controls. The haemodynamic investigation was performed three months after the induction of diabetes. Under pentobarbital anaesthesia (133 mmol/kg) mean arterial blood pressure, blood flow in the left anterior descending coronary artery, myocardial contractile force of left ventricular wall and heart rate were recorded continuously and the conductivity of coronary arterial bed was calculated during electrical stimulation ( 8V , 1-2-4-8-20 s-1) of the cardiac plexus or during the intracoronary infusion of adenosine (30-60-120-240-480 nmol/kg/min). In alloxan-diabetic dogs electrical stimulation evoked vasoconstriction in the coronary arterial bed, while vasodilation was observed in metabolically healthy animals. The vasodilator effect of adenosine was significantly smaller in diabetic than in control dogs. On the other hand there were no differences either in the alterations of heart rate caused by adenosine or in those of myocardial contractile force induced by adenosine or electric stimulation between the two groups. It is concluded that general alteration of sympathetic responses is not, but rather a modified relation of the receptors to the vessel wall might be responsible for the altered vascular responses in diabetes.


Inducement by fat feeding of basal hyperglycemia in rats with abnormal beta-cell function. Model for study of etiology and pathogenesis of NIDDM.
Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogenous disorder characterized by defects in insulin action and secretion. This study was aimed at developing a rat model in which these pathogenic factors might be studied. Male Wistar rats were injected at 2 days of age with 45 or 30 mg/kg streptozocin (STZ) or vehicle (control). Fasting plasma glucose and insulin levels were not significantly different between the two groups between 5 and 8 wk of age. At 8 wk, half of each group was randomly assigned to isocaloric diets high in either fat (59% of calories) or starch (70% of calories). After 1 wk on the diets, 45-mg/kg-STZ-administered fat-fed animals displayed significant fasting hyperglycemia (8.6 +/- 0.2 mM; P less than 0.01), which was exacerbated by the stress of anesthesia and/or cannulation, whereas no changes were observed in any of the other groups before (STZ starch fed, 6.7 +/- 0.1 mM; control fat fed, 6.8 +/- 0.1 mM; control starch fed; 6.4 +/- 0.1 mM) or after anesthesia and/or cannulation. In the 30-mg/kg-STZ animals, fat feeding did not significantly elevate plasma glucose concentration, but a significant hyperglycemic response was seen with anesthesia and/or cannulation. In all STZ groups, substantial impairment of glucose-induced insulin secretion was observed, particularly early-phase insulin secretion. Further studies indicated that STZ animals on a diet conferring normal insulin sensitivity (starch) maintained basal normoglycemia and mildly impaired (i.v.) glucose tolerance despite this gross insulin secretory defect.(ABSTRACT TRUNCATED AT 250 WORDS)


Bonding crowns and bridges with resin cement: An American Dental Association Clinical Evaluators Panel survey.
Bonding crowns and bridges with resin cement can improve retention and reinforcement of the restoration. However, there is variation in the steps taken by different practitioners to achieve this goal. The authors developed a survey on bonding dental crowns and bridges with resin cement and distributed it electronically to the American Dental Association Clinical Evaluators (ACE) Panel on May 22, 2020. The survey remained open for 2 weeks. Descriptive data analysis was conducted using SAS Version 9.4. A total of 326 panelists responded to the survey, and 86% of respondents who place crowns or bridges use resin cements for bonding. When placing a lithium disilicate restoration, an almost equal proportion of respondents etch it with hydrofluoric acid in their office or asked the laboratory to do it for them, and more than two-thirds use a silane primer before bonding. For zirconia restorations, 70% reported their restorations are sandblasted in the laboratory, and 39% use a primer containing 10-methacryloyloxydecyl dihydrogen phosphate. One-half of respondents clean their lithium disilicate or zirconia restorations with a cleaning solution. Resin cements used with a primer in the etch-and-rinse mode are the most widely used. The technique used to cure and clean excess resin cement varies among respondents. The types of resin cements used, tooth preparation, crown or bridge preparation, and bonding technique vary among this sample. Although many dentists bond crowns and bridges on the basis of best practices, improvement in the process may be achieved by dentists communicating with their laboratory to confirm the steps performed there, ensuring an effective cleaning technique is used after try-in and verifying that the correct primer is used with their chosen restorative material.


Specifying race-ethnic differences in risk for psychiatric disorder in a USA national sample.
Epidemiological studies have found lower than expected prevalence of psychiatric disorders among disadvantaged race-ethnic minority groups in the USA. Recent research shows that this is due entirely to reduced lifetime risk of disorders, as opposed to persistence. Specification of race-ethnic differences with respect to clinical and social characteristics can help identify the protective factors that lead to lower lifetime risk among disadvantaged minority groups. Data on 5424 Hispanics, non-Hispanic Blacks, and non-Hispanic Whites came from the National Comorbidity Survey Replication, a nationally representative survey conducted with the World Mental Health version of the Composite International Diagnostic Interview. Race-ethnic differences in risk of disorders were compared across specific diagnoses, ages of onset, cohorts and levels of education. Both minority groups had lower risk for common internalizing disorders: depression, generalized anxiety disorder, and social phobia. In addition, Hispanics had lower risk for dysthymia, oppositional-defiant disorder and attention deficit hyperactivity disorder; non-Hispanic Blacks had lower risk for panic disorder, substance use disorders and early-onset impulse control disorders. Lower risk among Hispanics, relative to non-Hispanic Whites, was found only among the younger cohort (age<or=43 years). Lower risk among minorities was more pronounced at lower levels of education. The pattern of race-ethnic differences in risk for psychiatric disorders suggests the presence of protective factors that originate in childhood and have generalized effects on internalizing disorders. For Hispanics, but not for non-Hispanic Blacks, the influence of these protective factors has emerged only recently.


Species-level bacterial community profiling of the healthy sinonasal microbiome using Pacific Biosciences sequencing of full-length 16S rRNA genes.
Pan-bacterial 16S rRNA microbiome surveys performed with massively parallel DNA sequencing technologies have transformed community microbiological studies. Current 16S profiling methods, however, fail to provide sufficient taxonomic resolution and accuracy to adequately perform species-level associative studies for specific conditions. This is due to the amplification and sequencing of only short 16S rRNA gene regions, typically providing for only family- or genus-level taxonomy. Moreover, sequencing errors often inflate the number of taxa present. Pacific Biosciences' (PacBio's) long-read technology in particular suffers from high error rates per base. Herein, we present a microbiome analysis pipeline that takes advantage of PacBio circular consensus sequencing (CCS) technology to sequence and error correct full-length bacterial 16S rRNA genes, which provides high-fidelity species-level microbiome data. Analysis of a mock community with 20 bacterial species demonstrated 100% specificity and sensitivity with regard to taxonomic classification. Examination of a 250-plus species mock community demonstrated correct species-level classification of > 90% of taxa, and relative abundances were accurately captured. The majority of the remaining taxa were demonstrated to be multiply, incorrectly, or incompletely classified. Using this methodology, we examined the microgeographic variation present among the microbiomes of six sinonasal sites, by both swab and biopsy, from the anterior nasal cavity to the sphenoid sinus from 12 subjects undergoing trans-sphenoidal hypophysectomy. We found greater variation among subjects than among sites within a subject, although significant within-individual differences were also observed. Propiniobacterium acnes (recently renamed Cutibacterium acnes) was the predominant species throughout, but was found at distinct relative abundances by site. Our microbial composition analysis pipeline for single-molecule real-time 16S rRNA gene sequencing (MCSMRT, https://github.com/jpearl01/mcsmrt ) overcomes deficits of standard marker gene-based microbiome analyses by using CCS of entire 16S rRNA genes to provide increased taxonomic and phylogenetic resolution. Extensions of this approach to other marker genes could help refine taxonomic assignments of microbial species and improve reference databases, as well as strengthen the specificity of associations between microbial communities and dysbiotic states.


Characterization of the functional specificity of a cloned T-cell receptor heterodimer recognizing the MART-1 melanoma antigen.
T cells can play a central role in the immune response to cancer, with tumor-specific T-lymphocyte reactivity provided by the T-cell receptor (TCR) alpha and beta chain heterodimer. This study is the first report of the definitive identification and characterization of a functional tumor-associated, antigen-specific TCR by reconstitution in an alternate cell line. Jurkat T cells were transfected with the cDNAs encoding the full-length alpha and beta T-cell receptor chains from the HLA-A2 restricted, melanoma-reactive T-cell clone, clone 5. Expression of the transfected TCR was evaluated by immunofluorescence after down-modulation of the endogenous receptor with Jurkat T-cell receptor beta chain-specific mAb. Jurkat clone 5 TCR+ cells recognized MART-1 peptides presented by T2 cells in a pattern and sensitivity equivalent to native MART-1-reactive T-cells. Recognition of HLA-A2+ melanoma cell lines by the Jurkat clone 5 TCR+ cells, however, did not occur without the addition of exogenous MART-1 peptide. The cloning and expression of functional TCR genes which are capable of specifically recognizing MART-1 antigen provides reagents which could be used for the study of the mechanisms of T-cell/tumor antigen interactions and creates immortalized reagents which can facilitate studies requiring detection of the MART-1 antigen. The tumor reactivity provided by these genes could also have application in novel immunotherapeutic strategies for treating patients with melanoma, including redirection of tumor-infiltrating lymphocyte specificity and bone marrow stem cell therapy.


A nuclear gene encoding mitochondrial proline dehydrogenase, an enzyme involved in proline metabolism, is upregulated by proline but downregulated by dehydration in Arabidopsis.
Proline is one of the most common compatible osmolytes in water-stressed plants. The accumulation of proline in dehydrated plants is caused both by the activation of proline biosynthesis and by the inactivation of proline degradation; a decrease in the level of accumulated proline in rehydrated plants is caused both by the inhibition of proline biosynthesis and by the activation of proline degradation. The proline biosynthetic pathway has been well characterized, but the degradation of proline is poorly understood. Sequence analysis of an Arabidopsis cDNA clone, ERD5 (for early responsive to dehydration stress), isolated from plants dehydrated for 1 hr, revealed that it encodes a protein with identity to products of the yeast PUT1 (for proline utilization) gene (23.6% over 364 amino acids) and the Drosophila sluggish-A gene (34.5% over 255 amino acids). Their gene products are precursors of proline oxidases (dehydrogenase) (EC 126.96.36.199), which are the first enzymes involved in the conversion of proline to glutamic acid. Proline oxidase is localized in mitochondria. RNA gel blot analysis demonstrated that transcripts of the ERD5 gene were undetectable when plants had been dehydrated for 10 hr, but large amounts of the transcript accumulated when plants subsequently were rehydrated. Elevated levels of the transcript were also found in plants that had been incubated in a medium that contained proline. Immunologically, we showed that the product of ERD5 is localized in the mitochondrial fraction and accumulates in response to proline in cultured cells. Fusion genes for ERD5 and PUT1 complemented a put1 mutant of yeast, allowing put1 to grow with proline as the source of nitrogen. These results suggest that ERD5 encodes a precursor of proline dehydrogenase (oxidase), which is regulated at the level of mRNA accumulation in both dehydrated and rehydrated plants.


Use of medicinal plants in patients with chronic kidney disease from Peru.
To describe the use of medicinal plants in patients with chronic kidney disease (CKD) in public healthcare centers in Peru. A cross-sectional study was conducted in patients with CKD in healthcare centers of three Peruvian regions: Lima, Arequipa, and Ucayali. A structured questionnaire which included socio-demographic data, medical antecedents and characteristics of the use of medicinal plants was used. Prevalence ratios (PR) and 95 % confidence intervals (95% CI) were calculated using crude Poisson regressions with robust variances. A total of 599 patients with CKD were evaluated, of which 300 (50.1%) reported the use of medicinal plants (160 [30.3%] used these plants for CKD), 379 reported that medicinal plants were not harmful, while 166 (27.8%) stopped using allopathic medicine to use medicinal plants only. In the adjusted analysis, the frequency of the use of medicinal plants for CKD was similar between Lima and Arequipa but was lower in Ucayali than in Lima (PR: 0.32, 95% CI: 0.14 - 0.76). In addition, a higher frequency of the use of medicinal plants for CKD was observed in patients with more advanced stages of CKD (PR: 1.55, 95% CI: 1.06-2.26) and in patients who were aware they had CKD (PR: 2.79 95% CI: 1.39-5.63). Half of the patients used medicinal plants and about one-third used it for CKD. This use was lower in Ucayali and higher in both the patients who knew they had CKD and those with more advanced stages of the disease. Given these results, physicians should ask and inform regarding medicinal plants consumption to their CKD patients.


CropSight: a scalable and open-source information management system for distributed plant phenotyping and IoT-based crop management.
High-quality plant phenotyping and climate data lay the foundation for phenotypic analysis and genotype-environment interaction, providing important evidence not only for plant scientists to understand the dynamics between crop performance, genotypes, and environmental factors but also for agronomists and farmers to closely monitor crops in fluctuating agricultural conditions. With the rise of Internet of Things technologies (IoT) in recent years, many IoT-based remote sensing devices have been applied to plant phenotyping and crop monitoring, which are generating terabytes of biological datasets every day. However, it is still technically challenging to calibrate, annotate, and aggregate the big data effectively, especially when they were produced in multiple locations and at different scales. CropSight is a PHP Hypertext Pre-processor and structured query language-based server platform that provides automated data collation, storage, and information management through distributed IoT sensors and phenotyping workstations. It provides a two-component solution to monitor biological experiments through networked sensing devices, with interfaces specifically designed for distributed plant phenotyping and centralized data management. Data transfer and annotation are accomplished automatically through an hypertext transfer protocol-accessible RESTful API installed on both device side and server side of the CropSight system, which synchronize daily representative crop growth images for visual-based crop assessment and hourly microclimate readings for GxE studies. CropSight also supports the comparison of historical and ongoing crop performance while different experiments are being conducted. As a scalable and open-source information management system, CropSight can be used to maintain and collate important crop performance and microclimate datasets captured by IoT sensors and distributed phenotyping installations. It provides near real-time environmental and crop growth monitoring in addition to historical and current experiment comparison through an integrated cloud-ready server system. Accessible both locally in the field through smart devices and remotely in an office using a personal computer, CropSight has been applied to field experiments of bread wheat prebreeding since 2016 and speed breeding since 2017. We believe that the CropSight system could have a significant impact on scalable plant phenotyping and IoT-style crop management to enable smart agricultural practices in the near future.