First Report of Bacterial Black Spot Disease in Watermelon Caused by Acidovorax valerianellae in Korea.
Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai), an important member of the Cucurbitaceae family, is cultivated on 21,000 ha that produces 850,000 t in Korea. In April 2011, we received grafted watermelon with necrotic leaf spots from a commercial watermelon grower in Andong, Korea. Black spots were observed on cotyledons of the plants in seedbeds, and approximately 9% of watermelon plants were infected with the disease. Initial symptoms on the seedling were black, greasy spots sometimes surrounded by a halo of discoloration. Younger leaves usually showed symptoms later than cotyledons. Bacteria isolated from the infected plants were gram-negative, motile, straight rods with a single flagellum and 0.84 to 0.89 μm wide and 1.54 to 1.69 μm long. They formed rough colonies with a white-cream color after 48 h of incubation on Luria-Bertani (LB) agar at 28°C. Colonies of isolates were nonfluorescent, smooth, and white on King's medium B. On YBGA (7 g of yeast extract, 7 g of bactopeptone, 7 g of glucose, 15 g of agar, 1,000 ml of distilled water; pH 7.2) colonies are circular, raised with an entire margin, and white to cream. Pathogenicity tests were conducted with potted, greenhouse-grown watermelon plants. Bacterial colonies grown on LB medium for 48 h at 28°C were suspended in sterile distilled water, and the suspension (1.0 × 108 CFU/ml) was infiltrated into mesophyll of watermelon leaves with a syringe as previously described (2). Inoculated plants were maintained at 28°C and 90% relative humidity in a growth chamber with a daily 12-h photoperiod of fluorescent light. Five plants were used for inoculation. Sterilized distilled water was used as a control. The bacterial isolates induced necrosis in the infiltrated area within 3 to 5 days. Typical water-soaked spots appeared after 3 days of incubation and became gray to black after 6 days. The bacterium was successfully reisolated from the diseased lesions, thus completing Koch's postulates. A cell suspension (50 μl of 1 × 106 CFU/ml) was infiltrated with a syringe into the intercellular spaces of tobacco leaves to determine the hypersensitive reaction (HR). A typical HR developed 20 h after leaf infiltration. The 16S rDNA region of the isolates, amplified by using universal PCR primers, shared 99% sequence identity with an Acidovorax valerianellae strain (GenBank Accession No. AJ431731) (1). The resulting sequences of 1,424 bp were deposited in GenBank (Accession No. JN983471). The isolates we obtained in this study clustered with A. valerianellae on a phylogenetic tree generated by the neighbor-joining method implemented in MEGA Version 4.1. In the Biolog Microbial Identification System, Version 4.2 (Biolog Inc., Hayward, CA), all isolates were 63 to 77% similar with a match probability of 100% to A. konjaci. Fatty acid composition analysis of isolates based on the MIDI Library version TSBA 5.0 and Library Generation system software version 5.0 showed that the isolates were 52 and 72% similar to an Acidovorax sp., respectively. To our knowledge, this is the first report of bacterial black spot disease in watermelon caused by A. valerianellae in Korea. A. valerianellae is a causal agent of bacterial black spot in corn salad and is transmitted by inoculated seeds (3). Further studies are required to determine whether it is seed transmitted in watermelon. References: (1) L. Gardan et al. Int. J. Syst. Evol. Microbiol. 53:795, 2003. (2) C. Grondeau et al. Plant Pathol. 56:302, 2007. (3) C. Grondeau et al. Plant Pathol. 58:846, 2009.


Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respiratory disease, SARS, with significant mortality. Although factors contributing to the highly pathogenic nature of SARS-CoV remain poorly understood, it has been reported that SARS-CoV infection does not induce type I interferons (IFNs) in cell culture. However, it is uncertain whether SARS-CoV evades host detection or has evolved mechanisms to counteract innate host defenses. We show here that infection of SARS-CoV triggers a weak IFN response in cultured human lung/bronchial epithelial cells without inducing the phosphorylation of IFN-regulatory factor 3 (IRF-3), a latent cellular transcription factor that is pivotal for type I IFN synthesis. Furthermore, SARS-CoV infection blocked the induction of IFN antiviral activity and the up-regulation of protein expression of a subset of IFN-stimulated genes triggered by double-stranded RNA or an unrelated paramyxovirus. In searching for a SARS-CoV protein capable of counteracting innate immunity, we identified the papain-like protease (PLpro) domain as a potent IFN antagonist. The inhibition of the IFN response does not require the protease activity of PLpro. Rather, PLpro interacts with IRF-3 and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid-inducible gene I/melanoma differentiation-associated gene 5 pathways. Our data suggest that regulation of IRF-3-dependent innate antiviral defenses by PLpro may contribute to the establishment of SARS-CoV infection.


Disentangling the Influence of Mutation and Migration in Clonal Seagrasses Using the Genetic Diversity Spectrum for Microsatellites.
The recurrent lack of isolation by distance reported at regional scale in seagrass species was recently suggested to stem from stochastic events of large-scale dispersal. We explored the usefulness of phylogenetic information contained in microsatellite loci to test this hypothesis by using the Genetic Diversity Spectrum (GDS) on databases containing, respectively, 7 and 9 microsatellites genotypes for 1541 sampling units of Posidonia oceanica and 1647 of Cymodocea nodosa The simultaneous increase of microsatellite and geographic distances that emerges reveals a coherent pattern of isolation by distance in contrast to the chaotic pattern previously described using allele frequencies, in particular, for the long-lived P. oceanica These results suggest that the lack of isolation by distance, rather than the resulting from rare events of large-scale dispersal, reflects at least for some species a stronger influence of mutation over migration at the scale of the distribution range. The global distribution of genetic polymorphism may, therefore, result predominantly from ancient events of step-by-step (re)colonization followed by local recruitment and clonal growth, rather than contemporary gene flow. The analysis of GDS appears useful to unravel the evolutionary forces influencing the dynamics and evolution at distinct temporal and spatial scales by accounting for phylogenetic information borne by microsatellites, under an appropriate mutation model. This finding adds nuance to the generalization of the influence of large-scale dispersal on the dynamics of seagrasses.


Crystal structures of the catalytic domain of human soluble guanylate cyclase.
Soluble guanylate cyclase (sGC) catalyses the synthesis of cyclic GMP in response to nitric oxide. The enzyme is a heterodimer of homologous α and β subunits, each of which is composed of multiple domains. We present here crystal structures of a heterodimer of the catalytic domains of the α and β subunits, as well as an inactive homodimer of β subunits. This first structure of a metazoan, heteromeric cyclase provides several observations. First, the structures resemble known structures of adenylate cyclases and other guanylate cyclases in overall fold and in the arrangement of conserved active-site residues, which are contributed by both subunits at the interface. Second, the subunit interaction surface is promiscuous, allowing both homodimeric and heteromeric association; the preference of the full-length enzyme for heterodimer formation must derive from the combined contribution of other interaction interfaces. Third, the heterodimeric structure is in an inactive conformation, but can be superposed onto an active conformation of adenylate cyclase by a structural transition involving a 26° rigid-body rotation of the α subunit. In the modelled active conformation, most active site residues in the subunit interface are precisely aligned with those of adenylate cyclase. Finally, the modelled active conformation also reveals a cavity related to the active site by pseudo-symmetry. The pseudosymmetric site lacks key active site residues, but may bind allosteric regulators in a manner analogous to the binding of forskolin to adenylate cyclase. This indicates the possibility of developing a new class of small-molecule modulators of guanylate cyclase activity targeting the catalytic domain.


Classification systems in psychiatry: diagnosis and global mental health in the era of DSM-5 and ICD-11.
The development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and- of the 11th edition of the International Classification of Disease (ICD-11) have led to renewed attention to the conceptual controversies surrounding the nosology of mental disorder. This article reviews recent work in this area, and suggests potential ways forward for psychiatric nosology, focusing in particular on the need for improved classification approaches for public and global mental health. DSM-5 and ICD-11 have taken somewhat different approaches, but both appropriately emphasize the importance of clinical utility and diagnosic validity in psychiatric nosology. The Research Domain Criteria framework provides a useful focus on the individual-level causal mechanisms that are relevant to vulnerability to mental disorder. An analogous approach to societal-level causal mechanisms would be useful from a public and global mental health perspective. In their day-to-day work, clinicians will continue to use the fuzzy constructs operationally defined and narratively depicted in DSM-5 and ICD-11. Advances in our understanding of the individual-level and society-level causal mechanisms that contribute to vulnerability to mental disorder may ultimately lead to improved classification systems, and in turn to better individualized care as well as improved global mental health.


Information content of the scattering matrix for spheroidal particles.
The T-matrix method is shown to be an efficient and accurate procedure for calculating the scattering matrix for randomly oriented nonspherical particles. Calculated scattering matrix elements for spheroidal particles are identical to those obtained by the spheroidal harmonic approach. T-matrix calculations for a randomly oriented finite length cylinder agree well with microwave scattering measurements. Analysis of the information content of the angular variation of the matrix elements for a set of moderately sized absorbing spheroidal particles is presented. It is found that the Fourier spectrum of the phase function and a parameter related to the depolarization ratio contain particle size and shape information, respectively.


Regio- and Stereoselective Alkylation of Pyridine-N-oxides: Synthesis of Substituted Piperidines and Pyridines.
Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.


Treatment of femoro-acetabular impingement with surgical dislocation and débridement in young adults.
Femoro-acetabular impingement has been associated with acetabular labral and/or articular cartilage damage that may ultimately result in osteoarthritis of the hip. Surgical treatment of femoro-acetabular impingement is directed at restoring a more normal femoral head-neck offset to alleviate femoral abutment against the acetabular rim and treating associated labral and articular cartilage damage. Thirty hips with femoro-acetabular impingement (in twenty-nine patients) underwent débridement through a greater trochanteric flip osteotomy and anterior dislocation of the femoral head. There were sixteen male patients and thirteen female patients with a mean age of thirty-one years. Cam (femoral based) impingement was noted in fourteen hips; pincer (acetabular based) impingement, in one hip; and combined cam and pincer impingement, in fifteen hips. The mean duration of clinical and radiographic follow-up was thirty-two months. All patients were followed according to a prospective protocol, with Harris hip scores and plain radiographs obtained preoperatively and at six months, one year, and annually for a minimum of two years. The mean Harris hip score improved from 70 points preoperatively to 87 points at the time of final follow-up (p < 0.0001). Osteonecrosis did not develop in any hip, and there were no trochanteric nonunions. In eighteen hips, severe damage of the acetabular articular cartilage that had not been appreciated on preoperative plain radiographs or magnetic resonance arthrography was noted on arthrotomy. Eight of these eighteen hips subsequently had radiographic evidence of progression of the osteoarthritis, and four of the eight hips required or were expected to soon require conversion to a total hip arthroplasty to treat progressive pain. At the time of early follow-up, we found that surgical dislocation and débridement of the hip for the treatment of femoro-acetabular impingement in hips without substantial damage to the articular cartilage can reduce pain and improve function. This procedure has a low rate of complications. Radiographic signs of progression of osteoarthritis and clinical failure requiring conversion to a total hip arthroplasty were seen only in patients with severe damage to the acetabular articular cartilage, a finding that emphasizes the need for better imaging methods to assess the extent of damage to the acetabular articular cartilage in patients with this disorder.


Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease.
Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.


Kras mutations and p53 overexpression in pseudomyxoma peritonei: association with phenotype and prognosis.
Little information exists on Kras mutations and p53 overexpression in pseudomyxoma peritonei (PMP). These genetic alterations are associated with poorer prognoses in colorectal cancer. We postulated that these mutations might be more frequent in high-grade (HG) PMP (peritoneal mucinous carcinomatosis) versus low-grade (LG) PMP (disseminated peritoneal adenomucinosis/peritoneal mucinous carcinomatosis), for which survival differences are well documented. We collected data retrospectively on patients with PMP of appendiceal origin tested for Kras mutation (commercial assay) and p53 overexpression (immunohistochemistry). We used Fisher's exact test, chi-square test, and Kaplan-Meier survival curves for analysis. Of 64 cases with Kras mutations, 25 were classified as LG and 39 as HG PMP. Median age at diagnosis was 53 ± 11.5 y. We detected Kras mutations in 37 of 64 patients (57.8%). In LG PMP, 15 of 25 (60%) were Kras mutant versus 22 of 39 (56.4%) in HG PMP (P=0.80). Nearly 89% of mutations were seen in codon 12. We noted overexpression of p53 in 44.3% (86 of 194) of patients overall, which was significantly different between LG PMP and HG PMP: 35.5% (37 of 104) versus 54.4% (49 of 90), respectively (P=0.009). Kras mutations did not affect prognosis. Overexpression of p53 was associated with a worse outcome. Kras mutation and p53 overexpression rates are comparable to those of colorectal adenomas and mucinous colorectal cancer. Codon 12 mutations may be associated with mucin production. Kras mutation status is not prognostic for overall survival. Overexpression of p53 was significantly correlated with female sex, higher-grade disease, and worse survival.


Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders.
Clinical evidence suggests comorbidity between depression and irritable bowel syndrome (IBS). Early-life stress and genetic predisposition are key factors in the pathophysiology of both IBS and depression. Thus, neonatal maternal separation (MS), and the Wistar-Kyoto (WKY) rat, a genetically stress-sensitive rat strain, are two animal models of depression that display increased visceral hypersensitivity and alterations in the hypothalamic-pituitary-adrenal axis. Corticotrophin-releasing factor (CRF) is the primary peptide regulating this axis, acting through two receptors: CRF1 and CRF2. The central CRF system is also a key regulator in the stress response. However, there is a paucity of studies investigating alterations in the central CRF system of adult MS or WKY animals. Using in-situ hybridization we demonstrate that CRF mRNA is increased in the paraventricular nucleus (PVN) of WKY rats and the dorsal raphé nucleus (DRN) of MS animals, compared to Sprague-Dawley and non-separated controls, respectively. Additionally, CRF1 mRNA was higher in the PVN, amygdala and DRN of both animal models, along with high levels of CRF1 mRNA in the hippocampus of WKY animals compared to control animals. Finally, CRF2 mRNA was lower in the DRN of MS and WKY rats compared to control animals, and in the hippocampus and amygdala of MS rats. These results show that the central CRF system is altered in both animal models. Such alterations may affect HPA axis regulation, contribute to behavioural changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients.


Mechanisms of aflatoxin B1 lung tumorigenesis.
Although aflatoxin B1 (AFB1) is best known as a hepatocarcinogen, the respiratory system can also be a target of this mycotoxin. In isolated lung cells from rabbits and mice, AFB1 is bioactivated by cytochromes P450, primarily in nonciliated bronchiolar epithelial (Clara) cells. However, mutagenesis experiments suggest that the DNA-binding AFB1 epoxide metabolite can leave the cells of origin, and potentially interact with other cell types. Consistent with DNA adduct studies, AFB1-induced AC3F1 mouse lung tumors contain point mutations at guanine residues in K-ras, with the anticipated bias for the A/J allele. Furthermore, following AFB1 treatment but prior to tumor development, K-ras mutations occur preferentially in mouse Clara cells. However, in contrast to findings with other carcinogens, AFB1-induced mouse lung tumors demonstrate frequent, but heterogeneously distributed, overexpression of p53 protein as well as p53 point mutations, suggesting a carcinogen-specific response. Unlike lung tissue from mice and rabbits, human peripheral lung bioactivates AFB1 primarily by prostaglandin H synthase--and/or lipoxygenase-catalyzed cooxidation, with activity concentrated in macrophages. In addition, although glutathione S-transferase M1-1 has high specific activity for AFB1 epoxide conjugation, lung tissues from GSTM1-null individuals do not demonstrate diminished rates of conjugation, compared to tissues from GSTM1-positive individuals. In summary, AFB1 tumorigenesis in mice demonstrates unique properties, and processes of bioactivation show significant species differences.


Enhancement of the cytotoxic effects of Cytarabine in synergism with Hesperidine and Silibinin in Acute Myeloid Leukemia: An in-vitro approach.
Acute Myeloid Leukemia (AML) therapy continues to be a daunting challenge. Cytosine Arabinoside (Ara-C) is widely used to treat hematological malignancy in humans, but often becomes ineffective because of increased resistance to the drug which may lead to a worse prognosis. Therefore new strategies are needed to understand the mechanism responsible for drug resistance and to develop new therapies to overcome it. Research evidence based on natural compounds used alone or in combination with current chemotherapeutic agents proved their efficacy to treat and prevent cancer. Hesperidin and Silibinin displayed anti-cancer activity against various types of cancers and cell lines and can be used in combination with Cytarabine with the aim to increase cytotoxicy profile and reduction in drug resistance. Experimental Work: Primary cells obtained from AML patient's bone marrow were used to develop in-vitro model and further exposed to various concentration of Cytarabine (10 nM-5000 nM), Hesperidin (0.5 μM-100 μM) and Silibinin (0.5 μM-100 μM) alone and in combination with Cytarabine (Hesperidin-25 μM, Silibinin10 μM) to check cytotoxicity using MTT assay. Synergistic effect was evaluated by Combination Index method. In-vitro study of Hesperidin and Silibinin indicated their cytotoxicity at IC 50 value 50.12 μM and 16.2 μM, respectively. Combination Index study revealed Hesperidin and Silibinin both showed synergistic potential and decreased the IC 50 value of Cytarabine by ~5.9 and ~4.5 folds, respectively. Both natural compounds showed potential anti-leukemic activity hence may be used for AML therapy alone or in combination with other chemotherapeutic agents.


[6]-Gingerol isolated from ginger attenuates sodium arsenite induced oxidative stress and plays a corrective role in improving insulin signaling in mice.
Arsenic toxicity induces type 2 diabetes via stress mediated pathway. In this study, we attempt to reveal how sodium arsenite (iAs) could induce stress mediated impaired insulin signaling in mice and if an isolated active fraction of ginger, [6]-gingerol could attenuate the iAs intoxicated hyperglycemic condition of mice and bring about improvement in their impaired insulin signaling. [6]-Gingerol treatment reduced elevated blood glucose level and oxidative stress by enhancing activity of super oxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and GSH. [6]-Gingerol also helped in increasing plasma insulin level, brought down after iAs exposure. iAs treatment to primary cell culture of β-cells and hepatocytes in vitro produced cyto-degenerative effect and accumulated reactive oxygen species (ROS) in pancreatic β-cells and hepatocytes of mice. [6]-Gingerol appeared to inhibit/intervene iAs induced cyto-degeneration of pancreatic β-cells and hepatocytes, helped in scavenging the free radicals. The over-expression of TNFα and IL6 in iAs intoxicated mice was down-regulated by [6]-gingerol treatment. iAs intoxication reduced expression levels of GLUT4, IRS-1, IRS-2, PI3K, AKT, PPARγ signaling molecules; [6]-gingerol mediated its action through enhancing the expressions of these signaling molecules, both at protein and mRNA levels. Thus, our results suggest that [6]-gingerol possesses an anti-hyperglycemic property and can improve impaired insulin signaling in arsenic intoxicated mice.


Effect of probiotic supplementation on cognitive function in children and adolescents: a systematic review of randomised trials.
Available reviews have shown potential effects of probiotics on neurobehavioral outcomes through 'gut-brain axis' mechanism in adults. However, reviews on cognitive function in children and adolescents are lacking. Therefore, we conducted a systematic review of randomised controlled trials (RCTs) of the effect of probiotic supplementation on cognitive function in children and adolescents. A search of four databases (Cochrane Central Register of Controlled Trials, PsycARTICLES, Scopus, PubMed) was conducted to identify RCTs published from January 1990 to December 2018. Seven studies met the inclusion criteria and their cognitive outcomes were analysed. Only one study found a positive result with Lactobacillus rhamnosus GG (LGG) 1×1010 cfu supplementation with outcomes on attention deficit hyperactivity disorder (ADHD) or Asperger syndrome (AS) manifestations as diagnosed using the International Classification of Diseases-10 criteria. The supplementations were administered to Finnish mothers for 4 weeks before delivery and continuously given for 6 months after delivery if they breastfed, or to the children. ADHD or AS was diagnosed at the age of 13 years in 17.1% children in the placebo and none in the probiotic group (P=0.008). This study found significant differences in species composition and number of cells belonging to the genus Bifidobacterium between healthy children and children who later developed ADHD or AS at different time points. Six remaining studies with varying strains, durations of intervention, start-time of administration, and outcomes demonstrated no difference in cognition after probiotic supplementation. Metagenomic analyses on gut microbiota composition were not performed in any of these studies. In conclusion, the favourable effect of probiotic supplementation on cognitive function in children and adolescents was observed in one study with LGG supplementation by a risk reduction of developing ADHD or AS (i.e. autism). More long-term and follow-up trials using probiotics identifying the effect on cognition are warranted before routine use.


Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.
A key requirement for Rab function in membrane trafficking is site-specific activation by GDP-GTP exchange factors (GEFs), but the majority of the 63 human Rabs have no known GEF. We have performed a systematic characterization of the 17 human DENN domain proteins and demonstrated that they are specific GEFs for 10 Rabs. DENND1A/1B localize to clathrin patches at the plasma membrane and activate Rab35 in an endocytic pathway trafficking Shiga toxin to the trans-Golgi network. DENND2 GEFs target to actin filaments and control Rab9-dependent trafficking of mannose-6-phosphate receptor to lysosomes. DENND4 GEFs target to a tubular membrane compartment adjacent to the Golgi, where they activate Rab10, which suggests a function in basolateral polarized sorting in epithelial cells that compliments the non-DENN GEF Sec2 acting on Rab8 in apical sorting. DENND1C, DENND3, DENND5A/5B, MTMR5/13, and MADD activate Rab13, Rab12, Rab39, Rab28, and Rab27A/27B, respectively. Together, these findings provide a basis for future studies on Rab regulation and function.


Psychiatry meets pharmacogenetics for the treatment of revolving door patients with psychiatric disorders.
Therapeutic failures (TFs) and adverse drug reactions (ADRs), together with the recurring nature of the clinical course of psychiatric disorders, mainly bipolar disorders (BDs), strongly contributed to the prevalence and frequency of hospital readmissions observed in these patients. This is the revolving door (RD) condition, dramatically rising costs for the management of these patients in psychiatric settings. Areas covered: We searched in the medical literature until May 2016 to review the role of functional variants in the cytochrome P450 (CYP) 2D6 gene on observed ADRs and TFs in RD patients with BDs, conferring a different capacity to metabolize psychotropic drugs. Expert commentary: CYP2D6 functional polymorphisms might directly contributed to the prevalence and frequency of the RD condition, commonly observed in BD patients. Although several environmental and socio-demographic/diagnostic variables such as alcohol/drug abuse, and medication non-compliance accounted for a significant proportion of the ability to predict RD prevalence and frequency, the pharmacogenetics of CYP, particularly CYP2D6, may help to identify BD patients at risk for ADRs and TFs. These patients may be addressed towards alternative treatments, thus improving their quality of life, and reducing RD prevalence and frequency and the overall costs for their management.


Chronic inflammatory demyelinating polyneuropathy associated with diabetes: a European multicentre comparative reappraisal.
The association between chronic inflammatory demyelinating polyneuropathy (CIDP) and diabetes is uncertain despite important diagnostic and management implications. We retrospectively analysed two European cohorts, totaling 257 patients with 'definite' or 'probable' CIDP, from Serbia and Birmingham, UK. Diabetes was present at CIDP diagnosis in 25/139 (18%) subjects in the Serbian cohort and in 23/118 (19.5%) in the UK cohort. In both cohorts, diabetes prevalence was higher than local general population prevalence rates (RR: 2.09; 95% CI 1.39 to 2.95 and RR: 2.22; 95% CI 1.46 to 3.17, respectively). Considering typical CIDP only, diabetes prevalence was greater than expected in both cohorts (RR: 2.58; 95% CI 1.60 to 3.82 and RR: 2.68; 95% CI 1.71 to 3.87, respectively). CIDP with diabetes occurred later in life than CIDP without diabetes (58.96 years, SD: 11.09 vs 51.71 years, SD: 16.02; p=0.003) and presented more frequently in the typical form than in patients without diabetes (79.2% vs 61.2%; p=0.02). Baseline Inflammatory Neuropathy Cause and Treatment disability scores were similar in patients with and without diabetes (p=0.90). Proportions of treatment responders were similar in both groups (70% vs 74.9%; p=0.65), as were response amplitudes (p=0.87). Our results, both for all CIDP and typical CIDP presentations, support a twofold increased relative risk of diabetes compared with the general population. CIDP with diabetes appears to present older and more frequently in the typical form, as compared with CIDP without diabetes. CIDP with diabetes appears similar to CIDP without diabetes in disability levels at diagnosis and probability, as well as amplitude of treatment response.


Heterogeneity in the composition of marijuana seized in California.
Marijuana contains multiple cannabinoids. Most attention is given to delta-9-tetrahydrocannabinol (THC) which produces euphoria and in some cases anxiety and panic reactions. Research suggests that another cannabinoid, cannabidiol (CBD), may offset some of these effects. Thus, there is growing interest in the health consequences of the THC to CBD ratio for marijuana. Using data from over 5000 marijuana samples in California from 1996 to 2008, we examine changes in the median THC-level, median CBD-level, and median THC:CBD-ratio. The median THC-level and median THC:CBD-ratio have dramatically increased for seizures in California, particularly north of the Mexican border. Research on the consequences of the THC:CBD ratio should continue, especially as more attention is devoted to thinking about how to regulate marijuana for medical and recreational use. Researchers should also consider the lack of uniformity in the chemical composition of marijuana when evaluating its health effects.


Identifying Hand Use and Hand Roles After Stroke Using Egocentric Video.
Upper limb (UL) impairment impacts quality of life, but is common after stroke. UL function evaluated in the clinic may not reflect use in activities of daily living (ADLs) after stroke, and current approaches for assessment at home rely on self-report and lack details about hand function. Wrist-worn accelerometers have been applied to capture UL use, but also fail to reveal details of hand function. In response, a wearable system is proposed consisting of egocentric cameras combined with computer vision approaches, in order to identify hand use (hand-object interactions) and the role of the more-affected hand (as stabilizer or manipulator) in unconstrained environments. Nine stroke survivors recorded their performance of ADLs in a home simulation laboratory using an egocentric camera. Motion, hand shape, colour, and hand size change features were generated and fed into random forest classifiers to detect hand use and classify hand roles. Leave-one-subject-out cross-validation (LOSOCV) and leave-one-task-out cross-validation (LOTOCV) were used to evaluate the robustness of the algorithms. LOSOCV and LOTOCV F1-scores for more-affected hand use were 0.64 ± 0.24 and 0.76 ± 0.23, respectively. For less-affected hands, LOSOCV and LOTOCV F1-scores were 0.72 ± 0.20 and 0.82 ± 0.22. F1-scores for hand role classification were 0.70 ± 0.19 and 0.68 ± 0.23 in the more-affected hand for LOSOCV and LOTOCV, respectively, and 0.59 ± 0.23 and 0.65 ± 0.28 in the less-affected hand. The results demonstrate the feasibility of predicting hand use and the hand roles of stroke survivors from egocentric videos.


Efficient freeform lens optimization for computational caustic displays.
Phase-only light modulation shows great promise for many imaging applications, including future projection displays. While images can be formed efficiently by avoiding per-pixel attenuation of light most projection efforts utilizing phase-only modulators are based on holographic principles which rely on interference of coherent laser light and a Fourier lens. Limitations of this type of an approach include scaling to higher power as well as visible artifacts such as speckle and image noise. We propose an alternative approach: operating the spatial phase modulator with broadband illumination by treating it as a programmable freeform lens. We describe a simple optimization approach for generating phase modulation patterns or freeform lenses that, when illuminated by a collimated, broadband light source, will project a pre-defined caustic image on a designated image plane. The optimization procedure is based on a simple geometric optics image formation model and can be implemented computationally efficient. We perform simulations and show early experimental results that suggest that the implementation on a phase-only modulator can create structured light fields suitable, for example, for efficient illumination of a spatial light modulator (SLM) within a traditional projector. In an alternative application, the algorithm provides a fast way to compute geometries for static, freeform lens manufacturing.


Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data.
Before the introduction of the immunomodulatory therapies for multiple sclerosis (MS), treatment options for MS consisted of symptomatic management (physical therapy and pharmacological treatment for symptom management). Symptomatic management for MS has been supplemented in the past decade by 2 new classes of immunomodulatory therapies that have been approved as first-line treatments for relapsing-remitting multiple sclerosis (RRMS): subcutaneous glatiramer acetate (SC GA) and 3 beta-interferons: intramuscular interferon beta-1a (IM IFNbeta-1a), SC IFNbeta-1a, and SC IFNbeta-1b. To estimate the economic outcomes of 5 treatment strategies: symptom management alone, symptom management combined with SC GA, IM IFNbeta1-a, SC IFNbeta1-a, or SC IFNbeta1-b in patients diagnosed with RRMS. A literature-based Markov model was developed to assess the cost-effectiveness of 5 treatment strategies for managing a hypothetical cohort of patients diagnosed with RRMS in the United States--4 immunomodulatory drug therapies and symptom management alone. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS), a widely accepted scale for assessing RRMS (higher EDSS scores = increased disease severity). Baseline relapse and disease progression transition probabilities for symptom management were obtained from natural history studies. Treatment effects of the immunomodulatory therapies were estimated by applying a percentage reduction to the symptom management transition probabilities for relapse (27% reduction) and disease progression (30% reduction). Transition probabilities were subsequently adjusted to account for (1) the effects of neutralizing antibodies, specifically on relapse rates by assuming no additional therapy benefits after the second year of continuous therapy, and (2) treatment discontinuation. Therapy-specific data were obtained from clinical trials and long-term follow-up observational studies. Transitions among health states occurred in 1-month cycles for the lifetime of a patient. Costs (2005 US$) and outcomes were discounted at 3% annually. The incremental cost per quality-adjusted life-year for the 4 immunomodulatory therapies is $258,465, $303,968, $416,301, and $310,691 for SC GA, IM IFNbeta-1a, SC IFNbeta-1a, and SC IFNbeta-1b, respectively, compared with symptom management alone. Sensitivity analyses demonstrated that results were sensitive to changes in utilities, disease progression rates, time horizon, and immunomodulatory therapy cost. The pharmacoeconomic model determined that SC GA was the best strategy of the 4 immunomodulatory therapies used to manage MS and resulted in better outcomes than symptom management alone. Sensitivity analyses indicated that the model was sensitive to changes in a number of key parameters, and thus changes in these key parameters would likely influence the estimated cost-effectiveness results. Head-to-head randomized clinical trials comparing the immunomodulatory therapies for the treatment of MS are necessary to validate the projections from the pharmacoeconomic analyses, particularly since the results available today from the clinical trials do not account adequately for treatment dropouts.


Patterns and predictors of colorectal cancer test use in the adult U.S. population.
Screening is effective in reducing the incidence and mortality of colorectal cancer. Rates of colorectal cancer test use continue to be low. The authors analyzed data from the National Health Interview Survey concerning the use of the home-administered fecal occult blood test (FOBT) and sigmoidoscopy/colonoscopy/proctoscopy to estimate current rates of colorectal cancer test use and to identify factors associated with the use or nonuse of tests. In 2000, 17.1% of respondents reported undergoing a home FOBT within the past year, 33.9% reported undergoing an endoscopy within the previous 10 years, and 42.5% reported undergoing either test within the recommended time intervals. The use of colorectal cancer tests varied by gender, race, ethnicity, age, education, income, health care coverage, and having a usual source of care. Having seen a physician within the past year had the strongest association with test use. Lack of awareness and lack of physician recommendation were the most commonly reported barriers to undergoing such tests. Less than half of the U.S. population age >/= 50 years underwent colorectal cancer tests within the recommended time intervals. Educational initiatives for patients and providers regarding the importance of colorectal cancer screening, efforts to reduce disparities in test use, and ensuring that all persons have access to routine primary care may help increase screening rates.


Experimental transmission of Besnoitia caprae in goats.
Experimental transmission of Besnoitia caprae from naturally chronically-infected goats to susceptible ones was achieved by intra-nasal instillation and intra-conjunctival inoculation of cystozoite-containing suspensions, subcutaneous implantation of fascia containing cysts and alternate needle pricking between the infected and non-infected goats. Typical chronic symptoms developed in the fascia-infected does. Cystozoite inoculation into the eyes and mouth did not result in infection. Kids born of dams with acute and chronic besnoitiosis did not contract the infection in utero, suggesting that intra-uterine transmission may not occur. In contrast to does with acute besnoitiosis, which occasionally aborted, the does with chronic besnoitiosis gave birth to healthy kids. Kids below the age of 4 months (pre-weaned period) born of both infected and non-infected does were susceptible to besnoitiosis but appeared to be more resistant than adult goats.


Implied motion activation in cortical area MT can be explained by visual low-level features.
To investigate form-related activity in motion-sensitive cortical areas, we recorded cell responses to animate implied motion in macaque middle temporal (MT) and medial superior temporal (MST) cortex and investigated these areas using fMRI in humans. In the single-cell studies, we compared responses with static images of human or monkey figures walking or running left or right with responses to the same human and monkey figures standing or sitting still. We also investigated whether the view of the animate figure (facing left or right) that elicited the highest response was correlated with the preferred direction for moving random dot patterns. First, figures were presented inside the cell's receptive field. Subsequently, figures were presented at the fovea while a dynamic noise pattern was presented at the cell's receptive field location. The results show that MT neurons did not discriminate between figures on the basis of the implied motion content. Instead, response preferences for implied motion correlated with preferences for low-level visual features such as orientation and size. No correlation was found between the preferred view of figures implying motion and the preferred direction for moving random dot patterns. Similar findings were obtained in a smaller population of MST cortical neurons. Testing human MT+ responses with fMRI further corroborated the notion that low-level stimulus features might explain implied motion activation in human MT+. Together, these results suggest that prior human imaging studies demonstrating animate implied motion processing in area MT+ can be best explained by sensitivity for low-level features rather than sensitivity for the motion implied by animate figures.


Obesity disparities in preventive care: findings from the National Ambulatory Medical Care Survey, 2005-2007.
Obesity and its consequences are a major health concern. There are conflicting reports regarding utilization of preventive health-care services among obese patients. Our objective was to determine whether obese patients receive the same preventive care as normal weight patients. Weighted patient clinic visit data from the National Ambulatory Medical Care Survey (NAMCS) were analyzed for all adult patient visits with height/weight data (N = 866,415,856) from 2005 to 2007. Preventive care practice patterns were compared among different weight groups of normal, obese, and morbidly obese. Obese patients received the least number of preventive exams with a clear gradient present by weight. Obese patients were significantly less likely to receive cancer screening including breast examination (normal weight, reference, obese, odds ratio (OR), 0.8), mammogram (obese OR, 0.7), pap smear (obese OR, 0.7), pelvic exam (obese OR, 0.8), and rectal exam (obese OR, 0.7). The obese population also received less tobacco (obese OR, 0.7) and injury prevention education (obese OR, 0.7), yet significantly more diet, exercise, and weight reduction education. Significant differences in clinic practice patterns relative to normal weight patients were also evident with more physician referral (obese OR, 1.2) and less likely to see physician at the index clinic visit (obese OR, 0.8) and less likely to receive psychotherapy referral (obese OR, 0.6). Significant gaps in preventive care exist for the obese including cancer screening, tobacco cessation and injury prevention counseling, and psychological referral. Although obese patients received more weight-related education, this emphasis may have the consequence of de-emphasizing other needed preventive health measures.


Lifetime prevalence, demographic risk factors, and diagnostic validity of nonaffective psychosis as assessed in a US community sample. The National Comorbidity Survey.
We seek to estimate lifetime prevalence and demographic correlates of nonaffective psychosis in the US population assessed by a computer-analyzed structured interview and a senior clinician. In the National Comorbidity Survey, a probability subsample of 5877 respondents were administered a screen for psychotic symptoms. Based on the response to this screening, detailed follow-up interviews were conducted by mental health professionals (n = 454). The initial screen and clinical reinterview were reviewed by a senior clinician. Results are presented for narrowly (schizophrenia or schizophreniform disorder) and broadly (all nonaffective psychoses) defined psychotic illness. One or more psychosis screening questions were endorsed by 28.4% of individuals. By computer algorithm, lifetime prevalences of narrowly and broadly defined psychotic illness were 1.3% and 2.2%, respectively. Of those assigned a narrow diagnosis by the computer, the senior clinician assigned narrow and broad diagnoses to 10% and 37%, respectively. By clinician diagnosis, lifetime prevalence rates of narrowly and broadly defined psychosis were 0.2% and 0.7%, respectively. A clinician diagnosis of nonaffective psychosis was significantly associated with low income; unemployment a marital status of single, divorced, or separated; and urban residence Clinician confirmation of a computer diagnosis was predicted by hospitalization, neuroleptic treatment, duration of illness, enduring impairment, and thought disorder. Lifetime prevalence estimates of psychosis in community samples are strongly influenced by methods of assessment and diagnosis. Although results using computer algorithms were similar in the National Comorbidity Survey and Epidemiologic Catchment Area studies, diagnoses so obtained agreed poorly with clinical diagnoses. Accurate assessment of psychotic illness in epidemiologic samples may require collection of extensive contextual information for clinician review.


A FAK-Cas-Rac-lamellipodin signaling module transduces extracellular matrix stiffness into mechanosensitive cell cycling.
Tissue and extracellular matrix (ECM) stiffness is transduced into intracellular stiffness, signaling, and changes in cellular behavior. Integrins and several of their associated focal adhesion proteins have been implicated in sensing ECM stiffness. We investigated how an initial sensing event is translated into intracellular stiffness and a biologically interpretable signal. We found that a pathway consisting of focal adhesion kinase (FAK), the adaptor protein p130Cas (Cas), and the guanosine triphosphatase Rac selectively transduced ECM stiffness into stable intracellular stiffness, increased the abundance of the cell cycle protein cyclin D1, and promoted S-phase entry. Rac-dependent intracellular stiffening involved its binding partner lamellipodin, a protein that transmits Rac signals to the cytoskeleton during cell migration. Our findings establish that mechanotransduction by a FAK-Cas-Rac-lamellipodin signaling module converts the external information encoded by ECM stiffness into stable intracellular stiffness and mechanosensitive cell cycling. Thus, lamellipodin is important not only in controlling cellular migration but also for regulating the cell cycle in response to mechanical signals.


Generalizability of established prostate cancer risk variants in men of African ancestry.
Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.


Assessment of the Role of Carotid Atherosclerosis in the Association Between Major Cardiovascular Risk Factors and Ischemic Stroke Subtypes.
A better understanding of the role of atherosclerosis in the development of ischemic stroke subtypes could help to improve strategies for prevention of stroke worldwide. To assess the role of carotid atherosclerosis in the association between major cardiovascular risk factors and ischemic stroke subtypes. The prospective China Kadoorie Biobank cohort study was conducted in the general population of 5 urban and 5 rural areas in China, with a baseline survey obtained between June 2004 and July 2008. A random sample of 23 973 participants with no history of cardiovascular disease at enrollment who had carotid artery ultrasonographic measurements recorded at a resurvey from September 2013 to June 2014 were included. Data analysis was performed from July 1, 2016, to April 10, 2019. Major cardiovascular risk factors (ie, blood pressure [BP], blood lipid levels, smoking, and diabetes). Carotid ultrasonographic measures of plaque burden (derived from number and maximum size of carotid artery plaques at resurvey) and first ischemic stroke during follow-up (n = 952), with subtyping (data release, August 2018) as lacunar (n = 263), probable large artery (n = 193), probable cardioembolic (n = 66), or unconfirmed (n = 430). Associations between cardiovascular risk factors, carotid plaque burden, and ischemic stroke subtypes were adjusted for age, sex, and geographic area. The 23 973 participants in the study had a mean (SD) age of 50.6 (10.0) years, and 14 833 (61.9%) were women. Systolic BP had a stronger association (odds ratio [OR] per SD, 1.51; 95% CI, 1.42-1.61) than plaque burden (OR per SD, 1.34; 95% CI, 1.26-1.44) with ischemic stroke, and the associations of systolic BP with each subtype of ischemic stroke were modestly attenuated by adjustment for plaque burden. After adjustment for BP, plaque burden had a stronger association with probable large artery stroke (OR, 1.43; 95% CI, 1.24-1.63) than with lacunar stroke (OR, 1.25; 95% CI, 1.10-1.43) but was not associated with probable cardioembolic stroke (OR, 1.06; 95% CI, 0.83-1.36). Although BP was an important risk factor for all ischemic stroke subtypes, carotid atherosclerosis was an important risk factor only for large artery and lacunar strokes, suggesting that drug treatments targeting atherosclerosis may reduce the risk of stroke subtypes to different extents.


Glycoproteins of 210,000 and 130,000 m.w. on activated T cells: cell distribution and antigenic relation to components on resting cells and T cell lines.
A glycoprotein complex of 210,000 and 130,000 m.w., found on mitogen or alloantigen-stimulated human T cells and not on other hematopoietic cells, has been defined by a monoclonal antibody (Mab). The components of this complex are a subset of a larger family of proteins (210,000, 165,000 and 130,000 m.w.) defined by a second Mab. In a panel of hematopoietic cell lines and cell types, only activated T cells (including the cell line HUT-102) express the 210,000/130,000 complex and these cells also express the IL 2 receptor, a characteristic marker for activated T cells. The 210,000/130,000 m.w. complex (reactive with the Mab TS2/7) is present on all long-term activated T cells, including both the OKT4 and OKT8 subsets. The 210,000 m.w. subunit is expressed only on activated T cells. Other lymphoid cells express either the 130,000 m.w. subunit alone (unactivated lymphocytes, thymocytes, HUT-78) or the 130,000 subunit together with a 165,000 subunit (MOLT-4, HSB, and other leukemic T cell lines). The 210,000/130,000 m.w., 165,000/130,000 m.w. and 130,000 m.w. complexes are antigenically related in that all share reactivity with the Mab A- 1A5 . Among non-lymphoid hematopoietic cells and cell lines, none express the 210,000 m.w. chain; adherent cells (monocytes) and myeloid cell lines each express single proteins of 130,000 to 155,000 m.w. Granulocytes and red blood cells are negative and platelets express multiple bands (165,000 and 140,000 m.w.). Immunoperoxidase staining of tissue sections showed that a broad range of tissues and cell types had material cross-reactive with the lymphoid 130,000 m.w. protein. However, only a discrete subset of those tissues and cells including blood vessel walls, connective tissue, smooth muscle, kidney mesangial cells, and some non-cellular matrix tissue, had material cross-reactive with the 210,000 m.w. protein on activated T lymphocytes.


Generation of arbitrary vector beams with cascaded liquid crystal spatial light modulators.
A flexible approach is presented to generate vector beams with arbitrary polarization and complex amplitude by means of two cascaded transmissive liquid crystal spatial light modulators (LCSLMs). The configuration of the cascaded LCSLM system and its modulation characteristic are introduced. Theoretical analysis and experimental demonstration prove that the system in combination with a double-pass computer-generated hologram and a black-and-white pattern can generate vector beams with arbitrary polarization and complex amplitude by respectively controlling the complex amplitudes of two orthogonal polarization components of the beams. Using this system, we successfully generate radially polarized vector beams with helical phase distributions and vector Bessel beams with inhomogeneous amplitude distributions in experiments.


Ventricular myocardial thicknesses in anencephalic fetuses.
The heart of an anencephalic baby can be used as a donor after death. There exists insufficient information in literature, however, for the possible morphological differences in anencephalic hearts. This study compares ventricular myocardial thicknesses of anencephalic fetuses with normal fetuses in the same gestational age group. The comparison was made histologically on the slices taken from three levels of anterior and posterior walls of the left and right ventricles and from two levels of the interventricular septum. When each level was taken into account separately, the middle part of the left ventricular anterior wall was detected thinner in anencephalics (P = 0.010). When the mean value for each wall (anterior and posterior) was taken into account, left ventricular anterior wall was found thinner in anencephalics (P = 0.005). When the mean value for each ventricle was compared, the left ventricular wall was detected thinner in anencephalics (P = 0.025). These results support the idea that absence of the cerebral cortex results in modifications of the fetal heart. Because differences were limited to the left ventricular anterior wall non-homogenously, factors other than the decrease in the heart load (e.g., changes in intrathoracic anatomy) might also affect the myocardial features. When the mean value of right ventricle was compared to the left within the normal and anencephalic groups separately, the left ventricle was thicker than the right in normal fetuses (P = 0.016). In anencephalics the difference between two ventricular walls was insignificant (P = 0.084). This supports the left ventricular dominance in normal fetuses but not in anencephalics for the 27-34 weeks of age group. We suggest that when an anencephalic heart is intended to use as a donor, possible alterations presented in this article should be taken into account.


Overview of cancer registration research in the Asian Pacific from 2008-2013.
Cancer registration provides a firm basis for cancer control efforts and research into changing patterns of incidence, mortality, survival and prevalence is of obvious importance. Most of the countries of Asia have already published relevant data although the level of coverage and accuracy do vary a great deal both between and within countries. The present review concerns the relevant literature for the period 2008-2013, focusing on the types of research conducted and the conclusions that can be drawn with regard to what should be done in the future to translate the information available into effective intervention efforts to reduce the burden of disease. A major emphasis has been on determining variation in incidence and mortality/survival on the basis of ethnicity and socioeconomic as well as geographical background, as well as trends over time, either for cancer in general or specific organ sites. In addition a small number of papers focused on methodological, quality and cancer control issues, very pertinent to the future development of cancer registry based research.


Chemical synthesis of a masked analogue of the fish antifreeze potentiating protein (AFPP).
A recently identified Antarctic fish protein termed antifreeze potentiating protein (AFPP) is thought to act as an adjunct to the previously characterised antifreeze glycoproteins (AFGPs), the two acting together to inhibit ice crystal growth in vivo. Elucidating the functional properties of the new AFPP requires access to large amounts of pure product, but the paucity of natural material necessitates alternative approaches. We therefore embarked on the total chemical synthesis of the AFPP, through a convergent ligation strategy. After many challenges, mostly due to the solubility issues of the peptide fragments, and several revisions of the original synthetic strategy, we have successfully synthesized a masked analogue of AFPP. The key to the successful synthesis was the use of a solubilising tag attached through a hydrolysable linker.


Performance analysis of multiplexed phase computer-generated hologram for modal wavefront sensing.
We investigate the performance and capability of a holographic modal wavefront sensor (HMWS) that is based on a multiplexed phase computer-generated hologram (MPCGH). The theoretical treatments of the HMWS are presented with scalar diffraction approximations and Fourier analysis. Several MPCGHs have been designed with different linear carrier frequencies, by using of the multiplexed coding scheme we have proposed, and by coding some common Zernike modes. The numerical simulation is carried out to investigate the performance of the HMWS to detect particular aberration mode(s), by considering the effect of different carrier frequency selections and the capability of coding a large number of modes. The results exhibit the expected characteristics of a corresponding symmetric spot pair, and indicate that the wavefront distorted by a particular Zernike mode(s) can be retrieved immediately through solving the amplitude of each mode coded in MPCGHs through the response curves of the HMWS.


Lebanese children are iodine deficient and urinary sodium and fluoride excretion are weak positive predictors of urinary iodine.
To assess iodine and fluoride status among Lebanese children. A nationally representative cross-sectional study of 6- to 10-year-old schoolchildren was conducted using multistage cluster sampling. Spot urine samples were collected from 1403 children, and urinary iodine, fluoride, creatinine and sodium levels were measured. Salt samples from markets (n = 30) were tested for iodine concentration by titration. Median urinary iodine concentration was 66.0 µg/l, indicating mild deficiency, and almost 75 % of Lebanese children had a urinary iodine concentration (UIC) <100 µg/l. UIC was higher among children from private schools and in areas of higher socioeconomic status. Most salt samples were fortified at levels far below the legislated requirement, and 56 % of samples contained less than 15 ppm iodine. Fluoride-to-creatinine ratio (F/Cr) was 0.250 (0.159-0.448) mg/g. There were weak positive correlations between UIC and urinary sodium (r 2 = 0.039, P value <0.001) and UIC and urinary fluoride (r 2 = 0.009, P value <0.001). Lebanese elementary school children are iodine deficient due to inadequately iodized salt. The weak correlation between UIC and urinary sodium suggests most dietary iodine does not come from iodized salt. The poor correlation between UIC and urinary fluoride suggests that fluoride intake is not affecting iodine metabolism. Efforts are needed in Lebanon to improve industry compliance with salt fortification through improved monitoring and enforcement of legislation.


COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer.
Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type XI alpha 1 (COL11A1) in cell invasiveness and tumor formation and the prognostic impact of COL11A1 expression in ovarian cancer. Microarray analysis suggested that COL11A1 is a disease progression-associated gene that is linked to ovarian cancer recurrence and poor survival. Small interference RNA-mediated specific reduction in COL11A1 protein levels suppressed the invasive ability and oncogenic potential of ovarian cancer cells and decreased tumor formation and lung colonization in mouse xenografts. A combination of experimental approaches, including real-time RT-PCR, casein zymography and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated MMP3 expression and suppressed binding of Ets-1 to its putative MMP3 promoter-binding site, suggesting that the Ets-1-MMP3 axis is upregulated by COL11A1. Transforming growth factor (TGF)-beta (TGF-β1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-β1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA-binding site on the COL11A1 promoter was identified as the major determinant of TGF-β1-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are associated with advanced disease stage. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.006 and P=0.018, respectively) among patients with high expression levels of tissue COL11A1 mRNA compared with those with low expression. We conclude that COL11A1 may promote tumor aggressiveness via the TGF-β1-MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients.


Evaluating Nonresponse Weighting Adjustment for the Population-Based HIV Impact Assessment Surveys on Incorporating Survey Outcomes.
The nonresponse weighting adjustment of the Population-based HIV Impact Assessment (PHIA) surveys uses the weighting class method in combination with a tree analysis to identify predictors significant to response propensity. Variable selection for this type of nonresponse adjustment identifies auxiliary variables correlated with response propensity alone and produces 1 set of weights applicable for all analyses of the survey data. An alternative approach identifies auxiliary variables correlated to both the response probability and selected key outcome variables. This approach may identify a different set of variables for the nonresponse adjustments and may produce more efficient estimates for the key outcome variables. The PHIA surveys from 2016 to 2017. Weighting class, joint-classification, and two-step modeling. There was little difference among estimates produced by the alternative weighting methods and the PHIA estimates. The joint-classification method produced more efficient estimates (ie, smaller design effects) compared with the PHIA method, while the two-step method was inconclusive. The efficiency of the estimates produced by the PHIA weighting method closely resembles those specifically targeted at key survey outcomes and serves well as a multipurpose weight.


Ubiquitin regulates GGA3-mediated degradation of BACE1.
BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1) is a membrane-tethered member of the aspartyl proteases, essential for the production of beta-amyloid, a toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. The BACE1 C-terminal fragment contains a DXXLL motif that has been shown to bind the VHS (VPS27, Hrs, and STAM) domain of GGA1-3 (Golgi-localized gamma-ear-containing ARF-binding proteins). GGAs are trafficking molecules involved in the transport of proteins containing the DXXLL signal from the Golgi complex to endosomes. Moreover, GGAs bind ubiquitin and traffic synthetic and endosomal ubiquitinated cargoes to lysosomes. We have previously shown that depletion of GGA3 results in increased BACE1 levels and activity because of impaired lysosomal degradation. Here, we report that the accumulation of BACE1 is rescued by the ectopic expression of GGA3 in H4 neuroglioma cells depleted of GGA3. Accordingly, the overexpression of GGA3 reduces the levels of BACE1 and beta-amyloid. We then established that mutations in the GGA3 VPS27, Hrs, and STAM domain (N91A) or in BACE1 di-leucine motif (L499A/L500A), able to abrogate their binding, did not affect the ability of ectopically expressed GGA3 to rescue BACE1 accumulation in cells depleted of GGA3. Instead, we found that BACE1 is ubiquitinated at lysine 501 and is mainly monoubiquitinated and Lys-63-linked polyubiquitinated. Finally, a GGA3 mutant with reduced ability to bind ubiquitin (GGA3L276A) was unable to regulate BACE1 levels both in rescue and overexpression experiments. These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery.


Analyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamics.
Microsecond molecular dynamics simulations of B-DNA oligomers carried out in an aqueous environment with a physiological salt concentration enable us to perform a detailed analysis of how potassium ions interact with the double helix. The oligomers studied contain all 136 distinct tetranucleotides and we are thus able to make a comprehensive analysis of base sequence effects. Using a recently developed curvilinear helicoidal coordinate method we are able to analyze the details of ion populations and densities within the major and minor grooves and in the space surrounding DNA. The results show higher ion populations than have typically been observed in earlier studies and sequence effects that go beyond the nature of individual base pairs or base pair steps. We also show that, in some special cases, ion distributions converge very slowly and, on a microsecond timescale, do not reflect the symmetry of the corresponding base sequence.


Statistical methods for assessment of added usefulness of new biomarkers.
The discovery and development of new biomarkers continues to be an exciting and promising field. Improvement in prediction of risk of developing disease is one of the key motivations in these pursuits. Appropriate statistical measures are necessary for drawing meaningful conclusions about the clinical usefulness of these new markers. In this review, we present several novel metrics proposed to serve this purpose. We use reclassification tables constructed on the basis of clinically meaningful disease risk categories to discuss the concepts of calibration, risk separation, risk discrimination, and risk classification accuracy. We discuss the notion that the net reclassification improvement (NRI) is a simple yet informative way to summarize information contained in risk reclassification tables. In the absence of meaningful risk categories, we suggest a 'category-less' version of the NRI and integrated discrimination improvement as metrics to summarize the incremental value of new biomarkers. We also suggest that predictiveness curves be preferred to receiver operating characteristic curves as visual descriptors of a statistical model's ability to separate predicted probabilities of disease events. Reporting of standard metrics, including measures of relative risk and the c statistic, is still recommended. These concepts are illustrated with a risk prediction example using data from the Framingham Heart Study.


A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study.
We developed a quantitative method to estimate long-term chemical-specific pesticide exposures in a large prospective cohort study of more than 58000 pesticide applicators in North Carolina and Iowa. An enrollment questionnaire was administered to applicators to collect basic time- and intensity-related information on pesticide exposure such as mixing condition, duration and frequency of application, application methods and personal protective equipment used. In addition, a detailed take-home questionnaire was administered to collect further intensity-related exposure information such as maintenance or repair of mixing and application equipment, work practices and personal hygiene. More than 40% of the enrolled applicators responded to this detailed take-home questionnaire. Two algorithms were developed to identify applicators' exposure scenarios using information from the enrollment and take-home questionnaires separately in the calculation of subject-specific intensity of exposure score to individual pesticides. The 'general algorithm' used four basic variables (i.e. mixing status, application method, equipment repair status and personal protective equipment use) from the enrollment questionnaire and measurement data from the published pesticide exposure literature to calculate estimated intensity of exposure to individual pesticides for each applicator. The 'detailed' algorithm was based on variables in the general algorithm plus additional exposure information from the take-home questionnaire, including types of mixing system used (i.e. enclosed or open), having a tractor with enclosed cab and/or charcoal filter, frequency of washing equipment after application, frequency of replacing old gloves, personal hygiene and changing clothes after a spill. Weighting factors applied in both algorithms were estimated using measurement data from the published pesticide exposure literature and professional judgment. For each study subject, chemical-specific lifetime cumulative pesticide exposure levels were derived by combining intensity of pesticide exposure as calculated by the two algorithms independently and duration/frequency of pesticide use from the questionnaire. Distributions of duration, intensity and cumulative exposure levels of 2,4-D and chlorpyrifos are presented by state, gender, age group and applicator type (i.e. farmer or commercial applicator) for the entire enrollment cohort and for the sub-cohort of applicators who responded to the take-home questionnaire. The distribution patterns of all basic exposure indices (i.e. intensity, duration and cumulative exposure to 2,4-D and chlorpyrifos) by state, gender, age and applicator type were almost identical in two study populations, indicating that the take-home questionnaire sub-cohort of applicators is representative of the entire cohort in terms of exposure.


Given diabetes, is fat better than thin?
To evaluate the association between BMI and mortality in women and men with type II diabetes. Fasting plasma glucose (FPG), height and weight measurements, and medical history were obtained from 4,483 community-dwelling adults, aged 40-79 years, in 1972-1974. A total of 373 persons with either a history of diabetes or FPG > or = 7.77 mmol/l were studied. Subjects were grouped into four sex-specific weight categories based on U.S. population data. Vital status after 14 years was known for 99.9% of the patients studied. Cox models were used to assess relative survival by weight category. Diabetic men and women of average weight had the lowest mortality. A J-shaped relative risk curve by weight category was found, with a poorer survival rate for those who were thin, overweight, or obese. This effect was not explained by early mortality or cigarette smoking. Being thin may not provide a mortality benefit for diabetic men and women. Average weight appears to be desirable.


Comparison of Two Formulas Used to Calculate Summarized Retinal Vessel Calibers.
To compare the Parr-Hubbard and Knudtson formulas to calculate retinal vessel calibers and to examine the effect of omitting vessels on the overall result. We calculated the central retinal arterial equivalent (CRAE) and central retinal venular equivalent (CRVE) according to the formulas described by Parr-Hubbard and Knudtson including the six largest retinal arterioles and venules crossing through a concentric ring segment (measurement zone) around the optic nerve head. Once calculated, we removed one arbitrarily selected artery and one arbitrarily selected vein and recalculated all outcome parameters again for (1) omitting one artery only, (2) omitting one vein only, and (3) omitting one artery and one vein. All parameters were compared against each other. Both methods showed good correlation (r 2for CRAE = 0.58; r2 for CRVE = 0.84), but absolute values for CRAE and CRVE were significantly different from each other when comparing both methods (p < 0.000001): CRAE had higher values for the Parr-Hubbard (165 [± 16] μm) method compared with the Knudtson method (148 [± 15] μm). In addition, CRAE and CRVE values dropped for both methods when omitting one arbitrarily selected vessel each (all p < 0.000001). Arteriovenous ratio (AVR) calculations showed a similar change for both methods when omitting one vessel each: AVR decreased when omitting one arteriole whereas it increased when omitting one venule. No change, however, was observed for AVR calculated with six or five vessel pairs each. Although the absolute value for CRAE and CRVE is changing significantly depending on the number of vessels included, AVR appears to be comparable as long as the same number of arterioles and venules is included.


The alpha2-polymorph of salicylideneaniline.
N-Salicylideneaniline (SA), C13H11NO, belongs to the large family of aromatic Schiff bases. It is of particular importance owing to its reversible photoreactivity. SA forms two photochromic polymorphs, both with two non-coplanar benzene rings. In addition, we have recently discovered a planar polymorph, named the beta-polymorph, which will be discussed in a subsequent paper. We report here the structure of the alpha2-polymorph in the orthorhombic crystal system. This compound exhibits a strong intramolecular O-H...N hydrogen bond and the dihedral angle between the two rings varies with temperature.


Investigation of toxin gene diversity, molecular epidemiology, and antimicrobial resistance of Clostridium difficile isolated from 12 hospitals in South Korea.
Clostridium difficile is a major cause of antibiotic-associated diarrhea. The objective of this study was to characterize clinical isolates of C. difficile obtained from various regions in Korea with regard to their toxin status, molecular type, and antimicrobial susceptibility. We analyzed a total of 408 C. difficile isolates obtained between 2006 and 2008 from 408 patients with diarrhea in 12 South Korean teaching hospitals. C. difficile toxin genes tcdA, tcdB, cdtA, and cdtB were detected by PCR. Molecular genotyping was performed by PCR ribotyping. Antimicrobial susceptibilities of the 120 C. difficile isolates were assessed by agar dilution methods. Among 337 toxigenic isolates, 105 were toxin A-negative and toxin B-positive (A(-)B(+)) and 29 were binary toxin-producing strains. PCR ribotyping showed 50 different ribotype patterns. The 5 most frequently occurring ribotypes comprised 62.0% of all identified ribotypes. No isolate was susceptible to cefoxitin, and all except 1 were susceptible to piperacillin and piperacillin-tazobactam. The resistance rates of isolates to imipenem, cefotetan, moxifloxacin, ampicillin, and clindamycin were 25%, 34%, 42%, 51%, and 60%, respectively. The isolates showed no resistance to metronidazole or vancomycin. This is the first nationwide study on the toxin status, including PCR ribotyping and antimicrobial resistance, of C. difficile isolates in Korea. The prevalence of A-B+ strains was 25.7%, much higher than that reported from other countries. Binary toxin-producing strains accounted for 7.1% of all strains, which was not rare in Korea. The most prevalent ribotype was ribotype 017, and all A-B+ strains showed this pattern. We did not isolate strains with decreased susceptibility to metronidazole or vancomycin.


Prevalence of smoking in northwest Iran: a meta-analysis.
Tobacco addiction is a major cause of preventable death worldwide. Thus, efforts to eliminate its use have the potential of producing significant health benefits. The purpose of this study was to conduct a meta-analysis to estimate the prevalence of cigarette smoking among people in the age range of 15 to 64. The specific objective of this meta-analysis was to provide valid data that policy makers can use to make evidence-based decisions. To determine the prevalence of smoking among the adult population in northwest Iran, we used reports published by the surveillance system used to assess the risk factors for non-communicable diseases in different provinces in northwest Iran for the years 2004 and 2006-2009. Several variables were extracted, including the years of study, gender, ages, and smoking prevalence. Based on the heterogeneity of the results, we used fixed or random effects models to estimate the overall prevalence of cigarette smoking. The analyses were performed using Stata 11 software. A total of 28,436 subjects (14,248 males and 14,188 females) in five age groups, i.e., 15-24, 25-34, 35-44, 45-54, and 55-64, were interviewed. Meta-analysis in men showed that, across the age groups, the lowest prevalence was 22.9%, the highest prevalence was 26.5%, and the average prevalence was 24.7%. Among women, the lowest prevalence was 0.3%, the highest prevalence was 0.8%, and the average prevalence was 0.5%. We found that approximately one-fourth of males in the age range of 15-64 in northwest Iran smoked cigarettes daily. Therefore, it is necessary to conduct effective interventions to reduce the prevalence of addiction to tobacco in this area.


Is late walking a marker of morbidity? Steering Committee, Oxford Region Child Development Project.
We identified 410 infants who were not walking independently by the age of 18 months from among a geographically defined population of 4275 infants who either were born weighing less than 2000 g or had needed admission to the special care nursery in the neonatal period. The outcome of the late walkers was ascertained at the age of 3 years by health visitors using a standard questionnaire. Of the late walkers, 230 (56%) had an associated abnormality diagnosed before the age of 3 years, and in 77 of these children (33%) this was definite or suspected cerebral palsy. The high prevalence of late walking among infants born before 28 weeks' gestation (46%) was almost entirely accounted for by a high incidence of impairment. Late walking is a simple marker of morbidity in this group of infants.


Biological effects of cigarette smoke in cultured human retinal pigment epithelial cells.
The goal of the present study was to determine whether treatment with cigarette smoke extract (CSE) induces cell loss, cellular senescence, and extracellular matrix (ECM) synthesis in primary human retinal pigment epithelial (RPE) cells. Primary cultured human RPE cells were exposed to 2, 4, 8, and 12% of CSE concentration for 24 hours. Cell loss was detected by cell viability assay. Lipid peroxidation was assessed by loss of cis-parinaric acid (PNA) fluorescence. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was detected by histochemical staining. Expression of apolipoprotein J (Apo J), connective tissue growth factor (CTGF), fibronectin, and laminin were examined by real-time PCR, western blot, or ELISA experiments. The results showed that exposure of cells to 12% of CSE concentration induced cell death, while treatment of cells with 2, 4, and 8% CSE increased lipid peroxidation. Exposure to 8% of CSE markedly increased the number of SA-ß-Gal positive cells to up to 82%, and the mRNA expression of Apo J, CTGF, and fibronectin by approximately 3-4 fold. Treatment with 8% of CSE also increased the protein expression of Apo J and CTGF and the secretion of fibronectin and laminin. Thus, treatment with CSE can induce cell loss, senescent changes, and ECM synthesis in primary human RPE cells. It may be speculated that cigarette smoke could be involved in cellular events in RPE cells as seen in age-related macular degeneration.


Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth.
Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.


Design of a microscopic electrical impedance tomography system using two current injections.
We describe a novel design of a microscopic electrical impedance tomography (micro-EIT) system for long-term noninvasive monitoring of cell or tissue cultures. The core of the micro-EIT system is a sample container including two pairs of current-injection electrodes and 360 voltage-sensing electrodes. In designing the container, we took advantage of a hexagonal structure with fixed dimensions and electrode configuration. This eliminated technical difficulties related to the unknown irregular boundary geometry of an imaging object in conventional medical EIT. Attaching a pair of large current-injection electrodes fully covering the left and right sides of the hexagonal container, we generated uniform parallel current density inside the container filled with saline. The 360 voltage-sensing electrodes were placed on the front, bottom and back sides of the hexagonal container in three sets of 8 × 15 arrays with equal gaps between them. We measured voltage differences between all neighboring pairs along the direction of the parallel current pathway. For the homogeneous container, all measured voltages must be the same since the voltage changes linearly along that direction. Any anomaly in the container perturbed the current pathways and therefore equipotential lines to produce different differential voltage data. For conductivity image reconstructions, we adopted a lately developed image reconstruction algorithm for this electrode configuration to first produce projected conductivity images on the front, bottom and back sides. Using a backprojection method, we reconstructed three-dimensional conductivity images from those projection images. To improve the image quality and also to meet the mathematical requirement on the uniqueness of a reconstructed image, we used a second pair of thin and long current-injection electrodes located at the middle of the front and back sides. This paper describes the design and construction of such a micro-EIT system with experimental results. Proposing the novel micro-EIT system design, we suggest future studies of miniaturizing the sample container for true microscopic conductivity imaging of cell or tissue cultures.


Engineering interactions in QDs-PCBM blends: a surface chemistry approach.
Here we present a comprehensive study on the photophysics of QDs-fullerene blends, aiming to elucidate the impact of ligands on the extraction of carriers from QDs. We investigated how three different ligands (oleylamine, octadecanethiol and propanethiol) influence the dynamics of charge generation, separation, and recombination in blends of CdSe/CdS core/shell QDs and PCBM. We accessed each relevant process directly by combining the results from both optical and magnetic spectroscopies. Transient absorption measurements revealed a faster interaction dynamics in thiol-capped ligands. Through phenomenological modeling of the interaction processes, i.e., energy transfer and electron transfer, we estimated the suppression of exciton migration and the enhancement of electron transfer processes when alkyl-thiols are employed as ligands. Contextually, we report the profound impact of the ligands' alkyl chain length, leading to strengthened interactions with PCBM acceptors. Quantitatively, we measured a 10-fold increase in the electron transfer rate when oleylamine ligands were exchanged with propanethiol ligands. EPR spectroscopy gave access to subtle details regarding both the enhanced charge generation and lower binding energy of charge-transfer states in blends compared to PCBM alone. Moreover, through pulsed EPR techniques, we inferred the localization of deep electron traps in localized sites close to QDs in the blends. Therefore, our thorough characterization evidenced the essential role of ligands in determining QD interactions. We believe that these discoveries will contribute to the efficient incorporation of QDs in existing organic PV technologies.


Adaptive learning from outcome contingencies in eating-disorder risk groups.
Eating disorders are characterised by altered eating patterns alongside overvaluation of body weight or shape, and have relatively low rates of successful treatment and recovery. Notably, cognitive inflexibility has been implicated in both the development and maintenance of eating disorders, and understanding the reasons for this inflexibility might indicate avenues for treatment development. We therefore investigate one potential cause of this inflexibility: an inability to adjust learning when outcome contingencies change. We recruited (n = 82) three groups of participants: those who had recovered from anorexia nervosa (RA), those who had high levels of eating disorder symptoms but no formal diagnosis (EA), and control participants (HC). They performed a reinforcement learning task (alongside eye-tracking) in which the volatility of wins and losses was independently manipulated. We predicted that both the RA and EA groups would adjust their learning rates less than the control participants. Unexpectedly, the RA group showed elevated adjustment of learning rates for both win and loss outcomes compared to control participants. The RA group also showed increased pupil dilation to stable wins and reduced pupil dilation to stable losses. Their learning rate adjustment was associated with the difference between their pupil dilation to volatile vs. stable wins. In conclusion, we find evidence that learning rate adjustment is unexpectedly higher in those who have recovered from anorexia nervosa, indicating that the relationship between eating disorders and cognitive inflexibility may be complex. Given our findings, investigation of noradrenergic agents may be valuable in the field of eating disorders.


Titanium dioxide nanotube membranes for solar energy conversion: effect of deep and shallow dopants.
Nanostructured titanium dioxide (TiO2) has been intensively investigated as a material of choice for solar energy conversion in photocatalytic, photoelectrochemical, photovoltaic, and other photosensitized devices for converting light into chemical feedstocks or electricity. Towards management of light absorption in TiO2, while the nanotubular structure improves light absorption and simultaneous charge transfer to mitigate problems due to the indirect bandgap of the semiconductor, typically dopants are used to improve light absorption of incident solar irradiation in the wide bandgap of TiO2. While these dopants can be critical to the success of these solar energy conversion devices, their effect on photophysical and photoelectrochemical properties and detailed photokinetics are relatively under-studied. Here, we show the effect of deep and shallow metal dopants on the kinetics of photogenerated charged carriers in TiO2 and the resulting effect on photocatalytic and photoelectrochemical processes using these nanotube membranes. We performed a detailed optical, electronic, voltammetry and electrochemical impedance study to understand the effect of shallow and deep metal dopants (using undoped and niobium- and copper-doped TiO2 nanotubes) on light absorption, charge transport and charge transfer processes. Using wireless photocatalytic methylene blue degradation and carbon dioxide reduction, and wired photoelectrochemical device measurements, we elucidate the effect of different dopants on solar-to-fuel conversion efficiency and simultaneously describe the photokinetics using a model, to help design better energy conversion devices.


Evaluation of Altered Functional Connections in Male Children With Autism Spectrum Disorders on Multiple-Site Data Optimized With Machine Learning.
No univocal and reliable brain-based biomarkers have been detected to date in Autism Spectrum Disorders (ASD). Neuroimaging studies have consistently revealed alterations in brain structure and function of individuals with ASD; however, it remains difficult to ascertain the extent and localization of affected brain networks. In this context, the application of Machine Learning (ML) classification methods to neuroimaging data has the potential to contribute to a better distinction between subjects with ASD and typical development controls (TD). This study is focused on the analysis of resting-state fMRI data of individuals with ASD and matched TD, available within the ABIDE collection. To reduce the multiple sources of heterogeneity that impact on understanding the neural underpinnings of autistic condition, we selected a subgroup of 190 subjects (102 with ASD and 88 TD) according to the following criteria: male children (age range: 6.5-13 years); rs-fMRI data acquired with open eyes; data from the University sites that provided the largest number of scans (KKI, NYU, UCLA, UM). Connectivity values were evaluated as the linear correlation between pairs of time series of brain areas; then, a Linear kernel Support Vector Machine (L-SVM) classification, with an inter-site cross-validation scheme, was carried out. A permutation test was conducted to identify over-connectivity and under-connectivity alterations in the ASD group. The mean L-SVM classification performance, in terms of the area under the ROC curve (AUC), was 0.75 ± 0.05. The highest performance was obtained using data from KKI, NYU and UCLA sites in training and data from UM as testing set (AUC = 0.83). Specifically, stronger functional connectivity (FC) in ASD with respect to TD involve (p < 0.001) the angular gyrus with the precuneus in the right (R) hemisphere, and the R frontal operculum cortex with the pars opercularis of the left (L) inferior frontal gyrus. Weaker connections in ASD group with respect to TD are the intra-hemispheric R temporal fusiform cortex with the R hippocampus, and the L supramarginal gyrus with L planum polare. The results indicate that both under- and over-FC occurred in a selected cohort of ASD children relative to TD controls, and that these functional alterations are spread in different brain networks.


Community of practice: a nurse practitioner collaborative model.
A study was undertaken with nurse practitioners (NPs) in 2008-2009 to examine post-legislation role development in British Columbia. The authors used a participatory action research approach to engage NPs in social investigation, education and action, and to explore, from the participants' perspective, how collaboration advances NP role integration in primary healthcare. A particular discovery of the study was the Interior Health Authority Community of Practice (CoP) established in collaboration with health leaders and NPs. The purpose of this paper is to report on the CoP and the five characteristics describing this collaborative CoP model, including sanctioned social structure, knowledge exchange network, practice discovery and innovation, generating meaning and value, and power sharing for strategic improvement. The CoP helped NPs to build collegial and collaborative relationships, enhance practice learning and competence, extend and apply new knowledge, enrich professional identities, and shape health organizational policy and politics. Because healthcare research about CoPs is limited, principles of a collaborative CoP model are offered for broader healthcare use. The authors conclude that a collaborative CoP model addresses the internal interests and needs of participating members while attending to the external concerns of the organization, and thus contributes to healthcare improvement.


Effects of Clavulanic Acid on the Acquisition and Reinstatement Following Morphine-induced Conditioned Place Preference in Mice.
β-Lactam antibiotics like Clavulanic Acid (CA) enhances cellular glutamate uptake through activation of Glutamate Transporter subtype 1 (GLT-1) and decreases the level of glutamate in the nervous system. Based on studies, blocking the glutamate activity inhibits morphine-induced Conditioned Place Preference (CPP) in animals. Therefore, the effects of CA on the acquisition of morphine craving were evaluated using the CPP model in the current study. CA (1, 50 and 150 mg/kg, ip) was co-administered with morphine (40 mg/kg) for 4 days in the conditioning phase. On day 8, the effects of CA on morphine preference was assessed. In another experiment, the effect of CA on reinstatement of morphine preference by a single morphine injection (10 mg/kg) was evaluated after an extinction period. In the first method, the morphine-induced place preference was markedly reduced following administration of CA (50 and 150 mg/kg). In the second experiment, a single administration of CA (50 and 150 mg/kg) markedly inhibited the reinstatement of morphine preference on day 16. The results indicated that CA (50, 150 mg/kg) can block both morphine-induced CPP and the reinstatement of place preference following priming dose of morphine. Also memantine (as a positive control) (10 mg/kg) significantly inhibited both acquisition and reinstatement of morphine CPP. Considering the important role of glutamate neurotransmission in morphine dependence, the effects of CA may be partly due to decrease in glutamate level in synaptic space and blockade of N-Methyl-D-aspartate Acid (NMDA) receptors. Although, we need further studies to determine exact cellular mechanism.