Positive factors associated with promoting health in low-risk and high-risk populations of 15- and 16-year-old pupils in Oslo, Norway.
To explore possible risk-reducing factors associated with the incidence of common illnesses and use of healthcare services among adolescents. Cross-sectional questionnaire study conducted in all Oslo schools among all 15- and 16-y-olds in 2000 and 2001. The adolescent population was divided into a low-risk (LR) and a high-risk (HR) group, and into quartiles, based on a sum score of different negative life experiences. The groups were compared with respect to potential risk-reducing factors. 88% of the 8316 pupils filled in the questionnaires. The difference between the LR and HR groups was largest for the possible risk-reducing factor "my family values my opinion" (LR group = 92%; HR group = 82%), and "I manage to solve serious problems myself" (LR = 91%; HR = 86%). The family valuing the adolescents' opinions was the risk-reducing factor most often associated with lower incidences of illness and healthcare utilization. Among the adolescents at highest risk, less depression was strongly related to positive relationships with friends, boys: odds ratio = 0.1 (CI 95%: 0.0-0.7); and girls: 0.2 (0.1-0.5). Adolescents reporting that they managed their own problems had about half the risk of depression. Good relations with family and friends, and a feeling of managing one's own life, are significantly related to lower rates of illness, in particular depression, and less healthcare-seeking behaviour. The risk-reducing effects increase with increasing risk. Healthcare workers therefore need to pay more attention to HR patients.


Untangling the Influence of a Protein Knot on Folding.
Entanglement and knots occur across all aspects of the physical world. Despite the common belief that knots are too complicated for incorporation into proteins, knots have been identified in the native fold of a growing number of proteins. The discovery of proteins with this unique backbone characteristic has challenged the preconceptions about the complexity of biological structures, as well as current folding theories. Given the intricacies of the knotted geometry, the interplay between a protein's fold, structure, and function is of particular interest. Interestingly, for most of these proteins, the knotted region appears critical both in folding and function, although full understanding of these contributions is still incomplete. Here, we experimentally reveal the impact of the knot on the landscape, the origin of the bistable nature of the knotted protein, and broaden the view of knot formation as uniquely decoupled from folding.


Computational simulation to assess patient safety of uncompensated COVID-19 two-patient ventilator sharing using the Pulse Physiology Engine.
The COVID-19 pandemic is stretching medical resources internationally, sometimes creating ventilator shortages that complicate clinical and ethical situations. The possibility of needing to ventilate multiple patients with a single ventilator raises patient health and safety concerns in addition to clinical conditions needing treatment. Wherever ventilators are employed, additional tubing and splitting adaptors may be available. Adjustable flow-compensating resistance for differences in lung compliance on individual limbs may not be readily implementable. By exploring a number and range of possible contributing factors using computational simulation without risk of patient harm, this paper attempts to define useful bounds for ventilation parameters when compensatory resistance in limbs of a shared breathing circuit is not possible. This desperate approach to shared ventilation support would be a last resort when alternatives have been exhausted. A whole-body computational physiology model (using lumped parameters) was used to simulate each patient being ventilated. The primary model of a single patient with a dedicated ventilator was augmented to model two patients sharing a single ventilator. In addition to lung mechanics or estimation of CO2 and pH expected for set ventilation parameters (considerations of lung physiology alone), full physiological simulation provides estimates of additional values for oxyhemoglobin saturation, arterial oxygen tension, and other patient parameters. A range of ventilator settings and patient characteristics were simulated for paired patients. To be useful for clinicians, attention has been directed to clinically available parameters. These simulations show patient outcome during multi-patient ventilation is most closely correlated to lung compliance, oxygenation index, oxygen saturation index, and end-tidal carbon dioxide of individual patients. The simulated patient outcome metrics were satisfactory when the lung compliance difference between two patients was less than 12 mL/cmH2O, and the oxygen saturation index difference was less than 2 mmHg. In resource-limited regions of the world, the COVID-19 pandemic will result in equipment shortages. While single-patient ventilation is preferable, if that option is unavailable and ventilator sharing using limbs without flow resistance compensation is the only available alternative, these simulations provide a conceptual framework and guidelines for clinical patient selection.


Custom gene expression panel for evaluation of potential molecular markers in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. It is a highly heterogeneous disease with poor prognosis and limited treatment options, which highlights the need for reliable biomarkers. This study aims to explore molecular markers that allow stratification of HCC and may lead to better prognosis and treatment prediction. We studied 20 candidate genes (HCC hub genes, potential drug target genes, predominant somatic mutant genes) retrieved from literature and public databases with potential to be used as the molecular markers. We analysed expression of the genes by RT-qPCR in 30 HCC tumour and adjacent non-tumour paired samples from Vietnamese patients. Fold changes in expression were then determined using the 2-∆∆CT method, and unsupervised hierarchical clustering was generated using Cluster v3.0 software. Clustering of expression data revealed two subtypes of tumours (proliferative and normal-like) and four clusters for genes. The expression profiles of the genes TOP2A, CDK1, BIRC5, GPC3, IGF2, and AFP were strongly correlated. Proliferative tumours were characterized by high expression of the c-MET, ARID1A, CTNNB1, RAF1, LGR5, and GLUL1 genes. TOP2A, CDK1, and BIRC5 HCC hub genes were highly expressed (> twofold) in 90% (27/30), 83% (25/30), and 83% (24/30) in the tissue samples, respectively. Among the drug target genes, high expression was observed in the GPC3, IGF2 and c-MET genes in 77% (23/30), 63% (19/30), and 37% (11/30), respectively. The somatic mutant Wnt/ß-catenin genes (CTNNB1, GLUL and LGR5) and TERT were highly expressed in 40% and 33% of HCCs, respectively. Among the HCC marker genes, a higher percentage of tumours showed GPC3 expression compared to AFP expression [73% (23/30) vs. 43% (13/30)]. The custom panel and molecular markers from this study may be useful for diagnosis, prognosis, biomarker-guided clinical trial design, and prediction of treatment outcomes.


Rapid identification of Candida glabrata by using a dipstick to detect trehalase-generated glucose.
Candida glabrata is a yeast frequently isolated from human specimens. Based upon its well-known ability to rapidly hydrolyze trehalose, we have developed a novel and cost-effective test incubating one yeast colony emulsified in 50 microl of citrate buffer (0.1 M [pH 5. 0]) containing 4% (wt/vol) trehalose for 3 h at 37 degrees C. Trehalase-generated glucose is detected with a commercially available dipstick (range, 1.0 to 50 g/liter). For evaluation, consecutive clinical isolates and several reference strains of C. glabrata (n = 160), C. albicans (n = 120), and other yeast species with potential ability for utilization of trehalose (C. dubliniensis, n = 11; C. famata, n = 15; C. guilliermondii, n = 5; C. lusitaniae, n = 16; C. parapsilosis, n = 20; C. tropicalis, n = 34; C. viswanathii, n = 5; Pichia angusta, n = 2; C. zeylanoides, n = 2; Saccharomyces cerevisiae, n = 16; C. neoformans, n = 7) were tested. Identification of C. glabrata is achieved within 3 h, with a specificity of 99.1% and a sensitivity of 98.8% when grown on Sabouraud dextrose agar supplemented with 4% glucose.


Consequences of variation in flowering phenology for seed head herbivory and reproductive success in Erigeron glaucus (Compositae).
We examined the relationship between flowering phenology, reproductive success (seed production only), and seed head herbivory for 20 similarly sized clones of Erigeron glaucus growing at Bodega Bay Reserve, northern California, USA. Although clones tended to reach peak flowering on the same date, they differed in the proportion of their total flowers produced around that date (flowering synchrony). Clones also differed in the number and density of flower heads presented at any one time to pollinators and herbivores (floral display). Both of these characteristics had consequences for herbivory and plant reproductive success. The proportion of flower heads damaged by insect herbivores was greater for clones that concentrated flowering activity during the main flowering period for the population as a whole (high synchrony) compared to clones that spread flowering out temporally. The primary reason for this result was that clones with low flowering synchrony produced a significant proportion of their flower heads during the fall and therefore, escaped attack by the tephritid fly, Tephritis ovatipennis. Clones with intermediate synchrony had lower seed success (total number of viable seeds produced over the year) than clones with either low or high synchrony. The proportion of flower heads damaged by insect herbivores and number of tephritid flies reared from flower heads were both negatively correlated to floral display while seed head mass and germination rates were positively related to display. Thus, clones which produced dense floral displays were favored both in terms of reduced herbivory and increased successful seed production.


Hypocholesterolemic action of 1-ethoxysilatrane.
Intraperitoneal administration of the organosilicon compound 1-ethoxysilatrane to the rat caused a 25% decrease in the concentration of cholesterol in serum without affecting that of triacylglycerols. The specific activity of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, was depressed in hepatic microsomes of silatrane-treated animals.


Oncologic Effects of Primary Tumor-Sidedness on Patients with Stages 1-3 Colon Cancer: A Meta-Analysis.
Previous studies comparing the oncologic outcomes of primary tumor-sidedness for patients with colon cancer have reported a worse prognosis for those with right-sided tumors. However, most of these studies evaluated patients with metastatic disease. PubMed, EMBASE, and the Cochrane Library were searched for studies that assessed the effects of primary tumor-sidedness on survival outcomes for patients with stages 1, 2, and 3 colon cancer. The hazard ratio (HR) for primary tumor location was estimated for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). The inclusion criteria were met by 37 studies involving 581,542 patients. The patients with a right-sided tumor had better CSS (HR, 0.67; 95% confidence interval [CI], 0.56-0.80; p < 0.0001) among those with stage 1 cancer as well as better OS (HR, 0.89; 95% CI 0.86-0.92; I2 = 19%) and CSS (HR, 0.78; 95% CI 0.70-0.86; I2 = 78%) among those with stage 2 cancer. In contrast, among the patients with stage 3 cancer, those with a right-sided tumor had worse OS (HR, 1.12; 95% CI 1.04-1.20; p = 0.002), CSS (HR, 1.05; 95% CI 1.01-1.10; p = 0.02), and DFS (HR, 1.32; 95% CI 1.07-1.63; p = 0.008). Primary tumor location may be a prognostic factor for patients with non-metastatic colon cancer. The prognosis for patients with right-sided tumor may be better for those with stage 1 or 2 cancer, but worse for those with stage 3 cancer.


Relationships between level of lipid peroxidation products and expression of Nrf2 and its activators/ inhibitors in non-small cell lung cancer tissue.
Lung cancer development is characterized by oxidative stress that leads to the oxidative modifications of cellular components, including phospholipid and protein. Lipid peroxidation products may be involved in intracellular signaling pathways or in the activity of transcription factors (Nrf2). Therefore, the aim of this study has been to evaluate the relationship between the level of reactive aldehydes and the activity of the transcription factor and a comparison of these parameters in different histological types and stages of non-small cell lung cancer. Lung cancer tissues and tissues without morphological changes were received during operation from patients with squamous cell lung carcinoma (SqCC), lung adenocarcinoma (AC) and large cell lung carcinoma (LCC). In the tissue homogenates the level of reactive aldehydes [4-HNE, MDA, 4-ONE] was determined by GCMS, while Nrf2 and its activators/inhibitors were evaluated by Western immunobloting. Tumor tissues showed several times higher reactive aldehydes level and those changes were accompanied by overexpression of Nrf2. The highest increase of 4-HNE and MDA level was observed in the SqCC and it was correlated with the highest increase in Nrf2 expression. Moreover, the aldehydes level and Nrf2 phosphorylation were significantly higher in the stage I than in the stage II. The level of Nrf2 inhibitor - Bach1 was lower in all histological types of tumor, but in AC was the most reduced, what is correlated with the lowest level of reactive aldehydes. The highest expression of p62 and p21 - Nrf2 activators was observed also in adenocarcinoma of the lung. However, the level of another Nrf2 activator - KAP1 was decreased in all histological types of tumor. Additionally, the cJun amount in the tumor tissue was increased, whereas reduction of its phosphorylated form in AC and LCC was observed. Understanding the relation between reactive aldehydes level and the Nrf2 activity may be applied in anticancer therapies.


Transposon Insertion Site Sequencing (TIS-Seq): An Efficient and High-Throughput Method for Determining Transposon Insertion Site(s) and Their Relative Abundances in a PiggyBac Transposon Mutant Pool by Next-Generation Sequencing.
The PiggyBac (PB) transposon has emerged as a novel mutagenesis tool for understanding gene function and for phenotypic screening in eukaryotes. Successful screening of PB transposon mutants relies on efficient identification of transposon insertion site(s) (TIS) in mutant cells. However, currently available methods suffer from time-consuming steps. Here, we present the method for transposon insertion site sequencing (TIS-Seq) for high-throughput identification of TIS in transposon mutants. TIS-Seq provides qualitative and quantitative information on mutants present in a given PB transposon mutant library. TIS-Seq also facilitates identification of TIS in up to 96 individual/hand-picked mutants in a single MiniSeq/MiSeq run. TIS-Seq is a versatile method that can be easily modified to identify TIS from any kind of transposon mutant, as long as one end of the DNA sequence is known. Therefore, TIS-Seq is a promising method for transposon mutant screening. © 2017 by John Wiley & Sons, Inc.


Platelet extracellular vesicles and their mitochondrial content improve the mitochondrial bioenergetics of cellular immune recipients.
Mitochondria play a critical role in the production of cell energy and the regulation of cell death. Therefore, mitochondria orchestrate numerous cell effector functions, including fine-tuning the immune system. While mitochondria are mainly found intracellularly, they can escape the confine of the cell during the process of extracellular vesicle release. Platelets patrol blood vessels to ensure vasculature integrity and to support the immune system. In blood, platelets are the primary source of circulating mitochondria. Activated platelets produce extracellular vesicles, including a subset of mitochondria-containing vesicles. We characterized mitochondrial functions in platelet-derived extracellular vesicles, and examined whether they could impact the bioenergetics of cellular immune recipients using an extracellular flux analyzer to measure real-time bioenergetics. We validated that extracellular vesicles derived from activated platelets contain the necessary mitochondrial machinery to respirate and generate energy. Moreover, neutrophils and monocytes efficiently captured platelet-derived extracellular vesicles, enhancing their mitochondrial fitness. This process required functional mitochondria from donor platelets, as it was abolished by the inactivation of extracellular mitochondria using mitochondrial poison. Together, the data suggest that extracellular mitochondria produced by platelets may support other metabolic functions through transcellular bioenergetics.


On evaporation dynamics of an acoustically levitated multicomponent droplet: Evaporation-triggered phase transition and freezing.
Multi-component droplet evaporation has received significant attention in recent years due to the broad range of applications such as material science, environmental monitoring, and pharmaceuticals. The selective evaporation induced by the different physicochemical properties of components is expected to influence the concentration distributions and the separation of mixtures, thereby leading to rich interfacial phenomena and phase interactions. A ternary mixture system containing hexadecane, ethanol, and diethyl ether is investigated in this study. The diethyl ether exhibits both surfactant-like and co-solvent properties. Systematic experiments were performed using acoustic levitation technique to achieve a contact-less evaporation condition. The evaporation dynamics and temperature information are acquired in the experiments, using high-speed photography and infrared thermography technologies. Three distinct stages, namely, 'Ouzo state', 'Janus state', and 'Encapsulating state', are identified for the evaporating ternary droplet in acoustic levitation. A self-sustaining periodic freezing & melting evaporation mode is reported. A theoretical model is developed to characterize the multi-stage evaporating behaviors. We demonstrate the capability to tune the evaporating behaviors by varying the initial droplet composition. This work provides a deeper understanding of the interfacial dynamics and phase transitions involved in multi-component droplets and proposes novel strategies for the design and control of droplet-based systems.


DSM-5 alternative model of personality disorder: testing the trait perspective captured in Criterion B.
We review the trait model (i.e., Criterion B) included as a central piece of the alternative model of personality disorder (PD) included in DSM-5. The pathological traits are organized into five domains with 25 facets that overlap substantially with basic personality models (e.g., five-factor model). These PD traits can be reliably assessed using a variety of measures; however, questions of poor discriminant validity have been raised. Concerns were raised that this model would result in the loss of clinically meaningful constructs (e.g., borderline personality disorder) but the empirical literature suggests that the traits can faithfully and adequately assess traditional PD constructs. Although personality dysfunction and pathological traits are required for this alternative model, impairment and traits largely overlap with only the latter demonstrating substantial and consistent incremental validity.


The development of automatic emotion regulation in an implicit emotional Go/NoGo paradigm and the association with depressive symptoms and anhedonia during adolescence.
Impaired automatic emotion regulation (AER) is closely related to major depressive disorder. Our research in adults has identified two AER-related components, Go N2 and NoGo P3, in an implicit emotional Go/NoGo paradigm. However, it is unclear whether Go N2 and NoGo P3 reflect the development of AER in adolescents and the relationship of these components with subclinical depressive symptoms and trait anhedonia. We collected EEG data from 55 adolescents while they completed the implicit emotional Go/NoGo task. After the experiment, the subjects completed the Chinese version of the Temporal Experience of Pleasure Scale and the Beck Depression Inventory. Consistent with results in adults, we determined that Go N2 represents automatic top-down attention to emotions in Go trials, whereas NoGo P3 represents automatic response inhibition in NoGo trials. These AER components exhibited age-dependent improvement during adolescence. Additionally, NoGo P3 amplitudes elicited by viewing positive faces were positively correlated with trait anhedonia, whereas NoGo P3 amplitudes elicited by viewing negative faces were negatively correlated with depressive symptoms. Our observations provide further understanding of the neurodevelopmental mechanism of AER and yield new insight into dissociable impairments in AER in adolescents with major depressive disorder during positive and negative implicit processing.


Synthesis and characterization of amino sulfonic acid functionalized graphene oxide as a potential carrier for quercetin.
In this investigation, a new nanocomposite as a nanocarrier based on functionalized graphene oxide was synthesized by reaction of tetraethylenepentamine and chlorosulfonic acid with functional groups on the surface of GO. The synthesized nanocomposite was characterized by FT-IR, XRD TGA, FE-SEM, EDAX, TEM, and AFM analysis. To explore the potential of nanocomposites in drug delivery, the loading and releases of quercetin as an anticancer drug were investigated. The result displayed that more than 90% of the drug was loaded on the nanocarrier and the release of the drug is depending on the pH of the environment such that the releases of the drug in Gastric and intestinal conditions were up to 50% and 30%, respectively. The analysis of toxicity effect on the normal and cancer cells indicated that the nanocarrier with the drug has potential for cancer cells therapy without cytotoxic effect on normal cells in IC50 concentration.


Sociodemographic Differences Among U.S. Children and Adults Exposed to Secondhand Smoke at Home: National Health Interview Surveys 2000 and 2010.
We examined the levels and change in prevalence of self-reported secondhand smoke (SHS) exposure at home, and analyzed sociodemographic differences in exposure among children (aged 0-17 years) and nonsmoking adults (aged ≥18 years) in the United States in 2000 and 2010. We included 18,731 children and 44,049 adults from the 2000 and 2010 National Health Interview Survey Cancer Control Supplements. We used multivariate logistic regression to determine the factors associated with exposure. The prevalence of self-reported SHS exposure declined from 2,627 of 10,636 (24.7%) to 663 of 8,095 (8.2%) for children and from 2,863 of 23,665 (12.1%) to 897 of 20,384 (4.4%) for adults from 2000 to 2010. SHS exposure declined for all population subgroups between the two years, but differences were found. Compared with 2000, children aged 12-17 years in 2010 were no longer more likely than children aged 0-5 years to be exposed to SHS. Non-Hispanic black children and adults were more likely than non-Hispanic white children and adults to be exposed to SHS in 2010. In 2010, no differences were found for children whose parents had a higher level of education, and no differences were observed for children or adults with high family income vs. other levels of family income. Children living in the Midwest and South had higher levels of SHS exposure than children in other regions in 2010. Self-reported SHS exposure at home declined for all population subgroups from 2000 to 2010, but socioeconomic differences existed for some subgroups in both years. Current tobacco control policies need to be improved to reach all population subgroups so that SHS exposure can be further reduced, especially among vulnerable populations.


Polymorphisms in genes HSD17B1 and HSD17B2 and uterine leiomyoma risk in Chinese women.
To evaluate the association of HSD17B1 and HSD17B2 gene polymorphisms with uterine leiomyoma in Chinese women. 121 Chinese women with clinically diagnosed uterine leiomyoma and 217 healthy normal Chinese women were investigated to compare three single nucleotide polymorphisms (SNPs) (rs605059 and rs676387 of HSD17B1 gene and rs8191246 of HSD17B2 gene) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method. All the SNPs were polymorphisms in Chinese women. Frequencies of rs605059 AA genotype and A allele were significantly increased in patients with uterine leiomyoma compared to healthy controls (GG vs. AA, OR 0.40, 95 % CI 0.20-0.82; G vs. A, OR 0.68, 95 % CI 0.50-0.94). The results suggest that the genotype of HSD17B1 rs605059 may play a role in the tumourgenesis of uterine leiomyoma.


The conformation of peptide thymosin alpha 1 in solution and in a membrane-like environment by circular dichroism and NMR spectroscopy. A possible model for its interaction with the lymphocyte membrane.
The 28-residue peptide thymosin alpha1 was studied by circular dichroism and two-dimensional NMR. Circular dichroism indicates that thymosin alpha1 in water solution does not assume a preferred conformation, while in the presence of small unilamellar vesicles of dimiristoylphosphatidylcholine and dimiristoylphosphatidic acid (10:1) and in sodium dodecyl sulphate, it assumes a partly structured conformation. Presence of zinc ions produces similar effects. In a more hydrophobic environment like a solution of a mixed solvent water-2,2,2 trifluoroethanol, it adopts a structured conformation. NMR spectra indicated that in this mixture as solvent, thymosin alpha1 has a structure characterized by two regions. A beta-turn is present between residue 5 and residue 8, while the region between residues 17 and 24 shows an alpha helix conformation. These changes of conformation in different environments may be considered structural requirements in the steps of its interaction with the lymphocyte membrane. In fact, these conformational changes may correspond to the first event of the mechanism of lymphocyte activation in the immune response modulation by thymosin alpha1.


Canadian Cardiovascular Society Cardiovascular Screening of Competitive Athletes: The Utility of the Screening Electrocardiogram to Predict Sudden Cardiac Death.
Prevention of sudden cardiac arrest/death (SCA/D) among athletes is a universal goal, although the optimal strategy for its achievement is controversial, with the inclusion of the 12-lead electrocardiogram (ECG) at the center of the debate. The ECG exhibits superior sensitivity over history and physical examination to detect conditions associated with SCA/D. However, the identification of disease does not necessarily lead to a significant reduction in SCA/D. The "Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Statement on the Cardiovascular Screening of Competitive Athletes" recommended against the routine performance of an ECG for the initial cardiovascular screening of competitive athletes. The incidence of SCA/D among athletes (<35 years of age), the risk of SCA/D during sport participation among individuals with abnormalities found on screening ECG, the efficacy of the ECG to identify conditions associated with SCA/D, and the positive predictive value of an abnormal ECG to predict SCA/D are critically examined. This review presents the evidence informing the panel's recommendation.


Physiology, genomics, and evolutionary aspects of desert plants.
Despite the exposure to arid environmental conditions across the globe ultimately hampering the sustainability of the living organism, few plant species are equipped with several unique genotypic, biochemical, and physiological features to counter such harsh conditions. Physiologically, they have evolved with reduced leaf size, spines, waxy cuticles, thick leaves, succulent hydrenchyma, sclerophyll, chloroembryo, and photosynthesis in nonfoliar and other parts. At the biochemical level, they are evolved to perform efficient photosynthesis through Crassulacean acid metabolism (CAM) and C4 pathways with the formation of oxaloacetic acid (Hatch-Slack pathway) instead of the C3 pathway. Additionally, comparative genomics with existing data provides ample evidence of the xerophytic plants' positive selection to adapt to the arid environment. However, adding more high-throughput sequencing of xerophyte plant species is further required for a comparative genomic study toward trait discovery related to survival. Learning from the mechanism to survive in harsh conditions could pave the way to engineer crops for future sustainable agriculture. The distinct physiology of desert plants allows them to survive in harsh environments. However, the genomic composition also contributes significantly to this and requires great attention. This review emphasizes the physiological and genomic adaptation of desert plants. Other important parameters, such as desert biodiversity and photosynthetic strategy, are also discussed with recent progress in the field. Overall, this review discusses the different features of desert plants, which prepares them for harsh conditions intending to translate knowledge to engineer plant species for sustainable agriculture. This review comprehensively presents the physiology, molecular mechanism, and genomics of desert plants aimed towards engineering a sustainable crop.


Sex chromatin analysis of unstained mouse amniotic cells using brightfield microscopy.
Sex chromatin of unstained mouse amniotic cells was identifiable using ordinary brightfield microscopy with optimal setting of the illumination.


Impact of a multidimensional infection control strategy on central line-associated bloodstream infection rates in pediatric intensive care units of five developing countries: findings of the International Nosocomial Infection Control Consortium (INICC).
To analyze the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional infection control strategy including a practice bundle to reduce the rates of central line-associated bloodstream infection (CLAB) in patients hospitalized in pediatric intensive care units (PICUs) of hospitals, which are members of the INICC, from nine cities of five developing countries: Colombia, India, Mexico, Philippines, and Turkey. CLAB rates were determined by means of a prospective surveillance study conducted on 1,986 patients hospitalized in nine PICUs, over a period of 12,774 bed-days. The study was divided into two phases. During Phase 1 (baseline period), active surveillance was performed without the implementation of the multi-faceted approach. CLAB rates obtained in Phase 1 were compared with CLAB rates obtained in Phase 2 (intervention period), after implementation of the INICC multidimensional infection control program. During Phase 1, 1,029 central line (CL) days were recorded, and during Phase 2, after implementing the CL care bundle and interventions, we recorded 3,861 CL days. The CLAB rate was 10.7 per 1,000 CL days in Phase 1, and in Phase 2, the CLAB rate decreased to 5.2 per 1,000 CL days (relative risk [RR] 0.48, 95% confidence interval [CI] 0.29-0.94, P = 0.02), showing a reduction of 52% in the CLAB rate. This study shows that the implementation of a multidimensional infection control strategy was associated with a significant reduction in the CLAB rates in the PICUs of developing countries.


Post-translational modifications in the active site region of methyl-coenzyme M reductase from methanogenic and methanotrophic archaea.
Methyl-coenzyme M reductase (MCR) catalyzes the methane-forming step in methanogenic archaea. Isoenzyme I from Methanothermobacter marburgensiswas shown to contain a thioxo peptide bond and four methylated amino acids in the active site region. We report here that MCRs from all methanogens investigated contain the thioxo peptide bond, but that the enzymes differ in their post-translational methylations. The MS analysis included MCR I and MCR II from Methanothermobacter marburgensis, MCR I from Methanocaldococcus jannaschii and Methanoculleus thermophilus, and MCR from Methanococcus voltae, Methanopyrus kandleri and Methanosarcina barkeri. Two MCRs isolated from Black Sea mats containing mainly methanotrophic archaea of the ANME-1 cluster were also analyzed.


First record of Jacobsoniidae (Coleoptera) from China with description of a new species of Sarothrias Grouvelle.
The family Jacobsoniidae Heller () is newly recorded from China upon the discovery of Sarothriassinicus Bi & Chen, sp. n. () from Motuo, Southeast Xizang. Description and illustrations of the habitus and major diagnostic features of the new taxon are provided. A key to the species of Sarothrias and some ecological notes on the new species are presented.


Anatomical plasticity in brainstem auditory nuclei following unilateral ablation of the inferior colliculus in neonatal rats.
Anatomical plasticity of projections from brainstem auditory structures to the inferior colliculus (IC) was examined in albino rats to determine the effects of unilateral destruction of the IC during early development. The IC in the right hemisphere was destroyed by aspiration on postnatal day 3. Upon reaching adulthood, the rats were examined by retrograde tract tracing methods with fluoro-gold (FG) and [3H]-glycine to determine patterns of brainstem projections to the undamaged left IC. In our FG experiments, the results confirmed the presence of aberrant crossed projections from the right medial superior olive (MSO) to the undamaged left IC. Following injections of [3H]-glycine or FG into the undamaged left IC, however, no other aberrant projections were found in the superior olive, including those from the ipsilateral lateral superior olive (LSO) or the superior paraolivary nucleus (SPN). These results suggest that projections from the MSO to the IC may have the latent ability to create aberrant crossed projections during development. On the other hand, the neurons in LSO and SPN do not form aberrant projections following early unilateral IC lesions.


Receptor-associated protein impairs ligand binding to megalin and megalin-dependent endocytic flux in proximal tubule cells.
Proximal tubule (PT) cells retrieve albumin and a broad array of other ligands from the glomerular ultrafiltrate. Efficient uptake of albumin requires PT expression of both megalin and cubilin receptors. Although most proteins engage cubilin selectively, megalin is required to maintain robust flux through the apical endocytic pathway. Receptor-associated protein (RAP) is a chaperone that directs megalin to the cell surface, and recombinant RAP dramatically inhibits the uptake of numerous megalin and cubilin ligands. The mechanism by which this occurs has been suggested to involve competitive inhibition of ligand binding and/or conformational changes in megalin that prevent interaction with ligands and/or with cubilin. To discriminate between these possibilities, we determined the effect of RAP on endocytosis of albumin, which binds to cubilin and megalin receptors with high and low affinity, respectively. Uptake was quantified in opossum kidney (OK) cells and in megalin or cubilin (Cubn) knockout (KO) clones. Surprisingly, RAP inhibited fluid-phase uptake in addition to receptor-mediated uptake in OK cells and Cubn KO cells but had no effect on endocytosis when megalin was absent. The apparent Ki for RAP inhibition of albumin uptake was 10-fold higher in Cubn KO cells compared with parental OK cells. We conclude that in addition to its predicted high-affinity competition for ligand binding to megalin, the primary effect of RAP on PT cell endocytosis is to globally dampen megalin-dependent endocytic flux. Our data explain the complex effects of RAP on binding and uptake of filtered proteins and reveal a novel role in modulating endocytosis in PT cells.NEW & NOTEWORTHY Receptor-associated protein inhibits binding and uptake of all known endogenous ligands by megalin and cubilin receptors via unknown mechanism(s). Here, we took advantage of recently generated knockout cell lines to dissect the effect of this protein on megalin- and cubilin-mediated endocytosis. Our study reveals a novel role for receptor-associated protein in blocking megalin-stimulated endocytic uptake of fluid-phase markers and receptor-bound ligands in proximal tubule cells in addition to its direct effect on ligand binding to megalin receptors.


Membrane lipid fluidity as rate limiting in the concanavalin A-mediated agglutination of pyBHK cells.
The initial rate of concanavalin A-mediated agglutination of polyoma transformed Baby Hamster Kidney (pyBHK) cells follows Arrhenius kinetics. There is a smooth decrease in the agglutination rate from 37 degrees C to 22 degrees C with an activation energy of 11.8 +/- 0.2 kcal/mol in this region. There is a sharp decrease in agglutination rate below 22 degrees C. The addition of 0.1 mM 1,3-di-tert-2-hydroxyl-5-methylbenzene, a lipid perturber, increases the agglutination rate by a factor of two and increases the membrane lipid fluidity as determined by the spin label method. The rotational correlation time of the spin label 2N14 (2,2-dimethyl-5-dodecyl-5-methyloxazolidine-N-oxide) was measured. The sum of the enthalpy of activation of rotational diffusion and the enthalpy of activation of translational diffusion is very nearly equal to the enthalpy of activation of agglutination. This is consistent with the rate limiting step of agglutination being receptor diffusion, which is probably limited in pyBHK cells by membrane lipid fluidity.


Displacement to separate host-cell proteins and aggregates in cation-exchange chromatography of monoclonal antibodies.
An efficient and consistent method of monoclonal antibody (mAb) purification can improve process productivity and product consistency. Although protein A chromatography removes most host-cell proteins (HCPs), mAb aggregates and the remaining HCPs are challenging to remove in a typical bind-and-elute cation-exchange chromatography (CEX) polishing step. A variant of the bind-and-elute mode is the displacement mode, which allows strongly binding impurities to be preferentially retained and significantly improves resin utilization. Improved resin utilization renders displacement chromatography particularly suitable in continuous chromatography operations. In this study we demonstrate and exploit sample displacement between a mAb and impurities present at low prevalence (0.002%-1.4%) using different multicolumn designs and recycling. Aggregate displacement depends on the residence time, sample concentration, and solution environment, the latter by enhancing the differences between the binding affinities of the product and the impurities. Displacement among the mAb and low-prevalence HCPs resulted in an effectively bimodal-like distribution of HCPs along the length of a multi-column system, with the mAb separating the relatively more basic group of HCPs from those that are more acidic. Our findings demonstrate that displacement of low-prevalence impurities along multiple CEX columns allows for selective separation of mAb aggregates and HCPs that persist through protein A chromatography.


Assessment, diagnosis and treatment of a patient with hirsutism.
A 20-year-old woman presented with excess facial and body hair, which she had noticed for the first time after her menarche and which had gradually worsened since then. In addition, the patient's menstrual cycles had always been irregular. Her family history revealed that her mother also had a history of excess body hair. Among the patient's family members there was no other history of chronic diseases, including type 2 diabetes. She denied taking any regular medications and had been shaving and waxing regularly to remove the excess hair. On examination, the patient was a lean woman with normal vital signs. Prominent coarse hair was noted over her upper lip, chin, lower abdomen, lower back and upper legs. The remainder of the physical examination was unremarkable. Physical examination, and investigations that included a transabdominal pelvic ultrasound scan and measurement of TSH, prolactin, 17-hydroxyprogesterone and total testosterone levels. Hirsutism associated with polycystic ovary syndrome. The patient was treated with cyproterone acetate 2 mg/day and ethinylestradiol 0.035 mg/day in combination with spironolactone 100 mg/day as well as with laser hair removal. The patient's symptoms had improved considerably after 1 year of treatment. A cardiometabolic risk assessment, including a standard oral glucose tolerance test and a lipid profile before and after treatment, revealed normal fasting and 2 h plasma glucose levels both at baseline and after 12 months, and a low-normal HDL-cholesterol level that returned to normal after 12 months.


The history of congenital diaphragmatic hernia from 1850s to the present.
Congenital diaphragmatic hernia (CDH) is believed to result from incomplete fusion of the pleuroperitoneal membrane, and passage of the abdominal contents into the chest. A historical review of the literature on this subject shows a wide divergence of opinion on the etiology of the various types of CDH, and on the recommended treatment. A variety of theories regarding its causes and the optimal way of approaching it have been published from the mid 19th century through the 20th century, and are reviewed in this article.


How do Specialists Address Contraceptive Care Compared to General Practitioners in a Federally Qualified Health Center in Maryland.
To determine associations between primary provider specialty and the contraceptive care that patients receive in a Federally Qualified Health Center setting in Maryland. A study of reproductive-age patients and their providers was performed from January 2018 to December 2021. A pooled crosssectional survey of electronic medical record data for 44 127 encounters of 22 828 patients was performed to calculate the odds of contraceptive care being addressed by patients who had General Practitioner, OB/GYN, pediatrician, or infectious disease (ID) specialists as their primary providers. In 19 041 encounters (43%), contraception was addressed through either counseling alone, documentation of a contraceptive prescription, or long-acting reversible contraceptive (LARC) placement procedure. After adjusting for insurance status and race/ethnicity, the odds ratio (OR) of contraceptive care delivery was statistically significantly higher for OB/GYN providers compared to General Practitioners-OR 2.42 (CI 2.29-2.53) and statistically significantly lower for ID providers-OR 0.69 (CI 0.61-0.79). There was a non-statistically significant difference for Pediatricians-OR 0.88 (CI 0.77-1.01). The provision of contraceptive care, a critical aspect of comprehensive primary care delivered in an FQHC setting, varies by provider specialty, and may be negatively influenced by Ryan White funding related structures. There is a need to intentionally design robust referral and tracking systems to ensure contraceptive care is equitably accessible to all, regardless of assigned primary care provider specialty or HIV status.


The synthesis and biologic evaluation of anti-platelet and cytotoxic β-nitrostyrenes.
Our previous studies demonstrated that two cytotoxic β-nitrostyrene derivatives, 3,4-methylenedioxy-β-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy-β-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of β-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC(50)≤0.7 μM) without significant cytotoxicity on a human cancer cell line (up to 20 μM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents.


Organisational and staff-related effects on cultural competence in the hospital setting: a cross-sectional online survey of nursing and medical staff.
Cultural competence is considered a core qualification for dealing with socio-cultural diversity and balancing disparities in health care. To explore features supporting and inhibiting cultural competence in the hospital at both organisational and staff levels. Cross-sectional online survey in the form of a full census from May to November 2018. Two organisations that run a total of 22 hospitals in Germany. Eight hundred nursing and medical professionals [nurses: n = 557; doctors: n = 243]. Using the Short Form Cultural Intelligence SCALE (SFCQ), cultural competence was measured and its relation to potential influencing factors at staff level and organisational level examined, using bivariate (t-Test, one-way ANOVA, Pearson and Spearman correlations) and multivariate (multiple linear regression) approaches. Model 1 examined features at organisational level, Model 2 at individual level and Model 3 included organisational and individual features. The mean cultural competence measured was 3.49 [min.: 1.3; max.: 5.0]. In the bivariate and isolated multivariate models [Models 1 and 2], factors on both organisational and individual levels were significantly related to the hospital staff's cultural competence. The multivariate overview [Model 3], however, revealed that individual features at staff level were the statistically relevant predictors. Positive influencing features included staff's assessment of the importance of cultural competence in their professional context [B: 0.368, 95% confidence interval 0.307; 0.429], participation in competence training [B: 0.193; 95% confidence interval 0.112; 0.276] and having a migration background [B: 0.175; 95% confidence interval 0.074; 0.278], while negative features included length of medical service [B: -0.004; 95% confidence interval -0.007; -0.001]. The development and practice of cultural competence appear to be determined less by organisational features and more on the level of individual actors. In addition to staff development, adequate organisational structures and an economic incentive system are required to promote sociocultural diversity in hospitals.


Developmental neurobiology of cerebellar and Basal Ganglia connections.
The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network. In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia. In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction. EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation.


Crossroads of telomere biology and anticancer drug discovery.
The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.


Intracardiac phased-array imaging: methods and initial clinical experience with high resolution, under blood visualization: initial experience with intracardiac phased-array ultrasound.
This study was designed to test the feasibility of high-resolution phased-array intracardiac imaging. Intracardiac echocardiographic imaging of the heart during interventional electrophysiologic (EP) procedures has been limited by inadequate ultrasound penetration and absence of Doppler hemodynamic and flow information produced by rotating mechanical ultrasound elements. A 10F (3.2 mm) phased-array, variable 5.5 to 10 MHz frequency imaging catheter with a four-way deflectable tip was applied in 24 patients undergoing EP studies. Sixteen prespecified cardiac targets were imaged from a right heart venue. Fifteen patients had no underlying organic heart disease; nine had ischemic, cardiomyopathic, valvular or congenital heart disorders. Longitudinal and short-axis imaging readily disclosed each cardiac valve, support structures and chamber, as well as the pericardium, right and left atrial appendages, the junction of the right atrium and superior vena cava, crista terminalis, tricuspid valve isthmus, coronary sinus orifice, membranous fossa ovalis and pulmonary veins. The average target depth was 8.8+/-1.5 cm (range 0.5 to 15 cm), with adequate penetration at a 7.5 MHz imaging frequency. Color flow and Doppler utilities clearly characterized transaortic and pulmonic valve and pulmonary vein blood flow, including during low output states. These first human studies with this technology demonstrate the methods, feasibility and utility of intracardiac phased-array vector and Doppler imaging for long-axis, apex-to-base global cardiac imaging. High resolution of endocardial structures and catheters suggests additional utility for visualizing interventional procedures from the right heart.


Detection and quantitation of adenovirus type 12 transforming DNA segments and their application in etiological studies of human neoplasia.
The oncogenic capacity of the tumour virus lies in a small region of the viral genome, and tumour cells and cells transformed by DNA tumour viruses often contain only a part of the viral genome, the portion including the transforming gene(s). The detection and quantitation of these gene(s) in tumour cell DNA can provide evidence for or against a possible etiological role of the virus in human neoplasia. In this communication, the isolation, purification and identification of the transforming segment of Ad 12 are described.


Frequency shift between near- and far-field scattering resonances in dielectric particles.
The near-field electromagnetic scattering intensity resonances are redshifted in frequency with respect to their far-field counterparts. We derive simple, approximate, analytical formulas for this shift in the case of a plane wave interacting with a dielectric sphere. Numerical results comparing the approximate formulas to the numerically exact solutions show that the two are in good agreement. We also consider the Rayleigh limit of the formulas to gain more insight into the phenomenon.


Patterns of Care and Outcomes of Low-Lying Adenocarcinoma and Squamous Cell Carcinoma of the Rectum.
Squamous cell carcinoma (SCC) of the rectum is a unique entity that lacks definitive guidelines regarding prognosis and treatment. This study aimed to analyze patterns of care and survival for SCC and adenocarcinoma (AC) of the rectum. This was a retrospective analysis of patients with stage I-III SCC or AC of the rectum treated from 2004 to 2016 from the National Cancer Database. The treatment groups analyzed were surgery alone (S), chemoradiation followed by surgery (CRT + S), surgery followed by chemoradiation (S + CRT), and definitive chemoradiation (CRT). Patient- and clinical-related factors were compared. Overall survival was assessed with the Kaplan-Meier method and Cox proportional regression models. Of the patients studied, 21,587 (97.1%) were AC and 640 (2.9%) were SCC. Among patients with AC, most (n = 8549, 59.4%) received chemoradiation followed by surgery; those with SCC (n = 305, 66.4%) received definitive chemoradiation. Among patients who received surgery, the majority (69.2%) with AC histology had a low anterior resection while the majority (52.1%) of SCC had an abdominoperineal resection. Five-year overall survival of AC versus SCC in the entire cohort was 61.6% versus 56.1%, respectively (p < 0.001). On multivariable analysis for AC, CRT + S (HR 0.61, p < 0.001), or S + CRT (HR 0.67, p < 0.001) had improved survival compared to S alone while those who had definitive CRT (HR 1.55, p < 0.001) had worse survival. SCC of the rectum tends to be treated like anal cancers with definitive chemoradiation, with similar survival to historical reports of anal cancer. AC of the rectum is most commonly treated under the rectal cancer paradigm.


Effects of berberine on rat jejunal motility.
The aim of the study was to evaluate berberine-induced bidirectional regulation on the contractility of jejunum. Different low and high contractile states of isolated jejunal segment from rat were established to investigate the effects of berberine. Stimulatory effects on jejunal segment were exerted by berberine in six low contractile states and inhibitory effects were produced on jejunal segment in six high contractile states. The effects of berberine on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin phosphorylation in jejunum were also bidirectional. Bidirectional regulation was not observed in the presence of tetrodotoxin. No regulatory effects of berberine on jejunal contractility were observed in the presence of verapamil. The stimulatory effects of berberine on jejunal contractility were blocked by atropine. The inhibitory effects of berberine on jejunal contractility were abolished by phentolamine, propranolol and L-NG-nitro-arginine, respectively. Berberine-induced bidirectional regulation needed the presence of the enteric nervous system, and depended on the influx of extracellular Ca(2+) , related to the cholinergic system while jejunum was in low contractile states, and related to the adrenergic system and nitric oxide relaxing mechanism while jejunum was in high contractile states. The results suggested the potential clinical implication of berberine for alternating-type irritable bowel syndrome.


Adsorptive removal and separation of chemicals with metal-organic frameworks: Contribution of π-complexation.
Efficient removal and separation of chemicals from the environment has become a vital issue from a biological and environmental point of view. Currently, adsorptive removal/separation is one of the most promising approaches for cleaning purposes. Selective adsorption/removal of various sulfur- and nitrogen-containing compounds, olefins, and π-electron-rich gases via π-complex formation between an adsorbent and adsorbate molecules is very competitive. Porous metal-organic framework (MOF) materials are very promising in the adsorption/separation of various liquids and gases owing to their distinct characteristics. This review summarizes the literature on the adsorptive removal/separation of various π-electron-rich compounds mainly from fuel and gases using MOF materials containing metal ions that are active for π-complexation. Details of the π-complexation, including mechanism, pros/cons, applications, and efficient ways to form the complex, are discussed systematically. For in-depth understanding, molecular orbital calculations regarding charge transfer between the π-complexing species are also explained in a separate section. From this review, readers will gain an understanding of π-complexation for adsorption and separation, especially with MOFs, to develop new insight for future research.


[Human hydatidosis: field echography for the determination of groups at high risk in the evaluation of a control program].
The development of small ultrasonographic equipment has permitted to incorporate this technique to the methods of early detection of Human Hydatidosis. 689 echographies were carried out in this experience, and 5.51% of compatible images in the whole population, and 12.24% in groups of risk (those living together with the operated ones) were found. It was observed a significant decrease in the infection percentages in man in the whole population of areas under Control Program, using the echographic screening. In conclusion, echography might be incorporated to the epidemiologic surveillance system of human Hydatidosis.


Non-additivity in protein-protein interactions.
The energy of binding between proteins may be seen as the sum of the contributions of the individual amino acid residues. These contributions are additive when the binding energy, due to different amino acid residues, is independent of the interactions between amino acids in the same polypeptide chain. A measure of non-additivity is the coupling free energy. In this communication it is shown that: (1) the coupling free energy is the sum of intramolecular and intermolecular contributions; and (2), when additivity exists, experimentally determined values for the free energy of transfer of amino acids from water to the hydrophobic protein-protein interface are a very good approximation of their contribution to the energy of binding. Additivity cycles can be useful in determining the precise conditions where this approximation holds.


Heavy metal exposure reduces hatching success of Acartia pacifica resting eggs in the sediment.
The potential effects of three heavy metals (Cu, Pb, and Cd) on hatching success of Acartia pacifica resting eggs in the sediment of Xiamen Bay were experimentally investigated. The number ofA. pacifica nauplii hatched from the sediment sharply decreased with the increase of metal concentration and exposure time from 3 to 30 d. An increase of the Cu concentration from 34.8 to 348 mg/kg, reduced the number of hatched nauplii by 46.6%-100%. An increase of the Pb concentration from 75.2 to 752 mg/kg, reduced the number of hatched nauplii by 21.4%-78.9%. An increase of the Cd concentration from 0.68 to 6.8 mg/kg, reduced the number of hatched nauplii by 31.6%-94.7%. The number of nauplii also significantly decreased with the increase of mixed-metal concentration and exposure time in the mixed-metal test. Trimmed Spearman-Karber analysis gave sediment metal 72-h LC50 values of 1.25 mmol Cu/kg, 1.73 mmol Pb/kg, and 0.054 mmol Cd/kg, which suggested that Cd was the most toxic to A. pacifica resting eggs in the three tested metals. The results indicate that heavy metals with higher concentrations can reduce recruitment of A. pacifica nauplii from benthic resting eggs to planktonic population.


A retrospection on the content, association, and significance of mercury in coals and coal ashes from Bulgarian thermoelectric power stations.
A short overview on the content, association, and significance of toxic Hg in 9 coal types and their fly ashes (FAs) from 12 Bulgarian thermoelectric power stations (TPSs) was conducted by a compilation of reference and our own data obtained by a combination of different chemical and mineralogical analyses, and separation procedures. The Bulgarian and Ukrainian coals studied are enriched in Hg (0.14-0.57 mg/kg) occurring in both organic and inorganic associations. The most abundant coals in Hg have higher S contents and ash yields, and are enriched in Fe sulphides, calcite, and Ca and Fe sulphates, as well as some clay minerals and feldspars. The dominant quantity (about 50-98%) from the fuel Hg was not captured by the coal ashes in TPSs. The significant Hg capture potential (38-50%) show FAs enriched in char, Ca and Fe sulphates and oxides, and Ca carbonates. It was found that the Hg concentrations in some FA water leachates are significantly higher in comparison with the Clarke values for fresh water and could provoke environmental risks. Alternative and sustainable biomass poor in Hg is suggested to substitute totally or partially the industrial coals used in Bulgarian TPSs to avoid the Hg problems.


Influence of Cu supplementation on toxic and essential trace element status in intensive reared beef cattle.
The aim of this study is to evaluate if dietary Cu supplementation that leads to a hepatic Cu accumulation over the normal range has an influence on trace element status that could contribute to the pathogenesis of other mineral related disorders. Samples (liver, kidney, spleen, diaphragm and brain) of beef calves receiving typical commercial diets Cu supplemented and non-supplemented were tested for differences in non-essential and essential trace elements determined by ICP-MS. As (kidney and diaphragm), Hg (liver and kidney), and Pb (liver, kidney and spleen) were significantly lower, while Cd residues (liver and kidney) were significantly higher in the Cu supplemented group. Mn and Ni significantly decreased and Mo increased in the brain, and Se (diaphragm) decreased in the Cu supplemented group. These interactions are unknown, and possibly with more than two metals involved as suggested in the case of the ratio Se:Cu in the animals of this study. The possible role of Cu supplementation on the status of certain metals associated to neurological diseases (Mn-Ni) in the brain deserves further investigation. Finally new research on Cu-Se supplementation is necessary to better understand the risk of the animals to suffer from Se deficiency.


Landfill leachate characterization for simulation of biological treatment with Activated Sludge Model No. 1 and Activated Sludge Model No. 3.
Landfill leachates can be characterized correctly in terms of Activated Sludge Model No. 1 (ASM1) and Activated Sludge Model No. 3 (ASM3) variables. The wastewater characterization of leachate from a Luxembourg landfill was based on a physical-chemical method combined with a BOD analysis for the COD fractions and on standard analysis for forms of nitrogen. The results show important differences compared with municipal wastewater. High amounts of organic matter with low biodegradability were found, as well as a high concentration of ammonium nitrogen. Based on average values, a generic ASM characterization is proposed for landfill leachates. It can be directly employed in the early stages of the simulation of landfill leachate treatment with activated sludge models.


Magnetic Precipitation: A New Platform for Protein Purification.
One of the trends in downstream processing comprises the use of "anything-but-chromatography" methods to overcome the current downfalls of standard packed-bed chromatography. Precipitation and magnetic separation are two techniques already proven to accomplish protein purification from complex media, yet never used in synergy. With the aim to capture antibodies directly from crude extracts, a new approach combining precipitation and magnetic separation is developed and named as affinity magnetic precipitation. A precipitation screening, based on the Hofmeister series, and a commercial precipitation kit are tested with affinity magnetic particles to assess the best condition for antibody capture from human serum plasma and clarified cell supernatant. The best conditions are obtained when using PEG3350 as precipitant at 4 °C for 1 h, reaching 80% purity and 50% recovery of polyclonal antibodies from plasma, and 99% purity with 97% recovery yield of anti-TNFα mAb from cell supernatants. These results show that the synergetic use of precipitation and magnetic separation can represent an alternative for the efficient capture of antibodies.


Single-phagosome imaging reveals that homotypic fusion impairs phagosome degradative function.
Immune cells degrade internalized pathogens in vesicle compartments called phagosomes. Many intracellular bacteria induce homotypic phagosome fusion to survive in host cells, but the fusion interaction between phagosomes and its consequence for phagosome function have scarcely been studied. Here, we characterize homotypic fusion between phagosomes in macrophages and identify how such interactions impact the degradative capacity of phagosomes. By developing a series of particle sensors for measuring biochemical changes of single phagosomes, we show that phagosomes undergo stable fusion, transient "kiss-and-run" fusion, or both in succession. Super-resolution three-dimensional fluorescence microscopy revealed that stably fused phagosomes are connected by membrane "necks" with submicron-sized fusion pores. Furthermore, we demonstrate that, after stable fusion, phagosomes have leaky membranes and thereby impaired degradative functions. Our findings, based on phagosomes that contain synthetic particles, illustrate that homotypic fusion is not exclusive to phagosomes that encapsulate pathogens, as previously believed. The physical process of homotypic fusion is alone sufficient to perturb the degradative functions of phagosomes.


Comparison of inhibition of polymerisation of mammalian tubulin and helminth ovicidal activity by benzimidazole carbamates.
The correlation between the inhibition of hatching of Haemonchus contortus eggs and inhibition of mammalian tubulin polymerisation by benzimidazole carbamates has been investigated. The hatching process was observed to be independent of the biomass (eggs plus debris) over a 6-fold range and the early (E1-E3) stages of egg development, but was dependent on the concentration of co-solvent (DMSO) and time of incubation. Benzimidazole carbamates with strong inhibitory activity against mammalian tubulin were potent inhibitors of egg hatch, while non-inhibitors failed to prevent hatching. It is postulated that the primary mode of action of these drugs on nematode eggs is the inhibition of microtubule-dependent processes within the developing egg. The implications and limitations of this correlation are discussed.


Predictors of chronic pain intensity, spread, and sensitivity in the general population: A two-year follow-up study from the SWEPAIN cohort.
To determine whether the intensity, spread and sensitivity of chronic pain can be predicted using demographic features, socioeconomic conditions and comorbidities. A longitudinal study design was employed. Data was collected at baseline and at 2-year follow-up. General population in south-eastern Sweden. A representative stratified random sample of 34,000 individuals, between 18 and 85 years of age, selected from a sampling frame of 404,661 individuals based on the Swedish Total Population Register. Eligible individuals were sent postal surveys in 2013 and 2015. The 2 surveys included the same questions about basic demographic data, comorbidities, and chronic pain intensity, spread and sensitivity. Several socio-demographic features and comorbidities at baseline were significant predictors of characteristics of pain (intensity, spread and sensitivity) at the 2-year follow-up. When characteristics of pain at baseline were included in the regression analyses they were relatively strong significant predictors of characteristics of pain after 2 years. After this adjustment there were fewer socio-demogra-phic and comorbidity predictors; the effect estimates for those significant predictors had decreased. Clinical assessment should focus on several characteristics of pain and include a broad medical screening to capture the overall burden of pain in adults from a longitudinal perspective.


Comparison of methods to study enzyme induction in man.
A combination of several in vivo parameters has been applied in male healthy volunteers to test the suitability of these parameters to indicate enzyme induction in man: Urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, activity of serum gamma-glut amyltranspeptidase, and pharmacokinetics of aminopyrine respond significantly to phenobarbital treatment. Glucaric acid excretion is enhanced about 7-fold. Its response to induction overcomes the large individual and inter-individual variations which exist in the untreated state for glucaric acid excretion and the other parameters applied, as well. Total body clearance of aminopyrine as obtained after an oral test dose increases more than twofold from 251 to 551 ml/min upon phenobarbital treatment. This arises from increases in both the elimination constant and the apparent volume of distribution, as well. Urinary excretion of aminoantipyrine during 24 hr is about doubled, whereas the elimination of acetyl-aminotipyrine is not much affected. 6 beta-hydroxycortisol excretion in urine and activity of serum gamma-glutamyltranspeptidase are significantly augmented to about 150% of control values. Half life times of phenobarbital measured after termination of treatment are in normal range, suggesting no self-induction of phenobarbital metabolism. Because of the complexity of drug metabolizing enzymes only a combination of different parameters reliably indicates alterations in this enzyme system by inducing agents.


Reversed-phase high-performance liquid chromatographic method for the assay of 1,4-dioxane in sulphated polyoxyethylene alcohol surfactants.
A rapid high-performance liquid chromatographic method has been developed for the assay of 1,4-dioxane in ethoxylated fatty alcohol sulphates. After solid-phase extraction using Bakerbond C18 cartridges, samples were directly analysed on a LiChrospher CH-8 reversed-phase column with UV detection at 200 nm and an acetonitrile-water eluent. Recovery of 1,4-dioxane from the surfactant matrix was 95.7% in the 40 to 120 micrograms g-1 range. The minimum quantifiable amount was 18 micrograms g-1. The procedure is simple, reproducible, specific and suitable for routine analyses of commercial surfactants.


Growth performance, liver and kidney functions, blood hormonal profile, and economic efficiency of broilers fed different levels of threonine supplementation during feed restriction.
The objective of the existing investigation was to determine the effect of dietary inclusion of threonine amino acid at different levels during feed restriction on growth indices, liver and kidney function parameters, and some hormonal profiles along with economic indicators in broiler chickens. A total of 1,600 from 2 different breeds (800 Ross 308 and 800 Indian River) at 21-day-old age were incorporated. Chicks were randomly assigned into 2 main groups, control and feed-restricted (8 h/d), during the fourth week of age. Each main group was subdivided into 4 groups. The first group was fed a basal diet without adding extra threonine (100%), the second, third, and fourth groups were fed a basal diet with extra threonine levels of 110, 120, and 130%, respectively. Each subgroup consisted of 10 replicates of 10 birds. We noticed that the dietary inclusion of threonine at extra levels in the basal diets significantly enhanced final body weight, body weight gain, and better feed conversion ratio. This was mainly due to the enhanced levels of growth hormone (GH), insulin-like growth factor (IGF1), triiodothyronine (T3), and thyroxine (T4). Moreover, the lowest feed cost per kilogram body weight gain and improved return parameters were reported in control and feed-restricted birds fed higher levels of threonine than other groups. Also, a significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and urea levels was observed in feed-restricted birds supplemented with 120 and 130% levels of threonine. Hence, we recommend supplementing threonine at levels of 120 and 130% in the diet of broilers to promote growth and profitability.


Humoral autoimmune responses to glutamic acid decarboxylase have similar target epitopes and subclass that show titer-dependent disease association.
Glutamic acid decarboxylase (GAD) is an autoantigen in stiff man syndrome (SMS) and type 1 diabetes (T1DM). Different GAD autoantibody characteristics in these disorders have suggested distinct underlying mechanisms of autoimmunity. Here, it is shown that increased prevalence of autoantibodies to GAD65 amino terminal and GAD67 epitopes and autoantibodies of IgG2, IgG3, or IgG4 subclass in patients with SMS (P < 0.001 vs. T1DM) are secondary to the markedly higher autoantibody titers in SMS patients (P < 0.0001) and that autoantibody epitopes and subclasses were similar when patients were matched for autoantibody titer. Exposure to autoantigen in the disorders is likely to involve similar humoral antigenic determinants, but different B cell regulation.


Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase.
Many fraudulent nucleosides including the antivirals acyclovir (ACV) and ganciclovir (GCV) must be metabolized to triphosphates to be active. Cyclopropavir (CPV) is a newer, related guanosine nucleoside analog that is active against human cytomegalovirus (HCMV) in vitro and in vivo. We have previously demonstrated that CPV is phosphorylated to its monophosphate (CPV-MP) by the HCMV pUL97 kinase. Consequently, like other nucleoside analogs phosphorylated by viral kinases, CPV most likely must be converted to a triphosphate (CPV-TP) in order to elicit antiviral activity. Once formed by pUL97, we hypothesized that guanosine monophosphate kinase (GMPK) is the enzyme responsible for the conversion of CPV-MP to CPV-DP. Incubation of CPV-MP with GMPK resulted in the formation of CPV-DP and, surprisingly, CPV-TP. When CPV-DP was incubated with GMPK, a time-dependent increase in CPV-TP occurred corresponding to a decrease in CPV-DP thereby demonstrating that CPV-DP is a substrate for GMPK. Substrate specificity experiments revealed that GMP, dGMP, GDP, and dGDP are substrates for GMPK. In contrast, GMPK recognized only acyclovir and ganciclovir monophosphates as substrates, not their diphosphates. Kinetic studies demonstrated that CPV-DP has a K(M) value of 45±15μM. We were, however, unable to determine the K(M) value for CPV-MP directly, but a mathematical model of experimental data gave a theoretical K(M) value for CPV-MP of 332±60μM. We conclude that unlike many other antivirals, cyclopropavir can be converted to its active triphosphate by a single cellular enzyme once the monophosphate is formed by a virally encoded kinase.


A quantitative assessment of the significance of molecular mobility as a determinant for the stability of lyophilized insulin formulations.
The purpose was to explore a method for quantitatively assessing the contribution of molecular mobility to the chemical reactivity of amorphous solids. Degradation of insulin in lyophilized formulations containing trehalose and poly(vinylpyrrolidone)(PVP) was chosen as a model system, and the temperature- and glass transition temperature (Tg)-dependence of the degradation rate was analyzed to obtain the relative contributions of molecular mobility and that of the chemical activational barrier reflected in the energy of activation. Insulin degradation and dimerization in lyophilized trehalose and PVP formulations were monitored at various relative humidities (6-60% RH) and temperatures (10-60 degrees C) by reverse-phase high-performance liquid chromatography (HPLC) and high-performance size-exclusion chromatography (HP-SEC), respectively. The Tg and fragility parameter of the lyophilized insulin formulations were determined by differential scanning calorimetry (DSC). Insulin degradation in the initial stage was describable with first-order kinetics for both of the trehalose and PVP formulations. The temperature- and Tg-dependence of the degradation rate indicated that the reactivity of insulin in the trehalose formulation is affected by molecular mobility at low humidity (12% RH), such that the ratio of the observed rate constant (k') to the rate constant governed only by the activational barrier (k) was 0.051 at the Tg. At higher humidities, in contrast, the value of k'/k was much higher (0.914, 0.978, and 0.994 for 23% RH, 33% RH, and 43% RH, respectively), indicating that insulin degradation rate is determined predominantly by the activational barrier. For insulin degradation in the PVP formulation at temperatures below Tg, the contribution of molecular mobility to the degradation rate appeared to be negligible, as the extrapolated value of t90 at the Tg exhibited a large difference between the formulations with differing Tg values (because of differing water contents). The reactivity of insulin in the trehalose and PVP formulations can be described by an equation including factors reflecting the activational barrier (activation energy and frequency coefficient) and factors reflecting the molecular mobility (Tg, fragility parameter and a constant representing the relationship between the molecular mobility and the reaction rate). Thus, analysis of temperature dependence based on the proposed equation allows quantitative assessment of the significance of molecular mobility as a factor affecting chemical reactivity.


Oral antidiabetic therapy in a large Italian sample: drug supply and compliance for different therapeutic regimens.
To define the main features of patients treated with oral antidiabetics, evaluating monotherapy (MT), loose-dose combination therapy (LDCT) and fixed-dose combination therapy (FDCT); to describe medication adherence to the different therapies; and to evaluate the differences in compliance with the prescribed therapy regimen among prevalent and incident patient cohorts. This study was a retrospective cohort analysis based on the ARNO database, a national record that tracks reimbursable prescription claims submitted from selected pharmacies to the Italian national health system. In total, 169,375 subjects, from an overall population of 4,040,624 were included in this study. The patients represented 12 different local health units. Each patient had at least one oral antidiabetic prescription claim (A10B ATC code). Patients were divided into four groups according to their treatment regimen during the recruitment period (1 January 2008-31 December 2008): MT, FDCT, LDCT and switching therapy. A timespan of 5 years was considered, from 4 years before to 1 year after the index date (i.e. date of the prescription selected in the recruitment period). A medication possession ratio (MPR) with a cut-off value of 80% was used to measure medication adherence. Descriptive statistics and multiple logistic regression were used to define the objectives, while P < 0.05 was considered to indicate significance. The median age of patients (n = 169,375, prevalence 4.2%) was 70 years [interquartile range (IQR) 17], and 49.1% were females. Considering the entire sample, the median MPRs for the treatment regimens were: MT, 0.73 (IQR 0.53; 43.9% compliant); FDCT, 1 (IQR 0.29, 68,5% compliant); and LDCT, 0.89 (IQR 0.33, 60.3% compliant). FDCT and LDCT were significantly correlated with MPR. Compliance was 48.9% in the prevalent patient cohort (i.e. patients prescribed oral antidiabetic therapy in both prerecruitment and recruitment periods); median MPRs for the treatment regimens were: MT, 0.73 (IQR 0.52); FDCT, 1 (IQR 0.28); and LDCT, 0.90 (IQR 0.32). Compliance was 43.0% in the incident patient cohort (i.e. patients who were first prescribed oral antidiabetic therapy in the recruitment period); median MPRs for the treatment regimens were: MT, 0.70 (IQR, 0.58); FDCT, 1 (IQR 0.34); and LDCT, 0.64 (IQR 0.39). Compliance was better for FDCT than the other therapeutic regimens in the study population. The same trend was observed in both the prevalent and incident patient cohorts. As type 2 diabetes is a chronic lifelong pathology, and multiple agents are often required to achieve glycaemic control, the preference for FDCT in the population, when clinically applicable, could be an effective strategy for functional administration of clinical outcome and sources. Evaluation of specific population fractions (age, sex, compliance, etc.) and specific agents or drug combinations could also be relevant in order to reach the healthcare objectives.


Experimental models in peritoneal dialysis: a European experience.
The development of adequate animal models is important for the in vivo study of selected aspects of peritoneal dialysis (PD) that cannot be evaluated by an in vitro model, such as peritoneal membrane transport, the influence of local defense mechanisms, and for testing new osmotic agents and their biocompatibilities. Our experience with animal models for PD, including the acute Stockholm model in non-uremic rats, the acute and chronic Amsterdam model in non-uremic rats, and the chronic Gent model in uremic rats, is described. The Stockholm model proved to be useful in understanding the normal physiology of peritoneal transport, and for testing new dialysis solutions and their biocompatibilities. It is a rather simple and inexpensive model, and thus is suitable for screening new solutions and additives. The Amsterdam model permits the study of chemokines and mesothelial cell regeneration in vivo, and is applied in a model of chronic peritonitis. The results of the Gent model suggest that chronic peritoneal dialysis in uremic rats is feasible for at least eight weeks. This model is, however, very laborious, time consuming, and expensive. Further improvement of the technique and increase of the dialysis dose should result in a better and more realistic model for peritoneal dialysis. It is hoped that in the future these models will be useful to test the effects of long-term intraperitoneal application of different dialysis solutions and additives in uremic animals.


The role of ketamine-induced beta activity in the treatment of refractory status epilepticus. Is the EEG useful to determine responder's rate? A retrospective study.
Multiple investigations have been done to evaluate the possible effect of ketamine in the treatment of status epilepticus (SE). To evaluate the electrographic effect of ketamine on EEG, and its clinical utility following-up refractory and super refractory status epilepticus (SRSE). Retrospective review of 24 patients with SE. Clinical record and Video-electroencephalogram (video-EEG) of all included patients were reviewed. The patients' EEGs were then monitored for any immediate changes after administration of the first dose of ketamine as well as at the time patients would be predicted to have peak serum concentration of ketamine. Patients with cessation of electrographic seizures and no SE recurrence within the same admissions were categorized as "Responders". Statistical differences between qualitative variables were analyzed using chi square test. Differences between median were analyzed by Mann-Whitney U test. Difference between groups were considered significant when p < 0.05. We identified 24 patients with SE. Twelve out of 24 (50%) had SRSE and 12 out of 24 (50%) had refractory status epilepticus (RSE). The appearance of superimposed beta activity after ketamine was initiated was associated with a higher responder rate (100% versus 33.3% in the responder group versus the non-responder group respectively). Notably, the presence of a burst suppression pattern had no significant association with one group compared to the other (41.6% versus 33.3%, in the responder group vs the non-responder group respectively). Background superimposed beta activity induced by ketamine is an early and reliable EEG finding associated with status epilepticus termination.


The visual P3a in schizophrenia and bipolar disorder: effects of target and distractor stimuli on the P300.
Amplitude reduction of the P300 event-related potential has long been suggested as a marker for schizophrenia. However, recent research has shown that this reduction in the P300 amplitude is not specific to schizophrenia as it can also be observed in related illnesses such as bipolar disorder. Due to this lack of specificity the P300 elicited using traditional oddball paradigms may be a less valuable endophenotypic marker. The current study employed a cognitively demanding three-stimulus oddball paradigm to elicit the P300 to visual target and distracting stimuli. Patients with schizophrenia showed amplitude reductions of P300 components to targets, distractors and frequent stimuli. The P300 in patients with bipolar disorder was not significantly different from either group. The pattern of results may further the understanding of the nature of the impairment in schizophrenia.


Macrophages in periodontitis: A dynamic shift between tissue destruction and repair.
Periodontitis is a chronic inflammatory disease associated with a dysbiotic bacterial biofilm in the subgingival environment that may disturb the balance between the oral microbiome and its host. The inability of the immune system to eliminate inflammation may result in the progressive destruction of tooth-support tissues. Macrophages are crucial cellular components of the innate immune system and play important roles in diverse physiological and pathological processes. In response to periodontitis-associated bacterial communities, macrophages contribute to inflammation and restoration of tissue homeostasis through pattern recognition receptor-induced signaling cascades; therefore, targeting macrophages can be a feasible strategy to treat patients with periodontitis. Although recent studies indicate that macrophages have a spectrum of activation states, ranging from pro-inflammatory to anti-inflammatory, the regulatory mechanism of the macrophage response to dysbiosis in a tissue-specific manner remains largely unclear. Herein, we attempt to summarize the potential role of macrophage activation in the progression of periodontitis, as well as its relevance to future approaches in the treatment of periodontitis.


Key articles and guidelines in pharmacotherapeutic management of arrhythmias.
Clinical studies are among the most important literature published in the area of cardiovascular pharmacotherapy and are the basis of many of the standards of practice today. We compiled a list of these clinical trials, as well as well-written, up-to-date review articles and important treatment guidelines, that focus on pharmacotherapeutic management of arrhythmias. This list should be useful not only to practitioners and trainees in cardiovascular pharmacotherapy, but also to other clinicians as an update.


MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia.
Cerebral ischemia causes damage to the structure and function of the blood-brain barrier (BBB) and alleviating BBB destruction will be of great significance for the treatment and prognosis of ischemic stroke. Recently, microRNAs have been shown to play a critical role in BBB integrity. However, the potential mechanism by which microRNA-182 (miR-182) affects the BBB in ischemic stroke remains unclear. We demonstrated for the first time that cerebral ischemia leads to a significant progressive increase in miR-182 after pMCAO, and bEnd.3 cells are the primary target cells of miR-182. In miR-182 KD transgenic mice, infarct volume, and BBB permeability were attenuated, and tight junction (TJ) proteins increased. Inhibition of miR-182 with an antagomir reduced OGD-induced apoptosis of bEnd.3 cells and the loss of ZO-1 and Occludin. To further explore the mechanism by which miR-182 regulates BBB integrity, we detected the apoptotic proteins Bcl-2/Bax and demonstrated that mTOR and FOXO1 were the targets of miR-182. Inhibition of mTOR/FOXO1 by rapamycin/AS1842856 decreased the ratio of Bcl-2/Bax and exacerbated TJ protein loss. Taken together, inhibition of miR-182 protects BBB integrity by reducing endothelial cell apoptosis through the mTOR/FOXO1 pathway. Thus, miR-182 may be a potential target for the treatment of BBB disruption during cerebral ischemia.


Association between gene polymorphism and depression in Parkinson's disease: A case-control study.
To investigate possible associations of Parkinson's disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. Of 330 patients, 125 (37.9%) had depression and 205 (62.1%) did not. Univariate analysis revealed significant differences between the two groups in minor allele frequency at the SNP rs1545843 in the SLC6A15 gene (p<0.05), as well as in frequencies of genotypes and minor alleles at rs78162420 in the TPH2 gene (all p<0.05). Logistic regression identified the following risk factors for depression among patients with PD: Hoehn and Yahr stage>2 (OR 1.759, 95%CI 1.035-2.989, p=0.037), AA genotype at rs1545843 (OR 1.866, 95%CI 1.017-3.426, p=0.044), and AC genotype at rs78162420 (OR 5.036, 95%CI 1.451-17.484, p=0.011). Among patients with PD, depression is associated with polymorphism at rs78162420 and rs1545843, both previously linked with depression. Our results may help clarify the pathogenesis of depression in PD.


Sustainable, three-component, one-pot procedure to obtain active anti-flavivirus agents.
The mosquito-borne viruses belonging to the genus Flavivirus such as Dengue virus (DENV) and Zika virus (ZIKV) cause human infections ranging from mild flu-like symptoms to hemorrhagic fevers, hepatitis, and neuropathies. To date, there are vaccines only for few flaviviruses while no effective treatments are available. Pyridobenzothiazole (PBTZ) derivatives are a class of compounds endowed with a promising broad-spectrum anti-flavivirus activity and most of them have been reported as potent inhibitors of the flaviviral NS5 polymerase. However, synthesis of PBTZ analogues entails a high number of purification steps, the use of hazardous reagents and environmentally unsustainable generation of waste. Considering the promising antiviral activity of PBTZ analogues which require further exploration, in this work, we report the development of a new and sustainable three-component reaction (3CR) that can be combined with a basic hydrolysis in a one-pot procedure to obtain the PBTZ scaffold, thus reducing the number of synthetic steps, improving yields and saving time. 3CR was significantly explored in order to demonstrate its wide scope by using different starting materials. In addition, taking advantage of these procedures, we next designed and synthesized a new set of PBTZ analogues that were tested as anti-DENV-2 and anti-ZIKV agents. Compound 22 inhibited DENV-2 NS5 polymerase with an IC50 of 10.4 μM and represented the best anti-flavivirus compound of the new series by inhibiting DENV-2- and ZIKV-infected cells with EC50 values of 1.2 and 5.0 μM, respectively, that translates into attractive selectivity indexes (SI - 83 and 20, respectively). These results strongly reaffirm PBTZ derivatives as promising anti-flavivirus agents that now can be synthesized through a convenient and sustainable 3CR in order to obtain more potent compounds for further pre-clinical development studies.


Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.
This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.


Top-emitting quantum dots light-emitting devices employing microcontact printing with electricfield-independent emission.
Recent breakthroughs in quantum dot light-emitting devices (QD-LEDs) show their promise in the development of next-generation displays. However, the QD-LED with conventional ITO-based bottom emission structure is difficult to realize the high aperture ratio, electricfield-independent emission and flexible full-color displays. Hence, we demonstrate top-emitting QD-LEDs with dry microcontact printing quantum dot films. The top-emitting structure is proved to be able to accelerate the excitons radiative transition rate, then contributing to stable electroluminescent efficiency with a very low roll-off, and preventing spectra from shifting and broadening with the electric field increases. The results suggest potential routes towards creating high aperture ratio, wide color gamut, color-stable and flexible QD-LED displays.


Mixed type I and II choledochal cyst: a new clinical subtype?
Traditionally, choledochal cyst (CC) is classified into five types according to Todani's classification. Of 356 cases of CC treated at our institute since 1965, we experienced four cases of mixed type I and II choledochal cyst (MTCC). The incidence of MTCC was 1.1%. All four patients had a fusiform common bile duct (CBD) with a diverticulum originating from the mid-portion of the CBD. The cystic duct drained into the right side of the diverticulum. All had pancreaticobiliary malunion (PBMU). All presented with recurrent abdominal pain. MTCC was suggested on ultrasonography or computerized tomography and confirmed by endoscopic retrograde cholangiopancreatography (three cases) or magnetic resonance cholangiopancreatography (one case). Age at surgery ranged from 3 to 12 years. All had hepaticoenterostomy, and total excision of the CC/diverticulum/gallbladder. There were no complications and all cases are currently well. In all cases, histopathology showed that the wall of the diverticulum was identical to the CBD. Although the incidence of MTCC is very low, pediatric surgeons should be aware of it as a new subtype of CC. Based on our experiences and a review of the literature, we suggest that its etiology does not affect treatment because the surgical management of choice is the same as for type I CC.