Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.
We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.


Bonding and Infants' Development and Quality of Life: A Study Among Mothers with Severe Mental Illnesses in Remission.
Maternal mental health has specific implications for bonding and infants' mental health. However, most of the evidence comes from mothers who are either symptomatic or did not have adequate mental health support. In this context, our objective was to explore if symptom status in mothers and bonding share any significant association with the infants' development and quality of life (QOL), in case of mothers with severe mental illnesses in remission. The study included 41 mother-infant dyads from the outpatient perinatal psychiatry services and the mother-baby unit of the current study center. Symptom status, self-reported bonding, mother-infant interactions, and infants' development and QOL were assessed with Clinical Global Impressions, Postpartum Bonding Questionnaire, Pediatric Infant-Parent Exam, Developmental Assessment Scales for Indian Infants, and Pediatric Quality of Life Scale, respectively. Most mothers had a complete recovery or minimal symptoms. Nine (22%) infants had a significant developmental delay. Atypical play-based interactions were observed in nine (22%) mothers. Self-reported bonding and bonding as evinced over play-based interactions did not significantly correlate with the QOL or development of the infants. Mothers who have recovered and are functioning well reported good bonding with their infants, though objective assessment revealed specific difficulties. Symptom severity correlated with poor physical QOL in infants. The association between mothers' bonding and infants' mental health is domain-specific and differential than linear and robust. Infants of mothers with severe mental illnesses postpartum should be routinely monitored for mother-infant bonding, development, and quality of life.


Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury.
Transplantation of exogenous cells is one approach to spinal cord repair that could potentially enhance the growth and myelination of endogenous axons. Here, we asked whether skin-derived precursors (SKPs), a neural crest-like precursor that can be isolated and expanded from mammalian skin, could be used to repair the injured rat spinal cord. To ask this question, we isolated and expanded genetically tagged murine SKPs and either transplanted them directly into the contused rat spinal cord or differentiated them into Schwann cells (SCs), and performed similar transplantations with the isolated, expanded SKP-derived SCs. Neuroanatomical analysis of these transplants 12 weeks after transplantation revealed that both cell types survived well within the injured spinal cord, reduced the size of the contusion cavity, myelinated endogenous host axons, and recruited endogenous SCs into the injured cord. However, SKP-derived SCs also provided a bridge across the lesion site, increased the size of the spared tissue rim, myelinated spared axons within the tissue rim, reduced reactive gliosis, and provided an environment that was highly conducive to axonal growth. Importantly, SKP-derived SCs provided enhanced locomotor recovery relative to both SKPs and forebrain subventricular zone neurospheres, and had no impact on mechanical or heat sensitivity thresholds. Thus, SKP-derived SCs provide an accessible, potentially autologous source of cells for transplantation into and treatment of the injured spinal cord.


A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy.
In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature-, pH-, and redox-responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N-isopropylacrylamide) (PNIPAM), 2-hydroxyethylmethacrylate (HEMA), and N,N'-bis(acryloyl)cystamine (BACy), a disulfide bond contained cross-linker, were polymerized by a distillation-precipitation polymerization. Doxorubicin (DOX), an anti-cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH-response of MMA and temperature-response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli-responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi-responsive NP is ideal drug carriers for developing novel drug delivery systems. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203-3210, 2018.


Stable carbon and hydrogen isotope analysis of methyl tert-butyl ether and tert-amyl methyl ether by purge and trap-gas chromatography-isotope ratio mass spectrometry: method evaluation and application.
In order to monitor the behaviour of contaminants in the aqueous environment effective enrichment techniques often have to be employed due to their low concentrations. In this work a robust and sensitive purge and trap-gas chromatography-isotope ratio mass spectrometry method for carbon and hydrogen isotope analysis of fuel oxygenates in water is presented. The method evaluation included the determination of method detection limits, accuracy and reproducibility of deltaD and delta(13)C values. Lowest concentrations at which reliable delta(13)C values could be determined were 5 microg L(-1) and 28 microg L(-1) for TAME and MTBE, respectively. Stable deltaD values for MTBE and TAME could be achieved for concentrations as low as 25 and 50 microg L(-1). Good long-term reproducibility of delta(13)C and deltaD values was obtained for all target compounds. But deltaD values varying more than 5 per thousand were observed using different thermal conversion tubes. Thus, a correction of deltaD values in the analysis of groundwater samples was necessary to guarantee comparability of the results. The applicability of this method was shown by the analysis of groundwater samples from a gasoline contaminated site. By two dimensional isotope analysis two locations within this site were identified at which anaerobic and aerobic degradation of methyl tert-butyl ether occurred.


Clinical Decision Support Systems in Breast Cancer: A Systematic Review.
Breast cancer is the most frequently diagnosed cancer in women, with more than 2.1 million new diagnoses worldwide every year. Personalised treatment is critical to optimising outcomes for patients with breast cancer. A major advance in medical practice is the incorporation of Clinical Decision Support Systems (CDSSs) to assist and support healthcare staff in clinical decision-making, thus improving the quality of decisions and overall patient care whilst minimising costs. The usage and availability of CDSSs in breast cancer care in healthcare settings is increasing. However, there may be differences in how particular CDSSs are developed, the information they include, the decisions they recommend, and how they are used in practice. This systematic review examines various CDSSs to determine their availability, intended use, medical characteristics, and expected outputs concerning breast cancer therapeutic decisions, an area that is known to have varying degrees of subjectivity in clinical practice. Utilising the methodology of Kitchenham and Charter, a systematic search of the literature was performed in Springer, Science Direct, Google Scholar, PubMed, ACM, IEEE, and Scopus. An overview of CDSS which supports decision-making in breast cancer treatment is provided along with a critical appraisal of their benefits, limitations, and opportunities for improvement.


The total condylar knee prosthesis. A report of two hundred and twenty cases.
The total condylar knee prosthesis is a non-hinged surface replacement which can be used for almost all knee deformities. This report discusses the first consecutive 220 arthroplasties in 183 patients. Follow-up time was three to five years. Before operation eighty-six knees had more than 10 degrees of fixed varus deformity and thirty-one knees had more than 10 degrees of fixed valgus deformity. All patients were assessed using The Hospital for Special Surgery scoring system. Of the total of 220 knees, 137 (62%) were rated excellent; sixty-one (28%), good; ten (4.5%), fair; and twelve (5.5%), poor. Of 139 osteoarthritic knees, 93% were rated excellent or good. Complications included three deep infections and four cases of posterior subluxation. The over-all reoperation rate was 3.6%.


Single cell origin of radiation-induced thymic lymphoma in mice with cellular mosaicism.
The clonal origin of radiation-induced thymic lymphoma was studied in mice with cellular mosaicism for phosphoglycerate kinase (PGK). Repeated whole-body X-irradiations (4 doses, 1.7 Gy each) with intervals of 7 days resulted in development of thymic lymphomas in the mosaic mice. PGK from all lymphomas gave only a single spot on electrophoresis. The results demonstrate the single cell origin of the thymic lymphoma.


Characterisation of gunshot residues from non-toxic ammunition and their persistence on the shooter's hands.
The aim of this work was to characterise three non-toxic ammunition (NTA) from the GECO and Fiocchi brands, which are available in the Italian market. Characterisation was carried out by considering both the elemental chemical composition and morphology, using scanning electron microscopy coupled with energy-dispersive X-ray analysis (SEM-EDS). Particles were collected from both the cartridge cases and the shooters' hands after shooting tests. Six volunteers fired two shots for each ammunition. Several elements, such as aluminium, potassium, silicon, sulphur, titanium and zinc were found in gunshot residue (GSR) particles from different ammunition. We also studied the persistence of these types of GSR on the hands of the shooters in a range between 1 and 6 h after shooting. The GSR particles from the three NTA tested were found on the hands of shooters until 6 h after the shots. The characterisations undertaken in this work will be useful for specialists in forensic science and legal medicine to evaluate trace evidence from these new NTA in casework, as such formulations are in growth.


Detection of bipolar disorder.
Major depressive episodes are common in bipolar disorder, which consequently may be misdiagnosed as major depressive disorder. Improved detection of bipolar disorder rests upon better ascertainment of a history of hypomania. Antidepressants are of dubious benefit in bipolar disorder and more accurate diagnosis of depression would promote better treatment.


Regional haemodynamic effects of depressor neuropeptides in conscious, unrestrained, Long Evans and Brattleboro rats.
1. The regional haemodynamic effects of i.v. bolus doses of atrial natriuretic peptide (ANP, 1 and 10 nmol), calcitonin gene-related peptide (CGRP, 0.05 and 0.5 nmol) and corticotropin-releasing factor (CRF, 1 and 5 nmol) were assessed in conscious Long Evans and Brattleboro rats chronically instrumented with miniaturized, pulsed Doppler probes. 2. The low dose of ANP was without effect on mean arterial pressure (MAP), but caused tachycardia and hindquarters vasodilatation with vasoconstriction in renal and mesenteric beds in Long Evans rats. With the high doses of ANP these effects were more pronounced and MAP fell. In Brattleboro rats there was a primary renal vasodilatation. 3. The low dose of CGRP caused a slight fall in MAP in Long Evans rats, tachycardia and a renal vasodilatation. The high dose of CGRP caused marked hypotension, tachycardia and renal, mesenteric and hindquarters vasodilatation in both strains of rat. However, only in Long Evans rats were there secondary renal and mesenteric vasoconstrictions. 4. The low dose of CRF caused falls in MAP in both strains of rat, accompanied by renal and, particularly, mesenteric vasodilatation. Administration of the high dose of CRF caused profound, prolonged hypotension, tachycardia and mesenteric vasodilatation. There was also (late onset) hindquarters vasodilatation accompanying renal vasoconstriction that followed the initial vasodilatation in this vascular bed. 5. These results indicate that appropriate doses of particular peptides may be capable of promoting flow through individual peripheral vascular beds.


Poly(ether urethane)s incorporating long alkyl side-chains with terminal carboxyl groups as fatty acid mimics: synthesis, structural characterization and protein adsorption.
The object of this work was to produce polyurethanes with greater affinity for albumin (Alb) and improved hemocompatibility by introduction of carboxyl-terminated alkyl side-chains that better mimic fatty acids, in contrast to methyl terminated alkyl side-chains used previously. Synthesis of poly(ether urethane)s (PEUs) with long alkyl side-chains via a multi-step solution addition polymerization is described. The synthesis is based upon the polymerization of a diisocyanate pre-polymer with various chain extenders and reaction with Br-terminated compound in the final stage. The side-chains had terminal methyl or carboxylic groups, and were attached either directly to the polymer backbone or to an oligo(ethylene glycol) spacer. The bulk structure of the PEUs was confirmed by 1H-NMR and the surface polymer structure was characterized by ToF-SIMS. The influence of the incorporated C16-alkyl, C16-carboxyalkyl and oxyethylene-C16-carboxyalkyl side-chains attached to the polymer backbone on fibrinogen (Fg) and Alb adsorption from blood plasma, and Fg adsorption from buffer solutions and binary mixtures with Alb was measured. Incorporation of C16-alkyl or C16-carboxyalkyl side-chains into PEUs caused relatively small changes in Fg and Alb adsorption. PEUs with oxyethylene-C16-carboxyalkyl side-chains exhibited the lowest Fg adsorption and the highest Alb adsorption among all the tested polymers.


Distribution and differentiation of wild, feral, and cultivated populations of perennial upland cotton (Gossypium hirsutum L.) in Mesoamerica and the Caribbean.
Perennial forms of Gossypium hirsutum are classified under seven races. Five Mesoamerican races would have been derived from the wild race 'yucatanense' from northern Yucatán. 'Marie-Galante', the main race in the Caribbean, would have developed from introgression with G. barbadense. The racial status of coastal populations from the Caribbean has not been clearly defined. We combined Ecological Niche Modeling with an analysis of SSR marker diversity, to elucidate the relationships among cultivated, feral and wild populations of perennial cottons. Out of 954 records of occurrence in Mesoamerica and the Caribbean, 630 were classified into four categories cultivated, feral (disturbed and secondary habitats), wild/feral (protected habitats), and truly wild cotton (TWC) populations. The widely distributed three first categories cannot be differentiated on ecological grounds, indicating they mostly belong to the domesticated pool. In contrast, TWC are restricted to the driest and hottest littoral habitats, in northern Yucatán and in the Caribbean (from Venezuela to Florida), as confirmed by their climatic envelope in the factorial analysis. Extrapolating this TWC climatic model to South America and the Pacific Ocean points towards places where other wild representatives of tetraploid Gossypium species have been encountered. The genetic analysis sample comprised 42 TWC accessions from 12 sites and 68 feral accessions from 18 sites; at nine sites, wild and feral accessions were collected in close vicinity. Principal coordinate analysis, neighbor joining, and STRUCTURE consistently showed a primary divergence between TWC and feral cottons, and a secondary divergence separating 'Marie-Galante' from all other feral accessions. This strong genetic structure contrasts strikingly with the absence of geographic differentiation. Our results show that TWC populations of Mesoamerica and the Caribbean constitute a homogenous gene pool. Furthermore, the relatively low genetic divergence between the Mesoamerican and Caribbean domesticated pools supports the hypothesis of domestication of G. hirsutum in northern Yucatán.


The epidemiology of acute renal failure in the world.
The aim of this article is to describe our current understanding of the epidemiology of acute renal failure, especially in severe cases requiring renal replacement therapy. Some data from an international observational study (the Beginning and Ending Supportive Therapy (BEST) for the kidney study) are also presented. Multiple epidemiological studies for acute renal failure have been conducted in different populations using various criteria and reported a wide range of incidence and mortality. In several multicenter studies reporting the incidence of renal replacement therapy requirement in a general intensive care unit population, however, renal replacement therapy requirement and hospital mortality was quite similar among the studies, approximately 4% and 60%, respectively. In North and South America, nephrologists typically manage acute renal failure patients with intermittent renal replacement therapy. On the other hand, in Asia, Australia and Europe, intensivists are commonly responsible for managing these patients with continuous renal replacement therapy. Although the epidemiology of acute renal failure is varied among regions and centers, the average incidence of renal replacement therapy requirement and hospital mortality in critical illness are similar in multicenter studies. Continuous renal replacement therapy is gaining popularity and intensivists are becoming responsible for managing patients with it. More studies are needed to understand acute renal failure epidemiology worldwide. To conduct such studies, consensus criteria for acute renal failure and a well performed acute renal failure-specific severity score will be required.


Solubilization and preformulation studies on PG-300995 (an anti-HIV drug).
This study investigates the solubilization of a potential anti-human immunodeficiency virus agent [PG-300995 or 2-(2-thiophenyl)-4-azabenzoimidazole] for oral administration. The intrinsic solubility of PG-300995 is 51 microg/mL. Multiple approaches including combinations of pH control and cosolvency, micellization, or complexation were used to improve the solubility of PG-300995. The combined techniques increased the solubility of both the unionized and ionized species. The solubility of the drug increased from 20 to 200 times depending on the pH and concentration of solubilization agents. The following formulations which contain the desired doses of 5 and 10 mg/mL were developed for oral administration. Formulation A: 10 mg/mL PG-300995 in 20% sulfobutyl ether-beta-cyclodextrin at pH 2; formulations B: 5 mg/mL PG-300995 in 10% sulfobutyl ether-beta-cyclodextrin at pH 2; formulation C: 5 mg/mL PG-300995 in 10% ethanol + 40% propylene glycol at pH 2. No precipitation was observed after series dilution of these three formulations with water or pH 2 buffers. These formulations are stable for at least 6 months after storing at room temperature and 37 degrees C.


A density functional theory approach to noncovalent interactions via interacting monomer densities.
A recently proposed "DFT + dispersion" treatment (Rajchel et al., Phys. Rev. Lett., 2010, 104, 163001) is described in detail and illustrated by more examples. The formalism derives the dispersion-free density functional theory (DFT) interaction energy and combines it with the dispersion energy from separate DFT calculations. It consists of the self-consistent polarization of DFT monomers restrained by the exclusion principle via the Pauli blockade technique. Within the monomers a complete exchange-correlation potential should be used, but between them only the exact exchange operates. The application to a wide range of molecular complexes from rare-gas dimers to hydrogen-bonds to π-electron interactions shows good agreement with benchmark values.


Premorbid use of selective beta-blockers improves sepsis incidence and course: Human cohort and animal model studies.
Beta-blockers are widely prescribed to manage hypertension and cardiovascular diseases and have been suggested as an attractive therapy to improve the prognosis of sepsis. Herein, we investigated the potential benefits of premorbid selective beta-blocker use in sepsis with a real-world database and explored the underlying mechanism by in vivo and in vitro experiments. A total of 64,070 sepsis patients and 64,070 matched controls who were prescribed at least one anti-hypertensive drug for more than 300 days within 1 year were selected for the nested case-control study. Female C57BL/6 J mice and THP-1 cells stimulated with lipopolysaccharide (LPS) were used for studying systemic responses during sepsis to validate our clinical findings. The risk of sepsis was lower in current selective beta-blocker users than in non-users (adjusted OR (aOR), 0.842; 95% CI, 0.755-0.939), and in recent users than in non-users (aOR, 0.773; 95% CI, 0.737-0.810). A mean daily dose of ≥0.5 DDD was associated with a lower risk of sepsis (aOR, 0.7; 95% CI, 0.676-0.725). Metoprolol, atenolol, and bisoprolol users had lower risk of sepsis than non-users. In a LPS-induced sepsis mouse model, mice pre-fed with atenolol had significantly reduced mortality. While atenolol had some mild effects on LPS-induced release of inflammatory cytokines in septic mice, it significantly reduced serum soluble PD-L1 levels. Notably, atenolol treatment reversed the negative correlation of sPD-L1 with inflammatory cytokines in septic mice. Moreover, atenolol markedly downregulated the PD-L1 expression on LPS-stimulated THP-1 monocytes/macrophages via targeting ROS-induced NF-κB and STAT3 activation. Atenolol pretreatment can reduce sepsis mortality in mice, and in vivo and in vitro studies of PD-L1 expression suggest a role for atenolol in the modulation of immune homeostasis. These findings may contribute to the reduced incidence of sepsis in hypertensive patients with premorbid treatment with selective beta-blockers, especially atenolol.


Influence of Ectopic Beats on Heart Rate Variability Analysis.
The analysis of heart rate variability (HRV) plays a dominant role in the study of physiological signal variability. HRV reflects the information of the adjustment of sympathetic and parasympathetic nerves on the cardiovascular system and, thus, is widely used to evaluate the functional status of the cardiovascular system. Ectopic beats may affect the analysis of HRV. However, the quantitative relationship between the burden of ectopic beats and HRV indices, including entropy measures, has not yet been investigated in depth. In this work, we analyzed the effects of different numbers of ectopic beats on several widely accepted HRV parameters in time-domain (SDNN), frequency-domain (LF/HF), as well as non-linear features (SampEn and Pt-SampEn (physical threshold-based SampEn)). The results showed that all four indices were influenced by ectopic beats, and the degree of influence was roughly increased with the increase of the number of ectopic beats. Ectopic beats had the greatest impact on the frequency domain index LF/HF, whereas the Pt-SampEn was minimally accepted by ectopic beats. These results also indicated that, compared with the other three indices, Pt-SampEn had better robustness for ectopic beats.


Psychometric validation of a brief self-report measure of misophonia symptoms and functional impairment: The duke-vanderbilt misophonia screening questionnaire.
Misophonia is a newly described disorder of sound tolerance characterized by strong negative emotional reactions to specific "trigger" sounds, resulting in significant distress, pathological avoidance, and impairment in daily life. Research on misophonia is still in its infancy, and most existing psychometric tools for assessing misophonia symptoms have not been extensively validated. The purpose of the current study was to introduce and psychometrically validate the duke-vanderbilt Misophonia Screening Questionnaire (DVMSQ), a novel self-report measure of misophonia symptoms that can be used to determine misophonia "caseness" in clinical and research settings. Employing large online samples of general population adults (n = 1403) and adults on the autism spectrum (n = 936), we rigorously evaluated the internal structure, reliability, validity, and measurement invariance of the DVMSQ. Results indicated that 17 of the 20 original DVMSQ items fit well to a bifactor structure with one "general misophonia" factor and four specific factors (anger/aggression, distress/avoidance, impairment, and global impact). DVMSQ total and subscale scores were highly reliable in both general population and autistic adult samples, and the measure was found to be approximately invariant across age, sex, education level, and autism status. DVMSQ total scores also correlated strongly with another measure of misophonia symptoms (Duke Misophonia Questionnaire-Symptom Scale), with correlations between these two measures being significantly stronger than correlations between the DVMSQ and scales measuring other types of sound intolerance (Inventory of Hyperacusis Symptoms [General Loudness subscale] and DSM-5 Severity Measure for Specific Phobia [modified for phonophobia]). Additionally, DVMSQ items were used to operationalize diagnostic criteria for misophonia derived from the Revised Amsterdam Criteria, which were further updated to reflect a recent consensus definition of misophonia (published after the development of the DVMSQ). Using the new DVMSQ algorithm, 7.3% of general population adults and 35.5% of autistic adults met criteria for clinically significant misophonia. Although additional work is needed to further investigate the psychometric properties of the DVMSQ and validate its theory-based screening algorithm using best-estimate clinical diagnoses, this novel measure represents a potentially useful tool to screen for misophonia and quantify symptom severity and impairment in both autistic adults and the general population.


Hepcidin and metallothioneins as molecular base for sex-dependent differences in clinical course of experimental autoimmune encephalomyelitis in chronic iron overload.
Multiple sclerosis is a chronic demyelinating disease of the central nervous system characterised by inflammatory and degenerative changes. It is considered that disease arises from the influence of environmental factors on genetically susceptible individuals. Recent researches, using magnetic resonance imaging, connected iron deposits in different brain regions with demyelinating process in multiple sclerosis patients. Although iron is an essential trace element important for many biological functions it could be harmful because iron excess can induce the production of reactive oxygen species, development of oxidative stress and lipid peroxidation which leads to demyelination. In experimental autoimmune encephalomyelitis model, the most common experimental animal model for multiple sclerosis, we recently found that chronic iron overload influences the clinical course of disease in Dark Agouti rats. In female rats iron overload accelerated the onset of disease, while in male rats it accelerated the progression of disease and increased mortality rate. We hypothesize that those differences arise on molecular level in different expression of stress response proteins hepcidin and metallothioneins in male and female iron overloaded rats. They are both upregulated by metal ions in both sexes. Hepcidin is additionally upregulated by estrogen in female rats and therefore causes higher degradation of iron exporter ferroportin and sequestration of iron in the cells, lowering the possibility for the development of oxidative stress. Antioxidative effect of metallothioneins could be increased in female rats because of their ability to reversibly exchange metal ions with the estrogen receptor. In case of iron excess metallothioneins release zinc, which is normally bound to them. Zinc binds to estrogen receptor and leaves metallothioneins binding domains free for iron, causing at least provisional cytoprotective effect. To test this hypothesis, we propose to determine and compare serum levels of hepcidin and estrogen using ELISA essay as well as expression and distribution of acute stress response proteins hepcidin and metallothioneins, iron and estrogen receptor in the brain and spinal cord tissue using immunohistochemistry in control and chronic iron overloaded male and female rats in experimental autoimmune encephalomyelitis model. It would be also possible to perform the same immunohistochemistry in the brain tissue of multiple sclerosis patients post mortem. The results of experiments could contribute to better understanding of cytoprotective mechanisms in chronic iron overload that could have possible therapeutic applications in iron disturbances. In order to elucidate whether common measure of systemic iron status, like ferritin, haemoglobin concentration and transferrin saturation levels, may be used to distinguish physiologic from potentially harmful iron levels in local disease, for example multiple sclerosis and Still's disease, well-designed clinical trials would be of great interest.


1-Deoxy-D-xylulose: synthesis based on molybdate-catalyzed rearrangement of a branched-chain aldotetrose.
1-Deoxy-D-xylulose has been prepared in seven steps and approximately 21% overall yield from 2,3-O-isopropylidene-D-erythrono-1,4-lactone. The key reaction involves transformation of a branched-chain aldotetrose to the 1-deoxy-2-ketopentose catalyzed by molybdic acid. Other branched-chain aldotetroses containing bulkier substituents at C2 also engage in the conversion, suggesting routes to protected 2-ketoses and alpha-ketoacids/esters. This synthetic route mimics reactions of the non-mevalonate isoprenoid pathway in plants and bacteria. [reaction: see text]


The first enzyme-promoted addition of nitromethane to imines (aza-Henry reaction).
Enzyme catalytic promiscuity is the ability of a single enzyme active site to catalyze several chemical transformations, among them those which are different from natural. We have attempted to use this feature of enzymes in the nucleophilic addition of nitromethane to aldimines (the aza-Henry reaction) whose chemically catalyzed version leads to synthetically useful β-nitroamines. We succeded in obtaining for the first time the desired products in the yields up to 81%. The most efficient proved lipase TL (from Pseudomonas stutzeri) and oxynitrilase from Arabidopsis thaliana. However, all the reactions investigated were non-stereoselective.


Expansion of enzymatic Friedel-Crafts alkylation on indoles: acceptance of unnatural β-unsaturated allyl diphospates by dimethylallyl-tryptophan synthases.
Prenyltransferases of the dimethylallyl-tryptophan synthase (DMATS) superfamily catalyze Friedel-Crafts alkylation with high flexibility for aromatic substrates, but the high specificity for dimethylallyl diphosphate (DMAPP) prohibits their application as biocatalysts. We demonstrate here that at least one methyl group in DMAPP can be deleted or shifted to the δ-position. For acceptance by some DMATS enzymes, however, a double bond must be situated at the β-position. Furthermore, the alkylation position of an analogue can differ from that of DMAPP.


The carbonate and fluoride in surfaces of remineralized enamel.
Analyses were made of samples of surface enamel collected before and after acid demineralization and after subsequent remineralization in solutions containing calcium and phosphate and various levels of bicarbonate and fluoride ions. Demineralization caused a preferential loss of carbonates. Remineralization was increased by both fluoride and bicarbonate ions. With no bicarbonate in the calcifying solution, 0.25 to 4.0 mM NaF increased mineral formation and thereby caused a relative reduction of its carbonate content. With 0.5 mM NaF (10 ppm F-) and 5, 15, and 25 mM HCO-3 in remineralizing solutions more carbonate was deposited than in the absence of NaF. Five and 15 mM HCO-3 increased, but 25 mM HCO-3 decreased, deposit of fluoride in enamel.


Weight gain, weight management and medical care for individuals living with overweight and obesity during the COVID-19 pandemic (EPOCH Study).
Medical care and weight related experiences have been challenged by the coronavirus disease 2019 (COVID-19) pandemic for those living with obesity. The magnitude of this impact requires further attention in order to optimize patient care and outcomes. The aim of this study was to assess the impact of the COVID-19 pandemic and lockdown on access to, and experience of, medical care, weight gain and management strategies, as well as predictors of weight gain. An online survey (June-October 2020) was conducted with two samples; one representative of Canadians living with overweight and obesity (n = 1089) and a second of individuals recruited through obesity clinical services or patient organizations (n = 980). Less than half of the total respondents thought that their providers were available for their medical care and most preferred in-person appointments over telemedicine. Only one quarter were satisfied with their obesity care. Sixty percent of the respondents reported weight gain (on average 5.65 kilograms [kg] gained), with 39.0% gaining more than 5% of their body weight (10.2% gained more than 10%). Over half of the respondents experienced decreased motivation for healthy eating or exercise. One third experienced more frequent and greater food consumption. Although worsening sleep occurred in approximately 20%, there was no significant increase in smoking, alcohol, or cannabis use. Predictors of weight gain were younger patients, higher weight categories, those who struggled with obtaining medical care during the pandemic, as well as those who struggled with eating. These results suggest that the COVID-19 pandemic negatively impacted patient care for those living with overweight and obesity and was associated with weight gain and interfered with weight management strategies. Greater attention to personalized weight management and interventions that focus on the predictors of weight gain should be undertaken.


Responses of the public towards the government in times of crisis.
We experimentally investigate how and when the public responds to government actions during times of crisis. Public reactions are shown to follow different processes, depending on whether government performs in exemplary or unsatisfactory ways to the COVID-19 pandemic. The 'how' question is addressed by proposing that negative moral emotions mediate public reactions to bad government actions, and positive moral emotions mediate reactions to good government actions. Tests of mediation are conducted while taking into account attitudes and trust in the government as rival hypotheses. The 'when' question is studied by examining self-regulatory moderators governing the experience of moral emotions and their effects. These include conspiracy beliefs, political ideology, attachment coping styles and collective values. A total of 357 citizens of a representative sample of adult Norwegians were randomly assigned to two experimental groups and a control group, where complaining, putting pressure on the government and compliance to Covid-19 policies were dependent variables. The findings show that negative moral emotions mediate the effects of government doing badly on complaining and pressuring the government, with conspiracy beliefs moderating the experience of negative moral emotions and attachment coping moderating the effects of negative moral emotions. The results also show that positive moral emotions mediate the effects of government doing well on compliance with COVID-19 regulations, with political ideology moderating the experience of positive moral emotions and collective values moderating the effects of positive moral emotions.


[Research progress in chemical constituents in plants of Polygonatum and their pharmacological effects].
Polygonatum plants are perennial plants of Liliaceae. There are about 60 species reported at home and abroad,32 species in China,mainly distributed in the north temperate zone. Their main chemical components are steroidal saponins,polysaccharides,flavonoids,alkaloids,etc. They have anti-aging,anti-tumor,immunomodulation,antibacterial,antiviral,hypoglycemic and blood lipid effects. With the development of health industry,Polygonati Rhizome used as medicine and food has attracted great attention in recent years,and has become a research hotspot. However,the material basis of its efficacy is unclear and the product quality is uneven,which seriously limited the rapid upgrading of the industry. This review summarizes Polygonatum plants system classification,the chemical composition and pharmacological activity to provide theoretical basis for the development and utilization of Polygonatum plants.


Emerging Trends in 2D TMDs Photodetectors and Piezo-Phototronic Devices.
The piezo-phototronic effect shows promise with regards to improving the performance of 2D semiconductor-based flexible optoelectronics, which will potentially open up new opportunities in the electronics field. Mechanical exfoliation and chemical vapor deposition (CVD) influence the piezo-phototronic effect on a transparent, ultrasensitive, and flexible van der Waals (vdW) heterostructure, which allows the use of intrinsic semiconductors, such as 2D transition metal dichalcogenides (TMD). The latest and most promising 2D TMD-based photodetectors and piezo-phototronic devices are discussed in this review article. As a result, it is possible to make flexible piezo-phototronic photodetectors, self-powered sensors, and higher strain tolerance wearable and implantable electronics for health monitoring and generation of piezoelectricity using just a single semiconductor or vdW heterostructures of various nanomaterials. A comparison is also made between the functionality and distinctive properties of 2D flexible electronic devices with a range of applications made from 2D TMDs materials. The current state of the research about 2D TMDs can be applied in a variety of ways in order to aid in the development of new types of nanoscale optoelectronic devices. Last, it summarizes the problems that are currently being faced, along with potential solutions and future prospects.


Deep breath reversal and exponential return of methacholine-induced obstruction in asthmatic and nonasthmatic subjects.
A deep breath (DB) during induced obstruction results in a transient reversal with a return to pre-DB levels in both asthmatic and nonasthmatic subjects. The time course of this transient recovery has been reported to be exponential by one group but linear by another group. In the present study, we estimated airway resistance (Raw) from measurements of respiratory system transfer impedance before and after a DB. Nine healthy subjects and nine asthmatic subjects were studied at their maximum response during a methacholine challenge. In all subjects, the DB resulted in a rapid decrease in Raw, which then returned to pre-DB levels. This recovery was well fit with a monoexponential function in both groups, and the time constant was significantly smaller in the asthmatic than the nonasthmatic subjects (11.6 +/- 5.0 and 35.1 +/- 15.9 s, respectively). Obstruction was completely reversed in the nonasthmatic subjects (pre- and postchallenge mean Raw immediately after the DB were 2.03 +/- 0.66 and 2.06 +/- 0.68 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects complete reversal did not occur (2.29 +/- 0.78 and 4.84 +/- 2.64 cmH2O.l-1.s, respectively). Raw after the DB returned to postchallenge, pre-DB values in the nonasthmatic subjects (3.78 +/- 1.56 and 3.97 +/- 1.63 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects it was higher but not significantly so (9.19 +/- 4.95 and 7.14 +/- 3.56 cmH2O.l-1.s, respectively). The monoexponential recovery suggests a first-order process such as airway wall-parenchymal tissue interdependence or renewed constriction of airway smooth muscle.


A strategy for system improvement and data processing in a national GP Sentinel Network.
This paper presents the results and strategies concerning the running of MediNET sentinel dispensaries network in Romania. MediNET stations network consists in 100 computerized dispensaries all around the country, where doctors collect data from primary care and send it to a central server through Internet. The network is fully functional and the collection of data started. We present a low-cost solution for developing the system, the preliminary results of collected data, the strategy for improving and developing the system and the strategy for future data processing.


The disabled driver: an unmet challenge.
A survey was undertaken to determine if driving impairment secondary to a disabling injury is addressed in state licensing laws and training programs. In 35 states drivers submit voluntarily to reevaluation after disabling injuries, but no provision is made for reporting such individuals. Only 15 states authorize physicians to report impaired drivers, and only seven require such reporting. Based on a survey of licensing bureaus in the capital or a major city of every state, clerks (who are likely to be the source of information to injured persons) are generally not aware of reporting requirements and supervisors are only slightly better informed. Of the 100 rehabilitation centers surveyed, only 36 provided on-site training for disabled drivers. Voluntary submission for reevaluation after head injury does not often occur. Despite being asked to do so, none of the 35 head injured patients, followed up to two years post-onset, sought reevaluation, although 21 had resumed regular driving. Two of the 21 were involved in subsequent traffic accidents. Common guidelines need to be established across states to ensure reevaluation of individuals with disabling conditions, delivery of accurate information concerning licensing, and availability of training programs.


Synthesis of corticosterone in the vascular wall.
Extra-adrenal steroid 21-hydroxylation and 11 beta-hydroxylation occur in a variety of human tissues. This study was undertaken to determine whether the rat mesenteric artery produces corticosterone and to demonstrate the CYP11B1 mRNA in the vascular tissue. Isolated rat mesenteric arteries were perfused with Krebs-Ringer solution for 4 h. The perfusate was collected and chromatographed in a reverse-phase HPLC system. The fraction corresponding to synthetic corticosterone was collected and analyzed by mass spectrometry. The concentration of corticosterone in the perfusate from the adrenalectomized rats was measured using radioimmunoassay after separation with the HPLC system. The mass spectra of synthetic corticosterone was identical with corticosterone isolated from the perfusate of the rat mesenteric arteries. The radioactive peak of corticosterone was detected in the perfusate after perfusing the mesenteric artery with Krebs-Ringer solution containing [14C]-pregnenolone. The expression of CYP11B1, 11B2, and 11A mRNA was detected in the mesenteric artery using a RT-PCR. The production of corticosterone in the vascular wall was increased in the adrenalectomized rats compared with that of the controls. This study shows that the rat mesenteric artery produces corticosterone, and the corticosterone synthase is existed in the vasculature.


Interaction of the fluorescence-labeled secretory component with human polymeric immunoglobulins.
The secretory component (SC) isolated from human milk was labeled with 2 mol of the fluorescent thiol reagent N-[7-(dimethylamino)-4-methylcoumarinyl]maleimide (DACM) per mol of SC through the reactive disulfide bond of SC. The binding of the labeled SC to polymeric immunoglobulins was examined by gel filtration by measuring the fluorescence of DACM at 478 nm. The labeled SC was bound to immunoglobulin M (IgM) and its (Fc)5 mu fragment and to dimeric immunoglobulin A (IgA). When the labeled SC was bound to IgM or the (Fc)5 mu fragment, the fluorescence of DACM increased about 30%. By use of this fluorescence change, quantitative studies were made on the equilibrium and kinetics of the reversible interactions of the labeled SC with two IgM proteins and their (Fc)5 mu fragments at pH 7.0 and 25 degrees C. All the IgM proteins and their (Fc)5 mu fragments had one binding site per mole of polymers. The affinity constant (6 X 10(8) M-1), the association rate constant (7 X 10(7) M-1 min-1), and the dissociation rate constant (0.1 min-1) of one IgM were different from those of the other IgM (1.7 X 10(9) M-1, 1.0 X 10(8) M-1 min-1, and 0.06 min-1, respectively). However, the values for the (Fc)5 mu fragments of the two proteins were the same (1.9 X 10(9) M-1, 1.1 X 10(8) M-1 min-1, and 0.06 min-1, respectively) and were very similar to those of the IgM with the higher affinity constant.(ABSTRACT TRUNCATED AT 250 WORDS)


Crystallization and preliminary X-ray diffraction studies of a protein disulfide oxidoreductase from Aeropyrum pernix K1.
A protein disulfide oxidoreductase from the archaeon Aeropyrum pernix K1 has been overexpressed in Escherichia coli and crystallized at 298 K using the hanging-drop vapour-diffusion method. Crystals belong to the space group I222 or I2(1)2(1)2(1), with unit-cell parameters a = 90.59, b = 102.43, c = 128.96 A. A complete data set has been collected at the Elettra synchrotron source in Trieste to 1.93 A resolution using a single frozen crystal.


OsWRKY62 is a negative regulator of basal and Xa21-mediated defense against Xanthomonas oryzae pv. oryzae in rice.
The rice Xa21 gene, which confers resistance to the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo), encodes a receptor-like kinase. Few components involved in transducing the Xa21-mediated defense response have yet been identified. Here, we report that XA21 binds to a WRKY transcription factor, called OsWRKY62. The OsWRKY62 gene encodes two splice variants (OsWRKY62.1 and OsWRKY62.2). OsWRKY62.1:smGFP2 and OsWRKY62.2:smGFP2 fusion proteins partially localize to the nucleus. Transgenic plants overexpressing OsWRKY62.1 are compromised in basal defense and Xa21-mediated resistance to Xoo. Furthermore, overexpression of OsWRKY62.1 suppresses the activation of defense-related genes. These results imply that OsWRKY62 functions as a negative regulator of innate immunity in rice, and serves as a critical mediator of both basal and race-specific defense responses.


Orchard Mapping with Deep Learning Semantic Segmentation.
This study aimed to propose an approach for orchard trees segmentation using aerial images based on a deep learning convolutional neural network variant, namely the U-net network. The purpose was the automated detection and localization of the canopy of orchard trees under various conditions (i.e., different seasons, different tree ages, different levels of weed coverage). The implemented dataset was composed of images from three different walnut orchards. The achieved variability of the dataset resulted in obtaining images that fell under seven different use cases. The best-trained model achieved 91%, 90%, and 87% accuracy for training, validation, and testing, respectively. The trained model was also tested on never-before-seen orthomosaic images or orchards based on two methods (oversampling and undersampling) in order to tackle issues with out-of-the-field boundary transparent pixels from the image. Even though the training dataset did not contain orthomosaic images, it achieved performance levels that reached up to 99%, demonstrating the robustness of the proposed approach.


Locked-in state in Borrelia burgdorferi meningitis.
The case is reported of a 28-year-old woman with persistent tetraplegia following acute meningitis due to Borrelia burgdorferi infection. The patient developed erythema chronicum migrans before radicular pain occurred in the upper extremities. The poor clinical outcome was suggestive of pontine infarction due to vasculitis of branches of the basilar artery.


[Visual mechanisms of recognition of vanishing figures].
The acuity test Landolt C's with a complex contour imitating various kinds of high-pass spatial frequency filtering generated as a printed visual acuity charts with a grey background were studied with regard to recognition thresholds. Comparisons were made for recognition thresholds with different complex contours. When the vanishing optotypes are out of focus, their image on the retina fades rapidly into the grey background, rendering them invisible rather than merely blurred as in the standard chart. The data obtained confirm that the recognition distance depends on physical property of complex contour profile and show the importance of the Landolt C spatial frequency spectrum for recognition of different types of the complex contour.


Expression and secretion of glycosylated barley oxalate oxidase in Pichia pastoris.
Oxalate oxidase is an enzyme that degrades oxalate and is used in commercial urinary assays to measure oxalate levels. The objective of this study was to establish an enhanced expression system for secretion and purification of oxalate oxidase using Pichia pastoris. A codon optimized synthetic oxalate oxidase gene derived from Hordeum vulgare (barley) was generated and cloned into the pPICZα expression vector downstream of the N-terminal alpha factor secretion signal peptide sequence and used for expression in P. pastoris X-33 strain. A novel chimeric signal peptide consisting of the pre-OST1 sequence fused to pro-αpp8 containing several amino acid substitutions was also generated to enhance secretion. Active enzyme was purified to greater than 90% purity using Q-Sepharose anion exchange chromatography. The purified oxalate oxidase enzyme had an estimated Km value of 256μM, and activity was determined to be 10U/mg. We have developed an enhanced oxalate oxidase expression system and method for purification.


Assessment of five different probes for lung ultrasound in critically ill patients: A pilot study.
The present study was aimed at comparing the diagnosis concordance of five echo probes of lung ultrasound (LUS) with CT scans in intensive care and emergency patients with acute respiratory failure. This prospective, observational, pilot study involved 10 acute patients in whom a thoracic CT scan was performed. An expert performed an LUS reference exam using five different probes: three probes with a high-quality conventional echo machine (cardiac phased-array probe, abdominal convex probe, linear probe) and two probes (cardiac and linear) with a pocket ultrasound device (PUD). Then, a trained physician and a resident performed 'blinded' analyses by viewing the video results on a computer. The primary objective was to test concordance between the blinded echo diagnosis and the CT scan. In the 100 LUS performed, the phased-array probe of the conventional machine and linear array probe of the PUD have the best concordance with the CT scan (Kappa coefficient=0.75 [CI 95%=0.54-0.96] and 0.62 [CI 95%=0.37-0.86], respectively) only for experts and trained physicians. The agreement was always poor for residents. Convex (abdominal) and linear transducers of conventional machines and the phased-array transducers (cardiac) of PUD have poor or very poor agreement, regardless of the physician's experience. Among the probes tested for LUS in acute patients, the cardiac probe of conventional machines and the linear probes of PUDs provide good diagnosis concordance with CT scans when performed by an expert and trained physician, but not by residents.


A simple micromethod for rapid kinetic analyses of yeast enzymes in situ.
A simple approach for rapid assay of enzymes in large numbers of samples of whole cells of yeast is described. The technique involves treatment of yeast cells with toluene dissolved in ethanol (1:4, v/v; TE), rendering them selectively permeable to small molecules, while letting the enzymes remain intracellular and catalytically active but accessible to exogenously added assay reagents. The permeated cell preparations permit rapid assay of nitrate reductase activity in situ [P. V. Choudary and G. Ramananda Rao (1976) Current Sci. 45, 324-327]. Investigation of enzyme kinetic parameters such as pH optima, temperature dependence, and substrate saturation, which involves several samples and needs to be investigated very rapidly and accurately, is greatly facilitated by permeated cells prepared from a very small culture of cells, eliminating the need for elaborate preparations of cell extracts. By using permeabilized cell preparations, the need to supplement the reaction mixture with expensive cofactors can also be obviated to a large extent. Further, the enzyme activity displays a broader range of tolerance in situ to variations in reaction conditions compared to that in vitro. Permeabilized cell preparations thus seem to present the enzymes in the form of relatively less disintegrated functional complexes, making them a valuable tool in biochemical and cell biological investigations, and facilitate the correlation of in vitro data with the in vivo phenomena more confidently.


[Clinical value of DC and DRs in warning sudden cardiac death of patients with coronary artery disease].
To make risk stratification of aged patients with coronary artery disease by deceleration capacity of rate (DC) and heart rate deceleration runs (DRs) and to investigate the value of the two detection technologies in warning sudden cardiac death. Two hundrend and eighteen patients diagnosed with coronary artery disease (CAD) by coronary angiography (CAG) were selected as observa-tion group:including 55 patients with latent coronary artery disease (LCHD), 56 patients with acute myocardial infarction (AMI), 53 patients with angina pectoris (AP), 54 patients with ischemic heart failure. Fifty-five healthy controls in our hospital were selected at the same time (control group). All patients were detected by 24-hour dynamic electrocardiogram while values of DC and DRs were automatically analyzed and calculated by software. The values of DC and DRs descended significantly in all CHD groups (AMI group, AP group, Ischemic Heart Failure group, LCHD group) and the difference was statistically significant (P < 0.01) compared with normal group; DC and DRs indicated the risk classification of each CAD subgroup was obviously higher than those in normal group and the difference was statistically significant(P < 0.01); CAG showed that the more coronary lesions, the larger the rage, prompt the heavier the illness, which was consistent with the risk classification of each CHD subgroup indicated by DC and DRs. DC and DRs can be used to analyze the function of vagus nerve, it also can be used to make risk classification of patients with CHD, and it has a higher value of pre-warning for high-risk groups. DC and DRs can be used as sensitive indexes in warning sudden cardiac death of patients with CHD.


Identification of mRNA that encodes an alternative form of H-CAM(CD44) in lymphoid and nonlymphoid tissues.
The cluster of differentiation 44 (CD44), hereafter referred to as H-CAM(CD44), represents a novel class of polymorphic (Mr 80,000-215,000) cell adhesion molecules that are involved in cell-cell and cell-matrix adhesion events in a variety of organ systems. We report the detection of distinct mRNAs, in both hematopoietic and nonhematopoietic human cell lines, that encode H-CAM(CD44) with different cytoplasmic domains. Genomic Southern blot analyses indicate that the exons encoding these two cytoplasmic domains are located on the same approximately 16 kilobase (kb) Eco RI restriction fragment. Restriction endonuclease and Southern blot analyses performed on polymerase chain reaction (PCR) amplification copies of these mRNAs confirm that their sequences correspond with previously reported cDNA sequences. A consensus splice donor site which is conserved in human, baboon, and mouse mRNAs that encode a molecule with an elongated cytoplasmic domain (H-CAM-L) is utilized to generate a distinct but low-abundance mRNA species that encodes H-CAM(CD44) with a truncated cytoplasmic domain of only three amino acids (H-CAM-S). Estimations of the relative abundance of these mRNA species in B-lymphoblastoid cells using the PCR amplification technique exhibit average H-CAM-L/H-CAM-S ratios ranging between 100 and 200. Therefore, H-CAM (CD44)-mediated adhesive events may be regulated through a differential capacity of H-CAM-L and H-CAM-S to interact with the cytoskeleton and to participate in intracellular signaling events.


How to feed cleft patient?
Cleft lip and palate patients have all rights like other normal individuals, to enjoy the benefits of nourishment. Knowledge has to be there about the different feeding positions like straddle, dancer hand position along with the use of specially designed bottles and nipples. Parent's should be trained about the correct positions of feeding, in extreme of the cases in which parents are not able to follow these instructions, feeding obturators can be given. How to cite this article: Jindal MK, Khan SY. How to Feed Cleft Patient? Int J Clin Pediatr Dent 2013;6(2):100-103.


Investigation of the dielectric function of solution-processed InGaZnO films using ellipsometry.
The optical properties of InGaZnO (IGZO) films grown through the sol-gel process as a function of sintering time were investigated with spectroscopic ellipsometry (SE). The IGZO precursor sol was prepared by mixing In nitrate, Ga nitrate, and Zn acetate at a molar ratio of In:Ga:Zn = 3:1:1. The solution was deposited on a SiO2/Si substrate via spin coating. Sintering was performed at 400 degrees C for 1-15 h in an ambient atmosphere. The optical properties were measured over the range 1.12-6.52 eV via variable angle SE, at room temperature. The angle of incidence was varied from 50 to 70 degrees in 5 degree steps. To extract the pure optical properties of IGZO, multilayer-structure calculation with Tauc-Lorentz dispersion relation for IGZO was performed. The changes in the dielectric function of the IGZO films with varying sintering time were observed. The resultant optical properties can be related to the concentration of oxygen vacancies in the material, which can be controlled by the sintering time.


Does corazonin signal nutritional stress in insects?
The undecapeptide corazonin, initially discovered from the American cockroach as a strong cardioaccelerator, is now known to be ubiquitously present in arthropods, although it is absent from some species, notably Coleoptera. The structure of its precursor is similar to the GnRH precursor, while it acts through a receptor related to the GnRH receptor; corazonin thus appears to be an arthropod homolog of GnRH. It is produced by neuroendocrine cells in the brain, as well as interneurons in the ventral nerve cord. These two cell types are generally present in insects; in most species there are also other neurons producing corazonin. Its function in insects has remained obscure; its cardioacceleratory effects are limited to a few cockroach species, while in other species different physiological effects have been described. Most spectacularly it induces changes associated with the gregarious phase in migratory locusts and in the silkworm it reduces the size of the cocoon formed. Corazonin is able to induce ecdysis in two moth species, however locusts and flies in which the corazonin gene is no longer expressed, ecdyse normally and, hence, it is not clear whether corazonin is essential for ecdysis. As the corazonin neuroendocrine cells in the brain express receptors for two midgut peptides, it seems likely that their activity is modulated by the midgut endocrine cells. I propose that in insects corazonin might be released under conditions of nutritional stress, which can explain several of the observed physiological effects of this neurohormone.


Human Ocular Thelaziasis: A Case Report from Indonesia.
Thelaziasis is a parasitic disease caused by a nematode of genus Thelazia, which is rare in the world, including Indonesia. The definitive hosts for Thelazia are canids, felids, mustelids, and other mammals, while the vector is drosophila flies. Consequently, this study reported an uncommon occurrence of human ocular thelaziasis in Indonesia. Based on the patient's complaints and physical examination, we found a living worm that move actively in the anterior chamber; then documentation is carried out both during the examination at the polyclinic and in the operating room. The surgery was performed using topical anaesthesia, clear corneal incision, and removing worm through the main port. Morphological examination from the parasitology laboratory showed that the worm was Thelazia callipaeda species. Following this intervention, the patient was given an oral anti-helminthics drug, topical and oral antibiotics, topical steroid, and surgical treatment. There was no recurrence or appearance of any other symptoms reported in 2 months of follow-up.


Some comments on Lohman (2008): pseudostuttering as a training method.
This letter addresses some issues in Lohman's (2008) article on students' perceptions of face-to-face pseudostuttering experiences. Concerns include the valuation of the pseudostuttering experiences on the telephone as compared to face-to-face experiences in training graduate students in speech-language pathology.


Association Between Adverse Childhood Experiences at Age 5 Years and Healthcare Utilization at Age 9 Years.
To determine associations between adverse childhood experiences (ACEs) at age 5 years and healthcare utilization patterns at age 9 years. We conducted a secondary analysis using longitudinal data from the Fragile Families and Child Wellbeing Study. Caregivers (n = 2521) provided data on their child's ACEs at age 5 years and on 4 types of healthcare utilization at age 9 years: past-year well visits, dental visits, primary care sick visits for injury or illness, and emergency room (ER) visits. Logistic regression analysis was used to examine the association between ACEs at age 5 and each type of healthcare utilization, adjusting for relevant sociodemographic covariates. Among the 2521 children (51% male, 48% Non-Hispanic Black), 77% had ≥1 ACE at age 5. Children with ≥4 ACEs had lower odds of a dental visit (aOR, 0.51; 95% CI, 0.29-0.91) and higher odds of a primary care sick visit (aOR, 1.77; 95% CI, 1.20-2.64) and an ER visit (aOR, 1.70; 95% CI, 1.11-2.59) compared with children with no reported ACEs. Our findings demonstrate suboptimal healthcare utilization patterns among families with ACEs and indicate a need for targeted interventions that support appropriate healthcare utilization for children who endure adversity.


Adaptive sport as affirmation: "We focus on our strengths, not our disabilities".
This paper offers a counter-narrative to the stereotype of people with physical and cognitive impairments being less inclined to participate in athletic activities. It contributes to the affirmative model proposed by Swain and French, which posits a non-tragic view of disability that encompasses positive social identities. We employed the tools of ethnography and phenomenology to explore the adaptive athlete experience among individuals practicing various sports and exhibiting divergent levels of proficiency. Findings confirm the appropriateness of the affirmative model and provide examples of movement from the state of liminality to that of communitas as defined by Victor Turner.


Lead and cadmium contents in pork, beef and chicken, and in pig and cow liver in Finland during 1991.
Nationally representative samples of pork, beef, chicken, and pig's and cow's liver were collected from slaughterhouses and pooled to represent the collection area of each slaughterhouse. The lead (Pb) and cadmium (Cd) contents of the freeze-dried samples were analysed after wet digestion in concentrated HNO3 using ETAAS (Varian Spectra AA 400), Zeeman background correction and (NH4)H2PO4 as the matrix modifier. A strict analytical quality control programme including reference materials and recovery tests was employed. The average Pb content of beef (tenderloin) was 10 micrograms/kg, ground beef 8 micrograms/kg, cow's liver 37 micrograms/kg, pork (regular loin) 9 micrograms/kg, pig's liver 11 micrograms/kg and chicken 6 micrograms/kg. The mean Cd contents of beef, pork and chicken were lower than the limit of detection of the method employed. The mean Cd content of cow's liver was 66 micrograms/kg (cow) and 36 micrograms/kg (heifer) and that of pig's liver 21 micrograms/kg. The contents of lead and cadmium were low in all samples studied, approximately the same level or lower than those found in earlier Finnish studies. These results are in good agreement with the earlier Finnish Market Basket Study in which very low average lead and cadmium intakes were found.


[Whipple's disease as a complication of chronic lymphocytic leukemia treated with fludarabine].
The case of 53-year-old man who suffered from chronic lymphocytic leukemia since 1993 was presented. In the 6th year of treatment fludarabine was administered. Few days after administration of drug the patient developed watery diarrhoea not responding to treatment. We excluded both infectious etiological factors and infiltration of intestine in course of chronic lymphocytic leukemia. Histopathological examination with monoclonal antibodies and periodic acid-Schiff stain (PAS) revealed Whipple's disease as the reason of enteropathy. During 6 months diarrhoea caused extreme dyselectrolitemia, renal insufficiency and finally death of the patient.


Assessment of Irrigation Water Use Efficiency in Citrus Orchards Using AHP.
Irrigation water use efficiency, the small size of the orchards, and part-time farmers are major issues for Spanish citriculture. How should irrigation water use efficiency be assessed? Does irrigation water use efficiency improve when increasing the size of the orchards? Are full-time farmers more efficient in irrigation water use than part-time ones? To address these three questions, we propose to apply a new multicriteria approach based on the analytic hierarchy process (AHP) technique and the participation of a group of experts. A new synthetic irrigation efficiency index (IEI) was proposed and tested using data from an irrigation community (IC) and a cooperative of farmers in the East of Spain. The results showed that the size of the orchards had no relation with the IEI scoring but full-time farmers tended to have better IEI scores and, thus, were more efficient. These results were obtained from a sample of 24 orchards of oranges, navelina variety, growing in a very similar environment, and agronomical characteristics. The proposed methodology can be a useful benchmarking tool for improving the irrigation water management in other ICs taking into account the issues related to farm data sharing recorded during the case study.


Temporal shape error concealment by global motion compensation with local refinement.
This paper presents an original temporal shape error concealment technique based on a combination of global and local motion compensation. For this technique, which is especially useful for object-based video applications in error-prone environments (e.g., mobile networks), it is assumed that the shape of the corrupted object at hand is in the form of a binary alpha plane and some of the shape data is missing due to channel errors. To conceal the corrupted shape, the decoder first assumes that a global motion model can describe the shape changes in consecutive time instants. This way, based on locally estimated global motion parameters, the decoder attempts to conceal the corrupted alpha plane by global motion compensating the shape data from the previous time instant. Afterwards, since a global motion model cannot perfectly describe all alpha plane changes, a local motion refinement is applied to improve the concealment in areas of the object with significant local motion.


New procedures for the confirmation of brain death in Brazil: results from the Central Estadual de Transplantes de Santa Catarina.
To analyze the impact of Resolution 2.173/2017 of the Federal Council of Medicine on results from the Central Estadual de Transplantes de Santa Catarina. This was a cross-sectional observational study of medical records of all patients (1,605) with suspected brain death notified to the Central Estadual de Transplantes de Santa Catarina; for this study, procedures to confirm this diagnosis were initiated between July 2016 and December 2017 and between January 2018 and June 2019. The median duration of the protocol in each period was considered for the comparison between the intervals. The collected data were transformed into rates (per million population). The mean rates for the periods before and after the implementation of the protocol were analyzed by Student's t-test, and qualitative variables were analyzed by Pearson's chi-squared test. The mean duration of brain death confirmation procedures decreased more than 1 hour in the second period compared to the first period, with statistical significance (p = 0.001). The rates of harvested livers and transplanted pancreas, the number of notifications by hospital size and the rate of cardiac arrest in the macro-region of the Itajaí Valley were significantly different between the two periods. In the period after the new resolution on brain death, there was a reduction in the duration for diagnosis. However, other indicators did not change significantly, providing evidence for the multidimensional nature of the organ transplantation process in Santa Catarina and the need for further studies to better understand and optimize the process.


Genetic variation and relationship among content of vitamins, pigments, and sugars in baby leaf lettuce.
Baby leaf lettuce harvested approximately 30 days after planting is the primary component of spring mix salads, a popular type of packaged salads. Very little is known, however, about the content of vitamins, sugars, and pigments in young lettuce plants. Therefore, plants of 42 accessions harvested at baby leaf stage were analyzed for the contents of vitamin C, ß-carotene, anthocyanins, chlorophylls, glucose, fructose, and sucrose. Significant differences among accessions were found for content of all seven compounds plus sucrose sweetness equivalency (SSE) and average vitamin load (AVLAC). "Floricos" was highest in all sugars, SSE and vitamin C; "Taiwan" was highest in ß-carotene and AVLAC, and "Annapolis" and "Darkland" were highest for anthocyanins and chlorophyll contents, respectively. The lowest content of glucose and sucrose was found in iceberg "Salinas," fructose in L. serriola accession UC96US23, vitamin C in PI 257288, and β-carotene in "Solar." The lowest relative sweetness (SSE) was calculated for UC96US23, followed by "Salinas," while the lowest AVLAC was estimated for PI 257288. There were very strong, positive correlations among contents of the three sugars, and between β-carotene and vitamin C, and β-carotene and anthocyanins. Composition profiles of accessions presented in this study, together with identified associations between compounds, can be used by breeders, growers, and producers to select lettuces with desirable combinations of sugars, pigments, and vitamins. This information can help in development of new cultivars and breeding lines with desirable combination of traits, pleasing taste, and higher vitamin content.


Three ubiquitin conjugation sites in the amino terminus of the dopamine transporter mediate protein kinase C-dependent endocytosis of the transporter.
Dopamine levels in the brain are controlled by the plasma membrane dopamine transporter (DAT). The amount of DAT at the cell surface is determined by the relative rates of its internalization and recycling. Activation of protein kinase C (PKC) leads to acceleration of DAT endocytosis. We have recently demonstrated that PKC activation also results in ubiquitylation of DAT. To directly address the role of DAT ubiquitylation, lysine residues in DAT were mutated. Mutations of each lysine individually did not affect ubiquitylation and endocytosis of DAT. By contrast, ubiquitylation of mutants carrying multiple lysine substitutions was reduced in cells treated with phorbol ester to the levels detected in nonstimulated cells. Altogether, mutagenesis data suggested that Lys19, Lys27, and Lys35 clustered in the DAT amino-terminus are the major ubiquitin-conjugation sites. The data are consistent with the model whereby at any given time only one of the lysines in DAT is conjugated with a short ubiquitin chain. Importantly, cell surface biotinylation, immunofluorescence and down-regulation experiments revealed that PKC-dependent internalization of multilysine mutants was essentially abolished. These data provide the first evidence that the ubiquitin moieties conjugated to DAT may serve as a molecular interface of the transporter interaction with the endocytic machinery.


Cardiac arrhythmias during aerobatic flight and its simulation on a centrifuge.
It is well known that accelerations during centrifuge training and during flight can provoke cardiac arrhythmias. Our study was designed to investigate both the similarities and differences between heart rhythm disturbances during flights and centrifuge tests. There were 40 asymptomatic, healthy pilots who performed two training flights and were also tested in a human centrifuge according to a program of rapid onset rate acceleration (ROR) and of centrifuge simulation of the actual acceleration experienced in flight (Simulation). During the flight and centrifuge tests ECG was monitored with the Holter method. ECG was examined for heart rhythm changes and disturbances. During flights, premature ventricular contractions (PVCs) were found in 25% of the subjects, premature supraventricular contractions (PSVCs) and PVCs with bigeminy in 5%, and pairs of PVCs in 2.5% of subjects. During the centrifuge tests, PVCs were experienced by 45% of the subjects, PSVCs and pairs of PVCs by 7.5%, and PVCs with bigeminy by 2.5%. Sinus bradycardia was observed during flights and centrifuge tests in 7.5% of subjects. Comparative evaluation of electrocardiographic records in military pilots during flights and centrifuge tests demonstrated that: 1) there were no clinically significant arrhythmias recorded; and 2) the frequency and kind of heart rhythm disturbances during aerobatic flight and its simulation on a centrifuge were not identical and did not occur repetitively in the same persons during equal phases of the tests.


Targeted downregulation of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase significantly mitigates chondroitin sulfate proteoglycan-mediated inhibition.
Chondroitin sulfate-4,6 (CS-E) glycosaminoglycan (GAG) upregulation in astroglial scars is a major contributor to chondroitin sulfate proteoglycan (CSPG)-mediated inhibition [Gilbert et al. (2005) Mol Cell Neurosci 29:545–558]. However, the role of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S6ST) catalyzed sulfation of CS-E, and its contribution to CSPG-mediated inhibition of CNS regeneration remains to be fully elucidated. Here, we used in situ hybridization to show localized upregulation of GalNAc4S6ST mRNA after CNS injury. Using in vitro spot assays with immobilized CS-E, we demonstrate dose-dependent inhibition of rat embryonic day 18 (E18) cortical neurons. To determine whether selective downregulation of CS-E affected the overall inhibitory character of extracellular matrix produced by reactive astrocytes, single [against (chondroitin 4) sulfotransferase 11 (C4ST1) or GalNAc4S6ST mRNA] or double [against C4ST1 and GalNAc4S6ST mRNA] siRNA treatments were conducted and assayed using quantitative real-time polymerase chain reaction and high-performance liquid chromatography to confirm the specific downregulation of CS-4S GAG (CS-A) and CS-E. Spot and Bonhoeffer stripe assays using astrocyte-conditioned media from siRNA-treated rat astrocytes showed a significant decrease in inhibition of neuronal attachment and neurite extensions when compared with untreated and TGF-treated astrocytes. These findings reveal that selective attenuation of CS-E via siRNA targeting of GalNAc4S6ST significantly mitigates CSPG-mediated inhibition of neurons, potentially offering a novel intervention strategy for CNS injury.


MccE provides resistance to protein synthesis inhibitor microcin C by acetylating the processed form of the antibiotic.
The heptapeptide-nucleotide microcin C (McC) is a potent inhibitor of enteric bacteria growth. McC is excreted from producing cells by the MccC transporter. The residual McC that remains in the producing cell can be processed by cellular aminopeptidases with the release of a non-hydrolyzable aspartyl-adenylate, a strong inhibitor of aspartyl-tRNA synthetase. Accumulation of processed McC inside producing cells should therefore lead to translation inhibition and cessation of growth. Here, we show that a product of another gene of the McC biosynthetic cluster, mccE, acetylates processed McC and converts it into a non-toxic compound. MccE also makes Escherichia coli resistant to albomycin, a Trojan horse inhibitor unrelated to McC that, upon processing, gives rise to a serine coupled to a thioxylofuranosyl pyrimidine, an inhibitor of seryl-tRNA synthetase. We speculate that MccE and related cellular acetyltransferases of the Rim family may detoxify various aminoacyl-nucleotides, either exogenous or those generated inside the cell.


Prevalence and implications of multiple cancer screening needs among Hispanic community health center patients.
To examine adherence rates for multiple cancer screening tests, which will inform prevention efforts in community health centers (CHCs). We report on the prevalence of screening for multiple cancers (cervical, breast and colorectal) among 43,000 patients who are predominantly Hispanic, in four CHC sites that share an integrated electronic medical record. Among the 20,057 patients eligible for at least one test, 43% of the population was current on all screening targets; 15,887 additional screening tests were needed among 11,526 individuals. Expanding use of health information technology in community health centers provides an opportunity to create an electronic infrastructure for addressing multiple screening needs from a patient-centered perspective.


Ameliorative Hematological and Histomorphological Effects of Dietary Trigonella foenum-graecum Seeds in Common Carp (Cyprinus carpio) Exposed to Copper Oxide Nanoparticles.
Different types of metal oxide nanoparticles (NPs) are being used for wastewater treatment worldwide but concerns have been raised regarding their potential toxicities, especially toward non-targeted aquatic organisms including fishes. Therefore, the present study aimed to evaluate the toxicity of copper oxide (CuO) NPs (1.5 mg/L; positive control group) in a total of 130 common carp (Cyprinus carpio), as well as the potential ameliorative effects of fenugreek (Trigonella foenum-graecum) seed extracts (100 mg/L as G-1 group, 125 mg/L as G-2 group, and 150 mg/L as G-3 group) administered to fish for 28 days. Significant changes were observed in the morphometric parameters: the body weight and length of the CuO-NP-treated fish respectively decreased from 45.28 ± 0.34 g and 14.40 ± 0.56 cm at day one to 43.75 ± 0.41 g and 13.57 ± 0.67 cm at day 28. Conversely, fish treated with T. foenum-graecum seed extract showed significant improvements in body weight and length. After exposure to CuO NPs, a significant accumulation of Cu was recorded in the gills, livers, and kidneys (1.18 ± 0.006 µg/kg ww, 1.38 ± 0.006 µg/kg ww, and 0.05 ± 0.006 µg/kg ww, respectively) of the exposed common carp, and significant alterations in fish hematological parameters and oxidative stress biomarkers (lipid peroxidation (LPO), glutathione (GSH), and catalase (CAT)) were also observed. However, supplementing diets with fenugreek extracts modulated the blood parameters and the oxidative stress enzymes. Similarly, histological observations revealed that sub-lethal exposure to CuO NPs caused severe histomorphological changes in fish gills (i.e., degenerative epithelium, fused lamellae, necrotic lamellae, necrosis of primary lamellae, complete degeneration, and complete lamellar fusion), liver (i.e., degenerative hepatocytes, vacuolization, damaged central vein, dilated sinusoid, vacuolated degeneration, and complete degeneration), and kidney (i.e., necrosis and tubular degeneration, abnormal glomerulus, swollen tubules, and complete degeneration), while the treatment with the fenugreek extract significantly decreased tissue damage in a dose-dependent manner by lowering the accumulation of Cu in the selected fish tissues. Overall, this work demonstrated the ameliorative effects of dietary supplementation with T. foenum-graecum seed extract against the toxicity of NPs in aquatic organisms. The findings of this study therefore provided evidence of the promising nutraceutical value of fenugreek and enhanced its applicative potential in the sector of fish aquaculture, as it was shown to improve the growth performance and wellness of organisms.


Effect of a High-Fat Meal on Single-Dose Rencofilstat (CRV431) Oral Bioavailability in Healthy Human Subjects.
Rencofilstat (RCF) is a novel cyclophilin inhibitor under development for the treatment of nonalcoholic steatohepatitis and hepatocellular carcinoma. This phase 1, randomized, open-label study in healthy participants assessed the relative bioavailability of a single dose of RCF 225-mg soft gelatin capsules in both fasted and high-fat conditions. Forty-four participants were enrolled to either the fasted (n = 24) or the high-fat fed (n = 20) arm. Noncompartmental pharmacokinetics were evaluated following a single 225-mg oral dose. Administration of RCF with a high-fat meal led to increases in maximum concentration, area under the concentration-time curve (AUC) from time 0 to 24 hours, and AUC from time 0 to infinity fed-to-fasted geometric mean ratios of 102.2%, 114.5%, and 132.9%, respectively. All AUC geometric mean ratios were outside of the 80% to 125% range, suggesting that a high-fat meal can increase the extent of RCF exposure. Time to maximum concentration increased from 1.5 to 1.8 hours in the fasted and high-fat groups, respectively, suggesting slightly delayed absorption. High fat intake may delay gastric emptying while increasing the absorption and bioavailability of RCF. No treatment-emergent adverse events were observed in the fasted group, and 1 treatment-emergent adverse event occurred in the high-fat meal group. The differences in observed whole-blood concentrations are unlikely to have clinically relevant effects given the wide therapeutic index of RCF demonstrated in previous phase 1 studies.


Feeding and foraging of wild and sterile Mediterranean fruit flies (Diptera: Tephritidae) in the presence of spinosad bait.
The sterile insect technique (SIT) is used to control wild Mediterranean fruit fly introductions in California and Florida in the U.S. In the past, bait sprays containing malathion proved invaluable in treating new outbreaks or large populations before the use of SIT. Recently, a spinosad protein bait spray, GF-120, has been developed as a possible alternative to malathion, the standard insecticide in protein bait sprays. In this study, protein-deficient and protein-fed Vienna-7 (sterile, mass-reared, "male-only" strain) flies and wild males and females were evaluated to determine the effectiveness of the GF-120 protein bait containing spinosad with respect to bait attraction, feeding, and toxicology. There were no effects of diet or fly type on feeding duration in small laboratory cages. Wild flies, however, registered more feeding events than Vienna-7 males. Flies that fed longer on fresh bait died faster. Protein-deficient flies were more active and found the bait more often than protein-fed flies. Data suggest that adding protein to the diet of SIT flies may decrease their response to baits, therefore, reduce mortality, and thus, allow the concurrent use of SIT and bait sprays in a management or eradication program.


High-Fat Diet Increases HMGB1 Expression and Promotes Lung Inflammation in Mice Subjected to Mechanical Ventilation.
This study aims to evaluate the effects of a high-fat diet and mechanical ventilation on the pulmonary and systemic inflammatory response in C57BL/6 mice. Male C57BL/6 mice were divided into two groups: one received a standard diet, and the other received a high-fat diet. After 10 weeks, the groups were further divided into two groups each: control group (CG), mechanical ventilation group (MVG), diet group (DG), and diet mechanical ventilation group (DMVG). MVG and DMVG underwent mechanical ventilation for 60 minutes. All animals were euthanized for subsequent analysis. Animals receiving a high-fat diet presented higher body mass, adipose index, and greater adipocyte area. In the lung, the expression of HMGB1 was greater in DG and DMVG than in CG and MVG. CCL2 and IL-22 levels in MVG and DMVG were increased compared to those in CG and DG, whereas IL-10 and IL-17 were decreased. Superoxide dismutase activity was higher in MVG and DMVG than in CG. Catalase activity was lower in DG than in CG, and in MV groups, it was lower than that in CG and DG. MV and obesity promote inflammation and pulmonary oxidative stress in adult C57BL/6 mice.


Sinusoidal-amplitude binary phase mask and its application in achieving an ultra-long optical needle.
Optical needle has become a hot research topic in recent years, due to the excellent properties and potential applications. To achieve a sub-diffraction optical needle, there are three common methods including planar diffractive lenses, reflective mirrors or axicons, and high-NA objective lenses with the designed phase or amplitude elements. Here, we propose a new kind of designed phase and amplitude element called the sinusoidal-amplitude binary phase mask (SA-BPM), which modulates the amplitude and phase distributions of the incident vector optical fields (VOFs) simultaneously. Based on Richards-Wolf vector diffraction integral, the corresponding parameters of SA-BPM and the optimal optical needle length are calculated by exhaustive method and genetic algorithm. We further upgrade the SA-BPM by adding a Gaussian function in the amplitude modulation, and design the Gaussian SA-BPM (GSA-BPM). We find that the ultra-long optical needles are achieved with the SA-BPM and GSA-BPM, and the depth of focus of the optical needles are improved by 30%-70% compared with the case of binary phase mask. Such SA-BPM and GSA-BPM we proposed have great potential for manipulation and utilization of the ultra-long optical needles.


Changing dynamical complexity with time delay in coupled fiber laser oscillators.
We investigate the complexity of the dynamics of two mutually coupled systems with internal delays and vary the coupling delay over 4 orders of magnitude. Karhunen-Loève decomposition of spatiotemporal representations of fiber laser intensity data is performed to examine the eigenvalue spectrum and significant orthogonal modes. We compute the Shannon information from the eigenvalue spectra to quantify the dynamical complexity. A reduction in complexity occurs for short coupling delays while a logarithmic growth is observed as the coupling delay is increased.


Accelerating bone healing in vivo by harnessing the age-altered activation of c-Jun N-terminal kinase 3.
We have recently demonstrated that c-Jun N-terminal kinase 3 (JNK3) is a key modulator of the enhanced osteogenic potential of stem cells derived from children when compared to those derived from adults. In this study, we formulated a JNK3-activator nanoparticle (JNK3*) that recapitulates the immense osteogenic potential of juvenile cells in adult stem cells by facilitating JNK3 activation. Moreover, we aimed to functionalize a collagen-based scaffold by incorporating the JNK3* in order to develop an advanced platform capable of accelerating bone healing by recruitment of host stem cells. Our data, in vitro and in vivo, demonstrated that the immense osteogenic potential of juvenile cells could be recapitulated in adult stem cells by facilitating JNK3 activation. Moreover, our results revealed that the JNK3* functionalized 3D scaffold induced the fastest bone healing and greatest blood vessel infiltration when implanted in critical-size rat calvarial defects in vivo. JNK3*scaffold fastest bone healing in vivo was associated with its capacity to recruit host stem cells to the site of injury and promote angiogenic-osteogenic coupling (e.g. Vegfa, Tie1, Runx2, Alp and Igf2 upregulation). In summary, this study has demonstrated the potential of harnessing knowledge of age-altered stem cell mechanobiology in order to develop a materials-based functionalization approach for the repair of large tissue defects.


Shared learning from a physiologically based pharmacokinetic modeling strategy for human pharmacokinetics prediction through retrospective analysis of Genentech compounds.
The quantitative prediction of human pharmacokinetics (PK) including the PK profile and key PK parameters are critical for early drug development decisions, successful phase I clinical trials, and the establishment of a range of doses to enable phase II clinical dose selection. Here, we describe an approach employing physiologically based pharmacokinetic (PBPK) modeling (Simcyp) to predict human PK and to validate its performance through retrospective analysis of 18 Genentech compounds for which clinical data are available. In short, physicochemical parameters and in vitro data for preclinical species were integrated using PBPK modeling to predict the in vivo PK observed in mouse, rat, dog, and cynomolgus monkey. Through this process, the in vitro to in vivo extrapolation (IVIVE) was determined and then incorporated into PBPK modeling in order to predict human PK. Overall, the prediction obtained using this PBPK-IVIVE approach captured the observed human PK profiles of the compounds from the dataset well. The predicted Cmax was within 2-fold of the observed Cmax for 94% of the compounds while the predicted area under the curve (AUC) was within 2-fold of the observed AUC for 72% of the compounds. Additionally, important IVIVE trends were revealed through this investigation, including application of scaling factors determined from preclinical IVIVE to human PK prediction for each molecule. Based upon the analysis, this PBPK-based approach now serves as a practical strategy for human PK prediction at the candidate selection stage at Genentech.


Fatal Shigella sepsis in a neutropenic patient.
Bacteremia during infection with Shigella is relatively rare and usually self-limited. Bacteremia during shigellosis bearing a high fatality rate has been reported in young infants and in persons with malnutrition or with the acquired immunodeficiency syndrome. We report a case of Shigella sonnei septicemia in a severely neutropenic patient who had fever, abdominal pain, diarrhea, malnutrition, and dehydration. She died after five days despite intensive care. We emphasize that Shigella should be considered among the possible pathogens causing sepsis in neutropenic patients.


Measuring symptoms in the irritable bowel syndrome: development of a framework for clinical trials.
There is uncertainty about how to measure patient-reported outcomes (PROs) in IBS. The Food and Drug Administration (FDA) emphasizes that PROs must be couched in a conceptual framework, yet existing IBS PROs were not based on such a framework. To perform qualitative analyses to inform a new conceptual framework for IBS symptoms. Following FDA guidance, we searched the literature for extant IBS questionnaires. We then performed interviews in IBS patients to learn about the illness experience in their own words. We cultivated vocabulary to inform a conceptual framework depicted with domains, sub-domains, and item categories, per FDA guidance. We identified 13 questionnaires with items encompassing 18 symptoms. We recruited 123 IBS patients for cognitive interviews. Major themes included: pain and discomfort are different - asking about discomfort is nonspecific and should be avoided in future PROs; bowel urgency is multifaceted - PROs should measure bowel immediacy, controllability, and predictability; and PROs should divide bloating into how it feels vs. how it looks. Symptom experience may be determined by 35-item categories within five domains: (i) pain; (ii) gas/bloat; (iii) diarrhoea; (iv) constipation; and (v) extraintestinal symptoms. We applied FDA guidance to develop a framework that can serve as the foundation for developing a PRO for IBS clinical trials.


The impact of immigration on env HIV-1 subtype distribution among heterosexuals in the Netherlands: influx of subtype B and non-B strains.
To examine the epidemiological factors influencing the distribution and spread of HIV-1 subtypes among heterosexuals in the Netherlands. A nationwide serosurveillance in 21 HIV/AIDS centres from 1997 to 1999 involved 200 individuals for whom the mode of HIV transmission was heterosexual contact or unknown. HIV-1 subtypes were determined by phylogenetic analysis of env V3 sequences and correlated with sociodemographic characteristics of the subjects and their sexual partners. HIV-1 subtype B infection occurred in 121 subjects (60%). Non-B subtypes were identified in 31 (A), 24 (C), 10 (D), six (E), four (F) and three (G) individuals; one had an unclassified subtype. The proportion of subtype B was about 60% in four of the six regions of the Netherlands, but in the Northwest and Southwest regions these proportions were 76% and 46%, respectively. The Surinamese and Antilleans, large immigrant groups, were all infected with subtype B, as were almost all individuals with an unknown source. The proportions of non-B viruses did not change significantly over time in Amsterdam, where subtyping was available from 1988 onward, but a shift in the various subtype B strains was observed, suggesting introductions of new subtype B strains in Amsterdam. To date, HIV-1 non-B subtypes in the Netherlands are still found predominantly among heterosexuals with an epidemiological link with sub-Saharan Africa. Despite continuing introductions of non-B subtypes, the B/non-B distribution has been stable over time, most likely as a result of introductions of subtype B strains from Caribbean and South American countries.


Photocatalyzed sulfide oxygenation with water as the unique oxygen atom source.
In our research program aiming to develop new ruthenium-based polypyridine catalysts for oxidation we were interested in combining a photosensitizer and a catalytic fragment within the same complex to achieve catalytic light-driven oxidation. To respond to the lack of such conjugates, we report here a new catalytic system capable of using light to activate water molecules in order to perform selective sulfide oxygenation into sulfoxide via an oxygen atom transfer from H(2)O to the substrate with a TON of up to 197 ± 6. On the basis of electrochemical and photophysical studies, a proton-coupled electron-transfer process yielding to an oxidant Ru(IV)-oxo species was proposed. In particular, the synergistic effect between both partners in the dyad yielding a more efficient catalyst compared to the bimolecular system is highlighted.


Intelligent Tire Sensor-Based Real-Time Road Surface Classification Using an Artificial Neural Network.
Vehicles today have many advanced driver assistance control systems that improve vehicle safety and comfort. With the development of more sophisticated vehicle electronic control and autonomous driving technology, the need and effort to estimate road surface conditions is increasing. In this paper, a real-time road surface classification algorithm, based on a deep neural network, is developed using a database collected through an intelligent tire sensor system with a three-axis accelerometer installed inside the tire. Two representative types of network, fully connected neural network (FCNN) and convolutional neural network (CNN), are learned with each of the three-axis acceleration sensor signals, and their performances were compared to obtain an optimal learning network result. The learning results show that the road surface type can be classified in real-time with sufficient accuracy when the longitudinal and vertical axis acceleration signals are trained with the CNN. In order to improve classification accuracy, a CNN with multiple input that can simultaneously learn 2-axis or 3-axis acceleration signals is suggested. In addition, by analyzing how the accuracy of the network is affected by number of classes and length of input data, which is related to delay of classification, the appropriate network can be selected according to the application. The proposed real-time road surface classification algorithm is expected to be utilized with various vehicle electronic control systems and makes a contribution to improving vehicle performance.