Prediction of amyloidogenic and disordered regions in protein chains.
The determination of factors that influence protein conformational changes is very important for the identification of potentially amyloidogenic and disordered regions in polypeptide chains. In our work we introduce a new parameter, mean packing density, to detect both amyloidogenic and disordered regions in a protein sequence. It has been shown that regions with strong expected packing density are responsible for amyloid formation. Our predictions are consistent with known disease-related amyloidogenic regions for eight of 12 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Our findings support the concept that the mechanism of amyloid fibril formation is similar for different peptides and proteins. Moreover, we have demonstrated that regions with weak expected packing density are responsible for the appearance of disordered regions. Our method has been tested on datasets of globular proteins and long disordered protein segments, and it shows improved performance over other widely used methods. Thus, we demonstrate that the expected packing density is a useful value with which one can predict both intrinsically disordered and amyloidogenic regions of a protein based on sequence alone. Our results are important for understanding the structural characteristics of protein folding and misfolding.


Multiple indicators of sexual interest in prepubescent or pubescent children as predictors of sexual recidivism.
Sexual interest in children is a well-known risk factor for sexual reoffending (recidivism). The present study examined the relationship between sexual interest in prepubescent children (pedophilia) or pubescent children (hebephilia) and sexual recidivism. It extended previous work by using multiple indicators of sexual interest, using a more sensitive phallometric procedure that measures change in penile blood volume, and examining both hebephilia alongside pedophilia, as well as noncontact sexual recidivism. Six hundred fifty-six men who had committed a sexual offense underwent a comprehensive sexological assessment that included multiple sexual interest measures: volumetric phallometry, self-report, and sexual behavior. Criminal record data were acquired to examine recidivism. Offenders were followed for an average of 10 years of opportunity. Indicators of hebephilia and pedophilia were significantly associated with noncontact sexual recidivism, but inconsistently associated with contact recidivism. The relationship with phallometrically assessed pedophilia and contact sexual recidivism was significant after controlling for offender age statistically. Phallometrically assessed sexual arousal to children did not add to risk appraised by an actuarial measure. Both hebephilia and pedophilia were predictive of noncontact sexual recidivism. The results for contact sexual recidivism are discussed, including a potential confound in previous work on the assessment of sexual interest in children. (PsycINFO Database Record


Lacteal junction zippering protects against diet-induced obesity.
Excess dietary lipid uptake causes obesity, a major global health problem. Enterocyte-absorbed lipids are packaged into chylomicrons, which enter the bloodstream through intestinal lymphatic vessels called lacteals. Here, we show that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of Neuropilin1 (Nrp1) and Vascular endothelial growth factor receptor 1 (Vegfr1; also known as Flt1) renders mice resistant to diet-induced obesity. Absence of NRP1 and FLT1 receptors increased VEGF-A bioavailability and signaling through VEGFR2, inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by VEGFR2 and vascular endothelial (VE)-cadherin signaling inhibition rescued chylomicron transport in the mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal VE-cadherin anchors prevented chylomicron uptake in wild-type mice. These data suggest that lacteal junctions may be targets for preventing dietary fat uptake.


An evaluation of precordial ultrasonic monitoring to avoid bends at altitude.
Several investigators have reported that intravascular bubbles can be detected in decompressed subjects before they develop bends. The altitude exposures were generally of short duration with a limited number of subjects. This important preliminary finding needed to be verified in a larger sampling of long duration altitude exposures. In this experiment, 32 subjects in 82 flights were taken to 27,500 ft simulated altitude for 8 h or until the subject developed mild but steady joint pain (bends). Many subjects took more than one flight. At altitude, the subjects were monitored for circulating bubbles by a team of well-trained, experienced technicians. It was determined that bubbles, clearly audible even to untrained observers, occurred in 77% of the flights in which the subjects developed bends. On the other hand, no bubbles were found in 61% of the flights in which the subjects remained bends free even though the subjects were monitored by more than one experienced technician. Therefore, at 27,500 ft ultrasonic monitoring will miss about 25% of the subjects who developed bends (false negatives) and will incorrectly identify a little less than half of the subjects who do not develop bends as potential benders (false positives).


Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.
During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)


Modeling Reference Production as the Probabilistic Combination of Multiple Perspectives.
While speakers have been shown to adapt to the knowledge state of their addressee in choosing referring expressions, they often also show some egocentric tendencies. The current paper aims to provide an explanation for this "mixed" behavior by presenting a model that derives such patterns from the probabilistic combination of both the speaker's and the addressee's perspectives. To test our model, we conducted a language production experiment, in which participants had to refer to objects in a context that also included a visually misleading object (e.g., a crayon shaped like a Lego brick) whose function was either known to both partners, or known just to the speaker but not the addressee. Modeling results indicate that the experimental findings cannot be explained by assuming that speakers tailor a referring expression solely to their own perspective or to the perspective of their addressee. Instead, accounting for the behavioral pattern requires an approach where both perspectives influence the choice of referring expressions. Nevertheless, in our situation, speakers consider their partner's perspective more than their own.


Mouse models of breast cancer in preclinical research.
Breast cancer remains the second leading cause of cancer death among woman, worldwide, despite advances in identifying novel targeted therapies and the development of treating strategies. Classification of clinical subtypes (ER+, PR+, HER2+, and TNBC (Triple-negative)) increases the complexity of breast cancers, which thus necessitates further investigation. Mouse models used in breast cancer research provide an essential approach to examine the mechanisms and genetic pathway in cancer progression and metastasis and to develop and evaluate clinical therapeutics. In this review, we summarize tumor transplantation models and genetically engineered mouse models (GEMMs) of breast cancer and their applications in the field of human breast cancer research and anti-cancer drug development. These models may help to improve the knowledge of underlying mechanisms and genetic pathways, as well as creating approaches for modeling clinical tumor subtypes, and developing innovative cancer therapy.


Phase stability and site preference of Tb-Fe-Co-V compounds.
The effect of cobalt on the structural properties of intermetallic Tb₃Fe(₂₇.₄-x)Co(x)V₁.₆ with Nd₃(Fe,Ti)₂₉ structure has been studied by using interatomic pair potentials obtained through the lattice inversion method. Calculated results show that the preferential occupation site of the V atom is found to be the 4i(Fe3) site, and Fe atoms are substituted for Co atoms with a strong preference for the 8j(Fe8) site. The calculated lattice constants coincide quite well with experimental values. The calculated crystal structure can recover after either an overall wide-range macrodeformation or atomic random motion, demonstrating that this system has the stable structure of Nd₃(Fe,Ti)₂₉. All these prove the effectiveness of interatomic pair potentials obtained through the lattice inversion method in the description of rare-earth materials.


[Neuromediators in dermatology. Therapeutic prospectives].
Neuropeptides are neurotransmitters and neurohormones that play a role in various cutaneous functions. Keratinocytes and dermal endothelial cells are able to synthesize neuropeptides which are transported by nerve fibers or immune cells. Specific receptors for neuropeptides are also present on cutaneous cells. Neuropeptides intervene as neurogenic modulators of inflammatory reactions and therefore participate in the pathogenesis of skin diseases. An increasing body of evidence supports the setting up of clinical trials using topically neuropeptide agonists and/or antagonists in the treatment of chronic inflammatory skin disorders such as post-herpetic neuralgia, prurigo nodularis, localized pruritus, psoriasis, atopic dermatitis, contact dermatitis, cold urticaria, nostalgia paresthetica, diabetic neuropathy, Raynaud's phenomenon. In the near future, neuropeptides will represent a new approach to skin therapy.


JAVA Memory Care program: Facilitating social and occupational engagement for older adults living with advanced dementia.
Residents in aged care homes often report lack of life purpose and meaning and limited opportunities to contribute to their community. The JAVA Memory Care program is designed to facilitate engagement for older adults with advanced dementia. This study explored whether JAVA Memory Care engaged such adults meaningfully, on social and occupational levels, within one Australian residential care home. A mixed method design guided this exploration. Trained staff facilitated six JAVA groups over 2 months. Three sources of data were utilised. Observational data (qualitative and quantitative) were obtained using a narratively enhanced Assessment Tool for Social and Occupational Engagement (ATOSE). The other two data sources were qualitative and analysed thematically: reflections by the lead JAVA facilitator and data generated by a research discussion group. The quantitative data comprised 564 ATOSE behaviour markers. Participants were categorised as being engaged in 93% of these markers. Two of the three qualitative themes focused on the collective and self-expressive nature of participant engagement. The third theme focused on practicalities such as time pressures, facilitator training, resident selection, and resource preparation. For residents, the groups provided a context for relating meaningfully to others. The JAVA program achieved a high level of engagement. However, it was a time intensive intervention and required a person-centred philosophy, appropriate staff training, organisational support, and a suitable quiet space. The program had positive benefits, but practical issues identified needed to be considered before implementation.


Cyclophosphamide, etoposide, and infusion cisplatin in refractory small cell lung cancer. A preliminary report.
Twelve patients (three with limited and nine with extensive disease) with small cell carcinoma of the lung who had plateaued or progressed on their chemotherapeutic regimens were switched to a program of combination chemotherapy consisting of cyclophosphamide, etoposide, and a 5-day continuous infusion of cisplatin. Nine of the 12 patients (75%) showed further tumor reduction, including four patients who achieved a clinical complete response. Also noted was a patient who previously failed on a regimen of short infusion cisplatin who responded to the continuous infusion platinum regimen. Toxicity was quite acceptable, considering the amount of prior treatment given these patients. Further studies seem warranted to confirm these encouraging preliminary results.


Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells.
Radioresistance in pre-irradiated human HT-R15 cells is associated with changes of the TNFR1-dependent death pathway. HT-R15 cells are characterized by elevated protein levels of TNFR1 and TNF and by increased sensitivity to exogenous TNFalpha compared to their parental HT-29 cells. Alterations are also observed downstream in the signaling cascade, such as the activation of NF-kappaB or the overexpression of the death domain kinase RIP and reduced caspase 8 activity. However, these changes seem to be a consequence of defective upstream TNFalpha signaling rather than the primary cause of cellular resistance in HT-R15 cells. Of major importance for resistance in HT-R15 cells is the silencer of death domain, SODD/BAG4. Following gamma-irradiation, the membrane-associated 49 kDa SODD decreases in the parental but not in the resistant cells, whereas after TNFalpha treatment, SODD expression declines only in the resistant cells. A 42 kDa cytoplasmic SODD protein is detected, which is elevated only in the resistant cells. This SODD protein is not involved in the regulation of cell survival after radiation or TNFalpha treatment but rather in altered TNFR1 shedding. Inhibition of TNFR1 release by the metalloprotease inhibitor BB-2516 results in a significant increase of the 42 kDa SODD protein without affecting cell survival in sensitive or resistant HT cells. Moreover, TNFR1 release into the culture medium is augmented in the resistant cells. These results suggest that defective TNFalpha signaling and/or altered silencing by SODD/BAG4 in HT-R15 cells are involved in the radiation resistance of HT-R15 cells and also affect the paracrine functions of TNFR1. Resistance is circumvented by TNFalpha treatment, independent of cytoplasmic TNFalpha/TNFR1 functions.


Exciton-polariton mediated superconductivity.
We revisit the exciton mechanism of superconductivity in the framework of microcavity physics, replacing virtual excitons as a binding agent of Cooper pairs by excitations of an exciton-polariton Bose-Einstein condensate. We consider a model microcavity where a quantum well with a two-dimensional electron gas is sandwiched between two undoped quantum wells, where a polariton condensate is formed. We show that the critical temperature for superconductivity dramatically increases with the condensate population, opening a new route towards high-temperature superconductivity.


Effect of chemical fogging on immature Aedes mosquitoes in natural field conditions.
Dengue and dengue haemorrhagic fever are common and serious arboviral diseases endemic in a number of countries situated in both the tropical and subtropical belts. A prospective study was carried out to examine the environmental factors influencing the ovipositing behaviour of gravid female Aedes mosquitoes in a typical urbanised residential environment in Malaysia. This study reports the effect of the usual ultra-low volume fogging of insecticides carried out by public health officers on the collection of immature Aedes mosquitoes using ovitraps. Throughout the study, no dead immature Aedes mosquitoes was noted in any of the ovitraps set up in all of the fogging and immediate post-fogging periods. The mean number of days of ovitrapping for immediate pre-fogging, fogging and post-fogging periods were 10.3, 10.1 and 10.4 days, respectively. There was no statistically significant difference in the mean duration of ovitrapping cycle among the immediate pre-fogging, fogging and immediate post-fogging periods. The total number of immature Aedes mosquitoes collected in the immediate post-fogging periods was more than the immediate pre-fogging periods, and both were more than the fogging periods. However, there was no statistically significant difference in the total number of immature Aedes mosquitoes collected at various periods. It was not unusual to find dead insects, spiders and even small animals collected in ovitraps or environment in the fogged locality within 48 hours of chemical fogging. In this study, the usual chemical fogging in natural environment was ineffective in breaking the reproductive lifecycle by eliminating gravid female Aedes mosquitoes.


Giant Rashba splitting in one-dimensional atomic tellurium chains.
The search for a one-dimensional (1D) system with purely 1D bands and strong Rashba spin splitting is essential for the realization of Majorana fermions and spin transport but presents a fundamental challenge to date. Herein, using first-principles calculations, we demonstrated that atomic Tellurium (Te) chains exhibit purely 1D bands and giant Rashba spin splitting, and their splitting parameters depend strongly on strain and structure distortion. This phenomenon stems from the helical structure of atomic Te chains, which can not only sustain significant strain but also realize the synergy of orbital angular momentum and in-chain potential gradient in enhancing spin splitting. The structure distortion of stretched helical Te chains is critical to execute this synergy, generating a large Rashba spin splitting among the known systems. Our findings proposed a potential 1D giant Rashba splitting system for exploring spintronics and Majorana fermions, and provide routes for engineering spin splitting in other materials.


Pleomorphic adenoma with extensive lipometaplasia: report of three cases.
We report a series of three cases of pleomorphic adenoma with extensive lipometaplasia, a recently described subtype of pleomorphic adenoma of salivary gland origin. Two patients were female and one male, ranging in age from 30 to 45 years. Two occurred in the minor salivary glands of the lip and palate, respectively, and one in the parotid. Typical histologic findings are presented. In addition, one case consists of a proliferation of spindle cells with an interesting combination of mature adipose tissue, hyaline cartilage, and bone in the absence of ductal structures. The differential diagnosis, as it pertains to other fat-containing tumors (such as lipoadenoma, spindle cell lipoma, interstitial lipomatosis, and benign mesenchymoma), is discussed. It is likely that the ability of myoepithelial cells to undergo various metaplasias is the cause of the unusual histologic appearances of this tumor.


Comparison of Cumulative Live Birth Rates Between GnRH-A and PPOS in Low-Prognosis Patients According to POSEIDON Criteria: A Cohort Study.
To compare the cumulative live birth rate (CLBR) of a gonadotropin-releasing hormone (GnRH) antagonist regimen and a progestin-primed ovarian stimulation (PPOS) regimen in low-prognosis patients according to POSEIDON criteria. Single-center, retrospective, observational study. Henan Provincial People's Hospital, Zhengzhou, China. Women aged ≤40 years, with a body mass index <25 kg/m2, who underwent in vitro fertilization (IVF) or intracytoplasmic sperm microinjection (ICSI) and met POSEIDON low-prognosis criteria. GnRH or PPOS regimen with IVF or ICSI. CLBR per oocyte retrieval cycle. Per oocyte retrieval cycle, CLBR was significantly higher with GnRH antagonist versus PPOS (35.3% vs 25.2%; P<0.001). In multivariable logistic regression analysis, CLBR per oocyte retrieval cycle was significantly lower with PPOS versus GnRH antagonist before (OR 0.62 [95% confidence intervals (CI): 0.46, 0.82; P=0.009]) and after (OR 0.66 [95% CI: 0.47, 0.93; P=0.0172]) adjustment for age, body mass index, infertility type, infertility duration, baseline follicle stimulating hormone, anti-Müllerian hormone (AMH), antral follicle count (AFC), and insemination method. CLBR was numerically higher with the GnRH antagonist regimen than with PPOS, across all of the POSEIDON groups, and was significantly higher in patients aged ≥35 years with poor ovarian reserve [AFC <5, AMH <1.2 ng/mL] (unadjusted, P=0.0108; adjusted, P=0.0243). In this single-center, retrospective, cohort study, patients had a higher CLBR with a GnRH antagonist versus PPOS regimen, regardless of other attributes.


[Systemic sclerosis after a long-term follow-up].
The authors suggest some remarks on the aetiopathogenesis of systemic sclerosis through a critical review of a group of 51 patients affected by this disease for many years. In this paper the authors report their previous studies regarding the correlation of immunological response, both cell-mediated and humoral, hemocoagulative aspects and haemorheological changes. From the results of immunological studies, the authors report a long-term treatment with an immunomodulating drug: thymopentin. Moreover they report a recent work about the connection among stressor event, production of endothelin-1 (ET-1) and serum levels of some stress hormones such as possible pathogenetic factors of Raynaud's phenomenon and of scleroderma. This work ends with a proposal of a pathogenetic scheme that, even if it doesn't exclude an infective pathogenesis, considers stress as a factor able to switch on a series of psycho-neuro-immunoendocrinological reactions that can support, through the activation of lymphocytes, fibroblastic proliferation and finally fibrosis.


Mechanisms of Drug Solubility Enhancement Induced by β-Lactoglobulin-Based Amorphous Solid Dispersions.
Protein-based amorphous solid dispersions (ASDs) have emerged as a promising approach for enhancing solubility in comparison to crystalline drugs. The dissolution behavior of protein-based amorphous solid dispersions (ASDs) was investigated in various pH media. ASDs of four poorly soluble model drugs with acidic (furosemide and indomethacin), basic (carvedilol), and neutral (celecoxib) properties were prepared by spray drying at 30 wt % drug loading with the protein β-lactoglobulin (BLG). The effect of spray-dried BLG (SD-BLG) solubility and protein binding ability with dissolved drugs in solution were investigated to retrieve the mechanisms governing the improvement of drug solubility from the BLG-based ASDs. Powder dissolution results showed that all ASDs obtained a higher maximum concentration (Cmax) compared to the respective pure crystalline drugs. It was found that the solubility increase of the drugs from the ASDs was to a large extent dependent on the solubility of the pure SD-BLG at the investigated pH values (low solubility at pH near the isoelectric point (pI) of BLG). Furthermore, drug-protein interactions in a solution were observed, in particular at pH values where the drugs were neutral. These drug-protein interactions also resulted, to some extent, in the stabilization of the drug in supersaturation.


Use of microfluidics to sort stallion sperm for intracytoplasmic sperm injection.
We determined if microfluidic sorting (MF) of frozen-thawed stallion sperm improves sperm population characteristics and results in embryo development after intracytoplasmic sperm injection (ICSI). The efficiency and efficacy of MF sperm separation was evaluated by comparing pre- and post-separation sperm population variables. Procedural comparisons were performed after sorting with MF, single-layer colloidal centrifugation (SLC) or swim-up (SU), and cleavage and embryo development were evaluated after ICSI using MF-sorted sperm. In Experiment 1, when compared to the original sperm sample, MF sorting resulted in a sperm subpopulation with greater motility, morphology, viability, and membrane as well as DNA integrity. After sorting by MF, SLC and SU in Experiment 2, motility, viability, and membrane integrity were similar for sperm sorted using MF and SLC; however, morphology and DNA integrity were greater in sperm sorted using MF when compared with SLC. Swim-up was the least effective sorting method. In Experiment 3, sperm were processed using MF and SLC prior to ICSI. Motility, morphology and DNA integrity were similar for sperm subpopulations sorted using either method; but viability was greater for sperm sorted using MF than SLC. Sorting did not improve sperm membrane integrity. Sorting with MF prior to ICSI resulted in similar cleavage and blastocyst development rates as SLC. We concluded that MF separation of stallion sperm resulted in a subpopulation with improved sperm population parameters, comparable or better than SLC and SU. Embryos were produced after ICSI using MF sperm sorting.


Misconceptions and Malpractices Toward Antibiotic Use in Childhood Upper Respiratory Tract Infections Among a Cohort of Lebanese Parents.
Antimicrobial resistance is an emerging global health threat. Misuse and abuse of antibiotics are of particular concern in the pediatric population. Since management of childhood illnesses depends considerably on parents' perceptions, the objectives of this study were to report parents' perspectives and assess their practices toward antibiotics used for upper respiratory tract infections (URTIs) in children. Using a cross-sectional design, anonymous structured questionnaires were completed by 1,037 parents in public and private schools across Lebanon's largest governorate. Descriptive statistics were used to report participants' responses. A multivariate analysis was performed to identify factors affecting knowledge and malpractice related to antibiotic use. Significant misconceptions and malpractices were identified among parents. For instance, 33.9% of parents considered that antibiotics are helpful in treating common cold among children and 36.2% believed antibiotics expedite the recovery of their child with common cold infection. Moreover, there was a lack of knowledge concerning antibiotic coverage, since 37.9% of the respondents believed that antibiotics treat viral infections and 21.5% were neutral toward this question. Around 20% of the participants believed they can reduce the dose of antibiotics if the child gets better. Significant factors associated with poor knowledge and misuses were parents' lower educational and socioeconomic levels. Despite extensive evidence on the limited role of antibiotics in URTIs, parents in Lebanon continue to misuse them. More concerted efforts are needed to improve parents' knowledge and practices with regard to the rational use of antibiotics.


Decorating a liquid interface promotes splashing.
We report on the role of a surfactant monolayer in the impact of small spheres on an air-water interface. We observe that an air cavity (splashing) is induced above a threshold impact velocity. We explore the dependence of this threshold velocity on the bath surface tension and on the bath viscosity using water-ethanol and water-glycerol mixtures, respectively. Interestingly, the threshold velocity for air entrainment is reduced by the presence of a stearic acid monolayer because the hydrophobic tails favor the forced entry of air during the sphere's impact. More generally, we show that this threshold velocity is determined by the wettability of the sphere by the bath, which can equivalently be controlled by tuning the bath properties (presence of a monolayer) or the sphere surface properties (via a surface treatment). These results provide insight into recently developed vesicle production techniques based on the impact of drops or jets on a lipid layer.


Vertical effect of the adjustable Harada-Ito procedure.
The adjustable Harada-Ito procedure, as described by Metz, was performed on four patients. A hypotropia of 10 to 12 prism diopters (PD), in addition to incyclotorsion, was induced in two patients in whom the superior oblique tendon was split 8 mm, only enough to permit mobilization to its new location. Splitting the tendon for 15 mm eliminated the induced hypotropia while preserving incyclotorsion.


Investigation of the effect of fly ash content on the bonding performance of CFRP-concrete interface in sulfate environment.
The present study focuses on the investigation of the interfacial bond behavior of carbon fiber-reinforced polymer (CFRP)-concrete under dry-wet sulfate cycles by double-sided shear testing. Besides, the effects of fly ash content on the interfacial failure characteristics, interfacial debonding bearing capacity, CFRP strain distribution, and interfacial shear stress peak were analyzed. The interfacial debonding capacity, maximum CFRP strain, and peak value of interfacial shear stress of the CFRP-concrete interface decreased with increasing erosion time under the sulfate dry-wet cycle's action, according to the sulfate dry-wet cycle test results. The sulfate resistance of the CFRP-concrete interface increased after the addition of fly ash. However, the final decrease amplitude of interfacial debonding capacity, CFRP maximum strain, and maximum interfacial shear stress all reduced as the fly ash content increased. The effective bond length of the interface gradually increased with increasing erosion time; however, the change in fly ash content had little effect on the effective bond length, and the final effective bond length of the samples with different fly ash content was the same. Moreover, the CFRP-concrete interfacial bearing capacity model under the sulfate dry-wet cycle was established by introducing sulfate's comprehensive influence coefficient and considering fly ash content's influence. In conclusion, the comparative analysis of the prediction model and test results revealed that the prediction model could well reflect the degradation law of interfacial debonding bearing capacity with sulfate attack time.


Novel Aspects of Extracellular Vesicles in the Regulation of Renal Physiological and Pathophysiological Processes.
Extracellular vesicles (EV) are nanosized particles released by a large variety of cells. They carry molecules such as proteins, RNA and lipids. While urinary EVs have been longer studied as a source of biomarkers for renal and non-renal disorders, research on EVs as regulatory players of renal physiological and pathological processes has experienced an outbreak recently in the past decade. In general, the microenvironment and (patho)physiological state of the donor cells affect the cargo of the EVs released, which then determines the effect of these EVs once they reach a target cell. For instance, EVs released by renal epithelial cells modulate the expression and function of water and solute transporting proteins in other cells. Also, EVs have been demonstrated to regulate renal organogenesis and blood flow. Furthermore, a dual role of EVs promoting, but also counteracting, disease has also been reported. EVs released by renal tubular cells can reach fibroblasts, monocytes, macrophages, T cells and natural killer cells, thus influencing the pathogenesis and progression of renal disorders like acute kidney injury and fibrosis, nephrolithiasis, renal transplant rejection and renal cancer, among others. On the contrary, EVs may also exert a cytoprotective role upon renal damage and promote recovery of renal function. In the current review, a systematic summary of the key studies from the past 5 years addressing the role of EVs in the modulation of renal physiological and pathophysiological processes is provided, highlighting open questions and discussing the potential of future research.


Effect of side-chain structures on gene transfer efficiency of biodegradable cationic polyphosphoesters.
Cationic polyphosphoesters (PPEs) with different side-chain charge groups were designed and synthesized as biodegradable gene carriers. Poly(N-methyl-2-aminoethyl propylene phosphate) (PPE-MEA), with a secondary amino group (-CH(2)CH(2)NHCH3) side chain released DNA in several hours at N/P (amino group of polymer to phosphate group of DNA) ratios from 0.5 to 5; whereas PPE-HA, bearing -CH(2)(CH2)(4)CH(2)NH(2) groups in the side chain, did not release DNA at the same ratio range for 30 days. Hydrolytic degradation and DNA binding results suggested that side chain cleavage, besides the polymer degradation, was the predominant factor affected the DNA release and transfection efficiencies. The side chain of PPE-MEA was cleaved faster than that of PPE-HA, resulting poor cellular uptake and no transgene expression for PPE-MEA/DNA complexes in COS-7 cells at charge ratios from 4 to 12. In contrast, PPE-HA/DNA complexes were stable enough to be internalized by cells and effected gene transfection (3400 folds higher than background at a charge ratio of 12). Interestingly, gene expression levels mediated by PPE-MEA and PPE-HA in mouse muscle following intramuscular injection of complexes showed a reversed order: PPE-MEA/DNA complexes mediated a 1.5-2-fold higher luciferase expression in mouse muscle as compared with naked DNA injection, while PPE-HA/DNA complexes induced delayed and lowered luciferase expression than naked DNA. These results suggested that the side chain structure is a crucial factor determining the mechanism and kinetics of hydrolytic degradation of PPE carriers, which in turn influenced the kinetics of DNA release from PPE/DNA complexes and their transfection abilities in vitro and in vivo.


Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients.
Early protein and energy feeding in critically ill patients is heavily debated and early protein feeding hardly studied. A prospective database with mixed medical-surgical critically ill patients with prolonged mechanical ventilation (>72 hours) and measured energy expenditure was used in this study. Logistic regression analysis was used to analyse the relation between admission day-4 protein intake group (with cutoffs 0.8, 1.0, and 1.2 g/kg), energy overfeeding (ratio energy intake/measured energy expenditure > 1.1), and admission diagnosis of sepsis with hospital mortality after adjustment for APACHE II (Acute Physiology and Chronic Health Evaluation II) score. A total of 843 patients were included. Of these, 117 had sepsis. Of the 736 non-septic patients 307 were overfed. Mean day-4 protein intake was 1.0 g/kg pre-admission weight per day and hospital mortality was 36%. In the total cohort, day-4 protein intake group (odds ratio (OR) 0.85; 95% confidence interval (CI) 0.73 to 0.99; P = 0.047), energy overfeeding (OR 1.62; 95%CI 1.07 to 2.44; P = 0.022), and sepsis (OR 1.77; 95%CI 1.18 to 2.65; P = 0.005) were independent risk factors for mortality besides APACHE II score. In patients with sepsis or energy overfeeding, day-4 protein intake was not associated with mortality. For non-septic, non-overfed patients (n = 419), mortality decreased with higher protein intake group: 37% for < 0.8 g/kg, 35% for 0.8 to 1.0 g/kg, 27% for 1.0 to 1.2 g/kg, and 19% for ≥ 1.2 g/kg (P = 0.033). For these, a protein intake level of ≥ 1.2 g/kg was significantly associated with lower mortality (OR 0.42, 95%CI 0.21 to 0.83, P = 0.013). In non-septic critically ill patients, early high protein intake was associated with lower mortality and early energy overfeeding with higher mortality. In septic patients early high protein intake had no beneficial effect on mortality.


Genome Evolution of a Symbiont Population for Pathogen Defense in Honeybees.
The honeybee gut microbiome is thought to be important for bee health, but the role of the individual members is poorly understood. Here, we present closed genomes and associated mobilomes of 102 Apilactobacillus kunkeei isolates obtained from the honey crop (foregut) of honeybees sampled from beehives in Helsingborg in the south of Sweden and from the islands Gotland and Åland in the Baltic Sea. Each beehive contained a unique composition of isolates and repeated sampling of similar isolates from two beehives in Helsingborg suggests that the bacterial community is stably maintained across bee generations during the summer months. The sampled bacterial population contained an open pan-genome structure with a high genomic density of transposons. A subset of strains affiliated with phylogroup A inhibited growth of the bee pathogen Melissococcus plutonius, all of which contained a 19.5 kb plasmid for the synthesis of the antimicrobial compound kunkecin A, while a subset of phylogroups B and C strains contained a 32.9 kb plasmid for the synthesis of a putative polyketide antibiotic. This study suggests that the mobile gene pool of A. kunkeei plays a key role in pathogen defense in honeybees, providing new insights into the evolutionary dynamics of defensive symbiont populations.


Screening of Anti-Inflammatory Components of Qin Jin Hua Tan Tang by a Multivariate Statistical Analysis Approach for Spectrum-Effect Relationships.
Qing Jin Hua Tan Tang (QJHTT) exerts therapeutic effects in patients with chronic obstructive pulmonary disease (COPD) by alleviating inflammation. However, the anti-inflammatory components of QJHTT have not yet been reported. Our study aimed to screen the active anti-inflammatory components of QJHTT using a multivariate statistical analysis approach for spectrum-effect relationships. Different polar fractions of QJHTT were prepared using ethanol, ethyl acetate, and n-butanol to analyze the phytochemical components. Phytochemical fingerprints were generated using ultrahigh-performance liquid chromatography. In total, 24 peaks were observed in ten batches of QJHTT extracts. The anti-inflammatory activity was evaluated using a xylene-induced ear-swelling mouse model. Additionally, the spectrum-effect relationship between the relative areas of the 24 peaks and pharmacological activity was investigated using multivariate statistical analysis. The potential anti-inflammatory ingredients obtained from the screening (multivariate statistical analysis) will be validated for their anti-inflammatory effects and mechanisms utilizing a lipopolysaccharide-induced macrophage inflammation model. QJHTT ethanol extract 1 exhibited good anti-inflammatory activity. Peaks 11, 12, 13, 14, and 16, which were closely correlated with anti-inflammatory activity, were identified as meranzin, baicalin, baicalein, chrysin-7-O-β-D-glucuronide, and wogonoside, respectively. The anti-inflammatory activities of meranzin, baicalin, baicalein, and wogonoside were verified in vitro. These four bioactive components significantly inhibited the secretion of inflammatory factors in the lipopolysaccharide-stimulated macrophage cell line. This research successfully screened the QJHTT anti-inflammatory active ingredient group. Meranzin, baicalin, baicalein, chrysin-7-O-β-D-glucuronide, and wogonoside were predicted to be the anti-inflammatory active ingredient groups of QJHTT.


[Surgery on virtual model and 3-dimensional printing of a surgical wafer for the correction of a severe mandibular asymmetry].
Correction of a severe facial asymmetry presents a challenge due to the geometric complexity of the dentition, the bony structures and the soft tissues. In most asymmetric cases two-jaw surgery is recommended. Manual model surgery is an essential part of treatment planning but it can be complicated, time-consuming and may contain potential errors. We present a case of a 26-year-old male with a severe right-sided hemimandibular elongation when computerized simulation surgery was performed instead of manual model surgery. High-resolution computer tomography scan was done following presurgical orthodontics and the stack images were reformatted into a three-dimensional structure. The symmetry of the maxilla was corrected via a virtual Le Fort I osteotomy with the help of a three-dimensional planning software. A virtual intermediate surgical wafer was designed and fabricated with a three-dimensional printer. Virtual bilateral sagittal split osteotomy was performed and the mandible was rotated into the correct position to visualize the movements of the osteotomized segments. Real surgery was accomplished according to the virtual plan. The splint fitted well. There is a significant improvement in the facial symmetry; the occlusion is good and stable. This case supports the usage of computer-aided surgical planning and three-dimensional rapid prototyping for the correction of facial asymmetries.


Vector correlations in photodissociation of polarized polyatomic molecules beyond the axial recoil limit.
We present the full quantum mechanical theory of the angular momentum distributions of photofragments produced in photolysis of oriented/aligned parent polyatomic molecules beyond the axial recoil limit. This paper generalizes the results of Underwood and Powis(28,29) to the case of non-axial recoil photodissociation of an arbitrary polyatomic molecule. The spherical tensor approach is used throughout this paper. We show that the recoil angular distribution of the angular momentum polarization of each of the photofragments can be presented in a universal spherical tensor form valid for photolysis in diatomic or polyatomic molecules, irrespective of the reaction mechanism. The angular distribution can be written as an expansion over the Wigner D-functions in terms of the set of the anisotropy-transforming coefficients c(K(i)q(i))(K) (k(d), K(0)) which contain all of the information about the photodissociation dynamics and can be either determined from experiment, or computed from quantum mechanical theory. An important new conservation rule is revealed through the analysis, namely that the component q(i) of the initial reagent polarization rank K(i) and the photofragment polarization rank K onto the photofragment recoil direction k is preserved in any photolysis reaction. Both laboratory and body frame expressions for the recoil angle dependence of the photofragment angular momentum polarization are presented. The parent molecule polarization is shown to lead to new terms in the obtained photofragment angular distributions compared with the isotropic case. In particular, the terms with |q(i)| > 2 can appear which are shown to manifest angular momentum helicity non-conservation in the reaction. The expressions for the coefficients c(K(i)q(i))(K) (k(d), K(0)) have been simplified using the quasiclassical approximation in the high-J limit which allows for introducing the dynamical functions and the rotation factors which describe the decreasing of the photofragment angular momentum orientation and alignment due to the rotation of the molecular axis during photodissociation. In this case, the resultant recoil angle dependence is also presented in a form where the anisotropy of the parent molecular ensemble is expressed in terms of the molecular axis distribution, rather than in terms of the molecular density matrix.


Aleutian disease in ferrets.
When 32 antibody-free ferrets were inoculated with the highly mink-virulent Utah-1 strain of Aleutian disease virus (ADV), most developed ADV antibody starting 15 days after infection, but the antibody titers were much lower than those seen in mink. Relatively small amounts of ADV were demonstrated in CRFK cell culture, using ferret spleen and lymph node homogenates only 4 to 10 days after experimental infection, but low-level viral persistence for 180 days was shown by mink inoculation. The ferrets inoculated with the Utah-1 strain of ADV did not develop elevated gamma globulin levels, but did have mild tissue lesions. Forty-two percent of a group of 214, approximately 1-year-old, recently pregnant, female ferrets were found to have antibody to ADV. An analysis of the serum proteins of the ferrets with ADV antibody showed that they had a significant, but mild, elevation of their serum gamma globulin. Serial ferret-to-ferret transmission of a ferret strain of ADV by inoculation of spleen homogenates was demonstrated, and some of these ferrets developed liver lesions. Mink inoculated with ferret ADV made antibody, but did not develop hypergammaglobulinemia or tissue lesions. Although both ferret and mink strains of ADV replicate and persist in the ferret, they fail to cause severe disease of the type usually seen in the closely related mink. Mink and ferret ADV strains appear to be biologically distinct.


Seasonal alterations in the daily rhythms in hypothalamic expression of genes involved in the photoperiodic transduction and neurosteroid-dependent processes in migratory blackheaded buntings.
The present study investigated seasonal alterations in the daily rhythms of hypothalamic expression of genes involved in the photoperiodic regulation of annual cycles in birds. We measured the 4-hourly mRNA expression of genes involved in the photoperiodic transduction (OPN5, EYA3, CGA, TSHβ, DIO2, DIO3) and neurosteroid-dependent processes (AR, CYP19, ERα, ERβ) in the hypothalamus of migratory blackheaded buntings photoinduced with photosensitive, photostimulated (early and late stimulated) and photorefractory seasonal states. There were significant differences in daily mRNA profiles between the photoperiodic states. Particularly, increased CGA, TSHβ and DIO2 and decreased DIO3 mRNA levels in the early photostimulated state, compared to the photosensitive state, suggest that thyroid hormones have a role in photostimulation in buntings. Similar differences in the expression of genes coding for the aromatase enzyme (CYP19) and receptors for oestrogen (ERα, ERβ) (but not androgen; AR) indicate that there is seasonal alteration in the neuro-oestrogen-mediated functions. Furthermore, peak expression times of CGA, TSHβ and DIO2 genes at hours 14-15 of the day in the early stimulated state indicated molecular regulation of the daily rhythm of photoinducibility in buntings. Most significantly, however, we found an attenuated daily rhythm in thyroid hormone modulatory genes and a switch of peak expression time from day to night in CYP19 mRNA rhythm in the subsequent late photostimulated state, although testicular maturation still persisted. These alterations in daily rhythms may have signalled the initiation of processes underlying other seasonal phenologies in parallel with the gonadal response, such as a manifestation of the night-time flight in buntings. These results show alterations in daily rhythms underlying the transcriptional regulation of the photoperiod-induced seasonal states in migratory blackheaded buntings.


1H-Azepine-4-amino-4-carboxylic acid: a new α,α-disubstituted ornithine analogue capable of inducing helix conformations in short Ala-Aib pentapeptides.
A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.


Drug-induced ego states. I. Cocaine: phenomenology and implications.
The ego state experienced by chronic users of cocaine is described in terms of sensorimotor functioning, cognitive functioning, emotionality, spatiality , temporality , causality, and materiality . At low use levels the state is pleasurable, but at high levels fear, anxiety, and paranoia increase, and ultimately reality contact breaks down. Q-sort, Semantic Differential, and other data suggest that low-level users take cocaine to overcome personal insecurities and relieve boredom. Heavy users take it to support overvaulting ambitions and intense strivings for self-sufficiency. Psychotherapy with such persons must deal with their counterdependency , anger, and despair, and with their underlying sense of betrayal . These persons have unacknowledged needs for spiritual experience that must be dealt with openly. A description of persons most vulnerable to heavy use of cocaine is provided, and recommendations for research and social policy are presented.


Synthesis and dopaminergic activity of (+/-)-, (+)-, and (-)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene.
In an effort to identify further the structural requirements for central dopamine receptor agonists, some monohydroxyl analogs of the known agonist 5,6-dihydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene were synthesized. They were examined for production of emesis in dogs and stereotyped behavior in rats. The most potent was 5-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, which was more potent than apomorphine but less so than the dihydroxyl analog. The two enantiomers of the monohydroxyl analog were synthesized by conventional methods from an optically active intermediate, 2-benzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene. The resolution of this amine was performed with the aid of mandelic acid. Dopaminergic activity was found to be confined to the levo enantiomer. Requirements for both substitution and chirality in the tetralines were found to correspond closely to those known for the dopaminergic aporphines.


Cathepsin-B induced controlled release from peptide-capped mesoporous silica nanoparticles.
New capped silica mesoporous nanoparticles for intracellular controlled cargo release within cathepsin B expressing cells are described. Nanometric mesoporous MCM-41 supports loaded with safranin O (S1-P) or doxorubicin (S2-P) containing a molecular gate based on a cathepsin B target peptidic sequence were synthesized. Solids were designed to show "zero delivery" and to display cargo release in the presence of cathepsin B enzyme, which selectively hydrolyzed in vitro the capping peptide sequence. Controlled delivery in HeLa, MEFs WT, and MEFs lacking cathepsin B cell lines were also tested. Release of safranin O and doxorubicin in these cells took place when cathepsin B was active or present. Cells treated with S2-P showed a fall in cell viability due to nanoparticles internalization, cathepsin B hydrolysis of the capping peptide, and cytotoxic agent delivery, proving the possible use of these nanodevices as new therapeutic tools for cancer treatment.


Low Risk of Persistent Pain, Sensory Disturbances, and Complications Following Mastectomy After Gender-Affirming Surgery.
Purpose: In recent years, there has been a significant increase in referrals for gender-affirming surgery to departments of plastic surgery in Denmark. There is currently no literature on postsurgical pain in trans men after mastectomy. We aimed at investigating the prevalence and severity of postsurgical persistent pain, sensory disturbances, and complications in trans men after mastectomy. Methods: The 90 trans men who underwent bilateral mastectomy between September 1, 2013 and August 31, 2018 were included. Patients' files were evaluated for complications, and 84 (response rate 93.3%) patients answered a questionnaire (validated for women undergoing oncologic mastectomy) regarding persistent pain and sensory disturbances. Results: Twenty-three patients (27.4%) reported either unilateral or bilateral persistent pain after mastectomy. Of these, 14 (60.9%) patients categorized the pain as mild. However, 77 (95.2%) of the patients did not use analgesics and nonopioid pain medication was sufficient for the remainder. Sensory disturbances were found in 44 (47.5%) of the patients, and 4 (4.8%) patients reported clear signs of neuropathic pain. Seven (7.8%) patients developed hematomas, and areola necrosis was seen in four (4.4%) patients. Due to infection, seven (7.8%) patients received antibiotics. Conclusion: Mastectomy as a part of gender-affirming surgery is a safe procedure with a few, nonsevere, complications. Although a quarter of the patients experienced persistent pain, the majority of that pain is mild, intermittent and can be treated with nonopioid pain medication.


[Management protocol in gastroschisis].
There are two classical managements in gastroschisis: primary or delayed closure. From 2007 on, a multidisciplinary approach protocol based in preterm caesarean delivery at 34-35th gestational age (in order to minimize peel injury) plus primary closure is followed in our institution. Prior to this, term delivery, either by caesarean section or not, was the rule. Retrospective study of gastroschisis's patients before (1978-2006) and after (2007-2016) protocol approval. Complex gastroschisis frequency, peel's presence, primary or delayed closure, complications, re-interventions, neonatal intensive care unit (NICU) length of stay, age at onset of enteral nutrition, total parenteral nutrition's length and length of stay were compared. Study groups: before (12 patients) and after (13 newborns) the protocol implantation (pre/post). Nine complex gastroschisis were observed in the pre-protocol period, compared to one in the post-protocol era (p= 0.001). The re-interventions also decreased: 58.33% in the pre-protocol vs. 15.38% in the post-protocol group (p= 0.025). Complications rate were 66.67% before protocol vs. 23.07% after protocol (p= 0.028). NICU length of stay decreased from 40 ± 32 to 17 ± 12 days (p= 0.025). Parenteral total nutrition length was 61 ± 36 in the pre-protocol vs. 15 ± 6 in the port-protocol eras, respectively (p= 0.043). The age at onset of enteral nutrition was 34 ± 26 vs. 9 ± 5 days (p= 0.004) and hospitalization length was 98 ± 81 days pre vs. 35 ± 15 days post protocol implantation (p= 0.011). The protocol implantation has allowed primary closure, decreased hospitalization; reduced complications and mortality rate as well.


Longitudinal risk factors for suicidal thoughts in depressed and non-depressed young adolescents.
Evidence regarding the role of risk factors in the longitudinal course of suicidal ideation among young adolescents is lacking. We aimed to assess the effects of a range of risk factors, including obesity, academic performance, child-parent relationship, physical maltreatment, and depressive symptoms, on the development of suicidal ideation in young adolescents. A school cohort of seventh and eighth graders was followed for 1 year and differences in the risk factors distributions were examined between depressed and non-depressed adolescents. We further examined risk factors for newly developed suicidal ideation and persistent suicidal ideation in the groups of adolescents based on the presence of suicidal ideation at baseline. A total of 1710 young adolescents were recruited, among whom 8.2% were categorised as having clinically significant depression. For depressed adolescents, being obese was associated with a three-fold increased risk of having suicidal ideation. For non-depressed adolescents, physical maltreatment, a feeling of not being cared about and sub-threshold depressive symptoms were the risk factors. The latter two remained robust in predicting newly developed suicidal ideation. The current study may shed light on the differential strategies to address suicidal thoughts in depressed and non-depressed adolescents. We emphasise the importance of recognition and management of sub-threshold depressive symptoms and the relevance of obesity, physical maltreatment and a feeling of not being cared about to suicide prevention programmes in early adolescence.


MqsR/MqsA Toxin/Antitoxin System Regulates Persistence and Biofilm Formation in Pseudomonas putida KT2440.
Bacterial toxin/antitoxin (TA) systems have received increasing attention due to their prevalence, diverse structures, and important physiological functions. In this study, we identified and characterized a type II TA system in a soil bacterium Pseudomonas putida KT2440. This TA system belongs to the MqsR/MqsA family. We found that PP_4205 (MqsR) greatly inhibits cell growth in P. putida KT2440 and Escherichia coli, the antitoxin PP_4204 (MqsA) neutralizes the toxicity of the toxin MqsR, and the two genes encoding them are co-transcribed. MqsR and MqsA interact with each other directly in vivo and MqsA is a negative regulator of the TA operon through binding to the promoter. Consistent with the MqsR/MqsA pair in E. coli, the binding of the toxin MqsR to MqsA inhibits the DNA binding ability of MqsA in P. putida KT2440. Disruption of the mqsA gene which induces mqsR expression increases persister cell formation 53-fold, while overexpressing mqsA which represses mqsR expression reduces persister cell formation 220-fold, suggesting an important role of MqsR in persistence in P. putida KT2440. Furthermore, both MqsR and MqsA promote biofilm formation. As a DNA binding protein, MqsA can also negatively regulate an ECF sigma factor AlgU and a universal stress protein PP_3288. Thus, we revealed an important regulatory role of MqsR/MqsA in persistence and biofilm formation in P. putida KT2440.


Multicomponent strategy to indeno[2,1-c]pyridine and hydroisoquinoline derivatives through cleavage of carbon–carbon bond.
A concise and efficient three-component domino reaction has been developed for the synthesis of polyfunctionalized indenopyridine and hydroisoquinoline derivatives via the cleavage of a C–C bond under transition-metal-free conditions. This reaction provides facile access to complex nitrogen-containing heterocycles by simply mixing three common starting materials in EtOH in the presence of 20 mol % NaOH under microwave irradiation conditions.


Hands-on experience can lead to systematic mistakes: A study on adults' understanding of sinking objects.
In line with theories of embodied cognition, hands-on experience is typically assumed to support learning. In the current paper, we explored this issue within the science domain of sinking objects. Adults had to make a guess about which of two objects in a pair would sink faster. The crucial manipulation was whether participants were handed real-life objects (real-objects condition) or were shown static images of objects (static-images condition). Results of Experiment 1 revealed more systematic mistakes in the real-objects than the static-images condition. Experiment 2 investigated this result further, namely by having adults make predictions about sinking objects after an initial training. Again, we found that adults made more mistakes in the real-objects than the static-images condition. Experiment 3 showed that the negative effect of hands-on experiences did not influence later performance. Thus, the negative effects of hands-on experiences were short-lived. Even so, our results call into question an undifferentiated use of manipulatives to convey science concepts. Based on our findings, we suggest that a nuanced theory of embodied cognition is needed, especially as it applies to science learning.


The evaluation of the immunomodulating properties of ERA-63 a pharmaceutical with estrogenic activity.
This paper describes studies performed with ERA-63 a low molecular weight pharmaceutical with intended immunomodulatory effects. Since this compound was also known to have estrogenic activity a non-conventional approach was taken in order to differentiate between estrogenic and non-estrogenic-induced immunomodulatory effects. EE was included not only for qualitative comparison (hazard identification) between immunomodulatory effects but also, in case of similar effects, to facilitate the extrapolation of the findings in the rat to anticipated effects in humans. After 28 days of treatment with dosages ranging from pharmacological up to clearly toxic levels for both compounds the immunotoxic potential was assessed by performing a T cell-dependent antibody response and a host resistance assay in rats. Selected ERA-63 dose levels (0.167-0.2, 1.67-2 and 16.7-20mg/kg) were expected to have comparable estrogenic activity to respective EE dose levels (0.05, 0.5 and 5mg/kg). General toxicity parameters reflecting estrogenic activity (i.e. decreased body- and organ weights of thymus and testis, and increased bilirubin and GGT levels) confirmed the comparable estrogenic activity for both compounds at the dose levels tested. Together with the comparable estrogen-related immune suppression (i.e. decreases in specific antibody responses and an increased susceptibility for Listeria monocytogenes infects) for both compounds, this indicates that available clinical data for EE facilitates the human risk assessment of ERA-63.


Chronic periodontitis and risk of cerebro-cardiovascular diseases among older Koreans.
There is a relative lack of evidence from observational studies of older populations investigating the association between chronic periodontitis and cerebro-cardiovascular diseases. Accordingly, we investigated the risk of cerebro-cardiovascular diseases according to the severity of chronic periodontitis among older adults. Data on older adults with chronic periodontitis were extracted from the Korea National Health Insurance Service-Senior Cohort Database using diagnosis codes and dental procedures. Participants were divided into two exposure groups. Among 46 737 participants eligible for inclusion, 21 905 (46.9%) had newly diagnosed mild chronic periodontitis, and 24 832 (53.1%) had newly diagnosed severe chronic periodontitis. To determine the risk of cerebro-cardiovascular diseases, including ischemic stroke, haemorrhagic stroke, and myocardial infarction, multivariable-adjusted Cox proportional hazards modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) in this retrospective follow-up study. A total of 3453 (7.4%) outcomes were identified during a mean follow-up of 6.1 years. Kaplan-Meier analysis revealed that disease-free probability was lower in the severe group than in the mild group (log-rank P < .001). In the multivariable-adjusted model, the HR for cerebro-cardiovascular diseases in the severe group (relative to the mild group) was 1.16 (95% CI: 1.09-1.25). In individual outcome analysis, ischemic stroke and myocardial infarction were associated with chronic periodontitis severity, but haemorrhagic stroke was not. The severity of chronic periodontitis could be associated with the risk of cerebro-cardiovascular diseases in older adults.


[Comparison of roxithromycin bioavailability of a conventional and a dispersible tablet formulation].
Following oral administrations of a single dose of 150 mg roxithromycin dispersible tablet (formulation A, a new formulation for clinical trial) and conventional tablet (formulation B, purchased from the market) to each of 10 healthy male volunteers in a randomized crossover design, the plasma levels of active drug at different times were determined by a microbial assay with Micrococcus luteus CMCC (B) 28001 and the plasma concentration-time profiles were obtained. The Tmax values of formulation A and B obtained were 1.7 +/- 0.9 and 3.7 +/- 1.6 h, the Cmax values were 4.97 +/- 1.17 and 2.04 +/- 1.26 micrograms.ml-1 and the AUC0-->infinity values were 62.2 +/- 11.9 and 35.0 +/- 16.9 micrograms.h.ml-1, respectively. Surprisingly, the relative bioavailability of formulation B was found to be only 59.8% +/- 32.6% (P < 0.01). The low bioavailability of the latter formulation was attributed to poor release of roxithromycin in the gastric site, which was proposed as a key factor to influence drug absorption. Other related factors were also discussed.


Downregulation of circETS1 disrupts Th17/Treg homeostasis by inhibiting FOXP3 transcription: A new potential biomarker in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with an imbalance of T helper 17 (Th17) to regulatory T cells (Tregs). However, the underlying mechanism remains unclear. Increasing evidence suggests that circular RNAs play a crucial role in SLE. Although circETS1 was discovered 30 years ago, detailed exploration of its functions remains limited. In this study, we measured the expression levels of circETS1 in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells of patients with SLE by quantitative polymerase chain reaction. The impact of circETS1 expression on the Th17/Treg balance and underlying mechanism were evaluated using double-luciferase reporter, gain-/loss-of-function, and rescue assays. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic value of circETS1. Both circETS1 and FOXP3 expression were downregulated in the PBMCs and CD4+ T cells of patients with SLE (n = 28) compared with those in the cells of healthy controls (n = 20). Mechanistically, we found that circETS1 can bind directly to the microRNA miR-1205, acting as a sponge to upregulate the transcription of FOXP3, thereby maintaining the Th17/Treg balance. Notably, ROC analysis showed that the expression level of circETS1 in PBMCs had an area under the curve of 0.873 (95% confidence interval: 0.771-0.976; p < .001) for diagnosing SLE, with a sensitivity of 80.00% and a specificity of 89.29%. Finally, we found negative correlations between the level of circETS1 in PBMCs and disease severity (according to the Systemic Lupus Erythematosus Disease Activity Index) in patients with SLE (r = -0.7712, 95% CI: -0.8910 to -0.5509; p < .001). The imbalance in Th17/Treg cells in SLE may be attributed, in part, to the circETS1/miR-1205/FOXP3 pathway. CircETS1 has potential to serve as a valuable biomarker for the diagnosis and evaluation of SLE.


Mitochondrial cascade hypothesis of Alzheimer's disease: myth or reality?
Mitochondria are recognized to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. Morphologic, biochemical, and molecular genetic studies suggest that mitochondria might be a convergence point for neurodegeneration, including Alzheimer's disease (AD). The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress. However, the question, "Is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. This review presents the ways in which malfunctioning mitochondria and oxidative stress might contribute to neuronal death in AD.


Confinement Effects for Lithium Borohydride: Comparing Silica and Carbon Scaffolds.
LiBH4 is a promising material for hydrogen storage and as a solid-state electrolyte for Li ion batteries. Confining LiBH4 in porous scaffolds improves its hydrogen desorption kinetics, reversibility, and Li+ conductivity, but little is known about the influence of the chemical nature of the scaffold. Here, quasielastic neutron scattering and calorimetric measurements were used to study support effects for LiBH4 confined in nanoporous silica and carbon scaffolds. Pore radii were varied from 8 Å to 20 nm, with increasing confinement effects observed with decreasing pore size. For similar pore sizes, the confinement effects were more pronounced for silica than for carbon scaffolds. The shift in the solid-solid phase transition temperature is much larger in silica than in carbon scaffolds with similar pore sizes. A LiBH4 layer near the pore walls shows profoundly different phase behavior than crystalline LiBH4. This layer thickness was 1.94 ± 0.13 nm for the silica and 1.41 ± 0.16 nm for the carbon scaffolds. Quasi-elastic neutron scattering confirmed that the fraction of LiBH4 with high hydrogen mobility is larger for the silica than for the carbon nanoscaffold. These results clearly show that in addition to the pore size the chemical nature of the scaffold also plays a significant role in determining the hydrogen mobility and interfacial layer thickness in nanoconfined metal hydrides.


Testing Pediatric Emergency Telemedicine Implementation Strategies Using Quality Improvement Methods.
Background: Despite the recognized benefits of telemedicine use for pediatric emergency consultations, there are barriers to the widespread uptake of this technology. Quality improvement methods can be used to rapidly test implementation strategies. Our objective was to test telemedicine implementation strategies in real-world application using quality improvement methods. Our quality improvement aim was to achieve high rates of telemedicine use for pediatric transfer consultations. Methods: A multidisciplinary multisite improvement team identified that key drivers of increasing telemedicine use included telemedicine resource awareness, streamlined telemedicine workflow, provider buy-in, and data transparency. Interventions focused on telemedicine trainings, disseminating telemedicine uptake data, telemedicine reminders, telemedicine test calls, and preparing for telemedicine use for every transfer consultation. The outcome measure was percentage of pediatric emergency transfer consultations that used telemedicine. The balancing measure was time (minutes) from the initial transfer center call to completion of the consultation. Results: Multiple plan-do-study-act cycles were associated with special cause variation, with an upward shift in mean percentage of telemedicine use from 5% to 22%. Time from initial call to consultation completion remained unchanged. Conclusion: Our study supports the use of quality improvement methods to test telemedicine implementation strategies for pediatric telemedicine emergency consultations.


Virus infection of culturable chlorella-like algae and dlevelopment of a plaque assay.
Four distinct viruses with double-stranded DNA are known to replicate in Chlorella-like algae symbiotic with hydras and paramecia. An attempt was made to infect a number of cultured Chlorella strains derived from invertebrate hosts with these viruses. One of the viruses, PBCV-1, replicated in two of the algal strains. Restriction endonuclease analysis of the viral DNA showed that the infectious progeny virus was identical to the input virus; thus, Koch's postulates were fulfilled. Viral infection of the two Chlorella strains has allowed the large-scale production of a eukaryotic algal virus and the development of a plaque assay for the virus.


BMTP-11 is active in preclinical models of human osteosarcoma and a candidate targeted drug for clinical translation.
Osteosarcoma occurs predominantly in children and young adults. High-grade tumors require multidisciplinary treatment consisting of chemotherapy in the neoadjuvant and adjuvant settings, along with surgical intervention. Despite this approach, death from respiratory failure secondary to the development and progression of pulmonary metastases remains a significant problem. Here, we identify the IL-11 receptor α subunit (IL-11Rα) as a cell surface marker of tumor progression that correlates with poor prognosis in patients with osteosarcoma. We also show that both IL-11Rα and its ligand, IL-11, are specifically up-regulated in human metastatic osteosarcoma cell lines; engagement of this autocrine loop leads to tumor cell proliferation, invasion, and anchorage-independent growth in vitro. Consistently, IL-11Rα promotes lung colonization by human metastatic osteosarcoma cells in vivo in an orthotopic mouse model. Finally, we evaluate the IL-11Rα-targeted proapoptotic agent bone metastasis-targeting peptidomimetic (BMTP-11) in preclinical models of primary intratibial osteosarcomas, observing marked inhibition of both tumor growth and lung metastases. This effect was enhanced when BMTP-11 was combined with the chemotherapeutic drug gemcitabine. Our combined data support the development of approaches targeting IL-11Rα, and establish BMTP-11 as a leading drug candidate for clinical translation in patients with high-risk osteosarcoma.


Pediatric Office Emergency Preparedness: An Intensive In-Office Training Curriculum.
Preparation is vital to improve resuscitation outcomes for children presenting to the primary care office with emergent conditions. Previous literature has provided recommendations for medications, equipment, and skills necessary to provide appropriate care. Most studies thus far demonstrated offices are unprepared according to those recommendations. We sought to provide an intensive emergency training and preparation curriculum to local primary care pediatric offices to improve their emergency readiness. Using a high-fidelity manikin, a simulation instructor team visited several offices and trained teams including physicians, nurse practitioners, nurses, medical assistants, front desk staff, and billing/management staff. Two emergency resuscitation simulations were performed per session with education after each scenario. The instructor team taught procedures, provided teamwork training, and provided feedback on medications, equipment, and resuscitation priorities. Eight primary care pediatric offices participated in the curriculum, 36 training sessions were conducted, and 229 staff were trained. Numerous issues with medications, equipment, teamwork dynamics, and pediatric emergency resuscitation were revealed. There was always significant improvement from the first to the second simulation in each session. Our intensive emergency training and preparation curriculum experience with local primary care pediatric offices highlighted discrepancies between the perceived level of office preparedness and actual experience during a simulated emergency. Office staff felt more prepared for an emergency after the training, and office medications and equipment were re-evaluated to provide a more efficient and effective resuscitation for their patients.


The benefits and acceptability of virtual reality interventions for women with metastatic breast cancer in their homes; a pilot randomised trial.
Women with metastatic breast cancer (MBC) report debilitating physical and psychological symptoms, including fatigue, anxiety, and pain, that greatly impact their quality of life. Immersive virtual reality (VR) has been proposed as an adjunctive pain therapy for patients with cancer, and evidence suggests it may also decrease symptoms of anxiety and depression. The purpose of this pilot study was to assess whether VR should be pursued as a feasible and acceptable adjunctive therapy to alleviate physical and psychological symptoms in women with MBC. We conducted a pilot study testing the acceptability and efficacy of VR interventions with MBC patients to improve quality of life and to produce enduring decreases in fatigue, pain, depression, anxiety, and stress. Participants completed two different week-long VR experiences, reporting the prevalence of symptoms immediately before and after each study week, and 48 h later. Linear mixed models including fixed effects (VR intervention, counterbalancing order, and study week) and random effects (participant) were used to assess the effect of immersive VR on all outcome measures. Thirty-eight women with MBC completed the VR interventions and were included in analyses. Significant improvements post-intervention and/or 48 h later were demonstrated for quality of life, fatigue, pain, depression, anxiety, and stress. Across the entire study period, these differences met the criteria of a clinically important difference for quality of life, fatigue, depression, and stress. Participants reported feelings of relaxation and enjoyment and were highly likely to use the interventions gain. Our results demonstrate that VR experiences offer enduring benefits to the physical and psychological well-being of women with MBC. VR interventions are a feasible and acceptable intervention that can be conducted in a patient's own home. Such interventions are worthy of future investigation as a novel approach to improving quality of life in a patient population that have often been overlooked. Prospectively registered on 25th October 2019 with Australian New Zealand Clinical Trials Registry (ref: ACTRN12619001480178 ).


[Preparation and property investigations of nanosized titanium oxide microcrystals].
A naosized TiO2 powder was successfully prepared by the hydrolysis of titanium isopropoxide through sol-gel process. The microstructure of TiO2 powder was investigated by transmission electron microscopy and X-ray diffraction. Both anatase and rutile phases were found in TiO2 powder annealed for 1 hour at 600 degrees C. The characteristics of X-ray photoelectron spectra and infrared spectra could be affected by the size and aggregation state of the microsrystalc constituting the TiO2 powder.


Early outcomes of radiofrequency ablation in unresectable metastatic colorectal cancer from a tertiary cancer hospital in India.
The study was carried out to evaluate the early outcomes using Radiofrequency Ablation (RFA) for unresectable liver metastases in the management of metastatic colorectal cancer (mCRC) from an area of low endemicity. 60 Patients with unresectable colorectal liver metastases had undergone 88 sessions of RFA from January 2007 till December 2013. The results were retrospectively analysed to evaluate the outcomes in terms of efficacy and survival rates. The median follow up of patients in our series was 24.8months. 35/52 (67.3%) patients had complete response at 3 months while 8 patients were lost to follow up. Of the 17 patients who had recurrence, 4 (23.5%) were at the ablated site while 13 patients (76.4%) progressed elsewhere. Abdominal pain was commonest post procedural symptom (20%). There was no procedure related mortality or any major complications. Mean disease free interval and Progression free survival was 6.7 and 13.1 months. Estimated median survival in patients with liver limited disease and those with small lesion (<3cm) was 3.79 years and 3.45 years respectively. Median survival in patients with lesion size 3-5 cms was 1.5 years. Annual survival rates would be 94.5%, 55.2% and 26.2% for 1, 3 and 5 years. Radiofrequency ablation of unresectable liver metastases is effective in treatment of mCRC. Estimated survival rates and Annual survival rates at our institute from the low endemic region also follow the global trend. Size of the lesion was an important predictor of efficacy of RFA. Presence of extrahepatic disease and lesion size >3 cm was associated with decreased survival.


[Evaluation of CT-Guided Percutaneous Needle Biopsy for Diagnosis of Renal Tumor].
We performed computed tomographic (CT)-guided percutaneous needle biopsy for renal tumors that were difficult to diagnose or were inoperable malignant renal tumors. Nineteen patients who underwent CT-guided percutaneous needle biopsy between November 2007 and March 2015 at Hamamatsu University Hospital were included in this study. The median tumor diameter was 78 mm (40-140 mm). Seventeen patients were diagnosed pathologically by biopsy, but 2 patients could not be diagnosed despite the existence of adequate sample volume. One patient had an adverse complication ; fever (CTCAE ver 4.0 grade 1). The median duration of follow-up was 21 months (0-111 months), no one had tumor seeding along a needle tract. CT-guided percutaneous needle biopsy of renal tumors is helpful for pathological diagnosis and further treatment planning. However, there are still some limitations to obtain an accurate diagnosis.


Effects of flavonoids and phenolic acids on the inhibition of adipogenesis in 3T3-L1 adipocytes.
Obesity has become a global epidemic in both developed and developing countries, and it is a significant risk factor for various diseases such as diabetes, cancer, heart disease, and hypertension. In the present study, the effect of naturally occurring antioxidants (flavonoids and phenolic acids) on the inhibition of adipogenesis in 3T3-L1 adipocytes was investigated. The results showed that o-coumaric acid and rutin had the highest inhibition on intracellular triglyceride (61.3 and 83.0%, respectively) among 15 phenolic acids and 6 flavonoids tested. However, the oil red o stained material (OROSM) showed that cell number in 3T3-L1 adipocytes was not influenced by those compounds. For glycerol-3-phosphate dehydrogenase (GPDH) activity, the data indicated that o-coumaric acid and rutin had the highest inhibition on GPDH activity (54.2 and 66.8%, respectively) among the compounds tested. o-Coumaric acid and rutin also inhibited the expression of PPARgamma, C/EBPalpha and leptin and then up-regulated expression of adiponectin at the protein level. Some naturally occurring antioxidants efficiently suppressed adipogenesis in 3T3-L1 adipocytes. These results suggest that o-coumaric acid and rutin targeted for adipocyte functions could be effective in improving the symptoms of metabolic syndrome.


Preoperative evaluation of collateral venous anastomoses in meningioma involving cerebral venous sinus by susceptibility weighted imaging.
Precise preoperative identification of the collateral venous anastomoses is critical for proper surgical management of patients with meningioma involving sinus. This study was to assess the feasibility of susceptibility weighted imaging (SWI) to delineate the collateral venous anastomoses before surgery. Twenty-five patients with meningiomas that were involved in sinuses underwent surgery and the collateral anastomoses were evaluated with SWI and phase-contrast magnetic resonance venography (MRV) before surgery. The results obtained with SWI were compared with those obtained with MRV. Intraoperative findings were used as the gold standard. By surgery, a total of 98 collateral anastomotic veins were identified in the 25 patients. SWI depicted 85 collateral anastomotic veins close to the meningioma with a sensitivity of 87%, whereas MRV showed 57 collateral anastomotic veins with a sensitivity of 58%. The detectability of collateral anastomotic veins in SWI images was superior to MRV. The results suggest that SWI is superior to MRV and could provide more reliable information on the collateral venous anastomoses in patients with meningioma.


Bio-photosensor: Cyanobacterial photosystem I coupled with transistor via molecular wire.
We report on the first successful output of electrons directly from photosystem I (PSI) of thermophilic cyanobacteria to the gate of a field-effect transistor (FET) by bypassing electron flow via a newly designed molecular wire, i.e., artificial vitamin K(1), and a gold nanoparticle; in short, this newly manufactured photosensor employs a bio-functional unit as the core of the device. Photo-electrons generated by the irradiation of molecular complexes composed of reconstituted PSI on the gate were found to control the FET. This PSI-bio-photosensor can be used to interpret gradation in images. This PSI-FET system is moreover sufficiently stable for use exceeding a period of 1 year.


Anesthetic action and virus replication: inhibition of measles virus replication in cells exposed to halothane.
Replication of measles virus in BSC cells was studied in the presence of halothane, a commonly used volatile anesthetic. At clinical concentrations of the anesthetic, appearance of progeny virus was decreased in a dose-related manner. This inhibition was reversible as the removal of halothane allowed virus replication to be resumed. Studies attempting to elucidate the mechanism of action of the anesthetic inhibition of virus replication revealed that halothane did not directly inactivate the virus particle or prevent viral adsorption to the cell. Infectious virus and nucleocapsid production were decreased or stopped, depending on the anesthetic dosage used. Direct immunofluorescent staining for measles virus antigen was negative in cells treated at the higher concentrations of halothane. Recovery of nucleocapsid production started within a few hours after removal of halothane. Furthermore, the combined inhibitory effects on viral ribonucleic acid synthesis of 5-azacytidine and halothane were additive. This evidence suggests that inhibition of measles virus replication occurs at or before ribonucleic acid synthesis.


[Distribution of efferent neurons of different types in the motor cortex of the cat].
Distribution of efferent neurones of different categories was studied in the cat sensorimotor cortex: pyramidal and extrapyramidal systems and cortico-thalamic cells, whose axons end in the ventroposterolateral nucleus and medial geniculate body. In the major part of cortical microareas (88%) several output cells were found which could belong equally to one or several different categories. In some vertical cortical tracks no output neurones of the investigated categories were discovered. In tracks with efferent neurones, cortical areas with a definite set of output cells usually represented cylinders of 500-700 mcm in height. Separate microareas differed from each other by sets of fast or slow cells.


The Indonesian EQ-5D-5L Value Set.
The EQ-5D is one of the most used generic health-related quality-of-life (HRQOL) instruments worldwide. To make the EQ-5D suitable for use in economic evaluations, a societal-based value set is needed. Indonesia does not have such a value set. The aim of this study was to derive an EQ-5D-5L value set from the Indonesian general population. A representative sample aged 17 years and over was recruited from the Indonesian general population. A multi-stage stratified quota method with respect to residence, gender, age, level of education, religion and ethnicity was utilized. Two elicitation techniques, the composite time trade-off (C-TTO) and discrete choice experiments (DCE) were applied. Interviews were undertaken by trained interviewers using computer-assisted face-to-face interviews with the EuroQol Valuation Technology (EQ-VT) platform. To estimate the value set, a hybrid regression model combining C-TTO and DCE data was used. A total of 1054 respondents who completed the interview formed the sample for the analysis. Their characteristics were similar to those of the Indonesian population. Most self-reported health problems were observed in the pain/discomfort dimension (39.66%) and least in the self-care dimension (1.89%). In the value set, the maximum value was 1.000 for full health (health state '11111') followed by the health state '11112' with value 0.921. The minimum value was -0.865 for the worst state ('55555'). Preference values were most affected by mobility and least by pain/discomfort. We now have a representative EQ-5D-5L value set for Indonesia. We expect our results will promote and facilitate health economic evaluations and HRQOL research in Indonesia.


DNA methylation of retrotransposons, DNA transposons and genes in sugar beet (Beta vulgaris L.).
The methylation of cytosines shapes the epigenetic landscape of plant genomes, coordinates transgenerational epigenetic inheritance, represses the activity of transposable elements (TEs), affects gene expression and, hence, can influence the phenotype. Sugar beet (Beta vulgaris ssp. vulgaris), an important crop that accounts for 30% of worldwide sugar needs, has a relatively small genome size (758 Mbp) consisting of approximately 485 Mbp repetitive DNA (64%), in particular satellite DNA, retrotransposons and DNA transposons. Genome-wide cytosine methylation in the sugar beet genome was studied in leaves and leaf-derived callus with a focus on repetitive sequences, including retrotransposons and DNA transposons, the major groups of repetitive DNA sequences, and compared with gene methylation. Genes showed a specific methylation pattern for CG, CHG (H = A, C, and T) and CHH sites, whereas the TE pattern differed, depending on the TE class (class 1, retrotransposons and class 2, DNA transposons). Along genes and TEs, CG and CHG methylation was higher than that of adjacent genomic regions. In contrast to the relatively low CHH methylation in retrotransposons and genes, the level of CHH methylation in DNA transposons was strongly increased, pointing to a functional role of asymmetric methylation in DNA transposon silencing. Comparison of genome-wide DNA methylation between sugar beet leaves and callus revealed a differential methylation upon tissue culture. Potential epialleles were hypomethylated (lower methylation) at CG and CHG sites in retrotransposons and genes and hypermethylated (higher methylation) at CHH sites in DNA transposons of callus when compared with leaves.


A multispecies approach for understanding neuroimmune mechanisms of stress.
The relationship between stress challenges and adverse health outcomes, particularly for the development of affective disorders, is now well established. The highly conserved neuroimmune mechanisms through which responses to stressors are transcribed into effects on males and females have recently garnered much attention from researchers and clinicians alike. The use of animal models, from mice to guinea pigs to primates, has greatly increased our understanding of these mechanisms on the molecular, cellular, and behavioral levels, and research in humans has identified particular brain regions and connections of interest, as well as associations between stress-induced inflammation and psychiatric disorders. This review brings together findings from multiple species in order to better understand how the mechanisms of the neuroimmune response to stress contribute to stress-related psychopathologies, such as major depressive disorder, schizophrenia, and bipolar disorder.


Trypanocidal and antileishmanial dihydrochelerythrine derivatives from Garcinia lucida.
Three benzo[ c]phenanthridine alkaloids have been isolated from the stem bark of Garcinia lucida: dihydrochelerythrine ( 1), 6-acetonyldihydrochelerythrine ( 2), and its new derivative, ( S)1''-(9,10-dihydro-2',3'-dihydroxy-7,8-dimethoxy-10-methyl-1,2-benzophenanthridin-9-yl)propan-2''-one (lucidamine A) ( 3). The new diisoprenylated derivative of lucidamine B ( 4) was obtained by semisynthesis. These dihydrochelerythrine derivatives as well as the crude extract displayed attractive antiprotozoal activity against Trypanosoma brucei brucei and Leishmania donovani, with little toxicity to Vero cells and the host cells. This is the first trypanocidal and antileishmanial bioguided study of G. lucida, and the activity of the crude extract as well as of the dihydrochelerythrine derivatives are reported for the first time.


Theoretical Insights into the Catalytic Mechanism of N-Heterocyclic Olefins in Carboxylative Cyclization of Propargyl Alcohol with CO2.
The mechanism of carboxylative cyclization of propargyl alcohol with CO2 catalyzed by N-heterocyclic olefins (NHOs) has been studied by density functional theory calculations. The calculations reveal that the catalytic reaction tends to proceed via the NHO-mediated basic ionic pair mechanism, in which free NHO primarily acts as a basic precursor to trigger the carboxylation of propargyl alcohol with CO2, leading to a [NHOH](+)[carbonate](-) ion pair intermediate. Then, the catalytic cycle proceeds, including isomerization of the [NHOH](+)[carbonate](-) ion pair intermediate, intramolecular nucleophilic addition of the carbonate oxygen anion to the alkynyl group, and protonation of the alkenyl carbon anion with an external propargyl alcohol molecule. Molecule orbital and nature population analysis discloses that the preference for the basic ionic pair mechanism is due to the favorable orbital and charge interactions between the α-carbon atom of NHO and the hydroxyl hydrogen of propargyl alcohol. The [NHOH](+) cation has proven to be crucial for stabilizing the [carbonate](-) anion, which allows the reaction to proceed through a more thermodynamically stable pathway. The investigations of the effect of substituents of NHOs predict that N-substituents with a strong electron donating effect and a bulky steric effect might improve the catalytic activity of NHOs for the reaction.


Cl- channels regulate lipid droplet formation via Rab8a expression during adipocyte differentiation.
Several studies have shown that Cl- channels regulate the differentiation of some cell types. Thus, we investigated the role of Cl- channels on adipocyte differentiation using adipose tissue-derived stem cells (ASCs) and Cl- channel blocker. We induced rabbit ASCs into adipocytes using Cl- channel blocker. The expression levels of adipocyte markers were no significant difference between the cells treated with a Cl- channel blocker NPPB and untreated cells. However, when the cells were treated with NPPB, lipid droplets (LDs) sizes decreased compared with the untreated control. Interestingly, the expression levels of Rab8a, which is known as a regulator of LD fusion, were also decreased in the cells treated with NPPB. Other Cl- channel blockers, DIDS and IAA-94, also inhibited large LDs formation and Rab8a expression. These results demonstrate that Cl- channels do not regulate the adipocyte differentiation, but do regulate the LDs formation via Rab8a expression.Abbreviations: ASCs: adipose tissue-derived stem cells; LDs: lipid droplets; RUNX2: runt-related transcription factor 2; CFTR: cystic fibrosis transmembrane conductance regulator; TG: triacylglycerol; FA: fatty acid; GLUT4: glucose transporter type 4; ER: endoplasmic reticulum; ADRP: adipose differentiation-related protein; TIP47: tail-interacting protein of 47 kD; HSL: hormone sensitive lipase; PBS: phosphate-buffered saline; DMEM: Dulbecco's modified Eagle Medium; FBS: fetal bovine serum; SMA: smooth muscle actin; FAS: fatty acid synthase; ZONAB: ZO-1 associated nucleic acid binding protein; PPAR-γ: peroxisome proliferator-activated receptor-γ; C/EBPα: CCAAT/enhancer binding protein α; CE: cholesteryl ester; V-ATPase: vacuolar H+ ATPase.


[Diseases of the peripheral and visual nervous system during infection with human immunodeficiency virus].
Infection with human immunodeficiency virus (HIV) is often accompanied by neurological complications. One of these includes disorders affecting the peripheral and visual nervous system, especially during the acquired immunodeficiency syndrome (AIDS) stage. The peripheral neuropathies associated with infection by HIV are an assorted group of disorders, which include acute or chronic inflammatory demyelinating polyneuropathy, multiple mononeuropathy and neuropathies related to the herpes zoster virus or cytomegalovirus. The most common and clinically important of the neuropathies is painful distal sensory polyneuropathy (DSP). The most severely affected cranial nerves are V and VII. The isolation of HIV from the affected nerves suggests a direct role, but an immune mechanism is also possible. Although cytomegalovirus may be associated with a variety of peripheral nerve syndromes, its clinical presentation as a primary demyelinating polyneuropathy is unusual. DSP and antiretroviral toxic neuropathy are the most common HIV-associated neuropathies. Both HIV infection, by itself, and the neurotoxicity of certain drugs in tritherapy contribute to the development of painful peripheral sensory neuropathy. In researching into the cause of HIV-associated neuropathy further studies are needed to determine the relative roles played by the viral infection and the activation of the immunological factors that contribute to the pathogenesis of the damage done in axons, the dorsal root ganglion and in the sensory pathways in the spinal cord.