An epigenetic and transcriptomic signature of immune tolerance in human monocytes through multi-omics integration.
The plasticity of monocytes enables them to exert multiple roles during an immune response, including promoting immune tolerance. How monocytes alter their functions to convey immune tolerance in the context of lower respiratory tract infections in humans is not well understood. Here, we sought to identify epigenetic and transcriptomic features of cytokine production capacity in circulating monocytes during community-acquired pneumonia (CAP). Circulating CD14+ monocytes were obtained from the blood of CAP patients included in a longitudinal, observational cohort study, on hospitalization (acute stage, n=75), and from the same patients after a 1-month follow-up (recovery stage, n=56). Age and sex-matched non-infectious participants were included as controls (n=41). Ex vivo cytokine production after lipopolysaccharide (LPS) exposure was assessed by multiplex assay. Transcriptomes of circulating monocytes were generated by RNA-sequencing, and DNA methylation levels in the same monocytes were measured by reduced representation bisulfite sequencing. Data were integrated by fitting projection-to-latent-structure models, and signatures derived by partial least squares discrimination. Monocytes captured during the acute stage exhibited impaired TNF, IL-1β, IL-6, and IL-10 production after ex vivo stimulation with LPS, relative to controls. IL-6 production was not resolved in recovery monocytes. Multivariate analysis of RNA-sequencing data identified 2938 significantly altered RNA transcripts in acute-stage monocytes (fold expression ≤-1.5 or ≥1.5; adjusted p ≤ 0.01), relative to controls. Comparing DNA methylation levels in circulating monocytes of CAP patients to controls revealed minimal differences, specifically in DNAse hypersensitive sites (HS) of acute-stage monocytes. Data integration identified a cholesterol biosynthesis gene signature and DNAse HS axis of IL-1β and IL-10 production (R2 =0.51). Circulating monocytes obtained from CAP patients during the acute stage exhibited impaired cytokine production capacities, indicative of reprogramming to a state of immune tolerance, which was not fully resolved after 1 month. Our split-sample study showed that 51% of the immune tolerance phenotype can be explained, at least in part, by coordinated shifts in cholesterol biosynthesis gene expression and DNAse HS methylation levels. A multi-scale model identified an epigenetic and transcriptomic signature of immune tolerance in monocytes, with implications for future interventions in immunosuppression. NCT number NCT02928367.


Health profile for Danish adults with activity limitation: a cross-sectional study.
Studies have indicated that people with disabilities die earlier and may experience a poorer health than the general population. This study investigated 31 factors related to health and well-being, health behaviour and social relations among Danish adults with activity limitation (AL). This study was based on data from the Danish Health and Morbidity Survey (DHMS) 2013 where 25,000 men and women aged 16 years or older were selected randomly from the adult Danish population. A total of 14,265 individuals answered the self-administered questionnaire including 100 questions on health-related quality of life, health behaviour, morbidity, consequences of illness and social relations. Based on an international standard question on AL, 888 individuals (6%) were defined as having profound AL and 4180 (29%) as having some AL. Multiple logistic regression analyses were used to analyse the associations between activity limitation and 31 indicators of health. The results were presented as relative risks 95% confidence intervals. Twenty-eight of 31 indicators showed consistently poorer health and well-being, health behaviour and social relations among individuals with AL as compared to individuals without AL. The increased relative risks were in a range of 7-661% the risk among individuals without AL. An example is obesity where RR (95% CI) was 2.07 (1.82-2.37). Only contact with internet friends was significantly higher among individuals with AL as compared to individuals with no AL. There was no association between alcohol and AL and no association between fast food and some AL. Danish adults with AL experience a poorer health and well-being, and have an unhealthier lifestyle and poorer social relations than adults without AL. People with activity limitation should be prioritized in public health and efforts done to secure availability and flexibility of health care services and primary prevention programs. Policies should address accessibility, availability and affordability of health care and health behaviour among people with activity limitation.


[Severe phimosis as cause of urosepsis with Actinobaculum schaalii].
Actinobaculum schaalii is a small, Gram-positive, facultative anaerobic, CO2-requiring rod. It is now an acknowledged uropathogen, but often overlooked because of its slow growth. It is part of the normal bacterial flora in the urogenital area, but can be the cause of both local and invasive infections. We present a case of A. schaalii urosepsis in a 68-year-old male with phimosis caused by a severe lichen sclerosus et atrophicus. The only bacteria found in blood and urine was A. schaalii.


Structural Properties of Quinoa Protein Isolate: Impact of Neutral to High Alkaline Extraction pH.
In this work, we extracted proteins from white quinoa cultivated in the northeast of Qinghai-Tibet plateau using the method of alkaline solubilization and acid precipitation, aiming to decipher how extraction pH (7-11) influenced extractability, purity and recovery rate, composition, multi-length scale structure, and gelling properties of quinoa protein isolate (QPI). The results showed that protein extractability increased from 39 to 58% with the increment of pH from 7 to 11 whereas protein purity decreased from 89 to 82%. At pH 7-11, extraction suspensions and QPI showed the similar major bands in SDS-PAGE with more minor ones (e.g., protein fractions at > 55 or 25-37 kDa) in suspensions. Extraction pH had limited effect on the secondary structure of QPI. In contrast, the higher-order structures of QPI were significantly affected, e.g., (1) emission maximum wavelength of intrinsic fluorescence increased with extraction pH; (2) surface hydrophobicity and the absolute value of zeta-potential increased with increasing extraction pH from 7 to 9, and then markedly decreased; (3) the particle size decreased to the lowest value at pH 9 and then increased to the highest value at pH 11; and (4) denaturation temperature of QPI had a large decrease with increasing extraction pH from 7/8 to 9/10. Besides, heat-set QPI gels were formed by loosely-connected protein aggregates, which were strengthened with increasing extraction pH. This study would provide fundamental data for industrial production of quinoa protein with desired quality.


Construction and Validation of a Novel Prognostic Signature for Intestinal Type of Gastric Cancer.
Intestinal type of gastric cancer (IGC) is the largest subtype of gastric cancer (GC) by Lauren classification. The purpose of this present study was to construct a prognostic signature for IGC patients, based on the high-grade dysplasia (HGD) and IGC tissues, to improve and enhance the prognostic accuracy. The microarray datasets and associated clinical characteristics of HGD and IGC were obtained from the Gene Expression Omnibus (GEO) database. Based on the differential expression analysis between HGD and IGC, the prognostic-related differential expression genes (DEGs) were identified in a training set by univariate COX regression analysis. The least absolute shrinkage and selection operator (LASSO) regression was used to construct an optimal prognostic signature. The enrichment analysis was performed by using Gene Set Enrichment Analysis (GSEA). The performance of the nomogram was assessed by the calibration curve and concordance index (C-index). The results were validated by using a testing set. We identified 35 prognostic-related DGEs in the training set. The nine-gene signature was established by LASSO analysis. The nine-gene signature was an independent risk factor in both the training and testing sets. The areas under the curve (AUC) values of receiver operating characteristic (ROC) analysis were 0.733 and 0.700 for the training and testing sets, respectively. In GSEA analysis, the gene expression in high-risk group was enriched in hedgehog signaling, epithelial mesenchymal transition, and angiogenesis. The nomogram for IGC showed good performance with C-index of 0.81 (95% CI: 0.76-0.86) and 0.70 (95% CI: 0.63-0.77) in the training and testing sets, respectively. We identified and verified a nine-gene signature for the prognostic prediction of IGC patients, which might identify subgroups of IGC patients and select more suitable therapeutic options.


Seroprotection against tetanus in patients attending an emergency department in Belgium and evaluation of a bedside immunotest.
In most emergency departments, tetanus prophylaxis currently relies on vaccination history. Bedside evaluation of tetanus immunity may improve this process. (i) To determine the seroprevalence of tetanus immunity; (ii) to evaluate the accuracy of vaccination history in assessing tetanus immunity; (iii) to identify factors predictive of seroprotection and incorrect history. In a prospective observational study, tetanus immunity was assessed in 784 adults using Tétanos Quick Stick (TQS). A questionnaire was completed to obtain vaccination and general histories. Immunity assessed by TQS and by vaccination history were compared with anti-tetanus antibody levels measured by the enzyme-linked immunosorbent assay (seroprotection threshold >0.15 IU/ml). Overall, 64.2% of patients were protected according to TQS results. Four independent predictors of seroprotection were identified: young age, birthplace in Belgium, male sex and occupational medicine consultation. TQS performance was good: kappa=0.71, sensitivity 85.3%, specificity 87.2%, positive predictive value 92.1% and negative predictive value 77.2%. Seven hundred and sixty-two participants responded to the vaccination history: 23.4% said they were protected, 22.1% that they were not and 54.5% did not know. History performance was poor: kappa=0.27, sensitivity 60.3%, specificity 73.3%, positive predictive value 81.8% and negative predictive value 45.8%. Compared with history, TQS offered a significantly better sensitivity, negative and positive predictive values, but specificity was similar. No predictor of an incorrect history was identified. Lack of protective immunity against tetanus is frequent but poorly evaluated by history taking. Several demographic characteristics are good predictors of seroprotection. TQS could be a valuable tool in selected patients to improve tetanus prophylaxis in the emergency department.


8 alpha-Estra-1,3,5(10)-triene-1,3, 17 beta-triol as a special type of estrogen having a high vaginotrophic activity and a low uterotrophic activity in castrated mice.
The vaginotrophic and uterotrophic activities of 1-OH-8-alpha-E2 and its acetate in comparison with E2 and E3 were assessed on the basis of the effect on weights, water/fat-and RNA/DNA-contents of mouse vagina and uterus. The multiple doses of 8 alpha-steroids or E3 sufficient to achieve a maximal effect on the vagina were not enough to stimulate the uterus fully. At various periods of time after multiple injections, 1-OH-8 alpha-E2 acetate was found to have a higher vaginotrophic potency than the uterotrophic potency, when compared with E2 as a standard. The study on the time course of organ response to 8 alpha-steroids, E2 and E3 after a single injection of daily dose, being equipotent when injected one daily for 3 days, demonstrated that 1-OH-8-alpha-E2 and E3 were less vaginotrophic and uterotrophic than E2 and had a short duration of action. 1-OH-8 alpha-E2 acetate in comparison with E2 produced a long-lasting vaginotrophic effect and an early regressing uterotrophic effect. It can be confirmed that 8 alpha-steroids, like E3, are a special type of estrogen having a high vaginotrophic activity and a low uterotrophic activity.


[Influence of sulfur on the bioavailability of arsenic uptake by rice (Oryza. sativa L. ) and its speciation in soil ].
Pot experiments using exogenous arsenic-polluted paddy soils were carried out to investigate the influence of different forms of sulfur fertilizers (sulfur and gypsum) on As uptake by rice and its chemical speciation. Soil solution pH value ranged 7. 38-7. 45 in different growth period of rice, and the pH value of AsS0 and AsS1 treatments was higher than that of AsS2 treatment. Variation of Eh value in soil solution was about 200 mV and the Eh of AsS0 was higher than those of AsS1 and AsS2 treatments. From dry matter weight of root and stem and grain of rice, S-fertilizer applied by sulfur and gypsum could improve the amounts of dry matter in rice, while the effects of sulfur treatments and gypsum treatments were not significant. Concentrations of Fe and Mn in iron-manganese plaque on rice roots were 10-30 g.kg-1 and 0.1-1.3 g.kg-1, respectively. Contents of Fe-Mn plaque were mainly different in the tiller stage. Elemental S treatment could more greatly promote the formation of Fe-Mn plaque of rice root than gypsum treatment. Concentrations of As adsorbed by rice roots surface plaque were 583-719 mg.kg-' in tiller stage, 466-621 mg.kg-1 in boot stage, and 310-384 mg kg-1 in flower and matur stage. And it was consistent with the thickness of Fe-Mn plaque on rice root surface. Concentrations of As uptake in roots and stem and leaf and grain were significantly reduced by the application of S fertilizer, and it may be related to the amount of As adsorbed by Fe-Mn plaque at boot stage. According to chemical speciation of soil arsenic, As of non-specific and specific adsorption was most active, and their amounts of As adsorbed in AsS, treatment were significantly lower by 2.85 mg kg-~' than that in AsS2 treatment in tiller stage, and was 0.77 mg.kg- higher than that in AsS2 treatment in the flower stage. Perhaps soil arsenic was easily dissolved in the soil solution and the bioavailability of AsS, treatment was better than that of AsS, treatment.


Carbohydrate metabolism in mutants of the cyanobacterium Synechococcus elongatus PCC 7942 defective in glycogen synthesis.
ADP-glucose pyrophosphorylase (AGPase) and glycogen synthase (GS) catalyze the first two reactions of glycogen synthesis in cyanobacteria. Mutants defective in each of these enzymes in Synechococcus elongatus PCC 7942 were constructed and characterized. Activities of the corresponding enzymes in the selected mutants were virtually undetectable, and their ability to synthesize glycogen was entirely abolished. The maximal activities of photosynthetic O(2) evolution and the rates of respiration in the dark were significantly decreased in the mutants compared to those in wild-type cells. Addition of 0.2 M NaCl or 3 mM H(2)O(2) to liquid cultures markedly inhibited the growth of the AGPase and GS mutants, while the same treatment had only marginal effects on the wild type. These results suggest a significant role for storage polysaccharides in tolerance to salt or oxidative stress.


Malformin-A1 inhibits the binding of interleukin-1 beta (IL1 beta) and suppresses the expression of tissue factor in human endothelial cells and monocytes.
Malformin-A1, a cyclic pentapeptide of microbial origin, antagonized in a competitive manner the binding of 125I-IL1 beta (interleukin-1 beta) to human monocytes and cultured human umbilical vein endothelial cells (HUVEC) with IC50 values (doses which reduce specific binding by 50%) of 250 +/- 80 and 230 +/- 25 nM, respectively (N = 3). IL1 increased in a dose-dependent manner the expression of tissue factor, a ubiquitous membrane-anchored glycoprotein that initiates blood coagulation at the surface of HUVEC and human monocytes. Malformin-A1 strongly inhibited IL1-induced tissue factor expression in HUVEC and monocytes with IC50 values of 420 +/- 35 and 105 +/- 25 nM, respectively (N = 3), and reduced IL1-induced expression of intercellular adhesion molecule-1 (ICAM-1, CD54) on HUVEC (IC50 = 125 +/- 18 nM) (N = 4). These observations demonstrate that malformin-A1 recognizes and blocks IL1 beta binding to its receptor sites on monocytes and endothelial cells and protects these cells from IL1-induced procoagulant changes.


The Effect of Ineffective Esophageal Motility on Gastroesophageal Reflux Disease.
Ineffective esophageal motility (IEM) is the most common gastrointestinal motility disorder. Studies have reported that IEM is related to gastroesophageal reflux disease (GERD). However, the relationship between IEM and GERD remains uncertain. This study aims to clarify this relationship retrospectively. We analyzed 195 subjects who underwent high-resolution manometry between January 2011 and September 2016. Of these subjects, 72 had normal esophageal motility (NEM) and 26 had IEM. We investigated differences in the clinical characteristics, severity and duration of GERD symptoms, and comorbid extra-esophageal symptoms of the subjects. Comorbid extra-esophageal symptoms were assessed with the Gastrointestinal Symptom Rating Scale questionnaire. Investigation-defined GERD was diagnosed when erosive esophagitis or abnormal multichannel intraluminal impedance was present. We found no significant difference in the prevalence of IEM between patients with and without GERD (37.5 and 21.1%, respectively; p = 0.174). There were no differences in age, gender, body mass index, presence of hiatal hernia, or duration of GERD between the groups. Compared to patients with NEM, those with IEM were significantly less likely to have comorbid extra-esophageal symptoms (p < 0.05). There is no association between IEM and GERD.


Canonical Structure and Orthogonality of Forces and Currents in Irreversible Markov Chains.
We discuss a canonical structure that provides a unifying description of dynamical large deviations for irreversible finite state Markov chains (continuous time), Onsager theory, and Macroscopic Fluctuation Theory (MFT). For Markov chains, this theory involves a non-linear relation between probability currents and their conjugate forces. Within this framework, we show how the forces can be split into two components, which are orthogonal to each other, in a generalised sense. This splitting allows a decomposition of the pathwise rate function into three terms, which have physical interpretations in terms of dissipation and convergence to equilibrium. Similar decompositions hold for rate functions at level 2 and level 2.5. These results clarify how bounds on entropy production and fluctuation theorems emerge from the underlying dynamical rules. We discuss how these results for Markov chains are related to similar structures within MFT, which describes hydrodynamic limits of such microscopic models.


Factors related to loss of root canal filled teeth.
This case-control study characterized factors related to loss of root canal filled (RCF) teeth among members of the Kaiser Permanente Dental Care Program, a dental health maintenance organization based in Portland, Oregon. Individuals were identified who were enrolled continuously from January 1, 1987, through December 31, 1994, underwent initial root canal therapy on a permanent tooth (excluding third molars) in 1987 or 1988, had a clinical examination within two years after endodontic access, and were at least 21 years old at access. Patients who lost the RCF tooth by December 31, 1994, were defined as cases (n = 96); those who did not were defined as controls (n = 120). Computerized data, dental radiographs, and chart entries were reviewed to ascertain variables of interest, and multivariable logistic regression was used to describe differences between the groups. RCF teeth of cases had fewer proximal contacts at access than RCF teeth of controls (odds ratio = 2.7; 95% Cl = 1.4, 5.1). Cases were older (odds ratio = 1.4; 95% Cl = 1.1, 1.9 per 10-year increase) and more likely to have had a facial injury than controls (odds ratio = 3.6; 95% Cl = 1.2, 10.5). Cases also had more missing teeth (odds ratio = 1.5; 95% Cl = 1.0, 2.1) and more plaque (odds ratio = 1.7; 95% Cl = 1.0, 2.6). Conditions evident during treatment planning may help dentists assess patients' chances of losing an RCF tooth.


[Sex behavior of patients attending a free, anonymous HIV screening center in Paris].
People's sexual behavior changes as they acquire knowledge od HIV infection. During a 10-week period (September-November 1994), we analysed the results of interviews conducted prior to free, anonymous tests in the Figuier HIV screening center (CDAG, Paris). Men accounted for 61% of the 1275 attendees, and 62% were aged between 20 and 29 years (both sexes). Consultants were homo/bisexuals in 26% cases and 23% had an HIV-infected partner. Male and female hetero-sexual represented respectively 35 and 38% of attendees, and 1.7% had an HIV-infected partner. Most of the subjects (76%) had had more than one sexual partner in the last 12 months. 72% of the homo/bisexuals of all ages stated that they used condoms systematically during sexual penetration, compared to 35% of the heterosexuals. In contrast, only 3.9% of homo/bisexual used condoms during oral intercourse. 12% of the subjects (21% of homo/bisexuals, and 8.5% of heterosexuals) stated that they had been treated for an STD during the previous year, and most were aged between 25 and 34 years. The most frequent stated STDs were anogenital papillomavirus and herpes virus infections, and chlamydial infections. 80% of the homo/bisexual considered they "too a risk" (oral intercourse), compared to 47% of heterosexuals. 10% of the subjects did not collect their result. In this study the seroprevalence of HIV was 1%, with the highest values in the 25-34 year age group and among homo/bisexuals (3%), and the lowest values among male and female heterosexuals (0.4% and 0.2%, respectively). Most of the subjects, on the basis of their stated sexual behavior, were aware of the risk of HIV infection, but the high frequency of STDs shows that prevention campaigns must be reinforced. Practician must offer advice on prevention and screening in order to reduce the frequency of infective and tumoral diseases due to sexually transmitted pathogens.


More severe violence exposure associated with poly-pharmaceutical use.
Exposure to emotional, physical, and sexual abuse carries varying psychological and somatic sequelae, including the increased use of alcohol and illicit drugs. Less studied is the association between violence exposure and prescription drug use. Using previously determined lifetime exposure profiles of 16,000 men and women, the current use of three specific drug categories was assessed and a strong relationship between victimization severity and prescription drugs used within the last month was found. Victimization screening has important implications in health care settings.


Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years.
The current interest in leishmaniasis stems from the importance of this disease with respect to travel medicine, veterans of Operation Desert Storm, humanitarian concerns, and infection with human immunodeficiency virus. Herein, I review aspects of leishmaniasis that are of practical value to practitioners, including presentation, diagnosis, and chemotherapy; I will emphasize advances in chemotherapy over the last 10 years. Amphotericin B and its new lipid formulations are now competitive with pentavalent antimony as primary therapy for visceral leishmaniasis. Pentamidine, paromomycin, and adjunctive therapy with interferon-gamma are secondary regimens for the treatment of this condition. High-dose long-term regimens of antimony have been shown to be highly effective for the treatment of cutaneous leishmaniasis. Preliminary evidence of efficacy has been observed with short courses of pentamidine for the treatment of Leishmania braziliensis complex disease and topical paromomycin/methylbenzethonium chloride for the treatment of Leishmania major disease.


Topochemical aspects of nucleic-acid and protein metabolism within the neuron-neuroglia unit of the hypothalamic supraoptic nucleus.
The RNA and both the total and basic protein content of individual cells were determined by cytospectrophotometry in neurons and perineuronal oligodendroglia of the hypothalamic supraoptic nucleus in rats subjected to various stresses, as well as in ground squirrels during natural hibernation. Barbiturate narcosis and deep cooling, which induced a decrease in body temperature in rats and hibernation in squirrels, caused a marked decrease of all macromolecular constituents in neurons. A similar decrease was found in the perineuronal oligodendroglia in rats, but an increase was observed in ground squirrels. After cessation of cooling, while the body temperature of the animals returned to normal, the neurons, but not the oligodendroglia, of rats showed a significant accumulation of RNA, while RNA accumulated in both neurons and perineuronal oligodendroglia in ground squirrels. Milder cooling of rats, which did not lower their body temperature, induced reciprocal changes in basic-protein content in neuronal and glial cell nuclei, with the accumulation of protein occurring initially in neurons, and subsequently in glia. When cold adaptation was accomplished, the basic protein content of neurons and glial cells returned to the control level. Four days after adrenalectomy in rats, the RNA content decreased in oligodendroglia but not in neurons of the supraoptic nucleus. This effect was completely abolished by daily injections of cortisol in the adrenalectomized animals. The data obtained indicate the existence of differences in metabolic responses to stress between neurons and glial cells of the supraoptic nucleus of the hypothalamus.


Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis.
Most cancer mortality results from metastatic tumor cells and not the localized tumor. Overcoming anoikis is one of the most important steps for detached tumor cells to migrate and metastasize. However, the molecular mechanisms remain to be fully deciphered. Herein, our study revealed upregulation of vacuolar ATPase (V-ATPase) in cancer cells during ECM detachment plays a key role in anoikis evasion. V-ATPase is an enzyme complex that utilizes energy from ATP hydrolysis to maintain cellular homeostasis and had been reported to enhance cancer progression. In this study, V-ATPase inhibition sensitized human cervical cancer, breast cancer, and murine melanoma cells to anoikis via increased ROS production, accumulation of misfolded protein, and impaired pulmonary metastasis in vivo. Scavenging ROS restored anoikis resistance and clearance of misfolded protein accumulation in the tumor cells. Mechanistically, STAT3 upregulates V-ATPase expression while blockade of STAT3 activity repressed V-ATPase expression in these tumor cells as well as sensitized cells to anoikis, increased ROS production, and misfolded protein accumulation. Altogether, our data demonstrate an unreported role of STAT3 in mediating the upregulation of V-ATPase to promote anoikis resistance, thus provides an alternative option to target cancer metastasis.


Invited article: physical and chemical analyses of impregnated cathodes operated in a plasma environment.
Destructive analyses of impregnated-cathode assemblies from an ion thruster life test were performed to characterize erosion and degradation after 30,472 h of operation. Post-test inspection of each cathode included examination of the emitter (insert), orifice plate, cathode tube, heater, anode assembly, insulator, and propellant isolator. The discharge-cathode assembly experienced significant erosion due to ion sputtering from the discharge plasma. The keeper electrode plate was removed and the heater and orifice plate were heavily eroded at the conclusion of the test. Had the test continued, these processes would likely have led to cathode failure. The discharge cathode insert experienced significant tungsten transport and temperature dependent barium oxide depletion within the matrix. Using barium depletion semiempirical relations developed by Palluel and Shroff, it is estimated that 25,000 h of operation remained in the discharge insert at the conclusion of the test. In contrast, the neutralizer insert exhibited significantly less tungsten transport and barium oxide depletion consistent with its lower current operation. The neutralizer was estimated to have 140,000 h of insert life remaining at the conclusion of the test. Neither insert had evidence of tungstate or oxide layer formation, previously known to have impeded cathode ignition and operation in similar long duration hollow-cathode tests. The neutralizer cathode was in excellent condition at the conclusion of the test with the exception of keeper tube erosion from direct plume-ion impingement, a previously underappreciated life-limiting mechanism. The most critical finding from the test was a power dependent deposition process within the neutralizer-cathode orifice. The process manifested at low-power operation and led to the production of energetic ions in the neutralizer plume, a potential life-limiting process for the neutralizer. Subsequent return of the engine and neutralizer operation to full-power removed the deposits and energetic ion production ceased.


Leisure-time physical activity and all-cause mortality and cardiovascular disease in adults with type 2 diabetes: Cross-country comparison of cohort studies.
This study aimed to quantify the dose-response association and the minimal effective dose of leisure-time physical activity (PA) to prevent mortality and cardiovascular disease in adults with type 2 diabetes. Cross-country comparison of 2 prospective cohort studies including 14,913 and 17,457 population-based adults with type 2 diabetes from the UK and China. Baseline leisure-time PA was self-reported and categorized by metabolic equivalent hours per week (MET-h/week) according to World Health Organization recommendations: none, below recommendation (>0-7.49 MET-h/week); at recommended level (7.5-14.9 MET-h/week); above recommendation (≥15 MET-h/week). Mortality and cardiovascular disease data were obtained from national registries. During a median follow-up of 12.4 and 9.7 years, higher levels of leisure-time PA were inversely associated with all-cause (1571 and 2351 events) and cardiovascular mortality (392 and 1060 events) in both cohorts, mostly consistent with a linear dose-response relationship. PA below, at, and above recommendations, compared with no activity, yielded all-cause mortality hazard ratios of 0.94 (95%CI: 0.79-1.12), 0.90 (95%CI: 0.74-1.10), and 0.85 (95%CI: 0.70-1.02) in British adults and 0.87 (95%CI: 0.68-1.10), 0.88 (95%CI: 0.74-1.03), and 0.77 (95%CI: 0.70-0.85) in Chinese adults. Associations with cardiovascular mortality were more pronounced in British adults (0.80 (95%CI: 0.58-1.11), 0.75 (95%CI: 0.52-1.09), and 0.69 (95%CI: 0.48-0.97)) but less pronounced in Chinese adults (1.06 (95%CI: 0.76-1.47), 1.01 (95%CI: 0.80-1.28), and 0.79 (95%CI: 0.69-0.92)). PA at recommended levels was not associated with lower rates of major adverse cardiovascular events (2345 and 4458 events). Leisure-time PA at the recommended levels was not convincingly associated with lower mortality and had no association with risk of major adverse cardiovascular events in British or Chinese adults with type 2 diabetes. Leisure-time PA above current recommendations may be needed to prevent cardiovascular disease and premature mortality in adults with type 2 diabetes.


Inducers of erythroleukemic differentiation. Relationship of structure to activity among planar-polar compounds.
Hexamethylenebisacetamide is a potent inducer of erythroid differentiation in murine erythroleukemia cells. A series of chemical compounds structurally related to hexamethylenebisacetamide were tested for inducing activity including polymethylene chains terminally substituted with various combinations of carboxylate, amino, amide, or sulfoxide groups. Effective "dimerization" of dimethyl sulfoxide through a linear polymethylene chain increases its inducing activity by a magnitude similar to that observed when N-methylacetamide is effectively dimerized in such a manner. It was found that all potent inducing agents possess both a hydrophilic and hydrophobic portion of the molecule, as well as a planar portion. All are Lewis bases, possessing a free electron pair available for hydrogen bonding. The polymethylene chain joining functional groups must be flexible and must be 5 to 6 carbon atoms in length to achieve maximal activity. Introduction of triple or double (cis or trans) bonds into the polymethylene chain does not alter activity.


Combined Effects of Gaze and Orientation of Faces on Person Judgments in Social Situations.
In social situations, faces of others can vary simultaneously in gaze and orientation. How these variations affect different kinds of social judgments, such as attractiveness or trustworthiness, is only partly understood. Therefore, we studied how different gaze directions, head angles, but also levels of facial attractiveness affect perceived attractiveness and trustworthiness. We always presented pairs of faces - either two average attractive faces or a highly attractive together with a less attractive face. We also varied gaze and head angles showing faces in three different orientations, front, three-quarter and profile view. In Experiment 1 (N = 62), participants rated averted gaze in three-quarter views as more attractive than in front and profile views, and evaluated faces with direct gaze in front views as most trustworthy. Moreover, faces that were being looked at by another face were seen as more attractive. Independent of the head orientation or gaze direction, highly attractive faces were rated as more attractive and more trustworthy. In Experiment 2 (N = 54), we found that the three-quarter advantage vanished when the second face was blurred during judgments, which demonstrates the importance of the presence of another person-as in a triadic social situation-as well as the importance of their visible gaze. The findings emphasize that social evaluations such as trustworthiness are unaffected by the esthetic advantage of three-quarter views of two average attractive faces, and that the effect of a faces' attractiveness is more powerful than the more subtle effects of gaze and orientations.


A new species of Aculus mite (Acari: Eriophyidae), a potential biocontrol agent for Australian swamp stonecrop, Crassula helmsii (Crassulaceae).
A new, gall-forming eriophyoid mite species is described from Australia. Aculus crassulae sp. nov. was found causing significant leaf deformation in Crassula helmsii (Kirk) Cockayne (Crassulaceae), a semi-aquatic, succulent plant. Native to Australia and New Zealand, this plant is now a highly invasive weed in the United Kingdom and Western Europe. The host specificity of the new mite species, and damage caused to the host plant, infer its potential to be a valuable biological control agent in countries where Australian swamp stonecrop is threatening native flora. The species description provided here, which also includes a revised diagnosis for the genus Aculus, incorporates line drawings and scanning electron micrographs (SEM). This is supplemented by a partial mitochondrial gene sequence of cytochrome c oxidase subunit I (mtCOI) and the sequence was compared with Aculus amygdali Xue Hong and Aculus ichnocarpi (Ghosh Chakrabarati) available in the NCBI database. Pairwise comparison of mtCOI sequences between A. crassulae sp. nov. and two congeneric species revealed 22.6% and 23.1% genetic divergence, respectively.


Thyroid dysfunction during late gestation is associated with excessive iodine intake in pregnant women.
Adequate iodine intake during pregnancy is essential for both the synthesis of maternal thyroid hormones and the maintenance of normal fetal brain development. Scant evidence is available on the effects of excessive iodine intake during pregnancy. The study assesses the relationship between iodine nutritional status and thyroid function of pregnant women with excessive iodine intake during late gestation. A cross-sectional study of 384 pregnant women was carried out in Tianjin and Haixing from April to October in 2010. Morning urine samples and blood samples were obtained from all subjects. Serum levels of free T(3), free T(4), and sensitive TSH and urinary iodine concentration were measured. The median urinary iodine concentration of pregnant women with excessive iodine intake was significantly higher than those with adequate iodine intake (P < 0.001). The prevalence of thyroid disease, especially subclinical hypothyroidism, in pregnant women with excessive iodine intake was significantly higher than in those with adequate iodine intake (P < 0.05). Subclinical hypothyroidism was the most frequent pattern of thyroid disease for pregnant women and those with positive or negative thyroid autoantibodies. Living with high water iodine content and having urinary iodine concentration higher than 250 μg/liter are associated risk factors for subclinical hypothyroidism in pregnant women (OR(1) = 41.822, OR(2) = 6.202; P < 0.05, where OR(1) is the odds ratio for living with high water iodine content and hypothyroidism and OR(2) is the odds ratio for urinary iodine concentration >250 μg/liter and hypothyroidism). Excessive iodine intake during late pregnancy may lead to maternal thyroid dysfunction, particularly subclinical hypothyroidism. The appropriate measurements should be performed to monitor the onset of hypothyroidism in pregnant women with excessive iodine intake.


Infective endocarditis of native valve after anterior nasal packing.
We present a case report of a patient who was previously treated for spontaneous epistaxis with a petroleum jelly gauze (0.5 in x 72 in) anterior nasal packing filled with an antibiotic ointment, along with prophylactic oral clindamycin. The patient presented with fever and hypotension 3 days after the nasal packing. Her blood cultures grew methicillin-resistant Staphylococcus aureus and the transesophageal echocardiography showed vegetation on the atrial surface of the posterior mitral valve leaflet, confirming the diagnosis of bacterial endocarditis attributable to nasal packing. Several case reports discuss toxic shock syndrome after nasal packing, but none describe endocarditis of the native heart valves subsequent to anterior nasal packing. Current guidelines on endocarditis prophylaxis produced by the American Heart Association, European Cardiac Society, and British Cardiac Society together with published evidence do not recommend endocarditis prophylaxis for patients with native heart valves undergoing anterior nasal packing.


Haloacid induced alterations in fertility and the sperm biomarker SP22 in the rat are additive: validation of an ELISA.
Dibromoacetic acid (DBA) and bromochloroacetic acid (BCA) are prevalent disinfection by-products of drinking water that produce defects in spermatogenesis and fertility in adult rats. Previously we demonstrated that BCA compromises the fertility of cauda epididymal rat sperm and SP22, a sperm membrane protein that is highly correlated with the fertility of these sperm. Herein, we administered DBA and BCA, individually and in combination, to determine whether fertility and levels of SP22 on sperm were diminished in an additive fashion. Moreover, we wished to validate an immunoassay for quantitation of SP22. In a dose finding study, animals were exposed by oral gavage daily for 14 days to: BCA alone at 1.6, 4, and 8 mg/kg; DBA at equimolar levels of 2, 5, and 10 mg/kg; and two binary mixtures of 1.6 mg/kg BCA + 2 mg/kg DBA and 4 mg/kg BCA + 5 mg/kg DBA. The ED(50)s for the decrease in SP22 quantified by two-dimensional SDS-PAGE were 7.2 and 4.6 mg/kg for DBA and BCA. The ED(50)s for the decrease in SP22 quantified by ELISA were 8.1 and 5.9 mg/kg for DBA and BCA. The definitive study consisted of 2 and 4 mg/kg DBA, 1.6 and 3.2 mg/kg BCA, and a 2 mg/kg DBA + 1.6 mg/kg BCA mixture. The ED(50)s for decreases in fertility assessed by intrauterine insemination were 3.5 mg/kg and 2.7 mg/kg for DBA and BCA. Immunolocalization of SP22 in spermatocytes and spermatids, as well as on the cytoplasmic droplet and the equatorial segment of luminal sperm, was decreased by the DBA + BCA mixture. The decrease in SP22 in testicular parenchyma was comparable to that observed for sperm extracts. Based on 2D SDS-PAGE, ELISA, or fertility the haloacid-induced decreases in SP22 or fertility were additive or synergistic. The correlation between SP22 levels by ELISA and fertility was r(2) = 0.72 compared to 0.82 for SP22 levels by 2D SDS-PAGE and fertility, validating SP22 quantitation by ELISA.


Educating registered nurses and healthcare support workers on nutrition and tissue viability.
This article provides an outline of an educational programme designed to inform and guide registered nurses and healthcare support workers on understanding the connection between nutrition and wound healing, with the aim of helping them recognise malnutrition in older community-dwelling adults with wounds. The Agents for Nutrition and Tissue Viability programme was set up 9 years ago, The Agents for Nutrition and Tissue Viability Programme was set up 9 years ago within an acute trust and has since then has been rolled out to a local community trust. Benefits have included greater networking between acute and community trusts and quality improvements for patients.


Large deviation theory for coin tossing and turbulence.
Large deviations play a significant role in many branches of nonequilibrium statistical physics. They are difficult to handle because their effects, though small, are not amenable to perturbation theory. Even the Gaussian model, which is the usual initial step for most perturbation theories, fails to be a starting point while discussing intermittency in fluid turbulence, where large deviations dominate. Our contention is: in the large deviation theory, the central role is played by the distribution associated with the tossing of a coin and the simple coin toss is the "Gaussian model" of problems where rare events play significant role. We illustrate this by applying it to calculate the multifractal exponents of the order structure factors in fully developed turbulence.


N-Heterocyclic Carbene Catalyzed Synthesis of Dihydroxybenzophenones from β-Methylenals and Aurones.
N-heterocyclic carbene catalyzed synthesis of 2,2'-dihydroxybenzophenones from β-methylenals and aurones was developed. The cleavage of the C-O bond by a retro-Michael addition is the key step from the spirocyclic intermediate to final product.


Dengue prediction by the web: Tweets are a useful tool for estimating and forecasting Dengue at country and city level.
Infectious diseases are a leading threat to public health. Accurate and timely monitoring of disease risk and progress can reduce their impact. Mentioning a disease in social networks is correlated with physician visits by patients, and can be used to estimate disease activity. Dengue is the fastest growing mosquito-borne viral disease, with an estimated annual incidence of 390 million infections, of which 96 million manifest clinically. Dengue burden is likely to increase in the future owing to trends toward increased urbanization, scarce water supplies and, possibly, environmental change. The epidemiological dynamic of Dengue is complex and difficult to predict, partly due to costly and slow surveillance systems. In this study, we aimed to quantitatively assess the usefulness of data acquired by Twitter for the early detection and monitoring of Dengue epidemics, both at country and city level at a weekly basis. Here, we evaluated and demonstrated the potential of tweets modeling for Dengue estimation and forecast, in comparison with other available web-based data, Google Trends and Wikipedia access logs. Also, we studied the factors that might influence the goodness-of-fit of the model. We built a simple model based on tweets that was able to 'nowcast', i.e. estimate disease numbers in the same week, but also 'forecast' disease in future weeks. At the country level, tweets are strongly associated with Dengue cases, and can estimate present and future Dengue cases until 8 weeks in advance. At city level, tweets are also useful for estimating Dengue activity. Our model can be applied successfully to small and less developed cities, suggesting a robust construction, even though it may be influenced by the incidence of the disease, the activity of Twitter locally, and social factors, including human development index and internet access. Tweets association with Dengue cases is valuable to assist traditional Dengue surveillance at real-time and low-cost. Tweets are able to successfully nowcast, i.e. estimate Dengue in the present week, but also forecast, i.e. predict Dengue at until 8 weeks in the future, both at country and city level with high estimation capacity.


RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer.
In order to metastasise, triple negative breast cancer (TNBC) must make dynamic changes in cell shape. The shape of all eukaryotic cells is regulated by Rho Guanine Nucleotide Exchange Factors (RhoGEFs), which activate Rho-family GTPases in response to mechanical and informational cues. In contrast, Rho GTPase-activating proteins (RhoGAPs) inhibit Rho GTPases. However, which RhoGEFs and RhoGAPS couple TNBC cell shape to changes in their environment is very poorly understood. Moreover, whether the activity of particular RhoGEFs and RhoGAPs become dysregulated as cells evolve the ability to metastasise is not clear. Towards the ultimate goal of identifying RhoGEFs and RhoGAPs that are essential for TNBC metastasis, we performed an RNAi screen to isolate RhoGEFs and RhoGAPs that contribute to the morphogenesis of the highly metastatic TNBC cell line LM2, and its less-metastatic parental cell line MDA-MB-231. For ~6 million cells from each cell line, we measured 127 different features following the depletion of 142 genes. Using a linear classifier scheme we also describe the morphological heterogeneity of each gene-depleted population.


Long-term study with gabapentin in patients with drug-resistant epileptic seizures.
To study the efficacy and safety of gabapentin in long-term treatment. A 4-year follow-up study of 25 patients with visits at 3-month intervals. The patients were followed up in the outpatient unit of the University Hospital of Kuopio (Finland). We treated 25 patients with drug-resistant complex partial seizures and secondarily generalized seizures in an open-label long-term study, using gabapentin as an additional means of therapy after a 3-month double-blind, placebo-controlled phase. Thirteen patients showed no benefit from gabapentin; the study medication was discontinued after 4 to 6 months of treatment. Of the 12 patients who responded enough to continue treatment, five were withdrawn due to different reasons, one because of loss of response. The number of patients receiving the study drug in the follow-up and reduction of seizure frequency from baseline level as analyzed by the Wilcoxon test. Seven patients received gabapentin therapy for more than 4 years. The median follow-up time was 54 months. There was a significant reduction in seizure frequency throughout the follow-up period. Five of seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the 25 patients who entered the study. Gabapentin possesses good efficacy in long-term treatment of patients with partial and secondarily generalized epileptic seizures. It is safe to use, and it is fairly well tolerated even in long-term treatment.


Safety Surveillance of Varicella Vaccines in the Vaccine Adverse Event Reporting System, United States, 2006-2020.
. The Vaccine Adverse Event Reporting System (VAERS) is the United States national passive vaccine safety surveillance system. We updated the data on the safety of single-antigen varicella vaccine (VAR) and assessed the safety of combination measles, mumps, rubella, and varicella vaccine (MMRV) licensed in the United States using VAERS data. US VAERS reports received after administration of VAR and MMRV during 2006-2020 were identified. Reports were analyzed by vaccine type, age, seriousness, most common adverse events (AEs), and concomitant vaccines. We reviewed medical records of selected reports of AEs of special interest and conducted empirical Bayesian data mining to identify disproportionally reported AEs. During 2006-2020, approximately 132.8 million VAR doses were distributed; 40 684 reports were received in VAERS (30.6/100 000 doses distributed), with 4.1% classified as serious (1.3/100 000 doses distributed). Approximately 35.5 million MMRV doses were distributed; 13 325 reports were received (37.6/100 000 doses distributed) with 3.3% classified as serious (1.3/100 000 doses distributed). The most common adverse health events after both VAR and MMRV were injection site reactions (31% and 27%), rash (28% and 20%), and fever (12% and 14%), respectively. Vaccination errors accounted for 23% of reports after VAR administration and 41% after MMRV administration, but ≥95% of them did not describe an adverse health event. AEs associated with evidence of vaccine strain varicella-zoster virus (vVZV) infection included meningitis, encephalitis, herpes zoster, and 6 deaths (all in immunocompromised persons with contraindications for vaccination). No new or unexpected AE was disproportionally reported. No new or unexpected safety findings were detected for VAR and MMRV given as recommended, reinforcing the favorable safety profiles of these vaccines. Providers should obtain specimens for viral testing and strain-typing for serious AEs if they consider vVZV as the possible causative agent.


Overexpression of MutSα Complex Proteins Predicts Poor Prognosis in Oral Squamous Cell Carcinoma.
The DNA mismatch repair (MMR) system is responsible for the detection and correction of errors created during DNA replication, thereby avoiding the incorporation of mutations in dividing cells. The prognostic value of alterations in MMR system has not previously been analyzed in oral squamous cell carcinoma (OSCC).The study comprised 115 cases of OSCC diagnosed between 1996 and 2010. The specimens collected were constructed into tissue microarray blocks. Immunohistochemical staining for MutSα complex proteins hMSH2 and hMSH6 was performed. The slides were subsequently scanned into high-resolution images, and nuclear staining of hMSH2 and hMSH6 was analyzed using the Nuclear V9 algorithm. Univariable and multivariable Cox proportional hazard regression models were performed to evaluate the prognostic value of hMSH2 and hMSH6 in OSCC.All cases in the present cohort were positive for hMSH2 and hMSH6 and a direct correlation was found between the expression of the proteins (P < 0.05). The mean number of positive cells for hMSH2 and hMSH6 was 64.44 ± 15.21 and 31.46 ± 22.38, respectively. These values were used as cutoff points to determine high protein expression. Cases with high expression of both proteins simultaneously were classified as having high MutSα complex expression. In the multivariable analysis, high expression of the MutSα complex was an independent prognostic factor for poor overall survival (hazard ratio: 2.75, P = 0.02).This study provides a first insight of the prognostic value of alterations in MMR system in OSCC. We found that MutSα complex may constitute a molecular marker for the poor prognosis of OSCC.


Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients.
Combination of disease-modifying antirheumatic drugs (DMARDs) is increasingly used in the treatment of rheumatoid arthritis (RA) patients. Hepatotoxicity has been an important safety concern with DMARDs therapy. Though leflunomide (CAS 75706-12-6) has emerged as an effective oral DMARD, its use is associated with hepatotoxicity. Limited data is available regarding hepatotoxic risk when leflunomide is used in combination therapy in RA patients. An open-label, prospective study was conducted to evaluate the hepatotoxic risk after addition of leflunomide with other DMARDs in RA patients, who did not respond to their ongoing DMARD therapy. A total of 46 patients were enrolled and leflunomide was given as add-on therapy with earlier DMARDs. Biochemical parameters of serum aminotransferase levels (AST and ALT) were estimated at the baseline and then every month after addition of leflunomide. Study results showed that 13.0% patients developed > 1.5 to < 2 times upper limit of normal (ULN) elevation; 6.5% patients developed > 2 to < 3 times the ULN elevation and 2.2% patients developed > 3 times the ULN elevation. In 20% of the patients with hepatic enzyme elevations, enzyme levels returned to normal within 4-6 weeks after discontinuation of leflunomide therapy, whereas in 50% of patients the dose of leflunomide was reduced from 20 mg/day to 10 mg/day for normalization of enzymes levels. 30% of patients were continued with leflunomide without dose reduction. None of the patients showed clinical signs and symptoms of hepatotoxicity. Leflunomide therapy with other DMARDs requires strict monitoring of serum aminotransferases.


The California Child Health and Development Studies of the School of Public Health, University of California at Berkeley.
The Child Health and Development Studies are prospective longitudinal studies on medical and social aspects of pregnancies and on the health and development of children. Data have been assembled on about 20,000 pregnancies occurring in one hospital between 1959 and 1967, and on follow-up of the children through adolescence. A currently ongoing project updates certain vital statistics of the entire study population. The data assembled in this longitudinal study supported a wide range of research projects, several of which proved to be important for the health of mothers and children. Notwithstanding, subsets of the assembled data, with potential value for public health, have not yet been explored. The data archive has been made accessible to the research community at large so that other significant research topics can be investigated. In the following article, brief descriptions are given of the history and design of the Child Health and Development Studies, of the contents of the data archive, and of the major areas of research that have been explored. Procedures to obtain access to the data and to the user's manual are explained, and a bibliography is included.


Stability of anthocyanins from red grape skins under pressurized liquid extraction and ultrasound-assisted extraction conditions.
The stability of anthocyanins from grape skins after applying different extraction techniques has been determined. The following compounds, previously extracted from real samples, were assessed: delphinidin 3-glucoside, cyanidin 3-glucoside, petunidin 3-glucoside, peonidin 3-glucoside, malvidin 3-glucoside, peonidin 3-acetylglucoside, malvidin 3-acetylglucoside, malvidin 3-caffeoylglucoside, petunidin 3-p-coumaroylglucoside and malvidin 3-p-coumaroylglucoside (trans). The techniques used were ultrasound-assisted extraction and pressurized liquid extraction. In ultrasound-assisted extraction, temperatures up to 75 °C can be applied without degradation of the aforementioned compounds. In pressurized liquid extraction the anthocyanins were found to be stable up to 100 °C. The relative stabilities of both the glycosidic and acylated forms were evaluated. Acylated derivatives were more stable than non-acylated forms. The differences between the two groups of compounds became more marked on working at higher temperatures and on using extraction techniques with higher levels of oxygen in the extraction media.


Characterization and developmental expression of AmphiNk2-2, an NK2 class homeobox gene from Amphioxus. (Phylum Chordata; Subphylum Cephalochordata).
The genome of amphioxus includes AmphiNk2-2, the first gene of the NK2 homeobox class to be demonstrated in any invertebrate deuterostome. AmphiNk2-2 encodes a protein with a TN domain, homeodomain, and NK2-specific domain; on the basis of amino acid identities in these conserved regions, AmphiNk2-2 is a homolog of Drosophila vnd and vertebrate Nkx2-2. During amphioxus development, expression of Amph- iNk2-2 is first detected ventrally in the endoderm of late gastrulae. In neurulae, endodermal expression divides into three domains (the pharynx, midgut, and hindgut), and neural expression commences in two longitudinal bands of cells in the anterior neural tube. These neural tube cells occupy a ventrolateral position on either side of the cerebral vesicle (the probable homolog of the vertebrate diencephalic forebrain). The dynamic expression patterns of AmphiNkx2-2 suggest successive roles, first in regionalizing the endoderm and nervous system and later during differentiation of specific cell types in the gut (possibly peptide endocrine cells) and brain (possibly including axon outgrowth and guidance).


Tinidazole in anaerobic infections: a review of its antibacterial activity, pharmacological properties and therapeutic efficacy.
Tinidazole, like the structurally-related drug metronidazole, was initially introduced for treating protozoal infections. However, both these nitroimidazole compounds are also active in vitro against most clinically important obligate anaerobes. Most of the clinical experience with tinidazole to date has involved prophylactic use to prevent postoperative anaerobic infection. Prospective placebo-controlled studies demonstrated that a single dose of tinidazole administered orally prior to elective colorectal surgery significantly reduced postoperative infection. Similarly, when given intravenously prior to appendectomy, tinidazole reduced the incidence of postoperative infection in some subgroups of patients. Although results of non-blinded studies with prophylactic tinidazole were encouraging when used in women undergoing gynaecological surgery (mainly hysterectomy), results from double-blind placebo-controlled studies in this situation have been somewhat equivocal. Thus, although the overall weight of evidence suggests that the drug is effective in this area of use, further study is needed to clarify its role in preventing anaerobic infection following gynaecological surgery compared with other antibiotics which can also be used for this purpose. Relatively few studies have been conducted with tinidazole in the treatment of established anaerobic infections, and this is an area needing further investigation. The drug is well tolerated when administered orally or intravenously.


Decrease of core body temperature in mice by dehydroepiandrosterone.
Dietary dehydroepiandrosterone (DHEA) reduces food intake in mice, and this response is under genetic control. Moreover, both food restriction and DHEA can prevent or ameliorate certain diseases and mediate other biological effects. Mice fed DHEA (0.45% w/w of food) and mice pair-fed to these mice (food restricted) for 8 weeks were tested for changes in body temperature. DHEA was more efficient than food restriction alone in causing hypothermia. DHEA injected intraperitoneally also induced hypothermia that reached a nadir at 1 to 2 hr, and slowly recovered by 20 to 24 hr. This effect was dose dependent (0.5-50 mg). Each mouse strain tested (four) was susceptible to this effect, suggesting that the genetics differ for induction of hypophagia and induction of hypothermia. Because serotonin and dopamine can regulate (decrease) body temperature, we treated mice with haloperidol (dopamine receptor antagonist), 5,7-dihydroxytryptamine (serotonin production inhibitor), or ritanserin (serotonin receptor antagonist) prior to injection of DHEA. All of these agents increased rather than decreased the hypothermic effects of DHEA. DHEA metabolites that are proximate (5-androstene-3beta, 17beta-diol and androstenedione) or further downstream (estradiol-17beta) were much less effective than DHEA in inducing hypothermia. However, the DHEA analog, 16alpha-chloroepiandrosterone, was as active as DHEA. Thus, DHEA administered parentally seems to act directly on temperature-regulating sites in the body. These results suggest that DHEA induces hypothermia independent of its ability to cause food restriction, to affect serotonin or dopamine functions, or to act via its downstream steroid metabolites.


The human glycinamide ribonucleotide transformylase domain: purification, characterization, and kinetic mechanism.
Glycinamide ribonucleotide transformylase catalyzes the third reaction of de novo purine biosynthesis, namely, the conversion of glycinamide ribonucleotide to N-formylglycinamide ribonucleotide, with concomitant conversion of 10-formyltetrahydrofolate to tetrahydrofolate. This activity has been shown to be a target for cancer chemotherapy, which has generated renewed interest in both the enzyme and the pathway. Moreover, in higher eukaryotes this activity constitutes the C-terminal domain of a monomeric protein which also catalyzes two additional reactions of de novo purine biosynthesis. In this study, the human glycinamide ribonucleotide transformylase domain has been expressed to high levels in Escherichia coli and purified to homogeneity. Our improved expression-purification system produces the desired activity exclusively in a soluble form and in higher abundance than previously achieved. The kinetic constants have been determined and the kinetic mechanism has been established as ordered-sequential, with the folate substrate binding first. The correspondence of these data to those obtained for the glycinamide ribonucleotide transformylase activity of the mammalian trifunctional enzyme indicates that the recombinant enzyme is fully functional.


Relationship between burden of infection in ungulate populations and wildlife/livestock interfaces.
In southern African transfrontier conservation areas (TFCAs), people, livestock and wildlife share space and resources in semi-arid landscapes. One consequence of the coexistence of wild and domestic herbivores is the risk of pathogen transmission. This risk threatens local livelihoods relying on animal production, public health in the case of zoonoses, national economies in the context of transboundary animal diseases, and the success of integrated conservation and development initiatives. The level of interaction between sympatric wild and domestic hosts, defining different wildlife/livestock interfaces, characterizes opportunities of pathogen transmission between host populations. Exploring the relationship between infection burden and different types of wildlife/domestic interfaces is therefore necessary to manage the sanitary risk in animal populations through control options adapted to these multi-host systems. Here, we assessed the infection burdens of sympatric domestic cattle (Bos taurus/Bos indicus) and African buffalo (Syncerus caffer) at an unfenced interface and compared the infection burdens of cattle populations at different wildlife/livestock interfaces in the Great Limpopo TFCA. Patterns of infection in ungulate populations varied between wild and domestic hosts and between cattle populations at different wildlife/livestock interfaces. Foot-and-mouth disease, Rift Valley fever and theileriosis infections were detected in buffalo and cattle at unfenced interfaces; bovine tuberculosis was only present in buffalo; and brucellosis and lumpy skin disease only in cattle. At unfenced interfaces, cattle populations presented significantly higher Theileria parva and brucellosis prevalence. We hypothesize that cattle populations at wildlife/livestock interfaces face an increased risk of infection compared to those isolated from wildlife, and that the type of interface could influence the diversity and quantity of pathogens shared. Additional host behavioural and molecular epidemiological studies need to be conducted to support this hypothesis. If it is confirmed, the management of wildlife/livestock interfaces will need to be considered through the prism of livestock and public health.


Lymphocyte surface markers and cytokines are suitable for detection and potency assessment of skin-sensitizing chemicals in an in vitro model of allergic contact dermatitis: the LCSA-ly.
Allergic contact dermatitis is a widespread health disorder and occupational skin disease. Hence, screening for contact-sensitizing chemicals is highly relevant to toxicology, dermatology, and occupational medicine. The use of animal tests for this purpose is constrained by ethical considerations, need for high-throughput screening, and legislation (e.g., for cosmetics in the European Union). T cell activation is the final and most specific key event of the "adverse outcome pathway" for skin sensitization and therefore a promising target for the development of in vitro sensitization assays. We present a novel in vitro sensitization assay with a lymphocyte endpoint as an add-on to the loose-fit coculture-based sensitization assay (LCSA): the LCSA-ly. While the LCSA measures dendritic cell activation, the LCSA-ly offers the option for an additional lymphocyte endpoint which can be measured concurrently. We incorporated lymphocytes in our previously established coculture of primary human keratinocytes and monocyte-derived dendritic cells and tested nine substances: five sensitizers [2,4-dinitrochlorobenzene (DNCB) 1.25-15 µmol/l, p-phenylenediamine (PPD) 15.6-125 µmol/l, 2-mercaptobenzothiazole (MBT) 50-1000 µmol/l, coumarin, and resorcinol (both: 250-1500 µmol/l)] and four non-sensitizers (monochlorobenzene, caprylic acid, glycerol, and salicylic acid (all: 125-1000 µmol/l)]. DNCB and MBT increased a subset of IL-23 receptor+/IFN-γ receptor 1 (CD119)+ lymphocytes. DNCB, PPD, and MBT enhanced a subunit of the IL-4 receptor (CD124) and a memory marker (CD44) on lymphocytes. Remarkably, DNCB, PPD, and MBT raised IL-4 concentrations in coculture supernatants while IFN-γ levels decreased, which might point to Th2 activation in vitro. Coumarin, resorcinol, and non-sensitizers did not alter any of the tested surface markers or cytokines. IL-17 was not affected by any of the substances. Relative strength of sensitizers according to lymphocyte markers was DNCB > PPD > MBT, which corresponds to earlier results from the LCSA without lymphocyte endpoint, the murine local lymph node assay, and human data. This study is the first to prove the suitability of lymphocyte surface markers for sensitization testing and potency assessment.


Prognostic Significance of the Dynamic Change of Programmed Death-ligand 1 Expression in Patients with Multiple Myeloma.
Background The inhibition of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway has been shown to be an effective targeted therapy in fighting both solid organ cancers and hematological malignancies. PD-L1 expression also serves as a prognostic marker in various cancers. However, the expression of PD-L1 and its prognostic significance in multiple myeloma remains largely unknown. Methods Immunohistochemistry staining of PD-L1 was performed in bone marrow biopsy samples (total of 85 samples) in 32 myeloma patients receiving autologous stem cell transplant (ASCT) at various time points: before ASCT, post-ASCT, and/or at relapse after ASCT. More than 1% of myeloma cells with PD-L1 staining was considered a positive expression of PD-L1. A correlation analysis was performed between post-ASCT overall survival (OS) and the status of PD-L1 expression. Results In this pilot study, a total of 11 patients (34%) out of our cohort (32 patients) were positive for PD-L1 expression at least once during the course of the disease. A dynamic change of PD-L1 expression was noted in three patients converting from negative (before ASCT) to positive (post-ASCT) and two patients converting from positive (before ASCT) to negative (post-ASCT). Patients with positive PD-L1 expression persisting or occurring post-ASCT had shorter post-ASCT overall survival than those with negative PD-L1 expression post-ASCT (median survival: 13 vs 23 months, p<0.05). No significant differences were detected in the known prognostic factors between these two groups at the time of ASCT. Pre-transplant PD-L1 expression status, however, showed no significant impact on post-ASCT overall survival. Furthermore, a few patients switching from positive PD-L1 expression before ASCT to negative PD-L1 expression post-ASCT had a relatively good post-ASCT overall survival (n=2, overall survival of 29 and 56 months, respectively). Conclusion Immunohistochemistry can be reliably used for measuring PD-L1 expression in decalcified marrow core biopsy materials. Our results suggest that positive PD-L1 expression persisting/occurring post-ASCT could be an adverse prognostic marker for post-ASCT OS. Additionally, PD-L1 expression appears to be dynamic and is subjected to change after ASCT. Our findings suggest that periodically monitoring PD-L1 expression in patients with multiple myeloma post-ASCT is warranted. Further studies are needed to confirm our initial observation and to evaluate if timely intervention with PD-L1 blockade can improve post-ASCT outcomes in myeloma patients.


The Language of Innovation.
Predicting innovation is a peculiar problem in data science. Following its definition, an innovation is always a never-seen-before event, leaving no room for traditional supervised learning approaches. Here we propose a strategy to address the problem in the context of innovative patents, by defining innovations as never-seen-before associations of technologies and exploiting self-supervised learning techniques. We think of technological codes present in patents as a vocabulary and the whole technological corpus as written in a specific, evolving language. We leverage such structure with techniques borrowed from Natural Language Processing by embedding technologies in a high dimensional euclidean space where relative positions are representative of learned semantics. Proximity in this space is an effective predictor of specific innovation events, that outperforms a wide range of standard link-prediction metrics. The success of patented innovations follows a complex dynamics characterized by different patterns which we analyze in details with specific examples. The methods proposed in this paper provide a completely new way of understanding and forecasting innovation, by tackling it from a revealing perspective and opening interesting scenarios for a number of applications and further analytic approaches.


Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.
Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.


Effect of in vivo and in vitro surface protein deposits on the oxygen permeability of polyhydroxyethylmethacrylate gel contact lenses.
The effect of surface protein deposits on the oxygen permeability of polyhydroxyethylmethacrylate ( polyHEMA ) gel contact lenses was studied using: (1) previously worn lenses with protein deposits accumulated in vivo, and (2) new lenses with protein deposited in vitro. The oxygen permeability (Dk) of the protein-deposited in vivo lenses was determined before and after cleaning, and that of the new lenses before and after in vitro protein deposition. For both groups of lenses, the oxygen permeability did not change significantly after either cleaning (in vivo lenses) or protein deposition (in vitro lenses). It is concluded that surface protein deposits on polyHEMA lenses do not alter the oxygen permeability of the lenses.


Expression of integrin beta1 and its roles on adhesion between different cell cycle hepatocellular carcinoma cells (SMMC-7721) and human umbilical vein endothelial cells.
To investigate expression of integrin beta1 and its roles on adhesion between different cell cycle hepatocellular carcinoma cell (HCC) and human umbilical vein endothelial cells (HUVEC), the synchronous G1 and S phase HCC were achieved through thymine-2-deoxyriboside and colchicines sequential blockage method and double thymine-2-deoxyriboside blockage method, respectively. Expression of integrin beta1 on hepatocellular carcinoma cells was detected with flow cytometer. Further, the adhesive force of HCC to HUVEC and the role of integrin beta1 in this adhesive course were studied by micropipette aspiration technique. The results showed that percentage of each cyclic phases of the controlled HCC (non-synchronous) are: G2 + M phase, 11%; G1 phase, 54%; S phase, 36%; the synchronous rates of G1 and S phase HCC amount to 74 and 98%, respectively. The expressive fluorescent intensity of integrin beta1 in G1 phase HCC is depressed significantly than the values of S phase and controlled HCC. Accordingly, the adhesive forces of G1 phase HCC to HUVEC was significantly lower than the value of S phase cells (P < 0.01), but it has no remarkable difference when compared the adhesive force values of S phase HCC with control; the contribution of integrin beta1 was about 50% in the adhesion of HCC to HUVEC. It suggested that HCC would be synchronized preferably in G1 and S phase with thymine-2-deoxyriboside and colchicines, the adhesive molecule integrin beta1 expressed in a high lever in HCC and presented differences in vary cell cycle, and integrin beta1 played an important roles in adhesion of HCC to HUVEC. Possibly, S phase HCC take a great action in this adhesive course.


Risk factors for intraoperative floppy iris syndrome: a meta-analysis.
To evaluate risk factors (hypertension, diabetes mellitus, and current tamsulosin, alfuzosin, terazosin, or doxazosin use) for intraoperative floppy iris syndrome (IFIS) in patients undergoing phacoemulsification cataract surgery. Systematic review and meta-analysis of the literature. Seventeen eligible studies (17 588 eyes) examining the association between IFIS and risk factors. Pertinent publications were identified through a systematic search of PubMed. All references of relevant reviews and eligible articles were also screened. Language restrictions were not used, and data were extracted from each eligible study by 2 investigators working independently. For medications, 2 separate analyses were performed: an analysis using a dichotomous criterion (use/non-use of the examined agent) and an alternative analysis performing comparisons with patients not receiving any α(1)-blocker. The fixed-effects model (Mantel-Haenszel method) or the random-effects (DerSimonian Laird) model was appropriately used to calculate the pooled odds ratio (OR). Publication bias was appropriately assessed. Pooled OR for the incidence of IFIS. The pooled OR for IFIS after tamsulosin use was approximately 40-fold greater (or 16.5 at the alternative analysis) than that after alfuzosin use, that is, the second α(1)-blocker in order of effect size. Alfuzosin and terazosin were also associated with IFIS with comparable ORs; the effect of doxazosin reached formal statistical significance at the alternative analysis. Intraoperative floppy iris syndrome was positively associated with hypertension (pooled OR = 2.2, 95% confidence interval [CI], 1.2-4.2, fixed effects) but not with diabetes mellitus (pooled OR = 1.3, 95% CI, 0.7-2.2, fixed effects). This meta-analysis has highlighted a hierarchy concerning the role of α(1)-blockers in IFIS, indicating an extremely sizeable effect size of tamsulosin; this may entail important physiologic implications. Alfuzosin, terazosin, and doxazosin presented with comparable effect sizes. Hypertension, but not diabetes mellitus, emerged as a risk factor for IFIS.


Vectorial extreme events in VCSEL polarization dynamics.
We report on the occurrence of extreme events (EEs) in the polarization dynamics of vertical cavity surface emitting lasers with optical feedback. We have identified two types of EEs based on numerical simulations: vectorial and scalar events corresponding, respectively, to the emission of a high-power pulse in both linear polarizations simultaneously and in single linear polarization. We show that these two types of events follow the typical statistics of rogue waves. Finally, we observe that an emission in both polarizations leads to a larger generation rate of EEs with a saturation over a wide range of feedback strength by comparison to a single-polarization mode emission.


Asymptotic shape of the region visited by an Eulerian walker.
We study an Eulerian walker on a square lattice, starting from an initial randomly oriented background using Monte Carlo simulations. We present evidence that, for a large number of steps N , the asymptotic shape of the set of sites visited by the walker is a perfect circle. The radius of the circle increases as N1/3, for large N , and the width of the boundary region grows as Nalpha/3, with alpha=0.40+/-0.06 . If we introduce stochasticity in the evolution rules, the mean-square displacement of the walker, <RN2> approximately <RN2> approximately N2nu, shows a crossover from the Eulerian (nu=1/3) to a simple random-walk (nu=1/2) behavior.


Geography of the circadian gene clock and photoperiodic response in western North American populations of the three-spined stickleback Gasterosteus aculeatus.
Controlled laboratory experiments were used to show that Oregon and Alaskan three-spined stickleback Gasterosteus aculeatus, collected from locations differing by 18° of latitude, exhibited no significant variation in length of the polyglutamine domain of the clock protein or in photoperiodic response within or between latitudes despite the fact that male and female G. aculeatus are photoperiodic at both latitudes. Hence, caution is urged when interpreting variation in the polyglutamine repeat (PolyQ) domain of the gene clock in the context of seasonal activities or in relationship to photoperiodism along geographical gradients.


Green chemical functionalization of single-walled carbon nanotubes in ionic liquids.
Single walled carbon nanotubes (SWNTs) are exfoliated and functionalized predominantly as individuals by grinding them for minutes at room temperature with aryldiazonium salts in the presence of ionic liquids (ILs) and K(2)CO(3). This constitutes an extremely rapid and mild green chemical functionalization process for obtaining the individualized nanotube structures. A number of ILs and various reaction conditions were surveyed. Raman, XPS, UV/vis/NIR spectroscopies, thermogravimetric analysis, and atomic force and transmission electron microscopies were used to characterize the products.


Frontiers in polymer chemistry.
The article shows how the initial concept of Staudinger on linear macromolecules was expanded topologically by increasing the cross-section diameter of polymer chains and by introducing sheet polymers with planar rather than the commonly known linear repeat units. The two concrete projects addressed are the synthesis of dendronized and of two-dimensional polymers. It is explained how these novel macromolecules were achieved and which obstacles had to be overcome but also where these frontiers in polymer chemistry might lead to new insights in polymer science in general and novel applications in particular. The article also provides insights into analytical issues because both target macromolecules are in an extraordinarily high molar mass range and contrast/sensitivity issues can turn rather serious in particular for the two-dimensional polymers.


Larval spirurida (Nematoda) from the crab Macrophthalmus hirtipes in New Zealand.
Previously undescribed third-stage larvae of two species of Spirurida were found in the haemocoel of the stalk-eyed mud crab Macrophthalmus hirtipes (Heller) (Ocypodidae) in New Zealand. Examinations by light and scanning electron microscopy showed that the larger larvae (about 7 mm long) belonged to a species of Ascarophis van Beneden, 1871 (Cystidicolidae), the genus including parasites of fishes, whereas the smaller larvae (about 4-5 mm long) belonged to the Acuariidae, a family with species parasitic as adults mostly in aquatic birds. In a sample of 82 specimens of M. hirtipes collected in July 2002 from Papanui Inlet, on Otago Peninsula, South Island, 74 crabs (90.2%) were infected with larval nematodes with an intensity of 1-18 (mean 4.6) nematodes per crab; no distinction between nematode species was made in these estimates, although juvenile Acuariidae greatly outnumbered larval Ascarophis. Apparently, crabs play a role as intermediate hosts of these nematode species. This is the first record of larval representatives of Cystidicolidae and Acuariidae from invertebrates in the Australasian Region.


[Premedication using intrarectal midazolam. Study of effective dosage in pediatric anesthesia].
The object of this study was to determine the optimal dose of midazolam given per rectum which would produce sedation adequate for inducing inhalational anaesthesia in paediatric practice. Five doses were studied: 0.15, 0.25, 0.30, 0.35 and 0.40 mg X kg-1. The criteria used to appreciate the effectiveness of the sedation at 30 min were the change in the child's behaviour, with a scale of 6 levels, and the acceptance of the mask and anaesthetic vapours. There was a significant correlation between the dose administered and the degree of sedation, as well as between the dose administered and the lack of reaction to the mask. Significantly better results were found with the higher doses of 0.35 and 0.40 mg X kg-1, when compared with the children who had received 0.15 and 0.25 mg X kg-1. Only in the groups who received 0.35 and 0.40 mg X kg-1 were the degrees of sedation and acceptance of induction considered as adequate. The dose of 0.35 mg X kg-1 seemed to be the best dose for adequately premedicating a child.


Reactive oxygen species signaling in plants.
The evolution of aerobic metabolism such as respiration and photosynthesis resulted in the generation of reactive oxygen species (ROS). A common property of all ROS types is that they can cause oxidative damage to proteins, DNA, and lipids. This toxicity of ROS explains the evolution of complex arrays of nonenzymatic and enzymatic detoxification mechanisms in plants. However, increasing evidence indicates that plants also make use of ROS as signaling molecules for regulating development and various physiological responses. In this review, novel insights into the mechanisms of how plants sense and respond to ROS are discussed in the context of the biological effects and functions of ROS in plants.


Analyzing the epidemic situation and influencing factors of childhood pneumonia during the COVID-19 epidemic period in Laiwu, China.
This study aimed to analyze the trends of childhood pneumonia before and after the corona virus disease 2019 (COVID-19) pandemic in Laiwu, China, and explore the associated risk factors to provide a reference for the prevention, control, and treatment of childhood pneumonia. In this cross-sectional study, data were collected from 11,716 children aged 3 to 12 years who underwent chest radiography/computed tomography from January 2018 to December 2021 in Laiwu, China. The generalized estimating equation model was used to analyze the time trend of the pneumonia detection rate. Multivariate logistic regression analysis was used to analyze the risk factors for pneumonia in children. The overall pneumonia detection rate was 40.3% (4721/11,716). The pneumonia detection rate was 41.5% and 39.5% in 2018 and 2019, respectively, before the COVID-19 pandemic, which decreased to 38.1% in 2020 during the pandemic and increased to 40.7% in 2021 after the pandemic. Multivariate logistic regression analysis showed that preterm birth (odds ratio [OR] = 1.68), frequent exposure to secondhand smoke (OR = 1.79), hospitalization ≥ 1 time in half a year (OR = 2.13), and history of allergic rhinitis (OR = 2.14) were risk factors for pneumonia in children. Wearing masks when outdoors (OR = 0.89) and engaging in regular physical activity (OR = 0.65) were protective factors. The pneumonia detection rate in children showed a decreasing trend during the COVID-19 pandemic in 2020 but an increasing trend after the pandemic in 2021. Premature birth, exposure to secondhand smoke, frequent hospitalization, and allergic rhinitis were risk factors for pneumonia in children. Wearing masks when outdoors and exercising may reduce the risk of pneumonia in children.


Would I take antipsychotics, if I had psychotic symptoms? Examining determinants of the decision to take antipsychotics.
Poor adherence to treatment in schizophrenia is mainly associated to patients-related factors. However, social negative representations of schizophrenia and its treatment may also contribute to patients' decision to take or not to take antipsychotics. A web-based study on 1,807 participants was conducted during which participants imagined that they had a particular chronic illness based on clinical vignettes (mental illnesses: schizophrenia, depression; somatic illnesses: multiple sclerosis, rheumatoid arthritis). Participants rated their subjective distress and perceived social stigma associated with each illness. They also rated the perceived treatability of the illness, their belief in the effectiveness of treatment, and their treatment preference regarding medication. Results show that schizophrenia was considered more distressful, less treatable and associated with higher social stigma than somatic illnesses. Medication was less preferred for treating schizophrenia compared to somatic illnesses. Perceived treatability of illness and belief in the effectiveness of pharmacological treatment were the factors driving preference for medication in schizophrenia and depression, respectively; these factors had weaker influence on preference for medication in somatic illnesses. Our study points out more severe negative representations of mental illnesses in general, and their treatment, particularly schizophrenia. These attitudes are not confined to patients, and may influence patients' decisions to take psychotropic drugs.


Molecular Characterization and Expression Profiling of NAC Transcription Factors in Brachypodium distachyon L.
NAC (NAM, ATAF1/2, CUC2) transcription factors are involved in regulating plant developmental processes and response to environmental stresses. Brachypodium distachyon is an emerging model system for cereals, temperate grasses and biofuel crops. In this study, a comprehensive investigation of the molecular characterizations, phylogenetics and expression profiles under various abiotic stresses of the NAC gene family in Brachypodium distachyon was performed. In total, 118 BNAC genes in B. distachyon were identified, of which 22 (18.64%) were tandemly duplicated and segmentally duplicated, respectively. The Bayesian phylogenetic inference using Markov Chain Monte Carlo (MCMC) algorithms showed that they were divided into two clades and fourteen subfamilies, supported by similar motif compositions within one subfamily. Some critical amino acids detected using DIVERGE v3.0 might contribute to functional divergence among subfamilies. The different exon-intron organizations among subfamilies revealed structural differentiation. Promoter sequence predictions showed that the BNAC genes were involved in various developmental processes and diverse stress responses. Three NAC domain-encoding genes (BNAC012, BNAC078 and BNAC108), orthologous of NAC1, were targeted by five miRNA164 (Bdi-miR164a-c, e, f), suggesting that they might function in lateral organ enlargement, floral development and the responses to abiotic stress. Eleven (~9.32%) BNAC proteins containing α-helical transmembrane motifs were identified. 23 representative BNAC genes were analyzed by quantitative real-time PCR, showing different expression patterns under various abiotic stresses, of which 18, 17 and 11 genes were up-regulated significantly under drought, H2O2 and salt stresses, respectively. Only four and two genes were up-regulated under cold and cadmium stresses, respectively. Dynamic transcriptional expression analysis revealed that six genes showed constitutive expression and period-specific expression. The current results provide novel insights into the structure and function of the plant NAC gene family.


Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy.
Immune checkpoint inhibitors (ICIs) have recently revolutionized cancer treatment, providing unprecedented clinical benefits. However, primary or acquired therapy resistance can affect up to two-thirds of patients receiving ICIs, underscoring the urgency to elucidate the mechanisms of treatment resistance and to design more effective therapeutic strategies. Conventional cancer treatments, including cytotoxic chemotherapy, radiation therapy, and targeted therapy, have immunomodulatory effects in addition to direct cancer cell-killing activities. Their clinical utilities in combination with ICIs have been explored, aiming to achieve synergetic effects with improved and durable clinical response. Here, we will review the immunomodulatory effects of chemotherapy, targeted therapy, and radiation therapy, in the setting of ICI, and their clinical implications in reshaping modern cancer immunotherapy.


Complex liquid crystal superstructures induced by periodic photo-alignment at top and bottom substrates.
The formation of nematic liquid crystal (LC) superstructures in cells with non-uniform photo-alignment at the confining substrates is studied experimentally and by simulations. An interference pattern of left- and right-handed circularly polarized light is used to define the alignment at both substrates separately, so that the alignment varies along the x-coordinate on one substrate and along the y-coordinate on the other substrate. The interplay between the complex surface alignment and the liquid crystalline soft matter leads to the formation of interesting 3D configurations. The periodic LC structures that are formed in the bulk of the cell are analyzed experimentally by polarizing optical microscopy (POM) for different applied voltages. In the region with strong photo-alignment at both substrates, a 2D LC polarization grating (PG) with a complex 3D director configuration is formed. Distinct periodic structures with different symmetry properties are observed in the regions with weak illumination at the top and/or bottom substrate. The director configuration in the different regions was successfully simulated with the help of finite element (FE) Q-tensor simulations. The agreement between the simulations and the experiments was verified by comparing the POM images with simulated results for the transmission between crossed polarizers.


Arizona porphyry copper/hydrothermal deposits II: crystal structure of ajoite, (K + Na)3Cu20Al3Si29O76(OH)16*~8H2O.
A crystal from the type locality Ajo, AZ, yielded just enough intensity from streaked diffractions using synchrotron x-rays at the Advanced Photon Source to solve the crystal structure with composition (K + Na)3Cu20Al3Si29O76(OH)16* approximately 8H2O; triclinic, P1, a = 13.634(5) A, b = 13.687(7), c = 14.522(7), alpha = 110.83(1) degrees, beta = 107.21(1), gamma = 105.68(1); refined to a final R = 12.5%. Electron microprobe analysis yielded a similar chemical composition that is slightly different from the combined chemical and electron microprobe analyses in the literature. The ajoite structure can be described as a zeolitic octahedral-tetrahedral framework that combines the alternate stacking of edge-sharing octahedral CuO6 layers and curved aluminosilicate layers and strings. Channels bounded by elliptical 12-rings and circular 8-rings of tetrahedra contain (K and Na) ions and water. The Al atoms occupy some of the Si tetrahedral sites. Each Cu atom has near-planar bonds to four oxygen atoms plus two longer distances that generate a distorted octahedron. Valence bond estimates indicate that 8 oxygen atoms of 46 are hydroxyl. Only one alkali atom was located in distorted octahedral coordination, and electron microprobe analyses indicate K and Na as major substituents. The water from chemical analysis presumably occurs as disordered molecules of zeolitic type not giving electron density from diffraction. The high R factor results from structural disorder and many weak intensities close to detection level. The crystal chemistry is compared with shattuckite, Cu5(SiO3)4(OH)2, and planchéite, Cu8Si8O22(OH)4.H2O, both found in oxidized copper deposits of Arizona but only the former directly with ajoite.


Delayed dislocation of the radial head associated with malunion of distal radial fracture: A case report.
Traumatic radial head dislocation (RHD) is a well-described injury in the pediatric population. It is usually associated with an injury to the ulna in Monteggia fracture-dislocation, although it can occur as an isolated injury. Traumatic RHD with ipsilateral radial shaft fracture has rarely been reported. Delayed RHD secondary to the malunion of an isolated radial shaft fracture is extremely rare. We report a 9-year-old boy with limited pronation of the right elbow. The patient was diagnosed with delayed RHD associated with the malunion of a distal radial fracture. Since the annular ligament was disrupted with forearm rotation causing subluxation of the radial head, a modified double-strip Bell Tawse procedure was performed to reconstruct the annular ligament without corrective osteotomy for the malunited site. Four years after surgery, the angulation deformity of the distal radius was corrected with the restoration of the normal curvature of the radius. There was no recurrence of RHD. Annular ligament reconstruction without corrective osteotomy could reduce RHD and restore the normal curve of the radial shaft in children with delayed dislocation of the radial head associated with malunion of the radial shaft. Annular reconstruction using double triceps tendon strips might be useful for maintaining a more stable reduction by augmenting anterolateral parts.


[Obsessive compulsive disorder (OCD) in the ultra-orthodox community--cultural aspects of diagnosis and treatment].
Obsessive compulsive disorder (OCD) is reflected similarly in different communities, while symptoms are affected by the patient's cultural and spiritual world. An ultra-orthodox Jew with OCD will perform compulsive actions and will have obsessive thoughts related to the Jewish religious world. The religious symptoms do not necessarily correspond with the main commandments. Despite their significance, Shabbat or moral commandments such as respecting one's parents do not play a central role in the compulsive pattern. The religious compulsiveness of OCD patients focuses on commandments having to do with order and cleanliness and is characterized by repetition, checking and slowness. Obsessive thoughts and compulsive actions of ultra-orthodox OCD patients are usually based on the Jewish scriptures. One might assume that religion, as a framework with rules and dictated rituals, serves as a strong foundation for the development of OCD. However, it is estimated that the prevalence of OCD in the ultra-orthodox community is similar to the general population. Rabbis acknowledge OCD as a psychiatric illness and do not encourage the obsessive punctuality in following the commandments. An ultra-orthodox patient will first consult his rabbi, and after receiving his recommendation, will turn to psychiatric treatment. He might prefer to receive drug treatment rather than Cognitive Behavioral Therapy that may oppose his beliefs. Understanding the cultural background of the patient is essential, in particular when the patient is ultra-orthodox and the treatment is considered "secular". Therefore, cooperation with the patient's rabbi is important in order to obtain the patient's trust and develop a treatment plan.