Potential role of N-carbamoyl glutamate in biosynthesis of arginine and its significance in production of ruminant animals.
Arginine (ARG) exerts many beneficial effects on animal body and enhanced angiogenesis, lactogenesis, which finally leads to the improvement in nitrogen (N) metabolism, reproduction, lactation, immunity and growth. Unfortunately, unprotected ARG will be degraded in the rumen and its price is high, thus feeding rumen-protected ARG seems to be uneconomical. Alternatively, N-carbamoyl glutamate (NCG) is structural analogue of N-acetyl glutamate, cofactor of cabamoyl phosphate synthetase1, is lower in rumen degradation compared to ARG. Additionally, rumen epithelial and duodenal cells have potentially utilized the NCG for ureagenesis. Supplementation of NCG to high yielding dairy cows increased plasma concentration of ARG and nitric oxide, decreased the plasma ammonia N and improved lactation performance and N utilization. Supplementation of NCG enhanced pregnancy rates in rats, improved litter size and fetal survival rate, thereby improved the reproductive performance of sows. Oral NCG supplementation increases plasma ARG and somatotropin levels, and increased growth rate and muscle protein synthesis in nursing piglets. The NCG is potential a relatively cheaper source of feed additive to offer vital compensation over oral administration of ARG, resulting in improved ruminant animal health and production. In this article, we reviewed the mechanism of ARG biosynthesis by NCG and their significance in growth, reproduction, milk production and N utilization in ruminant animals.


Cytosolic aspartate aminotransferase moonlights as a ribosome-binding modulator of Gcn2 activity during oxidative stress.
Regulation of translation is a fundamental facet of the cellular response to rapidly changing external conditions. Specific RNA-binding proteins (RBPs) co-ordinate the translational regulation of distinct mRNA cohorts during stress. To identify RBPs with previously under-appreciated roles in translational control, we used polysome profiling and mass spectrometry to identify and quantify proteins associated with translating ribosomes in unstressed yeast cells and during oxidative stress and amino acid starvation, which both induce the integrated stress response (ISR). Over 800 proteins were identified across polysome gradient fractions, including ribosomal proteins, translation factors, and many others without previously described translation-related roles, including numerous metabolic enzymes. We identified variations in patterns of PE in both unstressed and stressed cells and identified proteins enriched in heavy polysomes during stress. Genetic screening of polysome-enriched RBPs identified the cytosolic aspartate aminotransferase, Aat2, as a ribosome-associated protein whose deletion conferred growth sensitivity to oxidative stress. Loss of Aat2 caused aberrantly high activation of the ISR via enhanced eIF2α phosphorylation and GCN4 activation. Importantly, non-catalytic AAT2 mutants retained polysome association and did not show heightened stress sensitivity. Aat2 therefore has a separate ribosome-associated translational regulatory or 'moonlighting' function that modulates the ISR independent of its aspartate aminotransferase activity.


Presence of acetyl coenzyme A (CoA) carboxylase and propionyl-CoA carboxylase in autotrophic Crenarchaeota and indication for operation of a 3-hydroxypropionate cycle in autotrophic carbon fixation.
The pathway of autotrophic CO2 fixation was studied in the phototrophic bacterium Chloroflexus aurantiacus and in the aerobic thermoacidophilic archaeon Metallosphaera sedula. In both organisms, none of the key enzymes of the reductive pentose phosphate cycle, the reductive citric acid cycle, and the reductive acetyl coenzyme A (acetyl-CoA) pathway were detectable. However, cells contained the biotin-dependent acetyl-CoA carboxylase and propionyl-CoA carboxylase as well as phosphoenolpyruvate carboxylase. The specific enzyme activities of the carboxylases were high enough to explain the autotrophic growth rate via the 3-hydroxypropionate cycle. Extracts catalyzed the CO2-, MgATP-, and NADPH-dependent conversion of acetyl-CoA to 3-hydroxypropionate via malonyl-CoA and the conversion of this intermediate to succinate via propionyl-CoA. The labelled intermediates were detected in vitro with either 14CO2 or [14C]acetyl-CoA as precursor. These reactions are part of the 3-hydroxypropionate cycle, the autotrophic pathway proposed for C. aurantiacus. The investigation was extended to the autotrophic archaea Sulfolobus metallicus and Acidianus infernus, which showed acetyl-CoA and propionyl-CoA carboxylase activities in extracts of autotrophically grown cells. Acetyl-CoA carboxylase activity is unexpected in archaea since they do not contain fatty acids in their membranes. These aerobic archaea, as well as C. aurantiacus, were screened for biotin-containing proteins by the avidin-peroxidase test. They contained large amounts of a small biotin-carrying protein, which is most likely part of the acetyl-CoA and propionyl-CoA carboxylases. Other archaea reported to use one of the other known autotrophic pathways lacked such small biotin-containing proteins. These findings suggest that the aerobic autotrophic archaea M. sedula, S. metallicus, and A. infernus use a yet-to-be-defined 3-hydroxypropionate cycle for their autotrophic growth. Acetyl-CoA carboxylase and propionyl-CoA carboxylase are proposed to be the main CO2 fixation enzymes, and phosphoenolpyruvate carboxylase may have an anaplerotic function. The results also provide further support for the occurrence of the 3-hydroxypropionate cycle in C. aurantiacus.


Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression.
Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.


Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder.
Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73kDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing (TD) controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73kDa IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.


ICH Q3D Drug Product Elemental Risk Assessment: The Use of An Elemental Impurities Excipients Database.
The purpose of this publication is to show how an elemental impurities excipient database can be used in assisting the execution of a drug product elemental impurities risk assessment as required by the ICH Q3D guidelines. As a result of this exercise, we have demonstrated that the database, used in conjugation with other sources of information, is a credible source of elemental impurity levels in excipients therefore, a valuable source of information in completion of drug product risk assessments. This useful collection of data helps to reduce the burden of analytical testing for elemental impurities in excipients.


Psychological trauma at different developmental stages and ICD-11 CPTSD: The role of dissociation.
Background: Dissociation is commonly reported by individuals who meet criteria for posttraumatic stress disorder (PTSD) and complex posttraumatic stress disorder (CPTSD). However, the association between the age of trauma exposure, dissociation, and CPTSD is not well understood. This study aimed to test whether dissociation mediated the relationship between the developmental stage of trauma exposure and CPTSD symptoms.Method: A nationally representative sample from Ireland (N = 1020) completed self-report measures on trauma exposure in childhood, adolescence, adulthood, current trauma symptomatology, and dissociation symptoms. A mediation analysis was conducted.Results: Childhood, adolescent, and adulthood trauma exposure were all related to dissociation and ICD-11 CPTSD symptom clusters. Dissociation mediated the effect of developmental stage of trauma exposure on PTSD and disturbances in self-organization(DSO). The direct and indirect effect models provided the best fit of the data. Childhood trauma exposure was the only developmental stage that was directly associated with both PTSD and DSO symptoms in our sample.Conclusion: Dissociation mediates the relationship between reported trauma exposure and the presence of ICD-11 CPTSD symptom clusters, and this relationship appears at its strongest when trauma occurs in childhood. CPTSD interventions should also promote dissociation management to aid recovery from this debilitating condition.


Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis.
Citrulline is one of the non-essential amino acids that is thought to improve exercise performance and reduce post-exercise muscle soreness. We conducted a systematic review and meta-analysis to determine the effect of citrulline supplements on the post-exercise rating of perceived exertion (RPE), muscle soreness, and blood lactate levels. A random effects model was used to calculate the effect sizes due to the high variability in the study design and study populations of the articles included. A systematic search of PubMed, Web of Science, and ClinicalTrials.gov was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving healthy individuals and that investigated the acute effect of citrulline supplements on RPE, muscle soreness, and blood lactate levels. The supplementation time frame was limited to 2 h before exercise. The types and number of participants, types of exercise tests performed, supplementation protocols for L-citrulline or citrulline malate, and primary (RPE and muscle soreness) and secondary (blood lactate level) study outcomes were extracted from the identified studies. The analysis included 13 eligible articles including a total of 206 participants. The most frequent dosage used in the studies was 8 g of citrulline malate. Citrulline supplementation significantly reduced RPE (n = 7, p = 0.03) and muscle soreness 24-h and 48-h after post-exercise (n = 7, p = 0.04; n = 6, p = 0.25, respectively). However, citrulline supplementation did not significantly reduce muscle soreness 72-h post-exercise (n = 4, p = 0.62) or lower blood lactate levels (n = 8, p = 0.17). Citrulline supplements significantly reduced post-exercise RPE and muscle soreness without affecting blood lactate levels.


Preventing mental health conditions in adolescents living with HIV: an urgent need for evidence.
As adolescents transition from childhood to adulthood, they experience major physical, social and psychological changes, and are at heightened risk for developing mental health conditions and engaging in health-related risk behaviours. For adolescents living with HIV (ALHIV), these risks may be even more pronounced. Research shows that this population may face additional mental health challenges related to the biological impact of the disease and its treatment, the psychosocial burdens of living with HIV and HIV-related social and environmental stressors. Psychosocial interventions delivered to adolescents can promote positive mental health, prevent mental health problems and strengthen young people's capacity to navigate challenges and protect themselves from risk. It is likely that these interventions can also benefit at-risk populations, such as ALHIV, yet there is little research on this. There is an urgent need for more research evaluating the effects of interventions designed to improve the mental health of ALHIV. We highlight four priorities moving forward. These include: generating more evidence about preventive mental health interventions for ALHIV; including mental health outcomes in research on psychosocial interventions for ALHIV; conducting intervention research that is sensitive to differences among ALHIV populations and involving adolescents in intervention design and testing. More robust research on promotive and preventive mental health interventions is needed for ALHIV. Programmes should be informed by adolescent priorities and preferences and responsive to the specific needs of these groups.


Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory CD8 T-Cell Dysfunction.
Type 2 diabetes (T2D) causes an increased risk of morbidity and mortality in response to viral infection. T2D is characterized by hyperglycemia and is typically associated with insulin resistance and compensatory hyperinsulinemia. CD8 T cells express the insulin receptor, and previously, we have shown that insulin is able to directly modulate effector CD8 T-cell function. We therefore hypothesized that memory CD8 T-cell responsiveness in the context of T2D is negatively impacted by hyperinsulinemia or hyperglycemia. Using a mouse model for T2D, we could show that memory CD8 T-cell function was significantly reduced in response to rechallenge by viral infection or with melanoma cells. Basal insulin injection of mice increased GLUT-1 expression and glucose uptake in memory CD8 T-cell precursors early after infection, which was prevented when these cells were deficient for the insulin receptor. However, neither insulin injection nor insulin receptor deficiency resulted in a difference in metabolism, memory formation, cytokine production, or recall responses of memory CD8 T cells compared with controls. Importantly, in context of obesity, insulin receptor deficiency on CD8 T cells did not affect the functional capacity of memory CD8 T cells. In contrast, we could show in vitro and in vivo that hyperglycemia significantly impairs the antiviral capacity of memory CD8 T cells. Our findings indicate that obesity impairs the memory CD8 T-cell response against viral infection and cancer through the detrimental effects of hyperglycemia rather than hyperinsulinemia.


Epidemiology and Trend of Head and Neck Cancers in Iran.
Head and neck cancers are the sixth common cancer worldwide. It is necessary to inform the trend of incidence for health planning. This study aimed to investigate the trend of head and neck cancers in Iran. This study was carried out based on national report on cancer registry in Iran. The crude incidence rate was calculated as per 100,000 people, and Age Standardized incidence Rate (ASR) was estimated using direct standardization and the standard population of World Health Organization (W.H.O). Data was analyzed using the Cochran-Armitage test for linear trend and software of WinPepi 2.1. A total of 25,952 cases of cancers of the head and neck have been registered between 2003 and 2009. The age-standardized incidence rate reached from 4.8 cases per 100,000 in 2003 to 8.5 and 7.4 in 2008 and 2009, respectively, which revealed significantly increasing trends. According to increasing trend age-standardized rate of head and neck cancer in Iran, it is recommended to identify risk factors and vulnerable groups in order to reduce the burden of this type of cancers.


Investigating Dual-Species Candida auris and Staphylococcal Biofilm Antiseptic Challenge.
Candida auris can persistently colonize human skin, alongside a diverse bacterial microbiome. In this study we aimed to investigate the efficacy of antiseptic activities on dual-species interkingdom biofilms containing staphylococci to determine if antiseptic tolerance was negatively impacted by dual-species biofilms. Chlorhexidine, povidone iodine, and hydrogen peroxide (H2O2), were able to significantly reduce biofilm viable cell counts following exposure at 2%, 10%, and 3%, respectively. Notably, H2O2-treated biofilms were able to significantly recover and considerably repopulate following treatment. Fortunately, inter-kingdom interactions in dual-species biofilms of C. auris and staphylococci did not increase the tolerance of C. auris against antiseptics in vitro. These data indicate mixed infections are manageable with chlorhexidine and povidone iodine, but caution should be exercised in the consideration of H2O2.


Depolarization, bacterial membrane composition, and the antimicrobial action of ceragenins.
Ceragenins are cholic acid-derived antimicrobial agents that mimic the activity of endogenous antimicrobial peptides. Ceragenins target bacterial membranes, yet the consequences of these interactions have not been fully elucidated. The role of the outer membrane in allowing access of the ceragenins to the cytoplasmic membrane of gram-negative bacteria was studied using the ML-35p mutant strain of Escherichia coli that has been engineered to allow independent monitoring of small-molecule flux across the inner and outer membranes. The ceragenins CSA-8, CSA-13, and CSA-54 permeabilize the outer membrane of this bacterium, suggesting that the outer membrane does not play a major role in preventing the access of these agents to the cytoplasmic membrane. However, only the most potent of these ceragenins, CSA-13, was able to permeabilize the inner membrane. Interestingly, neither CSA-8 nor CSA-54 caused inner membrane permeabilization over a 30-min period, even at concentrations well above those required for bacterial toxicity. To further assess the role of membrane interactions, we measured membrane depolarization in gram-positive bacteria with different membrane lipid compositions, as well as in gram-negative bacteria. We found greatly increased membrane depolarization at the minimal bactericidal concentration of the ceragenins for bacterial species containing a high concentration of phosphatidylethanolamine or uncharged lipids in their cytoplasmic membranes. Although membrane lipid composition affected bactericidal efficiency, membrane depolarization was sufficient to cause lethality, providing that agents could access the cytoplasmic membrane. Consequently, we propose that in targeting bacterial cytoplasmic membranes, focus be placed on membrane depolarization as an indicator of potency.


In vitro toxicological assessment of flumethrin's effects on MCF-7 breast cancer cells.
Pyrethroid pesticides are frequently used for household insect control of insects and in agriculture and livestock. Flumethrin is a pyrethroid that is used against ectoparasites in many animals. The goal of this study was to evaluate the cytotoxic, apoptotic, genotoxic, and estrogenic effects of flumethrin on the mammalian breast cancer cell line (MCF-7). Compared with control groups, a dose-dependent decrease was observed in cell viability at concentrations of 100 µM and higher. The cytotoxic and apoptotic effects detected by LDH assay and AO/EtBr staining increased significantly at a concentration of 1000 µM. The expression of BCL2, which is an anti-apoptotic gene, significantly decreased, whereas BAX, TP53, and P21 expression significantly increased. The results of a comet assay indicated that flumethrin significantly changed tail length, tail % DNA, tail moment, and Olive tail moment in concentrations above 1 and 10 µM. In addition, a 0.1 µM concentration of flumethrin affected ERα receptor mediated cell proliferation and increased transcription of estrogen-responsive pS2 (TFF1) and progesterone receptor (PGR) genes. As a result, flumethrin-induced apoptosis and cytotoxicity at a high concentration, while induced genotoxicity even at lower concentrations. Flumethrin is an endocrine disrupting insecticide with estrogenic effects at very low concentrations.


Evaluation of data transformations used with the square root and schoolfield models for predicting bacterial growth rate.
A comparison was made between mathematical variations of the square root and Schoolfield models for predicting growth rate as a function of temperature. The statistical consequences of square root and natural logarithm transformations of growth rate use in several variations of the Schoolfield and square root models were examined. Growth rate variances of Yersinia enterocolitica in brain heart infusion broth increased as a function of temperature. The ability of the two data transformations to correct for the heterogeneity of variance was evaluated. A natural logarithm transformation of growth rate was more effective than a square root transformation at correcting for the heterogeneity of variance. The square root model was more accurate than the Schoolfield model when both models used natural logarithm transformation.


2,2'-Dichlorobiphenyl decreases amplitude and synchronization of uterine contractions through MAPK1-mediated phosphorylation of GJA1 (connexin43) and inhibition of myometrial gap junctions.
The present study examined the hypothesis that inhibition of myometrial gap junctions through MAPK1-induced phosphorylation of GJA1 (connexin43) leads to inhibition of spontaneous phasic uterine contractions by 2,2'-dichlorobiphenyl (2,2'-DCB). Uterine strips from Gestation Day 10-pregnant rats exposed in muscle baths to 2,2'-DCB exhibited increased oscillatory frequency and decreased amplitude and synchronization of contractions. To assess effects on gap junctions, Lucifer yellow was injected into myometrial cells and transfer to adjacent cells was scored. After a 1-h treatment, 100 microM 2,2'-DCB decreased Lucifer yellow intercellular transfer in a concentration-dependent manner. The MAP2K1 inhibitor PD98059 increased percentage of dye transfer to adjacent myometrial cells from 18% in cultures exposed for 1 h to 100 microM 2,2'-DCB alone to 48% in cultures cotreated with 50 microM PD98059 and 100 microM 2,2'-DCB. In contrast, the conventional PRKC inhibitor Gö6976 (10 microM) had no significant effect on 2,2'-DCB-induced inhibition of dye transfer. Western blotting showed about a 4.5-fold increase in phosphorylation of GJA1 at S255, a MAPK1 site, after exposure to 100 microM 2,2'-DCB compared to untreated and solvent controls. However, there was no difference in phosphorylation of GJA1 at S368, a PRKC site. Cells treated with 2,2'-DCB increased phosphorylated MAPK1, implicating the increase of activation of MAPK1. Cotreatment with 100 microM 2,2'-DCB and 5 microM PD98059 reversed 2,2'-DCB-induced modification of uterine contractions and increase of pGJA1(S255) in uterine strips. Therefore, this study suggests that 2,2'-DCB decreases amplitude and synchronization of uterine contractions mediated through MAPK1-mediated phosphorylation of GJA1 and subsequent inhibition of myometrial gap junctions.


Performance Pressure Enhances Speech Learning.
Real-world speech learning often occurs in high pressure situations such as trying to communicate in a foreign country. However, the impact of pressure on speech learning success is largely unexplored. In this study, adult, native speakers of English learned non-native speech categories under pressure or no-pressure conditions. In the pressure conditions, participants were informed that they were paired with a (fictitious) partner, and that each had to independently exceed a performance criterion for both to receive a monetary bonus. They were then informed that their partner had exceeded the bonus and the fate of both bonuses depended upon the participant's performance. Our results demonstrate that pressure significantly enhanced speech learning success. In addition, neurobiologically-inspired computational modeling revealed that the performance advantage was due to faster and more frequent use of procedural learning strategies. These results integrate two well-studied research domains and suggest a facilitatory role of motivational factors in speech learning performance that may not be captured in traditional training paradigms.


Leptin, but not Estradiol, Signaling in PACAP Neurons Modulates Puberty Onset.
The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females.


Oncogene-induced senescence: a double edged sword in cancer.
Oncogene-induced cellular senescence (OIS) is a complex program that is triggered in response to aberrant activation of oncogenic signaling. Initially, OIS was thought to be a barrier to malignant transformation because of its suppression on cell proliferation. Later studies showed that senescence induced by oncogenes can also promote the initiation and development of cancer. The opposing effects of OIS occur through different combinations of downstream effectors as well as the interplay of senescent cells and the microenvironment, such as senescence-associated inflammation. Here, we review the common features and molecular mechanisms underlying OIS and the interaction between senescent cells and the microenvironment. We propose that targeting senescent cells may have a beneficial therapeutic effect during the treatment of cancer.


Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities.
Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity. Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds' activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1's homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.


Antiestrogen action in the medial basal hypothalamus and pituitary of immature female rats: insights concerning relationships among estrogen, dopamine, and prolactin.
We have examined the effects of nonsteroidal antiestrogens (AEs) and estradiol (E) on dopamine (DA) levels and turnover rates in the medial basal hypothalamus (MBH) and on serum and pituitary PRL to gain insight into DA-PRL-E/AE interrelationships. In 21-day-old female rats, E was found to increase MBH DA levels and turnover and serum PRL concentrations in a time- and concentration-dependent manner. Changes were observed by 1 day, and after 3 days of E treatment (1 microgram/day), MBH DA levels increased 2-fold (to 1300 pg/mg tissue), and DA turnover rates increased 5-fold (to 1170 pg/mg tissue . h). The AEs tamoxifen, monohydroxytamoxifen, CI628, and LY117018 (50 micrograms/day for 3 days) weakly stimulated uterine weight gain and significantly suppressed the uterotropic action of E. The AEs LY117018, monohydroxytamoxifen, CI628, and tamoxifen competed with E for binding to the MBH estrogen receptor and displayed relative binding affinities of 190%, 185%, 6.7%, and 1.4%, with E set at 100%; these affinities are similar to those found for uterine estrogen receptors. The AEs increased DA turnover rates only 2-fold, and they antagonized the E-induced 5-fold increase in DA turnover rates very successfully. In animals treated with bromocriptine, E and AE failed to increase the low serum PRL levels, yet they evoked significant (approximately 2-fold) increases in DA turnover rates and nearly 2-fold increases in MBH DA content. Hence, a part of the actions of E and AE on MBH DA appears to be exerted independently of changes in circulating PRL and may occur by direct action of these compounds on the estrogen receptor system present in the MBH. In addition, these studies reveal that AEs behave as partial estrogen agonists/antagonists in terms of their effects on MBH DA turnover.


Septic olecranon bursitis: recognition and treatment.
The superficial location of the olecranon bursa places it at high risk for injury, possibly leading to the entry of bacteria into the bursal sac. Early differentiation between septic and nonseptic olecranon bursitis is paramount to direct therapy, to hasten recovery, and to prevent chronic inflammation. A literature review was performed using MEDLINE files from 1967 to the present. Additional references from the bibliographies of these were also utilized. Olecranon bursitis is a common condition that requires the treating physician to be aware of the predisposing factors, clinical signs and symptoms, and laboratory findings of both septic and nonseptic olecranon bursitis. With early recognition, prompt therapy, and preventive measures, the morbidity of septic olecranon bursitis can be considerably reduced, but surgical incision and drainage or excision could be required if conservative therapy fails.


Survival and success of composite resin restorations in endodontically treated maxillary incisors with minimal structure loss.
The primary aim of this study was to evaluate the clinical performance of nanofilled composite resin restorations in traumatized, endodontically treated maxillary incisors with structural loss of 40% or less. The performance of the restorations was assessed in terms of longevity (survival) and esthetics (success) over a 20-month period. The secondary objective was to employ a novel digital method to quantify preoperative tooth structure loss. Sixty-one fractured maxillary incisors in 55 patients were included in the study. The teeth were photographed with a digital single-lens reflex camera equipped with a macro ring flash. The amount of lost tooth structure was calculated with digital photography software. The teeth were restored with a nanohybrid composite resin and self-etching adhesive system bonding agent. To assess esthetics, color change in the blue-yellow axis (Δb*) of the composite resin restoration was evaluated digitally with the Commission Internationale de l'Eclairage (CIE) L*a*b color system. The Wilcoxon signed-rank test was used to assess Δb*, and a Kaplan-Meier survival analysis was used to assess the longevity of the restorations. The study findings showed a statistically significant difference between pretreatment and posttreatment b* values (P < 0.05), but the difference was too small to be clinically perceptible to the human eye. A total of 5 restorations (9.8%) failed. The remaining restorations survived for a mean (SD) period of 18.6 (4.4) months. The log-rank test did not show any significant association between the amount of residual tooth structure and success of the restoration. The results of this study showed that use of direct composite resin restorations in endodontically treated maxillary incisors resulted in acceptable survival and success rates. Trial registration: Clinical Trial Registry of India No. CTRI/2020/01/023019.


Antitumor chemosensitivity differs between clinical sarcoma and adenocarcinoma tissues.
The chemosensitivity of 43 human sarcoma tissues, including 18 osteosarcomas, 16 leiomyosarcomas and 9 liposarcomas, was compared with that of 28 adenocarcinomas of the stomach, using the in vitro succinate dehydrogenase inhibition (SDI) test. These tissues were exposed for 3 days to each antitumor drug, including adriamycin (ADM), 5-fluorouracil (5-FU), mitomycin C (MMC), cisplatin (CDDP), aclacinomycin A (ACR) and carboquone (CQ), them the cell viability was estimated based on the succinate dehydrogenase (SD) activity, determined using [3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H tetrazolium bromide] (MTT). SD activity was significantly lower in the osteosarcoma as compared to that in the adenocarcinoma, for ADM, MMC, CDDP, ACR and CQ (p < 0.01), and was higher for ADM (p < 0.05) in cases of leiomyosarcoma and for CDDP (p < 0.01) and ACR (p < 0.05) in cases of liposarcoma. The sensitivity rate was higher in osteosarcoma than in adenocarcinoma for ADM, MMC and CDDP. These findings suggest that patients with osteosarcoma will probably show a fairly good response to antitumor drugs, and that when liposarcoma or leiomyosarcoma tumors show resistance to antitumor drugs, then resection at the time of initial exploration and combined modalities, including radiation and hyperthermia, should be considered.


Organically grown food provides health benefits to Drosophila melanogaster.
The "organic food" market is the fastest growing food sector, yet it is unclear whether organically raised food is nutritionally superior to conventionally grown food and whether consuming organic food bestows health benefits. In order to evaluate potential health benefits of organic foods, we used the well-characterized fruit fly Drosophila melanogaster as a model system. Fruit flies were raised on a diets consisting of extracts of either conventionally or organically raised produce (bananas, potatoes, raisins, soy beans). Flies were then subjected to a variety of tests designed to assess overall fly health. Flies raised on diets made from organically grown produce had greater fertility and longevity. On certain food sources, greater activity and greater stress resistance was additionally observed, suggesting that organic food bestows positive effects on fly health. Our data show that Drosophila can be used as a convenient model system to experimentally test potential health effects of dietary components. Using this system, we provide evidence that organically raised food may provide animals with tangible benefits to overall health.


Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.
Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.


Enzyme-like catalysis via ternary complex mechanism: alkoxy-bridged dinuclear cobalt complex mediates chemoselective O-esterification over N-amidation.
Hydroxy group-selective acylation in the presence of more nucleophilic amines was achieved using acetates of first-row late transition metals, such as Mn, Fe, Co, Cu, and Zn. Among them, cobalt(II) acetate was the best catalyst in terms of reactivity and selectivity. The combination of an octanuclear cobalt carboxylate cluster [Co4(OCOR)6O]2 (2a: R = CF3, 2b: R = CH3, 2c: R = (t)Bu) with nitrogen-containing ligands, such as 2,2'-bipyridine, provided an efficient catalytic system for transesterification, in which an alkoxide-bridged dinuclear complex, Co2(OCO(t)Bu)2(bpy)2(μ2-OCH2-C6H4-4-CH3)2 (10), was successfully isolated as a key intermediate. Kinetic studies and density functional theory calculations revealed Michaelis-Menten behavior of the complex 10 through an ordered ternary complex mechanism similar to dinuclear metallo-enzymes, suggesting the formation of alkoxides followed by coordination of the ester.


Construction of magnetically separable NiAl LDH/Fe3O4-RGO nanocomposites with enhanced photocatalytic performance under visible light.
Magnetic NiAl layered doubled hydroxide (LDH)/Fe3O4-RGO composites were successfully synthesized via a simple hydrothermal route. The as-prepared samples were well characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). The results showed that NiAl LDH nanoplatelets and Fe3O4 nanoparticles sized around 15 nm were uniformly anchored on the surface of graphene sheets. The NiAl LDH/Fe3O4-RGO25 photocatalyst was employed to degrade ciprofloxacin (CIP) in an aqueous solution under visible light irradiation. It exhibited enhanced photocatalytic activity compared to pure NiAl LDH, the degradation rate of the as-prepared NiAl LDH/Fe3O4-RGO25 was 1.5 and even 3 times faster than that of NiAl LDH/RGO25 and pure NiAl LDH, respectively. This enhancement of photocatalytic activity is attributed to the addition of graphene and Fe3O4 NPs, which both efficiently promote the separation of charge carriers and improve the optical absorption properties, synergistically facilitating the photocatalysis process. Furthermore, the NiAl LDH/Fe3O4-RGO25 photocatalyst was magnetically separable and exhibited stable catalytic activity, which is beneficial to its practical application.


STUDIES ON STREPTOCOCCAL FIBRINOLYSIS : V. THE IN VITRO PRODUCTION OF FIBRINOLYSIN BY VARIOUS GROUPS AND TYPES OF BETA HEMOLYTIC STREPTOCOCCI; RELATIONSHIP TO ANTIFIBRINOLYSIN PRODUCTION.
A method for the measurement of fibrinolysin production by beta hemolytic streptococci is described. The test was shown to be highly accurate in that repeated determinations showed only small variations. A study of 766 strains of beta hemolytic streptococci isolated from normal soldiers and patients with respiratory disease showed that fibrinolysin was produced by Lancefield groups A, C, and G, and, in addition, by a few strains of groups B and F. Group A streptococci produced more fibrinolysin on the average than the other groups. The median titers were 117 for group A, 61 for group C, and 20 for group G streptococci. In a study of 388 typed group A streptococci from different subjects the fibrinolytic capacity of an organism was shown to be related to the serological type. The importance of this observation in relation to the role of streptococcal fibrinolysis in infections is discussed. Finally, it was demonstrated that strains of streptococci which produced large amounts of fibrinolysin were capable of stimulating antifibrinolysin formation in patients whereas strains that produced small amounts only occasionally caused antibody formation.


The power of charisma--perceived charisma inhibits the frontal executive network of believers in intercessory prayer.
This study used functional magnetic resonance imaging to investigate how assumptions about speakers' abilities changed the evoked BOLD response in secular and Christian participants who received intercessory prayer. We find that recipients' assumptions about senders' charismatic abilities have important effects on their executive network. Most notably, the Christian participants deactivated the frontal network consisting of the medial and the dorsolateral prefrontal cortex bilaterally in response to speakers who they believed had healing abilities. An independent analysis across subjects revealed that this deactivation predicted the Christian participants' subsequent ratings of the speakers' charisma and experience of God's presence during prayer. These observations point to an important mechanism of authority that may facilitate charismatic influence, a mechanism which is likely to be present in other interpersonal interactions as well.


What are the most important unanswered research questions on rapid review methodology? A James Lind Alliance research methodology Priority Setting Partnership: the Priority III study protocol.
Background: The value of rapid reviews in informing health care decisions is more evident since the onset of the coronavirus disease 2019 (COVID-19) pandemic. While systematic reviews can be completed rapidly, rapid reviews are usually a type of evidence synthesis in which components of the systematic review process may be simplified or omitted to produce information more efficiently within constraints of time, expertise, funding or any combination thereof. There is an absence of high-quality evidence underpinning some decisions about how we plan, do and share rapid reviews. We will conduct a modified James Lind Alliance Priority Setting Partnership to determine the top 10 unanswered research questions about how we plan, do and share rapid reviews in collaboration with patients, public, reviewers, researchers, clinicians, policymakers and funders. Methods: An international steering group consisting of key stakeholder perspectives (patients, the public, reviewers, researchers, clinicians, policymakers and funders) will facilitate broad reach, recruitment and participation across stakeholder groups. An initial online survey will identify stakeholders' perceptions of research uncertainties about how we plan, do and share rapid reviews. Responses will be categorised to generate a long list of questions. The list will be checked against systematic reviews published within the past three years to identify if the question is unanswered. A second online stakeholder survey will rank the long list in order of priority. Finally, a virtual consensus workshop of key stakeholders will agree on the top 10 unanswered questions. Discussion: Research prioritisation is an important means for minimising research waste and ensuring that research resources are targeted towards answering the most important questions. Identifying the top 10 rapid review methodology research priorities will help target research to improve how we plan, do and share rapid reviews and ultimately enhance the use of high-quality synthesised evidence to inform health care policy and practice.


Supporting peritoneal dialysis in remote Australia.
Peritoneal dialysis is usually considered a first-choice treatment for end-stage renal disease for patients living in remote areas. The advantages of peritoneal dialysis over haemodialysis are that peritoneal dialysis preserves the residual renal function for longer, provides patients with more independence and gives patients a greater opportunity to return home quickly. In Australia, Aboriginal people suffer end-stage renal failure at disproportionately higher rates than the general population. Given that many Aboriginal people live in remote communities a task of peritoneal dialysis units is to ensure the successful setting up and maintenance of peritoneal dialysis programmes in the outback. This paper examines how peritoneal dialysis units located in the city are able to deliver peritoneal dialysis to patients located often hundreds of kilometres and at times thousands of kilometres away in very remote communities. In preparing this paper interviews were conducted with renal and remote community-based health professionals in Western Australia and the Northern Territory, and with peritoneal dialysis patients in Western Australia. The success of remote peritoneal dialysis programmes relies on many elements, most importantly an integrated approach to care by all members of the peritoneal dialysis team. The peritoneal dialysis team included not just health professionals but also patients, their families, their communities and other support people such as those involved in the transport of peritoneal dialysis supplies to the outback. Careful communication, a willingness to participate, friendliness and delivering care and supplies with a smile are essential ingredients to a winning program. Without all of these ingredients dialysis in the bush may fail.


Which tasks measure what? Reflections on executive function development and a commentary on Podjarny, Kamawar, and Andrews (2017).
This article provides a selective review of the literature on executive function development and related topics, focusing on the conceptual and terminological confusions that might hinder communication among researchers in the field. The distinctions between working memory and updating, and between shifting and flexibility, are discussed. Methodological problems, which have implications regarding whether a certain task can be considered a measure of a psychological construct, are also discussed. Research on preschoolers is examined with particular attention because it is a rapidly growing but controversial field that seems in particular need of greater conceptual clarity. As a specific touchstone case, we discuss whether the Multidimensional Card Selection Task (MCST) created by Podjarny, Kamawar, and Andrews (2017) should better be considered a measure of concurrent cognitive flexibility or working memory capacity. It is argued that connecting tasks to theoretical constructs is not warranted unless based on rigorous empirical testing of well-formulated models.


Serum fetuin-A levels in patients with systolic heart failure.
Inflammation and dystrophic calcification have been associated with cardiovascular disease (CVD) and chronic heart failure (CHF). The aim of the present study was to investigate the potential usefulness of fetuin-A as a biomarker in CHF. Serum fetuin-A was measured in 66 CHF patients with left ventricular function < 50% and in 31 healthy controls at baseline. Fetuin-A was evaluated as a diagnostic marker for systolic heart failure and compared with C-reactive protein (CRP) and pro-brain natriuretic peptide (pro-BNP). The levels of serum fetuin-A were significantly decreased in the CHF patients compared to the control group (P < 0.01). Although there were significant correlations between fetuin-A and certain parameters in patients and controls, none of these were present consistently in either group. It was found that serum fetuin-A levels could identify patients with systolic heart failure with a high degree of sensitivity and specificity. Serum fetuin-A is decreased in CHF patients, indicating that anti-inflammatory activity is downregulated in CHF and that calcification may be associated with CHF.


Discovery of Pyrobaculum small RNA families with atypical pseudouridine guide RNA features.
In the Eukarya and Archaea, small RNA-guided pseudouridine modification is believed to be an essential step in ribosomal RNA maturation. While readily modeled and identified by computational methods in eukaryotic species, these guide RNAs have not been found in most archaeal genomes. Using high-throughput transcriptome sequencing and comparative genomics, we have identified ten novel small RNA families that appear to function as H/ACA pseudouridylation guide sRNAs, yet surprisingly lack several expected canonical features. The new RNA genes are transcribed and highly conserved across at least six species in the archaeal hyperthermophilic genus Pyrobaculum. The sRNAs exhibit a single hairpin structure interrupted by a conserved kink-turn motif, yet only two of ten families contain the complete canonical structure found in all other H/ACA sRNAs. Half of the sRNAs lack the conserved 3'-terminal ACA sequence, and many contain only a single 3' guide region rather than the canonical 5' and 3' bipartite guides. The predicted sRNA structures contain guide sequences that exhibit strong complementarity to ribosomal RNA or transfer RNA. Most of the predicted targets of pseudouridine modification are structurally equivalent to those known in other species. One sRNA appears capable of guiding pseudouridine modification at positions U54 and U55 in most or all Pyrobaculum tRNAs. We experimentally tested seven predicted pseudouridine modifications in ribosomal RNA, and all but one was confirmed. The structural insights provided by this new set of Pyrobaculum sRNAs will augment existing models and may facilitate the identification and characterization of new guide sRNAs in other archaeal species.


APC2 and Axin promote mitotic fidelity by facilitating centrosome separation and cytoskeletal regulation.
To ensure the accurate transmission of genetic material, chromosome segregation must occur with extremely high fidelity. Segregation errors lead to chromosomal instability (CIN), with deleterious consequences. Mutations in the tumor suppressor adenomatous polyposis coli (APC) initiate most colon cancers and have also been suggested to promote disease progression through increased CIN, but the mechanistic role of APC in preventing CIN remains controversial. Using fly embryos as a model, we investigated the role of APC proteins in CIN. Our findings suggest that APC2 loss leads to increased rates of chromosome segregation error. This occurs through a cascade of events beginning with incomplete centrosome separation leading to failure to inhibit formation of ectopic cleavage furrows, which result in mitotic defects and DNA damage. We test several hypotheses related to the mechanism of action of APC2, revealing that APC2 functions at the embryonic cortex with several protein partners, including Axin, to promote mitotic fidelity. Our in vivo data demonstrate that APC2 protects genome stability by modulating mitotic fidelity through regulation of the cytoskeleton.


The Effects of Training on Anxiety and Task Performance in Simulated Suborbital Spaceflight.
In commercial spaceflight, anxiety could become mission-impacting, causing negative experiences or endangering the flight itself. We studied layperson response to four varied-length training programs (ranging from 1 h-2 d of preparation) prior to centrifuge simulation of launch and re-entry acceleration profiles expected during suborbital spaceflight. We examined subject task execution, evaluating performance in high-stress conditions. We sought to identify any trends in demographics, hemodynamics, or similar factors in subjects with the highest anxiety or poorest tolerance of the experience. Volunteers participated in one of four centrifuge training programs of varied complexity and duration, culminating in two simulated suborbital spaceflights. At most, subjects underwent seven centrifuge runs over 2 d, including two +Gz runs (peak +3.5 Gz, Run 2) and two +Gx runs (peak +6.0 Gx, Run 4) followed by three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz, peak +6.0 Gx and +4.0 Gz). Two cohorts also received dedicated anxiety-mitigation training. Subjects were evaluated on their performance on various tasks, including a simulated emergency. Participating in 2-7 centrifuge exposures were 148 subjects (105 men, 43 women, age range 19-72 yr, mean 39.4 ± 13.2 yr, body mass index range 17.3-38.1, mean 25.1 ± 3.7). There were 10 subjects who withdrew or limited their G exposure; history of motion sickness was associated with opting out. Shorter length training programs were associated with elevated hemodynamic responses. Single-directional G training did not significantly improve tolerance. Training programs appear best when high fidelity and sequential exposures may improve tolerance of physical/psychological flight stressors. The studied variables did not predict anxiety-related responses to these centrifuge profiles.Blue RS, Bonato F, Seaton K, Bubka A, Vardiman JL, Mathers C, Castleberry TL, Vanderploeg JM. The effects of training on anxiety and task performance in simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(7):641-650.


Tuning the spectral response of ultraviolet organic-inorganic hybrid photodetectors via charge trapping and charge collection narrowing.
Organic-inorganic hybrid ultraviolet photodetectors with tunable spectral response are desirable for many different applications. In this work, we blended poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine] (PTAA) with ZnO nanoparticles in weight ratios of 1 : 1 and 2 : 1 to create charge traps within the active layers for devices with the conventional structure ITO/PEDOT : PSS/PTAA : ZnO/BCP/Al. Thin (150-200 nm) and thick (1400-1900 nm) active layers were employed to utilize charge collection narrowing (CCN). Both thickness and composition of the active layer impacted the spectral tunability of the photoresponse. A single narrow response peak centered at 420 nm (the PTAA absorption edge) with a full width at half maximum of 12 nm was achieved from the device with a 1900 nm active layer and PTAA : ZnO weight ratio of 1 : 1. Decreasing the active layer thickness to 150 nm resulted in a broad spectral response between 320-420 nm with an external quantum efficiency (EQE) value of 295% under 350 nm illumination and a -1 V bias, exhibiting photomultiplication via charge trapping and injection even at small reverse biases. Increasing the weight ratio of PTAA : ZnO to 2 : 1 lowered both the dark current and photocurrent, eliminated photomultiplication in the thin device, and diminished the efficacy of CCN to narrow the spectral photoresponse in the thick device. Transfer matrix method (TMM) and 3-dimensional finite-difference time-domain (3D-FDTD) simulations were performed to understand the impact of thickness and composition of the active layer on the spectral response of UV photodetectors in terms of exciton generation rate and electric field distribution within the devices.


Monoclonal antibodies to various morphologic components of human skin.
Somatic cell hybrids were established from the mouse myeloma, P3x63Ag8.653 cells, and the spleen cells of a mouse hyperimmune to human epidermal cells. Indirect immunofluorescence test with hybridoma culture fluids displayed that 253 out of 263 hybridoma cultures secreted antibodies reactive with the frozen sections of human skin. The hybridomas secreting unique antibodies to skin components were cloned and designated as AHS-1 to -8. Monoclonal antibodies (MoAb) from AHS-1, AHS-2, and AHS-3 hybridomas did detect cytoplasmic antigens present in the epidermal layer, eccrine ducts and glands (except MoAb AHS-1), and hair follicles. Enzyme-linked immunosorbent assay showed that the antigen recognized by either MoAb AHS-1 or MoAb AHS-2, but not by MoAb AHS-3, shares the antigenic determinant with antigen(s) present in keratin polypeptides isolated from human callus. MoAb AHS-4 to -8 distinctly stained each morphologic component of the skin tissues: cell membranes of epidermal cells by MoAb AHS-4, cytoplasms in upper layer cells of epidermis by MoAb AHS-5, dermis by MoAb AHS-6, basement membrane zone by MoAb AHS-7, and eccrine ducts by MoAb AHS-8.


TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis.
Cotranslational insertion of type I collagen chains into the lumen of the endoplasmic reticulum (ER) and their subsequent folding into a heterotrimeric helix is a complex process which requires coordinated action of the translation machinery, components of translocons, molecular chaperones, and modifying enzymes. Here we describe a role for the protein TRAM2 in collagen type I expression in hepatic stellate cells (HSCs) and fibroblasts. Activated HSCs are collagen-producing cells in the fibrotic liver. Quiescent HSCs produce trace amounts of type I collagen, while upon activation collagen synthesis increases 50- to 70-fold. Likewise, expression of TRAM2 dramatically increases in activated HSCs. TRAM2 shares 53% amino acid identity with the protein TRAM, which is a component of the translocon. However, TRAM2 has a C terminus with only a 15% identity. The C-terminal part of TRAM2 interacts with the Ca(2+) pump of the ER, SERCA2b, as demonstrated in a Saccharomyces cerevisiae two-hybrid screen and by immunoprecipitations in human cells. TRAM2 also coprecipitates with anticollagen antibody, suggesting that these two proteins interact. Deletion of the C-terminal part of TRAM2 inhibits type I collagen synthesis during activation of HSCs. The pharmacological inhibitor of SERCA2b, thapsigargin, has a similar effect. Depletion of ER Ca(2+) with thapsigargin results in inhibition of triple helical collagen folding and increased intracellular degradation. We propose that TRAM2, as a part of the translocon, is required for the biosynthesis of type I collagen by coupling the activity of SERCA2b with the activity of the translocon. This coupling may increase the local Ca(2+) concentration at the site of collagen synthesis, and a high Ca(2+) concentration may be necessary for the function of molecular chaperones involved in collagen folding.


Exam Wrappers: It Is Time to Adopt a Nursing Student Metacognitive Tool for Exam Review.
Examining test performance, a common practice in nursing education, can be a vital learning tool, as well as a means of assessment. Exam or cognitive wrappers, performed by students after an exam but before the exam review, can explicitly teach students to discern between what they do and what they do not know. The process teaches metacognition, the highest level of critical thinking. Nursing students need to be proficient in metacognition for professional growth well beyond the classroom. However, little information about these cognitive exercises, known as exam wrappers, exists in nursing education today.


CT radiomic features of photodynamic priming in clinical pancreatic adenocarcinoma treatment.
Photodynamic therapy (PDT) offers localized focal ablation in unresectable pancreatic tumors while tissues surrounding the treatment volume experience a lower light dose, termed photodynamic priming (PDP). While PDP does not cause tissue damage, it has been demonstrated to promote vascular permeability, improve drug delivery, alleviate tumor cell density, and reduce desmoplasia and the resultant internal pressure in pre-clinical evaluation. Preclinical data supports PDP as a neoadjuvant therapy beneficial to subsequent chemotherapy or immunotherapy, yet it is challenging to quantify PDP effects in clinical treatment without additional imaging and testing. This study investigated the potential of radiomic analysis using CT scans acquired before and after PDT to identify areas experiencing PDT-induced necrosis as well as quantify PDP effects in the surrounding tissues. A total of 235 CT tumor slices from seven patients undergoing PDT for pancreatic tumors were examined. Radiomic features assessed included intensity metrics (CT number in Hounsfield Units) and texture analysis using several gray-level co-occurrence matrix (GLCM) parameters. Pre-treatment scans of tumor areas that resulted in PDT-induced necrosis showed statistically significant differences in intensity and texture-based features that could be used to predict the regions that did respond (paired t-test, response versus no response,p < 0.001). Evaluation of PDP effects on the surrounding tissues also demonstrated statistically significant differences, in tumor mean value, standard deviation, and GLCM parameters of contrast, dissimilarity and homogeneity (t-test, pre versus post,p < 0.001). Using leave-one-out cross validation, six intensity and texture-based features were combined into a support-vector machine model which demonstrated reliable prediction of treatment effects for six out of seven patients (ROC curve, AUC = 0.93). This study provides pilot evidence that texture features extracted from CT scans could be utilized as an effective clinical diagnostic prediction and assessment of PDT and PDP effects in pancreatic tumors. (clinical trial NCT03033225).


High-Fat and Combined High-Fat and Sucrose Diets Promote Cardiac Oxidative Stress Independent of Nox2 Redox Regulation and Obesity in Rats.
Oxidative stress is associated with cardiometabolic alterations, and the involvement of excess glucose and fatty acids has been demonstrated in this process. Thus, the aim of this study was to investigate the effects of different hypercaloric diets on cardiac oxidative stress. Wistar rats were randomized into four groups: control (C), high-sucrose (HS), high-fat (HF), and high-fat with sucrose (HFS). Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. Cardiac oxidative stress was analyzed by malondialdehyde (MDA) and carbonylated proteins, and the cardiac protein expression levels of type 1 angiotensin receptor (AT-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), superoxide dismutase (SOD 1 e 2), glutathione peroxidase (GPX), and catalase (CAT) were determined by western blot. The HF group showed an increase in adiposity; however, it did not present adipocyte hypertrophy and comorbidities. Cardiac MDA and carbonylated protein levels were higher in the HF and HFS compared with the C group. The levels of oxidant and antioxidant proteins showed no difference between the groups. HF and HFS dietary interventions promoted cardiac oxidative stress, in the presence and absence of obesity, respectively. However, this process was neither mediated by the pro-oxidants AT1 and Nox2, nor by the quantitative reduction of antioxidant enzymes.


The discovery of quarks.
Quarks are widely recognized today as being among the elementary particles of which matter is composed. The key evidence for their existence came from a series of inelastic electron-nucleon scattering experiments conducted between 1967 and 1973 at the Stanford Linear Accelerator Center. Other theoretical and experimental advances of the 1970s confirmed this discovery, leading to the present standard model of elementary particle physics.


Therapeutic equivalence of risperidone given once daily and twice daily in patients with schizophrenia. The Risperidone Study Group.
A study was conducted to determine whether once-daily administration of risperidone was as effective and safe as twice-daily administration. In a double-blind 6-week trial, 211 patients with acute exacerbation according to DSM-III-R criteria were randomly assigned to receive risperidone at 8 mg once daily or 4 mg twice daily. The primary efficacy measure was the treatment response rate, defined as a 20% or greater reduction in total Positive and Negative Syndrome Scale (PANSS) scores. Severity of extrapyramidal symptoms was assessed by the Extrapyramidal Symptom Rating Scale. The percentage of patients who showed a treatment response at endpoint was not significantly different between groups (76%, once-daily; 72%, twice-daily), nor was the median time to first treatment response (14 days, both groups). Significant reductions in PANSS total and subscale scores and PANSS-derived Brief Psychiatric Rating Scale were observed in both groups, with no significant between-group differences. Extrapyramidal Symptom Rating Scale scores did not differ significantly between groups. There were no clinically relevant changes in vital signs, electrocardiograms, or clinical laboratory test results in either group. Gradual dosage titration over the first 3 days of treatment was well-tolerated in both groups. The median trough plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone were significantly lower with once-daily than with twice-daily administration; median plasma concentrations measured within the first 8 hours after administration tended to be higher with once-daily administration. These differences did not affect the safety and efficacy of risperidone. Risperidone given once daily at 8 mg is as effective as twice-daily administration of 4 mg in the treatment of acute exacerbations of schizophrenia. Both regimens were equally well-tolerated.


High glucose-enhanced acetylcholine stimulated CGMP masks impaired vascular reactivity in tail arteries from short-term hyperglycemic rats.
Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following: (1) the effects of high glucose exposure in vitro (7-10 days) on vascular relaxation to acetylcholine (Ach) and contractility to norepinephrine (NE) and KCl; (2) if NO-dependent cGMP generation is affected under these conditions; and (3) aortic redox status. Non-diabetic rat tail artery rings were incubated in normal (5mM) (control NG) or high (20 mM) glucose buffer (control HG). Vascular responses to Ach, NE and KCl were compared to those of streptozotocin (SZ) diabetic animals in the same buffers (diabetic NG, diabetic HG). Ach-stimulated cGMP levels were quantitated as an indirect assessment of endothelial nitric oxide (NO) production and oxidative stress evaluated by measuring vascular glutathione and oxidized glutathione. Rings from diabetic rats in NG showed impaired relaxation to Ach (P = 0.002) but relaxed normally, when maintained in HG. Similarly, contractile responses to NE were attenuated in diabetic rings in NG but similar to controls in HG. HG markedly augmented maximal contraction to KCl compared to control and diabetic vessels in NG (P < 0.0001). Diabetic vessels in a hyperosmolar, but normoglycemic, milieu respond like those in HG. In vitro, HG for 2 hours changed neither relaxation nor contractile responses to NE and KCl in control rings. Basal cGMP levels were lower in aortae from diabetic animals pre-incubated in NG than in HG/LG or in control rings in NG (P < 0.05). cGMP responses to Ach were exaggerated in diabetic vessels in HG (P = 0.035 vs. control NG, P = 0.043 vs. diabetic NG) but not different between control and diabetic rings in NG. Vessels from diabetic animals had lower levels of GISH (P < 0.0001) and higher levels of GSSG (P < 0.0001) indicating oxidative stress. Our data indicate that endothelium-dependent relaxation is altered early in the diabetic state and that increased NO responses may compensate for augmented oxidative stress but the lack of effect of short-term exposure of normal vessels to HG suggests that short-term hyperglycemia per se does not cause abnormal vascular responses.


Correlation of Urethral Ratio and Bladder Wall Thickness with Cystoscopic Findings in Posterior Urethral Valve Patients to Assess Residual Valves.
Posterior urethral valve (PUV) is life threatening congenital anomaly of urinary tract. Aim of the study was to correlate urethral ratio (UR) and bladder wall thickness (BWT) with cystoscopic findings in PUV patients to assess residual valves and to validate UR as a diagnostic tool for residual valves. It also aimed to assess the utility of bladder wall thickness in diagnosis of residual valves. A total of 31 patients were included in the prospective study done from 2017 to 2019. Calculation of UR was done in oblique VCUG films by dividing maximum posterior and anterior urethral diameter without the catheter insitu. Measurement of BWT was done at dome and bladder neck at full distension with feeding tube insitu and was done at same volume in follow up. The procedure was repeated at 3 months follow up. The findings were compared with cystoscopic findings for the status of residual valves as gold standard. Each patient served as control for self in the study. Median age of presentation was 1 years with range of 1day to 10 years. The most common complains at the time of presentation in our study was straining (35.48%) followed by antenatally diagnosed patients (25.81%) and recurrent UTI (19.36%). Pre fulguration median UR was 2.45. Post Fulguration median UR was 1.20. It showed a statistically significant reduction (p < 0.001) after fulguration. Pre fulguration median BWT was 4 mm. Post fulguration median BWT was 2.5 mm. BWT showed a statistically significant reduction (p < 0.001) after fulguration as well. ROC curve was plotted for UR and BWT. BWT more than 1.95 mm (sensitivity-80%) and UR more than 1.2 (sensitivity-70%) indicates residual valves. A step ladder approach including BWT, UR and check cystoscopy can serve as a new diagnostic algorithm for the assessment of residual valves thereby avoiding extra radiation and general anesthesia exposure.


All fiber-based 160-Gbit/s add/drop multiplexer incorporating a 1-m-long Bismuth Oxide-based ultra-high nonlinearity fiber.
We experimentally demonstrate an all fiber-based, compact add/drop multiplexer (ADM) of a 160 Gbit/s optical time division multiplexed signal using only 1-m length of our fabricated Bi2O3-based step index type optical fiber with an ultra-high nonlinearity of ~1100 W-1.km-1 The ADM is based on the cross phase modulation-induced nonlinear polarization rotation principle and simultaneous add/drop operation was easily achieved by use of a polarization beam splitter after the Bi2O3-based nonlinear fiber. Error-free add/drop operation is readily achieved at multiplexed data rates of both 80 Gbit/s and 160 Gbit/s.


The basis for spinal manipulation: chiropractic perspective of indications and theory.
It is reasonable to think that patients responding to spinal manipulation (SM), a mechanically based therapy, would have mechanical derangement of the spine as a critical causal component in the mechanism of their condition. Consequently, SM practitioners routinely assess intervertebral motion, and treat patients on the basis of those assessments. In chiropractic practice, the vertebral subluxation has been the historical raison d'etre for SM. Vertebral subluxation is a biomechanical spine derangement thought to produce clinically significant effects by disturbing neurological function. This paper reviews the putative mechanical features of the subluxation and three theories that form the foundation for much of chiropractic practice. It concludes with discussion of subluxation as an indicator for SM therapy, particularly from the perspective that subluxation may be one contributory cause of ill-health within a "web of causation".


Lymphocytic and granulomatous hypophysitis: experience with nine cases.
Lymphocytic hypophysitis and granulomatous hypophysitis are rarely encountered. The aim of this study was to demonstrate their clinical peculiarities among pituitary disorders and to provide an approach for their clinical management. In a retrospective study, we reviewed our surgical experience with nine patients harboring hypophysitis. The series included six cases of lymphocytic hypophysitis, two cases of granulomatous hypophysitis, and one case with evidence of coexisting lymphocytic and granulomatous hypophysitis. A striking similarity of clinical signs was found for our nine patients. Headache or aseptic meningitis, thickening of the sphenoid sinus mucosa, pituitary stalk enlargement, and tongue-shaped extension of the lesion along the basal hypothalamus were characteristic signs. Lymphocytic hypophysitis was not associated with pregnancy in any of the seven cases. No recurrence has been observed in six cases with total removal of the inflammatory tissue. Lymphocytic hypophysitis and granulomatous hypophysitis represent related inflammatory disorders. Their conspicuous clinical features frequently allow preoperative diagnosis of hypophysitis. In view of their sometimes insidious clinical course, early surgical exploration is justified.


Which Nebulizer Position Should Be Avoided? An Extended Study of Aerosol Delivery and Ventilator Performance during Noninvasive Positive Pressure Ventilation.
Research on the effect of nebulizer location on aerosol delivery during noninvasive ventilation has reached inconsistent conclusions. To investigate the effects of nebulizer position on aerosol delivery efficiency and ventilator performance during noninvasive ventilation. The Active Servo Lung 5000 respiratory simulation system (ASL5000) was used to simulate a COPD patient. The noninvasive ventilator was set to the spontaneous breathing mode. Six nebulizer positions, 2 exhalation valve types (single-arch exhalation port and whisper swivel), 4 combinations of inspiratory and expiratory pressure, and 2 respiratory rates were used. Significant differences between nebulizer positions existed in aerosol delivery (p < 0.05). Aerosol delivery efficiency was lower for nebulizer locations on either side of the exhalation valve and next to the ventilator outlet. When the nebulizer was located between the exhalation valve and the simulated lung, increased inspiratory pressure increased and increased expiratory pressure decreased delivery efficiency (both p < 0.05). When the nebulization device was located between the exhalation valve and the ventilator, no obvious trend was observed. Compared to baseline, nebulization lowered the air leakage volume displayed on the ventilator. There were no differences in ventilator performance between different nebulizer positions. The closer the nebulizer was to the exhalation valves or ventilator, the lower the aerosol delivery efficiency. Nebulizer position had little clinically significant effect on ventilator performance.


Chronic breathlessness and sleep problems: a population-based survey.
This study aimed to explore the relationship (presence and severity) between chronic breathlessness and sleep problems, independently of diagnoses and health service contact by surveying a large, representative sample of the general population. Analysis of the 2017 South Australian Health Omnibus Survey, an annual, cross-sectional, face-to-face, multistage, clustered area systematic sampling survey carried out in Spring 2017.Chronic breathlessness was self-reported using the ordinal modified Medical Research Council (mMRC; scores 0 (none) to 4 (housebound)) where breathlessness has been present for more than 3 of the previous 6 months. 'Sleep problems-ever' and 'sleep problem-current' were assessed dichotomously. Regression models were adjusted for age; sex and body mass index (BMI). 2900 responses were available (mean age 48.2 years (SD=18.6); 51% were female; mean BMI 27. 1 (SD=5.9)). Prevalence was: 2.7% (n=78) sleep problems-past; 6.8% (n=198) sleep problems-current and breathlessness (mMRC 1-4) was 8.8% (n=254). Respondents with sleep problemspast were more likely to be breathless, older with a higher BMI and sleep problems-present also included a higher likelihood of being female.After adjusting for age, sex and BMI, respondents with chronic breathlessness had 1.9 (95% CI=1.0 to 3.5) times the odds of sleep problems-past and sleep problems-current (adjusted OR=2.3; 95% CI=1.6 to 3.3). There is a strong association between the two prevalent conditions. Future work will seek to understand if there is a causal relationship using validated sleep assessment tools and whether better managing one condition improves the other.


Idling time of motile bacteria contributes to retardation and dispersion in sand porous medium.
The motility of microorganisms affects their transport in natural systems by altering their interactions with the solid phase of the soil matrix. To assess the effect of these interactions on transport parameters, a series of breakthrough curves (BTCs) for motile and nonmotile bacteria, including E. coli and P. putida species, were measured from a homogeneously packed sand column under three different interstitial velocities of 1 m/d, 5 m/d, and 10 m/d. BTCs for the nonmotile bacteria were nearly identical for all three flow rates, except that the recovery percentage at 1 m/d was reduced by 5% compared to the higher flow rates. In contrast, for the motile bacteria, the recovery percentages were not affected by flow rate, but their BTCs exhibited a higher degree of retardation and dispersion as the flow velocity decreased, which was consistent with increased idling times of the motile strains. The smooth-swimming mutant E. coli HCB437, which is unable to change its swimming direction after encountering the solid surfaces and thus has the largest idling time, also exhibited the greatest degree of retardation and dispersion. All of the experimental observations were compared to results from an advection-dispersion transport model with three fitting parameters: retardation factor (R), longitudinal dispersivity (α(L)), and attachment rate coefficient (k(att)). In addition, the single-collector efficiency (η₀) and collision efficiency (α) were calculated according to the colloid filtration theory (CFT), and confirmed that motile bacteria had lower collision efficiencies than nonmotile bacteria. This is consistent with previously reported observations that motile bacteria can avoid attachment to a solid surface by their active swimming capabilities. By quantifying the effect of bacterial motility on various transport parameters, more robust fate and transport models can be developed for decision-making related to environmental remediation strategies and risk assessment.


Study on the distribution features of bone metastases in prostate cancer.
The aim of this study was to explore the distribution features of metastatic bony lesions in prostate cancer. Bone scans with 99mTc-methylene diphosphonate were performed in 144 patients with pathologically proven prostate cancer, and distribution regularity of metastatic bony lesions was analyzed retrospectively. A total of 2000 lesions of bone metastasis were detected in 102 patients, 28.9% of which were distributed in the ribs, 14.8% in thoracic vertebrae, 13.8% in the ilium, and 8.0% in the lumbar vertebrae. The distribution of metastatic bony lesions was correlated with the total number of lesions. The proportion of metastatic lesions of vertebrae and pelvis was up to 84.5% (49/58) in fewer bone metastases. The proportion gradually decreased with an increase in the total number of lesions, but the proportion of the bony lesions, except for the vertebrae and pelvis, gradually increased with an increase in the total number of lesions. Ninety-nine percent (903/912) of metastatic bony lesions, except for the vertebrae and pelvis, coexisted with metastasis of vertebrae or pelvis, whereas only 1.0% (9/912) of those were detected in no metastasis of the vertebrae and pelvis; their difference was significant (χ2=876.4, P=0.000). About 98.8% (571/578) of metastatic costal lesions coexisted with vertebrae metastasis, but only 1.2% (7/578) of these were detected in no metastasis of vertebrae; their difference was significant (χ2=550.3, P=0.000). The difference between left body and right body was not significant (χ=1.3, P=0.249). Metastatic bony lesions of prostate cancer are located mainly in the vertebrae and pelvis in the early stage. The distribution of metastatic bony lesions is not only characterized by spreading to left body and right body randomly, but also presents the tendency of developing with orderliness to a certain extent in the whole body.


Influence of hypoxia and ischemia preconditioning on bilirubin damage to astrocytes.
Hypoxia-ischemia in the perinatal period is a common cause of neurologic disability in children and is often associated with neonatal morbidity and mortality. Another frequent condition of the newborn is hyperbilirubinemia and it is well known that deposition of unconjugated bilirubin (UCB) in the central nervous system can damage nerve cells and cause encephalopathy. Interestingly, some studies report the onset of cerebral hypoxia-ischemia as a risk factor for UCB encephalopathy, since that condition often precedes neonatal hyperbilirubinemia. However, the cellular mechanisms triggered by hypoxia-ischemia that may enforce UCB deleterious effects are not well elucidated. Therefore, we designed this study to investigate whether hypoxia (HP) or combined oxygen-glucose deprivation (OGD) followed by reoxygenation, modifies glial cell susceptibility to UCB injury. Thus, cultured astrocytes were exposed to HP or OGD for 4 h and returned to normoxic conditions for another 12 h prior to incubation with UCB for 4 h. HP and OGD effects in UCB toxicity were compared to normoxic conditions. Our results demonstrate that HP and OGD preconditioning increase the vulnerability of glial cells to UCB damage by enhancing some of the deleterious effects of UCB, namely cell death by both apoptosis and necrosis. This preconditioning also augments the UCB-induced stimulation of an inflammatory response by an effect that involves the activation of the nuclear factor kappaB activation. These findings provide a novel basis for the increased risk of brain damage in jaundiced newborns that were previously exposed to hypoxia or ischemia during the perinatal period, namely during delivery.


The COVID-19 pandemic and sleep medicine: a look back and a look ahead.
The coronavirus disease 2019 (COVID-19) pandemic is a reminder that global infectious disease outbreaks are not new and they have the potential to cause catastrophic morbidity and mortality, disrupt health care delivery, demand critical decision making in the absence of scientific certainty, interrupt trainee education, inflict economic damage, and cause a spike in demand for health care services that exceeds societal capacity. In this article, we look back at how the sleep medicine community adapted to challenges imposed by the COVID-19 pandemic. To mitigate viral transmission perhaps the single most effective and efficient adaptation was the rapid adoption of telemedicine. Many additional strategies were taken up virtually overnight, including more home sleep apnea testing, reconsideration of potential risks of positive airway pressure therapy, a reduction or cessation of laboratory services, and deployment of workers to provide frontline care to infected patients. During some periods, critical shortages in essential personal protective equipment, respiratory assist devices, and even oxygen added to logistical challenges, which were exacerbated by persistent financial threats and insufficient staffing. Through ongoing innovation, resiliency, and adaptability, breakthroughs were made in assigning staff responsibilities and designing workflows, using clinical spaces, obtaining legislative support, and achieving professional society collaboration and guidance so that the missions of providing health care, teaching, and academic pursuits could continue. Here we summarize what we have learned through these critical months and highlight key adaptations that deserve to be embraced as we move forward. Khosla S, Beam E, Berneking M, et al. The COVID-19 pandemic and sleep medicine: a look back and a look ahead. J Clin Sleep Med. 2022;18(8):2045-2050.


HIV prevention outreach in commercial gay venues in large cities: evaluation findings from London.
Human immunodeficiency virus (HIV) prevention delivered in gay venues in US cities has been found to be effective in reducing HIV transmission in the 1990s but effects might not be generalizable to different times and settings. Doubts have been raised about: outreach's ability to address skills and explore personal behaviour; big-city commercial gay venues being appropriate sites for outreach because of gossip and social surveillance; and acceptability of outreach by professionals rather than 'popular opinion formers'. We evaluated coverage, feasibility, acceptability and perceived impact of venue-based HIV prevention outreach by professionals in London, employing observation, surveys and interviews with venue-users, and focus groups/semi-structured interviews with workers. We found high coverage especially among target groups. Addressing negotiation skills and personal behaviour was feasible but required worker motivation and skill. Social surveillance rarely impeded work. Gay men generally found outreach acceptable and useful, and professionals were not regarded negatively. Impact on knowledge was commonly reported; impacts on negotiation skills and reflection on personal behaviour were more common among men experiencing longer contacts. In conclusion, professional HIV prevention outreach in gay venues in large cities is a feasible and acceptable intervention with significant potential impacts. Workers need to be well briefed and trained to maximize impact.


[Roentgenotopographic forms of aseptic necrosis of the femur head in adults].
On the basis of the data of X-ray examination of 378 patients (466 joints) with aseptic necrosis of the femoral head and their surgical treatment (314 patients) the authors have distinguished four roentgenotopographic forms of avascular lesions: peripheral, central, segmental and total. Certain dependence of the localization of the necrotic focus on a number of determined etiologic factors has been pointed out, such as the character of the preceding injury and the type the hip lesion, supercooling or the patient's occupation. The authors believe that the choice of the most adequate type of surgical intervention should be based not only on the stage of the process, but also on the size and the localization of the femoral head lesion.


Chia seed (Salvia hispanica L.) consumption and lipid profile: a systematic review and meta-analysis.
Chia (Salvia hispanica L.) is an annual herbaceous plant, originally from southern Mexico and northern Guatemala - nowadays grown all over the world. In recent years, there has been an increase in demand for plant foods with health-promoting properties, and chia is a main actor in this process due to its high nutritional and functional value and its chemical composition rich in PUFAs, mainly ω-3, as well as protein, dietary fiber, and bioactive compounds. Chia has been explored in different research models for health and the prevention of human diseases. Evidence has suggested potential for improving insulin resistance, disordered lipid profiles, glucose tolerance and even adiposity. The aim of this study was to evaluate the effect of consumption of chia seeds on the lipid profile, triglycerides, and serum ω-3 fatty acids in adults. This systematic review included all randomized controlled trials (parallel or crossover design) published up to August 2020 in the main databases Medline, Embase, Scopus, Web of Science, and Scielo. Two independent authors selected and extracted data from those articles. After the selection process, 10 clinical trials were included. Forest plots and summary tables were constructed to present data and sensitivity subgroup analyses were performed for some of the outcomes. The results showed that chia consumption suggests a protective effect on the lipid profile, decreasing TC (MD = -2.98, 95% CI = [-9.98; 4.02]), TG (MD = -14.09 mg dL-1, 95% CI = [-33.46; 5.28]), and LDL (MD = 2.07 mg dL-1; 95% CI = [-5.05; 9.19]) and increasing HDL (MD = -2.92 mg dL-1, 95% CI = [-5.91; 0.06]). Regarding serum fatty acids, chia reduced FFA and SFA and increased PUFAs, ALA, EPA, and LA. It has also reduced DHA while not changing DPA. The intake of chia appears to have a neutral or beneficial effect on some markers of the lipid and fatty acid profile.


Defective protein folding and aggregation as the basis of neurodegenerative diseases: the darker aspect of proteins.
The ability of a polypeptide to fold into a unique, functional, and three-dimensional structure depends on the intrinsic properties of the amino acid sequence, function of the molecular chaperones, proteins, and enzymes. Every polypeptide has a finite tendency to misfold and this forms the darker side of the protein world. Partially folded and misfolded proteins that escape the cellular quality control mechanism have the high tendency to form inter-molecular hydrogen bonding between the same protein molecules resulting in aggregation. This review summarizes the underlying and universal mechanism of protein folding. It also deals with the factors responsible for protein misfolding and aggregation. This article describes some of the consequences of such behavior particularly in the context of neurodegenerative conformational diseases such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and other non-neurodegenerative conformational diseases such as cancer and cystic fibrosis etc. This will encourage a more proactive approach to the early diagnosis of conformational diseases and nutritional counseling for patients.


Resetting of tubuloglomerular feedback: evidence for a humoral factor in tubular fluid.
Experiments were performed on chronically salt-loaded rats to determine whether resetting of tubuloglomerular feedback is caused by changes in the sensitivity of the juxtaglomerular apparatus itself or by changes of tubular fluid composition. The feedback response was quantified in both salt-loaded and salt-deplete rats by measuring early proximal flow rate (EPF) during loop perfusion at 40, 10, and 0 nl/min using tubular fluid harvested from both groups and with Ringer solution. In salt-loaded rats endogenous tubular fluid produced only a small feedback response (EPF40-0 = 1.9 +/- 1.5 nl/min), whereas exogenous tubular fluid from salt-deplete rats or Ringer solution produced normal feedback responses (EPF40-0 = 15.4 +/- 2.0 and 10.6 +/- 1.7 nl/min, respectively). In salt-deplete rats, endogenous tubular fluid and Ringer solution produced feedback responses of similar magnitude (EPF40-0 = 14.2 +/- 1.8 and 13.0 +/- 2.0 nl/min, respectively) but exogenous tubular fluid from salt-loaded rats elicited only a small feedback response (EPF40-0 = 1.5 +/- 1.6 nl/min), indistinguishable from that seen in salt-loaded rats with endogenous tubular fluid. It is concluded that an inhibitory factor in the tubular fluid of chronically salt-loaded rats causes a reduction in tubuloglomerular feedback response.


CAR2 displays unique ligand binding and RXRalpha heterodimerization characteristics.
The constitutive androstane receptor (CAR; NR1I3) regulates the expression of genes involved in xenobiotic metabolism. Alternative splicing of the human CAR gene yields an array of mRNAs that encode structurally diverse proteins. One form of CAR, termed CAR2, contains an additional four amino acids (SPTV) that are predicted to reshape the ligand-binding pocket. The current studies show a marked, ligand-independent, CAR2-mediated transactivation of reporters containing optimal DR-3, DR-4, and DR-5 response elements, and reporters derived from the natural CYP2B6 and CYP3A4 gene promoters. Overexpression of the RXRalpha ligand binding domain was critical for achieving these effects. CAR2 interaction with SRC-1 was similarly dependent on the coexpression of RXRalpha. Mutagenesis of Ser233 (SPTV) to an alanine residue yielded a receptor possessing higher constitutive activity. Alternatively, mutating Ser233 to an aspartate residue drastically reduced the transactivation capacity of CAR2. The respective abilities of these mutagenized forms of CAR2 to transactivate a DR-4 x 3 reporter element correlated with their ability to interact with RxRalpha and to recruit SRC-1 in a ligand-regulated manner. Together, these results demonstrate a robust RXRalpha-dependent recruitment of coactivators and transactivation by CAR2. In addition, CAR2 displays novel dose responses to clotrimazole and androstanol compared with the reference form of the receptor while at the same time retaining the ability to bind CITCO. This result supports a hypothesis whereby the four-amino-acid insertion in CAR2 structurally modifies its ligand binding pocket, suggesting that CAR2 is regulated by a set of ligands distinct from those governing the activity of reference CAR.


Preoperative discrimination between malignant and benign adnexal masses with transvaginal ultrasonography and colour blood flow imaging.
Ovarian cancer is one of the causes of death in women, and in about 70% of cases is recognized only in advanced stages. This study was undertaken to evaluate distinctive values of transvaginal and color Doppler ultrasonography in differentiating malignant and benign adnexal masses through analysis of ultrasonic morphological features of malignancy and estimation of location and intensification of angiogenesis as well as values of resistance of flow in examined masses. 329 women with malignant and benign adnexal masses underwent ultrasonographic and colour Doppler examination 1-5 days before surgery (laparotomy, laparoscopy) thus allowing histological verification of diagnosis. The ultrasonographic structure was assessed using a morphological scoring system devised by Sassone, Jain and Benacerraf. Regions showing vasculature, especially within septae and solid parts of tumours were examined by means of transvaginal colour Doppler. Location and intensification of angiogenesis as well as resistance index (RI) were investigated. Sensitivity, specificity, PPV and NPV of both techniques were assessed. Statistical analysis of obtained data were based on the Student's t test; p < 0.05 level was considered significant. Postoperatively 255 (77.5%) benign and 74 (22.5%) malignant tumours were seen. In the group of benign masses the average age of women was 42.6+/-12.3 and in the malignant it was 53.1+/-12.6 (p<0.0001). The transverse dimension of benign lesions was 77.2+/-19, whereas for malignant it was 107.0+/-31 (p<0.0001). Benign tumours in 63.0% were cystic, in 26.0% mixed cystic-solid and in 11.0% solid echostructures while in malignant they were respectively, 6.8%, 56.8% and 36.4% (p<0.0001). Doppler flow within the tumour was 74.5% in benign and 98.6% in malignant masses (p<0.0001). In benign lesions homogenous superficial or peripheral vasculature was visualized, and in the majority of cases (82.7%) it was of medium intensification. However in malignant central, peripheral or mixed vascularisation. in the majority intensified character was found. Average value of the resistance index in all benign masses amounted to 0.77+/-0.14, however in malignant it was 0.39+/-0.07 (p<0.0001). We contend that complete ultrasonographic estimation of ovarian neoplasms outside the qualification of structural details should include Doppler analysis of vasculature parameters. Most important is the qualification of resistance of flow, and location and intensification of vascularisation in examined masses which permit the differentiation of malignant and benign lesions. Preoperatively recognizing malignant processes with colour Doppler ultrasonography shows higher accuracy, specificity and PPV.