Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core.
In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.


The insertion Green Monster (iGM) method for expression of multiple exogenous genes in yeast.
Being a simple eukaryotic organism, Saccharomyces cerevisiae provides numerous advantages for expression and functional characterization of proteins from higher eukaryotes, including humans. However, studies of complex exogenous pathways using yeast as a host have been hampered by the lack of tools to engineer strains expressing a large number of genetic components. In addition to inserting multiple genes, it is often desirable to knock out or replace multiple endogenous genes that might interfere with the processes studied. Here, we describe the "insertion Green Monster" (iGM) set of expression vectors that enable precise insertion of many heterologous genes into the yeast genome in a rapid and reproducible manner and permit simultaneous replacement of selected yeast genes. As a proof of principle, we have used the iGM method to replace components of the yeast pathway for methionine sulfoxide reduction with genes encoding the human selenoprotein biosynthesis machinery and generated a single yeast strain carrying 11 exogenous components of the selenoprotein biosynthetic pathway in precisely engineered loci.


An international survey of training in adult intensive care medicine.
The aim of this international survey of training in adult intensive care medicine (ICM) was to characterise current structures, processes, and outcomes to determine the potential for convergence to a common competency-based training programme across national borders. This survey is the first phase of a 3 year project which will use consensus methods to build an international competency-based training programme in ICM in Europe (CoBaTrICE). A survey by questionnaire, e-mail, and direct discussion was undertaken with national ICM representatives from seven geographical regions. Responses were obtained from 41 countries (countries which share common training programmes were grouped together; n=38). Fifty-four different training programmes were identified, 37 within the European region; three (6%) were competency-based. Twenty (53%) permitted multidisciplinary access to a common training programme; in nine (24%) training was only available within anaesthesia. The minimum duration of ICM training required for recognition as a specialist varied from 3 months to 72 months (mode 24 months). The content of most (75%) ICM programmes was standardised nationally. Work-based assessment of competence was formally documented in nineteen (50%) countries. An exam was mandatory in twenty-nine (76%). There are considerable variations in the structures and processes of ICM training worldwide. However, as competency-based training is an outcome strategy rather than a didactic process, these differences should not impede the development of a common international competency-based training programme in ICM.


Difference Between Users and Nonusers of a Patient Portal in Health Behaviors and Outcomes: Retrospective Cohort Study.
Patient portals are frequently used in modern health care systems as an engagement and communication tool. An increased focus on the potential value of these communication channels to improve health outcomes is warranted. This paper aimed to quantify the impact of portal use on patients' preventive health behavior and chronic health outcomes. We conducted a retrospective, observational cohort study of 10,000 patients aged 50 years or older who were treated at the University of Pennsylvania Health System (UPHS) from September 1, 2014, to October 31, 2016. The data were sourced from the UPHS electronic health records. We investigated the association between patient portal use and patients' preventive health behaviors or chronic health outcomes, controlling for confounders using a novel cardinality matching approach based on propensity scoring and a subsequent bootstrapping method to estimate the variance of association estimates. Patient-level characteristics differed substantially between portal users, comprising approximately 59.32% (5932/10000) of the cohort, and nonusers. On average, users were more likely to be younger (63.46 years for users vs 66.08 years for nonusers), white (72.77% [4317/5932] for users vs 52.58% [2139/4068] for nonusers), have commercial insurance (60.99% [3618/5932] for users vs 40.12% [1632/4068] for nonusers), and have higher annual incomes (US $74,172/year for users vs US $62,940/year for nonusers). Even after adjusting for these potential confounders, patient portal use had a positive and clinically meaningful impact on patients' preventive health behaviors but not on chronic health outcomes. This paper contributes to the understanding of the impact of patient portal use on health outcomes and is the first study to identify a meaningful subgroup of patients' health behaviors that improved with portal use. These findings may encourage providers to promote portal use to improve patients' preventive health behaviors.


Multiple point mutations in virulence genes explain the low virulence of Listeria monocytogenes field strains.
In order to understand the causes of the low virulence of Listeria monocytogenes field strains, five low-virulence strains were analysed. These five strains showed changes in relation to invasion, phosphatidyl-inositol phospholipase C (PI-PLC) activity, plaque formation and in vivo virulence. Molecular analyses revealed the same mutations in the plcA, inlA and inlB genes in all five strains. The Thr262Ala substitution in the PI-PLC protein was responsible for the absence of PI-PLC activity. This residue, conserved in certain L. monocytogenes species, is located at the outer rim of the active site pocket and could impair the cleavage activity of the enzyme. The low invasion rate of these strains was due to a nonsense codon leading to a lack of InlA protein synthesis, and to an Ala117Thr substitution in the leucine-rich repeat of InlB, which altered the interaction with the Met receptor. Single trans complementation with the inlA(EGDe), inlB(EGDe) or plcA(EGDe) genes restored the capacity of low-virulence strains either to enter epithelial and fibroblastic cells or to express PI-PLC activity. Complementation by allelic exchange of the plcA(EGDe) gene on the chromosome and trans complementation with either the inlA(EGDe) or the inlB(EGDe) gene restored the ability to form plaques, but only partly restored the in vivo virulence, suggesting that there were other gene mutation(s) with consequences that could mainly be observed in vivo. These results indicate that the low virulence of L. monocytogenes strains can be explained by point mutations in a number of virulence genes; these could therefore be important for detecting low-virulence strains. Moreover, the fact that all the strains had the same substitutions suggests that they have a common evolutionary pathway.


An accurate estimation of bone density improves the accuracy of subject-specific finite element models.
An experimental-numerical study was performed to investigate the relationships between computed tomography (CT)-density and ash density, and between ash density and apparent density for bone tissue, to evaluate their influence on the accuracy of subject-specific FE models of human bones. Sixty cylindrical bone specimens were examined. CT-densities were computed from CT images while apparent and ash densities were measured experimentally. The CT/ash-density and ash/apparent-density relationships were calculated. Finite element models of eight human femurs were generated considering these relationships to assess their effect on strain prediction accuracy. CT and ash density were linearly correlated (R(2)=0.997) over the whole density range but not equivalent (intercep t <0, slope >1). A constant ash/apparent-density ratio (0.598+/-0.004) was found for cortical bone. A lower ratio, with a larger dispersion, was found for trabecular bone (0.459+/-0.100), but it became less dispersed, and equal to that of cortical tissue, when testing smaller trabecular specimens (0.598+/-0.036). This suggests that an experimental error occurred in apparent-density measurements for large trabecular specimens and a constant ratio can be assumed valid for the whole density range. Introducing the obtained relationships in the FE modelling procedure improved strain prediction accuracy (R(2)=0.95, RMSE=7%). The results suggest that: (i) a correction of the densitometric calibration should be used when evaluating bone ash-density from clinical CT scans, to avoid ash-density underestimation and overestimation for low- and high-density bone tissue, respectively; (ii) the ash/apparent-density ratio can be assumed constant in human femurs and (iii) the correction improves significantly the model accuracy and should be considered in subject-specific bone modelling.


Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of nonalcoholic fatty liver disease.
Efflux transporters are responsible for the excretion of numerous xenobiotics and endobiotics and thus play an essential role in proper liver and kidney function. Nonalcoholic fatty liver diseases (NAFLDs) comprise a spectrum of disorders that range from simple fatty liver (SFL) to nonalcoholic steatohepatitis (NASH). Although the precise events leading to NAFLD are unclear, even less is known about the effects on efflux transporter expression and drug disposition. The purpose of this study was to determine the effect of NAFLD on efflux transporter expression in rat liver as well as on acetaminophen (APAP) metabolite excretion. To simulate SFL and NASH, rats were fed either a high-fat (HF) or a methionine- and choline-deficient (MCD) diet for 8 weeks. In the livers of MCD rats, there were striking increases in both mRNA and protein levels of multidrug resistance-associated protein (Mrp) 3, Mrp4, and breast cancer resistance protein, as well as increased Mrp2 protein. After administration of a nontoxic dose of APAP, biliary concentrations of APAP-sulfate, APAP-glucuronide (APAP-GLUC), and APAP-glutathione were reduced in MCD rats. The effects of the HF diet on both transporter expression and APAP disposition were by comparison far less dramatic than the MCD diet-induced alterations. Whereas APAP-sulfate levels were also decreased in MCD rat plasma, the levels of the Mrp3 substrate APAP-GLUC were elevated. Urinary elimination of APAP metabolites was identical between groups, except for APAP-GLUC, the concentration of which was 80% higher in MCD rats. These studies correlate increased hepatic Mrp3 protein in the MCD model of NASH with increased urinary elimination of APAP-GLUC. Furthermore, the proportional shift in elimination of APAP metabolites from bile to urine indicates that MCD-induced alterations in efflux transporter expression can affect the route of drug elimination.


Fluctuations in spo0A transcription control rare developmental transitions in Bacillus subtilis.
Phosphorylated Spo0A is a master regulator of stationary phase development in the model bacterium Bacillus subtilis, controlling the formation of spores, biofilms, and cells competent for transformation. We have monitored the rate of transcription of the spo0A gene during growth in sporulation medium using promoter fusions to firefly luciferase. This rate increases sharply during transient diauxie-like pauses in growth rate and then declines as growth resumes. In contrast, the rate of transcription of an rRNA gene decreases and increases in parallel with the growth rate, as expected for stable RNA synthesis. The growth pause-dependent bursts of spo0A transcription, which reflect the activity of the spo0A vegetative promoter, are largely independent of all known regulators of spo0A transcription. Evidence is offered in support of a "passive regulation" model in which RNA polymerase stops transcribing rRNA genes during growth pauses, thus becoming available for the transcription of spo0A. We show that the bursts are followed by the production of phosphorylated Spo0A, and we propose that they represent initial responses to stress that bring the average cell closer to the thresholds for transition to bimodally expressed developmental responses. Measurement of the numbers of cells expressing a competence marker before and after the bursts supports this hypothesis. In the absence of ppGpp, the increase in spo0A transcription that accompanies the entrance to stationary phase is delayed and sporulation is markedly diminished. In spite of this, our data contradicts the hypothesis that sporulation is initiated when a ppGpp-induced depression of the GTP pool relieves repression by CodY. We suggest that, while the programmed induction of sporulation that occurs in stationary phase is apparently provoked by increased flux through the phosphorelay, bet-hedging stochastic transitions to at least competence are induced by bursts in transcription.


Human hydration indices: acute and longitudinal reference values.
It is difficult to describe hydration status and hydration extremes because fluid intakes and excretion patterns of free-living individuals are poorly documented and regulation of human water balance is complex and dynamic. This investigation provided reference values for euhydration (i.e., body mass, daily fluid intake, serum osmolality; M +/- SD); it also compared urinary indices in initial morning samples and 24-hr collections. Five observations of 59 healthy, active men (age 22 +/- 3 yr, body mass 75.1 +/- 7.9 kg) occurred during a 12-d period. Participants maintained detailed records of daily food and fluid intake and exercise. Results indicated that the mean total fluid intake in beverages, pure water, and solid foods was >2.1 L/24 hr (range 1.382-3.261, 95% confidence interval 0.970-3.778 L/24 hr); mean urine volume was >1.3 L/24 hr (0.875-2.250 and 0.675-3.000 L/24 hr); mean urine specific gravity was >1.018 (1.011-1.027 and 1.009-1.030); and mean urine color was > or = 4 (4-6 and 2-7). However, these men rarely (0-2% of measurements) achieved a urine specific gravity below 1.010 or color of 1. The first morning urine sample was more concentrated than the 24-h urine collection, likely because fluids were not consumed overnight. Furthermore, urine specific gravity and osmolality were strongly correlated (r2 = .81-.91, p < .001) in both morning and 24-hr collections. These findings provide euhydration reference values and hydration extremes for 7 commonly used indices in free-living, healthy, active men who were not exercising in a hot environment or training strenuously.


Mass screening for neuroblastoma in Japan. Committee of the Neuroblastoma Mass Screening Study of the Japanese Society of Pediatric Oncology.
The present status of NB mass screening in Japan, which is the first national trial in the world, is presented. This program was conducted in cooperation with infants' mothers, local health centers, screening centers and hospitals. Three hundred and thirty-seven cases detected by the program, from the start in Kyoto in 1974 to the end of 1989, are analyzed. As many cases were detected at early stages, 97% of them were expected to be cured. Several clinical, technical and programmatic problems are also discussed.


Embryolethality induced by metronidazole (MTZ) in Rattus norvegicus.
Parasitic illnesses is increasing all over the world, especially in developing countries, and metronidazole (MTZ) is the therapeutic agent usually administered to children as well as adults at the reproductive age. In this work, we propose an evaluation of MTZ in order to analyze the potential reproductive damage in females by using Rattus norvegicus (Sprague-Dawley) as an animal model. Adult female rats were mated after MTZ treatments, and they were sacrificed at 21 days of gestation. Different types of damage were evaluated by using mortality, phenotypic abnormalities and reproductive capacity as parameters, and were studied and scored in 70 adult specimens (450 g/bw). They were divided into five groups: a) untreated females as a control group; females treated with b) DMSO as a solvent control group or c) 500 mg/kg/bw of MTZ per day for 7 days as therapeutic dose (TD); d) a half therapeutic dose (HD); and e) a double therapeutic dose (DD). Pre-implantation death in MTZ-treated groups was not significantly different from controls. However, drug treatments significantly increased the frequency of post-implantation deaths and the dominant lethals were ranged between 12.0 % and 17.8 %.


Specific inhibition of TET1 in the spinal dorsal horn alleviates inflammatory pain in mice by regulating synaptic plasticity.
DNA demethylation mediated by ten-eleven translocation 1 (TET1) is a critical epigenetic mechanism in which gene expression is regulated via catalysis of 5-methylcytosine to 5-hydroxymethylcytosine. Previously, we demonstrated that TET1 is associated with the genesis of chronic inflammatory pain. However, how TET1 participates in enhanced nociceptive responses in chronic pain remains poorly understood. Here, we report that conditional knockout of Tet1 in dorsal horn neurons via intrathecal injection of rAAV-hSyn-Cre in Tet1fl/fl mice not only reversed the inflammation-induced upregulation of synapse-associated proteins (post-synaptic density protein 95 (PSD95) and synaptophysin (SYP)) in the dorsal horn but also ameliorated abnormalities in dendritic spine morphology and alleviated pain hypersensitivities. Pharmacological blockade of TET1 by intrathecal injection of a TET1-specific inhibitor-Bobcat 339-produced similar results, as did knockdown of Tet1 by intrathecal injection of siRNA. Thus, our data strongly suggest that increased TET1 expression during inflammatory pain upregulates the expression of multiple synapse-associated proteins and dysregulates synaptic morphology in dorsal horn neurons, suggesting that Tet1 may be a potential target for analgesic strategies.


Non-Abelian SU(2) Lattice Gauge Theories in Superconducting Circuits.
We propose a digital quantum simulator of non-Abelian pure-gauge models with a superconducting circuit setup. Within the framework of quantum link models, we build a minimal instance of a pure SU(2) gauge theory, using triangular plaquettes involving geometric frustration. This realization is the least demanding, in terms of quantum simulation resources, of a non-Abelian gauge dynamics. We present two superconducting architectures that can host the quantum simulation, estimating the requirements needed to run possible experiments. The proposal establishes a path to the experimental simulation of non-Abelian physics with solid-state quantum platforms.


The poly-alpha- and -beta-1,4-glucuronic acid moiety of teichuronopeptide from the cell wall of the alkalophilic Bacillus strain C-125.
Teichuronopeptide is a structural component of the cell wall of alkalophilic Bacillus strain C-125 and is a complex composed of polyglutamate and polyglucuronate. A structural analysis of the polyglucuronic acid moiety was carried out. Periodate oxidation and Smith degradation of the moiety, and enzymic analysis after reduction of glucuronic acid to glucose, revealed that glucuronic acid bound together with alternately alpha- and beta-1,4-linkages.


Molecular characterization of a phytoplasma affiliated with the 16SrVII group representative of the novel 16SrVII-F subgroup.
Vernonia brasiliana is a wild perennial shrub frequently found in pasture areas. Plants of this species have been observed displaying typical symptoms induced by phytoplasmas, which were characterized by shoot proliferation, deformed leaves and leaf chlorosis. The present study confirmed the presence of phytoplasmas in association with affected plants. Sequencing of the 16S rRNA gene, computer-simulated RFLP analysis and phylogenetic analysis revealed that one of the phytoplasmas identified was representative of novel subgroup. The sequence identity scores between the novel strain and those of previously described 'CandidatusPhytoplasma fraxini'-related strains was 99 %, while similarity coefficient values were lower than 0.97. These findings provide support to delineate the phytoplasma found in vernonia plants as a reference phytoplasma for a novel subgroup designated 16SrVII-F. This representative of the novel subgroup was denominated VbSP phytoplasma (Vernonia brasiliana Shoot Proliferation; GenBank KX342018). The results of the present study revealed V. brasiliana to be a host of phytoplasmas, evidenced a novel phytoplasma associated with phytoplasmal disease in Brazil and extended the knowledge of the genetic diversity existing within the 16SrVII group.


School-Based Health Centers and Pediatric Practice.
School-based health centers (SBHCs) are unique health care settings for our nation's school-aged children and adolescents. SBHCs represent the collaboration between the health and school communities to support the health and mental health needs and the academic achievements of children and adolescents, particularly students with health disparities or poor access to health care. SBHCs improve access to health care services for students by decreasing financial, geographic, age, and cultural barriers. This policy statement provides an overview of SBHCs, including the scope of services as well as some of the documented benefits and challenges. This policy statement also reviews the role of SBHCs in working with the pediatric medical home and provides recommendations that support the coordination of SBHCs with pediatric primary care providers and the pediatric medical home.


Persistent Depression as a Novel Diagnostic Category: Results from the Menderes Depression Study.
Persistent depressive disorder (PDD) introduced in the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 as a novel diagnostic category represents a consolidation of two separate DSM-IV categories, chronic major depressive disorder (MDD) and dysthymic disorder. The present study aims to investigate the frequency and clinical as well as socio-demographic correlates of PDD in comparison with those of episodic MDD among patients seeking treatment for depressive symptoms. Participants were 140 depressive out-and in-patients under treatment at the psychiatry clinic of the Adnan Menderes University Research Hospital. Each patient was assessed by means of a structured clinical interview (SCID-I) and relevant psychometric instruments including the Hamilton Depression Inventory and Eskin Suicidal Behavior Inventory. Among the depressive patients, 61% fulfilled the criteria for PDD and 39% for episodic MDD. As compared with patients with episodic MDD, the PDD patients were older (d=.54), lower in educational attainment (d=.55), more likely to have comorbid generalized anxiety disorder (OR=3.7), and more prone to report symptoms of anxiety, hopelessness, pessimism, and somatic complaints. Nevertheless, the PDD patients displayed heterogeneous characteristics with respect to clinical severity and suicidal behavior. Our findings suggest that majority of depressive patients, including those fulfilling the criteria for MDD, have been suffering from a persistent ailment rather than an episodic disorder. Clinicians with a cross-sectional perspective are more likely to diagnose MDD, whereas those with a longitudinal perspective are more likely to identify PDD in the majority of depressive patients. The incorporation of both of these perspectives into DSM-5 in a complementary manner will possibly enhance our insight into depressive disorders and improve our treatment results.


Changes in life expectancy in Russia in the mid-1990s.
Between 1987 and 1994, life expectancy in Russia declined substantially. Between 1994 and 1998, this trend reversed, and mortality rates returned to those of the early 1980s. Although the decline in life expectancy has been examined previously, much less is known about the subsequent improvement in mortality rates. We used recently published cause-specific mortality data up to 1998 to clarify this issue. Changes in cause-specific death rates at ages 15-74 years were examined. Rates for 1998 were compared with those for 1994 (the year of lowest life expectancy) and for 1991 (the year the Soviet Union broke up). Death rates among children fell steadily throughout the 1990s, and those in elderly people changed little. The reduction in mortality since 1994 was mainly due to a decrease in the death rate among middle-aged adults, which had increased until 1994. Deaths among those aged 15-30 years, which rose during 1991-94, remained high. Some causes of death, such as stomach cancer and road-traffic accidents, declined throughout the 1990s, whereas others, such as breast and prostate cancers and tuberculosis, increased. The decline in mortality since 1994 was, however, mainly due to a reduction in the rate of deaths from a group of causes associated with alcohol consumption. The changing life expectancy in Russia is a consequence of a complex pattern of trends in different causes of death, some of which have their origins long in the past, and others that result from contemporary circumstances. This study provides further support for the view that alcohol has played an important part in the fluctuations in life expectancy in Russia in the 1990s, although there remains a need for a much better understanding of the factors underlying these continuing changes.


University students' attitudes toward gender roles and infertility: A descriptive and correlational study.
To examine the relationship between university students' attitudes toward gender roles and infertility. This descriptive and correlational study was conducted with 743 university students between September and December 2020. Data were collected using a personal information form, the Gender Roles Attitude Scale, and the Attitudes Towards Infertility Scale through online forms. It was found that attitudes toward gender roles and infertility could be influenced by some sociodemographic factors, for instance, students' sex, education, and family type. There was also a moderate and positive correlation between attitudes toward gender roles and infertility. The present study contributes to a better understanding of the social construction and attitudes toward gender roles and infertility. For a better future, it is recommended that nurses help and support university students in raising awareness about such an important social problem.


Long-term outcomes of robotic mesh sacrocolpopexy.
The aim of the study is to evaluate anatomic and functional late-term outcomes of robotic mesh sacrocolpopexy (RMS) at a single tertiary-care institution. Following IRB approval, a retrospective chart review of a prospectively collected database on consecutive patients who underwent RMS for symptomatic pelvic organ prolapse and had 3 year minimum follow-up was performed. Data collected included physical examination, validated questionnaires including Urogenital Distress Inventory, Incontinence Impact Questionnaire, and global Quality of Life (QOL). The primary outcome was failure defined as the need for re-operation and/or prolapse recurrence by examination. Those with office follow-up < 36 months underwent structured phone interviews. Between 12/2007 and 2/2012, 56 women underwent RMS. Thirty women had follow-up ≥ 3 years (median 64 (IQR 48-85) months). Mean C-point went from - 2.33 (range 0 to - 5) to - 9.00 (0 to - 12) (p < 0.01), and mean QOL score from 3.93 (0-10) to 1.93 (0-8) (p < 0.01). Two developed recurrent vault prolapse later on at 26 and 34 months, respectively. Four women (13%) required surgery for secondary prolapses, with three for anterior compartment and one for posterior compartment. Sixteen of twenty six were contacted via structured phone interviews, with 14 doing well, one deceased, and one who underwent a secondary posterior compartment prolapse 6 years later at an outside facility. This long-term study indicates durability for RMS in the management of symptomatic pelvic organ prolapse.


Sample size determination for studies designed to estimate covariate-dependent reference quantile curves.
Accuracy and sample size issues concerning the estimation of covariate-dependent quantile curves are considered. It is proposed to measure the precision of an estimate of the pth quantile at a given covariate value by the probability with which this estimate lies between the p1 th and p2 th quantile, where p1 < p < p2 . Requiring that this probability exceeds a given confidence bound for all covariate values in a specified range leads to a sample size criterion. Approximate formulae for the precision and sample size are derived for the normal parametric regression approach and for the semiparametric quantile regression method. A simulation study is performed to evaluate the accuracy of the approximations. Numerical evaluations show that rather large numbers of subjects are needed to construct quantile curves with a reasonable amount of accuracy, especially if the quantile regression method is applied.


Acetate catabolism by Methanosarcina barkeri: evidence for involvement of carbon monoxide dehydrogenase, methyl coenzyme M, and methylreductase.
The pathway of acetate catabolism in Methanosarcina barkeri strain MS was studied by using a recently developed assay for methanogenesis from acetate by soluble enzymes in cell extracts. Extracts incubated with [2-14C]acetate, hydrogen, and ATP formed 14CH4 and [14C]methyl coenzyme M as products. The apparent Km for acetate conversion to methane was 5 mM. In the presence of excess acetate, both the rate and duration of methane production was dependent on ATP. Acetyl phosphate replaced the cell extract methanogenic requirement for both acetate and ATP (the Km for ATP was 2 mM). Low concentrations of bromoethanesulfonic acid and cyanide, inhibitors of methylreductase and carbon monoxide dehydrogenase, respectively, greatly reduced the rate of methanogenesis. Precipitation of CO dehydrogenase in cell extracts by antibodies raised to 95% purified enzyme inhibited both CO dehydrogenase and acetate-to-methane conversion activity. The data are consistent with a model of acetate catabolism in which methylreductase, methyl coenzyme M, CO dehydrogenase, and acetate-activating enzymes are components. These results are discussed in relation to acetate uptake and rate-limiting transformation mechanisms in methane formation.


A comparative study of oral health attitudes and behavior using the Hiroshima University-Dental Behavioral Inventory (HU-DBI) between dental and civil engineering students in Colombia.
The aim of this study was to use the Hiroshima University - Dental Behavioral Inventory (HU-DBI) to compare oral health attitudes and behavior of dental and civil engineering students in Colombia. The HU-DBI's survey consisting of twenty dichotomous responses (agree-disagree) regarding tooth brushing, was completed at University Antonio Narino for the dental students and the University of Cauca for the civil engineering students. The Spanish version of the HU-DBI questionnaire was taken by 182 of 247 dental students and 411 of 762 engineering students. The data was-statistically analyzed by the chi-square test and backward logistic regression. Compared to the engineering students, the dental students were more likely to agree with questions such as "I am bothered by the color of my gums"(OR = 2.2, 95% CI: 1.3-3.7),"I think I can clean my teeth well without using toothpaste" (OR = 3.0, 95% CI: 1.5-5.9), "I have used a dye to see how clean my teeth are" (OR = 2.9, 95% CI: 1.9-4.3), and "I have had my dentist tell me that I brush very well" (OR = 2.0, 95% CI: 1.3-3.1). The dental education curriculum in a dental school compared to a civil engineering school in Colombia indicated that a three-phase curriculum in didactics and clinics increased oral health attitudes and behavior from entry to graduation.


[The diagnosis of hemochromatosis in the era of the gene].
The discovery of the hemochromatosis gene has deeply changed and simplified the diagnosis of the disease. In a given individual, establishing the diagnosis relies, from now on, on a simple blood sample showing the couple: elevated transferrin saturation and homozygous C282Y mutation (= C282Y +/+). Liver biopsy should only be performed when iron overload is massive in order to detect cirrhosis (or bridging fibrosis), i.e. in a prognostic view. Practically, liver biopsy is confined to the following two situations: when the C282Y +/+ patient exhibits hepatomegaly and/or an increase in serum transaminases and/or a serum ferritin level above 1,000 micrograms/L; whenever, despite a strong bio-clinical suspicion of iron overload, genetic testing does not show the expected homozygosity for C282Y. At the family level, evaluating the risk for hemochromatosis is now "instantaneous" thanks to genetic testing. One must, however, keep in mind in interpreting the data of the family members that: clinical expression of the homozygous status is not constant; heterozygosity for C282Y does not per se lead to significant iron overload, but may constitute a co-factor exacerbating (or increasing the risk of) other hepatic or non hepatic diseases. Heterozygosity exposes also to the risk of homozygosity among the offspring; this knowledge of C282Y status must be balanced by the negative impact from the standpoint of possible societal genetic discrimination.


Helping behaviour and regard for others in capuchin monkeys (Cebus apella).
Altruism is an evolutionary puzzle. To date, much debate has focused on whether helping others without regard to oneself is a uniquely human behaviour, with a variety of empirical studies demonstrating a lack of altruistic behaviour in chimpanzees even when the demands of behaving altruistically seem minimal. By contrast, a recent experiment has demonstrated that chimpanzees will help a human experimenter to obtain an out-of-reach object, irrespective of whether or not they are offered a reward for doing so, suggesting that the cognitions underlying altruistic behaviour may be highly sensitive to situational demands. Here, we examine the cognitive demands of other-regarding behaviour by testing the conditions under which primates more distantly related to humans--capuchin monkeys--help an experimenter to obtain an out-of-reach object. Like chimpanzees, capuchin monkeys helped human experimenters even in the absence of a reward, but capuchins systematically failed to take into account the perspective of others when they stood to obtain food for themselves. These results suggest an important role for perspective taking and inhibition in altruistic behaviour and seem to reflect a significant evolutionary development in the roots of altruism, and specifically in other-regarding behaviour, between the divergence of New World monkeys and apes.


Modeling of x-ray fluorescence full field imaging using planar square pore micro-channel plate optics.
X-ray fluorescence imaging using perfect planar square pore micro-channel plate x-ray optics (MPO) is investigated through the modeling of the MPO point spread function (PSF). A semi-continuous model based on the use of a simplified two parameters reflectivity curve is developed including, in particular, three kinds of contributions. A validation of this model is carried out by calculating variations of several PSF characteristics with the MPO and fluorescence imaging parameters and comparing the results with ray-tracing simulations. A good agreement is found in a large range of x-ray energies; however, it is shown that for the lower values of the working distance a discrete model should be used to take into account the periodic nature of the PSF. Ray-tracing simulated images of extended monochromatic sources are interpreted in light of both the semi-continuous and discrete models. Finally, solutions are proposed to improve the imaging properties of the MPOs.


Bootstrapping language acquisition.
The semantic bootstrapping hypothesis proposes that children acquire their native language through exposure to sentences of the language paired with structured representations of their meaning, whose component substructures can be associated with words and syntactic structures used to express these concepts. The child's task is then to learn a language-specific grammar and lexicon based on (probably contextually ambiguous, possibly somewhat noisy) pairs of sentences and their meaning representations (logical forms). Starting from these assumptions, we develop a Bayesian probabilistic account of semantically bootstrapped first-language acquisition in the child, based on techniques from computational parsing and interpretation of unrestricted text. Our learner jointly models (a) word learning: the mapping between components of the given sentential meaning and lexical words (or phrases) of the language, and (b) syntax learning: the projection of lexical elements onto sentences by universal construction-free syntactic rules. Using an incremental learning algorithm, we apply the model to a dataset of real syntactically complex child-directed utterances and (pseudo) logical forms, the latter including contextually plausible but irrelevant distractors. Taking the Eve section of the CHILDES corpus as input, the model simulates several well-documented phenomena from the developmental literature. In particular, the model exhibits syntactic bootstrapping effects (in which previously learned constructions facilitate the learning of novel words), sudden jumps in learning without explicit parameter setting, acceleration of word-learning (the "vocabulary spurt"), an initial bias favoring the learning of nouns over verbs, and one-shot learning of words and their meanings. The learner thus demonstrates how statistical learning over structured representations can provide a unified account for these seemingly disparate phenomena.


Perinatal factors and atopic disease in childhood.
Recent work has suggested possible linkages between perinatal factors and notably, head circumference and risks of subsequent atopic illness. To examine the linkages between perinatal factors and risks of atopic conditions in a birth cohort of New Zealand children studied to the age of 16. Measures of atopic illness including asthma, eczema, and other allergies were assessed prospectively during the course of a 16 year longitudinal study of a birth cohort of 1265 New Zealand children. In the initial stage of this research, measures of perinatal variables including birthweight, gestational age, head circumference and length at birth were obtained from hospital record data. Children with head circumference at birth of 37 cm or greater had (unadjusted) odds of asthma that were 1.8 (P < 0.01) to 3.0 (P < 0.0001) times higher than the odds for children of lesser head circumference. However, risks of asthma were not related to other perinatal measures including birthweight, gestational age or length or ratios of these measures. There were no consistent associations between perinatal measures and other measures of childhood atopy including eczema, allergic rhinitis and other allergies. The associations between head circumference and asthma risks persisted when due allowance was made for potentially confounding social and perinatal factors. It is concluded that large head circumference at birth may be associated with increased risks for the development of asthma. Possible explanations for the linkages between head circumference and asthma risks are considered.


Gordonia polyisoprenivorans sp. nov., a rubber-degrading actinomycete isolated from an automobile tyre.
A rubber-degrading bacterium (strain Kd2T) was isolated from fouling tyre water inside a deteriorated automobile tyre. The strain was aerobic, Grampositive, produced elementary branching hyphae which fragmented into rod/coccus-like elements and showed chemotaxonomic markers which were consistent with the classification of Gordonia, i.e. meso-diaminopimelic acid, N-glycolyl muramic acid, arabinose and galactose as diagnostic sugars, a fatty acid pattern composed of unbranched saturated and monounsaturated fatty acids with a considerable amount of tuberculostearic acid, and mycolic acids comprising 58-66 carbon atoms with two principal mycolic acids C60 and C62 counting for over 60%. Results of 16S rDNA analyses as well as chemotaxonomic results, led to the conclusion that Gordonia sp. strain Kd2T (= DSM 44302T) represents a new species within the genus Gordonia for which the name Gordonia polyisoprenivorans is proposed.


[Nuclear magnetic resonance study of the conformation of nucleotides, oligonucleotides, and their analogs in solution. IV. Syn--anti-equilibrium in aqueous solutions of 2'-deoxynucleosides and nucleotides].
The method of determination of syn-anti-equilibrium constants by experimental measuring of spin-lattice relaxation rates of the H (1') atom of the carbohydrate ring recently elaborated by us for the ribonucleosides and nucleotides was applied to deoxy compounds. For calculation of the contribution of the H (2') and H (2") nuclei rapid relaxation to the relaxation rate of H (1'), the emprical expression was proposed. Conformation situation in aqueous solution of 2'-deoxynucleoside 5'-phosphates and pyrimidine 2'-deoxynucleosides was demonstrated to be characterized by the substantial preponderance of the anti-state. In the solution of dGuo and dAdo the relative weight of the anti-population was decreased to 0.5 and 0.3, respectively. The time average values of glycosidictorsional angle chi in the anti-state was calculated.


Projections to the superior colliculus from inferior parietal, ventral premotor, and ventrolateral prefrontal areas involved in controlling goal-directed hand actions in the macaque.
We found that the macaque inferior parietal (PFG and anterior intraparietal [AIP]), ventral premotor (F5p and F5a), and ventrolateral prefrontal (rostral 46vc and intermediate 12r) areas forming a network involved in controlling purposeful hand actions ("lateral grasping network") are a source of corticotectal projections. Based on injections of anterograde tracers at the cortical level, the results showed that all these areas displayed relatively dense projections to the intermediate and deep gray layers of the ipsilateral superior colliculus (SC) and to the ventrally adjacent mesencephalic reticular formation. In the SC, the labeling tended to be richer in the lateral part along almost the entire rostro-caudal extent, that is, in regions controlling microsaccades and downward gaze shifts and hosting arm-related neurons and neurons modulated by the contact of the hand with the target. These projections could represent a descending motor pathway for controlling proximo-distal arm synergies. Furthermore, they could broadcast to the SC information related to hand action goals and object affordances extraction and selection. This information could be used in the SC for controlling orienting behavior (gaze and reaching movements) to the targets of object-oriented actions and for the eye-hand coordination necessary for appropriate hand-object interactions.


Structure-independent analysis of the breadth of the positional distribution of disordered groups in macromolecules from order parameters for long, variable-length vectors using NMR paramagnetic relaxation enhancement.
Quantitative information regarding structurally disordered groups is crucial for a complete understanding of the relationship between structure, dynamics, and function in biological macromolecules. Experimental analysis, however, of the positional distribution of disordered groups in the macromolecular frame is extremely difficult. While NMR order parameters, S(2), for fixed-length bond vectors such as N-H and C-H are commonly used for investigations of conformational dynamics of macromolecules, these order parameters provide only angular information about internal motions and are totally insensitive to translational motions. Although analysis of S(2) for bond vectors permits identification of disordered groups in macromolecules, this type of order parameter cannot provide any information about the distribution radii of disordered groups. Here we describe an NMR approach to directly determine the distribution radius of a disordered group independent of any structural knowledge. This approach makes use of order parameters for long, variable-length vectors (including proton-paramagnetic center and proton-proton vectors) between a disordered group and a rigid portion of the macromolecule. We demonstrate the application of this formalism to paramagnetic relaxation enhancement vectors. In addition, the potential utility of the same formalism to (1)H-(1)H cross-relaxation rates is considered as an alternative approach for analyzing the breadth of the positional distribution of disordered groups.


Effects of 66 years of water management and hydroclimatic change on the urban hydrology and water quality of the Panke catchment, Berlin, Germany.
Long-term records of combined stream flow and water chemistry can be an invaluable source of information on changes in the quantity and quality of water resources. To understand the effect of hydroclimate and water management on the heavily urbanized Panke catchment in Berlin, Germany, an extensive search, collation and digitization of historic data from various sources was undertaken. This integrated a unique 66-year spatially distributed record of stream water quality, a 21-year record of groundwater quality and a 31-year stream flow record. These data were analysed in the context of hydroclimatic variability, as well as the history and technological evolution of water resource management in the catchment. To contextualize the effect of droughts, "average" and wet years the Standard Precipitation Index (SPI) was applied. As upstream sites have been less regulated by human impacts, the flow regime is most sensitive to changes in hydroclimatic conditions, while downstream sites are more influenced by wastewater effluents, urban storm drains and inter-basin transfers for flood alleviation. However, at all sites, a general increase in maximum event discharge was observed until a recent drought, starting in 2018. In general, water quality in the catchment has gradually improved as a result of management change and increasingly effective wastewater treatment, though in some places legacy and/or contemporary urban and rural groundwater contamination may be affecting the stream. Hydroclimatic changes, particularly drought years can affect water quality classes, and alter the chemostatic/dynamic behaviour of catchment export patterns. These insights from the Panke catchment underline the importance of strategic adaptation and improvement of water treatment and water resource management in order to enhance the quality of urban water courses. It also demonstrates the importance of long-term integrated data sets.


Improving care through health economics analyses: cost of illness and headache.
The impact of headache disorders is a problem of enormous proportions, both for individual and society. The medical literature tried to assess its effects on individuals, by examining prevalence, distribution, attack frequency and duration, and headache-related disability, as well as effects on society, looking at the socio-economic burden of headache disorders [Rasmussen (Cephalalgia 19:20-23, 1999)]; [Lanteri-Minet et al. (Pain 102:143-149, 2003)]. The issue of costs represents an important problem too, concerning both direct and indirect costs. Direct costs concern mainly expenses for drugs. Migraine has a considerable impact on functional capacity, resulting in disrupted work and social activities: many migraineurs do not seek medical attention because they have not been accurately diagnosed by a physician or do not use prescribed medication [Solomon and Price (Pharmacoeconomics 11:1-10, 1997)]. Indirect costs associated with reduced productivity represent a substantial proportion of the total cost of migraine as well. Migraine has a major impact on the working sector of the population, and therefore, determining the indirect costs outweighs the direct costs. This study will explain the notion of cost of illness, examining how it could be applied in such a framework. Then, an overview of the studies aimed at measuring direct and indirect costs of migraine and headache disorders will be carried out, later shifting on to the relationship between costs and quality of life for people affected by headache disorders. Finally, a brief review on advantages of new pharmaceuticals and preventive treatments for migraine for patients and society will outline improvements in the context of cost-effectiveness and cost-utility analysis.


Are routine repeat imaging and intensive care unit admission necessary in mild traumatic brain injury?
More than 1.5 million Americans suffer a traumatic brain injury (TBI) each year. Seventy-five percent of these patients have a mild TBI, with Glasgow Coma Scale (GCS) Score 13-15. At the authors' institution, the usual practice has been to admit those patients with an associated intracranial hemorrhage (ICH) to an ICU and to obtain repeat head CT scans 12-24 hours after admission. The purpose of this study was to determine if there exists a subpopulation of mild TBI patients with an abnormal head CT scan that requires neither repeat brain imaging nor admission to an ICU. This group of patients was further classified based on initial clinical factors and imaging characteristics. A retrospective review of all patients admitted to a Level I trauma center from January 2007 through December 2008 was performed using the hospital Trauma Registry Database, medical records, and imaging data. The inclusion criteria were as follows: 1) an admission GCS score ≥ 13; 2) an isolated head injury with no other injury requiring ICU admission; 3) an initial head CT scan positive for ICH; and 4) an initial management plan that was nonoperative. Collected data included age, etiology, initial GCS score, time of injury, duration of ICU stay, duration of hospital stay, and anticoagulation status. Primary outcomes measured were the occurrence of neurological or medical decline and the need for neurosurgical intervention. Imaging data were analyzed and classified based on the predominant blood distribution found on admission imaging. Data were further categorized based on the Marshall CT classification, Rotterdam score, and volume of intraparenchymal hemorrhage (IPH). Progression was defined as an increase in the Marshall classification, an increase in the Rotterdam score, or a 30% increase in IPH volume. Three hundred twenty-one of 1101 reviewed cases met inclusion criteria for the study. Only 4 patients (1%) suffered a neurological decline and 4 (1%) required nonemergent neurosurgical intervention. There was a medical decline in 18 of the patients (6%) as a result of a combination of events such as respiratory distress, myocardial infarction, and sepsis. Both patient age and the transfusion of blood products were significant predictors of medical decline. Overall patient mortality was 1%. Based on imaging data, the rate of injury progression was 6%. The only type of ICH found to have a significant rate of progression (53%) was a subfrontal/temporal intraparenchymal contusion. Other variables found to be significant predictors of progression on head CT scans were the use of anticoagulation, an age over 65 years, and a volume of ICH > 10 ml. Most patients with mild TBI have a good outcome without the necessity of neurosurgical intervention. Mild TBI patients with a convexity SAH, small convexity contusion, small IPH (≤ 10 ml), and/or small subdural hematoma do not require admission to an ICU or repeat imaging in the absence of a neurological decline.


Community capacity-building in disaster mental health resilience: a pilot study of an academic/faith partnership model.
We describe an academic/faith partnership approach for enhancing the capacity of communities to resist or rebound from the impact of terrorism and other mass casualty events. Representatives of several academic health centers (AHCs) collaborated with leaders of urban Christian-, Jewish-, and Muslim faith-based organizations (FBOs) to design, deliver, and preliminarily evaluate a train-the-trainer approach to enhancing individual competencies in the provision of psychological first aid and in disaster planning for their respective communities. Evidence of partner commitment to, and full participation in, project implementation responsibilities confirmed the feasibility of the overall AHC/FBO collaborative model, and individual post-training, self-report data on perceived effectiveness of the program indicated that the majority of community trainees evaluated the interventions as having significantly increased their: (a) knowledge of disaster mental health concepts; (b) skills (self-efficacy) as providers of psychological first aid and bereavement support services, and (c) (with somewhat less confidence because of module brevity) capabilities of leading disaster preparedness planning efforts within their communities. Notwithstanding the limitations of such early-phase research in ensuring internal and external validity of the interventions, the findings, particularly when combined with those of earlier and subsequent work, support the rationale for continuing to refine this participatory approach to fostering community disaster mental health resilience, and to promoting the translational impact of the model. An especially important (recent) example of the latter is the formal recognition by local and state health departments of program-trained lay volunteers as a vital resource in the continuum of government assets for public health emergency preparedness planning and response.


Resolution of distinct selenium-containing formate dehydrogenases from Escherichia coli.
Formate dehydrogenase, a component activity of two alternative electron transport pathways in anaerobic Escherichia coli, has been resolved as two distinguishable enzymes. One, which was induced with nitrate reductase as a component of the formate-nitrate reductase pathway, utilized phenazine methosulfate (PMS) in preference to benzyl viologen (BV) as an artificial electron acceptor and appeared to be exclusively membrane-bound. A second formate dehydrogenase, which was induced as a component of the formate hydrogenlyase pathway, appeared to exist both as a membrane-bound form and as a cytoplasmic enzyme; the cytoplasmic activity was resolved completely from the PMS-linked activity on a sucrose gradient. When E. coli was grown in the presence of 75Se-selenite, a 110,000-dalton selenopeptide, previously shown to be a component of the PMS-linked enzyme, was induced and repressed with this activity. In contrast, an 80,000-dalton selenopeptide was induced and repressed with the BV-linked activity and exhibited a distribution similar to the BV-linked formate dehydrogenase in cell fractions and in sucrose gradients. The results indicate that the two formate dehydrogenases are distinguishable on the basis of their artificial electron acceptor specificity, their cellular localization, and the size of their respective selenoprotein components.


Clinical decision-making in complex endodontic cases between postgraduate students across dental specialties at a UK dental school: A pilot study.
Treatment decisions for a heavily restored endodontically treated tooth vary amongst clinicians owing to multitude of factors. This phenomenon not only often poses dilemmas to clinicians of different clinical backgrounds, but also exerts a degree of treatment difficulty to the treating clinician. Previous studies indicated that specialty training and clinical experience significantly impacted clinical decision-making process. Master of Science postgraduate students in endodontics, prosthodontics, periodontics, oral surgery and implantology participated in a questionnaire-based cross-sectional study. The dental specialties were further categorised into restorative and surgical dentistry. A multiple-choice questionnaire with three clinical cases was distributed to the students. Data were analysed for trends using descriptive statistics. There was a 44% response rate; the majority of respondents were from restorative dentistry specialties. Cases 1 and 2 were rated as moderate to high difficulty, and Case 3 was predominantly rated as high difficulty with procedure predictability being the main factor affecting their clinical decision-making in three cases. Endodontic retreatment was selected as the preferred treatment in Cases 1 and 2 and periradicular surgery in Case 3. The students were fairly confident in managing Cases 1 and 2, but not in Case 3. Referral patterns were consistent in Cases 1 and 2 with endodontists being the first choice of referral except for Case 3 where 48% preferred to refer to oral surgeons and 35% choosing endodontists. Some indication of differences between specialties were noted throughout. Years in practice appeared to be related to the importance of predictability in Case 3 only. Considerable inter-clinician variability was noted whereby specialty postgraduate training impacted on clinical decision-making. Overall, procedural predictability, technical difficulty, risk of damage to the tooth and patient preference were the most highly ranked factors affecting clinical decision-making. Evidence-based treatment guidelines and dental curricula should be reviewed to enhance inter-clinician agreement in clinical decision-making, ultimately improving patient care.


Scent of a Killer: Microbial Volatilome and Its Role in the Biological Control of Plant Pathogens.
The use of synthetic fungicides represents the most common strategy to control plant pathogens. Excessive and/or long-term distribution of chemicals is responsible for increased levels of environmental pollution, as well as adverse health consequence to humans and animals. These issues are deeply influencing public perception, as reflected by the increasing demand for safer and eco-friendly agricultural commodities and their by-products. A steadily increasing number of research efforts is now devoted to explore the use of safer and innovative approaches to control plant pathogens. The use of microorganisms as biological control agents (BCAs) represents one of the most durable and promising strategies. Among the panoply of microbial mechanisms exerted by BCAs, the production of volatile organic compounds (VOCs) represents an intriguing issue, mostly exploitable in circumstances where a direct contact between the pathogen and its antagonist is not practicable. VOCs are potentially produced by all living microorganisms, and may be active in the biocontrol of phytopathogenic oomycetes, fungi, and bacteria by means of antimicrobial activity and/or other cross-talk interactions. Their biological effects, the reduced residuals in the environment and on agricultural commodities, and the ease of application in different agricultural systems make the use of VOCs a promising and sustainable approach to replace synthetic fungicides in the control of plant pathogens. In this review, we focus on VOCs produced by bacteria and fungi and on their role in the cross-talk existing between the plant pathogens and their host. Biologic systemic effect of the microbial volatile blends on both pathogen and host plant cells is also briefly reviewed.


Effects of COVID-19 on the environment: An overview on air, water, wastewater, and solid waste.
The COVID-19 pandemic has hit the world hardly as of the beginning of 2020 and quickly spread worldwide from its first-reported point in early Dec. 2019. By mid-March 2021, the COVID-19 almost hit all countries worldwide, with about 122 and 2.7 million confirmed cases and deaths, respectively. As a strong measure to stop the infection spread and deaths, many countries have enforced quarantine and lockdown of many activities. The shutdown of these activities has resulted in large economic losses. However, it has been widely reported that these measures have resulted in improved air quality, more specifically in highly polluted areas characterized by massive population and industrial activities. The reduced levels of carbon, nitrogen, sulfur, and particulate matter emissions have been reported and confirmed worldwide in association with lockdown periods. On the other hand, ozone levels in ambient air have been found to increase, mainly in response to the reduced nitrogen emissions. In addition, improved water quality in natural water resources has been reported as well. Wastewater facilities have reported a higher level of organic load with persistent chemicals due to the increased use of sanitizers, disinfectants, and antibiotics. The solid waste generated due to the COVID-19 pandemic was found to increase both qualitatively and quantitatively. This work presents and summarizes the observed environmental effects of COVID-19 as reported in the literature for different countries worldwide. The work provides a distinct overview considering the effects imposed by COVID-19 on the air, water, wastewater, and solid waste as critical elements of the environment.


Spinocerebellar ataxia 46 in a young female.
Spinocerebellar ataxias (SCAs) are a group of both clinically and genetically heterogeneous neurodegenerative disorders. SCA 46 is a rare autosomal dominant ataxia initially described in a Dutch family, clinically characterized by ataxia, peripheral neuropathy, cerebellar dysarthria, and varied oculomotor abnormalities. SCA 46 has recently been discovered to be associated with a mutation in phospholipase D 3 gene.


The internalization of a short acyl chain analogue of ganglioside GM1 in polarized neurons.
In order to study the endocytosis of membrane lipids during the development of neuronal polarity, we examined the internalization of a short acyl chain fluorescent derivative of ganglioside GM1, N-(6-(4-nitrobenz-2-oxa-1,3-diazole-7-yl)-aminohexanoyl)-GM1 (C6-NBD-GM1), in hippocampal neurons cultured at low density. C6-NBD-GM1 was internalized by temperature- and energy-dependent mechanisms, and after short times of incubation, accumulated in endosomes in the axon, cell body and dendrites of neurons maintained for up to 4-5 days in culture. C6-NBD-GM1 was subsequently transported in a retrograde direction to a pool of recycling endosomes in the cell body, with little transport to lysosomes, as indicated by the lack of degradation of C6-NBD-GM1 even after long times, and the re-appearance of intact C6-NBD-GM1 at the cell surface after recycling; similarly, little degradation of C6-NBD-GM1 was detected in N18TG-2 neuroblastoma cells. In hippocampal neurons maintained for longer than 6 days in culture, there was little internalization of C6-NBD-GM1 along the length of axons, but the amount of endocytosis from dendrites was similar to that observed in younger neurons. These results demonstrate that gangliosides turnover rapidly in dendritic membranes at all stages of neuronal development, whereas ganglioside turnover in axons is much less rapid, at least in mature, polarized neurons.


Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach.
The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration. HIV-infected adults receiving oral nevirapine for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and nevirapine concentrations in plasma were determined by HPLC. Pharmacokinetic parameters, inter-individual variability and residual error were estimated using non-linear mixed effects modelling. The influence of patient characteristics on the pharmacokinetics of nevirapine was explored, and the predictive performance of the final model was evaluated in an external data set of observations. Totals of 40 and 18 Caucasian patients were included in two data sets for model building and model validation, respectively. A mono-compartmental model with first-order absorption and elimination best described the pharmacokinetics of nevirapine. Body weight influenced oral clearance (CL/F) and volume of distribution (V/F). The estimated population pharmacokinetic parameters (inter-individual variability) for an individual weighing 70 kg were CL/F 2.95 L/h (24%), V/F 95.2 L (30%) and k(a) 1.8 h(-1) (96%). The final model predicted nevirapine concentrations in the external model-validation data set with no systematic bias and adequate precision. Bayesian estimates of nevirapine trough concentrations were lower when nevirapine was administered once instead of twice daily, and nearly half of the patients weighing 90 kg had drug concentrations <3.0 mg/L when nevirapine was dosed once daily. A population model to describe the pharmacokinetics of nevirapine was developed and validated in HIV-infected patients. Body weight influenced CL/F and V/F. Based on Bayesian estimates of individual nevirapine concentrations, twice- instead of once-daily administration of nevirapine would be more optimal in patients weighing >70 kg.


Examining the validity and utility of two secondary sources of food environment data against street audits in England.
Secondary data containing the locations of food outlets is increasingly used in nutrition and obesity research and policy. However, evidence evaluating these data is limited. This study validates two sources of secondary food environment data: Ordnance Survey Points of Interest data (POI) and food hygiene data from the Food Standards Agency (FSA), against street audits in England and appraises the utility of these data. Audits were conducted across 52 Lower Super Output Areas in England. All streets within each Lower Super Output Area were covered to identify the name and street address of all food outlets therein. Audit-identified outlets were matched to outlets in the POI and FSA data to identify true positives (TP: outlets in both the audits and the POI/FSA data), false positives (FP: outlets in the POI/FSA data only) and false negatives (FN: outlets in the audits only). Agreement was assessed using positive predictive values (PPV: TP/(TP + FP)) and sensitivities (TP/(TP + FN)). Variations in sensitivities and PPVs across environment and outlet types were assessed using multi-level logistic regression. Proprietary classifications within the POI data were additionally used to classify outlets, and agreement between audit-derived and POI-derived classifications was assessed. Street audits identified 1172 outlets, compared to 1100 and 1082 for POI and FSA respectively. PPVs were statistically significantly higher for FSA (0.91, CI: 0.89-0.93) than for POI (0.86, CI: 0.84-0.88). However, sensitivity values were not different between the two datasets. Sensitivity and PPVs varied across outlet types for both datasets. Without accounting for this, POI had statistically significantly better PPVs in rural and affluent areas. After accounting for variability across outlet types, FSA had statistically significantly better sensitivity in rural areas and worse sensitivity in rural middle affluence areas (relative to deprived). Audit-derived and POI-derived classifications exhibited substantial agreement (p < 0.001; Kappa = 0.66, CI: 0.63-0.70). POI and FSA data have good agreement with street audits; although both datasets had geographic biases which may need to be accounted for in analyses. Use of POI proprietary classifications is an accurate method for classifying outlets, providing time savings compared to manual classification of outlets.


Successful reversal of pulmonary hypertension in Eisenmenger complex.
We present a case of a 19-year old female with systemic pulmonary artery (PA) pressure due to a congenital ventricular septal defect (VSD) and atrial septal defect (ASD). She was pink at rest and cyanotic on exercise. Lung biopsy revealed grade IV pulmonary vascular changes. As a preliminary step PA was banded to increase right-to-left shunt and decrease aortic (Ao) saturation with consequent decrease in PA saturation. After one year, when she was no longer cyanotic, even on exercise, lung biopsy revealed total regression of pulmonary vascular changes. As a definitive procedure VSD and ASD were closed and PA was debanded. Cardiac catheterization one week postoperatively showed PA pressure to be 50% of systemic pressure. We postulate that reversal of pulmonary vascular changes were due to lowered PA saturation. We further believe that lower PA pressure could have contributed to this regression of pulmonary vascular changes. We performed the same procedure in six more patients with similar positive clinical response. This new concept brings renewed hope to many children who otherwise are candidates for heart lung transplantation.


Shear bond strengths of 10 adhesive resin/amalgam combinations.
This study compared the shear bond strengths of amalgam to dentin using two amalgam alloys and five adhesive resin systems. One hundred extracted human third molars were flattened occlusally to expose dentin. Dentin surfaces were treated with one of five adhesive resins: All-Bond 2, Amalgambond Plus, Amalgambond Plus with HPA Powder, OptiBond, and Resinomer. Tytin (spherical) or Dispersalloy (admixed) amalgam was condensed onto the treated dentin surface through a Teflon split mold. The samples were stored 7-10 days and thermocycled before shear testing using a Zwick Materials Testing Machine. Two-way ANOVA revealed significant differences among the 10 groups (P < 0.05). The combination of Tytin/OptiBond produced the highest bond strength to dentin (14.17 MPa), while Dispersalloy/Amalgambond Plus produced the lowest (3.89 MPa). In general, the filled resin systems (Amalgambond Plus with HPA Powder, OptiBond, Resinomer) produced higher bond strengths than the unfilled systems (All-Bond 2, Amalgambond Plus). Additionally, for four of the five resins, bond strengths were higher with Tytin than with Dispersalloy, although differences were statistically significant in only two groups.


Time series based road traffic accidents forecasting via SARIMA and Facebook Prophet model with potential changepoints.
Road traffic accident (RTA) is a critical global public health concern, particularly in developing countries. Analyzing past fatalities and predicting future trends is vital for the development of road safety policies and regulations. The main objective of this study is to assess the effectiveness of univariate Seasonal Autoregressive Integrated Moving Average (SARIMA) and Facebook (FB) Prophet models, with potential change points, in handling time-series road accident data involving seasonal patterns in contrast to other statistical methods employed by key governmental agencies such as Ghana's Motor Transport and Traffic Unit (MTTU). The aforementioned models underwent training with monthly RTA data spanning from 2013 to 2018. Their predictive accuracies were then evaluated using the test set, comprising monthly RTA data from 2019. The study employed the Box-Jenkins method on the training set, yielding the development of various tentative time series models to effectively capture the patterns in the monthly RTA data. SARIMA(0,1,1)×(1,0,0)12 was found to be the suitable model for forecasting RTAs with a log-likelihood value of -266.28, AIC value of 538.56, AICc value of 538.92, BIC value of 545.35. The findings disclosed that the SARIMA(0,1,1)×(1,0,0)12 model developed outperforms FB-Prophet with a forecast accuracy of 93.1025% as clearly depicted by the model's MAPE of 6.8975% and a Theil U1 statistic of 0.0376 compared to the FB-Prophet model's respective forecasted accuracy and Theil U1 statistic of 84.3569% and 0.1071. A Ljung-Box test on the residuals of the estimated SARIMA(0,1,1)×(1,0,0)12 model revealed that they are independent and free from auto/serial correlation. A Box-Pierce test for larger lags also revealed that the proposed model is adequate for forecasting. Due to the high forecast accuracy of the proposed SARIMA model, the study recommends the use of the proposed SARIMA model in the analysis of road traffic accidents in Ghana.


Influence of the peritoneal lavage with bupivacaine on the survival and resistance of colonic anastomoses performed under fecal peritonitis in rats.
To evaluate the effects of peritoneal lavage with bupivacaine on survival and initial resistance of anastomosis on distal colon, performed under peritonitis or not. Forty rats, weighing from 300 to 350 g (321.29 ± 11.3 1g), were randomly divided in four groups and underwent laparotomy and anastomosis on the distal colon six hours after induction of peritonitis by intraperitoneal injection of autologous fecal material or not. Group 1: No peritonitis and lavage with 3 ml NS; Group 2: No peritonitis and lavage with 8 mg.kg-1 (± 0.5 mL) of 0.5% bupivacaine added to 2.5 mL of NS; Group 3: Peritonitis and lavage with 3 ml NS; Group 4: Peritonitis and lavage with 8 mg.kg-1 (± 0.5 mL) of 0.5% bupivacaine added to 2.5 mL of NS. Necropsies were performed on the animals that died and the time of death was recorded. Surviving animals were submitted to euthanasia on the fifth post-operative day and Total Energy of Rupture biomechanical test (TER) was applied. Group 4 showed survival increase compared to Group 3, without statistical significance. Group 3 presented the smallest average TER, with statistical significance. Peritonitis increased mortality and influenced negatively the resistance of colic anastomosis in rats. Peritoneal lavage with bupivacaine increased anastomotic resistance.


Comparing the effect of cross-group friendship on generalized trust to its effect on prejudice: The mediating role of threat perceptions and negative affect.
Intergroup relations theory posits that cross-group friendship reduces threat perceptions and negative emotions about outgroups. This has been argued to mitigate the negative effects of ethnic diversity on generalized trust. Yet, direct tests of this friendship-trust relation, especially including perceptions of threat and negative affect as mediators, have remained rare at the individual level. In this article, we bridge this research gap using representative data from eight European countries (Group-Focused Enmity). We employ structural equation modelling (SEM) to model mediated paths of cross-group friendship on generalized trust via perceptions of threat and negative affect. We find that both the total effect as well as the (mediated) total indirect effect of cross-group friendship on generalized trust are weak when compared with similar paths estimated for prejudice.


A 56-Year-Old Woman with Recurrent Strokes: A Clear Case with a Therapeutic Dilemma.
A 56-year-old woman with a history of cerebral amyloid angiopathy (CAA) complicated by prior intracranial hemorrhage (ICH) was evaluated for an asymptomatic ischemic stroke discovered on screening brain MRI. On echocardiogram, she was found to have a mass on her mitral valve and strongly positive antiphospholipid antibodies. She was diagnosed with nonbacterial thrombotic (Libman-Sacks) endocarditis associated with the primary antiphospholipid syndrome (APS). The treatment decision was complicated by the history of CAA with ICH within the last year with very high risk for bleeding complications if on anticoagulation. A multidisciplinary decision was made to initiate a trial of warfarin for 3 months. She fared well and warfarin was continued. She has not had any further bleeding or ischemic events over the subsequent 1.5 years and remains on warfarin for her APS.


Expansion and inflammation of white adipose tissue - focusing on adipocyte progenitors.
Adipose tissue is an important organ in our body, participating not only in energy metabolism but also immune regulation. It is broadly classified as white (WAT) and brown (BAT) adipose tissues. WAT is highly heterogeneous, composed of adipocytes, various immune, progenitor and stem cells, as well as the stromal vascular populations. The expansion and inflammation of WAT are hallmarks of obesity and play a causal role in the development of metabolic and cardiovascular diseases. The primary event triggering the inflammatory expansion of WAT remains unclear. The present review focuses on the role of adipocyte progenitors (APS), which give rise to specialized adipocytes, in obesity-associated WAT expansion, inflammation and fibrosis.


Colocalization of thrombin, PAI-1, and vitronectin in the atherosclerotic vessel wall: A potential regulatory mechanism of thrombin activity by PAI-1/vitronectin complexes.
The serine protease thrombin is a mitogen for vascular smooth muscle cells. To that end, thrombin cleaves the surface-exposed, protease-activated receptor type 1 (PAR-1), resulting in signal transduction and ultimately, proliferation of these cells. Regulation of thrombin activity in the human atherosclerotic vessel wall has not been studied in great detail, conceivably because the traditional plasma thrombin inhibitor, anti-thrombin III, is not encountered at this location. By using immunofluorescence confocal microscopy, we demonstrate that the antigens of thrombin, plasminogen activator inhibitor 1 (PAI-1), and vitronectin (Vn) colocalize in human neointimal atherosclerotic arterial tissue. Furthermore, it is shown by in situ reverse zymography that these specimens harbor the active form of PAI-1, which is the only configuration of PAI-1 capable of complexing with Vn and inhibiting serine proteases, eg, thrombin. Two different criteria were used to establish that neointimal atherosclerotic material contains active alpha-thrombin, namely, its ability to bind to the thrombin inhibitor hirudin and to convert the thrombin-specific chromogenic substrate S2238. The latter activity could be fully prevented by preincubation with the thrombin-specific inhibitor, phenyl-prolyl-arginyl-chloromethyl ketone. The thrombin concentration measured by conversion of the chromogenic substrate was 7 to 12 nmol/L in the vascular specimens studied. This concentration range suffices to activate the PAR-1 receptor on vascular smooth muscle cells and to cause neointimal proliferation. It is concluded that the human atherosclerotic arterial vessel wall provides conditions that favor a regulatory mechanism of thrombin activity by PAI-1/Vn complexes.


Memory systems do not divide on consciousness: Reinterpreting memory in terms of activation and binding.
There is a popular hypothesis that performance on implicit and explicit memory tasks reflects 2 distinct memory systems. Explicit memory is said to store those experiences that can be consciously recollected, and implicit memory is said to store experiences and affect subsequent behavior but to be unavailable to conscious awareness. Although this division based on awareness is a useful taxonomy for memory tasks, the authors review the evidence that the unconscious character of implicit memory does not necessitate that it be treated as a separate system of human memory. They also argue that some implicit and explicit memory tasks share the same memory representations and that the important distinction is whether the task (implicit or explicit) requires the formation of a new association. The authors review and critique dissociations from the behavioral, amnesia, and neuroimaging literatures that have been advanced in support of separate explicit and implicit memory systems by highlighting contradictory evidence and by illustrating how the data can be accounted for using a simple computational memory model that assumes the same memory representation for those disparate tasks.


Borderline personality features moderate the effect of a fear induction on impulsivity.
This study examined the effects of laboratory-induced fear on impulsivity among participants who were high (n = 28) or low (n = 44) in borderline personality (BP) features. Participants were randomly assigned to complete a laboratory measure of impulsivity (passive avoidance learning task) following either a neutral mood induction or a fear induction. BP features moderated the association of the emotion condition (fear vs. neutral) with impulsivity: High-BP participants, but not low-BP participants, committed a greater number of impulsive responses in the fear condition compared with the neutral condition. Findings indicated that impulsivity among persons with BP features may not be a trait-like deficit, but rather, depends on emotional context. These findings suggest that future research should examine impulsivity under differing emotional conditions, and that clinical interventions to reduce impulsivity among persons with BP features should focus on responses to emotional contexts.


iASPP is a novel autophagy inhibitor in keratinocytes.
The protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fission-fusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses.


An antibody to the lutheran glycoprotein (Lu) recognizing the LU4 blood type variant inhibits cell adhesion to laminin α5.
The Lutheran blood group glycoprotein (Lu), an Ig superfamily (IgSF) transmembrane receptor, is also known as basal cell adhesion molecule (B-CAM). Lu/B-CAM is a specific receptor for laminin α5, a major component of basement membranes in various tissues. Previous reports have shown that Lu/B-CAM binding to laminin α5 contributes to sickle cell vaso-occlusion. However, as there are no useful tools such as function-blocking antibodies or drugs, it is unclear how epithelial and sickled red blood cells adhere to laminin α5 via Lu/B-CAM. In this study, we discovered a function-blocking antibody that inhibits Lu binding to laminin α5 using a unique binding assay on tissue sections. To characterize the function-blocking antibody, we identified the site on Lu/B-CAM recognized by this antibody. The extracellular domain of Lu/B-CAM contains five IgSF domains, D1-D2-D3-D4-D5. The antibody epitope was localized to D2, but not to the D3 domain containing the major part of the laminin α5 binding site. Furthermore, mutagenesis studies showed that Arg(175), the LU4 blood group antigenic site, was crucial for forming the epitope and the antibody bound sufficiently close to sterically hinder the interaction with α5. Cell adhesion assay using the antibody also showed that Lu/B-CAM serves as a secondary receptor for the adhesion of carcinoma cells to laminin α5. This function-blocking antibody against Lu/B-CAM should be useful for not only investigating cell adhesion to laminin α5 but also for developing drugs to inhibit sickle cell vaso-occlusion.


Functional proteomics within the genus Lactobacillus.
Lactobacillus are mainly used for the manufacture of fermented dairy, sourdough, meat, and vegetable foods or used as probiotics. Under optimal processing conditions, Lactobacillus strains contribute to food functionality through their enzyme portfolio and the release of metabolites. An extensive genomic diversity analysis was conducted to elucidate the core features of the genus Lactobacillus, and to provide a better comprehension of niche adaptation of the strains. However, proteomics is an indispensable "omics" science to elucidate the proteome diversity, and the mechanisms of regulation and adaptation of Lactobacillus strains. This review focuses on the novel and comprehensive knowledge of functional proteomics and metaproteomics of Lactobacillus species. A large list of proteomic case studies of different Lactobacillus species is provided to illustrate the adaptability of the main metabolic pathways (e.g., carbohydrate transport and metabolism, pyruvate metabolism, proteolytic system, amino acid metabolism, and protein synthesis) to various life conditions. These investigations have highlighted that lactobacilli modulate the level of a complex panel of proteins to growth/survive in different ecological niches. In addition to the general regulation and stress response, specific metabolic pathways can be switched on and off, modifying the behavior of the strains.


Role of iron in brain injury after intraventricular hemorrhage.
Intraventricular extension of hemorrhage is a predictor of poor outcome in intracerebral hemorrhage, and iron overload contributes to brain injury after intracerebral hemorrhage. The current study investigated the role of iron in ventricular dilatation and neuronal death in a rat model of intraventricular hemorrhage (IVH). There were 2 parts in this study. First, male Sprague-Dawley rats had a 200-μL injection of either autologous blood or saline into the right lateral ventricle and were euthanized at different time points. Rats had MRI and brains were used for Western blot analysis, immunohistochemistry, histology, and brain tissue nonheme iron measurements. Second, rats had IVH and were treated with deferoxamine or vehicle, and rats were euthanized 4 weeks later for brain tissue loss and lateral ventricle size measurements. IVH resulted in brain iron accumulation, bilateral enlargement of the lateral ventricles, and hippocampal brain tissue loss. Iron accumulation was associated with upregulation of heme oxygenase-1 and ferritin. Systemic deferoxamine treatment reduced IVH-induced ventricular enlargement (eg, day 28: 32.7±10.6 vs 43.8±9.7 mm(3) in vehicle-treated group, n=8 to 9; P<0.05) and hippocampal brain tissue loss (hippocampal volume: 89.0±2.7 vs 85.2±4.1 mm(3) in the vehicle-treated group; P<0.05). Iron has a role in brain injury after IVH. Deferoxamine may be a therapy for patients with IVH or intraventricular extension after intracerebral hemorrhage.


Relationship between spontaneous and evoked spike-time correlations in primate visual cortex.
Coincident spikes have been implicated in vision-related processes such as feature binding, gain modulation, and long-distance communication. The source of these spike-time correlations is unknown. Although several studies have proposed that cortical spikes are correlated based on stimulus structure, others have suggested that spike-time correlations reflect ongoing cortical activity present even in the absence of a coherent visual stimulus. To examine this issue, we collected single-unit recordings from primary visual cortex (V1) of the anesthetized and paralyzed prosimian bush baby using a 100-electrode array. Spike-time correlations for pairs of cells were compared under three conditions: a moving grating at the cells' preferred orientation, an equiluminant blank screen, and a dark condition with eyes covered. The amplitudes, lags, and widths of cross-correlation histograms (CCHs) were strongly correlated between these conditions although for the blank stimulus and dark condition, the CCHs were broader with peaks lower in amplitude. In both preferred stimulus and blank conditions, the CCH amplitudes were greater when the cells within the pair had overlapping receptive fields and preferred similar orientations rather than nonoverlapping receptive fields and different orientations. These data suggest that spike-time correlations present in evoked activity are generated by mechanisms common to those operating in spontaneous conditions.


Enhancement of aerobic fitness improves social functioning in individuals with schizophrenia.
Individuals with schizophrenia display substantial deficits in social functioning (SF), characterized by chronic, lifelong presentations. Yet, at present there are few effective interventions to enhance SF in this population. Emerging evidence from studies of clinical populations that display similar SF deficits suggests that aerobic exercise (AE) may improve social skills. However, this putative impact has not been investigated in schizophrenia. Employing a single-blind, randomized clinical trial design, 33 individuals with schizophrenia were randomized to receive 12 weeks of Treatment-As-Usual (TAU; n = 17) or TAU + AE (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed an evaluation of aerobic fitness (VO2max) as well as self-, informant-, and clinician-reported SF measures at baseline and after 12 weeks. Twenty-six participants completed the study (79%; TAU = 13; AE = 13). At follow-up, the AE participants improved their VO2max by 18.0% versus - 0.5% in the controls (group x time interaction, F1,24 = 12.88; p = .002). Hierarchical stepwise regression analyses indicated improvements in VO2max significantly predicted enhancement in SF as indexed by self-, informant-, and clinician-reported measures, predicting 47%, 33%, and 25% of the variance, respectively (controlling for baseline demographics, medications, mood symptoms, and social networks). Compared to the TAU group, AE participants reported significant improvement in SF (23.0% vs. - 4.2%; group × time interaction, F1,24 = 7.48, p = .012). The results indicate that VO2max enhancement leads to improvements in SF in people with schizophrenia. Furthermore, low VO2max represents a modifiable risk factor of SF in people with schizophrenia, for which AE training offers a safe, non-stigmatizing, and nearly side-effect-free intervention.


Zinc-deficient rat embryos have increased caspase 3-like activity and apoptosis.
Caspase activity is a hallmark of apoptosis. Given that maternal zinc (Zn) deficiency results in apoptosis in the rat embryo, we assessed caspase activity in Zn-deficient embryos. Mid-gestation rat embryos were collected from dams fed either a Zn-deficient (0.5 Zn/g) diet ad libitum, or a Zn-adequate (25 microg Zn/g) diet ad libitum or pair fed to dams fed the Zn-deficient diet. Embryos from dams fed the Zn-adequate diet had a normal level of cell death, while embryos from the dams fed the Zn-deficient diet had either increased or normal levels of cell death. Zn-deficient embryos displaying increased cell death had increased caspase activity. Embryos with normal levels of cell death, regardless of maternal diet, had similar caspase activities. Thus, Zn-deficiency-induced apoptosis in vivo is associated with increased caspase activity.


Systemic and regional haemodynamic effects of a synthetic atrial natriuretic peptide in conscious rats.
The effect of the intravenous injection of synthetic atrial natriuretic peptide (ANP, 2 micrograms) on systemic haemodynamics and blood flow to several organs has been studied in conscious rats by the radioactive microsphere technique. ANP induced a 540% increase in sodium excretion and a 310% increase in urine flow. Mean arterial pressure decreased by 21 mmHg and the peripheral resistances decreased by 26%, without significant changes in cardiac output. Renal blood flow increased by 37.7% and small intestine and portal blood flow increased by 39% and by 28% respectively. No other alterations in organ blood flows were observed. From these data it can be concluded that atrial natriuretic peptide shows acute vascular relaxant properties, which seem to be specific for renal and mesenteric territories.


Missing exposure data in stereotype regression model: application to matched case-control study with disease subclassification.
With advances in modern medicine and clinical diagnosis, case-control data with characterization of finer subtypes of cases are often available. In matched case-control studies, missingness in exposure values often leads to deletion of entire stratum, and thus entails a significant loss in information. When subtypes of cases are treated as categorical outcomes, the data are further stratified and deletion of observations becomes even more expensive in terms of precision of the category-specific odds-ratio parameters, especially using the multinomial logit model. The stereotype regression model for categorical responses lies intermediate between the proportional odds and the multinomial or baseline category logit model. The use of this class of models has been limited as the structure of the model implies certain inferential challenges with nonidentifiability and nonlinearity in the parameters. We illustrate how to handle missing data in matched case-control studies with finer disease subclassification within the cases under a stereotype regression model. We present both Monte Carlo based full Bayesian approach and expectation/conditional maximization algorithm for the estimation of model parameters in the presence of a completely general missingness mechanism. We illustrate our methods by using data from an ongoing matched case-control study of colorectal cancer. Simulation results are presented under various missing data mechanisms and departures from modeling assumptions.


Human bronchial and parenchymal fibroblasts display differences in basal inflammatory phenotype and response to IL-17A.
Chronic inflammation, typified by increased expression of IL-17A, together with airway and parenchymal remodelling are features of chronic lung diseases. Emerging evidence suggests that phenotypic heterogeneity of repair and inflammatory capacities of fibroblasts may contribute to the differential structural changes observed in different regions of the lung. To investigate phenotypic differences in parenchymal and bronchial fibroblasts, either in terms of inflammation and remodelling or the ability of these fibroblasts to respond to IL-17A. Four groups of primary fibroblasts were used: normal human bronchial fibroblast (NHBF), normal human parenchymal fibroblast (NHPF), COPD human bronchial fibroblast (CHBF) and COPD human parenchymal fibroblast (CHPF). Cytokine and extracellular matrix (ECM) expression were measured at baseline and after stimulation with IL-17A. Actinomycin D was used to measure cytokine mRNA stability. At baseline, we observed higher protein production of IL-6 in NHPF than NHBF, but higher levels of IL-8 and GRO-α in NHBF. IL-17A induced a higher expression of GRO-α (CXCL1) and IL-6 in NHPF than in NHBF, and a higher level of IL-8 expression in NHBF. IL-17A treatment decreased the mRNA stability of IL-6 in NHBF when compared with NHPF. CHPF expressed higher protein levels of fibronectin, collagen-I and collagen-III than CHBF, NHBF and NHPF. IL-17A increased fibronectin and collagen-III protein only in NHPF and collagen-III protein production in CHBF and CHPF. These findings provide insight into the inflammatory and remodelling processes that may be related to the phenotypic heterogeneity of fibroblasts from airway and parenchymal regions and in their response to IL-17A.


Uncovering Knowledge of Core Syntactic and Semantic Principles in Individuals With Williams Syndrome.
We investigate knowledge of core syntactic and semantic principles in individuals with Williams Syndrome (WS). Our study focuses on the logico-syntactic properties of negation and disjunction (or) and tests knowledge of (a) core syntactic relations (scope and c-command), (b) core semantic relations (entailment relations and DeMorgan's laws of propositional logic), and (c) the relationship between (a) and (b). We examine the performance of individuals with WS, children matched for mental age (MA), and typical adult native speakers of English. Performance on all conditions suggests that knowledge of (a-c) is present and engaged in all three groups. Results also indicate slightly depressed performance on (c) for the WS group, compared to MA, consistent with limitation in processing resources. Implications of these results for competing accounts of language development in WS, as well as for the relevance of WS to the study of cognitive architecture and development are discussed.