Authentication of Schisandra chinensis and Schisandra sphenanthera in Chinese patent medicines.
Authentication of species is crucial for ensuring the safety and efficacy of herbal medicines. The fruits of Schisandra chinensis and S. sphenanthera have been used for the same traditional Chinese drug, Wuweizi, but are found to be quite different according to their constituents, pharmacological effects, and qualities. These two fruits have been recorded as Schisandrae Chinensis Fructus (Wuweizi) and Schisandrae Sphenantherae Fructus (Nan-wuweizi), respectively, by Chinese Pharmacopoeia, 2000 edition. However, Nan-wuweizi is often found to be taken as Wuweizi in some Chinese patent drugs intentionally or by mistake because of its lower price and similar characteristics to Wuweizi. In this study, the selection and validation of special chemical markers for the identification of Schisandra species were established by HPLC-DAD-MS profiling analysis. Simple TLC and HPLC methods were proposed for the accurate determination of Nan-wuweizi from Wuweizi in Chinese patent medicines, using schisandrin and anwulignan as the identifying markers for Wuweizi and Nan-wuweizi, respectively. Through the establishment of a statistical model, adulterated or misused ratios of Nan-wuweizi in Wuweizi (w/w), as well as in Fenghan Kesou pills, can be determined. The limit of detection of Nan-wuweizi in a mixture (w/w) using both TLC and HPLC methods is 5% (mixed crude drugs of 50mg and 5g in a 1000g prescribed amount). The constructed statistical model relating the HPLC peak area ratio (anwulignan/schisandrin) and adulteration ratio is suitable for mixed crude drugs and Fenghan Kesou pills, and the two fitting equations have a good correlation (r=0.9979). Furthermore, 36 commercial Chinese patent medicines containing Wuweizi or Nan-wuweizi according to their labels were checked by these methods, and Nan-wuweizi was detected in Renshen Wuweizi Granules and Fenghan Kesou Pills. The ratios of Nan-wuweizi in these mixtures (w/w) were 100:0 for both, which does not comply with the statutory prescription. This study provided a simple and reliable method to prevent the adulteration or misuse of Nan-wuweizi in crude drugs and patent medicines of Wuweizi.


Cinnamtannin B-1 regulates cell proliferation of spinal cord astrocytes and protects the cell from oxygen-glucose-serum deprivation/reoxygenation-induced apoptosis.
Astrocytes are important for protecting neurons in the central nervous system. It has been reported that some antioxidants could protect astrocytes from ischemia/reperfusion-induced dysfunction. Cinnamtannin B-1 is a naturally occurring A-type proanthocyanidin that exhibits anti-oxidant properties. In this study, we investigated the effects of cinnamtannin B-1 on spinal cord astrocytes. Astrocytes were subjected to oxygen-glucose-serum deprivation for eight hours followed by reoxygenation with or without cinnamtannin B-1. We found that cinnamtannin B-1 protected astrocytes from oxygen-glucose-serum deprivation and reoxygenation-induced apoptosis. Concurrently, cinnamtannin B-1 promoted the proliferation of astrocytes whereas the extracellular regulated protein kinase (ERK) inhibitor reversed this effect. The results indicated that cinnamtannin B-1 protects astrocytes from oxygen-glucose-serum deprivation/reoxygenation-induced apoptosis by promoting astrocyte proliferation via an ERK pathway. Therefore, as an anti-oxidant, cinnamtannin B-1 might provide extra benefit for astrocyte protection during ischemia/reperfusion in the central nervous system.


Assessment of some pulmonary parameters and cardiorespiratory fitness status in Nepalese medical students.
Some pulmonary function tests along with cardio respiratory fitness test were performed to assess the health status of the young (19-21 years) non-smokers Nepalese medical students. Results revealed that the vital capacity was 3.46 liters and 2.40 liters among the boys and girls respectively. PEFR was found to be 597.98 l/min among the boys and 456.53 l/min among the girls. Likewise, VO2 max among the boys and girls were 54.32 ml/kg/min and 44.88 ml/kg/min respectively. It was evident from the result that the health status of the Nepalese medical students ill the present study group was fairly well. It might be due to their health awareness, balanced-nutritious diet and the habits of occasional physical exercise.


Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.
Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.


Understanding the effect of retirement on health behaviors in China: Causality, heterogeneity and time-varying effect.
Retirement is an important turning point during the course of life, but few studies have examined the effects of retirement on a broad range of health behaviors in China. We use the longitudinal data of the China Health and Nutrition Survey (CHNS) from 2004 to 2015 to conduct empirical analysis. Fuzzy discontinuity regression was used to assess the association between retirement and health behaviors in the entire sample and subgroups based on gender and education. A time-varying effect model was used to measure the anticipatory effect, immediate effect and lag effect of retirement. We observed that the transition to retirement was associated with healthier lifestyle habits, such as reduced smoking and alcohol consumption and increased exercise motivation. However, the transition was associated with worse sedentary behavior. No significant statistical association was found between retirement and sleep duration. Men and those with higher education levels are more likely to experience the impact of retirement. The anticipatory effect suggests that as the statutory pension age is predictable, workers adjust their behaviors 4 and 5 years before retirement. The lagged effect indicates that it takes time to develop new habits; thus, retirees change their behaviors 2-3 years after retirement. The paper discusses possible reasons for our findings and proposes several policy implications from the perspectives of the government and society to facilitate the realization of healthy aging.


Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase.
DNA methyltransferase Dnmt1 ensures clonal transmission of lineage-specific DNA methylation patterns in a mammalian genome during replication. Dnmt1 is targeted to replication foci, interacts with PCNA, and favors methylating the hemimethylated form of CpG sites. To understand the underlying mechanism of its maintenance function, we purified recombinant forms of full-length Dnmt1, a truncated form of Dnmt1-(291-1620) lacking the binding sites for PCNA and DNA and examined their processivity using a series of long unmethylated and hemimethylated DNA substrates. Direct analysis of methylation patterns using bisulfite-sequencing and hairpin-PCR techniques demonstrated that full-length Dnmt1 methylates hemimethylated DNA with high processivity and a fidelity of over 95%, but unmethylated DNA with much less processivity. The truncated form of Dnmt1 showed identical properties to full-length Dnmt1 indicating that the N-terminal 290-amino acid residue region of Dnmt1 is not required for preferential activity toward hemimethylated sites or for processivity of the enzyme. Remarkably, our analyses also revealed that Dnmt1 methylates hemimethylated CpG sites on one strand of double-stranded DNA during a single processive run. Our findings suggest that these inherent enzymatic properties of Dnmt1 play an essential role in the faithful and efficient maintenance of methylation patterns in the mammalian genome.


Stigma in Consultation Liaison Psychiatry: A Qualitative Study of Trainee Psychiatrists.
Stigma related to mental illness can impact service-user care and clinician wellbeing. The aim of this study was to explore experiences of stigma in consultation-liaison psychiatry from the perspectives of trainee psychiatrists and suggest interventions to tackle stigma within a hospital environment. Ethics approval and consent were obtained for the study. In-depth interviews were conducted by telephone with six participants in four New Zealand district health boards. De-identified data was analysed using thematic analysis. An independent co-coder was employed to enhance analytic rigour. Participants experienced stigma during their consultation-liaison rotations. Some felt isolated and undervalued. Education, intergration and role clarification within the hospital environment were identified as ways to reduce stigma. Stigma experienced by trainee psychiatrists completing consultation-liaison rotations may lead to them feeling devalued and perceiving service-users to experience poorer care. Multidisciplinary education may potentially combat stigma and contribute to improved integration of services.


Gel-Based Nanocarrier for Intravesical Chemotherapy Delivery: In Vitro and In Vivo Study.
Intravesical administration of chemotherapeutic agents can enhance drug accumulation in tumors and reduce systemic side effects. Nanocarriers were developed for intravesical administration and exploit the permeation enhancement effect. In vitro permeation evaluation, the drug transdermal amount and accumulation amounts in the tissue of gemcitabine-loaded nanocarriers through biological membrane significantly increased about 14.8~33.0-fold and 1.5~14.1-fold respectively, when compared to a control group of 1% gemcitabine saline solution. In in vivo intravesical administration, the drug accumulation amount in bladder tissue of nanocarrier of 75.2 ± 5.4 μg was revealed as being comparably higher than that of the control group of 44.8 ± 6.4 μg. In confocal laser scanning microscopy imagery, the penetration depth of fluorescent dyes-rhodamine was increased from 80 μm up to 120 μm when a nanocarrier was used. This result implies that the nanocarrier is a promising drug delivery agent for intravesical administration.


The rice OsLTP6 gene promoter directs anther-specific expression by a combination of positive and negative regulatory elements.
Characterization of tissue-specific plant gene promoters will benefit genetic improvement in crops. Here, we isolated a novel rice anther-specific plant lipid transfer protein (OsLTP6) gene through high through-put expressional profiling. The promoter of OsLTP6 was introduced to the upstream of the uidA gene, which encodes β-glucuronidase (GUS), and transformed into rice plants for functional analysis. Histochemical and fluorometric GUS assay showed that GUS was specifically expressed in the anthers and pollens in OsLTP6 promoter::uidA transgenic plants. Transverse section of the rice anther further indicated that the OsLTP6 promoter directed the reporter gene specifically expressed in anther tapetum. To identify regulatory elements within OsLTP6 promoter region, four progressive deletions of the OsLTP6 promoter were constructed. The results indicated that the OsLTP6 promoter achieved anther-specific expression through a combination of positive and negative regulatory elements. A 26-bp motif upstream of TATA box was a key transcriptional activator for OsLTP6 gene. CAAT box and GTGA box were the putative motifs to increase the transcription level to full expression. Two negative regulatory elements were also found in two distinct regions within this promoter. They repressed the expression in leaf and stem, respectively. These results revealed the regulating complexity of anther-specific expression.


[Expression of HOXC4 gene during early development in zebrafish].
To investigate the mechanism of HOXC4 gene during early development in zebrafish, study it's expression in hematopoiesis system with whole mount in situ hybridization (WISH), then make a foundation work for further study of HOXC4 gene in hematopoiesis development. The total RNA of different phases of zebrafish embryos was extracted, and a fragment of HOXC4 gene was cloned with RT-PCR, then HOXC4 gene fragment and pCS2 was digested with BamH I and Xho I restriction enzyme, after that HOXC4 gene fragment was inserted into pCS2+ vector. After confirming the constructed plasmid, the digoxingenin-labeled anti-sence mRNA probe of HOXC4 gene was synthesized in vitro by using T3 RNA polymerase, the exprression pattern of HOXC4 during zebrafish embryogenesis using anti-sence probe with WISH was conducted. HOXC4 gene was cloned by RT-PCR and HOXC4-pCS2+ plasmid was constructed and confirmed, expression of HOXC4 showed that it was expressed highly in nervous system of wild-type (WT) Tuebingen zebrafish. The expression pattern of HOXC4 during early development in zebrafish was obtained, and it is very important for further study of HOXC4 gene function in zebrafish.


Use of Biochar as Filler for Biocomposite Blown Films: Structure-Processing-Properties Relationships.
In this work, biocomposite blown films based on poly(butylene adipate-co-terephthalate) (PBAT) as biopolymeric matrix and biochar (BC) as filler were successfully fabricated. The materials were subjected to a film-blowing process after being compounded in a twin-screw extruder. The preliminary investigations conducted on melt-mixed PBAT/BC composites allowed PBAT/BC 5% and PBAT/BC 10% to be identified as the most appropriate formulations to be processed via film blowing. The blown films exhibited mechanical performances adequate for possible application as film for packaging, agricultural, and compost bags. The addition of BC led to an improvement of the elastic modulus, still maintaining high values of deformation. Water contact angle measurements revealed an increase in the hydrophobic behavior of the biocomposite films compared to PBAT. Additionally, accelerated degradative tests monitored by tensile tests and spectroscopic analysis revealed that the filler induced a photo-oxidative resistance on PBAT by delaying the degradation phenomena.


Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy.
Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal-like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention.


Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27-year-long longitudinal study.
Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation. We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint. In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4+ T-cell numbers and frailty. Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.


Contrasted cis-acting effects of downstream 5' splice sites on the splicing of a retained intron: the adenoviral E1A pre-mRNA model.
The adenoviral E1A pre-mRNA contains an upstream intron (the 216 nucleotide intron) which is spliced only weakly both in vivo and in vitro. We have chosen the E1A transcript as a model to analyse, in vitro, the role of downstream cis-elements involved in the alternative splicing of this retained intron. By using a series of constructs containing specific deletions, mutations and/or truncations, we show that the 13S 5' splice site, positioned 259 nucleotides downstream of the 216 nucleotide intron, is the main cis-element which activates the splicing of this intron. Our results establish the importance of a downstream 5' splice site for the activation of the 3' splice site, which is known to be suboptimal within this retained intron. Unexpectedly, the 12S 5' splice site, although positioned at an ideal distance (121 nucleotides) from the upstream intron, does not exhibit such a cis-acting effect. In contrast, its improvement to a consensus sequence may even result in a slight negative cis-acting effect in the presence of the 13S 5' splice site, which is the first observation of such a feature. We have shown that this unexpected behaviour is due, at least partly, to the unusual characteristics of the wild-type upstream intron, which requires a hairpin structure between the branch sites and the 3' splice site to reduce the operational distance between these two sites. Possible mechanisms involved in the contrasted cis-acting effects of the 13S and 12S 5' splice sites are discussed.


Evidence for an attentional bias for washing- and checking-relevant stimuli in obsessive-compulsive disorder.
There is equivocal evidence whether or not patients with obsessive-compulsive disorder (OCD) share an attentional bias for concern-related material and if so, whether this reflects hypervigilance towards or problems to disengage from disorder-related material. In a recent study, we failed to detect an attentional bias in OCD patients using an emotional variant of the inhibition of return (IOR) paradigm containing OCD-relevant and neutral words. We reinvestigated the research question with a more stringent design that addressed potential moderators. A new IOR paradigm was set up using visual stimuli. Forty-two OCD patients and 31 healthy controls were presented with neutral (e.g., cup), anxiety-relevant (e.g., shark), checking-relevant (e.g., broken door), and washing-relevant (e.g., dirty toilet) cue pictures at one of two possible locations. Following a short or long interval sensitive to automatic versus controlled processes, a simple target stimulus appeared at either the cued or the uncued location. OCD patients responded significantly slower to targets that were preceded by an OCD-relevant cue. Results lend support to the claim that OCD patients share a processing abnormality for concern-related visual material.


Weather indicators and improving air quality in association with COVID-19 pandemic in India.
The COVID-19 pandemic enforced nationwide lockdown, which has restricted human activities from March 24 to May 3, 2020, resulted in an improved air quality across India. The present research investigates the connection between COVID-19 pandemic-imposed lockdown and its relation to the present air quality in India; besides, relationship between climate variables and daily new affected cases of Coronavirus and mortality in India during the this period has also been examined. The selected seven air quality pollutant parameters (PM10, PM2.5, CO, NO2, SO2, NH3, and O3) at 223 monitoring stations and temperature recorded in New Delhi were used to investigate the spatial pattern of air quality throughout the lockdown. The results showed that the air quality has improved across the country and average temperature and maximum temperature were connected to the outbreak of the COVID-19 pandemic. This outcomes indicates that there is no such relation between climatic parameters and outbreak and its associated mortality. This study will assist the policy maker, researcher, urban planner, and health expert to make suitable strategies against the spreading of COVID-19 in India and abroad. The online version contains supplementary material available at 10.1007/s00500-021-06012-9.


"More crop per drop": Exploring India's cereal water use since 2005.
India has the highest national freshwater demand globally and 91% of India's freshwater is used in the agriculture sector. Cereals account for over 50% of the dietary water footprint in India and represent a potential opportunity for reducing water use in Indian agriculture. This study combines governmental production and irrigation statistics with crop distribution maps to examine trends in annual water use for cereal production in India between 2005 and 2014. A new online water assessment tool, Cool Farm Tool Water (CFTW), was used to calculate water use and derive seasonal state-level blue and green water footprints for rice, wheat, sorghum, millet and maize. The analysis indicates that India achieved 26.4% increased total cereal production between 2005 and 2014 without additional water or land use. Cereal water footprints have declined due to higher yields for most crops and slightly lower rates of evapotranspiration. There has also been a shift in the area under production away from the Kharif (monsoon) towards the Rabi (dry) season in which total water footprints for all cereals except rice are substantially lower (-33.4% to -45.0% compared to Kharif), but show a significantly higher dependency on ground and surface water. The value of this study is two-fold. First, it provides a full assessment of production trends for the five major cereals in India for each year from 2005 to 2014 and links it to water use. Secondly, it uses updated seasonal water footprints, which demonstrate the potential for changes in cereal production practices to contribute to improved efficiency of water use in India. Future pressures on scarce water resources may encourage transition to cereals with lower irrigation dependency, in particular maize, but also sorghum and millet. In addition, increased emphasis on improving millet and sorghum yields would be of benefit to secure cereal production and reduce its overall water footprint.


Tricyclic antidepressants and calcium channel blockers: interactions at the (-)-desmethoxyverapamil binding site and the serotonin transporter.
The activity of various calcium channel blockers at the serotonin transporter, as determined by their effects on imipramine binding and serotonin uptake, was investigated in rat brain and human platelets. In addition, the effect of tricyclic antidepressants on the binding of calcium channel blockers was evaluated. Verapamil was found to be a competitive inhibitor of both imipramine binding and serotonin uptake in brain and platelets. The inhibitory activity of verapamil was calcium-independent. Chronic verapamil treatment resulted in a significant decrease (28%) in [3H]imipramine binding in the rat hypothalamus but had no effect on [3H]imipramine binding to cerebral cortex membranes or on [3H]serotonin uptake in these two brain regions. Tricyclic antidepressants inhibited (-)-[3H]desmethoxyverapamil binding but did not affect [3H]nitrendipine binding to rat cerebral cortex membranes. Chronic imipramine treatment induced a non-significant increase (34%) in (-)-[3H]desmethoxyverapamil binding but did not alter [3H]nitrendipine binding in rat cerebral cortex. These interactions may be relevant to an understanding of the beneficial effects of verapamil in major affective disorders and may suggest an involvement of calcium channels in the pharmacological activity of tricyclic antidepressants.


Beneficial effects of pioglitazone on retardation of persistent atrial fibrillation progression in diabetes mellitus patients.
This study aimed to explore the effects of pioglitazone treatment on progression from persistent atrial fibrillation (AF) to permanent atrial fibrillation in diabetes mellitus (DM) patients and to investigate the possible mechanisms involved in those effects.A total of 146 diabetes mellitus (DM) patients with firstly identified persistent AF were selected. Seventy patients were randomized into the pioglitazone (30 mg/day) group and 76 into the placebo group. Pro-collagen type I carboxyterminal peptide (PICP), advanced glycation end products (AGEs), and angiotensin II were assayed and left atrial diameter (LA diameter) was measured at the first presence of persistent AF, and at 6 and 14 months of follow-up. The time point of identification of permanent AF and the incidence of permanent AF in the patients were all recorded.Thirty-seven (49%) of the 76 patients in the placebo group and 21 (30%) of the 70 patients in the pioglitazone group progressed to permanent AF (P = 0.028). No significant differences existed in the follow-up time (20.5 ± 3.97 months for pioglitazone group versus 20.9 ± 4.14 months for placebo group) between the two groups (P = 0.535). In the pioglitazone group, no significant change was found in angiotensin II level. The PICP level did not change significantly at 6-months of follow-up, but decreased significantly at 14-months of follow-up (P = 0.032). The AGE (P = 0.037 at 6-month follow-up, P < 0.035 at 14-month follow-up) level was significantly lower at both 6 and 14-months of followup.By lowering the PICP level, pioglitazone treatment may decrease the incidence of permanent AF in DM patients with persistent AF, which may be associated with the suppressing effect of pioglitazone on AGEs.


Regulation of the EGFR Pathway by HSP90 Is Involved in the Pathogenesis of Cushing's Disease.
To investigate the role of heat-shock protein Hsp90 in adrenocorticotropic hormone (ACTH)-secreting cells, and to explore the potential clinical application of an inhibitor of Hsp90, 17-N-allylamino-17-demethoxygeldanamycin(17-AAG) in corticotropinomas [also known as "Cushing's disease" (CD)]. Culture of mouse pituitary tumor [AtT-20/D16v-F2 (ATCC® CRL-1795™)] cells and human pituitary ACTH-secreting tumor cells were employed. Hepatocellular carcinoma cell line (HLE) was used to evaluate EGFR inhibition by 17-AAG. Cell viability was evaluated using a commercial kit. The ACTH level was measured by a radioimmunoassay. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to measure expression of proopiomelanocortin (POMC) mRNA. Western blotting was done to measure protein levels. 17-AAG suppressed the viability and proliferation, and promoted the apoptosis, of AtT-20/D16v-F2 cells. 17-AAG suppressed the synthesis and secretion of ACTH in AtT-20/D16v-F2 cells and down-regulated POMC transcription. 17-AAG acted in a similar pattern upon treatment with human pituitary ACTH-secreting tumor cells. Inhibition by 17-AAG was stronger in human pituitary ACTH-secreting tumor cells carrying the ubiquitin-specific protease-8 (USP8) mutant in comparison with cells carrying wild-type USP8. The HSP90 inhibitor 17-AAG reduced the viability and secretory function of human pituitary ACTH-secreting tumor cells, and tumor cells carrying the USP8 mutant were more sensitive to 17-AAG than tumor cells carrying wild-type USP8. 17-AAG could be a potential treatment option for CD.


Effect of simulated pulpal pressure on dentin bond strength of self-etching bonding systems.
To evaluate in vitro the influence of dentin perfusion on dentin bond strengths of etch and rinse and self-etch adhesives. 64 extracted human molars were ground flat and resin composite (Brilliant) was bonded using the following bonding systems (each n=16): OptiBond FL including phosphoric acid etching (OFL+), OptiBond FL without phosphoric acid etching (OFL-), Clearfil SE-Bond (CSE) and Prompt L-Pop (LP). In each bonding system, half of the specimens (n=8) were bonded without (PP-) and half with (PP+) simulated intrapulpal pressure. After water storage (37 degrees C, 24 hours), a 1 mm thick slice was cut vertically from the middle of each sample. Microtensile bond strength (microTBS) was determined and the debonded surfaces were investigated in SEM for the mode of failure. Statistical significance was determined by ANOVA, Tukey-test, and t-test (P= 0.05). Mean microTBS measured were (MPa +/- SD): OFL+/PP- 58.6 (5.8), OFL+/PP+ 38.1 (3.8), OFL-/PP- 37.9 (3.7), OFL-/PP+ 33.3 (3.5), CSE/PP- 41.1 (4.1), CSE/PP+ 39.0 (4.4), LP/PP- 35.8 (6.4), LP/PP+ 29.0 (4.8). The presence of PP resulted in a decrease of microTBS in all bonding systems, which reached significance in OFL+ (P< 0.0001), OFL- (P= 0.023) and LP (P= 0.032). Both, with and without PP, the bonding systems showed significant differences in bond strength (ANOVA: P< 0.0001).


Burning fire-prone Mediterranean shrublands: immediate changes in soil microbial community structure and ecosystem functions.
Wildfires subject soil microbes to extreme temperatures and modify their physical and chemical habitat. This might immediately alter their community structure and ecosystem functions. We burned a fire-prone shrubland under controlled conditions to investigate (1) the fire-induced changes in the community structure of soil archaea, bacteria and fungi by analysing 16S or 18S rRNA gene amplicons separated through denaturing gradient gel electrophoresis; (2) the physical and chemical variables determining the immediate shifts in the microbial community structure; and (3) the microbial drivers of the change in ecosystem functions related to biogeochemical cycling. Prokaryotes and eukaryotes were structured by the local environment in pre-fire soils. Fire caused a significant shift in the microbial community structure, biomass C, respiration and soil hydrolases. One-day changes in bacterial and fungal community structure correlated to the rise in total organic C and NO(3)(-)-N caused by the combustion of plant residues. In the following week, bacterial communities shifted further forced by desiccation and increasing concentrations of macronutrients. Shifts in archaeal community structure were unrelated to any of the 18 environmental variables measured. Fire-induced changes in the community structure of bacteria, rather than archaea or fungi, were correlated to the enhanced microbial biomass, CO(2) production and hydrolysis of C and P organics. This is the first report on the combined effects of fire on the three biological domains in soils. We concluded that immediately after fire the biogeochemical cycling in Mediterranean shrublands becomes less conservative through the increased microbial biomass, activity and changes in the bacterial community structure.


[Risk assessment: a concept analysis].
Risk assessments are conducted to assess the negative influences and potential losses related to a prospective goal or decision. The main practical purpose of risk assessment is to provide information, which can then be used to manage identified potential risks to avoid their occurrence or minimize their influence. To date, the risk assessments have primarily been applied to finance, environmental pollution and employment. Risk assessment has been applied only in a limited manner in the fields of medical treatment and nursing. Literature on risk assessment lack analysis that is systematic and complete. This article applies the methodology of Walker and Avant (2005) to analyze the concept of risk assessment. Steps include a review of the literature on conceptual definitions of risk assessment, determining the defining attributes of risk assessment, model construction, defining parameters and related cases, and identifying antecedents and consequences. Once completed, empirical references of risk assessment were explored. The authors hope that this analysis can assist nursing stuff to gain a better understanding of risk assessment concepts in order to apply knowledge gained to clinical practice. As such, nursing stuff will be able to apply the concept of risk assessment to identify risk, control risk, and reduce the occurrence and loss of accidents.


Phased diploid genome assemblies and pan-genomes provide insights into the genetic history of apple domestication.
Domestication of the apple was mainly driven by interspecific hybridization. In the present study, we report the haplotype-resolved genomes of the cultivated apple (Malus domestica cv. Gala) and its two major wild progenitors, M. sieversii and M. sylvestris. Substantial variations are identified between the two haplotypes of each genome. Inference of genome ancestry identifies ~23% of the Gala genome as of hybrid origin. Deep sequencing of 91 accessions identifies selective sweeps in cultivated apples that originated from either of the two progenitors and are associated with important domestication traits. Construction and analyses of apple pan-genomes uncover thousands of new genes, with hundreds of them being selected from one of the progenitors and largely fixed in cultivated apples, revealing that introgression of new genes/alleles is a hallmark of apple domestication through hybridization. Finally, transcriptome profiles of Gala fruits at 13 developmental stages unravel ~19% of genes displaying allele-specific expression, including many associated with fruit quality.


Physical home environment is associated with prefrontal cortical thickness in adolescents.
Biologically embedded experiences alter developmental trajectories in ways that can influence health, learning, and/or behavior. These systematic differences in experiences may contribute to different biological outcomes as individuals grow and develop, including at the neural level. Previous studies of biologically embedded experiences on neurodevelopment have focused on large-scale institutional or economic factors (e.g. socioeconomic status [SES]) and psychosocial factors (e.g. caregiving behavior). Less attention has focused on how the quality of the immediate home settings, such as the physical home environment (PHYS), influences neurodevelopment. Moreover, no study has investigated these effects in adolescents, who undergo significant physical maturation and neurodevelopment that may influence how they respond to their physical environments. The goal of the current study was to examine whether PHYS quality is biologically embedded in the developing adolescent brain as evidenced by cognitive achievement and cortical development in 56 (48% female) healthy adolescents (14-18 years (M = 16.83 years, SD = 1.17). Using in-home assessments of the physical home environment, anatomical brain scans, and indices of academic achievement, we found that adolescents who have more physical problems in the home (e.g. structural hazards, crowding, excessive noise, poorly lit) have thinner prefrontal cortices, which was associated with lower levels of reading achievement, independent of SES and psychosocial factors. By conducting home visits to assess physical characteristics of adolescents' home, we highlight a typically overlooked aspect of the home environment that has relevance for adolescents' cognitive and brain development.


Characteristics of zinc transport by two bacterial cation diffusion facilitators from Ralstonia metallidurans CH34 and Escherichia coli.
CzcD from Ralstonia metallidurans and ZitB from Escherichia coli are prototypes of bacterial members of the cation diffusion facilitator (CDF) protein family. Expression of the czcD gene in an E. coli mutant strain devoid of zitB and the gene for the zinc-transporting P-type ATPase zntA rendered this strain more zinc resistant and caused decreased accumulation of zinc. CzcD, purified as an amino-terminal streptavidin-tagged protein, bound Zn2+, Co2+, Cu2+, and Ni2+ but not Mg2+, Mn2+, or Cd2+, as shown by metal affinity chromatography. Histidine residues were involved in the binding of 2 to 3 mol of Zn2+ per mol of CzcD. ZitB transported 65Zn2+ in the presence of NADH into everted membrane vesicles with an apparent Km of 1.4 microM and a Vmax of 0.57 nmol of Zn2+ min(-1) mg of protein(-1). Conserved amino acyl residues that might be involved in binding and transport of zinc were mutated in CzcD and/or ZitB, and the influence on Zn2+ resistance was studied. Charged or polar amino acyl residues that were located within or adjacent to membrane-spanning regions of the proteins were essential for the full function of the proteins. Probably, these amino acyl residues constituted a pathway required for export of the heavy metal cations or for import of counter-flowing protons.


Is Newborn Hearing Screening Cost Effective? Economic Consideration for Policy Makers.
Hearing loss is the most common congenital disorder that appears as a unilateral or bilateral deafness. Early detection by screening and appropriate intervention lead to better oral communication and language development. The aim of this study was to evaluate the cost per new case identification of neonate hearing screening. The cost effectiveness of two stage hospital based newborn hearing loss screening was evaluated in this study. We gathered data for 11168 newborns born in 10 hospitals. We included a direct cost and new case identification as cost and outcome measures from health system prospective in our model. We found 19 new cases with hearing loss from 11168 screened neonates (1.7 per 1000). The referral rates in the first and second stages were respectively 28% and 7%. The total cost of screening program was 132167 US$. The main cost item is screening test (OAE). We concluded cost per new case detection is 6956 US$ in Iranian neonate hearing screening program. Almost, it is equal to GDP per capita and it may be cost effective. Since there are many strategies to screening of newborn, it is suggested that all alternative screening strategies be analyzed by a cost effectiveness method to find the best strategy for hearing loss screening.


Irreversible Electroporation Treatment With Intraoperative Biliary Stenting for Unresectable Perihilar Cholangiocarcinoma: A Pilot Study.
Treating perihilar cholangiocarcinoma (PHCC) is particularly difficult due to the fact that it is usually in an advanced stage at the time of diagnosis. Irreversible electroporation treatment (IRE) involves the local administration of a high-voltage electric current to target lesions without causing damage to surrounding structures. This study investigated the safety and efficacy of using IRE in conjunction with intraoperative biliary stent placement in cases of unresectable PHCC. This study enrolled 17 patients with unresectable Bismuth type III/IV PHCC who underwent IRE in conjunction with intraoperative biliary stent placement (laparotomic) in two medical centers in Asia between June 2015 and July 2018. Analysis focused on the perioperative clinical course, the efficacy of biliary decompression, and outcomes (survival). Mean total serum bilirubin levels (mg/dL) on postoperative day (POD) 7, POD30, and POD90 were significantly lower than before IRE (respectively 3.46 vs 4.54, p=0.007; 1.21 vs 4.54, p<0.001; 1.99 vs 4.54, p<0.001). Mean serum carbohydrate antigen 19-9 (CA19-9, U/ml) levels were significantly higher on POD3 than before the operation (518.8 vs 372.4, p=0.001) and significantly lower on POD30 and POD90 (respectively 113.7 vs 372.4, p<0.001; 63.9 vs 372.4, p<0.001). No cases of Clavien-Dindo grade III/IV adverse events or mortality occurred within 90 days post-op. The median progression-free survival was 21.5 months, and the median overall survival was 27.9 months. All individuals who survived for at least one year did so without the need to carry percutaneous biliary drainage (PTBD) tubes. It appears that IRE treatment in conjunction with intraoperative biliary stent placement is a safe and effective approach to treating unresectable PHCC. The decompression of biliary obstruction without the need for PTBD tubes is also expected to improve the quality of life of patients.


Developing Scattering Morphology Resolved Total Internal Reflection Microscopy (SMR-TIRM) for Orientation Detection of Colloidal Ellipsoids.
Micrometer scale colloidal particles experiencing ∼kT scale interactions and suspended in a fluid are relevant to a broad spectrum of applications. Often, colloidal particles are anisotropic, either by design or by nature. Yet, there are few techniques by which ∼kT scale interactions of anisotropic particles can be measured. Herein, we present the initial development of scattering morphology resolved total internal reflection microscopy (SMR-TIRM). The hypothesis of this work is that the morphology of light scattered by an anisotropic particle from an evanescent wave is a sensitive function of particle orientation. This hypothesis was tested with experiments and simulations mapping the scattered light from colloidal ellipsoids at systemically varied orientations. Scattering morphologies were first fitted with a two-dimensional (2D) Gaussian surface. The fitted morphology was parameterized by the morphology's orientation angle Mϕ and aspect ratio MAR. Data from both experiments and simulations show Mϕ to be a function of the particle azimuthal angle, while MAR was a sensitive function of the polar angle. This analysis shows that both azimuthal and polar angles of a colloidal ellipsoid could be resolved from scattering morphology as well or better than using bright-field microscopy. The integrated scattering intensity, which will be used for determining the separation distance, was also found to be a sensitive function of particle orientation. A procedure for interpreting these confounding effects was developed that in principle would uniquely determine the separation distance, the azimuthal angle, and the polar angle. Tracking these three quantities is necessary for calculating the potential energy landscape sampled by a colloidal ellipsoid.


Regulatory role of anesthetics on heme oxygenase-1.
As an enzyme, heme oxygenase (HO) can provide substantial cellular protection. By eliminating free heme and generating iron, biliverdin, as well as carbon monoxide, HO exerts anti-inflammatory, anti-proliferative, antioxidative, and vasodilatory effects. The inducible form of HO, heme oxygenase-1 (HO-1) can be upregulated by harmful stimuli in most human cell types. In such a way, cells utilize HO-1 as a mechanism of self-protection. Many studies have shown that upregulation of HO-1 prior to injurious stimuli conferred protection to cells and organs against subsequent injury. Therefore, manipulation of HO-1 gene expression might represent a valuable strategy for the prevention of organ dysfunction. In recent studies, intravenous and inhaled anesthetics (e.g., ketamine, propofol, opioids, isoflurane, sevoflurane, desflurane, etc.) not only upregulate HO-1 to varying extents, but account for organ protection via the HO pathway. The major advantage of anesthetics over other HO-inducing agents is related to their clinically proven safety. Another important issue is that patients receiving anesthetics in anesthesia or intensive care medicine are often suffering from pathological conditions involving pro-oxidative or pro-inflammatory states. Therefore, it would be interesting to know whether the impact of anesthetics on HO-1 regulation might influence outcome of these patients. This overview summarizes the effects of different anesthetics on HO-1 regulation and function in disease models.


Hypersensitivity reactions associated with platinum-containing antineoplastic agents for thoracic malignancies.
Recently, the use of platinum-containing antineoplastic agents for extended periods has increased. In this study, we determined the relationship between the hypersensitivity reactions to cisplatin or carboplatin and the frequency of administration among patients with thoracic malignancies. The study included 255 patients with thoracic malignancies who were treated with chemotherapy containing cisplatin or carboplatin in our institution between April 2007 and October 2008. A total of 89 patients received a median of 3 courses of cisplatin and 140 patients a median of 4 courses of carboplatin. A median of 6 courses of cisplatin plus carboplatin was administered to a further 26 patients. The total incidence of hypersensitivity reactions was 1.96%. Patients who were treated with <6 courses of platinum-containing antineoplastic agent did not experience any hypersensitivity reaction, but one patient, who was administered with 6 courses of platinum-containing antineoplastic agent experienced a hypersensitivity reaction (0.44%), as did four patients who were administered ≥7 courses (13.8%). Univariate and multivariate analyses indicated that the number of courses of platinum-containing antineoplastic agents was significantly correlated to the incidence of hypersensitivity reactions to these agents.


[Expression of interferon-induced protein with tetratricopetide repeats 1 and liver cell apoptosis in mice with severe burns].
To explore the relationship between the expression of interferon-induced protein with tetratricopetide repeats 1 (IFIT1) and liver cell apoptosis in the acute stress period after severe burns. A total of 25 C57/129 adult mice were randomly divided into the normal control group (0 h) and the groups at 1, 6, 12 or 24 after severe burns (n=5 per group). A model with third degree (20% of the total body surface area) burn injury was established and then liver tissues were taken. IFIT1 expression was examined by Western blot. The expression of caspase-3 and -8 was measured by immunohistochemistry. Liver cell apoptosis was detected by terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL). After burns, IFIT1 expression was increased at 1 h, which reached the highest level at 6 h followed by a decrease at 12 h, which reached minimum level at 24 h. The differences between groups were significant (P<0.01). The caspase-3 and -8 levels significantly increased after burns in a time-dependent manner (P<0.01). Although at 0 h and 1 h there was no significant increase in liver cell apoptosis, the increase reached significance from 6 h to 24 h (P<0.01). The increase in IFIT1 expression after severe burns promotes liver cell apoptosis.


Phenolic-Rich Extract from Almond (Prunus dulcis) Hulls Improves Lipid Metabolism in Triton WR-1339 and High-Fat Diet-Induced Hyperlipidemic Mice and Prevents Lipoprotein Oxidation: A Comparison with Fenofibrate and Butylated Hydroxyanisole.
Hyperlipidemia and oxidative stress are risk factors for atherosclerosis. In this study, we investigated the hypolipidemic and anti-lipoprotein oxidation activities of polyphenol-rich extracts from almond hulls using Triton WR-1339 and high-fat diet-induced hyperlipemic mice as experimental models. We demonstrated that the almond hull extract significantly reduced total cholesterol, triglycerides and low-density lipoprotein-related plasma cholesterol (LDL-C) in the two experimental models of hyperlipidemia, but significantly increased high-density lipoprotein-related plasma cholesterol (HDL-C). Another beneficial effect of the extract was its ability to reduce the atherogenic index and LDL-C/HDL-C ratio. However, the extract exhibited effective antiradical activity against 2,2-diphenyl-1-picrylhydrazyl and significantly protected lipoprotein-rich plasma from mice against oxidation induced by copper ion. The extract contains 342.63±3.44 mg/g total phenolics, 144.67±6.83 mg/g tannins, and 20.66±0.92 mg/g flavonoids. These finding indicate that almond hulls contain polar products able to lower plasma lipid concentrations and which might be beneficial for the treatment of hyperlipidemia and prevention of atherosclerosis.


B cell signature during inactive systemic lupus is heterogeneous: toward a biological dissection of lupus.
Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomas of quiescent lupus patients to normal B cell transcriptomas. When the statistical analysis is performed on the entire group of patients, the differences between patients and controls appear quite weak with only 14 mRNA genes having a false discovery rate ranging between 11 and 17%, with 6 underexpressed genes (PMEPA1, TLR10, TRAF3IP2, LDOC1L, CD1C and EGR1). However, unforced hierarchical clustering of the microarrays reveals a subgroup of lupus patients distinct from both the controls and the other lupus patients. This subgroup has no detectable clinical or immunological phenotypic peculiarity compared to the other patients, but is characterized by 1/an IL-4 signature and 2/the abnormal expression of a large set of genes with an extremely low false discovery rate, mainly pointing to the biological function of the endoplasmic reticulum, and more precisely to genes implicated in the Unfolded Protein Response, suggesting that B cells entered an incomplete BLIMP1 dependent plasmacytic differentiation which was undetectable by immunophenotyping. Thus, this microarray analysis of B cells during quiescent lupus suggests that, despite a similar lupus phenotype, different biological roads can lead to human lupus.


A Four-miRNA-Based Diagnostic Signature for Rheumatoid Arthritis.
As a chronic inflammatory disease, rheumatoid arthritis (RA) usually leads to cartilage and bone damage, even disability. Earlier detection and diagnosis are crucial to improve the therapeutic efficacy, and the aim of our study is to identify a potential diagnostic signature for RA. We downloaded the GSE124373 dataset from the Gene Expression Omnibus (GEO) database. And differential expression analysis of miRNAs was conducted using the limma package of R language. The potential targeted mRNAs of differentially expressed miRNAs were predicted using the MiRTarBase database. The clusterProfiler package in R language was used to conduct functional enrichment analysis (GO term and KEGG pathway). Then, based on the key miRNAs screened by stepwise regression analysis, the logistic regression model was built and it was evaluated using a 5-fold cross-validation method. A total of 19 differentially expressed miRNAs in the blood sample of RA patients compared with that of healthy subjects were identified. Nine optimal miRNAs were screened by using stepwise regression analysis, and four key miRNAs hsa-miR-142-5p, hsa-miR-1184, hsa-miR-1246, and hsa-miR-99b-5p were further optimized. Finally, a logistic regression model was built based on the four key miRNAs, which could reliably separate RA patients from healthy subjects. Our study established a logistic regression diagnostic model based on four crucial miRNAs, which could separate the sample type reliably.


Increased expression of inducible nitric oxide synthase for human oral submucous fibrosis, verrucous hyperplasia, and verrucous carcinoma.
Three isoforms of nitric oxide synthase (NOS), endothelial, neuronal and inducible NOS (iNOS), have been identified in humans. Enhanced expression of iNOS protein has been previously reported for human oral epithelial dysplasias, a human oral premalignant epithelial lesion; however, this expression has not been demonstrated for other premalignant epithelial lesions, namely, oral submucous fibrosis (SF) and verrucous hyperplasia (VH). On the other hand, iNOS protein expression has not been reported in human oral verrucous carcinoma (VCa). The aim of this current study was to determine whether iNOS protein also occurs for oral SF, VH and VCa lesions. We found that membranous stainings were observed chiefly in oral SF lesions (17/20, 85%), whereas cytoplasmic stainings were mainly found in the VH variants (16/20, 80%). By contrast, cytoplasmic and/or nuclear stainings were observed in the specimens of verrucous carcinoma (17/20, 85%). Since no iNOS activity could be detected for any of our specimens of normal buccal mucosa in the present immunohistochemical study, this suggests that an NOS-dependent mechanism may be involved in the malignant transformation of these two premalignant oral epithelial lesions.


Phenotypic differences between asymptomatic airway hyperresponsiveness and remission of asthma.
The present study aimed to illustrate differences in characteristics and perception of dyspnea between young atopic adults who have no history of asthma (never-asthmatics) with or without asymptomatic airway hyperresponsiveness (AHR) and those who had childhood asthma and consider themselves to be grown out of the disease (past-asthmatics). Blood parameters, lung function and methacholine PC(20) were measured in 88 never-asthmatics and 24 past-asthmatics. A perception score of dyspnea at 20% fall in FEV(1) (PS(20)) was obtained by interpolation of the two last points on the perception (modified Borg scale)/fall in FEV(1) curve during methacholine challenge. Thirty-one of 88 never-asthmatics and eighteen of 24 past-asthmatics exhibited AHR (PC(20) was <8 mg/ml). Higher levels of specific IgE to house dust mite in past-asthmatics were observed than never-asthmatics with and without AHR. Mean values of FEV(1) and FEF(25-75) (%predicted) were significantly lower in past-asthmatics than never-asthmatics without AHR, and the values in never-asthmatics with AHR were intermediate between never-asthmatics without AHR and past-asthmatics. PC(20) was not significantly different between past-asthmatics and never-asthmatics with AHR. Of particular interest was that PS(20) was significantly lower in never-asthmatics with AHR compared with past-asthmatics. The present findings suggest the possibilities that presence or absence of past history of outgrow of childhood asthma might be associated with airway narrowing, sensitization to house dust mite and perception of dyspnea in young asymptomatic adults with atopy and AHR.


The effect of bee prepolis on primary dysmenorrhea: a randomized clinical trial.
Primary dysmenorrhea typically occurs with no associated pelvic pathology and is common in adolescents and young women. This study evaluated the effect of bee propolis on relief of primary dysmenorrhea. The study was performed in 2018 in Hamadan, in western Iran, among female students with primary dysmenorrhea. Participants were randomly divided into two groups, using balanced block randomization, and were administered a placebo or bee propolis capsules for 5 days during two menstruation cycles. The number of participants required was estimated to be 86 in total, with 43 students in each group according to the inclusion criteria. We used the visual analog scale to assess pain severity. The independent t-test was conducted for comparing between two groups, using SPSS 16.0. A significant change was found in the mean pain scores during the first (P<0.001) and second (P<0.001) months after using bee propolis in comparison with placebo. The means of the pain scores in the bee propolis group were 5.32±2.28 and 4.74±2.40 in first and second months after the intervention, respectively, whereas the means of the pain scores in the placebo group were 7.40±1.21 and 7.17±1.24 in first and second months after the intervention, respectively. Our study showed that the use of bee propolis for two months compared with placebo reduced primary dysmenorrhea during the first and second months after use, with no adverse effects. Therefore, it could be used as an alternative to nonsteroidal anti-inflammatory drugs for relief of primary dysmenorrhea.


A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions.
There is solid evidence that rare variants contribute to complex disease etiology. Next-generation sequencing technologies make it possible to uncover rare variants within candidate genes, exomes, and genomes. Working in a novel framework, the kernel-based adaptive cluster (KBAC) was developed to perform powerful gene/locus based rare variant association testing. The KBAC combines variant classification and association testing in a coherent framework. Covariates can also be incorporated in the analysis to control for potential confounders including age, sex, and population substructure. To evaluate the power of KBAC: 1) variant data was simulated using rigorous population genetic models for both Europeans and Africans, with parameters estimated from sequence data, and 2) phenotypes were generated using models motivated by complex diseases including breast cancer and Hirschsprung's disease. It is demonstrated that the KBAC has superior power compared to other rare variant analysis methods, such as the combined multivariate and collapsing and weight sum statistic. In the presence of variant misclassification and gene interaction, association testing using KBAC is particularly advantageous. The KBAC method was also applied to test for associations, using sequence data from the Dallas Heart Study, between energy metabolism traits and rare variants in ANGPTL 3,4,5 and 6 genes. A number of novel associations were identified, including the associations of high density lipoprotein and very low density lipoprotein with ANGPTL4. The KBAC method is implemented in a user-friendly R package.


Extractable Free Polymer Chains Enhance Actuation Performance of Crystallizable Poly(ε-caprolactone) Networks and Enable Self-Healing.
Crosslinking of thermoplastics is a versatile method to create crystallizable polymer networks, which are of high interest for shape-memory actuators. Here, crosslinked poly(ε-caprolactone) thermosets (cPCLs) were prepared from linear starting material, whereby the amount of extractable polymer was varied. Fractions of 5⁻60 wt % of non-crosslinked polymer chains, which freely interpenetrate the crosslinked network, were achieved leading to differences in the resulting phase of the bulk material. This can be described as "sponge-like" with open or closed compartments depending on the amount of interpenetrating polymer. The crosslinking density and the average network chain length remained in a similar range for all network structures, while the theoretical accessible volume for reptation of the free polymer content is affected. This feature could influence or introduce new functions into the material created by thermomechanical treatment. The effect of interpenetrating PCL in cPCLs on the reversible actuation was analyzed by cyclic, uniaxial tensile tests. Here, high reversible strains of up to ∆ε = 24% showed the enhanced actuation performance of networks with a non-crosslinked PCL content of 30 wt % resulting from the crystal formation in the phase of the non-crosslinked PCL and co-crystallization with network structures. Additional functionalities are reprogrammability and self-healing capabilities for networks with high contents of extractable polymer enabling reusability and providing durable actuator materials.


A novel role of 'pseudo'γ-butyrolactone receptors in controlling γ-butyrolactone biosynthesis in Streptomyces.
In streptomycetes, a quorum-sensing mechanism mediated by γ-butyrolactones (GBLs) and their cognate receptors was known to trigger secondary metabolism and morphological differentiation. However, many aspects on the control of GBL signal production are not understood. In this work, we report that ScbR2, the pseudo GBL receptor in Streptomyces coelicolor, negatively controls the biosynthesis of γ-butyrolactone (SCB1) by directly repressing the transcription of scbA, which encodes the key enzyme for SCB1 biosynthesis. Similarly, the pseudo GBL receptor JadR2 in Streptomyces venezuelae was shown to repress the expression of jadW1, which also encodes the putative GBL synthase. These regulatory relationships were verified in Escherichia coli using lux-based reporter constructs. Additionally, the temporal expression profiles of scbA, scbR2 and scbR (receptor gene for SCB1) were examined in Streptomyces coelicolor, which showed the sequential expression of ScbR/R2 regulators in the control of SCB1 production. Overall, our results clearly demonstrated that pseudo GBL receptors play a novel role in controlling GBL biosynthesis in streptomycetes. As ScbR/R2 homologues and their binding sites upstream of GBL synthase genes are commonly found in Streptomyces species, and ScbR2 homologues cross-recognize each other's target promoters, the ScbA/R/R2 quorum-sensing regulatory system appears to represent an evolutionarily conserved signal control mechanism.


Equine herpesviruses type 1 (EHV-1) and 4 (EHV-4)--masters of co-evolution and a constant threat to equids and beyond.
The equine herpesviruses type 1 (EHV-1) and 4 (EHV-4) are ubiquitous pathogens that affect horse populations on all continents. Despite widespread vaccination, EHV-1 and EHV-4 infections remain a permanent risk. While the two viruses share a high degree of genetic and antigenic similarity, they differ significantly in host range and pathogenicity. Compared to EHV-4, which mainly infects horses and causes respiratory disease, EHV-1 has a broader host range and can result in respiratory disease, abortions, neonatal death, and equine herpesvirusmyeloencephalopathy (EHM). Recent studies have elucidated a number of mechanisms that may, at least partly, explain the differential pathogenic potential of the two viruses. While both EHV-1 and EHV-4 can escape host immune responses and establish latent infection, there are differences with respect to virus entry and their ability to interfere with the innate immune response. Understanding the virus' repertoire of immunomodulatory mechanisms may lead the way to develop more efficient vaccines.


Plasmid-based STAT3-siRNA efficiently inhibits breast tumor growth and metastasis in mice.
Signal transducer and activator of transcription 3 (STAT3) plays an important role in the tumor formation and metastasis. In this study, short hairpin RNA targeting STAT3 was cloned into pGenesil-2 plasmid vector and the effects of STAT3 silencing in 4T1 breast cancer cells were analyzed both in vitro and in vivo. Forty-eight hours after transfecting with pSi-STAT3, the expression level of STAT3, the upstream regulator and downstream targets were measured using Western blot. Moreover, the effects of pSi-STAT3 on migration and invasion in 4T1 cells were tested using wound-healing and tube formation assay. Furthermore, 4T1 subcutaneous mice model was used to evaluate the effects of pSi-STAT3 on tumor growth and metastasis. Proliferation, apoptosis, angiogenesis in tumor tissues and lung metastases were measured by PCNA, TUNEL, and CD31 immunostaining, respectively. Our results indicated that siRNA targeting STAT3 could significantly silence STAT3 expression in 4T1 breast cancer cells and result in inhibition of 4T1 breast cells migration and HUVECs tube formation. In vivo, pSi-STAT3 delayed tumor growth (pknockdown of STAT3 by plasmid-based siRNA might be a potential therapy against breast cancer.


Camp Superteens. An asthma education program for adolescents.
Camp Superteens, an asthma self-management educational program, was designed for and offered to adolescents ages 13 to 16 at a large local shopping mall. The 6-hour program was divided into four main categories: presentation of asthma information; non-pharmacological management; pharmacological management; and dealing with self and others. A pilot study on asthma self-efficacy, completed during the first year of camp, found a significant improvement in self-efficacy in five instances, with demonstrated increased confidence in ability to manage asthma when: 1. exercising; 2. at the doctor's office; 3. breathing improperly; 4. afraid; and 5. angry. While pilot study results are encouraging and have already been useful for curricular refinement purposes, the small sample size (n = 17) and other limitations suggest the need for further research.


An alteration in the structure of the minor groove of duplex DNA induced by the formation of an intermolecular d(GA)n:d(GA)n.d(TC)n triplex.
A simple homopolymeric purine:purine.pyrimidine, d(GA)n:d(GA)n.d(TC)n, triplex DNA was generated in the presence of magnesium ion at neutral pH. Hydrogen bonding of the N7 positions of guanines and adenines was investigated by 7-deaza base substitutions and protection from chemical modification by dimethyl sulfate (DMS). Chemical modification of this triplex with DMS revealed an unexpected triplex specific hypermodification in the N3 positions of the adenines in addition to the protection in the N7 positions of the guanines. The significance of this increase in the chemical accessibility of the N3 positions of adenines in the minor groove and possible relevance of dehydration to the mechanism of triplex formation and stability is discussed.


Psychometric Examination of an Arabic Version of the State-Trait Anger Expression Inventory.
This study aimed to examine the psychometric properties of an Arabic version of the trait anger and anger expression scales of the State-Trait Anger Expression Inventory (STAXI). This study took place between April 2005 and August 2014. Adults in Yemen (n = 334) and Tunisia (n = 200) were recruited from university campuses and a smoking cessation clinic, respectively. The STAXI was translated into Arabic using back-translation methods. An explanatory principal component analysis was conducted to explore the factor structure of the anger expression scale, utilising parallel analyses to determine the number of retained factors. Good internal consistency of the trait anger scale was observed among the Yemeni (Cronbach's alpha = 0.76) and Tunisian (Cronbach's alpha = 0.86) samples. The parallel analysis suggested a three-factor solution for the anger expression scale (anger in, anger out and anger control), in accordance with the original STAXI. The internal consistency of anger in, anger out and anger control factors ranged between 0.51-0.79 in the Yemeni sample and 0.66-0.81 in the Tunisian sample. Overall, items loaded on the anger control factor included all items proposed by the original authors and this factor had higher reliability than the other two factors in both samples. The results of the current study provide initial support for the use of the trait anger and anger expression scales of the STAXI in Arabic-speaking countries.


Novel ultrasonic fusion imaging method based on cyclic variation in myocardial backscatter.
Quantitative ultrasonic tissue characterisation of the myocardium based on integrated backscatter (IB) has the potential of becoming an effective method for detecting and evaluating myocardial ischaemia. To facilitate IB-based clinical applications, a new imaging method has been developed that combines the anatomical information of a B-mode image with the contractile performance of a selected myocardial region. To produce such a fusion image, a region of interest (ROI) in a B-mode cardiac image was first selected by the user. Algorithms for detection of the endocardium and epicardium were developed, and the resulting mean distance between the computer-detected curve and the manually traced curve was 0.83mm for the endocardium and 0.58mm for the epicardium. The cyclic variation of IB (CVIB) of each myocardial tissue element within the ROI was then calculated over one cardiac cycle. Finally, a grey-scale B-mode image at the end of diastole was displayed as a still image, and the pixels representing the myocardial tissue in the ROI colour-coded according to the corresponding CVIB over the past heart cycle. Both the B-mode image and the colour-coded region were refreshed (up-dated) at the next end-of-diastole. Preliminary results from normal (CVIB= 10-12dB) and ischaemic (CVIB = 5-7 dB) canine hearts are presented that demonstrate the utility of this new imaging method.


Ethnic variation of self-reported psychopathology among incarcerated youth.
Research on ethnic minority populations has shown them to be undertreated, underdiagnosed and perceived as more psychopathological in comparison to the Caucasian population. This study aimed to assess ethnic variation of self-perceived psychopathology in a population of incarcerated youths. The Youth Self-Report (YSR) was completed by 5964 incarcerated adolescents (95% male; mean age = 16.5) in the California Youth Authority (CYA) system. Overall, ethnic minorities (African-Americans and Hispanics) self-report lower levels of psychiatric problems than Caucasians. These differences were more pronounced in males than females. Further research is needed to better ascertain the reasons for these differences.


Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population.
The pathogenetic mechanisms of organ-specific autoimmune diseases remain obscured by the complexity of the genetic and environmental factors participating in the breakdown of tolerance. A unique opportunity to study the pathogenesis of human autoimmunity is provided by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare inherited autoimmune disease caused by mutations in Autoimmune Regulator (AIRE) gene. Loss of AIRE function disrupts the deletion of autoreactive T cells and impairs the suppressive function of regulatory T (Treg) cells. Here we show by multiparameter flow cytometry that in healthy controls the peripheral naive Treg cell subset forms a slowly dividing, persistent reservoir of recent thymic emigrants (RTEs). In APECED patients the RTE Treg cells show accelerated turnover and shift to the activated pool and the RTE reservoir is depleted. Moreover, the activated Treg cell population in the patients expresses significantly less Forkhead box protein P3 (FOXP3) than in the healthy controls, consistent with the impairment of peripheral activation. Our results indicate that in addition to their thymic effects, loss-of-function mutations in AIRE disrupt the peripheral homeostasis and activation of Treg cells. This may synergize with failed negative selection to cause APECED.


Feather and nest mites of two common resident birds in two ecologically different Egyptian governorates.
The study of the role played by birds in the distribution of various bacterial, viral and parasitic infections is increasingly from year to year, taking into consideration the flying ability of birds and their migration for food and vital processes. Two of the common Egyptian resident birds, house sparrow (Passer d. niloticus) and laughing dove (Streptopelia s. aegyptiaca) were chosen to study their mite fauna. The overall mite index was 4.74 on the house sparrow and 7.22 on the laughing dove. As to mites, a total of 31 species belonging to 23 genera, 17 families and 3 suborders were collected. The common mites on both types of birds were 22 species. Three species only on house sparrow, and six species only on laughing dove. The house sparrow served host for 25 mite species and the laughing dove served host for 28 mite species. The infestation rates of mites on house sparrow ranged between 1.11% to 23.33% and 0.21% to 34.54% in Sharkia and Qalyobia governorates respectively. For laughing dove, the mite infestation rates ranged between 0.82% to 50% and 3.45% to 55.17% for both governorates respectively. Some of the collected mites have medical and/or veterinary importance. The whole results were discussed.


Reverse Mössbauer effect as a possible source of "hot" molecules absorbed in crystalline solids at low temperature.
As an attempt to explain some of the many anomalies and unresolved problems which have been reported about the dynamic behavior of particles and molecules absorbed in crystalline solids, the "reverse Mössbauer effect" (RME) is proposed. RME theory posits that a particle in non-equilibrium state with respect to a crystal (colliding with the crystal or absorbed in it, but set out of thermal equilibrium by some external cause) is scattered by the whole crystal with a momentum proportional to a vector representing a reciprocal lattice point. The scattering is expected to occur with a well-defined probability and the momentum transferable to the particle is expected to follow a predictable distribution. The RME theory, in practice, is an extension of the Bragg-von Laue scattering law to high-energy colliding particles, in general, and can be applied to any particle or molecule colliding with the surface of a crystalline solid or absorbed in it, but not in thermal equilibrium with the crystal lattice. We verified the RME theory by considering a well-defined unresolved problem. In an experimental study about methane adsorbed in the zeolite Na-ZSM-5 [H. Jobic, Chem. Phys. Lett. 170, 217 (1990)] reporting neutron inelastic-scattering spectra (recoiled bands) at 10 K, the translational kinetic energy of methane resulted to be much higher than equilibrium expected value, namely, about 85 K (or 7.3 meV). The author concluded that "the interpretation of this unusual behavior has yet to be found." In the present study, on the basis of the RME, an explanation of this behavior is put forward.


Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a French, multi-ethnic, multicentre cohort.
Sarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups.The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis.A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes.This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category.


New developments in colorectal surgery.
New developments in colorectal surgery have been driven primarily by technical innovations, which in turn are responsible for changes in practice. This review examines recent publications that describe and have contributed to these changes. We identified and reviewed recent publications in the areas of fecal incontinence, constipation, single incision and robotic surgical techniques, complex anal fistulas, diverticulitis, local excision techniques for rectal neoplasms, surgical care improvement, use of mechanical bowel preparation, and magnetic resonance imaging after neoadjuvant chemoradiotherapy for rectal cancer. New technologies and practice innovations will enhance patient outcomes and quality of life. Multiinstitutional studies, randomized when practical, will be necessary to further define the safety and efficacy of these new surgical techniques and to further define best practices in colon and rectal surgery.


Understanding Health-Related Quality of Life in Patients with Mantle Cell Lymphoma.
Mantle cell lymphoma (MCL) is a unique lymphoma that is heterogeneous in its clinical course, and lacks consensus treatment approaches. It is often treated with immunochemotherapy at diagnosis and chronic therapies in relapse. Despite significant advances in therapy, MCL remains incurable. Maintaining patients' health-related quality of life (HRQOL) is an important treatment goal. Assessment of HRQOL elucidates the impact of an illness and its treatment on patients' lives. This review highlights the relevance of HRQOL assessment in MCL, evaluates existing evidence, current knowledge gaps and challenges in HRQOL assessment, and defines future directions for improving HRQOL evaluation in MCL patients.


Optical surface profiling of orb-web spider capture silks.
Much spider silk research to date has focused on its mechanical properties. However, the webs of many orb-web spiders have evolved for over 136 million years to evade visual detection by insect prey. It is therefore a photonic device in addition to being a mechanical device. Herein we use optical surface profiling of capture silks from the webs of adult female St Andrews cross spiders (Argiope keyserlingi) to successfully measure the geometry of adhesive silk droplets and to show a bowing in the aqueous layer on the spider capture silk between adhesive droplets. Optical surface profiling shows geometric features of the capture silk that have not been previously measured and contributes to understanding the links between the physical form and biological function. The research also demonstrates non-standard use of an optical surface profiler to measure the maximum width of a transparent micro-sized droplet (microlens).


Parasitological and molecular diagnosis of cutaneous leishmaniasis among indigenous peoples in the state of Roraima, Brazil.
We diagnose cases of cutaneous leishmaniasis (CL) among indigenous peoples of the state of Roraima, Brazil, and discuss some aspects of its epidemiology. Skin imprints, and lesion exudate samples collected on filter paper were examined using parasitological and molecular techniques, respectively. Of 30 indigenous individuals, representing several ethnic groups, with suspected cases of CL, 27 (90%) tested positive for Leishmania spp. by PCR, and 21 (70%) by parasitological microscopy. Cutaneous leishmaniasis is indistinctly present among indigenous peoples from different regions of the state of Roraima. Individuals from seven of the ten existing ethnic groups in the state tested positive for CL, demonstrating the need for further investigation of the disease among these ethnic groups.


Inhibition of calmodulin dependent c-AMP-phosphodiesterase by moxaverine and papaverine.
Vasodilator properties of papaverine and moxaverine have been attributed to an inhibition of cyclic adenosine monophosphate (c-AMP) phosphodiesterase (PDE). The discovery of the calmodulin (CaM) dependence of c-AMP PDE activity necessitates a reinvestigation of the molecular mode of action of papaverine-like compounds. Separately analyzing the inhibition of basal and CaM-stimulated enzyme activity by these drugs proves the preferred inhibition of the CaM stimulated c-AMP PDE. Lipophilicity is assumed to represent an indicator of CaM-inhibitory potency.


Nej1 recruits the Srs2 helicase to DNA double-strand breaks and supports repair by a single-strand annealing-like mechanism.
Double-strand breaks (DSBs) represent the most severe DNA lesion a cell can suffer, as they pose the risk of inducing loss of genomic integrity and promote oncogenesis in mammals. Two pathways repair DSBs, nonhomologous end joining (NHEJ) and homologous recombination (HR). With respect to mechanism and genetic requirements, characterization of these pathways has revealed a large degree of functional separation between the two. Nej1 is a cell-type specific regulator essential to NHEJ in Saccharomyces cerevisiae. Srs2 is a DNA helicase with multiple roles in HR. In this study, we show that Nej1 physically interacts with Srs2. Furthermore, mutational analysis of Nej1 suggests that the interaction was strengthened by Dun1-dependent phosphorylation of Nej1 serines 297/298. Srs2 was previously shown to be recruited to replication forks, where it promotes translesion DNA synthesis. We demonstrate that Srs2 was also efficiently recruited to DSBs generated by the HO endonuclease. Additionally, efficient Srs2 recruitment to this DSB was dependent on Nej1, but independent of mechanisms facilitating Srs2 recruitment to replication forks. Functionally, both Nej1 and Srs2 were required for efficient repair of DSBs with 15-bp overhangs, a repair event reminiscent of a specific type of HR called single-strand annealing (SSA). Moreover, absence of Rad51 suppressed the SSA-defect in srs2 and nej1 strains. We suggest a model in which Nej1 recruits Srs2 to DSBs to promote NHEJ/SSA-like repair by dismantling inappropriately formed Rad51 nucleoprotein filaments. This unexpected link between NHEJ and HR components may represent cross-talk between DSB repair pathways to ensure efficient repair.


An update on brain death criteria: a simple algorithm with complex questions.
Brain death criteria have been based on 3 cardinal features throughout history: coma, brainstem areflexia, and apnea, and thus have undergone little change. In 1995, the American Academy of Neurology (AAN) detailed these criteria in a step-by-step fashion that included meeting prerequisites, performing the clinical examination, performing ancillary testing, and documentation. Fifteen years later, many questions still remain regarding the diagnosis of brain death. The Quality Standards Subcommittee of the AAN sought to answer 5 of these outstanding questions. Ultimately, their data supported the utility of the 1995 criteria and warned against the use of new technologies before proper validation. This review briefly tells the story of brain death criteria, making mention of the steps outlined by the AAN in 1995 and discussing the recent evidence released by the Quality Standards Subcommittee in the new 2010 Practice Parameter Update.


Abnormal Overcharging during Lithium-Ether Co-Intercalation in a Graphite System: Formation of Shuttling Species by the Reduction of the TFSI Anion.
Materializing an ultrafast charging system is one of the crucial technologies for next-generation Li-ion batteries (LIBs). Among many studies aimed at achieving fast charging systems, Li-ether solvent cointercalation into the graphite electrodes in LIB has been identified as a novel concept for achieving high power performance because this system does not consist of the sluggish desolvation step and a resistive solid-electrolyte interface (SEI) layer. Interestingly, while studying the Li-ether solvent cointercalation into graphite electrodes, employing lithium bis-trifluoromethane sulfonimide (LiTFSI) as the Li salt, we observed an abnormal overcharging phenomenon. Here, we screened the specific conditions, under which the abnormal overcharging occurred, and revealed that this abnormal overcharging was attributable to the shuttling mechanism. The formation of shuttling species could have been derived by the reduction of TFSI- anion. With this understanding of the underlying mechanism, we efficiently suppressed the abnormal overcharging by adding LiNO3 to the electrolyte. The shuttling and resulting overcharging could be prevented by the synergistic contributions of LiNO3 and SxOy, dissolved in the electrolyte, to the formation of a dense solid LiSxOy SEI layer on Li-metal. We expect that this work could be a great reference in analyzing many unsolved phenomena in systems utilizing TFSI-.


A case of tacrolimus-induced supraventricular arrhythmia after kidney transplantation.
CONTEXT Tacrolimus is a potent immunosuppressive drug often administered to transplant recipient patients and exhibits a variety of adverse cardiovascular effects. CASE REPORT We report a case of a 53-year-old Asian female who developed various arrhythmic phenomena including atrial premature complexes and supraventricular tachycardia after administration of tacrolimus. CONCLUSION Tacrolimus-associated arrhythmia after kidney transplantation may be life-threatening, and so patients undergoing this procedure should be carefully monitored.


Galactose-modified streptavidin-GC4 antifibrin monoclonal antibody conjugates: application for two-step thrombus/embolus imaging.
Diagnostic and therapeutic procedures utilizing the high affinity streptavidin (SA)/biotin system are being investigated for in vivo use. We are developing a rapid two-step imaging technique for the diagnosis of deep venous thrombosis and pulmonary embolism. The optimal SA-bound targeting moiety would circulate adequately for sufficient lesion accumulation, but nonbound reagent would clear in a reasonably short time before the injection of radiolabeled biotin. The objective of this study was to cross-link SA and galactose-modified SA to GC4 antifibrin monoclonal antibody and to study the pharmacokinetics and biodistribution of the radiolabeled GC4-SA conjugates after injection into rabbits. A cross-linking method was developed for the synthesis of the GC4-SA conjugates via the addition reaction of sulfhydryl containing SA derivatives with maleimide-GC4. In vivo, radiolabeled trigalactose modified SA-GC4 exhibited a much faster blood clearance compared to mono-galactose modified GC4-SA or GC4-SA containing no galactose.


Optimization and evaluation of a coarse-grained model of protein motion using x-ray crystal data.
Simple coarse-grained models, such as the Gaussian network model, have been shown to capture some of the features of equilibrium protein dynamics. We extend this model by using atomic contacts to define residue interactions and introducing more than one interaction parameter between residues. We use B-factors from 98 ultra-high resolution (<or=1.0 A) x-ray crystal structures to optimize the interaction parameters. The average correlation between Gaussian network-model fluctuation predictions and the B-factors is 0.64 for the data set, consistent with a previous large-scale study. By separating residue interactions into covalent and noncovalent, we achieve an average correlation of 0.74, and addition of ligands and cofactors further improves the correlation to 0.75. However, further separating the noncovalent interactions into nonpolar, polar, and mixed yields no significant improvement. The addition of simple chemical information results in better prediction quality without increasing the size of the coarse-grained model.


Neuro-oncological diagnosis in patients without histological confirmation.
The impossibility to conduct a histological diagnosis could be due to different reasons: (1) patient's refusal to undergo surgery/biopsy. (2) Technical difficulties: despite the advance in surgical procedures, the removal of lesions that are located either in critical or in deep areas represents a considerable risk for patients. (3) Quality/quantity of the sample. In rare cases even when the surgical sample is achieved it could be impossible to reach a histological confirmation, for example due to the small amount of tissue obtained. The lack of histology leads to suboptimal therapy, incorrect prognosis, and misinterpretation of clinical trials and furthermore undermines the possibility to perform most radiation and chemotherapy protocols. In this setting the morphological data obtained with conventional MR imaging may be integrated with the metabolic, structural and perfusional information provided by new MR and metabolic techniques (spectroscopy, SPECT, PET in particular).


Spatial resolution of atrial pace mapping as determined by unipolar atrial pacing at adjacent sites.
The purpose of this study was to examine the spatial resolution of unipolar atrial pace mapping by pacing at adjacent sites within the coronary sinus and the right atrium. Unipolar pacing from each pole of a quadripolar catheter was performed in the coronary sinus (n = 29) and in the right atrium (n = 10). Pacing from the distal electrode was used to simulate the site of origin of an atrial tachycardia. These P waves were compared with the P waves generated by unipolar pacing from each of the three proximal electrodes. The P waves were analyzed for changes in amplitude, duration, and configuration. Pacing within the coronary sinus resulted in significant changes in amplitude and duration at distances of 17 and 21 mm from the distal pole, respectively. Similarly, pacing in the right atrium resulted in significant changes in amplitude and duration at distances of 17 and 32 mm from the distal pole, respectively. No significant changes in configuration were noted in the coronary sinus in any lead at packing sites < or = 32 mm from the distal pole. Configurational changes were noted in the right atrium at pacing sites 17 mm from the distal pole. The spatial resolution of unipolar atrial pace mapping is approximately 17 mm. These findings indicate that mapping techniques that depend on the accurate discrimination of P-wave morphology, such as pace mapping or concealed entertainment, are likely to be imprecise when used in the atria.


A case of hepatic intraductal papillary neoplasm of the bile duct.
In this report, we present a 57-year-old female with a history of mild alcoholic liver disease during a medical check-up. Abdominal computed tomography and magnetic resonance imaging showed a multicystic mass with a solid enhancing mural nodule in the right lobe of the liver. Subsequently, laparoscopic right liver lobectomy was performed and pathological findings revealed intraductal papillary neoplasm of the bile duct (IPNB) with an associated invasive carcinoma. IPNB is a relatively rare disease that should be considered in the differential diagnosis of hepatic cystic tumours. Our case report highlights the importance of capturing image findings of the IPNB as this disease has a high potential for malignancy.


Dictyostelium discoideum has a single diacylglycerol kinase gene with similarity to mammalian theta isoforms.
Diacylglycerol kinases (DGKs) phosphorylate the neutral lipid diacylglycerol (DG) to produce phosphatidic acid (PA). In mammalian systems DGKs are a complex family of at least nine isoforms that are thought to participate in down-regulation of DG-based signalling pathways and perhaps activation of PA-stimulated signalling events. We report here that the simple protozoan amoeba Dictyostelium discoideum appears to contain a single gene encoding a DGK enzyme. This gene, dgkA, encodes a deduced protein that contains three C1-type cysteine-rich repeats, a DGK catalytic domain most closely related to the theta subtype of mammalian DGKs and a C-terminal segment containing a proline/glutamine-rich region and a large aspargine-repeat region. This gene corresponds to a previously reported myosin II heavy chain kinase designated myosin heavy chain-protein kinase C (MHC-PKC), but our analysis clearly demonstrates that this protein does not, as suggested by earlier data, contain a protein kinase catalytic domain. A FLAG-tagged version of DgkA expressed in Dictyostelium displayed robust DGK activity. Earlier studies indicating that disruption of this locus alters myosin II assembly levels in Dictyostelium raise the intriguing possibility that DG and/or PA metabolism may play a role in controlling myosin II assembly in this system.


Selective laser trabeculoplasty versus argon laser trabeculoplasty in patients with uncontrolled open-angle glaucoma.
To compare the efficacy of selective laser trabeculoplasty (SLT) to argon laser trabeculoplasty (ALT) as treatment and retreatment to lower intraocular pressure (IOP) in patients with uncontrolled open-angle glaucoma (OAG) on maximally tolerated medication therapy with a follow-up of 12 months. A total of 120 eyes of 120 patients with uncontrolled OAG were enrolled in the study. Group A included patients with IOP >22 mmHg on maximal medical therapy. A total of 43 eyes underwent SLT treatment and 41 eyes underwent ALT treatment. At the end of the follow-up IOP was <18 mmHg. Group B included patients with IOP >20 mmHg at 3 months follow-up after SLT or ALT treatment. These patients were retreated randomly, 18 with SLT and 18 with ALT. In Group A at the end of the follow-up there was no statistically significant difference in IOP lowering between SLT (6.01 mmHg) and ALT (6.12) (p=0.794). In Group B at the end of the follow-up patients undergoing SLT presented IOP lowering statistically significant to ALT treatment (6.24 mmHg and 4.65 mmHg, respectively, p<0.01). SLT is effective as treatment for patients with OAG and appears to be equivalent to ALT in IOP lowering at 12 months only in patients without a prior treatment. In case of retreatment SLT appears to be better than ALT in IOP lowering.


UVA-induced ultrastructural changes in hairless mouse skin: a comparison to UVB-induced damage.
In this ultrastructural study, albino hairless mice were irradiated with long-wavelength ultraviolet (UVA) (340-400 nm) thrice weekly for 32 weeks for a cumulative dose of 8000 J/cm2. Biopsies were taken from these mice, from age-matched unirradiated controls, and from mice irradiated with UVB for 20-30 weeks with a cumulative dose of approximately 6-9 J/cm2. The most striking UVA-induced changes were 1) elastic fiber hyperplasia without evidence of fiber disintegration, 2) a large increase in randomly deposited microfibrils; 3) massive duplication of vascular basement membrane; 4) extensive endothelial cell damage; and 5) collagen fibers with smaller diameters but without apparent damage. By contrast, after UVB, the hyperplastic elastic fibers frequently appeared to be degraded. Microfibrils were only moderately increased and remained in an organized array. Also, unlike with UVA, the epidermal basement membrane was duplicated whereas that of the vessels was mainly spared. Collagen fibers showed evidence of dissolution. Thus, ultrastructural features provide further evidence that skin damage induced by UVA can be dissimilar to that induced by UVB.


The effect of a maxillary lip bumper on tooth positions.
The effect of the use of a lip bumper with anterior vestibular shields on the maxilla was studied in twenty-two 9-14-year-old children with a space deficiency in the maxillary dental arch. The lip bumper was used for 1 year. The effect of the treatment was evaluated from dental casts and profile cephalograms made before and after treatment. Both the width of the maxillary dental arch at the premolars and the length of the arch increased significantly by about 2 mm. The effect of the treatment on the antero-posterior position of the first molars was small. In one subject the molar was distalized 2.8 mm. The average effect was, however, a reduction in the anterior movement of the molar within the face by about 0.5 mm, i.e. the maxilla moved anteriorly 1 mm, but the molar only 0.4 mm. No skeletal effects were found when the group of subjects treated with a lip bumper was compared with a reference sample of untreated individuals. The main effects of a maxillary lip bumper thus seem to be a widening of the dental arch across the premolars, a moderate increase in arch length due to eruption and slight proclination of the incisors, and moderate distal tipping of the first molars.


Agreement among judges of personality: interpersonal relations, similarity, and acquaintanceship.
Personality judgments of 184 targets were provided by the self, college acquaintances, hometown acquaintances, parents, and strangers. Study 1 found that knowing the target in the same context enhanced but was not necessary for interjudge agreement and that acquaintances who had never met agreed with each other as well as those who had met. Study 2 found that personality judgements by acquaintances manifested much better interjudge and self-other agreement than did judgments by strangers. Acquaintances were not more similar to their targets than were strangers, and their accuracy derived more from their distinctive judgment of the target than from assumed similarity. These results rule out overlap, communication, and assumed similarity as necessary bases of interjudge agreement and thereby support the simpler hypothesis that interjudge agreement stems from mutual accuracy.