Unravelling biogeochemical drivers of methylmercury production in an Arctic fen soil and a bog soil.
Arctic tundra soils store a globally significant amount of mercury (Hg), which could be transformed to the neurotoxic methylmercury (MeHg) upon warming and thus poses serious threats to the Arctic ecosystem. However, our knowledge of the biogeochemical drivers of MeHg production is limited in these soils. Using substrate addition (acetate and sulfate) and selective microbial inhibition approaches, we investigated the geochemical drivers and dominant microbial methylators in 60-day microcosm incubations with two tundra soils: a circumneutral fen soil and an acidic bog soil, collected near Nome, Alaska, United States. Results showed that increasing acetate concentration had negligible influences on MeHg production in both soils. However, inhibition of sulfate-reducing bacteria (SRB) completely stalled MeHg production in the fen soil in the first 15 days, whereas addition of sulfate in the low-sulfate bog soil increased MeHg production by 5-fold, suggesting prominent roles of SRB in Hg(II) methylation. Without the addition of sulfate in the bog soil or when sulfate was depleted in the fen soil (after 15 days), both SRB and methanogens contributed to MeHg production. Analysis of microbial community composition confirmed the presence of several phyla known to harbor microorganisms associated with Hg(II) methylation in the soils. The observations suggest that SRB and methanogens were mainly responsible for Hg(II) methylation in these tundra soils, although their relative contributions depended on the availability of sulfate and possibly syntrophic metabolisms between SRB and methanogens.


Dendrite extension by methanol extract of Ashwagandha (roots of Withania somnifera) in SK-N-SH cells.
Extension of dendrites and axons in neurons may compensate for and repair damaged neuronal circuits in the dementia brain. Our aim in the present study was to explore drugs activating neurite outgrowth and regenerating the neuronal network. We found that the methanol extract of Ashwagandha (roots of Withania somnifera; 5 microg/ml) significantly increased the percentage of cells with neurites in human neuroblastoma SK-N-SH cells. The effect of the extract was dose- and time-dependent mRNA levels of the dendritic markers MAP2 and PSD-95 by RT-PCR were found to be markedly increased by treatment with the extract, whereas those of the axonal marker Tau were not. Immunocytochemistry demonstrated the specific expression of MAP2 in neurites extended by the extract. These results suggest that the methanol extract of Ashwagandha promotes the formation of dendrites.


[An improved method for selective determination of serum albumin by the bromcresol green method, using the SMAR 12/60 (author's transl)].
The estimation of serum albumin obtained with SMAR 12/60 by the bromcresol green method are in good agreement with values determined by electrophoresis only in the normal range. Interestingly marked discrepancies occur in the clinically relevant cases of hypalbuminosis. The shortening of the reaction time between bromcresol green and serum results in a better agreement between the values obtained with SMAR 12/60 and the values determined by electrophoresis over the whole range.


Improving the delivery of global tobacco control.
Tobacco control must remain a critical global health priority given the growing burden of tobacco-induced disease in the developing world. Insights from the emerging field of global health delivery suggest that tobacco control could be improved through a systematic, granular analysis of the processes through which it is promoted, implemented, and combated. Using this framework, a critical bottleneck to the delivery of proven health promotion emerges in the role that the tobacco industry plays in promoting tobacco use and blocking effective tobacco-control policies. This "corporate bottleneck" can also be understood as a root cause of massive disease and suffering upon vulnerable populations worldwide, for the goal of maximizing corporate profit. Naming, understanding, and responding to this corporate bottleneck is crucial to the success of tobacco-control policies. Three case studies of tobacco-control policy--South Africa, the Framework Convention on Tobacco Control, and Uruguay--are presented to explore and understand the implications of this analysis.


Unusual dengue virus 3 epidemic in Nicaragua, 2009.
The four dengue virus serotypes (DENV1-4) cause the most prevalent mosquito-borne viral disease affecting humans worldwide. In 2009, Nicaragua experienced the largest dengue epidemic in over a decade, marked by unusual clinical presentation, as observed in two prospective studies of pediatric dengue in Managua. From August 2009-January 2010, 212 dengue cases were confirmed among 396 study participants at the National Pediatric Reference Hospital. In our parallel community-based cohort study, 170 dengue cases were recorded in 2009-10, compared to 13-65 cases in 2004-9. In both studies, significantly more patients experienced "compensated shock" (poor capillary refill plus cold extremities, tachycardia, tachypnea, and/or weak pulse) in 2009-10 than in previous years (42.5% [90/212] vs. 24.7% [82/332] in the hospital study (p<0.001) and 17% [29/170] vs. 2.2% [4/181] in the cohort study (p<0.001). Signs of poor peripheral perfusion presented significantly earlier (1-2 days) in 2009-10 than in previous years according to Kaplan-Meier survival analysis. In the hospital study, 19.8% of subjects were transferred to intensive care, compared to 7.1% in previous years - similar to the cohort study. DENV-3 predominated in 2008-9, 2009-10, and 2010-11, and full-length sequencing revealed no major genetic changes from 2008-9 to 2010-11. In 2008-9 and 2010-11, typical dengue was observed; only in 2009-10 was unusual presentation noted. Multivariate analysis revealed only "2009-10" as a significant risk factor for Dengue Fever with Compensated Shock. Interestingly, circulation of pandemic influenza A-H1N1 2009 in Managua was shifted such that it overlapped with the dengue epidemic. We hypothesize that prior influenza A H1N1 2009 infection may have modulated subsequent DENV infection, and initial results of an ongoing study suggest increased risk of shock among children with anti-H1N1-2009 antibodies. This study demonstrates that parameters other than serotype, viral genomic sequence, immune status, and sequence of serotypes can play a role in modulating dengue disease outcome.


Implications of headwater contact zones for the riverine barrier hypothesis: a case study of the Blue-capped Manakin (Lepidothrix coronata).
Rivers frequently delimit the geographic ranges of species in the Amazon Basin. These rivers also define the boundaries between genetic clusters within many species, yet river boundaries have been documented to break down in headwater regions where rivers are narrower. To explore the evolutionary implications of headwater contact zones in Amazonia, we examined genetic variation in the Blue-capped Manakin (Lepidothrix coronata), a species previously shown to contain several genetically and phenotypically distinct populations across the western Amazon Basin. We collected restriction site-associated DNA sequence data (RADcap) for 706 individuals and found that spatial patterns of genetic structure indicate rivers, particularly the Amazon and Ucayali, are major dispersal barriers for L. coronata along a distance of more than 3000 km. We also found evidence that genetic connectivity is elevated across several headwater regions, highlighting the importance of headwater gene flow for models of Amazonian diversification. The headwater region of the Ucayali River provided a notable exception to findings of headwater gene flow by harboring non-admixed populations of L. coronata on opposite sides of a <1-km-wide river channel with a known dynamic history, suggesting that additional prezygotic barriers may be limiting gene flow in this region.


Coping with sensory changes after stroke: a qualitative study.
Coping strategies were found to predict success in rehabilitation. Research is lacking in identifying the specific coping strategies used to adjust to sensory changes after stroke. This study utilized a qualitative descriptive method to understand how individuals handle sensory changes after stroke. Researchers developed open-ended questions with probes to facilitate semi-structured interviews. Thirteen stroke survivors younger than 75 years old who were 1-5 years past their stroke were recruited. Researchers used an inductive content analysis approach to analyze the data gathered from the interviews. Two themes were identified; Coping strategies and the Amount of therapy received targeting sensory changes. Results from this study can inform occupational therapists about what strategies stroke survivors use to cope with sensory changes so that similar strategies can be implemented in therapy. Rehabilitation in the early stages of recovery can help stroke survivors identify adaptive strategies to cope with sensory changes.


Audiological practice in India: an internet-based survey of audiologists.
The field of Audiology in India has expanded exponentially in recent years. Audiologists practice in a variety of work places. However, little is known about the practice trends across these several work places. An Internet-based survey probing into Audiology practice was conducted between June and September 2012. The survey focused on four domains, namely, demography, assessment, hearing aid (HA) fitting and protocol usage. A total of 199 audiologists completed the survey. A large proportion of these audiologists were from Southern India. Majority of the respondents provide hearing assessment and HA services for children and adults. Results indicate diverse practice among respondents, even in essential procedures such as otoscopy. Although a large proportion of audiologists reported performing HA fitting in children as well as adults, less than 12 % of them performed real ear or simulated real ear verification during any HA fitting. Implications for the development of preferred practice guidelines in India have been discussed.


Evaluation and improvements of clustering algorithms for detecting remote homologous protein families.
An important problem in computational biology is the automatic detection of protein families (groups of homologous sequences). Clustering sequences into families is at the heart of most comparative studies dealing with protein evolution, structure, and function. Many methods have been developed for this task, and they perform reasonably well (over 0.88 of F-measure) when grouping proteins with high sequence identity. However, for highly diverged proteins the performance of these methods can be much lower, mainly because a common evolutionary origin is not deduced directly from sequence similarity. To the best of our knowledge, a systematic evaluation of clustering methods over distant homologous proteins is still lacking. We performed a comparative assessment of four clustering algorithms: Markov Clustering (MCL), Transitive Clustering (TransClust), Spectral Clustering of Protein Sequences (SCPS), and High-Fidelity clustering of protein sequences (HiFix), considering several datasets with different levels of sequence similarity. Two types of similarity measures, required by the clustering sequence methods, were used to evaluate the performance of the algorithms: the standard measure obtained from sequence-sequence comparisons, and a novel measure based on profile-profile comparisons, used here for the first time. The results reveal low clustering performance for the highly divergent datasets when the standard measure was used. However, the novel measure based on profile-profile comparisons substantially improved the performance of the four methods, especially when very low sequence identity datasets were evaluated. We also performed a parameter optimization step to determine the best configuration for each clustering method. We found that TransClust clearly outperformed the other methods for most datasets. This work also provides guidelines for the practical application of clustering sequence methods aimed at detecting accurately groups of related protein sequences.


Body size, age and paternity in common brushtail possums (Trichosurus vulpecula).
Sexual selection should produce sexual size dimorphism in species where larger members of one sex obtain disproportionately more matings. Recent theory suggests that the degree of sexual size dimorphism depends on physical and temporal constraints involving the operational sex ratio, the potential reproductive rate and the trade-off between current reproductive effort and residual reproductive value. As part of a large-scale experiment on dispersal, we investigated the mating system of common brushtail possums inhabiting old-growth Eucalyptus forest in Australia. Paternity was assigned to 20 of 28 pouch-young (maternity known) genotyped at six microsatellite loci. Male mating success was strongly related to body size and age; male body weight and age being highly correlated. Despite disproportionate mating success favouring larger males, sexual size dimorphism was only apparent among older animals. Trapping and telemetry indicated that the operational sex ratio was effectively 1 : 1 and the potential reproductive rate of males was at most four times that of females. Being larger appeared to entail significant survival costs because males 'died-off' at the age at which sexual size dimorphism became apparent (8-9 years). Male and female home ranges were the same size and males appeared to be as sedentary as females. Moreover, longevity appears to be only slightly less important to male reproductive success than it is to females. It is suggested that a sedentary lifestyle and longevity are the key elements constraining selection for greater sexual size dimorphism in this 'model' medium-sized Australian marsupial herbivore.


[Expression and prognostic value of Polo-like kinase 1, E-cadherin in the patients with hepatocellular carcinoma].
To study the expression of Polo-like kinase 1 (PLK1) and E-cadherin in the tissues of hepatocellular carcinoma, and to discuss the relationship between them and clinical-pathological features, and to evaluate their prognostic value of hepatocellular carcinoma after liver transplantation. mRNA and protein expression of PLK1, E-cadherin were detected by RT-PCR and immunohistochemistry method respectively, the correlations of them with clinical-pathological data, tumor free time, recurrence rate were compared and analyzed. The mRNA expression was observed in 90.0% for PLK1 and 96.0% for E-cadherin, and higher in cancerous' tissues than paracancerous' of all cases for PLK1 but no trend for E-cadherin. The positive and decreased expression rate for PLK1 and E-cadherin was observed in 60.0% and 50.0% respectively, the positive PLK1 expression was correlated with preoperative serum alpha-fetoprotein (AFP) only (chi2 = 4.433, P = 0.035), while E-cadherin expression was associated with none of the clinical-pathological features. There was a correlation between the positive PLK1 and decreased E-cadherin expression (chi2 = 5.333, P = 0.021). PLK1 (P = 0.006), E-cadherin (P = 0.019) and larger tumor (P = 0.019), portal vein tumor thrombi (P = 0.030), Edmondson grading (P = 0.019), preoperative serum AFP (P = 0.020) were all correlated with recurrence rate under Kaplan-Meier analysis, while only PLK1 (RR = 3.104, P = 0.009) had significant difference under Cox regression analysis. The positive PLK1 expression and the decreased E-cadherin expression indicate higher recurrence rate of HCC after liver transplantation, and PLK1 is a independent risk factor.


Single cell confocal Raman spectroscopy of human osteoarthritic chondrocytes: a preliminary study.
A great deal of effort has been focused on exploring the underlying molecular mechanism of osteoarthritis (OA) especially at the cellular level. We report a confocal Raman spectroscopic investigation on human osteoarthritic chondrocytes. The objective of this investigation is to identify molecular features and the stage of OA based on the spectral signatures corresponding to bio-molecular changes at the cellular level in chondrocytes. In this study, we isolated chondrocytes from human osteoarthritic cartilage and acquired Raman spectra from single cells. Major spectral differences between the cells obtained from different International Cartilage Repair Society (ICRS) grades of osteoarthritic cartilage were identified. During progression of OA, a decrease in protein content and an increase in cell death were observed from the vibrational spectra. Principal component analysis and subsequent cross-validation was able to associate osteoarthritic chondrocytes to ICRS Grade I, II and III with specificity 100.0%, 98.1%, and 90.7% respectively, while, sensitivity was 98.6%, 82.8%, and 97.5% respectively. The overall predictive efficiency was 92.2%. Our pilot study encourages further use of Raman spectroscopy as a noninvasive and label free technique for revealing molecular features associated with osteoarthritic chondrocytes.


An unusual case of tumor thrombus in the inferior vena cava. A case report.
Adrenal cortical carcinoma (ACC) is a rare malignancy. Patients present either with a functional tumor or secondary to mass effect. In non-functioning tumors, the tumor size often exceeds 5 cm by the time of diagnosis, and tumor thrombus can occur. We report on a case of a small non-functioning ACC causing a large tumor thrombus in the inferior vena cava.


Variations of olfactory function with circadian timing and chronotype.
Cumulative animal studies have suggested that olfaction can be regulated by circadian clock. However, human studies on the topic are relatively limited. The present study thus aimed to investigate diurnal variation in olfaction in healthy adults while examining potential modulating factors. We conducted four rounds of testing on 56 healthy adults (32 women) aged 31 ± 12 years, throughout a single day, during morning (8:00-10:00 h), noon (12:00-14:00 h), afternoon (16:00-18:00 h), and evening (20:00-22:00 h). At the first appointment, participants completed full olfactory function testing using the Sniffin' Sticks, questionnaires on medical history, nasal symptoms, sleep quality, and chronotype, and were assessed for blood pressure, heart rate, peak nasal inspiratory flow (PNIF), attention level, and rated their smell ability, nasal patency, wakefulness, and concentration level using visual analog scale (VAS) ratings. Subsequent appointments measured olfactory threshold, attentional level, PNIF, blood pressure, heart rate and VAS ratings repeatedly. Olfactory threshold (OT) scores varied significantly between different times of the day, with the highest score in the evening and the lowest in the morning. Similar differences were also observed in PNIF, with the highest value in the evening and the lowest in the morning. However, there were no significant correlations between OT score and PNIF across all four-time testing, as well as between differences in [OT evening â€" OT morning] and [PNIF evening â€" PNIF morning]. Furthermore, a generalized linear mixed model indicated that the testing time of the morning, evening chronotype, self-reported body mass index (BMI), rated smell ability, and rated nasal patency significantly predicted the Sniffin' Sticks OT score. Olfactory function fluctuates throughout the waking hours of the day, with the highest olfactory sensitivity observed in the evening and the lowest in the morning. This pattern is also seen in nasal patency. However, it appears that the circadian changes of nasal airflow may not significantly depend on the circadian changes of the olfactory sensitivity. In addition, chronotype and BMI may regulate such olfactory-circadian variation. These findings provide important insights for future research on the accurate diagnosis and treatment of olfactory dysfunction.


Sorption of tebuconazole onto selected soil minerals and humic acids.
The aim of the present study was to investigate tebuconazole sorption on common soil minerals (birnessite, ferrihydrite, goethite, calcite and illite) and humic acids (representing soil organic matter). Tebuconazole was used (i) in the commercial form Horizon 250 EW and (ii) as an analytical grade pure chemical. In the experiment with the commercially available tebuconazole, a significant pH-dependent sorption onto the oxides was observed (decreasing sorption with increasing pH). The highest sorption was found for ferrihydrite due to its high specific surface area, followed by humic acids, birnessite, goethite and illite. No detectable sorption was found for calcite. The sorption of analytical grade tebuconazole on all selected minerals was significantly lower compared to the commercial product. The sorption was the highest for humic acids, followed by ferrihydrite and illite and almost negligible for goethite and birnessite without any pH dependence. Again, no sorption was observed for calcite. The differences in sorption of the commercially available and analytical grade tebuconazole can be attributed to the additives (e.g., solvents) present in the commercial product. This work proved the importance of soil mineralogy and composition of the commercially available pesticides on the behavior of tebuconazole in soils.


Co-created in vivo pharmacology practical classes using the novel organism Lumbriculus variegatus.
Co-creation within higher education emphasizes learner empowerment to promote collaboration between the students and staff, enabling students to become active participants in their learning process and the construction of resources with academic staff. Concurrently, a diminishing number of higher education institutions offer in vivo practical classes, resulting in an in vivo skills shortage. To address this, and to actively engage students in their own learning, we describe the co-creation of a student-led drug trial using Lumbriculus variegatus. Under blinded conditions, final-year undergraduate biomedical science students, under the tutelage of academic staff and fellow students, were involved in the co-creation of an in vivo practical class to determine the effects of histamine and histamine receptor inverse agonists mepyramine and loratadine. Throughout this process, undergraduate- and masters-level students played key roles in every aspect of practical delivery and data analysis. Herein, students demonstrated the test compounds, both in isolation and in combination, resulted in reduced stereotypical movements of L. variegatus (p < .05, n ≥ 6). 15% of students in the class responded to a feedback survey (n = 8) after the class. Students reported the class provided "real life" insights into in vivo research and enabled the development of hands-on skills which would be useful in applying in their future careers. All students reported that they enjoyed the class with 25% (n = 2) reporting concerns about animal use in research, enabling useful discussions about animals in research. Moreover, these student-led in vivo trials add to the pharmacological knowledge of L. variegatus promoting education-led research.


Lipopolysaccharide and the glycoside ring of staurosporine induce CD14 expression on bone marrow granulocytes by different mechanisms.
We established previously that lipopolysaccharide (LPS) can induce the expression of LPS-binding sites on bone marrow cells (BMC). We now report that staurosporine (STP), a glycosylated indolocarbazole alkaloid with potent inhibitory activity for various protein kinases, can induce the same effect. With both agents, the newly expressed LPS receptor was found to be CD14. The STP-induced effect was independent of its protein kinase inhibitory activity because several other protein kinase inhibitors, such as the indolocarbazole K-252a, the bisindolylmaleimide RO-31-8220, the perylenequinone calphostin C, and the isoquinolinesulfonamide H7, did not induce CD14 expression. The observation that the STP analog K-252a with an identical polyaromatic aglycon moiety was inactive yet the analog UCN-01 with an identical glycoside ring was active suggests that the induction of CD14 expression is triggered by the sugar moiety of STP. Three lines of evidence show that the mechanism of CD14 expression induced by STP differs from that induced by LPS: (i) unlike LPS, STP can stimulate BMC from LPS-unresponsive C3H/HeJ mice, (ii) LPS and STP effects are additive at a saturating dose of LPS, and (iii) the protein kinase inhibitor K-252a inhibits the LPS-induced but not STP-induced stimulation. Therefore, our findings show that both a protein kinase-dependent (LPS-induced) and a protein kinase-independent (STP-induced) mechanism can lead to the expression of the LPS receptor CD14 on BMC. We also found that the STP-induced stimulation of BMC is modulated by cyclosporin A, vinblastine, and verapamil. This observation may suggest that the inducible effect of STP could be initiated by its interaction with P-glycoprotein, a membrane pump with drug efflux function that plays a critical role in the multidrug resistance of cancer cells.


Prevalence of low body mass in rheumatoid arthritis: association with the acute phase response.
To ascertain the prevalence of low body mass in a rheumatoid arthritis (RA) population and to explore a possible relation with the acute phase response. 97 patients who fulfilled the American College of Rheumatology (ACR) criteria for RA were recruited. Change in weight from initial presentation was noted. Body mass index (BMI), upper arm fat and muscle areas were recorded together with fat free mass calculated from the waist measurement. Blood samples were taken for erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and serum albumin. 13% of the RA group fell into the lowest 5th centile for BMI for the general population. The loss of body mass was greater for lean tissue than fat, with over 50% of the RA group falling into the lowest 10th centile of a reference population for the upper arm muscle area. Female patients who lost greater than 15% of their initial weight had higher health assessment questionnaire (HAQ) results than the rest of the group (p = 0.020). In female patients there was a significant correlation between reduced fat free mass and the acute phase response (ESR p = 0.016 and CRP p = 0.003) There is an increased prevalence of low body mass, greatest for lean tissue, in the RA population. In the female group there was an inverse relation between the acute phase response and fat free mass. Female patients with RA who lose a significant amount of weight are more disabled as assessed by HAQ.


DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.
Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over one year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.


Acute myelogenous leukemia following immunosuppressive therapy for rheumatoid arthritis.
A 51-year-old woman had acute myelogenous leukemia following log-term cyclophosphamide therapy for rheumatoid arthritis. After standard methods of management had failed, the rheumatoid arthritis showed considerable improvement in response to approximately 25 mg cyclophosphamide per day over a four-year period. At the end of this period, pancytopenia developed, and cyclophosphamide was discontinued. A bone-marrow aspirate showed nonspecific changes. However, four months later because of severe progressive pancytopenia, another bone-marrow examination was performed; it showed acute myelogenous leukemia. Therapy failed to induce a remission, and two months after diagnosis the patient died of aspergillosis. Autopsy confirmed the presence of leukemic infiltration of bone marrow, lymph nodes, liver and spleen. These findings suggest a possible leukemogenic role of cyclophosphamide in this case and suggest that caution should be exercised in treating non-fatal diseases with antitumor drugs.


[Effect of aldosterone antagonism in heart failure: pharmacotherapeutic options].
Aldosterone escape during chronic angiotensin-converting enzyme (ACE) inhibition may contribute to the high mortality among patients with heart failure. Aldosterone exerts several detrimental effects in the pathophysiology of heart failure. Spironolactone, an aldosterone antagonist, has proved beneficial when added to ACE inhibitors in patients with severe heart failure. However, spironolactone has substantial side effects mostly due to anti-androgen and anti-progestagen actions. This may limit its use in less severe heart failure. Recently, more selective aldosterone antagonists have been developed, which appear to have the same potential as spironolactone with fewer side effects. Trials to assess efficacy of these drugs in hypertension and mild heart failure are now being started.


Comparative analysis of peroxiredoxin activation in the brown macroalgae Scytosiphon gracilis and Lessonia nigrescens (Phaeophyceae) under copper stress.
Among thiol-dependent peroxidases (TDPs) peroxiredoxins (PRXs) standout, since they are enzymes capable of reducing hydrogen peroxide, alkylhydroperoxides and peroxynitrite, and have been detected in a proteomic study of the copper-tolerant species Scytosiphon gracilis. In order to determine the importance of these enzymes in copper-stress tolerance, TDP activity and type II peroxiredoxin (II PRX) protein expression were compared between the opportunistic S. gracilis and the brown kelp Lessonia nigrescens, a species absent from copper-impacted sites due to insufficient copper-tolerance mechanisms. Individuals of both species were cultured with increasing copper concentrations (0-300 µg l(-1) Cu) for 96 h and TDP activity and lipoperoxides (LPXs) were determined together with II PRX expression by immunofluorescence and Western blot analysis. The results showed that TDP activity was higher in S. gracilis than L. nigrescens in all copper concentrations, independent of the reducing agent used (dithiothreitol, thioredoxin or glutaredoxin). This activity was copper inhibited in L. nigrescens at lower copper concentrations (20 µg l(-1) Cu) compared to S. gracilis (100 µg l(-1) Cu). The loss of activity coincided in both species with an increase in LPX, which suggests that TDP may control LPX production. Moreover, II PRX protein levels increased under copper stress only in S. gracilis. These results suggest that in S. gracilis TDP, particularly type II peroxiredoxin (II PRX), acts as an active antioxidant barrier attenuating the LPX levels generated by copper, which is not the case in L. nigrescens. Thus, from an ecological point of view these results help explaining the inability of L. nigrescens to flourish in copper-enriched environments.


Overview of foot and mouth disease in southern Africa.
The prevalence of foot and mouth disease (FMD) in the southern African subcontinent between 1931 and 1990 is summarised, together with the major features of the epidemiology and control of the disease. The author emphasises the role of wildlife, especially African buffalo (Syncerus caffer). A proposal is made for a more structured and co-operative approach to investigating the extent and nature of antigenic variation within the Southern African Territories (SAT) types of FMD virus. Quantification of the economic impact of FMD on the agro-economics of the subcontinent is attempted, and the importance of the social values of rural peoples in this respect is explained.


The carbon neutrality principle: A case study in the French spirits sector.
According to the 2019 Intergovernmental Panel on Climate Change (IPCC) report, putting in place policies that support sustainable development is imperative. The carbon neutrality concept introduced in 2002 is an efficient way to manage the risks and reduce the vulnerabilities in the land and the food system. Given the pivotal role of sustainability for todays' consumers, the low risk and high rewards of carbon neutral production could help businesses transform their entire sector. This article is among the first to show that the carbon neutrality principle offers advantages that far outweigh the costs of maintaining the status quo. The case study of a cognac producer in France suggests that prioritizing sustainable development by reducing emissions could be a beneficial solution, particularly in the high energy spirits industry. Specifically, implementing the three stages (and substages) of the carbon neutral methodology to calculate carbon footprint, this study provides evidence that distilling 1 hL of pure alcohol produces 0.9 tons of CO2 emissions. Proposing actions to reduce emissions by 10%, and calculating the offset costs to evaluate the remaining emissions, the study also offers a practical implementation approach and discusses several potential legislative scenarios that might accelerate the transition to carbon neutral production output.


On-demand synthesis of phosphoramidites.
Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites.


Increased Hip Stresses Resulting From a Cam Deformity and Decreased Femoral Neck-Shaft Angle During Level Walking.
It is still unclear why many individuals with a cam morphology of the hip do not experience pain. It was recently reported that a decreased femoral neck-shaft angle may also be associated with hip symptoms. However, the effects that different femoral neck-shaft angles have on hip stresses in symptomatic and asymptomatic individuals with cam morphology remain unclear. We examined the effects of the cam morphology and femoral neck-shaft angle on hip stresses during walking by asking: (1) Are there differences in hip stress characteristics among symptomatic patients with cam morphology, asymptomatic individuals with cam morphology, and individuals without cam morphology? (2) What are the effects of high and low femoral neck-shaft angles on hip stresses? Six participants were selected, from a larger cohort, and their cam morphology and femoral neck-shaft angle parameters were measured from CT data. Two participants were included in one of three groups: (1) symptomatic with cam morphology; (2) asymptomatic with a cam morphology; and (3) asymptomatic control with no cam morphology with one participant having the highest femoral neck-shaft angle and the other participant having the lowest in each subgroup. Subject-specific finite element models were reconstructed and simulated during the stance phase, near pushoff, to examine maximum shear stresses on the acetabular cartilage and labrum. The symptomatic group with cam morphology indicated high peak stresses (6.3-9.5 MPa) compared with the asymptomatic (5.9-7.0 MPa) and control groups (3.8-4.0 MPa). Differences in femoral neck-shaft angle influenced both symptomatic and asymptomatic groups; participants with the lowest femoral neck-shaft angles had higher peak stresses in their respective subgroups. There were no differences among control models. Our study suggests that the hips of individuals with a cam morphology and varus femoral neck angle may be subjected to higher mechanical stresses than those with a normal femoral neck angle. Individuals with a cam morphology and decreased femoral neck-shaft angle are likely to experience severe hip stresses. Although asymptomatic participants with cam morphology had elevated stresses, a higher femoral neck-shaft angle was associated with lower stresses. Future research should examine larger amplitudes of motion to assess adverse subchondral bone stresses.


Interferon-gamma activation of polymorphonuclear neutrophil function.
As current research illuminates the dynamic interplay between the innate and acquired immune responses, the interaction and communication between these two arms has yet to be fully investigated. Polymorphonuclear neutrophils (PMNs) and interferon-gamma (IFN-gamma) are known critical components of innate and acquired immunity, respectively. However, recent studies have demonstrated that these two components are not entirely isolated. Treatment of PMNs with IFN-gamma elicits a variety of responses depending on stimuli and environmental conditions. These responses include increased oxidative burst, differential gene expression, and induction of antigen presentation. Many of these functions have been overlooked in PMNs, which have long been classified as terminal phagocytic cells incapable of protein synthesis. As this review reports, the old definition of the PMN is in need of an update, as these cells have demonstrated their ability to mediate the transition between the innate and acquired immune responses.


Phthalate exposure through different pathways and allergic sensitization in preschool children with asthma, allergic rhinoconjunctivitis and atopic dermatitis.
Studies in rodents indicate that phthalates can function as adjuvants, increasing the potency of allergens. Meanwhile, epidemiological studies have produced inconsistent findings regarding relationships between phthalate exposures and allergic disease in humans. The present study examined phthalate exposure and allergic sensitization in a large group of 3-5 year old children: 300 random controls and 200 cases with asthma, rhinoconjunctivitis or atopic dermatitis as reported in questionnaires. The children were clinically examined to confirm their health status. Blood samples were analyzed for IgE sensitization to 20 allergens. Adjusted logistic regressions were used to look for associations between phthalate exposure indicators (mass fractions in dust from children's homes and daycares, metabolites in urine, and estimated daily indoor intakes from dust ingestion, inhalation and dermal absorption) and sensitization and allergic disease. No direct associations were found between phthalate exposures and asthma, rhinoconjunctivitis or atopic dermatitis. However, among children with these diseases, there were significant associations between non-dietary exposures to DnBP, BBzP and DEHP in the indoor environment (mass fractions in dust or daily indoor intakes from dust ingestion, inhalation and dermal absorption) and allergic sensitization. Some exposure pathways were more strongly associated with sensitization than others, although the results are not conclusive and require confirmation. A number of the associations depended on accounting for a child's exposure in more than one environment (i.e., daycare facility as well as home). Significant associations were not observed between phthalate metabolites in urine, which reflected exposure from diet as well as indoor pathways, and allergic sensitization.


[Prevalence of Antimicrobial Resistance in Escherichia coli Isolated from Retail Meat in Tokyo, Japan].
This study aimed to survey the trend of antimicrobial resistance in Escherichia coli obtained from retail meat. We examined the susceptibilities of 1,115 E. coli isolates obtained from chicken, beef, pork, venison, and wild boar meat from 2011 to 2017 in Tokyo to 14 antimicrobials (ampicillin, cefotaxime (CTX), streptomycin, gentamicin, kanamycin, tetracycline (TC), chloramphenicol, nalidixic acid, ciprofloxacin, sulfamethoxazole-trimethoprim, fosfomycin, amikacin, imipenem, and meropenem). Of all the tested isolates, 18.7% (135/721) isolates from chicken, 77.0% (117/152) from beef, 46.6% (89/187) from pork, 100% (28/28) from venison, and 92.6% (25/27) from wild boar meat were susceptible to all tested antimicrobials. Furthermore, TC resistance was the most common, with rates as high as 56.7% (409/721) and 40.6% (76/187) in the isolates from chicken and pork, respectively. CTX resistance was detected in 4.9% (25/506) of the isolates from domestic chicken and 23.7% (51/215) of the isolates from imported chicken. Moreover, CTX resistance rate in isolates from domestic chicken was significantly lower in 2016 (0.9%, 1/111) and in 2017 (0.8%, 1/121) than in 2012 (10.6%, 17/161). In conclusion, E. coli isolates from retail meat were most commonly resistant to TC, and CTX resistance was higher in E. coli isolates from imported chicken than in E. coli isolates from domestic chicken.


Stimulation of the gerbil's gustatory receptors by saccharin.
The gustatory responses from the chorda tympani nerve of the Mongolian gerbil, Meriones unguiculatus, were tested with saccharin and some closely related compounds. Only two compounds, saccharin and 6-chlorosaccharin, stimulated the gerbil's taste receptors to any degree and in the same order in which they are sweet to man, saccharin greater than 5-chlorosaccharin. Those compounds which are tasteless to man did not stimulate and include N-methyl saccharin, phthalimide, and O-sulfobenzoic acid. These nonstimulating derivatives did not inhibit the saccharin electrophysiological response. The saccharin taste response pH optimum is from 5 to 8. At pH 7 and 8, saccharin is fully ionized and is binding to the receptor site by an anionic mechanism. Kinetic plots of the taste response at pH 7 indicate that saccharin is forming 1:1 complexes with it. In addition, mixtures of saccharin and sucrose stimulate in such a manner as to suggest that they are interacting at different receptor sites.


Cell size control - a mechanism for maintaining fitness and function.
The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on 'what regulates cell size', the question 'why cell size needs to be maintained' has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative cell surface area impose biophysical limitations on cells, which can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity.


Bolus oral or continuous intestinal amino acids reduce hypothermia during anesthesia in rats.
We hypothesized that, with oral or intestinal administration of amino acids (AA), we may reduce hypothermia during general anesthesia as effectively as with intravenous AA. We, therefore, examined the effect of bolus oral and continuous intestinal AA in preventing hypothermia in rats. Male Wistar rats were anesthetized with sevoflurane for induction and with propofol for maintenance. In the first experiment, 30 min before anesthesia, rats received one bolus 42 mL/kg of AA solution (100 g/L) or saline orally. Then for the next 3 h during anesthesia, they received 14 mL/kg/h of AA and/or saline intravenously. They were in 4 groups: I-A/A, both AA; I-A/S, oral AA and intravenous saline; I-S/A, oral saline and intravenous AA; I-S/S, both saline. In the second experiment, rats received 14 mL/kg/h duodenal AA and/or saline for 2 h. They were in 3 groups: II-A/S, duodenal AA and intravenous saline; II-S/A, duodenal saline and intravenous AA; II-S/S, both saline. Core body temperature was measured rectally. After the second experiment, serum electrolytes were examined. In both experiments, rectal temperature decreased in all groups during anesthesia. However, the decrease in rectal temperature was significantly less in groups receiving AA than in groups receiving only saline. In the second experiment, although there was no significant difference in the decrease in body temperature between II-A/S and II-S/A, Na(+) concentration was significantly lower in II-S/A. In conclusion, AA, administered orally or intestinally, tended to keep the body temperature stable during anesthesia without disturbing electrolyte balance. These results suggest that oral or enteral AA may be useful for prevention of hypothermia in patients.


[Problems in the use of personal computers in the military polyclinic].
Problems, connecting with use of the personal computer in military polyclinic and arising at creation of automated working places of medical purpose are analyzed. A role and place of unified medical qualifiers, directories and dictionaries, formalized descriptions is opened. A combined way is supposed, at which through directory the static diagnosis (main and accompanying) is chosen, but the doctor supplements record by the individual characteristics of particular patients. These records fill up the appropriate directories in order of the formalized conclusions. Here in after they can be caused on screen, having reduced sharply hand-operated input. Besides, these data are means of training for doctors with small experience, because information maintenance have been created during development by the experienced experts.


Caring for a child with cystic fibrosis: the children's nurse's role.
This article presents a narrative literature review of the psychosocial impact on family life of caring for a child diagnosed with cystic fibrosis. Diagnosis of long-term illness in a child causes major upheaval in the lives of both the child and family. Normal family life is often emotionally, socially, physically and financially disrupted. Amid such disruption, parents attempt to cope by creating a semblance of order in their lifestyle. Within an interdisciplinary approach to caring, the children's nurse plays a pivotal role in supporting families to establish such order and reconstruct their lives, while coming to terms with the knowledge that their child could die prematurely. In addition, the nurse, in his/her role as teacher and educator, empowers parents, children and young people with the knowledge to make informed decisions and assists parents in developing the skills (often technical) to care for their child. Cystic fibrosis is one such condition in childhood, and this article explores the main psychosocial issues experienced by families caring for their child following diagnosis of CF, as raised in the literature.


Patient-controlled analgesia infusion pumps for adults.
Patient-controlled analgesia (PCA) via an infusion pump enables patients experiencing pain as a result of surgery, trauma or acute exacerbation of chronic conditions, to administer their own analgesia. Opioids are commonly used in the pumps because of their effectiveness and availability. This article, one of series on pain, describes the main features of opioid PCA, highlighting potential risks associated with this method of drug administration and common side effects of opioids. The article emphasises the importance of educating patients in PCA use to maintain safety. It is suggested that nurses must provide the same level of care to patients using PCA as patients receiving analgesia by other means.


[Family caregiver help and self-help in Alzheimer dementia].
Beside the loss of the memory capacity, non-cognitive disturbances occur up to 70%-90% in patients suffering from Alzheimer's disease due to pathological changes in the brain. Delusion, hallucination and changes of the circadian rhythm can appear in addition to the five kinds of disorder--agitation, aggressive behaviour, screaming, depression and constant hyperkinesia. The consequences of these changes in perception and behaviour constitute severe problems for the patient as well as for the main caregiver. The burden of caring often exceeds their energy and resources. Not only do many of those caregivers suffer themselves from exhaustion but also from feelings of guilt and depression. The therapeutic concept includes the involvement of the relatives through information, support, counselling and guidance as much as the investigation of the causes and interrelation of the problematic behaviour in each individual case and further involves the carer in creating a concept to deal in an optimal way with the patient.


Electrophysiological Correlates of Absolute Pitch in a Passive Auditory Oddball Paradigm: a Direct Replication Attempt.
Humans with absolute pitch (AP) are able to effortlessly name the pitch class of a sound without an external reference. The association of labels with pitches cannot be entirely suppressed even if it interferes with task demands. This suggests a high level of automaticity of pitch labeling in AP. The automatic nature of AP was further investigated in a study by Rogenmoser et al. (2015). Using a passive auditory oddball paradigm in combination with electroencephalography, they observed electrophysiological differences between musicians with and without AP in response to piano tones. Specifically, the AP musicians showed a smaller P3a, an event-related potential (ERP) component presumably reflecting early attentional processes. In contrast, they did not find group differences in the mismatch negativity (MMN), an ERP component associated with auditory memory processes. They concluded that early cognitive processes are facilitated in AP during passive listening and are more important for AP than the preceding sensory processes. In our direct replication study on a larger sample of musicians with (n = 54, 27 females, 27 males) and without (n = 50, 24 females, 26 males) AP, we successfully replicated the non-significant effects of AP on the MMN. However, we could not replicate the significant effects for the P3a. Additional Bayes factor analyses revealed moderate to strong evidence (Bayes factor > 3) for the null hypothesis for both MMN and P3a. Therefore, the results of this replication study do not support the postulated importance of cognitive facilitation in AP during passive tone listening.


Investigating the Roles of Active Site Residues in Mycobacterium tuberculosis Indole-3-glycerol Phosphate Synthase, a Potential Target for Antitubercular Agents.
Mycobacterium tuberculosis drug resistance is emerging and new drug targets are needed. Tryptophan biosynthesis is necessary for M. tuberculosis replication and virulence. Indole-3-glycerol phosphate synthase (IGPS) catalyzes a step in M. tuberculosis tryptophan biosynthesis and has been suggested as a potential anti-infective target, but our understanding of this enzyme is limited. To aid in inhibitor design and gain a greater mechanistic picture of this enzyme, there is a need to understand the roles of active site amino acids in ligand binding and catalysis. In this work, we explored the roles of conserved active site amino acids Glu57, Lys59, Lys119, Glu168, and Glu219. Mutation of each to Ala results in loss of all detectable activity. The Glu57Gln, Lys59Arg, Lys119Arg, Glu168Gln, and Glu219Asp mutations result in large activity losses, while Glu219Gln has enhanced activity. Analysis of the enzymatic data yields the following main conclusions: (A) Lys119 is the likely catalytic acid in the CdRP ring closure step. (B) Glu168 stabilizes a charged reaction intermediate and may also be the catalytic base. (C) Glu57, Glu219, and Lys119 form a closely arranged triad in which Glu57 and Glu219 modulate the pKa of Lys119, and thus overall activity. This increased understanding of inter- and intramolecular interactions and demonstration of the highly coordinated nature of the M. tuberculosis IGPS active site provide new mechanistic information and guidance for future work with this potential new drug target.


[Dengue: epidemiological aspects and the first outbreak in the Middle Solimões Region of Coari in the State of Amazonas from 2008 to 2009].
Dengue is one of the most prevalent infectious diseases in Brazil and is a major public health problem worldwide. It is most prevalent in tropical and subtropical regions with 2.5 to 3 billion people at risk of becoming infected. Thus, this study sought to demonstrate the epidemiological characteristics of individuals affected by dengue, its prevalence and its epidemic process in the Middle Solimões region of Coari in the state of Amazonas between 2008 and 2009. Epidemiological data were obtained through epidemiological monitoring by the Municipal Health Facility of the city of Coari, AM. The variables analyzed were the month of notification, the number of confirmed cases, the cases' genders, the cases' ages and their neighborhoods of residence. In total, 1,003 cases were reported (635 in 2008 and 368 in 2009), and 639 cases were diagnosed as positive. Of these, +54% involved female subjects, and +46% were male. The majority of the affected individuals were between 10 and 49 years of age, and the spatial distribution was concentrated in neighborhoods near streams, lakes and areas in which housing had recently been disrupted. We concluded that, during the period studied, there was an outbreak of dengue in the City of Coari, AM. However, it is possible that a dengue epidemic may have occurred earlier in Coari without proper diagnosis or follow-up and that previously infected individuals may have traveled to the capital of Amazonas (Manaus), where the virus has circulated since 1998.


Is the $1000 Genome as Near as We Think? A Cost Analysis of Next-Generation Sequencing.
The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings. Although several commercial parties report to have broken the $1000 barrier for sequencing an entire human genome, a valid cost overview for NGS is currently lacking. This study provides a complete, transparent and up-to-date overview of the total costs of different NGS applications. Cost calculations for targeted gene panels (TGP), whole exome sequencing (WES) and whole genome sequencing (WGS) were based on the Illumina NextSeq500, HiSeq4000, and HiSeqX5 platforms, respectively. To anticipate future developments, sensitivity analyses are performed. Per-sample costs were €1669 for WGS, € 792 for WES and €333 for TGP. To reach the coveted $1000 genome, not only is the long-term and efficient use of the sequencing equipment needed, but also large reductions in capital costs and especially consumable costs are also required. WES and TGP are considerably lower-cost alternatives to WGS. However, this does not imply that these NGS approaches should be preferred in clinical practice, since this should be based on the tradeoff between costs and the expected clinical utility of the approach chosen. The results of the present study contribute to the evaluation of such tradeoffs.


Effect of Bridgehead Methyl Substituents on the Gas Permeability of Tröger's-Base Derived Polymers of Intrinsic Microporosity.
A detailed comparison of the gas permeability of four Polymers of Intrinsic Microporosity containing Tröger's base (TB-PIMs) is reported. In particular, we present the results of a systematic study of the differences between four related polymers, highlighting the importance of the role of methyl groups positioned at the bridgehead of ethanoanthracene (EA) and triptycene (Trip) components. The PIMs show BET surface areas between 845-1028 m2 g-1 and complete solubility in chloroform, which allowed for the casting of robust films that provided excellent permselectivities for O2/N2, CO2/N2, CO2/CH4 and H2/CH4 gas pairs so that some data surpass the 2008 Robeson upper bounds. Their interesting gas transport properties were mostly ascribed to a combination of high permeability and very strong size-selectivity of the polymers. Time lag measurements and determination of the gas diffusion coefficient of all polymers revealed that physical ageing strongly increased the size-selectivity, making them suitable for the preparation of thin film composite membranes.


A discrete geometric approach to cell membrane and electrode contact impedance modeling.
This paper presents a novel discrete model for cell membranes and electrodes contact impedances alternative to the widely used finite elements. The finite element approach can be considered as a tool for constructing finite dimensional systems of equations that approximate the specific electroquasistatic biological problem on the discrete level. Although the finite element technique is explained typically in terms of variational or weighted-residual approaches, another, less familiar way is available to reformulate geometrically the same physical problem. This approach, referred to as discrete geometric approach, allows a direct link between geometry and the degrees of freedom describing the specific biological problem. It is straightforward to implement in any finite element open software and it assures a correct modeling of voltages and currents playing a fundamental role in a biological problem. The validation has been performed, as a first step, against analytical solutions; then, we considered impedance measurements regarding erythrocytes in whole blood flowing in microchannels at high shear rates.


Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus.
Cannabidiol (CBD) is a non-psychotomimetic compound derived from Cannabis sativa. Preclinical and clinical studies have shown therapeutic potential of CBD in a variety of disorders. Despite several research efforts on CBD, its antidepressant activity has been poorly investigated and the exact mechanism of action remains unclear. Thus, this study aimed to further explore the mechanism of CBD after chronic administration (7 days). First, the dose level of CBD that is enough to produce antidepressant effects after chronic administration was explored. Second, the changes in key proteins and neurotransmitters through such methods as real-time polymerase chain reaction (RT-PCR), western blotting, and high-performance liquid chromatography-electrochemical detection (HPLC-ECD) were critically studied. Furthermore, correlation between behavioral phenotypes with protein and neurotransmitters was established and the possible mechanism was herein postulated. The results showed that only the high dose CBD 100 mg/kg chronic administration induced antidepressant-like effects in mice subjected to forced swim test. Chronic CBD 100 mg/kg administration resulted in significant increases in serotonin (5-HT) and noradrenaline (NA) levels in the hippocampus (HPC). Similarly, the chronic administration of CBD 30 mg/kg and CBD 100 mg/kg significantly decreased nuclear factor kappa B (NF-κB) expression in the HPC. Moreover, none of the treatments were observed to induce locomotor effects. Thus, we concluded that chronic administration of CBD (100 mg/kg) induced antidepressant-like effects by increasing 5-HT and NA levels in the HPC. These results shed new light on further discovery of the antidepressant effect of CBD.


Gene transfer with subsequent removal of the selection gene from the host genome.
A general method of gene transfer that does not leave behind a selectable marker in the host genome is described. A luciferase gene was introduced into the tobacco genome by using the hygromycin phosphotransferase gene (hpt) as a linked selectable marker. Flanked by recombination sites from the bacteriophage P1 Cre/lox recombination system, the hpt gene was subsequently excised from the plant genome by the Cre recombinase. The Cre-catalyzed excision event in the plant genome was precise and conservative--i.e., without loss or alteration of nucleotides in the recombinant site. After removal of the Cre-encoding locus by genetic segregation, plants were obtained that had incorporated only the desired transgene. Gene transfer without the incorporation of antibiotic-resistance markers in the host genome should ease public concerns over the field release of transgenic organisms expressing such traits. Moreover, it would obviate the need for different selectable markers in subsequent rounds of gene transfer into the same host.


Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options.
We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment. Monogenic forms of diabetes account for approximately 1-2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether. Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.


Liver regeneration after living donor transplantation: adult-to-adult living donor liver transplantation cohort study.
Adult-to-adult living donors and recipients were studied to characterize patterns of liver growth and identify associated factors in a multicenter study. Three hundred and fifty donors and 353 recipients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) receiving transplants between March 2003 and February 2010 were included. Potential predictors of 3-month liver volume included total and standard liver volumes (TLV and SLV), Model for End-Stage Liver Disease (MELD) score (in recipients), the remnant and graft size, remnant-to-donor and graft-to-recipient weight ratios (RDWR and GRWR), remnant/TLV, and graft/SLV. Among donors, 3-month absolute growth was 676 ± 251 g (mean ± SD), and percentage reconstitution was 80% ± 13%. Among recipients, GRWR was 1.3% ± 0.4% (8 < 0.8%). Graft weight was 60% ± 13% of SLV. Three-month absolute growth was 549 ± 267 g, and percentage reconstitution was 93% ± 18%. Predictors of greater 3-month liver volume included larger patient size (donors and recipients), larger graft volume (recipients), and larger TLV (donors). Donors with the smallest remnant/TLV ratios had larger than expected growth but also had higher postoperative bilirubin and international normalized ratio at 7 and 30 days. In a combined donor-recipient analysis, donors had smaller 3-month liver volumes than recipients adjusted for patient size, remnant or graft volume, and TLV or SLV (P = 0.004). Recipient graft failure in the first 90 days was predicted by poor graft function at day 7 (HR = 4.50, P = 0.001) but not by GRWR or graft fraction (P > 0.90 for each). Both donors and recipients had rapid yet incomplete restoration of tissue mass in the first 3 months, and this confirmed previous reports. Recipients achieved a greater percentage of expected total volume. Patient size and recipient graft volume significantly influenced 3-month volumes. Importantly, donor liver volume is a critical predictor of the rate of regeneration, and donor remnant fraction affects postresection function. Liver Transpl 21:79-88, 2015. © 2014 AASLD.


Comparison of the diagnostic ability of blue laser imaging magnification versus pit pattern analysis for colorectal polyps.
Background and study aims There have been few evaluations of the diagnostic ability of new narrow band light observation blue laser imaging (BLI). The present prospective study compared the diagnostic ability of BLI magnification and pit pattern analysis for colorectal polyps. Patients and methods We collected lesions prospectively, and the analysis of images was made by two endoscopists, retrospectively. A total of 799 colorectal polyps were examined by BLI magnification and pit pattern analysis at Nagoya University Hospital. The Hiroshima narrow-band imaging classification was used for BLI. Differentiation of neoplastic from non-neoplastic lesions and diagnosis of deeply invasive submucosal cancer (dSM) were compared between BLI magnification and pit pattern analysis. Type C2 in the Hiroshima classification was evaluated separately, because application of this category as an index of the depth of cancer invasion was considered difficult. Results We analyzed 748 colorectal polyps, excluding 51 polyps that were inflammatory polyps, sessile serrated adenoma/polyps, serrated adenomas, advanced colorectal cancers, or other lesions. The accuracy of differential diagnosis between neoplastic and non-neoplastic lesions was 98.4 % using BLI magnification and 98.7 % with pit pattern analysis. In addition, the diagnostic accuracy of BLI magnification and pit pattern analysis for dSM for cancer was 89.5 % and 92.1 %, respectively. When type C2 lesions were excluded, the diagnostic accuracy of BLI for dSM was 95.9 %. The 18 type C2 lesions comprised 1 adenoma, 9 intramucosal or slightly invasive submucosal cancers, and 8 dSM. Pit pattern analysis allowed accurate diagnosis of the depth of invasion in 13 lesions (72.2 %). Conclusions Most colorectal polyps could be diagnosed accurately by BLI magnification without pit pattern analysis, but we should add pit pattern analysis for type C2 lesions in the Hiroshima classification.


[The influence of hirudotherapy on the biochemical status of patients with gonarthrosis].
The results of conservative treatment with the use of hirudotherapy of patients presenting with bilateral gonarthrosis were evaluated by biochemical analysis of their serum and urine samples. The study revealed changes of mineral, carbohydrate, and lipid metabolism suggestive of the positive homeostatic effect of hirudotherapy at the local and systemic levels. This finding gives reason to recommend hirudotherapy for the treatment and prevention of osteoarthrosis.


Estimation of pyrazinamidase activity using a cell-free In vitro synthesis of pnca and its association with pyrazinamide susceptibility in Mycobacterium tuberculosis.
The main mechanism of resistance to PZA in Mycobacterium tuberculosis relies on mutations on its pyrazinamidase/nicotinamidase. Recently, a rapid colorimetric test relying on the PCR-based in vitro-synthesized-PZase assay has been reported for PZase activity determination from clinical M. tuberculosis isolates but the assay has not been compared with other tests to evaluate PZA susceptibility in M. tuberculosis isolates. In this study, we have used the PCR-based in vitro-synthesized-PZase assay to analyze the specific pyrazinamidase (PZase) activity of PncA mutants and have correlated the results to the PZA susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA-resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene were tested. Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R and P77L+V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 were expressed in vitro at yields > 50% relative to the wild type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) showed no detectable activity, while the relative activities for the 3 others, V9A (27%), G97D (10%) and A146V (28%) were low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants were expressed from PZA-susceptible isolates. Their expression was similar to the wild type enzyme and behaved as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results were observed for two mutants, V7A and P62T. Thus, this study provides the proof of concept that the PCR-based in vitro-synthesized-PZase assay represents a promising rapid approach for the evaluation of PZA susceptibility based on the estimation of the relative PZase activity from clinical isolates.


A training system of orientation and mobility for blind people using acoustic virtual reality.
A new auditory orientation training system was developed for blind people using acoustic virtual reality (VR) based on a head-related transfer function (HRTF) simulation. The present training system can reproduce a virtual training environment for orientation and mobility (O&M) instruction, and the trainee can walk through the virtual training environment safely by listening to sounds such as vehicles, stores, ambient noise, etc., three-dimensionally through headphones. The system can reproduce not only sound sources but also sound reflection and insulation, so that the trainee can learn both sound location and obstacle perception skills. The virtual training environment is described in extensible markup language (XML), and the O&M instructor can edit it easily according to the training curriculum. Evaluation experiments were conducted to test the efficiency of some features of the system. Thirty subjects who had not acquired O&M skills attended the experiments. The subjects were separated into three groups: a no-training group, a virtual-training group using the present system, and a real-training group in real environments. The results suggested that virtual-training can reduce "veering" more than real-training and also can reduce stress as much as real training. The subjective technical and anxiety scores also improved.


The local skin blood flow in areas at risk for pressure sores treated with massage.
In order to evaluate methods to prevent pressure sores the effect of massage on the local skin blood flow was studied in normal skin and in skin with discolouration (red or reddish blue). In this study massage is defined as small circular movements with the fingertips using liniment. The cutaneous blood flow was measured with a laser Doppler flowmeter. To study the long term effect of massage on normal skin ten patients were measured over a twenty day period with five days before and after a ten day period with massage. Twenty-nine patients with cerebral haemorrhage were measured for two days each to examine the effect immediately after the massage on normal skin. Fifteen patients with discolouration were measured for one day each both on normal skin and injured skin. The difference in blood flow before and after the ten day period of massage was inconsistent and insignificant. The effect of massage which appeared one to two minutes after the stimulus was implemented varies between individuals and within individuals; significantly more women than men increased their skin blood flow bilaterally after massage. In the centre of the injured skin the basal blood flow was higher than in normal skin and it decreased after the massage was implemented. The results stress the importance of continued research to provide an opportunity for individualization in the selection of methods to prevent and treat pressure sores.


Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis.
Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. ACTRN12613000339752.


The level of aberrant cells in various tissues of bank vole depending on doses and radionuclide balance in organism.
A regression analysis shows the direct linear relation between 137Cs accumulation in rodents and the level of aberrant cells. For 90Sr this trend was negative. The dose relationship was the same with 137Cs. The trends were negative 1 month later after feeding of animals with clean food. Correspondingly the dose relationship was also negative. The levels of cells with apoptosis features were different in animals from the control and the radiocontaminated sites. The analysis has revealed the correlation between the 90Sr content in animal body and the number of alveolar macrophages containing micronuclei. The relationship was revealed between the 137Cs content in the animal body and the number of intestinal epithelial cells with micronuclei.


"Where does it hurt?": Exploring EDA Signals to Detect and Localise Acute Pain.
Pain is a highly unpleasant sensory experience, for which currently no objective diagnostic test exists to measure it. Identification and localisation of pain, where the subject is unable to communicate, is a key step in enhancing therapeutic outcomes. Numerous studies have been conducted to categorise pain, but no reliable conclusion has been achieved. This is the first study that aims to show a strict relation between Electrodermal Activity (EDA) signal features and the presence of pain and to clarify the relation of classified signals to the location of the pain. For that purpose, EDA signals were recorded from 28 healthy subjects by inducing electrical pain at two anatomical locations (hand and forearm) of each subject. The EDA data were preprocessed with a Discrete Wavelet Transform to remove any irrelevant information. Chi-square feature selection was used to select features extracted from three domains: time, frequency, and cepstrum. The final feature vector was fed to a pool of classification schemes where an Artificial Neural Network classifier performed best. The proposed method, evaluated through leave-one-subject-out cross-validation, provided 90% accuracy in pain detection (no pain vs. pain), whereas the pain localisation experiment (hand pain vs. forearm pain) achieved 66.67% accuracy.Clinical relevance- This is the first study to provide an analysis of EDA signals in finding the source of the pain. This research explores the viability of using EDA for pain localisation, which may be helpful in the treatment of noncommunicable patients.


Molecular and biochemical characterization of OXA-45, an extended-spectrum class 2d' beta-lactamase in Pseudomonas aeruginosa.
As part of the CANCER Antimicrobial Surveillance Program in North America, a clinical strain of Pseudomonas aeruginosa, strain 07-406, isolated in Texas was found to be resistant to all antimicrobials except polymyxin B. Genetic analysis of this isolate identified two unique extended-spectrum beta-lactamase genes. One, bla(VIM-7), encoded a metallo-beta-lactamase (unpublished data), and the other, bla(OXA-45), described here, encoded a class D extended-spectrum beta-lactamase. bla(OXA-45) was isolated on a Sau3A1 genomic fragment of 1.8 kb and encodes a protein of 264 amino acids with the highest identities to OXA-18 (65.9%), OXA-9 (42.8%), OXA-22 (40.2%), OXA-12 (38.6%), and OXA-29 (35.2%) but weak identities with other class D beta-lactamases. bla(OXA-45) was found to be harbored on a 24-kb plasmid in a region that displays high identities with a section of the 43-kb genomic island of Salmonella enterica serovar Typhimurium DT104. Biochemically OXA-45 is most similar to OXA-18 in its substrate profile and inhibition by clavulanic acid and is a member of the 2d' class of beta-lactamases.


Choline-binding protein D (CbpD) in Streptococcus pneumoniae is essential for competence-induced cell lysis.
Streptococcus pneumoniae is an important human pathogen that is able to take up naked DNA from the environment by a quorum-sensing-regulated process called natural genetic transformation. This property enables members of this bacterial species to efficiently acquire new properties that may increase their ability to survive and multiply in the human host. We have previously reported that induction of the competent state in a liquid culture of Streptococcus pneumoniae triggers lysis of a subfraction of the bacterial population resulting in release of DNA. We have also proposed that such competence-induced DNA release is an integral part of natural genetic transformation that has evolved to increase the efficiency of gene transfer between pneumococci. In the present work, we have further elucidated the mechanism behind competence-induced cell lysis by identifying a putative murein hydrolase, choline-binding protein D (CbpD), as a key component of this process. By using real-time PCR to estimate the amount of extracellular DNA in competent relative to noncompetent cultures, we were able to show that competence-induced cell lysis and DNA release are strongly attenuated in a cbpD mutant. Ectopic expression of CbpD in the presence or absence of other competence proteins revealed that CbpD is essentially unable to cause cell lysis on its own but depends on at least one additional protein expressed during competence.


Maurice Klippel.
Maurice Klippel (1858-1942) was a turn-of-the-century French internist with a special interest in neurology and psychiatry. He authored numerous medical papers in these disciplines, but is best known to spine surgeons for his description, co-authored with Andre Feil, of a patient with congenital fusion of the cervical vertebrae, a condition now known as Klippel-Feil syndrome.


Analysis of the Continuous Feeding of Catalyst Particles during the Growth of Vertically Aligned Carbon Nanotubes by Aerosol-Assisted CCVD.
Aerosol-assisted catalytic chemical vapor deposition (AACCVD) is a powerful one-step process to produce vertically aligned carbon nanotubes (VACNTs), characterized by the continuous supply of the catalyst precursor (metallocene). The behavior of catalyst species all along the synthesis is essential for the continuous growth of VACNTs. It is there investigated through detailed observations and elemental analyses at scales of VACNT carpets and of individual CNTs. Our approach is based on two complementary experiments: quenching of the sample cooling, and sequential injection of two distinct metallocenes. Metal-based nanoparticles nucleated in the gas-phase during the whole synthesis duration are shown to diffuse in between the growing VACNTs from the top of the CNT carpet towards the substrate. They are much smaller than the catalyst particles formed on the substrate in the initial steps of the process and evidences are given that they continuously feed these catalyst particles at the VACNT roots. Particularly, the electron energy-loss spectroscopy (EELS) analyses of metal-based segments found into a single CNT show that the second injected metal is very gradually incorporated in the particle initially formed from the metal firstly injected. The feeding of the catalyst particles by the nanoparticles continuously nucleated in the gas-phase is therefore an essential feature of the base-growth of CNTs by AACCVD.


Topological Learning Approach to Characterizing Biological Membranes.
Biological membranes play key roles in cellular compartmentalization, structure, and its signaling pathways. At varying temperatures, individual membrane lipids sample from different configurations, a process that frequently leads to higher-order phase behavior and phenomena. Here we present a persistent homology-based method for quantifying the structural features of individual and bulk lipids, providing local and contextual information on lipid tail organization. Our method leverages the mathematical machinery of algebraic topology and machine learning to infer temperature-dependent structural information of lipids from static coordinates. To train our model, we generated multiple molecular dynamics trajectories of DPPC membranes at varying temperatures. A fingerprint was then constructed for each set of lipid coordinates by a persistent homology filtration, in which interactions spheres were grown around the lipid atoms while tracking their intersections. The sphere filtration formed a simplicial complex that captures enduring key topological features of the configuration landscape, using homology, yielding persistence data . Following fingerprint extraction for physiologically relevant temperatures, the persistence data were used to train an attention-based neural network for assignment of effective temperature values to selected membrane regions. Our persistence homology-based method captures the local structural effects, via effective temperature, of lipids adjacent to other membrane constituents, e.g. sterols and proteins. This topological learning approach can predict lipid effective temperatures from static coordinates across multiple spatial resolutions. The tool, called MembTDA , can be accessed at https://github.com/hyunp2/Memb-TDA .


Bayesian support is larger than bootstrap support in phylogenetic inference: a mathematical argument.
In phylogenetic inference, the support of an estimated phylogenetic tree topology and its interior branches is usually measured either with non-parametric bootstrap support (BS) values or with Bayesian posterior probabilities (BPPs). Extensive empirical evidence indicates that BPP values are systematically larger than BS when measured on the same data set, but there are no theoretical results supporting such a systematic difference. In the present note, we give a heuristic mathematical argument supporting the empirically observed phenomenon. The argument uses properties of the marginal and profile likelihoods of the normal distribution. The heuristic arguments are supported in a simulation study evaluating different steps in the argument.


Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk.
The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk. We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls. The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)). HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.


Anaesthesia for ambulatory paediatric surgery: common techniques and complications.
Ambulatory surgical care accounts for over 70% of elective procedures in Northern America. Ambulatory paediatric surgical practice is not widespread in Nigeria. This report examined clinical indicators for quality care in paediatric ambulatory surgery using common outcomes after day case procedures as benchmark. This was a cross-sectional study of children who were presented for ambulatory surgical care in the University of Benin Teaching Hospital. A standardized questionnaire was employed to record the age, gender, indication for surgery, type of anaesthesia, timelines for the surgery and associated complications. A total of 93 patients had surgical procedures on ambulatory basis. The mean age of the patients was 4.1(4.0) yr and duration of surgical procedure 31.3(12.1) min. The male to female ratio was 3:1, and herniotomy was the most frequent procedure on ambulatory paediatric surgical care 60 (64.5%). The common anaesthetic techniques employed in the paediatric ambulatory setting were spontaneous respiration with face mask 40 (43%), Inhalation technique with tracheal intubations 31 (33.3%), general anaesthesia with relaxant technique five (5.4%), local infiltration with or without sedation eight (8.6%), GA plus caudal block eight(8.6%), and subarachnoid block one(1.1%). The indicators of quality care were unanticipated admission (5.4%), repeat hospital visit (4.3%), readmission (2.2%) and delayed discharge (21.5%). The practices of paediatric surgery on ambulatory services are feasible in our setting. The observable complications are within acceptable limits. The timelines in the scheduling and discharge appear not to be optimal for an effective ambulatory service.


Coronary artery disease and experiences of losses.
In literature, depression is associated with cardiovascular diseases. From clinical experience, we observed that the psychological category 'experience of loss' was associated with the onset and development of coronary heart disease. The experience of loss caused by self-reported significant event(s) leads to grief and the psychosocial factors which predispose the patient to diseases. To study the impact of the experience of loss by investigating the relationship between mourning and depression, in hospitalized patients with coronary heart disease. 44 inpatients (50% men and 50% women, aged 33 to 65 years), with a diagnosis of acute myocardial infarction or angina, were evaluated. Two instruments were used: a semi-structured interview, for investigating the experience of loss and evaluating the state of grief; and the Beck Depression Inventory, for measuring the severity of depression. The results were expressed using the computer program Statistical Package for Social Sciences version 11.0. 66% of the patients were in mourning, the relationship between mourning and depression was significant (p<0,05), and we verified that 100% of the patients who had serious depression were in mourning. The most frequent self-reported significant event was death of a family member (47%) and death of a close person (13%), totaling 60% of the events, reported by 84% of the participants. According to the results of Beck Depression Inventory, 48% of them had depression. This study suggests that the psychological category 'experience of loss' should be used as an indicator of the existence of psychological factors that could predispose the patient to CAD, and also confirms the relationship between a state of mourning and depression.


Bayesian Joint Matrix Decomposition for Data Integration with Heterogeneous Noise.
Matrix decomposition is a popular and fundamental approach in machine learning and data mining. It has been successfully applied into various fields. Most matrix decomposition methods focus on decomposing a data matrix from one single source. However, it is common that data are from different sources with heterogeneous noise. A few of the matrix decomposition methods have been extended for such multi-view data integration and pattern discovery while only a few methods were designed to consider the heterogeneity of noise in such multi-view data for data integration explicitly. To this end, in this article, we propose a joint matrix decomposition framework (BJMD), which models the heterogeneity of noise by the Gaussian distribution in a Bayesian framework. We develop two algorithms to solve this model: one is a variational Bayesian inference algorithm, which makes full use of the posterior distribution; and another is a maximum a posterior algorithm, which is more scalable and can be easily paralleled. Extensive experiments on synthetic and real-world datasets demonstrate that BJMD is superior or competitive to the state-of-the-art methods.


[The brachycephalisation problem, a nutrition constitutional problem?].
A hypothesis is framed about which any influences of the nutrition may cause variations of the cranium, but concerning physiological data, kinds of nutrition and special victuals' ingredients cannot still be mentioned. If such connexions are proved, at last the well known brachycephalization among European populations since the Middle Ages and the beginning debrachycephalization in the present time could partially be interpreted.


[Murphy's Law].
Non-surgical treatment of acute phlegmonous appendicitis has been receiving increasing attention in recent years, representing a reversal of policy. The appendectomy came into vogue at the beginning of the 20th century. It is true that prompt surgical intervention in all patients with appendicitis or an indication thereof almost guarantees success, but it gradually came to be forgotten that this intervention was not always necessary. In this article we will document the historical development of this disease and its treatment, and return to the original reports made by pathologist Reginald Fitz and the internist William Osler to show that their opinion was not black and white. Many surgeons in the Netherlands were also initially more restrained. In the course of time recognition of the natural progression of the disease vanished, until new developments placed this more sharply in the limelight.


Purity homophily in social networks.
Does sharing moral values encourage people to connect and form communities? The importance of moral homophily (love of same) has been recognized by social scientists, but the types of moral similarities that drive this phenomenon are still unknown. Using both large-scale, observational social-media analyses and behavioral lab experiments, the authors investigated which types of moral similarities influence tie formations. Analysis of a corpus of over 700,000 tweets revealed that the distance between 2 people in a social-network can be predicted based on differences in the moral purity content-but not other moral content-of their messages. The authors replicated this finding by experimentally manipulating perceived moral difference (Study 2) and similarity (Study 3) in the lab and demonstrating that purity differences play a significant role in social distancing. These results indicate that social network processes reflect moral selection, and both online and offline differences in moral purity concerns are particularly predictive of social distance. This research is an attempt to study morality indirectly using an observational big-data study complemented with 2 confirmatory behavioral experiments carried out using traditional social-psychology methodology.


Freeze tolerance and intolerance as strategies of winter survival in terrestrially-hibernating amphibians.
The ability to tolerate extracellular freezing as an adaptation for winter survival was tested in seven species of terrestrially-hibernating amphibians found in eastern Canada. All species had only moderate supercooling abilities, with whole animal supercooling points of -1.5 to -3 degrees C. Two salamander species, Plethodon cinereus and Ambystoma laterale, and the toad, Bufo americanus, were freezing intolerant and were killed when frozen for 24 hr at temperatures just below their supercooling points. The major winter strategy of these animals appears to behavioural avoidance of subzero temperatures. Four species of frogs Rana sylvatica, Hyla versicolor, Hyla crucifer and Pseudacris triseriata, survived extracellular freezing at moderate subzero temperatures (-2 to -4 degrees C) for periods of time ranging up to 2 weeks. All four frog species accumulated low molecular weight carbohydrates as cryoprotectants, glycerol being the major cryoprotectant in adult H. versicolor, while immature adults of this species as well as the other three species all produced high levels of glucose as the cryoprotectant.


Accuracy and validity of stitching sectional cone beam computed tomographic images.
To determine whether three-dimensionally reconstructed images of skulls created by stitching multiple cone beam computed tomographic (CBCT) images are as accurate as single images obtained using multidetector computed tomography (MDCT), 10 skull models were scanned using an optical three-dimensional scanner, MDCT, and CBCT. Cone beam CT images at 3 different levels of the skull were manually superimposed and stitched. The reconstructed CBCT images at each level were aligned and fused using computer software and then compared to the nominal reference image obtained from the optical three-dimensional scanner by determining positional errors. The reconstructed MDCT images were also compared, and the differences in the mean errors for the 3 image types compared with the nominal reference image data were evaluated. There were no significant differences between the MDCT images and the manually merged CBCT images (Wilcoxon signed rank test, P = 0.017). In contrast, there were significant differences between the MDCT images and the software-aligned CBCT images (P = 0.005). Manual stitching of CBCT sectional images at different levels can provide accurate anatomic details of the oral and maxillofacial regions.


Effect of sequences of the active-site dipeptides of DsbA and DsbC on in vivo folding of multidisulfide proteins in Escherichia coli.
We have examined the role of the active-site CXXC central dipeptides of DsbA and DsbC in disulfide bond formation and isomerization in the Escherichia coli periplasm. DsbA active-site mutants with a wide range of redox potentials were expressed either from the trc promoter on a multicopy plasmid or from the endogenous dsbA promoter by integration of the respective alleles into the bacterial chromosome. The dsbA alleles gave significant differences in the yield of active murine urokinase, a protein containing 12 disulfides, including some that significantly enhanced urokinase expression over that allowed by wild-type DsbA. No direct correlation between the in vitro redox potential of dsbA variants and the urokinase yield was observed. These results suggest that the active-site CXXC motif of DsbA can play an important role in determining the folding of multidisulfide proteins, in a way that is independent from DsbA's redox potential. However, under aerobic conditions, there was no significant difference among the DsbA mutants with respect to phenotypes depending on the oxidation of proteins with few disulfide bonds. The effect of active-site mutations in the CXXC motif of DsbC on disulfide isomerization in vivo was also examined. A library of DsbC expression plasmids with the active-site dipeptide randomized was screened for mutants that have increased disulfide isomerization activity. A number of DsbC mutants that showed enhanced expression of a variant of human tissue plasminogen activator as well as mouse urokinase were obtained. These DsbC mutants overwhelmingly contained an aromatic residue at the C-terminal position of the dipeptide, whereas the N-terminal residue was more diverse. Collectively, these data indicate that the active sites of the soluble thiol- disulfide oxidoreductases can be modulated to enhance disulfide isomerization and protein folding in the bacterial periplasmic space.