Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability

Lack of privileged access to awareness for rewarding social scenes in Autism Spectrum Disorder

Reduced social motivation is hypothesised to underlie social behavioural symptoms of Autism Spectrum Disorder (ASD). The extent to which rewarding social stimuli are granted privileged access to awareness in ASD is currently unknown. We use continuous flash suppression to investigate whether individuals with and without ASD show privileged access to awareness for social over nonsocial rewarding scenes that are closely matched for stimulus features. Strong evidence for a privileged access to awareness for rewarding social over nonsocial scenes was observed in neurotypical adults. No such privileged access was seen in ASD individuals, and moderate support for the null model was noted. These results suggest that the purported deficits in social motivation in ASD may extend to early processing mechanisms

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Temporal Dynamics of Visual Attention Allocation

We often temporally prepare our attention for an upcoming event such as a starter pistol. In such cases, our attention should be properly allocated around the expected moment of the event to process relevant sensory input efficiently. In this study, we examined the dynamic changes of attention levels near the expected moment by measuring contrast sensitivity to a target that was temporally cued by a five-second countdown. We found that the overall attention level decreased rapidly after the expected moment, while it stayed relatively constant before it. Results were not consistent with the predictions of existing explanations of temporal attention such as the hazard rate or the stimulus-driven oscillations. A control experiment ruled out the possibility that the observed pattern was due to biased time perception. In a further experiment with a wider range of cue-stimulus-intervals, we observed that attention level increased until the last 500 ms of the interval range, and thereafter, started to decrease. Based on the performances of a generative computational model, we suggest that our results reflect the nature of temporal attention that takes into account the subjectively estimated hazard rate and the probability of relevant events occurring in the near future

Etiopathogenic features of acne vulgaris

Acne vulgaris is one of the most frequent dermatoses in the general population. Numerous scientific articles are available on acne, mostly relating to its etiopathogeny. This notwithstanding, the large amount of scientific information generated by works on acne vulgaris has made it difficult to converge knowledge on its etiopathogeny into a single understanding. Therefore, this review has been proposed to analyze the four classic mechanisms of this dermatosis (sebum production, follicular hyperkeratinization, bacterial colonization and glandular inflammation), as well as its secondary mechanism, namely hormonal mediation.A acne vulgar é uma das dermatoses mais freqüentes na população em geral. Encontra-se na literatura grande número de trabalhos científicos referentes sobretudo a sua etiopatogenia. No entanto, dado o grande número de informações geradas a respeito, dificilmente consegue-se reuni-las em entendimento comum. Esta revisão literária foi proposta a fim de abordar os mecanismos etiopatogênicos clássicos da acne vulgar (produção sebácea, hiperqueratinização folicular, colonização bacteriana folicular e inflamação glandular) e o mecanismo coadjuvante principal, a influência hormonal.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Depto. de DermatologiaPontifícia Universidade Católica de Campinas Hospital e Maternidade Celso Pierro Serviço de DermatologiaUNIFESP, EPM, Depto. de DermatologiaSciEL

Guiding principles for the development and application of solid-phase phosphorus adsorbents for freshwater ecosystems

While a diverse array of phosphorus (P)-adsorbent materials is currently available for application to freshwater aquatic systems, selection of the most appropriate P-adsorbents remains problematic. In particular, there has to be a close correspondence between attributes of the P-adsorbent, its field performance, and the management goals for treatment. These management goals may vary from a rapid reduction in dissolved P to address seasonal enrichments from internal loading, targeting external fluxes due to anthropogenic sources, or long term inactivation of internal P inventories contained within bottom sediments. It also remains a challenge to develop new methods and materials that are ecologically benign and cost-effective. We draw on evidence in the literature and the authors’ personal experiences in the field, to summarise the attributes of a range of P-adsorbent materials. We offer 'guiding principles' to support practical use of existing materials and outline key development needs for new materials

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

The accuracy and precision of radiostereometric analysis in monitoring tibial plateau fractures

Background and purpose: The application of radiostereometric analysis (RSA) to monitor stability of tibial plateau fractures during healing is both limited and yet to be validated. We therefore evaluated the accuracy and precision of RSA in a tibial plateau fracture model. Methods: Combinations of 3, 6, and 9 markers in a lateral condyle fracture were evaluated with reference to 6 proximal tibial arrangements. Translation and rotation accuracy was assessed with displacement-controlled stages, while precision was assessed with dynamic double examinations. A comparison of error according to marker number and arrangement was completed with 2-way ANOVA models. Results: The results were improved using more tantalum markers in each segment. In the fracture fragment, marker scatter in all axes was achieved by a circumferential arrangement (medial, anterior, and lateral) of the tantalum markers above the fixation devices. Markers placed on either side of the tibial tuberosity and in the medial aspect of the fracture split represented the proximal tibial reference segment best. Using 6 markers with this distribution in each segment, the translation accuracy (root mean square error) was less than 37 μm in all axes. The precision (95% confidence interval) was less than ± 16 μm in all axes in vitro. Rotation, tested around the x-axis, had an accuracy of less than 0.123° and a precision of ± 0.024°. Interpretation: RSA is highly accurate and precise in the assessment of lateral tibial plateau fracture fragment movement. The validation of our center's RSA system provides evidence to support future clinical RSA fracture studies.Lucian B Solomon, Aaron W Stevenson, Stuart A Callary, Thomas R Sullivan, Donald W Howie, and Mellick J Chehad

Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2

The complement system is an important immune mechanism mediating both recognition and elimination of foreign bodies. The lectin pathway is one pathway of three by which the complement system is activated. The characteristic protease of this pathway is Mannan-binding lectin (MBL)-associated serine protease 2 (MASP2), which cleaves complement proteins C2 and C4. We present a novel and alternative role of MASP2 in the innate immune system. We have shown that MASP2 is capable of promoting fibrinogen turnover by cleavage of prothrombin, generating thrombin. By using a truncated active form of MASP2 as well as full-length MASP2 in complex with MBL, we have shown that the thrombin generated is active and can cleave both factor XIII and fibrinogen, forming cross-linked fibrin. To explore the biological significance of these findings we showed that fibrin was covalently bound on a bacterial surface to which MBL/MASP2 complexes were bound. These findings suggest that, as has been proposed for invertebrates, limited clotting may contribute to the innate immune response