Infection Parameters in the Sand Fly Vector That Predict Transmission of Leishmania major

To identify parameters of Leishmania infection within a population of infected sand flies that reliably predict subsequent transmission to the mammalian host, we sampled groups of infected flies and compared infection intensity and degree of metacyclogenesis with the frequency of transmission. The percentage of parasites within the midgut that were metacyclic promastigotes had the highest correlation with the frequency of transmission. Meta-analysis of multiple transmission experiments allowed us to establish a percent-metacyclic “cutoff” value that predicted transmission competence. Sand fly infections initiated with variable doses of parasites resulted in correspondingly altered percentages of metacyclic promastigotes, resulting in altered transmission frequency and disease severity. Lastly, alteration of sand fly oviposition status and environmental conditions at the time of transmission also influenced transmission frequency. These observations have implications for transmission of Leishmania by the sand fly vector in both the laboratory and in nature, including how the number of organisms acquired by the sand fly from an infection reservoir may influence the clinical outcome of infection following transmission by bite

A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly.

Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S-adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster

A qualitative study of health professionals’ views on using iPads to facilitate distraction during paediatric burn dressing changes

Introduction: Distraction is a non-pharmacologic pain management technique commonly used to avert a person’s attention from procedural pain and distress during stressful procedures such as treatment after a burn injury. In recent years, computer tablets (such as iPads) have been used within paediatric burns services to facilitate distraction by way of apps, games, cartoons and videos during dressing changes. However, we know very little about health professionals’ experiences of using them in this context.Methods: The current study explored health professionals’ experiences of using iPads to facilitate distraction during paediatric burn dressing changes. Fifteen health professionals from a single paediatric burns unit were interviewed. Thematic analysis revealed two key themes: (1) the iPad is a universal panacea for distraction; and (2) trials and tribulations.Discussion: Participants considered iPads to be potentially useful and effective distraction tools, suitable for use with a wide range of patients with burn injuries including young children, adolescents and young adults. However, issues including health professionals’ understandings of one another’s roles, the challenge of working in a busy burns service, and lack of experience and confidence were identified as possible barriers to their use within routine burn care. Training for staff on the use of iPads as a means of facilitating distraction, development of guidelines and a review of how they are incorporated into routine burn care are recommended

Applying blockchain to improve the integrity of the software development process

Software development is a complex endeavor that encompasses application and implementation layers with functional (refers to what is done) and non-functional (how is done) aspects. The efforts to scale agile software development practices are not wholly able to address issues such as integrity, which is a crucial non-functional aspect of the software development process. However, if we consider most software failures are Byzantine failures (i.e., where components may fail and there is imperfect information on which a component has failed.) that might impair the operation but do not completely disable the production line. In this paper, we assume software practitioners who cause defects as Byzantine participants and claim that most software failures can be mitigated by viewing software development as the Byzantine Generals Problem. Consequently, we propose a test-driven incentive mechanism based on a blockchain concept to orchestrate the software development process where production is controlled by a similar infrastructure based on the working principles of blockchain. We discuss the model that integrates blockchain with the software development process, and provide some recommendations for future work to address the issues while orchestrating software productio

α-Syntrophin Modulates Myogenin Expression in Differentiating Myoblasts

α-Syntrophin is a scaffolding protein linking signaling proteins to the sarcolemmal dystrophin complex in mature muscle. However, α-syntrophin is also expressed in differentiating myoblasts during the early stages of muscle differentiation. In this study, we examined the relationship between the expression of α-syntrophin and myogenin, a key muscle regulatory factor.The absence of α-syntrophin leads to reduced and delayed myogenin expression. This conclusion is based on experiments using muscle cells isolated from α-syntrophin null mice, muscle regeneration studies in α-syntrophin null mice, experiments in Sol8 cells (a cell line that expresses only low levels of α-syntrophin) and siRNA studies in differentiating C2 cells. In primary cultured myocytes isolated from α-syntrophin null mice, the level of myogenin was less than 50% that from wild type myocytes (p<0.005) 40 h after differentiation induction. In regenerating muscle, the expression of myogenin in the α-syntrophin null muscle was reduced to approximately 25% that of wild type muscle (p<0.005). Conversely, myogenin expression is enhanced in primary cultures of myoblasts isolated from a transgenic mouse over-expressing α-syntrophin and in Sol8 cells transfected with a vector to over-express α-syntrophin. Moreover, we find that myogenin mRNA is reduced in the absence of α-syntrophin and increased by α-syntrophin over-expression. Immunofluorescence microscopy shows that α-syntrophin is localized to the nuclei of differentiating myoblasts. Finally, immunoprecipitation experiments demonstrate that α-syntrophin associates with Mixed-Lineage Leukemia 5, a regulator of myogenin expression.We conclude that α-syntrophin plays an important role in regulating myogenesis by modulating myogenin expression

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma

Following an i.p. dose of 150 mg x kg(-1) 5-fluorouracil (5-FU), drug uptake and metabolism over a 2-h period were studied by in vivo (19)F magnetic resonance spectroscopy (MRS) for the murine colon carcinoma lines C26-B (5-FU-insensitive; n=11) and C26-10 (5-FU-sensitive; n=15) implanted s.c. in Balb/C mice. Time courses for tumour growth, intracellular levels of FdUMP, thymidylate synthase (TS) activity, and 5-FU in RNA were also determined, and the effects of a 9.5-min period of carbogen breathing, starting 1 min before drug administration, on MRS-detected 5-FU metabolism and tumour growth curves were examined. Both tumour variants generated MRS-detectable 5-FU nucleotides and showed similar initial growth inhibition after treatment. However, the growth rate of C26-B tumours returned to normal, while the sensitive C26-10 tumours, which produced larger fluoronucleotide pools, still showed moderate growth inhibition. Carbogen breathing did not significantly influence 5-FU uptake or fluoronucleotide production but did significantly enhance growth inhibition in C26-10 tumours. While both tumour variants exhibited incorporation of 5-FU into RNA and inhibition of TS via FdUMP, clearance of 5-FU from RNA and recovery of TS activity were greater for the insensitive C26-B line, indicating that these processes, in addition to 5-FU uptake and metabolism, may be important determinants of drug sensitivity and treatment respons

Perspective of the Surviving Sepsis Campaign on the Management of Pediatric Sepsis in the Era of Coronavirus Disease 2019

Severe acute respiratory syndrome coronavirus 2 is a novel cause of organ dysfunction in children, presenting as either coronavirus disease 2019 with sepsis and/or respiratory failure or a hyperinflammatory shock syndrome. Clinicians must now consider these diagnoses when evaluating children for septic shock and sepsis-associated organ dysfunction. The Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children provide an appropriate framework for the early recognition and initial resuscitation of children with sepsis or septic shock caused by all pathogens, including severe acute respiratory syndrome coronavirus 2. However, the potential benefits of select adjunctive therapies may differ from non-coronavirus disease 2019 sepsis

From Demonstrations to Task-Space Specifications:Using Causal Analysis to Extract Rule Parameterization from Demonstrations

Learning models of user behaviour is an important problem that is broadly applicable across many application domains requiring human-robot interaction. In this work, we show that it is possible to learn generative models for distinct user behavioural types, extracted from human demonstrations, by enforcing clustering of preferred task solutions within the latent space. We use these models to differentiate between user types and to find cases with overlapping solutions. Moreover, we can alter an initially guessed solution to satisfy the preferences that constitute a particular user type by backpropagating through the learned differentiable models. An advantage of structuring generative models in this way is that we can extract causal relationships between symbols that might form part of the user's specification of the task, as manifested in the demonstrations. We further parameterize these specifications through constraint optimization in order to find a safety envelope under which motion planning can be performed. We show that the proposed method is capable of correctly distinguishing between three user types, who differ in degrees of cautiousness in their motion, while performing the task of moving objects with a kinesthetically driven robot in a tabletop environment. Our method successfully identifies the correct type, within the specified time, in 99% [97.8 - 99.8] of the cases, which outperforms an IRL baseline. We also show that our proposed method correctly changes a default trajectory to one satisfying a particular user specification even with unseen objects. The resulting trajectory is shown to be directly implementable on a PR2 humanoid robot completing the same task.Comment: arXiv admin note: substantial text overlap with arXiv:1903.0126