Seeing the Invisibles:Detection of Peptide Enantiomers, Diastereomers, and Isobaric Ring Formation in Lanthipeptides Using Nanopores

Mass spectrometry (MS) is widely used in proteomic analysis but cannot differentiate between molecules with the same mass-to-charge ratio. Nanopore technology might provide an alternative method for the rapid and cost-effective analysis and sequencing of proteins. In this study, we demonstrate that nanopore currents can distinguish between diastereomeric and enantiomeric differences in l- and d-peptides, not observed by conventional MS analysis, down to individual d-amino acids in small opioid peptides. Molecular dynamics simulations suggest that similar to chiral chromatography the resolution likely arises from multiple chiral interactions during peptide transport across the nanopore. Additionally, we used nanopore recordings to rapidly assess 4- and 11-amino acid ring formation in lanthipeptides, a process used in the synthesis of pharmaceutical peptides. The cyclization step requires distinguishing between constitutional isomers, which have identical MS signals and typically involve numerous tedious experiments to confirm. Hence, nanopore technology offers new possibilities for the rapid and cost-effective analysis of peptides, including those that cannot be easily differentiated by mass spectrometry.</p

Effectiveness of three commonly used transition phase diets in the inpatient management of children with severe acute malnutrition: a pilot randomized controlled trial in Malawi.

BACKGROUND: The case fatality rate of severely malnourished children during inpatient treatment is high and mortality is often associated with diarrhea. As intestinal carbohydrate absorption is impaired in severe acute malnutrition (SAM), differences in dietary formulations during nutritional rehabilitation could lead to the development of osmotic diarrhea and subsequently hypovolemia and death. We compared three dietary strategies commonly used during the transition of severely malnourished children to higher caloric feeds, i.e., F100 milk (F100), Ready-to-Use Therapeutic Food (RUTF) and RUTF supplemented with F75 milk (RUTF + F75). METHODS: In this open-label pilot randomized controlled trial, 74 Malawian children with SAM aged 6-60 months, were assigned to either F100, RUTF or RUTF + F75. Our primary endpoint was the presence of low fecal pH (pH ? 5.5) measured in stool collected 3 days after the transition phase diets were introduced. Secondary outcomes were duration of hospital stay, diarrhea and other clinical outcomes. Chi-square test, two-way analysis of variance and logistic regression were conducted and, when appropriate, age, sex and initial weight for height Z-scores were included as covariates. RESULTS: The proportion of children with acidic stool (pH ?5.5) did not significantly differ between groups before discharge with 30, 33 and 23% for F100, RUTF and RUTF + F75, respectively. Mean duration of stay after transitioning was 7.0 days (SD 3.4) with no differences between the three feeding strategies. Diarrhea was present upon admission in 33% of patients and was significantly higher (48%) during the transition phase (p < 0.05). There was no significant difference in mortality (n = 6) between diets during the transition phase nor were there any differences in other secondary outcomes. CONCLUSIONS: This pilot trial does not demonstrate that a particular transition phase diet is significantly better or worse since biochemical and clinical outcomes in children with SAM did not differ. However, larger and more tightly controlled efficacy studies are needed to confirm these findings. TRIAL REGISTRATION: ISRCTN13916953 Registered: 14 January 2013

Urinary Organic Acids Increase After Clinical Stabilization of Hospitalized Children With Severe Acute Malnutrition

Background: Despite a reduction of child mortality in low-income countries, acutely ill undernourished children still have an elevated risk of death. Those at highest risk are children with severe acute malnutrition (SAM) who often show metabolic dysregulations that remains poorly understood. Objective: We performed a pilot study to examine changes in urinary organic acids during nutritional rehabilitation of children with SAM, and to identify metabolites associated with the presence of edema or with mortality. Methods: This study included 76 children aged between 6 and 60 months, hospitalized for SAM at the Moyo Nutritional Rehabilitation and Research Unit in Blantyre, Malawi. Urine was collected at admission and 3 days after clinical stabilization and metabolomics were performed using gas chromatography-mass spectrometry. Metabolite concentrations were evaluated with both uni- and multivariate approaches. Results: Most metabolites increased 3 days after clinical stabilization, and total urinary concentration changed from 1.2 mM (interquartile range [IQR], 0.78-1.7) at admission to 3.8 mM (IQR, 2.1-6.6) after stabilization (P <.0001). In particular, 6 metabolites showed increases: 3-hydroxybutyric, 4-hydroxyhippuric, p-hydroxyphenylacetic, oxoglutaric, succinic, and lactic acids. Urinary creatinine was low at both time points, but levels did increase from 0.63 mM (IQR, 0.2-1.2) to 2.6 mM (IQR,1.6-4.4; P <.0001). No differences in urinary profiles were found between children who died versus those who survived, nor between children with severe wasting or edematous SAM. Conclusions: Total urinary metabolites and creatinine increase after stabilization and may reflect partial recovery of overall metabolism linked to refeeding. The use of urinary metabolites for risk assessment should be furthered explored

Optimum single-gap solar cells for missions to Mercury

The power supply for space probes is usually based on photovoltaic (PV) systems. The first solar cells used in these systems were single-gap solar cells fabricated with Si and GaAs. Later on, multijunction solar cells (MJSC) based on III–V semiconductors were developed because of their higher efficiency and tolerance to a radiation environment [1]. All these solar cells have been based on semiconductors that fulfill the needs of most near-Earth missions. However, those same semiconductors fail to meet the needs of some other missions involving harsh environments such as high-intensity high-temperature (HIHT) environments [2]. In this work, we investigate which semiconductor material is optimum to implement single-gap solar cells for missions to Mercury, where HIHT conditions are expected. Because solar cell efficiency decreases as temperature increases [3], achieving high-efficiency photovoltaic conversion at HIHT conditions is a big challenge. Previous works have pointed out the need of using wide-bandgap semiconductors to reach this goal [4,5]. In this context, we will study the potential of solar cells based on AlxGa1−xAs, a well-known semiconductor whose physical properties have been extensively investigated. The limiting efficiency of these solar cells performing in near-Mercury missions will be calculated to determine the optimum composition for AlxGa1−xAs

Manifestation and parental assessment of children’s cancer pain at home: an exploratory mixed methods study

Aims and objectives To describe pain manifestation in children with cancer at home and understand how parents assess this pain. Background Pain is experienced by children with cancer throughout their cancer journey. Short‐term, and into survivorship, pain has negative physical and psychological consequences. Changes in treatment location mean children with cancer spend more time at home. Little is known about pain experienced by children at home or how parents assess this pain. Design A mixed methods convergent parallel study was reported using STROBE. Method Parents of children with cancer on active treatment were recruited from one tertiary cancer centre. Parental attitudes towards pain expression were assessed using surveys. Parents recorded their child’s pain manifestation in pain diaries kept for one month. Interviews captured a deeper understanding of pain manifestation and how parents assess this pain at home. Integration occurred after each data collection method was analysed separately. Results Predominantly children were not in pain at home. However, most children experienced at least one episode of problematic pain over the pain diary period. Surveys showed parents held misconceptions regarding children’s pain expression. Interviews diverge from surveys and suggest parents used a range of information sources to assess pain. Conclusion Children with cancer may differ from one another in the manifestation of pain at home resulting in multiple pain trajectories. Parents of children with cancer are able to adequately assess their child’s pain using information from multiple source

Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation:an observational cohort study

Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear.Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM.Design: Intestinal pathogens (n = 15), cytokines (n= 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling.Results: Fatal subjects (n = 14; 18%) were younger (mean +/- SD age: 17 +/- 11 compared with 25 +/- 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800 [49 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation.Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies.</p

Performance of the LHCb Vertex Detector Alignment Algorithm determined with Beam Test Data

LHCb is the dedicated heavy flavour experiment at the Large Hadron Collider at CERN. The partially assembled silicon vertex locator (VELO) of the LHCb experiment has been tested in a beam test. The data from this beam test have been used to determine the performance of the VELO alignment algorithm. The relative alignment of the two silicon sensors in a module and the relative alignment of the modules has been extracted. This alignment is shown to be accurate at a level of approximately 2 micron and 0.1 mrad for translations and rotations, respectively in the plane of the sensors. A single hit precision at normal track incidence of about 10 micron is obtained for the sensors. The alignment of the system is shown to be stable at better than the 10 micron level under air to vacuum pressure changes and mechanical movements of the assembled system.Comment: accepted for publication in NIM