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BackgroundPreterm birth is associated with decreased nephron endowment. Currently, there is no reliable non-invasive biomarker to identify or monitor decreased nephron number in at-risk patients. Urinary Kidney Injury Molecule-1 (KIM-1) is a biomarker of acute and chronic renal injury. We measured urinary KIM-1 among a wide array of other potential biomarkers.MethodsWe conducted an ambispective cohort study of 5-years-old children born prematurely and healthy controls identified from city schools. Detailed anthropometrics, renal ultrasound dimensions, and biochemical parameters were measured. Urinary KIM-1 was measured using Luminex® technology. Age independent z-scores were calculated and compared. Spearman correlations were used for estimating the association between measures and KIM-1.ResultsWe enrolled 129 children, 97 (75.2%) born pre-term and 32 (24.8%) healthy controls born at full-term. Pre-term patients had significantly lower weight and body surface area than controls. Pre-term patients and controls did not differ in current age, sex, race, height, blood pressure, urinary sodium, fractional sodium excretion, serum creatinine and estimated GFR. All spearman correlation between KIM-1 and gestational age, renal and serum measurements were weak without statistical significanceConclusionIn 5-year-old children born prematurely, KIM-1 was not correlated with gestational age. Further prospective studies need to confirm this finding.

BACKGROUND Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. METHODS We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. RESULTS The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). CONCLUSIONS These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

The COVID-19 pandemic dramatically affected parks and protected areas and overall recreation visitation across the United States. While outdoor recreation has been demonstrated to be beneficial, especially during a pandemic, the resulting increase in recreation visitation raises concerns regarding the broader influence of social, situational, ecological, and behavioral factors upon overall visitor experiences. This study investigated the extent to which recreation visitors’ behaviors and experiences have been impacted by the COVID-19 pandemic within the White Mountain National Forest (WMNF). A modified drop-off pick-up survey method was employed to collect population-level data from WMNF visitors from June to August of 2020 (n=317), at the height of the pandemic. Results from this mixed-method study suggest social factors (e.g., crowding and conflict), situational factors (e.g., access and closures), ecological factors (e.g., vegetation damage), behavioral factors (e.g., substitution), and sociodemographic factors (e.g., gender and income) significantly influenced overall visitor decision-making and experience quality within the WMNF. For example, more than one-third of visitors indicated the pandemic had either a major or severe impact upon their WMNF recreation experience. A more nuanced investigation of qualitative data determined that the majority of pandemic-related recreation impacts revolved around the themes of social impacts, general negative recreation impacts, situational and ecological impacts, and behavioral adaptation impacts. Moreover, historically marginalized populations (e.g., low-income households and females) within the sample reported significantly higher recreation experience impacts during the pandemic. This study demonstrates the influence of the pandemic upon outdoor recreation visitor experiences and behaviors and considers outdoor recreation as a central component within the broader social-ecological systems framework. This study demonstrates the influence of the pandemic upon outdoor recreation visitor experiences and behaviors and considers resource users a central component within the broader social-ecological systems conceptual framework.

The synthesis, characterization and reactivity studies of the NHC-stabilized complex IDipp ⋅ GeH2BH2OTf (1) (IDipp=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) are reported. Nucleophilic substitution of the triflate (OTf) group in 1 by phosphine or arsine donors provides access to the cationic group 13/14/15 chains [IDipp ⋅ GeH2BH2ERR1R2]+ (2 E=P; R, R1=H; R2=tBu; 3 E=P; R=H; R1, R2=Ph; 4 a E=P; R, R1, R2=Ph; 4 b E=As; R, R1, R2=Ph). These novel cationic chains were characterized by X-ray crystallography, NMR spectroscopy and mass spectrometry. Moreover, the formation of the parent complexes [IDipp ⋅ GeH2BH2PH3][OTf] (5) and [IDipp ⋅ GeH3][OTf] (6) were achieved by reaction of 1 with PH3. Accompanying DFT computations give insight into the stability of the formed chains with respect to their decomposition.

Eukaryotic messenger RNA (mRNA) is modified by the addition of an inverted guanosine cap to the 5' triphosphate. The cap guanosine and initial transcribed nucleotides are further methylated by a series of cap methyltransferases to generate the mature cap structures which protect RNA from degradation and recruit proteins involved in RNA processing and translation. Research demonstrating that the cap methyltransferases are regulated has generated interest in determining the methylation status of the mRNA cap structures present in cells. Here, we present CAP-MAP: cap analysis protocol with minimal analyte processing, a rapid and sensitive method for detecting cap structures present in mRNA isolated from tissues or cultured cells.

The current revolution in quantum technologies relies on the ability to isolate, coherently control, and measure the state of quantum systems. The act of measurement in quantum mechanics, however, is naturally invasive as the measurement apparatus becomes entangled with the system that it observes. Even for ideal detectors, the measurement outcome always leads to a disturbance in the observed system, a phenomenon called quantum measurement backaction. Here we report a profound change in the many-body properties of the measured system due to quantum measurements. We observe this backaction-induced transition in a mesoscopic double quantum-dot in the Coulomb-blockade regime, where we switch the electron population through measurement with a charge sensor dot. Our finding showcases the important changes in behaviour that can arise due to quantum detectors, which are ubiquitous in quantum technologies., Comment: 6 pages with 4 figures, supplementary: 8 pages with 8 figures. Comments welcome

Leishmaniases are a set of tropical and sub-tropical diseases caused by protozoan parasites of the genus Leishmania whose severity ranges from self-healing cutaneous lesions to fatal visceral infections. Leishmania parasites synthesise a wide array of cell surface and secreted glycoconjugates that play important roles in infection. These glycoconjugates are particularly abundant in the promastigote form and known to be essential for establishment of infection in the insect midgut and effective transmission to the mammalian host. Since they are rich in galactose, their biosynthesis requires an ample supply of UDP-galactose. This nucleotide-sugar arises from epimerisation of UDP-glucose but also from an uncharacterised galactose salvage pathway. In this study, we evaluated the role of the newly characterised UDP-sugar pyrophosphorylase (USP) of Leishmania major in UDP-galactose biosynthesis. Upon deletion of the USP encoding gene, L. major lost the ability to synthesise UDP-galactose from galactose-1-phosphate but its ability to convert glucose-1-phosphate into UDP-glucose was fully maintained. Thus USP plays a role in UDP-galactose activation but does not significantly contribute to the de novo synthesis of UDP-glucose. Accordingly, USP was shown to be dispensable for growth and glycoconjugate biosynthesis under standard growth conditions. However, in a mutant seriously impaired in the de novo synthesis of UDP-galactose (due to deficiency of the UDP-glucose pyrophosphorylase) addition of extracellular galactose increased biosynthesis of the cell surface lipophosphoglycan. Thus under restrictive conditions, such as those encountered by Leishmania in its natural habitat, galactose salvage by USP may play a substantial role in biosynthesis of the UDP-galactose pool. We hypothesise that USP recycles galactose from the blood meal within the midgut of the insect for synthesis of the promastigote glycocalyx and thereby contributes to successful vector infection.

European Commission FP7 Marie Curie Initial Training Network ‘ParaMet’ [290080 to S.S.]; ANR project MetaboHub [ANR-11-INBS-0010 to B.M.]; Wellcome Trust [085349]; The work of Fiona Achcar was part of the SysMO SilicoTryp project coordinated by R.B. Funding for open access charge: European Commission FP7 Marie Curie Initial Training Network ‘ParaMet’ [290080]. The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individual metabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome. Metabolic network databases are of increasing importance in allowing us to contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments. Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes the generic and condition-specific metabolic network of Trypanosoma brucei, a parasitic protozoan responsible for human and animal African trypanosomiasis. In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have also implemented a network-based representation of the information through MetExplore, yielding a novel environment in which to visualise the metabolism of this important parasite. Publisher PDF

A strong coupling between an electronic cavity and a quantum dot has been recently demonstrated [Phys. Rev. Lett. 115, 166603 (2015)] and described in a comprehensive theoretical framework [Phys. Rev. B 96, 235431 (2017)]. Here, we focus on the signatures that demonstrate the cavity's impact on inelastic singlet-triplet transport through the dot. We find the same transport signatures in the experiment as predicted by the model that describes the coupled dot--cavity system. Interestingly, a lowest-order treatement of the coupling to the electronic leads on top of an exact diagonalisation of the dot-cavity system is sufficient to highlight the interplay between the cavity and the higher-order inelastic singlet-triplet cotunneling., Comment: 8 pages, 3 figures, comments welcome

Triflate salts of trications [(bipy)2E]3+ ([6E][OTf]3) and [(tbbipy)2E]3+ ([6′E][OTf]3) (bipy = 2,2′-bipyridine, tbbipy = 4,4′-di-tbutyl-2,2′-bipyridine; E = P, As, Sb, Bi) have been synthesized and comprehensively characterized., Triflate salts of trications [(bipy)2E]3+ ([6E][OTf]3) and [(tbbipy)2E]3+ ([6′E][OTf]3) (bipy = 2,2′-bipyridine, tbbipy = 4,4′-di-tbutyl-2,2′-bipyridine; E = P, As, Sb, Bi) have been synthesized and comprehensively characterized. The unique molecular and electronic structures of this new class of complexes involving pnictogen Lewis acids has been assessed in the solid, solution and gas phases to reveal systematic variations in metric parameters, ligand lability and charge concentration. While the Lewis acidity of E3+ has the trend E = Bi < Sb < As < P as determined by gas-phase calculations and 1H NMR spectroscopy, the Lewis acidity of [6E]3+ has the trend E = P < As < Sb < Bi according to gas-phase calculations. Derivatives of [6′E][OTf]3 (E = P, As) are latent sources of E(OTf)3 as demonstrated by their reactions with dmap, which give the corresponding derivatives of [(dmap)3E][OTf]3. The highly oxidizing nature of P(OTf)3 and As(OTf)3 is evidenced in reactions of [6′E][OTf]3 (E = P, As) with phosphines, which give EI-containing monocations [(R3P)2E]1+ and oxidatively coupled dications [R3PPR3]2+, illustrating new P–P and P–As bond forming strategies. Cations [6′E]3+ (E = P, As) are C–H bond activating agents that dehydrogenate 1,4-cyclohexadiene, with higher activity observed for E = P. Combinations of [6′E]3+ and tBu3P activate H2 and D2 under mild conditions, evidencing frustrated Lewis pair activity. Oxidation of [6′P][OTf]3 with SO2Cl2 gives [(tbbipy)2PCl2][OTf]3, containing a PV-trication, but there is no evidence of the analogous reaction with [6′As][OTf]3. The observations highlight new directions in the chemistry of highly charged cations and reveal a rich reactivity for p-block triflates E(OTf)3, which can be accessed through derivatives of [6E][OTf]3 and [6′E][OTf]3.

Trypanosoma brucei is the causative agent of human African sleeping sickness and the cattle disease nagana. T. brucei is dependent on glycoproteins for its survival and infectivity throughout its life cycle. Here we report the functional characterization of TbGT3, a glycosyltransferase expressed in the bloodstream and procyclic-form of the parasite. Bloodstream and procyclic-form TbGT3 conditional null mutants were created and both exhibited normal growth under permissive and non-permissive conditions. Under non-permissive conditions, the normal glycosylation of the major glycoprotein of bloodstream form T. brucei, the variant surface glycoprotein, and the absence of major alterations in lectin binding to other glycoproteins suggested that the major function of TbGT3 occurs in the procyclic form of the parasite. Consistent with this, the major surface glycoprotein of the procyclic form, procyclin, exhibited a marked reduction in molecular weight due to changes in glycosylphosphatidylinositol (GPI) anchor side-chains. Structural analysis of the mutant procyclin GPI anchors indicated that TbGT3 encodes a UDP-Gal: beta-GlcNAc-GPI beta1-3 Gal transferase. Despite the alterations in GPI anchor side chains, TbGT3 conditional null mutants remained infectious to tsetse flies under non-permissive conditions.

BACKGROUND: The diagnosis of Human African Trypanosomiasis relies mainly on the Card Agglutination Test for Trypanosomiasis (CATT). While this test is successful, it is acknowledged that there may be room for improvement. Our aim was to develop a prototype lateral flow test based on the detection of antibodies to trypanosome antigens. METHODOLOGY/PRINCIPAL FINDINGS: We took a non-biased approach to identify potential immunodiagnostic parasite protein antigens. The IgG fractions from the sera from Trypanosoma brucei gambiense infected and control patients were isolated using protein-G affinity chromatography and then immobilized on Sepharose beads. The IgG-beads were incubated with detergent lysates of trypanosomes and those proteins that bound were identified by mass spectrometry-based proteomic methods. This approach provided a list of twenty-four trypanosome proteins that selectively bound to the infection IgG fraction and that might, therefore, be considered as immunodiagnostic antigens. We selected four antigens from this list (ISG64, ISG65, ISG75 and GRESAG4) and performed protein expression trials in E. coli with twelve constructs. Seven soluble recombinant protein products (three for ISG64, two for ISG65 and one each for ISG75 and GRESAG4) were obtained and assessed for their immunodiagnostic potential by ELISA using individual and/or pooled patient sera. The ISG65 and ISG64 construct ELISAs performed well with respect to detecting T. b. gambiense infections, though less well for detecting T. b. rhodesiense infections, and the best performing ISG65 construct was used to develop a prototype lateral flow diagnostic device. CONCLUSIONS/SIGNIFICANCE: Using a panel of eighty randomized T. b. gambiense infection and control sera, the prototype showed reasonable sensitivity (88%) and specificity (93%) using visual readout in detecting T. b. gambiense infections. These results provide encouragement to further develop and optimize the lateral flow device for clinical use.

Trypanosoma cruzi, the etiological agent of Chagas' disease, affects 8 million people predominantly living in socioeconomic underdeveloped areas. T. cruzi trypomastigotes (Ty), the classical infective stage, interact with the extracellular matrix (ECM), an obligatory step before invasion of almost all mammalian cells in different tissues. Here we have characterized the proteome and phosphoproteome of T. cruzi trypomastigotes upon interaction with ECM (MTy) and the data are available via ProteomeXchange with identifier PXD010970. Proteins involved with metabolic processes (such as the glycolytic pathway), kinases, flagellum and microtubule related proteins, transport-associated proteins and RNA/DNA binding elements are highly represented in the pool of proteins modified by phosphorylation. Further, important metabolic switches triggered by this interaction with ECM were indicated by decreases in the phosphorylation of hexokinase, phosphofructokinase, fructose-2,6-bisphosphatase, phosphoglucomutase, phosphoglycerate kinase in MTy. Concomitantly, a decrease in the pyruvate and lactate and an increase of glucose and succinate contents were detected by GC-MS. These observations led us to focus on the changes in the glycolytic pathway upon binding of the parasite to the ECM. Inhibition of hexokinase, pyruvate kinase and lactate dehydrogenase activities in MTy were observed and this correlated with the phosphorylation levels of the respective enzymes. Putative kinases involved in protein phosphorylation altered upon parasite incubation with ECM were suggested by in silico analysis. Taken together, our results show that in addition to cytoskeletal changes and protease activation, a reprogramming of the trypomastigote metabolism is triggered by the interaction of the parasite with the ECM prior to cell invasion and differentiation into amastigotes, the multiplicative intracellular stage of T. cruzi in the vertebrate host.