Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy

Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2′deoxyuridine (5F,2′dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2′dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2′dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2′dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy

Quantum Error Correcting Codes Using Qudit Graph States

Graph states are generalized from qubits to collections of $n$ qudits of arbitrary dimension $D$, and simple graphical methods are used to construct both additive and nonadditive quantum error correcting codes. Codes of distance 2 saturating the quantum Singleton bound for arbitrarily large $n$ and $D$ are constructed using simple graphs, except when $n$ is odd and $D$ is even. Computer searches have produced a number of codes with distances 3 and 4, some previously known and some new. The concept of a stabilizer is extended to general $D$, and shown to provide a dual representation of an additive graph code.Comment: Version 4 is almost exactly the same as the published version in Phys. Rev.

Unemployment and Midlife Suicide Rates in Australia 2001-2015: Implications During the COVID-19 Pandemic

The world is experiencing a massive economic shock from the COVID-19 pandemic. Resulting unemployment and socioeconomic disruption have the potential to lead to a major upswing in the population rate of suicide in Europe and elsewhere. We assessed the association between midlife suicide rates and unemployment for Australia. For the midlife group we found a rapid decrease in the rate from 1970s to 1980s, but a more apparent increase after 2007. The increased male suicide rate coincided with the 2008 global financial crisis. The relationship between worsening employment outcomes, including suicide, is a great tragedy and deserves urgent further investigation

Comparison of monsoon variations over groundwater hydrochemistry changes in small Tropical Island and its repercussion on quality

Study on the spatial and temporal distribution of groundwater hydrochemistry in the small tropical islands is important as their insular character may expose the groundwater aquifer to too many sources of pollution, especially salinization. A total of 216 groundwater samples were collected from the monitoring boreholes during two different monsoon seasons; pre- and post-monsoon. As overall, data of groundwater concentration illustrated a trend of Ca > Na > Mg > K and HCO3 > Cl > SO4 dominations with the major finding of two different groundwater types. Pre-monsoon reported Na-HCO3 and Ca-HCO3 types while post-monsoon were only dominated by the Ca-HCO3 type. The statistical analysis shows the in situ parameters (Temp, pH, EC, Salinity, DO, TDS and Eh) and major ions (Ca, Mg, Na, K, HCO3, Cl and SO4) were strongly correlated with the monsoon changes (p < 0.01). From the analysis, its reveals that the seasonal changes have significantly affects the groundwater composition. While, the analytical calculations of the ionic ratio (Na vs. Cl; Cl/HCO3 vs. Cl; Ca + Mg vs. SO4 + HCO3) describes the groundwater is influenced by the cation exchanges processes, simple mixing and water–rock interaction. Saturation indices of carbonate minerals shows strong correlationship (p < 0.01) with Ca constituent indicating solubility on minerals, which led to dissolution or precipitation condition of water. Results of present study contribute to a better understanding of a complex groundwater system and the hydrochemical processes related

In situ XRD studies of the effect of catalyst pre-treatment strategies on the bulk structure and performance of Mo-V-Te-Nb catalysts for selective oxidation of propane.

Current research efforts are concentrated towards utilizing propane rather than propylene as the feedstock in the industrial process for producing acrylic acid because of its significant lower price. The discovery of the MoVTe family of catalysts has brought this goal within sight. This study investigates the effect of different calcination protocols using in situ XRD. A series of catalyst precursors were treated at different calcination temperatures and atmospheres, while analysing their structures with XRD. The conditions necessary for crystallization of known active phases were determined. The activity of the same catalysts was also tested using a nanoflow high throughput reactor. A structure – activity study leads to correlations between synthesis, phase equilibria and performance of these Mo-V-Te-Nb catalysts for selective oxidation of propane

Emotional bias training as a treatment for anxiety and depression: evidence from experimental medicine studies in healthy and medicated samples.

BACKGROUND: Anxiety and depression are leading causes of disability worldwide, yet individuals are often unable to access appropriate treatment. There is a need to develop effective interventions that can be delivered remotely. Previous research has suggested that emotional processing biases are a potential target for intervention, and these may be altered through brief training programs. METHODS: We report two experimental medicine studies of emotional bias training in two samples: individuals from the general population (n = 522) and individuals currently taking antidepressants to treat anxiety or depression (n = 212). Participants, recruited online, completed four sessions of EBT from their own home. Mental health and cognitive functioning outcomes were assessed at baseline, immediately post-training, and at 2-week follow-up. RESULTS: In both studies, our intervention successfully trained participants to perceive ambiguous social information more positively. This persisted at a 2-week follow-up. There was no clear evidence that this change in emotional processing transferred to improvements in symptoms in the primary analyses. However, in both studies, there was weak evidence for improved quality of life following EBT amongst individuals with more depressive symptoms at baseline. No clear evidence of transfer effects was observed for self-reported daily stress, anhedonia or depressive symptoms. Exploratory analyses suggested that younger participants reported greater treatment gains. CONCLUSIONS: These studies demonstrate the effectiveness of delivering a multi-session online training program to promote lasting cognitive changes. Given the inconsistent evidence for transfer effects, EBT requires further development before it can be considered as a treatment for anxiety and depression

Cough and reflux esophagitis in children: their co-existence and airway cellularity

BACKGROUND: There are no prospective studies that have examined for chronic cough in children without lung disease but with gastroesophageal reflux (GER). In otherwise healthy children undergoing flexible upper gastrointestinal endoscopy (esophago-gastroscopy), the aims of the study were to (1) define the frequency of cough in relation to symptoms of GER, (2) examine if children with cough and reflux esophagitis (RE) have different airway cellularity and microbiology in bronchoalveolar lavage (BAL) when compared to those without. METHODS: Data specific for chronic cough (>4-weeks), symptoms of GER and cough severity were collected. Children aged <16-years (n = 150) were defined as 'coughers' (C+) if a history of cough in association with their GER symptoms was elicited before BAL were obtained during elective esophago-gastroscopy. Presence of esophagitis on esophageal biopsies was considered reflux esophagitis positive (E+). RESULTS: C+ (n = 69) were just as likely as C- (n = 81) to have esophagitis, odds ratio 0.87 (95%CI 0.46, 1.7). Median neutrophil percentage in BAL was significantly different between groups; highest in C+E- (7, IQR 28) and lowest in C-E+ (5, IQR 6). BAL positive bacterial culture occurred in 20.7% and were more likely present in current coughers (OR 3.37, 95%CI 1.39, 8.08). Airway neutrophilia (median 20%, IQR 34) was significantly higher in those with BAL positive bacterial cultures than those without (5%, 4; p = 0.0001). CONCLUSION: In children without lung disease, the common co-existence of cough with symptoms of GER is independent of the occurrence of esophagitis. Airway neutrophilia when present in these children is more likely to be related to airway bacterial infection and not to esophagitis

Erratum to:The Neurocognitive Architecture of Individual Differences in Math Anxiety in Typical Children (Scientific Reports, (2018), 8, 1, (8500), 10.1038/s41598-018-26912-5)

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