Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein

The adenosine A2A receptor (A2AR) is a prototypical G protein-coupled receptor (GPCR) that couples to the heterotrimeric G protein GS. Here, we determine the structure by electron cryo-microscopy (cryo-EM) of A2AR at pH 7.5 bound to the small molecule agonist NECA and coupled to an engineered heterotrimeric G protein, which contains mini-GS, the βγ subunits and nanobody Nb35. Most regions of the complex have a resolution of ~3.8 Å or better. Comparison with the 3.4 Å resolution crystal structure shows that the receptor and mini-GS are virtually identical and that the density of the side chains and ligand are of comparable quality. However, the cryo-EM density map also indicates regions that are flexible in comparison to the crystal structures, which unexpectedly includes regions in the ligand binding pocket. In addition, an interaction between intracellular loop 1 of the receptor and the β subunit of the G protein was observed

Breastfeeding and the risk of dental caries: a systematic review and meta-analysis

Aim To synthesise the current evidence for the associations between breastfeeding and dental caries, with respect to specific windows of early childhood caries risk. Methods Systematic review, meta-analyses and narrative synthesis following searches of PubMed, CINAHL and EMBASE databases. Results Sixty-three papers included. Children exposed to longer versus shorter duration of breastfeeding up to age 12 months (more versus less breastfeeding), had a reduced risk of caries (OR 0.50; 95%CI 0.25, 0.99, I2 86.8%). Children breastfed > 12 months had an increased riskof caries when compared with children breastfed 12 months, those fed nocturnally or more frequently had afurther increased caries risk (five studies, OR 7.14; 3.14, 16.23, I2 77.1%). There was a lack of studies on children aged > 12 months simultaneously assessing caries risk in breastfed, bottle-fed and children not bottle or breastfed, alongside specific breastfeeding practices, consuming sweet drinks and foods, and oral hygiene practices limiting our ability to tease out the risks attributable to each. Conclusion Breastfeeding in infancy may protect against dental caries. Further research needed to understand the increased risk of caries in children breastfed after 12 month

Resting energy expenditure by indirect calorimetry versus the ventilator-VCO2 derived method in critically ill patients: The DREAM-VCO2 prospective comparative study

Background & aims: Both overfeeding and underfeeding of intensive care unit (ICU) patients are associated with worse outcomes. Predictive equations of nutritional requirements, though easily implemented, are highly inaccurate. Ideally, the individual caloric target is based on the frequent assessment of energy expenditure (EE). Indirect calorimetry is considered the gold standard but is not always available. EE estimated by ventilator-derived carbon dioxide consumption (EEVCO2) has been proposed as an alternative to indirect calorimetry, but there is limited evidence to support the use of this method. Methods: We prospectively studied a cohort of adult critically ill patients requiring mechanical ventilation and artificial nutrition. We aimed to compare the performance of the EEVCO2 with the EE measured by indirect calorimetry through the calculation of bias and precision (accuracy), agreement, reliability and 10% accuracy rates. The effect of including the food quotient (nutrition intake derived respiratory quotient) in contrast to a fixed respiratory quotient (0.86), into the EEVCO2 formula was also evaluated. Results: In 31 mechanically ventilated patients, a total of 414 paired measurements were obtained. The mean estimated EEVCO2 was 2134 kcal/24 h, and the mean estimated EE by indirect calorimetry was 1623 kcal/24 h, depicting a significant bias of 511 kcal (95% CI 467–560, p < 0.001). The precision of EEVCO2 was low (lower and upper limit of agreement −63.1 kcal and 1087. o kcal), the reliability was good (intraclass correlation coefficient 0.613; 95% CI 0.550–0.669, p < 0.001) and the 10% accuracy rate was 7.0%. The food quotient was not significantly different from the respiratory quotient (0.870 vs. 0.878), with a small bias of 0.007 (95% CI 0.000–0.015, p = 0.54), low precision (lower and upper limit of agreement −0.16 and 0.13), poor reliability (intraclass correlation coefficient 0.148; 95% CI 0.053–0.240, p = 0.001) and a 10% accuracy rate of 77.5%. Estimated mean EEVCO2, including the food quotient, was 2120 kcal/24 h, with a significant bias of 496 kcal (95% CI 451–542; p < 0.001) and low precision (lower and upper limit of agreement −157.6 kcal and 1170.3 kcal). The reliability with EE estimated by indirect calorimetry was good (intraclass correlation coefficient 0.610, 95% CI 0.550–0.661, p < 0.001), and the 10% accuracy rate was 9.2%. Conclusions: EEVCO2, compared with indirect calorimetry, overestimates actual energy expenditure. Although the reliability is acceptable, bias is significant, and the precision and accuracy rates are unacceptably low when the VCO2 method is used. Including the food quotient into the EEVCO2 equation does not improve its performance. Predictive equations, although inaccurate, may even predict energy expenditure better compared with the VCO2-method. Indirect calorimetry remains the gold standard method

Mg3(Bi,Sb)2 single crystals towards high thermoelectric performance

The rapid growth of the thermoelectric cooler market makes the development of novel room temperature thermoelectric materials of great importance. Ternary n-type Mg3(Bi,Sb)2 alloys are promising alternatives to the state-of-the-art Bi2(Te,Se)3 alloys but grain boundary resistance is the most important limitation. n-type Mg3(Bi,Sb)2 single crystals with negligible grain boundaries are expected to have particularly high zT but have rarely been realized due to the demanding Mg-rich growth conditions required. Here, we report, for the first time, the thermoelectric properties of n-type Mg3(Bi,Sb)2 alloyed single crystals grown by a one-step Mg-flux method using sealed tantalum tubes. High weighted mobility ∼140 cm2 V−1 s−1 and a high zT of 0.82 at 315 K are achieved in Y-doped Mg3Bi1.25Sb0.75 single crystals. Through both experimental angle-resolved photoemission spectroscopy and theoretical calculations, we denote the origin of the high thermoelectric performance from a point of view of band widening effect and electronegativity, as well as the necessity to form high Bi/Sb ratio ternary Mg3(Bi,Sb)2 alloys. The present work paves the way for further development of Mg3(Bi,Sb)2 for near room temperature thermoelectric applications

Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice

Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signali ng to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution

Thermoelectric Properties of Novel Semimetals: A Case Study of YbMnSb2

The emerging class of topological materials provides a platform to engineer exotic electronic structures for a variety of applications. As complex band structures and Fermi surfaces can directly benefit thermoelectric performance it is important to identify the role of featured topological bands in thermoelectrics particularly when there are coexisting classic regular bands. In this work, the contribution of Dirac bands to thermoelectric performance and their ability to concurrently achieve large thermopower and low resistivity in novel semimetals is investigated. By examining the YbMnSb2 nodal line semimetal as an example, the Dirac bands appear to provide a low resistivity along the direction in which they are highly dispersive. Moreover, because of the regular-band-provided density of states, a large Seebeck coefficient over 160 µV K−1 at 300 K is achieved in both directions, which is very high for a semimetal with high carrier concentration. The combined highly dispersive Dirac and regular bands lead to ten times increase in power factor, reaching a value of 2.1 mW m−1 K−2 at 300 K. The present work highlights the potential of such novel semimetals for unusual electronic transport properties and guides strategies towards high thermoelectric performance. © 2020 The Authors. Advanced Materials published by Wiley-VCH Gmb

Quantification of diffuse auroral electron precipitation driven by whistler mode waves at Jupiter

While previous studies suggested whistler mode waves as a potential driver of Jupiter's diffuse aurora, their quantitative contribution to generate diffuse aurora remains unclear. We perform an in-depth analysis of an intriguing diffuse auroral electron precipitation event using coordinated observations of precipitating electrons and whistler mode waves from the Juno satellite. A physics-based technique is used to quantify energetic electron precipitation driven by whistler mode waves. We find that the modeled electron precipitation features are consistent with the electron measurements from several keV to several hundred keV over M-shells of 8–18, while additional mechanisms are needed to explain the observed electron precipitation at lower energies (<several keV). Our result provides new quantitative evidence that whistler mode waves are potentially a primary driver of precipitating electrons from several keV to several hundred keV through pitch angle scattering over M ∼ 8–18 and thus generate Jupiter's diffuse aurora.Accepted manuscrip

Co-Morbidity between Early-Onset Leukemia and Type 1 Diabetes – Suggestive of a Shared Viral Etiology?

Background: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are common early-onset malignancies. Their causes are largely unknown but infectious etiology has been implicated. Type 1 diabetes (T1D) is an autoimmune disease for which infectious triggers of disease onset have been sought and increasing pointing to enteroviruses. Based on our previous results on co-morbidity between leukemia and T1D, we updated the Swedish dataset and focused on early onset leukemias in patients who had been hospitalized for T1D, comparing to those not hospitalized for T1D. Methods and Findings: Standardized incidence ratios (SIRs) were calculated for leukemia in 24,052 patients hospitalized for T1D covering years 1964 through 2008. T1D patients were included if hospitalized before age 21 years. Practically all Swedish children and adolescents with T1D are hospitalized at the start of insulin treatment. SIR for ALL was 8.30 (N = 18, 95% confidence interval 4.91-13.14) when diagnosed at age 10 to 20 years after hospitalization for T1D and it was 3.51 (13, 1.86-6.02) before hospitalization for T1D. The SIR for ALL was 19.85 (N = 33, 13.74-27.76) and that for AML was 25.28 (8, 10.80-50.06) when the leukemias were diagnosed within the year of T1D hospitalization. The SIRs increased to 38.97 (26, 25.43-57.18) and 40.11 (8, 17.13-79.42) when T1D was diagnosed between ages 10 to 20 years. No consistent time-dependent changes were found in leukemia risk. Conclusion: A shared infectious etiology could be a plausible explanation to the observed co-morbidity. Other possible contributing factors could be insulin therapy or T1D related metabolic disturbances

Higher incidence of perineal community acquired MRSA infections among toddlers

<p>Abstract</p> <p>Background</p> <p>A six-fold increase in pediatric MRSA infections, prompted us to examine the clinical profile of children with MRSA infections seen at Mercy Children's Hospital, Toledo, Ohio and to characterize the responsible strains.</p> <p>Methods</p> <p>Records were reviewed of pediatric patients who cultured positive for MRSA from June 1 to December 31, 2007. Strain typing by pulsed field gel electrophoresis (PFT) and DiversiLab, SCC<it>mec </it>typing, and PCR-based <it>lukSF-PV </it>gene (encodes Panton-Valentine leukocidin), arginine catabolic mobile element (ACME) and <it>cap</it>5 gene detection was performed.</p> <p>Results</p> <p>Chart review of 63 patients with MRSA infections revealed that 58(92%) were community acquired MRSA (CAMRSA). All CAMRSA were skin and soft tissue infections (SSTI). Twenty five (43%) patients were aged < 3 yrs, 19(33%) aged 4-12 and 14(24%) aged 13-18. Nineteen (76%) of those aged < 3 yrs had higher incidence of perineal infections compared to only 2(11%) of the 4-12 yrs and none of the 13-18 yrs of age. Infections in the extremities were more common in the older youth compared to the youngest children. Overall, there was a significant association between site of the infection and age group (Fisher's Exact p-value < 0.001). All CAMRSA were USA300 PFT, clindamycin susceptible, SCC<it>mec </it>type IVa and <it>lukSF-PV gene </it>positive. Nearly all contained ACME and about 80% were <it>cap</it>5 positive. Of the 58 USA300 strains by PFT, 55(95%) were also identified as USA300 via the automated repetitive sequence-based PCR method from DiversiLab.</p> <p>Conclusions</p> <p>CAMRSA SSTI of the perineum was significantly more common among toddlers and that of the extremities in older children. The infecting strains were all USA300 PFT. Further studies are needed to identify the unique virulence and colonization characteristics of USA300 strains in these infections.</p