The chemistry of ZnWO₄ nanoparticle formation

The need for a change away from classical nucleation and growth models for the description of nanoparticle formation is highlighted. By the use of in situ total X-ray scattering experiments the transformation of an aqueous polyoxometalate precursor mixture to crystalline ZnWO$_{4}$ nanoparticles under hydrothermal conditions was followed. The precursor solution is shown to consist of specific Tourné-type sandwich complexes. The formation of pristine ZnWO$_{4}$ within seconds is understood on the basis of local restructuring and three-dimensional reordering preceding the emergence of long range order in ZnWO$_{4}$ nanoparticles. An observed temperature dependent trend in defect concentration can be rationalized based on the proposed formation mechanism. Following nucleation the individual crystallites were found to grow into prolate morphology with elongation along the unit cell c-direction. Extensive electron microscopy characterization provided evidence for particle growth by oriented attachment; a notion supported by sudden particle size increases observed in the in situ total scattering experiments. A simple continuous hydrothermal flow method was devised to synthesize highly crystalline monoclinic zinc tungstate (ZnWO$_{4}$) nanoparticles in large scale in less than one minute. The present results highlight the profound influence of structural similarities in local structure between reactants and final materials in determining the specific nucleation of nanostructures and thus explains the potential success of a given synthesis procedure in producing nanocrystals. It demonstrates the need for abolishing outdated nucleation models, which ignore subtle yet highly important system dependent differences in the chemistry of the forming nanocrystals

Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson’s disease. The two aromatic amino acids (L)-Trp and (L)-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization

The orphan G protein-coupled receptor GPR139 is activated by the peptides:Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC(50) values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle “similar targets bind similar ligands”, we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca(2+)-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH(1-9) was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH(1-9). Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides

Age-related patterns of vigorous-intensity physical activity in youth:the International Children’s Accelerometry Database

Abstract Physical activity declines during youth but most evidence reports on combined moderate and vigorous-intensity physical activity. We investigated how vigorous-intensity activity varies with age. Cross-sectional data from 24,025 participants (5.0–18.0 y; from 20 studies in 10 countries obtained 2008–2010) providing ≥ 1 day accelerometer data (International Children's Accelerometry Database (ICAD)). Linear regression was used to investigate age-related patterns in vigorous-intensity activity; models included age (exposure), adjustments for monitor wear-time and study. Moderate-intensity activity was examined for comparison. Interactions were used to investigate whether the age/vigorous-activity association differed by sex, weight status, ethnicity, maternal education and region. A 6.9% (95% CI 6.2, 7.5) relative reduction in mean vigorous-intensity activity with every year of age was observed; for moderate activity the relative reduction was 6.0% (5.6%, 6.4%). The age-related decrease in vigorous-intensity activity remained after adjustment for moderate activity. A larger age-related decrease in vigorous activity was observed for girls (− 10.7%) versus boys (− 2.9%), non-white (− 12.9% to − 9.4%) versus white individuals (− 6.1%), lowest maternal education (high school (− 2.0%)) versus college/university (ns) and for overweight/obese (− 6.1%) versus healthy-weight participants (− 8.1%). In addition to larger annual decreases in vigorous-intensity activity, overweight/obese individuals, girls and North Americans had comparatively lower average vigorous-intensity activity at 5.0–5.9 y. Age-related declines in vigorous-intensity activity during youth appear relatively greater than those of moderate activity. However, due to a higher baseline, absolute moderate-intensity activity decreases more than vigorous. Overweight/obese individuals, girls, and North Americans appear especially in need of vigorous-intensity activity promotion due to low levels at 5.0–5.9 y and larger negative annual differences

Influence of Guideline Operationalization on Youth Activity Prevalence in the International Children's Accelerometry Database

Introduction The United Kingdom and World Health Organization recently changed their youth physical activity (PA) guidelines from 60 min of moderate- to vigorous-intensity PA (MVPA) every day, to an average of 60 min of MVPA per day, over a week. The changes are based on expert opinion due to insufficient evidence comparing health outcomes associated with different guideline definitions. This study used the International Children’s Accelerometry Database to compare approaches to calculating youth PA compliance and associations with health indicators. Methods Cross-sectional accelerometer data (n = 21,612, 5–18 yr) were used to examine compliance with four guideline definitions: daily method (DM; ≥60 min MVPA every day), average method (AM; average of ≥60 min MVPA per day), AM5 (AM compliance and ≥5 min of vigorous PA [VPA] on ≥3 d), and AM15 (AM compliance and ≥15 min VPA on ≥3 d). Associations between compliance and health indicators were examined for all definitions. Results Compliance varied from 5.3% (DM) to 29.9% (AM). Associations between compliance and health indicators were similar for AM, AM5, and AM15. For example, compliance with AM, AM5, and AM15 was associated with a lower BMI z-score (statistics are coefficient [95% CI]): AM (−0.28 [−0.33 to −0.23]), AM5 (−0.28 [−0.33 to −0.23], and AM15 (−0.30 [−0.35 to −0.25]). Associations between compliance and health indicators for DM were similar/weaker, possibly reflecting fewer DM-compliant participants with health data and lower variability in exposure/outcome data. Conclusions Youth completing 60 min of MVPA every day do not experience superior health benefits to youth completing an average of 60 min of MVPA per day. Guidelines should encourage youth to achieve an average of 60 min of MVPA per day. Different guideline definitions affect inactivity prevalence estimates; this must be considered when analyzing data and comparing studies.publishedVersionPaid open acces

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia:The HypoDeg randomized, controlled, open-label, crossover trial

AIM: To investigate whether the long‐acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2‐year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal‐bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run‐in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention‐to‐treat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%‐43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%‐53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%‐58%; P = .04) RRR in all‐day severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all‐day severe hypoglycaemia with insulin degludec compared with insulin glargine U100

SNHG16 is regulated by the Wnt pathway in colorectal cancer and affects genes involved in lipid metabolism

It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA‐sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up‐regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt‐regulated transcription factors, including ASCL2, ETS2, and c‐Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO‐CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) “sponging” miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3′UTR of Stearoyl‐CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down‐regulated upon SNHG16 silencing. In conclusion, up‐regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms

Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes

Interaction between the complement system and carbon nanotubes (CNTs) can modify their intended biomedical applications. Pristine and derivatised CNTs can activate complement primarily via the classical pathway which enhances uptake of CNTs and suppresses pro-inflammatory response by immune cells. Here, we report that the interaction of C1q, the classical pathway recognition molecule, with CNTs involves charge pattern and classical pathway activation that is partly inhibited by factor H, a complement regulator. C1q and its globular modules, but not factor H, enhanced uptake of CNTs by macrophages and modulated the pro-inflammatory immune response. Thus, soluble complement factors can interact differentially with CNTs and alter the immune response even without complement activation. Coating CNTs with recombinant C1q globular heads offers a novel way of controlling classical pathway activation in nanotherapeutics. Surprisingly, the globular heads also enhance clearance by phagocytes and down-regulate inflammation, suggesting unexpected complexity in receptor interaction. From the Clinical Editor: Carbon nanotubes (CNTs) maybe useful in the clinical setting as targeting drug carriers. However, it is also well known that they can interact and activate the complement system, which may have a negative impact on the applicability of CNTs. In this study, the authors functionalized multi-walled CNT (MWNT), and investigated the interaction with the complement pathway. These studies are important so as to gain further understanding of the underlying mechanism in preparation for future use of CNTs in the clinical setting.L.P., A.G.T., L.K., G.S. and U.K. thank Brunel University London for strategic Infrastructure funding. H.A.K. acknowledges the Deanship of Scientific Research at King Saud University for funding via Group No. RGP-009

LOFAR Detection of 110-188 MHz Emission and Frequency-Dependent Activity from FRB 20180916B

FRB 20180916B is a well-studied repeating fast radio burst source. Its proximity (~150 Mpc), along with detailed studies of the bursts, have revealed many clues about its nature -- including a 16.3-day periodicity in its activity. Here we report on the detection of 18 bursts using LOFAR at 110-188 MHz, by far the lowest-frequency detections of any FRB to date. Some bursts are seen down to the lowest-observed frequency of 110 MHz, suggesting that their spectra extend even lower. These observations provide an order-of-magnitude stronger constraint on the optical depth due to free-free absorption in the source's local environment. The absence of circular polarization and nearly flat polarization angle curves are consistent with burst properties seen at 300-1700 MHz. Compared with higher frequencies, the larger burst widths (~40-160 ms at 150 MHz) and lower linear polarization fractions are likely due to scattering. We find ~2-3 rad/m^2 variations in the Faraday rotation measure that may be correlated with the activity cycle of the source. We compare the LOFAR burst arrival times to those of 38 previously published and 22 newly detected bursts from the uGMRT (200-450 MHz) and CHIME/FRB (400-800 MHz). Simultaneous observations show 5 CHIME/FRB bursts when no emission is detected by LOFAR. We find that the burst activity is systematically delayed towards lower frequencies by ~3 days from 600 MHz to 150 MHz. We discuss these results in the context of a model in which FRB 20180916B is an interacting binary system featuring a neutron star and high-mass stellar companion.Comment: Accepted for publication by ApJ

Does Birth Weight Influence Physical Activity in Youth? A Combined Analysis of Four Studies Using Objectively Measured Physical Activity

Animal models suggest growth restriction in utero leads to lower levels of motor activity. Furthermore, individuals with very low birth weight report lower levels of physical activity as adults. The aim of this study was to examine whether birth weight acts as a biological determinant of physical activity and sedentary time. This study uses combined analysis of three European cohorts and one from South America (n = 4,170). Birth weight was measured or parentally reported. Height and weight were measured and used to calculate Body Mass Index (BMI). PA was objectively measured using accelerometry for ≥3 days, ≥10 hours day. Data was standardized to allow comparisons between different monitors. Total physical activity was assessed as counts per minute (cpm), with time spent above moderate activity (MVPA) >2,000 counts and time spent sedentary (<100 counts). There was no evidence for an association between birth weight and total physical activity (p = 0.9) or MVPA (p = 0.7). Overall there was no evidence for an association between birth weight and sedentary time (p = 0.8). However in the Pelotas study we did find an association between higher birth weight (kg) and lower overall physical activity (cpm) (β = −31, 95%CI: −58, −46, p = 0.03) and higher birth weight and greater sedentary time (mins/day) (β = 16.4, 95%CI: 5.3, 27.5, p = 0.004), although this was attenuated and no longer significant with further adjustment for gestational age. Overall this combined analysis suggests that birth weight may not be an important biological determinant of habitual physical activity or sedentary behaviour in children and adolescents