Neonicotinoid insecticides are widely used in both urban and agricultural settings around the world. Historically, neonicotinoid insecticides have been viewed as ideal replacements for more toxic ...compounds, like organophosphates, due in part to their perceived limited potential to affect the environment and human health. This critical review investigates the environmental fate and toxicity of neonicotinoids and their metabolites and the potential risks associated with exposure. Neonicotinoids are found to be ubiquitous in the environment, drinking water, and food, with low-level exposure commonly documented below acceptable daily intake standards. Available toxicological data from animal studies indicate possible genotoxicity, cytotoxicity, impaired immune function, and reduced growth and reproductive success at low concentrations, while limited data from ecological or cross-sectional epidemiological studies have identified acute and chronic health effects ranging from acute respiratory, cardiovascular, and neurological symptoms to oxidative genetic damage and birth defects. Due to the heavy use of neonicotinoids and potential for cumulative chronic exposure, these insecticides represent novel risks and necessitate further study to fully understand their risks to humans.
There is increasing evidence indicating that the climate response to variations in the El Niño–Southern Oscillation (ENSO) includes not only thermally forced zonal wind anomalies in the subtropics ...but also eddy-driven zonal wind anomalies that extend into the mid–high latitudes of both hemispheres. In this study, new insights into the observed seasonally varying signature of ENSO in the extratropical zonal-mean circulation are provided and the associated linkages with the dominant patterns of extratropical variability are examined.
The zonal-mean extratropical atmospheric response to ENSO is characterized by two principal features: an equivalent barotropic dipole in the Southern Hemisphere (SH) zonal-mean zonal flow with centers of action located near ∼40° and ∼60° during austral summer, and a weaker, but analogous, dipole in the Northern Hemisphere (NH) with centers of action located near ∼25° and ∼45° during early and late boreal winter. Both structures are accompanied by eddy momentum flux anomalies that exhibit a remarkable degree of hemispheric symmetry. In the SH, the extratropical signature of ENSO projects strongly onto the primary mode of large-scale variability, the southern annular mode (SAM). During the austral summer, roughly 25% of the temporal variability in the SAM is linearly related to fluctuations in the ENSO cycle. An analogous relationship is not observed in association with the principal mode of climate variability in the NH, the northern annular mode (NAM).
It is argued that the seasonally varying impact of ENSO on the extratropical circulation is consistent with the impact of the thermally forced subtropical wind anomalies on the dissipation of equatorward-propagating wave activity at subtropical latitudes.
Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L ...is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.
The development of the infant intestinal microbiome in response to dietary and other exposures may shape long-term metabolic and immune function. We examined differences in the community structure ...and function of the intestinal microbiome between four feeding groups, exclusively breastfed infants before introduction of solid foods (EBF), non-exclusively breastfed infants before introduction of solid foods (non-EBF), EBF infants after introduction of solid foods (EBF+S), and non-EBF infants after introduction of solid foods (non-EBF+S), and tested whether out-of-home daycare attendance was associated with differences in relative abundance of gut bacteria. Bacterial 16S rRNA amplicon sequencing was performed on 49 stool samples collected longitudinally from a cohort of 9 infants (5 male, 4 female). PICRUSt metabolic inference analysis was used to identify metabolic impacts of feeding practices on the infant gut microbiome. Sequencing data identified significant differences across groups defined by feeding and daycare attendance. Non-EBF and daycare-attending infants had higher diversity and species richness than EBF and non-daycare attending infants. The gut microbiome of EBF infants showed increased proportions of Bifidobacterium and lower abundance of Bacteroidetes and Clostridiales than non-EBF infants. PICRUSt analysis indicated that introduction of solid foods had a marginal impact on the microbiome of EBF infants (24 enzymes overrepresented in EBF+S infants). In contrast, over 200 bacterial gene categories were overrepresented in non-EBF+S compared to non-EBF infants including several bacterial methyl-accepting chemotaxis proteins (MCP) involved in signal transduction. The identified differences between EBF and non-EBF infants suggest that breast milk may provide the gut microbiome with a greater plasticity (despite having a lower phylogenetic diversity) that eases the transition into solid foods.
Over the past decade several studies have reported that the gut microbiomes of mammals with similar dietary niches exhibit similar compositional and functional traits. However, these studies rely ...heavily on samples from captive individuals and often confound host phylogeny, gut morphology, and diet. To more explicitly test the influence of host dietary niche on the mammalian gut microbiome we use 16S rRNA gene amplicon sequencing and shotgun metagenomics to compare the gut microbiota of 18 species of wild non-human primates classified as either folivores or closely related non-folivores, evenly distributed throughout the primate order and representing a range of gut morphological specializations. While folivory results in some convergent microbial traits, collectively we show that the influence of host phylogeny on both gut microbial composition and function is much stronger than that of host dietary niche. This pattern does not result from differences in host geographic location or actual dietary intake at the time of sampling, but instead appears to result from differences in host physiology. These findings indicate that mammalian gut microbiome plasticity in response to dietary shifts over both the lifespan of an individual host and the evolutionary history of a given host species is constrained by host physiological evolution. Therefore, the gut microbiome cannot be considered separately from host physiology when describing host nutritional strategies and the emergence of host dietary niches.
Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as ...proband-parent trios.
Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected).
Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP.
Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.
Background. Although vaccination with trivalent inactivated influenza vaccine (TIV) is recommended for all pregnant women, no vaccine effectiveness (VE) studies of TIV in pregnant women have assessed ...laboratory-confirmed influenza outcomes. Methods. We conducted a case-control study over 2 influenza seasons (2010–2011 and 2011–2012) among Kaiser Permanente health plan members in 2 metropolitan areas in California and Oregon. We compared the proportion vaccinated among 100 influenza cases (confirmed by reverse transcription polymerase chain reaction) with the proportions vaccinated among 192 controls with acute respiratory illness (ARI) who tested negative for influenza and 200 controls without ARI (matched by season, site, and trimester). Results. Among influenza cases, 42% were vaccinated during the study season compared to 58% and 63% vaccinated among influenza-negative controls and matched ARI-negative controls, respectively. The adjusted VE of the current season vaccine against influenza A and B was 44% (95% confidence interval CI, 5%–67%) using the influenza-negative controls and 53% (95% CI, 24%–72%) using the ARI-negative controls. Receipt of the prior season's vaccine, however, had an effect similar to receipt of the current season's vaccine. As such, vaccination in either or both seasons had statistically similar adjusted VE using influenza-negative controls (VE point estimates range = 51%–76%) and ARI-negative controls (48%–76%). Conclusions. Influenza vaccination reduced the risk of ARI associated with laboratory-confirmed influenza among pregnant women by about one-half, similar to VE observed among all adults during these seasons.
Aims
Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).
Methods
This study included Part A: 10 ...healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open‐label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging‐normal appearing (Part B) and affected muscle identified by abnormal short‐tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol‐stimulated blood.
Results
PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0–12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose‐dependent concentrations in muscle (42.1 ± 10.5 ng/g 7.5 mg to 97.2 ± 22.4 ng/g 15 mg) were observed, with plasma‐to‐muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self‐limited.
Conclusion
Losmapimod was well tolerated, with no serious AEs. Dose‐dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD.
Clinical Trial Registration
Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.
Glioblastoma (GB) is one of the deadliest brain cancers to afflict humans, and it has a very poor survival rate even with treatment. The extracellular adenosine-generating enzyme CD73 is involved in ...many cellular functions that can be usurped by tumors, including cell adhesion, proliferation, invasion, and angiogenesis. We set out to determine the role of CD73 in GB pathogenesis. To do this, we established a unique GB mouse model (CD73-FLK) in which we spatially expressed CD73 on endothelial cells in CD73−/− mice. This allowed us to elucidate the mechanism of host CD73 versus GB-expressed CD73 by comparing GB pathogenesis in WT, CD73−/−, and CD73-FLK mice. GB in CD73−/− mice had decreased tumor size, decreased tumor vessel density, and reduced tumor invasiveness compared with GB in WT mice. Interestingly, GBs in CD73-FLK mice were much more invasive and caused complete distortion of the brain morphology. We showed a 20-fold upregulation of A2B AR on GB compared with sham, and its activation induced matrix metalloproteinase-2, which enhanced GB pathogenesis. Inhibition of A2B AR signaling decreased multidrug resistance transporter protein expression, including permeability glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Further, we showed that blockade of A2B AR signaling potently increased GB cell death induced by the chemotherapeutic drug temozolomide. Together, these findings suggest that CD73 and A2B AR play a multifaceted role in GB pathogenesis and progression and that targeting the CD73–A2B AR axis can benefit GB patients and inform new approaches for therapy to treat GB patients.
Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered ...question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight.
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