A deep neural network to assess spontaneous pain from mouse facial expressions

Grimace scales quantify characteristic facial expressions associated with spontaneous pain in rodents and other mammals. However, these scales have not been widely adopted largely because of the time and effort required for highly trained humans to manually score the images. Convoluted neural networks were recently developed that distinguish individual humans and objects in images. Here, we trained one of these networks, the InceptionV3 convolutional neural net, with a large set of human-scored mouse images. Output consists of a binary pain/no-pain assessment and a confidence score. Our automated Mouse Grimace Scale integrates these two outputs and is highly accurate (94%) at assessing the presence of pain in mice across different experimental assays. In addition, we used a novel set of “pain” and “no pain” images to show that automated Mouse Grimace Scale scores are highly correlated with human scores (Pearson’s r = 0.75). Moreover, the automated Mouse Grimace Scale classified a greater proportion of images as “pain” following laparotomy surgery when compared to animals receiving a sham surgery or a post-surgical analgesic. Together, these findings suggest that the automated Mouse Grimace Scale can eliminate the need for tedious human scoring of images and provide an objective and rapid way to quantify spontaneous pain and pain relief in mice

The Troubled Touch of Autism

A study finds that deficits in touch-sensing somatosensory neurons contribute to social interaction and anxiety phenotypes in mouse models of autism and Rett syndrome. These findings suggest that some core symptoms of autism might originate from aberrant development or function of the peripheral nervous system. A study finds that deficits in touch-sensing somatosensory neurons contribute to social interaction and anxiety phenotypes in mouse models of autism and Rett syndrome. These findings suggest that some core symptoms of autism might originate from aberrant development or function of the peripheral nervous system

Genetically similar temperate phages form coalitions with their shared host that lead to niche-specific fitness effects.

Temperate phages engage in long-term associations with their hosts that may lead to mutually beneficial interactions, of which the full extent is presently unknown. Here, we describe an environmentally relevant model system with a single host, a species of the Roseobacter clade of marine bacteria, and two genetically similar phages (ɸ-A and ɸ-D). Superinfection of a ɸ-D lysogenized strain (CB-D) with ɸ-A particles resulted in a lytic infection, prophage induction, and conversion of a subset of the host population, leading to isolation of a newly ɸ-A lysogenized strain (CB-A). Phenotypic differences, predicted to result from divergent lysogenic-lytic switch mechanisms, are evident between these lysogens, with CB-A displaying a higher incidence of spontaneous induction. Doubling times of CB-D and CB-A in liquid culture are 75 and 100 min, respectively. As cell cultures enter stationary phase, CB-A viable counts are half of CB-D. Consistent with prior evidence that cell lysis enhances biofilm formation, CB-A produces twice as much biofilm biomass as CB-D. As strains are susceptible to infection by the opposing phage type, co-culture competitions were performed to test fitness effects. When grown planktonically, CB-A outcompeted CB-D three to one. Yet, during biofilm growth, CB-D outcompeted CB-A three to one. These results suggest that genetically similar phages can have divergent influence on the competitiveness of their shared hosts in distinct environmental niches, possibly due to a complex form of phage-mediated allelopathy. These findings have implications for enhanced understanding of the eco-evolutionary dynamics of host-phage interactions that are pervasive in all ecosystems.publishedVersio

Choice of vehicle affects pyraclostrobin toxicity in mice

Pyraclostrobin is a strobilurin fungicide that inhibits mitochondrial complex III of fungal and mammalian cells. In toxicity studies that were used to estimate the safety factor, pyraclostrobin was added to animal feed or to aqueous vehicles. However, foods containing residues of pyraclostrobin and other strobilurin fungicides (azoxystrobin, trifloxystrobin, fluoxastrobin) are frequently prepared in vegetable oil prior to human consumption. The primary objective of this study was to determine if pyraclostrobin dissolved in an oil-based vehicle had adverse health outcomes in mice when compared to aqueous-based vehicles. We found that pyraclostrobin does not fully dissolve in aqueous methyl cellulose (MC) or carboxymethyl cellulose (CMC), two vehicles used in industry-sponsored toxicity studies, but does fully dissolve in corn oil. Moreover, C57BL/6 mice receiving pyraclostrobin in corn oil displayed adverse health outcomes, including loss of body weight, hypothermia and diarrhea at lower doses than when added to feed or to aqueous vehicles. Our data suggest that previous studies underestimated the true toxicity of pyraclostrobin in mammals. Additional toxicity tests using oil-based vehicles are recommended to verify current safety recommendations for strobilurin fungicides

Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

Background: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. Methods: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). Results: Chd8 V986/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8 V986/+ mutant mice at 1 year of age. Pup survival was reduced in wild-Type x Chd8 V986/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8 V986/+ mice and then equalized relative to wild-Type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8 V986/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression. Limitations: It is unclear whether the transcriptional changes observed with age in Chd8 V986/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. Conclusions: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8 V986/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8 V986/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice

Development of an International Standard Set of Value-Based Outcome Measures for Patients With Chronic Kidney Disease

Value-based health care is increasingly promoted as a strategy for improving care quality by benchmarking outcomes that matter to patients relative to the cost of obtaining those outcomes. To support the shift toward value-based health care in chronic kidney disease (CKD), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international working group of health professionals and patient representatives to develop a standardized minimum set of patient-centered outcomes targeted for clinical use. The considered outcomes and patient-reported outcome measures were generated from systematic literature reviews. Feedback was sought from patients and health professionals. Patients with very high-risk CKD (stages G3a/A3 and G3b/A2-G5, including dialysis, kidney transplantation, and conservative care) were selected as the target population. Using an online modified Delphi process, outcomes important to all patients were selected, such as survival and hospitalization, and to treatment-specific subgroups, such as vascular access survival and kidney allograft survival. Patient-reported outcome measures were included to capture domains of health-related quality of life, which were rated as the most important outcomes by patients. Demographic and clinical variables were identified to be used as case-mix adjusters. Use of these consensus recommendations could enable institutions to monitor, compare, and improve the quality of their CKD care

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Search for long-lived doubly charged Higgs bosons in p(p)over-bar collisions at root s=1.96 TeV

We present a search for long-lived doubly charged Higgs bosons (H+/-+/-), with signatures of high ionization energy loss and muonlike penetration. We use 292 pb(-1) of data collected in p (p) over bar collisions at root s=1.96 TeV by the CDF II detector at the Fermilab Tevatron. Observing no evidence of long-lived doubly charged particle production, we exclude H-L(+/-+/-) and H-R(+/-+/-) bosons with masses below 133 GeV/c(2) and 109 GeV/c(2), respectively. In the degenerate case we exclude H+/-+/- mass below 146 GeV/c(2). All limits are quoted at the 95% confidence level

Complete remission in the nephrotic syndrome study network

Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)<0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. Results We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m2 (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. Conclusions In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission