Lucius Chittenden\u27s journey to the inside of the earth transcribed and annotated by Michael N. Stanton.

Occasional paper (University of Vermont. Center for Research on Vermont) ; #17. Introduction -- A note on the text -- [ To the inside of the Earth! ] -- The nebular hypothesis -- Chambers makes planets -- They plan the expedition -- Las diablos del Volcan -- A discussion concerning air and heat -- Appendix : the discussion -- A note on the transcriber and annotater

Dynamic Density Functional Theory of Multicomponent Cellular Membranes

We present a continuum model trained on molecular dynamics (MD) simulations for cellular membranes composed of an arbitrary number of lipid types. The model is constructed within the formalism of dynamic density functional theory and can be extended to include features such as the presence of proteins and membrane deformations. This framework represents a paradigm shift by enabling simulations that can access cellular length-scales ($\mu$m) and time-scales on the order of seconds, all while maintaining near-fidelity to the underlying MD models. Membrane interactions with RAS, a potentially oncogenic protein, are considered as an application. Simulation results are presented and verified with MD simulations, and implications of this new capability are discussed

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Effect of pasture versus indoor feeding systems on raw milk composition and quality over an entire lactation

peer-reviewedThe aim of this study was to investigate the effects of different feeding systems on milk quality and composition. Fifty-four multiparous and primiparous Friesian lactating cows were divided into 3 groups (n=18) to study the effects of 3 feeding systems over a full lactation. Group 1 was housed indoors and offered a total mixed ration diet (TMR), group 2 was maintained outdoors on a perennial ryegrass pasture (referred to as grass), and group 3 was also grazed outdoors on a perennial ryegrass/white clover pasture (referred to as clover). Bulk milk samples were collected from each group at morning and afternoon milkings once weekly from March 11 to October 28 in 2015. Milk from pasture-fed cows (grass and clover) had significantly higher concentrations of fat, protein, true protein, and casein. The pasture feeding systems induced significantly higher concentrations of saturated fatty acids C11:0, C13:0, C15:0, C17:0, C23:0, and unsaturated fatty acids C18:2n-6 trans, C18:3n-3, C20:1, and C20:4n-6 and a greater than 2-fold increase in the conjugated linoleic acid C18:2 cis-9,trans-11 content of milk compared with that of the TMR feeding system. The TMR feeding system resulted in milks with increased concentrations of C16:0, C18:2n-6 cis, C18:3n-6 cis, C22:0 C22:1n-9, and C18:2 cis-10,trans-12. Principal component analysis of average fatty acid profiles showed clear separation of milks from the grazed pasture-based diets to that of a TMR system throughout lactation, offering further insight into the ability to verify pasture-derived milk by fatty acid profiling

A time-lagged association between the gut microbiome, nestling weight and nestling survival in wild great tits

Natal body mass is a key predictor of viability and fitness in many animals. While variation in body mass and therefore juvenile viability may be explained by genetic and environmental factors, emerging evidence points to the gut microbiota as an important factor influencing host health. The gut microbiota is known to change during development, but it remains unclear whether the microbiome predicts fitness, and if it does, at which developmental stage it affects fitness traits. We collected data on two traits associated with fitness in wild nestling great tits Parus major: weight and survival to fledging. We characterised the gut microbiome using 16S rRNA sequencing from nestling faeces and investigated temporal associations between the gut microbiome and fitness traits across development at Day-8 (D8) and Day-15 (D15) post-hatching. We also explored whether particular microbial taxa were ‘indicator species’ that reflected whether nestlings survived or not. There was no link between mass and microbial diversity on D8 or D15. However, we detected a time-lagged relationship where weight at D15 was negatively associated with the microbial diversity at D8, controlling for weight at D8, therefore reflecting relative weight gain over the intervening period. Indicator species analysis revealed that specificity values were high and fidelity values were low, suggesting that indicator taxa were primarily detected within either the survived or not survived groups, but not always detected in birds that either survived or died. Therefore these indicator taxa may be sufficient, but not necessary for determining either survival or mortality, perhaps owing to functional overlap in microbiota. We highlight that measuring microbiome-fitness relationships at just one time point may be misleading, especially early in life. Instead, microbial-host fitness effects may be best investigated longitudinally to detect critical development windows for key microbiota and host traits associated with neonatal weight. Our findings should inform future hypothesis testing to pinpoint which features of the gut microbial community impact on host fitness, and when during development this occurs. Such confirmatory research will shed light on population level processes and could have the potential to support conservation

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors

Effect of dietary n-3 polyunsaturated fatty acid supplementation and post-insemination plane of nutrition on systemic concentrations of metabolic analytes, progesterone, hepatic gene expression and embryo development and survival in beef heifers

peer-reviewedNutrition, and particularly dietary energy intake, plays a fundamental role in reproductive function in cattle. There is some evidence that supplemental omega-3 dietary polyunsaturated fatty acids (n-3 PUFA) can exert positive effects on fertility. The objectives of this study were to evaluate the effect of dietary n-3 PUFA supplementation, post-insemination energy plane of nutrition and their interaction on embryo survival in cattle. Crossbred beef heifers (n = 185) were individually offered barley straw ad libitum and 6 kg DM of concentrate supplemented with either a rumen-protected source of saturated fatty acid (palmitic; control, CON) or a partially rumen-protected n-3 PUFA-enriched supplement (n-3 PUFA). Estrous was synchronised using two injections of PG administered at 11-d intervals and following artificial insemination (AI = Day 0) 179 heifers exhibiting oestrus were inseminated and assigned to one of two dietary treatments: (i) remain on their pre-insemination high dietary plane of nutrition (High) or (ii) restricted to 0.6 × estimated maintenance energy requirements (Low) in a 2 × 2 factorial design. The heifers were then maintained on their assigned diets until slaughter and embryo recovery on Day 16 (n = 92) or pregnancy diagnosis by ultrasound scanning at Day 30 post-AI (n = 87). Plasma concentrations of fatty acids, metabolites, insulin, progesterone (P4) and insulin-like growth factor 1 (IGF-1) were measured at appropriate intervals. Hepatic expression of mRNA for aldo-keto reductase (AKR1C), cytochrome P450 2C (CYP 2C) and cytochrome P450 3A (CYP 3A) was examined. The n-3 PUFA supplementation increased plasma n-3 PUFA concentration (P < 0.05) and reduced n-6: n-3 PUFA ratio (P < 0.05). Plasma IGF-1 was higher for n-3 PUFA relative to the CON (P < 0.05) and for High compared with Low plane of nutrition post-AI (P < 0.05) groups. A low plane of nutrition post-AI increased plasma concentrations of progesterone from Days 7–16 after insemination (P < 0.001) but reduced embryo length (P < 0.001). Supplementation with n-3 PUFA reduced and tended to reduce hepatic expression of CYP2C (P = 0.01) and CYP3A (P = 0.08), respectively. However, while dietary n-3 PUFA supplementation and an abrupt reduction in nutrient status following insemination elevated plasma concentrations of n-3 PUFA and mid and late phase P4, respectively, there was no effect of either PUFA supplementation or post-insemination plane of nutrition on embryo survival

A systematic review and meta-analysis of the effect of dispatcher-assisted CPR on outcomes from sudden cardiac arrest in adults and children

Background: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) has been reported in individual studies to significantly increase the rate of bystander CPR and survival from cardiac arrest. Methods: We undertook a systematic review and meta-analysis to evaluate the impact of DA-CPR programs on key clinical outcomes following out-of-hospital cardiac arrest. We searched the PubMED, EMBASE, CINAHL, ERIC and Cochrane Central Register of Controlled Trials databases from inception until July 2018. Eligible studies compared systems with and without dispatcher-assisted CPR programs. The results of included studies were classified into 3 categories for the purposes of more accurate analysis: comparison of outcomes in systems with DA-CPR programs, case-based comparison of DA-CPR to bystander CPR, and case-based comparisons of DA-CPR to no CPR before EMS arrival. The GRADE system was used to assess certainty of evidence at an outcome level. We used random-effects models to produce summary effect sizes across all outcomes. Results: Of 5531 citations screened, 33 studies were eligible for inclusion. All included studies were observational. Evidence certainty across all outcomes was assessed as low or very low. In system-level and patient-level comparisons, the provision of DA-CPR compared with no DA-CPR was consistently associated with improved outcome across all analyses. Comparison of DA-CPR to bystander CPR produced conflicting results. Findings were consistent across sensitivity analyses and the pediatric sub-group. Conclusion: These results support the recommendation that dispatchers provide CPR instructions to callers for adults and children with suspected OHCA. Review registration: PROSPERO- CRD42018091427