Cytolytic T lymphocyte function is independent of growth phase and position in the mitotic cycle

We have investigated mitotic cell cycle and growth phase regulation of homogeneous cytolytic T lymphocytes (CTL). Two independently derived CTL clones were stained with the DNA-binding dye Hoechst 33342, sorted in a fluorescence-activated cell sorter according to their position in the cell cycle, and then assayed for specific lytic activity using a short-term (30 min) (51)Cr release assay. Results show that lytic activity remained unchanged throughout the cell cycle. Furthermore, there was no significant difference in the lytic activity of CTL clones growing exponentially or arrested in a plateau phase. These results demonstrate that T cell-mediated cytolysis is independent of growth phase and position in the cell cycle

Decision-making without a brain: how an amoeboid organism solves the two-armed bandit

Several recent studies hint at shared patterns in decision-making between taxonomically distant organisms, yet few studies demonstrate and dissect mechanisms of decision-making in simpler organisms. We examine decision-making in the unicellular slime mould Physarum polycephalum using a classical decision problem adapted from human and animal decision-making studies: the two-armed bandit problem. This problem has previously only been used to study organisms with brains, yet here we demonstrate that a brainless unicellular organism compares the relative qualities of multiple options, integrates over repeated samplings to perform well in random environments, and combines information on reward frequency and magnitude in order to make correct and adaptive decisions. We extend our inquiry by using Bayesian model selection to determine the most likely algorithm used by the cell when making decisions. We deduce that this algorithm centres around a tendency to exploit environments in proportion to their reward experienced through past sampling. The algorithm is intermediate in computational complexity between simple, reactionary heuristics and calculation-intensive optimal performance algorithms, yet it has very good relative performance. Our study provides insight into ancestral mechanisms of decision-making and suggests that fundamental principles of decision-making, information processing and even cognition are shared among diverse biological systems

A Selberg integral for the Lie algebra A_n

A new q-binomial theorem for Macdonald polynomials is employed to prove an A_n analogue of the celebrated Selberg integral. This confirms the g=A_n case of a conjecture by Mukhin and Varchenko concerning the existence of a Selberg integral for every simple Lie algebra g.Comment: 32 page

Longevity of daily oral Vitamin D3 supplementation:Differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomized controlled trial (VICtORy RECALL)

Purpose To determine the longevity of vitamin D status following cessation of vitamin D3 supplementation, 2 and 3 years after a 1 year randomised double blind placebo controlled trial: (Vitamin D and Cardiovascular Risk (VICtORY)); and to investigate possible predictive factors. Method Of the 305 Caucasian non-smoking postmenopausal women randomised to ViCtORY (2009-2010), participants who had not taken vitamin D supplements since the trial ended were invited to attend follow up visits. Total 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25OH2D) were measured by dual tandem mass spectrometry of serum samples following removal of protein and de-lipidation; the original RCT samples were re-analysed simultaneously. Vitamin D binding protein (VDBP) was measured by monoclonal immunoassay. Results In March 2012 and March 2013, 159 women (mean (SD) age 67.6 (2.1) years) re-attended, distributed between the original treatment groups: daily vitamin D3 400IU; 1000IU; and placebo. One month after the RCT ended (March 2010) the proportion of women in placebo, 400IU, and 1000IU vitamin D3 groups, respectively, with 25OHD0.001, n=46,44,54); 42%, 33%, 12% (2y, p=0.002,n=50,48,57) and 45%, 27%, 29% (3y, p=0.138, n=47,45,51,). VDBP was a predictor of circulating 25OHD longevity (beta for VDBP in µg/ml:0.736; 95% CI 0.216-1.255,p=0.006) but not 24,25OH2D

The role of RIPK1 mediated cell death in acute on chronic liver failure

Acute-on-chronic liver failure (ACLF) is characterized predominantly by non-apoptotic forms of hepatocyte cell death. Necroptosis is a form of programmed lytic cell death in which receptor interacting protein kinase (RIPK) 1, RIPK3 and phosphorylated mixed lineage kinase domain-like (pMLKL) are key components. This study was performed to determine the role of RIPK1 mediated cell death in ACLF. RIPK3 plasma levels and hepatic expression of RIPK1, RIPK3, and pMLKL were measured in healthy volunteers, stable patients with cirrhosis, and in hospitalized cirrhotic patients with acutely decompensated cirrhosis, with and without ACLF (AD). The role of necroptosis in ACLF was studied in two animal models of ACLF using inhibitors of RIPK1, necrostatin-1 (NEC-1) and SML2100 (RIPA56). Plasma RIPK3 levels predicted the risk of 28- and 90-day mortality (AUROC, 0.653 (95%CI 0.530–0.776), 0.696 (95%CI 0.593–0.799)] and also the progression of patients from no ACLF to ACLF [0.744 (95%CI 0.593–0.895)] and the results were validated in a 2nd patient cohort. This pattern was replicated in a rodent model of ACLF that was induced by administration of lipopolysaccharide (LPS) to bile-duct ligated rats and carbon tetrachloride-induced fibrosis mice administered galactosamine (CCL4/GalN). Suppression of caspase-8 activity in ACLF rodent model was observed suggesting a switch from caspase-dependent cell death to necroptosis. NEC-1 treatment prior to administration of LPS significantly reduced the severity of ACLF manifested by reduced liver, kidney, and brain injury mirrored by reduced hepatic and renal cell death. Similar hepato-protective effects were observed with RIPA56 in a murine model of ACLF induced by CCL4/GalN. These data demonstrate for the first time the importance of RIPK1 mediated cell death in human and rodent ACLF. Inhibition of RIPK1 is a potential novel therapeutic approach to prevent progression of susceptible patients from no ACLF to ACLF

Do contaminants originating from state-of-the-art treated wastewater impact the ecological quality of surface waters?

Since the 1980s, advances in wastewater treatment technology have led to considerably improved surface water quality in the urban areas of many high income countries. However, trace concentrations of organic wastewater-associated contaminants may still pose a key environmental hazard impairing the ecological quality of surface waters. To identify key impact factors, we analyzed the effects of a wide range of anthropogenic and environmental variables on the aquatic macroinvertebrate community. We assessed ecological water quality at 26 sampling sites in four urban German lowland river systems with a 0–100% load of state-of-the-art biological activated sludge treated wastewater. The chemical analysis suite comprised 12 organic contaminants (five phosphor organic flame retardants, two musk fragrances, bisphenol A, nonylphenol, octylphenol, diethyltoluamide, terbutryn), 16 polycyclic aromatic hydrocarbons, and 12 heavy metals. Non-metric multidimensional scaling identified organic contaminants that are mainly wastewater-associated (i.e., phosphor organic flame retardants, musk fragrances, and diethyltoluamide) as a major impact variable on macroinvertebrate species composition. The structural degradation of streams was also identified as a significant factor. Multiple linear regression models revealed a significant impact of organic contaminants on invertebrate populations, in particular on Ephemeroptera, Plecoptera, and Trichoptera species. Spearman rank correlation analyses confirmed wastewater-associated organic contaminants as the most significant variable negatively impacting the biodiversity of sensitive macroinvertebrate species. In addition to increased aquatic pollution with organic contaminants, a greater wastewater fraction was accompanied by a slight decrease in oxygen concentration and an increase in salinity. This study highlights the importance of reducing the wastewater-associated impact on surface waters. For aquatic ecosystems in urban areas this would lead to: (i) improvement of the ecological integrity, (ii) reduction of biodiversity loss, and (iii) faster achievement of objectives of legislative requirements, e.g., the European Water Framework Directive

The relationship between vitamin D status and muscle strength in young healthy adults from sunny climate countries currently living in the northeast of Scotland

Summary: The current study examined the relationship between vitamin D status and muscle strength in young healthy adults: residents (>6 months) and newcomers (0–3 months), originally from sunny climate countries but currently living in the northeast of Scotland. Our longitudinal data found a positive, albeit small, relationship between vitamin D status and knee extensor isometric strength.  Introduction: Vitamin D has been suggested to play a role in muscle health and function, but studies so far have been primarily in older populations for falls prevention and subsequent risk of fractures.  Methods: Vitamin D status was assessed in a healthy young adults from sunny climate countries (n = 71, aged 19–42 years) with 56% seen within 3 months of arriving in Aberdeen [newcomers; median (range) time living in the UK = 2 months (9–105 days)] and the remainder resident for >6 months [residents; 23 months (6–121 months)]. Participants attended visits every 3 months for 15 months. At each visit, fasted blood samples were collected for analysis of serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type I collagen (P1NP). Maximal voluntary contractions (MVC) were performed for grip strength (both arms) and for maximal isometric strength of the knee extensors (right knee).  Results: There were small seasonal variations in 25(OH)D concentrations within the newcomers and residents, but no seasonal variation in bone turnover markers. There was a positive, albeit small, association between 25(OH)D and knee extensor maximal isometric strength. Mixed modelling predicted that for each 1 nmol/L increase in 25(OH)D, peak torque would increase by 1 Nm (p = 0.04).  Conclusions: This study suggests that vitamin D may be important for muscle health in young adults migrating from sunnier climates to high latitudes, yet the potential effect is small

Empowerment and Parent Gain as Mediators and Moderators of Distress in Mothers of Children with Autism Spectrum Disorders

Mothers of children with Autism Spectrum Disorders (ASD) experience considerable amounts of distress and experiences of crisis. The Family Adjustment and Adaptation Response model provides a theory for understanding the experience of distress and family crisis in families, and the purpose of the present study was to examine experiences of distress in mothers of individuals with ASD using this framework. We specifically investigated how parent empowerment and positive gain are related to their experiences of distress, whether as mediators or as moderators of child aggression. Participants included 156 mothers of children with ASD ranging in age from 4 – 21 years. Mothers completed an online survey of demographics, problem behaviors, family empowerment, positive gain, and distress. We conducted path analyses of multiple mediation and moderation. Results indicated that greater child problem behavior was related to less parent empowerment, which was related to greater maternal distress, supporting empowerment as a partial mediator. At the same time, greater child aggression was not related to maternal distress in mothers who report high rates of positive gain, suggesting that parent gain functions as a moderator. The implications for how and when clinicians intervene with families of children with ASD are discussed