Development of a mouse model for assessing fatigue during chemotherapy

Fatigue and disturbed sleep are common problems for cancer patients and affect both quality of life and compliance with treatment. Fatigue may be associated with cancer itself and with the treatment, particularly for therapies with neurotoxic side effects. To develop a model system for evaluation of chemotherapy-related fatigue, we studied mice treated with either a commonly used formulation of the chemotherapeutic agent paclitaxel (paclitaxel; Taxol), which is known to have neurotoxic properties, or a nano- particle formulation of paclitaxel (nab-paclitaxel; Abraxane) that is reported to have greater potency and efficacy yet fewer side effects than does paclitaxel. Mice were treated with 1 of these 2 agents (10 mg/kg IV daily for 5 consecutive days) and were monitored from 1 wk before through 4 wk after treatment. Dependent measures included running wheel activity, locomotor activity on the cage floor, core temperature, sleep patterns, CBC count, serum cytokine and chemokine concentrations, and neurologic assessment. For both drugs, mice showed the most severe perturbations of activity during the first recovery week after drug administration. Mice treated with paclitaxel showed greater neutropenia and motor deficits than did mice treated with nab-paclitaxel. However, deficits had largely resolved by 4 wk after administration of either drug. We conclude that these measures provide an assessment of chemotherapy-related fatigue that potentially can distinguish toxicity associated with different formulations of the same agent.     

Composition of human skin microbiota affects attractiveness to malaria mosquitoes

The African malaria mosquito Anopheles gambiae sensu stricto continues to play an important role in malaria transmission, which is aggravated by its high degree of anthropophily, making it among the foremost vectors of this disease. In the current study we set out to unravel the strong association between this mosquito species and human beings, as it is determined by odorant cues derived from the human skin. Microbial communities on the skin play key roles in the production of human body odour. We demonstrate that the composition of the skin microbiota affects the degree of attractiveness of human beings to this mosquito species. Bacterial plate counts and 16S rRNA sequencing revealed that individuals that are highly attractive to An. gambiae s.s. have a significantly higher abundance, but lower diversity of bacteria on their skin than individuals that are poorly attractive. Bacterial genera that are correlated with the relative degree of attractiveness to mosquitoes were identified. The discovery of the connection between skin microbial populations and attractiveness to mosquitoes may lead to the development of new mosquito attractants and personalized methods for protection against vectors of malaria and other infectious diseases.     

Parental height differences predict the need for an emergency caesarean section

More than 30% of all pregnancies in the UK require some form of assistance at delivery, with one of the more severe forms of assistance being an emergency Caesarean section (ECS). Previously it has been shown that the likelihood of a delivery via ECS is positively associated with the birth weight and size of the newborn and negatively with maternal height. Paternal height affects skeletal growth and mass of the fetus, and thus might also affect pregnancy outcomes. We hypothesized that the effect of newborn birth weight on the risk of ECS would decrease with increasing maternal height. Similarly, we predicted that there would be an increase in ECS risk as a function of paternal height, but that this effect would be relative to maternal height (i.e., parental height differences). We used data from the Millennium Cohort Study: a large-scale survey (N = 18,819 births) with data on babies born and their parents from the United Kingdom surveyed 9 to 12-months after birth. We found that in primiparous women, both maternal height and parental height differences interacted with birth weight and predicted the likelihood of an ECS. When carrying a heavy newborn, the risk of ECS was more than doubled for short women (46.3%) compared to tall women (21.7%), in agreement with earlier findings. For women of average height carrying a heavy newborn while having a relatively short compared to tall partner reduced the risk by 6.7%. In conclusion, the size of the baby, the height of the mother and parental height differences affect the likelihood of an ECS in primiparous women.     

Magnetic resonace-based attenuation correction for micro-single-photon emission computed tomography

Attenuation correction is necessary for quantification in micro-single-photon emission computed tomography (micro-SPECT). In general, this is done based on micro-computed tomographic (micro-CT) images. Derivation of the attenuation map from magnetic resonance (MR) images is difficult because bone and lung are invisible in conventional MR images and hence indistinguishable from air. An ultrashort echo time (UTE) sequence yields signal in bone and lungs. Micro-SPECT, micro-CT, and MR images of 18 rats were acquired. Different tracers were used: hexamethylpropyleneamine oxime (brain), dimercaptosuccinic acid (kidney), colloids (liver and spleen), and macroaggregated albumin (lung). The micro-SPECT images were reconstructed without attenuation correction, with micro-CT-based attenuation maps, and with three MR-based attenuation maps: uniform, non-UTE-MR based (air, soft tissue), and UTE-MR based (air, lung, soft tissue, bone). The average difference with the micro-CT-based reconstruction was calculated. The UTE-MR-based attenuation correction performed best, with average errors ≤ 8% in the brain scans and ≤ 3% in the body scans. It yields nonsignificant differences for the body scans. The uniform map yields errors of ≤ 6% in the body scans. No attenuation correction yields errors ≥ 15% in the brain scans and ≥ 25% in the body scans. Attenuation correction should always be performed for quantification. The feasibility of MR-based attenuation correction was shown. When accurate quantification is necessary, a UTE-MR-based attenuation correction should be used.     

Stimulation of steviol glycoside accumulation in Stevia rebaudiana by red LED light

The aim of this study was to determine whether steviol glycoside accumulation is under phytochrome control. The results indicate that Stevia rebaudiana Bertoni plants grown under short-day conditions showed precocious flowering and stagnation of steviol glycoside accumulation. Long night interruption by red LED light stimulated and sustained the vegetative growth as well as the accumulation of steviol glycosides in the leaves. After 7 weeks of treatment, steviol glycoside content was about two-fold higher in LED-treated plants than in the short-day control group. The effects of red LED light were measured both in a greenhouse and in a phytotron, irrespective of cultivar-specific differences. Therefore, it can be concluded that a mid-night interruption by red LED light during short photoperiods provides an easy and inexpensive method to increase vegetative leaf biomass production with an increased steviol glycoside yield.     

Role of the AMP-activated protein kinase (AMPK) signaling pathway in the orexigenic effects of endogenous ghrelin

Ghrelin, released from the stomach, stimulates food intake through activation of the ghrelin receptor (GHS-R) located on neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the hypothalamus. A role for the energy sensor AMP-activated protein kinase (AMPK) and its downstream effector uncoupling protein 2 (UCP2) in the stimulatory effect of exogenous ghrelin on NPY/AgRP expression and food intake has been suggested. This study aimed to investigate whether a rise in endogenous ghrelin levels is able to influence hypothalamic AMPK activity, pACC, UCP2 and NPY/AgRP expression through activation of GHS-R. An increase in endogenous ghrelin levels was established by fasting (24h) or by induction of streptozotocin(STZ)-diabetes (15 days) in GHS-R(+/+) and GHS-R(-/-) mice. GHS-R(+/+) mice showed a significant increase in AgRP and NPY mRNA expression after fasting, which was not observed in GHS-R(-/-) mice. Fasting did not affect AMPK activity nor ACC phosphorylation in both genotypes and increased UCP2 mRNA expression. The hyperghrelinemia associated with STZ-induced diabetes was accompanied by an increased NPY and AgRP expression in GHS-R(+/+) but not in GHS-R(-/-) mice. AMPK activity and UCP2 expression in GHS-R(+/+) mice after induction of diabetes were decreased to a similar extent in both genotypes. Exogenous ghrelin administration tended to decrease hypothalamic AMPK activity. In conclusion, an increase in endogenous ghrelin levels triggered by fasting or STZ-induced diabetes stimulates the expression of AgRP and NPY via interaction with the GHS-R. The changes in AMPK activity, pACC and UCP2 occur independently from GHS-R suggesting that they do not play a major role in the orexigenic effect of endogenous ghrelin.     

Finger-loop inhibitors of the HCV NS5b polymerase. Part 1: Discovery and optimization of novel 1,6- and 2,6-macrocyclic indole series

Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.     

Glucose-induced posttranslational activation of protein phosphatases PP2A and PP1 in yeast

The protein phosphatases PP2A and PP1 are major regulators of a variety of cellular processes in yeast and other eukaryotes. Here, we reveal that both enzymes are direct targets of glucose sensing. Addition of glucose to glucose-deprived yeast cells triggered rapid posttranslational activation of both PP2A and PP1. Glucose activation of PP2A is controlled by regulatory subunits Rts1, Cdc55, Rrd1 and Rrd2. It is associated with rapid carboxymethylation of the catalytic subunits, which is necessary but not sufficient for activation. Glucose activation of PP1 was fully dependent on regulatory subunits Reg1 and Shp1. Absence of Gac1, Glc8, Reg2 or Red1 partially reduced activation while Pig1 and Pig2 inhibited activation. Full activation of PP2A and PP1 was also dependent on subunits classically considered to belong to the other phosphatase. PP2A activation was dependent on PP1 subunits Reg1 and Shp1 while PP1 activation was dependent on PP2A subunit Rts1. Rts1 interacted with both Pph21 and Glc7 under different conditions and these interactions were Reg1 dependent. Reg1-Glc7 interaction is responsible for PP1 involvement in the main glucose repression pathway and we show that deletion of Shp1 also causes strong derepression of the invertase gene SUC2. Deletion of the PP2A subunits Pph21 and Pph22, Rrd1 and Rrd2, specifically enhanced the derepression level of SUC2, indicating that PP2A counteracts SUC2 derepression. Interestingly, the effect of the regulatory subunit Rts1 was consistent with its role as a subunit of both PP2A and PP1, affecting derepression and repression of SUC2, respectively. We also show that abolished phosphatase activation, except by reg1Δ, does not completely block Snf1 dephosphorylation after addition of glucose. Finally, we show that glucose activation of the cAMP-PKA (protein kinase A) pathway is required for glucose activation of both PP2A and PP1. Our results provide novel insight into the complex regulatory role of these two major protein phosphatases in glucose regulation.     

Metabolic ageing in individual zebra finches

Oxidative stress is suggested as a contributor to the ageing process. Knowledge of the relationship between age and energy expenditure may contribute to our understanding of ageing patterns, due to the link between oxygen consumption and free radical production. However, studies on basal metabolic rate (BMR) and age have generally been cross-sectional, which may confound estimates of the age effect due to disproportionate mortality (also known as 'selective disappearance'). We therefore performed a longitudinal study of BMR using captive zebra finches (Taeniopygia guttata) up to 5 years of age. BMR declined with age in individuals of both sexes when body mass was controlled for. Males gained mass with age while females did not. There was no evidence for disproportionate mortality with respect to BMR in either sex. To our knowledge, this is the first longitudinal study of avian BMR over such a long proportion of the lifespan of the study species.     

The prediction of breast reduction weight

Reimbursement for reduction mammaplasty has become more stringent because many insurers require specific documentation of patient symptoms and estimated weight of planned breast resection. The purpose of this study was to develop a simple, clinically useful method for predicting weight of breast tissue to be removed, using routine, easily obtained predictors (i.e., height, weight, age, measurements from sternal notch to nipple, and measurements from sternal notch to inframammary crease). Data were available from a retrospective review of 263 women undergoing reduction mammaplasty. Analyses were performed to predict resected weights obtained both in the operating room and by a pathologist for left and right breasts separately. Regression analyses showed that the sternal notch-to-nipple measurement accounted for nearly all of the explained variance in the resected weights, with correlations around 0.80 between sternal notch to nipple and resected weight. For sternal notch-to-nipple measurements > or 28.5 cm, predicted resected weights were approximately 600 g or more, and in general, 80 percent or more patients had specimen weights >500 grams. From 25.5 to 28 cm, the predicted weights ranged from about 400 to 600 g and the prediction rate of weights >500 g was 50 percent. The senior author predicted the resected breast weight to be >500 g 94 percent of the time. The equation alone did not produce an accurate prediction in the critical range, 400 to 600 g. The experienced surgeon more accurately predicted resected weights with use of practiced spatial relationship skills.