Group-specific component in Macaca.

The group-specific component in 17 Macaca mulatta was examined. All the individuals revealed the same Gc 1--1 pattern.     

Analysis of the effect of α-dinitrophenol on cleavage and development of the sea urchin embryo

Summary The influence of DNP on the developing sea urchin embryo was studied by means of time-lapse cinematography and staining methods. In the concentrations of DNP which affect oxidative phosphorylation cleavage is rapidly brought to a standstill. DNP inflicts morphological changes of the mitochondria, which also show a lowered affinity for Janus green B. Some new aspects on the effect of DNP on morphogenesis are discussed.     

The High Energy Demand of Neuronal Cells Caused by Passive Leak Currents is Not a Waste of Energy

It is estimated that maintenance of the resting potential of neurons consumes between 15 % (in gray matter) and 44 % (in fully myelinated white matter) of the brain’s total energy budget [1]. This poses the intriguing question why evolution has not strived to lower the permeability of passive ion channels to cut the high resting-state energy budget of the brain. Based on a conceptual mathematical model of neuronal ion currents and action potential (AP) firing we demonstrate that a neuron endowed with small leak currents and correspondingly low energy consumption by the Na⁺/K⁺-ATPase in the resting state may indeed recapitulate all features of normal AP firing. However, the activation and inactivation of such a “low-energy-cost neuron” turns out to be extremely sensitive to small fluctuation of Na⁺ currents associated with Na⁺-dependent secondary-active transport that is indispensable for the metabolic integrity of the cell and neurotransmitter recycling. We provide evidence that sufficiently large leak currents function as important stabilizers of the membrane potential and thus are required to allow robust AP firing. Our simulations suggest that the energy demand of the Na⁺/K⁺-ATPase needed to counterbalance passive leak currents cannot be significantly dropped below observed values.     

Age-Specific Mortality During the 1918 Influenza Pandemic: Unravelling the Mystery of High Young Adult Mortality

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889–90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.

“The war is over – and I must go” Egon Schiele, 1890–1918.

     

Angiotensin II Signaling in Human Preadipose Cells: Participation of ERK1,2-Dependent Modulation of Akt

The renin-angiotensin system expressed in adipose tissue has been implicated in the modulation of adipocyte formation, glucose metabolism, triglyceride accumulation, lipolysis, and the onset of the adverse metabolic consequences of obesity. As we investigated angiotensin II signal transduction mechanisms in human preadipose cells, an interplay of extracellular-signal-regulated kinases 1 and 2 (ERK_1,2) and Akt/PKB became evident. Angiotensin II caused attenuation of phosphorylated Akt (p-Akt), at serine 473; the p-Akt/Akt ratio decreased to 0.5±0.2-fold the control value without angiotensin II (p<0.001). Here we report that the reduction of phosphorylated Akt associates with ERK_1,2 activities. In the absence of angiotensin II, inhibition of ERK_1,2 activation with U0126 or PD98059 resulted in a 2.1±0.5 (p<0.001) and 1.4±0.2-fold (p<0.05) increase in the p-Akt/Akt ratio, respectively. In addition, partial knockdown of ERK₁ protein expression by the short hairpin RNA technique also raised phosphorylated Akt in these cells (the p-Akt/Akt ratio was 1.5±0.1-fold the corresponding control; p<0.05). Furthermore, inhibition of ERK_1,2 activation with U0126 prevented the reduction of p-Akt/Akt by angiotensin II. An analogous effect was found on the phosphorylation status of Akt downstream effectors, the forkhead box (Fox) proteins O1 and O4. Altogether, these results indicate that angiotensin II signaling in human preadipose cells involves an ERK_1,2-dependent attenuation of Akt activity, whose impact on the biological functions under its regulation is not fully understood.     

Inter-Physician Variation in Follow-Up Colonoscopies after Screening Colonoscopy

Background and Aims

Surveillance is an integral part of the colorectal cancer (CRC) screening process. We aimed to investigate inter-physician variation in follow-up procedures after screening colonoscopy in an opportunistic CRC screening program.

Methods

A historical cohort study in the German statutory health insurance system was conducted. 55,301 individuals who underwent screening colonoscopy in 2006 in Bavaria, Germany, and who were not diagnosed with CRC were included. Utilization of follow-up colonoscopies performed by the same physician (328 physicians overall) within 3 years was ascertained. Mixed effects logistic regression modelling was used to assess the effect of physicians and other potential predictors (screening result, age group, and sex) on re-utilization of colonoscopy. Physicians were grouped into quintiles according to individual effects estimated in a preliminary model. Predicted probabilities of follow-up colonoscopy by screening result and physician group were calculated.

Results

The observed rate of follow-up colonoscopy was 6.2% (95% confidence interval: 5.9-6.4%), 18.6% (17.8-19.4%), and 37.0% (35.5-38.4%) after negative colonoscopy, low-risk adenoma and high-risk adenoma detection, respectively. All considered predictors were statistically significantly associated with follow-up colonoscopy. The predicted probabilities of follow-up colonoscopy ranged from 1.7% (1.4-2.0%) to 11.0% (10.2-11.7%), from 7.3% (6.2-8.5%) to 35.1% (32.6-37.7%), and from 17.9% (15.5-20.6%) to 56.9% (53.5-60.3%) in the 1^st quintile (lowest rates of follow-up) and 5^th quintile (highest rates of follow-up) of physicians after negative colonoscopy, low-risk adenoma and high-risk adenoma detection, respectively.

Conclusions

This study suggests substantial inter-physician variation in follow-up habits after screening colonoscopy. Interventions, including organizational changes in CRC screening should be considered to reduce this variation.     

Efficient isotopic tryptophan labeling of membrane proteins by an indole controlled process conduct

A protocol for the efficient isotopic labeling of large G protein‐coupled receptors with tryptophan in Escherichia coli as expression host was developed that sufficiently suppressed the naturally occurring L‐tryptophan indole lyase, which cleaves tryptophan into indole, pyruvate, and ammonia resulting in scrambling of the isotopic label in the protein. Indole produced by the tryptophanase is naturally used as messenger for cell–cell communication. Detailed analysis of different process conducts led to the optimal expression strategy, which mimicked cell–cell communication by the addition of indole during expression. Discrete concentrations of indole and ¹⁵N₂‐L‐tryptophan at dedicated time points in the fermentation drastically increased the isotopic labeling efficiency. Isotope scrambling was only observed in glutamine, asparagine, and arginine side chains but not in the backbone. This strategy allows producing specifically tryptophan labeled membrane proteins at high concentrations avoiding the disadvantages of the often low yields of auxotrophic E. coli strains. In the fermentation process carried out according to this protocol, we produced ～15 mg of tryptophan labeled neuropeptide Y receptor type 2 per liter medium. Biotechnol. Bioeng. 2013; 110: 1681–1690. © 2013 Wiley Periodicals, Inc.     

Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying “causal” rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.     

Termite mounds differ in their importance for herbivores across savanna types,seasons and spatial scales

Herbivores do not forage uniformly across landscapes, but select for patches of higher nutrition and lower predation risk. Macrotermes mounds contain higher concentrations of soil nutrients and support grasses of higher nutritional value than the surrounding savanna matrix, attracting mammalian grazers that preferentially forage on termite mound vegetation. However, little is known about the spatial extent of such termite influence on grazing patterns and how it might differ in time and space. We measured grazing intensity in three African savanna types differing in rainfall and foliar nutrients and predicted that the functional importance of mounds for grazing herbivores would increase as the difference in foliar nutrient levels between mound and savanna matrix grasses increases and the mounds become more attractive. We expected this to occur in nutrient‐poor areas and during the dry season when savanna matrix grass nutrient levels are lower. Tuft use and grass N and P content were measured along transects away from termite mounds, enabling calculation of the spatial extent of termite influence on mammalian grazing. Using termite mound densities estimated from airborne light detection and ranging (LiDAR), we further upscaled field‐based results to determine the percentage of the landscape influenced by termite activity. Grasses in close proximity to termite mounds were preferentially grazed at all sites and in both seasons, but the strength of mound influence varied between savanna types and seasons. In the wet season, mounds had a relatively larger effect on grazers at the landscape scale in the nutrient‐poor, wetter savanna, whereas in the dry season the pattern was reversed with more of the landscape influenced at the nutrient‐rich, driest site. Our results reveal that termite mounds enhance the value of savanna landscapes for herbivores, but that their functional importance varies across savanna types and seasons.