Unraveling the Beautiful Complexity of Simple Lattice Model Polymers and Proteins Using Wang-Landau Sampling

We describe a class of "bare bones” models of homopolymers which undergo coil-globule collapse and proteins which fold into their native states in free space or into denatured states when captured by an attractive substrate as the temperature is lowered. We then show how, with the use of a properly chosen trial move set, Wang-Landau Monte Carlo sampling can be used to study the rough free energy landscape and ground (native) states of these intriguingly simple systems and thus elucidate their thermodynamic complexit

Low specificity of the bacterial index for the diagnosis of bacterial pneumonia by bronchoalveolar lavage

The bacterial index (BI) as defined by the sum of log10 colony-forming units (cfu) of microorganisms per milliliter of bronchoalveolar lavage (BAL) fluid, i.e., a multiplication of the single cfu/ml, has been used to distinguish between polymicrobial pneumonia (BI≥5) and colonization (BI<5). Since many false-positive results are to be expected using this parameter, the diagnostic value of the BI was studied prospectively by obtaining bacteriologic cultures of BAL fluid in 165 consecutive unselected patients. In 27 cases the diagnosis of bacterial pneumonia was established on clinical criteria. In 133 patients pneumonia could be excluded, and in five patients the diagnosis remained unclear. Using a cut-off of ≥105 cfu/ml BAL fluid, sensitivity and specificity for the diagnosis of pneumonia were 33% (9/27) and 99% (132/133), respectively. Sensitivity was mainly influenced by prior treatment with antibiotics, being 70% (7/10) in untreated and 12% (2/17) in treated patients. Applying the BI methodology at a cut-off of ≥ 5, however, resulted in an unacceptably high rate of 16 additional false-positive results, thus lowering the specificity to 87% (116/133;P<0.0001) while increasing the sensitivity to only 41% (11/27;P=0.77). In conclusion, given the high rate of false-positive results, the methodology of the BI is of doubtful value for the diagnosis of bacterial pneumonia by BAL in an unselected patient group. By applying the absolute number of cfu/ml BAL fluid, however, positive bacteriologic cultures of BAL fluid are highly specific for the diagnosis of pneumonia. Their sensitivity is limited by previous antibiotic therap

Skeletal muscle properties and fatigue resistance in relation to smoking history

Although smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are often accompanied by increased peripheral muscle fatigability, the extent to which this is a feature of the disease or a direct effect of smoking per se is not known. Skeletal muscle function was investigated in terms of maximal voluntary isometric torque, activation, contractile properties and fatigability, using electrically evoked contractions of the quadriceps muscle of 40 smokers [19 men and 21 women; mean (SD) cigarette pack years: 9.9 (10.7)] and age- and physical activity level matched non-smokers (22 men and 23 women). Maximal strength and isometric contractile speed did not differ significantly between smokers and non-smokers. Muscle fatigue (measured as torque decline during a series of repetitive contractions) was greater in smokers (P = 0.014), but did not correlate with cigarette pack years (r = 0.094, P = 0.615), cigarettes smoked per day (r = 10.092, P = 0.628), respiratory function (%FEV1pred) (r = −0.187, P = 0.416), or physical activity level (r = −0.029, P = 0.877). While muscle mass and contractile properties are similar in smokers and non-smokers, smokers do suffer from greater peripheral muscle fatigue. The observation that the cigarette smoking history did not correlate with fatigability suggests that the effect is either acute and/or reaches a ceiling, rather than being cumulative. An acute and reversible effect of smoking could be caused by carbon monoxide and/or other substances in smoke hampering oxygen delivery and mitochondrial function

Assessment of the cortisol awakening response: expert consensus guidelines

The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30–45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research

Spin-photon interface and spin-controlled photon switching in a nanobeam waveguide

Access to the electron spin is at the heart of many protocols for integrated and distributed quantum-information processing [1-4]. For instance, interfacing the spin-state of an electron and a photon can be utilized to perform quantum gates between photons [2,5] or to entangle remote spin states [6-9]. Ultimately, a quantum network of entangled spins constitutes a new paradigm in quantum optics [1]. Towards this goal, an integrated spin-photon interface would be a major leap forward. Here we demonstrate an efficient and optically programmable interface between the spin of an electron in a quantum dot and photons in a nanophotonic waveguide. The spin can be deterministically prepared with a fidelity of 96\%. Subsequently the system is used to implement a "single-spin photonic switch", where the spin state of the electron directs the flow of photons through the waveguide. The spin-photon interface may enable on-chip photon-photon gates [2], single-photon transistors [10], and efficient photonic cluster state generation [11]

Contrasting demographic history and gene flow patterns of two mangrove species on either side of the Central American Isthmus

Comparative phylogeography offers a unique opportunity to understand the interplay between past environmental events and life-history traits on diversification of unrelated but co-distributed species. Here, we examined the effects of the quaternary climate fluctuations and palaeomarine currents and present-day marine currents on the extant patterns of genetic diversity in the two most conspicuous mangrove species of the Neotropics. The black (Avicennia germinans, Avicenniaceae) and the red (Rhizophora mangle, Rhizophoraceae) mangroves have similar geographic ranges but are very distantly related and show striking differences on their life-history traits. We sampled 18 Atlantic and 26 Pacific locations for A.germinans (N=292) and R.mangle (N=422). We performed coalescence simulations using microsatellite diversity to test for evidence of population change associated with quaternary climate fluctuations. In addition, we examined whether patterns of genetic variation were consistent with the directions of major marine (historical and present day) currents in the region. Our demographic analysis was grounded within a phylogeographic framework provided by the sequence analysis of two chloroplasts and one flanking microsatellite region in a subsample of individuals. The two mangrove species shared similar biogeographic histories including: (1) strong genetic breaks between Atlantic and Pacific ocean basins associated with the final closure of the Central American Isthmus (CAI), (2) evidence for simultaneous population declines between the mid-Pleistocene and early Holocene, (3) asymmetric historical migration with higher gene flow from the Atlantic to the Pacific oceans following the direction of the palaeomarine current, and (4) contemporary gene flow between West Africa and South America following the major Atlantic Ocean currents. Despite the remarkable differences in life-history traits of mangrove species, which should have had a strong influence on seed dispersal capability and, thus, population connectivity, we found that vicariant events, climate fluctuations and marine currents have shaped the distribution of genetic diversity in strikingly similar ways

Altered mitochondrial metabolism in the insulin-resistant heart.

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.COST Action MitoEAGL

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function

Commentary on Viewpoint: Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose?: Skeletal muscle wasting in hypoxia; a matter of altitude.

SKELETAL MUSCLE WASTING IN HYPOXIA; A MATTER OF ALTITUDE TO THE EDITOR: D’Hulst and Deldicque (1) argue that the severity of muscle atrophy incurred at high altitude is dependent on the combined effect of duration and degree of hypoxia exposure, or “hypoxic dose” (1). We do see a limitation of this concept, as it implies that someone residing in Leuven (altitude: 28 m) for 10 years would be subjected to a hypoxic dose of 2,454 km·h and incur 5% atrophy. Although the authors wrote that “it is unknown which parameter, altitude, or time spent at altitude is most decisive in the overall metric of hypoxic dose,” our illustration suggests that altitude is the prime determinant. This is further supported by the cut-off point at 4,000 m in a plot of the degree of atrophy vs. altitude (using the data in Table 1), whereas there was no clear relationship with duration of altitude residence. This cut-off point is likely related to the shape of the hemoglobin dissociation curve, where the oxygen tension at 4,000 m is such that physiologically significant arterial hemoglobin desaturation occurs (2). We acknowledge that one cannot entirely dismiss the importance of duration of hypoxic exposure, simply because skeletal muscle atrophy can only be noticed some time after net protein breakdown is initiated. However, muscle atrophy will not continue indefinitely, but will reach a new steady state (how otherwise can Tibetans still have muscle?). Finally, other adaptations than atrophy, such as an increase in hematocrit and capillarization, serve to attenuate muscle tissue hypoxia and atrophy (3) during residence at altitude. REFERENCES 1. D=Hulst G, Deldicque L. Viewpoint: Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose? J Appl Physiol. doi:10.1152/ japplphysiol.00264.2016. 2. Wagner PD, Wagner HE, Groves BM, Cymerman A, Houston CS. Hemoglobin P(50) during a simulated ascent of Mt. Everest, Operation Everest II. High Alt Med Biol 8: 32–42, 2007. doi:10.1089/ham.2006. 1049. 3. Wüst RCI, Jaspers RT, van Heijst AF, Hopman MT, Hoofd LJ, van der Laarse WJ, Degens H. Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia. Am J Physiol Heart Circ Physiol 297: H364–H374, 2009. doi:10.1152/ajpheart.00272.2009