Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles

The protein wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. Mutations in Wfs1 gene cause autosomal recessive disorder Wolfram syndrome (WS). The first symptom of the WS is diabetes mellitus, so accurate diagnosis of the disease as WS is often delayed. In this study we aimed to characterize the role of the Wfs1 deficiency on bioenergetics of muscles. Alterations in the bioenergetic profiles of Wfs1-exon-5-knock-out (Wfs1KO) male rats in comparison with their wild-type male littermates were investigated using high-resolution respirometry, and enzyme activity measurements. The changes were followed in oxidative (cardiac and soleus) and glycolytic (rectus femoris and gastrocnemius) muscles. There were substrate-dependent alterations in the oxygen consumption rate in Wfs1KO rat muscles. In soleus muscle, decrease in respiration rate was significant in all the followed pathways. The relatively small alterations in muscle during development of WS, such as increased mitochondrial content and/or increase in the OxPhos-related enzymatic activity could be an adaptive response to changes in the metabolic environment. The significant decrease in the OxPhos capacity is substrate dependent indicating metabolic inflexibility when multiple substrates are available.     

Jelly-falls historic and recent observations: a review to drive future research directions

The biological pump describes the transport of particulate matter from the sea surface to the ocean’s interior including the seabed. The contribution by gelatinous zooplankton bodies as particulate organic matter (POM) vectors (“jelly-falls”) has been neglected owing to technical and spatiotemporal sampling limitations. Here, we assess the existing evidence on jelly-falls from early ocean observations to present times. The seasonality of jelly-falls indicates that they mostly occur after periods of strong upwelling and/or spring blooms in temperate/subpolar zones and during late spring/early summer. A conceptual model helps to define a jelly-fall based on empirical and field observations of biogeochemical and ecological processes. We then compile and discuss existing strategic and observational oceanographic techniques that could be implemented to further jelly-falls research. Seabed video- and photography-based studies deliver the best results, and the correct use of fishing techniques, such as trawling, could provide comprehensive regional datasets. We conclude by considering the possibility of increased gelatinous biomasses in the future ocean induced by upper ocean processes favouring their populations, thus increasing jelly-POM downward transport. We suggest that this could provide a “natural compensation” for predicted losses in pelagic POM with respect to fuelling benthic ecosystems.     

Hagenia from the early Miocene of Ethiopia: Evidence for possible niche evolution?

Fossil pollen believed to be related to extant Hagenia abyssinica were discovered in the early Miocene (21.73 Ma) Mush Valley paleoflora, Ethiopia, Africa. Both the fossil and extant pollen grains of H. abyssinica were examined with combined light microscopy, scanning electron microscopy, and transmission electron microscopy to compare the pollen and establish their relationships. Based on this, the fossil pollen grains were attributed to Hagenia. The presence of Hagenia in the fossil assemblage raises the questions if its habitat has changed over time, and if the plants are/were wind pollinated. To shed light on these questions, the morphology of extant anthers was also studied, revealing specialized hairs inside the anthers, believed to aid in insect pollination. Pollen and anther morphology are discussed in relation to the age and origin of the genus within a molecular dated phylogenetic framework, the establishment of complex topography in East Africa, other evidence regarding pollination modes, and the palynological record. The evidence presented herein, and compiled from the literature, suggests that Hagenia was an insect‐pollinated lowland rainforest element during the early Miocene of the Mush Valley. The current Afromontane habitat and ambophilous (insect and wind) pollination must have evolved in post‐mid‐Miocene times.     

MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms

Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions.     

On the Effect of Prevalent Carbazole Homocoupling Defects on the Photovoltaic Performance of PCDTBT:PC71BM Solar Cells

The photophysical properties and solar cell performance of the classical donor–acceptor copolymer PCDTBT (poly(N‐9′‐heptadecanyl‐2,7‐carbazole‐alt ‐5,5‐(4′,7′‐di‐2‐thienyl‐2′,1′,3′‐benzothiadiazole))) in relation to unintentionally formed main chain defects are investigated. Carbazole–carbazole homocouplings (Cbz hc) are found to significant extent in PCDTBT made with a variety of Suzuki polycondensation conditions. Cbz hc vary between 0 and 8 mol% depending on the synthetic protocol used, and are quantified by detailed nuclear magnetic resonance spectroscopy including model compounds, which allows to establish a calibration curve from optical spectroscopy. The results are corroborated by extended time‐dependent density functional theory investigations on the structural, electronic, and optical properties of regularly alternating and homocoupled chains. The photovoltaic properties of PCDTBT:fullerene blend solar cells significantly depend on the Cbz hc content for constant molecular weight, whereby an increasing amount of Cbz hc leads to strongly decreased short circuit currents J_SC. With increasing Cbz hc content, J_SC decreases more strongly than the intensity of the low energy absorption band, suggesting that small losses in absorption cannot explain the decrease in J_SC alone, rather than combined effects of a more localized LUMO level on the TBT unit and lower hole mobilities found in highly defective samples. Homocoupling‐free PCDTBT with optimized molecular weight yields the highest efficiency up to 7.2% without extensive optimization.     

In vivo evidence for instability of episomal human immunodeficiency virus type 1 cDNA

Current regimens for the management of human immunodeficiency virus type 1 (HIV-1) infection suppress plasma viremia to below detectable levels for prolonged intervals. Nevertheless, there is a rapid resumption in plasma viremia if therapy is interrupted. Attempts to characterize the extent of viral replication under conditions of potent suppression and undetectable plasma viremia have been hampered by a lack of convenient assays that can distinguish latent from ongoing viral replication. Using episomal viral cDNA as a surrogate for ongoing replication, we previously presented evidence that viral replication persists in the majority of infected individuals with a sustained aviremic status. The labile nature of viral episomes and hence their validity as surrogate markers of ongoing replication in individuals with long-term-suppressed HIV-1 infection have been analyzed in short-term in vitro experiments with conflicting results. Since these in vitro experiments do not shed light on the long-term in vivo dynamics of episomal cDNA or recapitulate the natural targets of infection in vivo, we have analyzed the dynamics of episomal cDNA turnover in vivo by following the emergence of an M184V polymorphism in plasma viral RNA, in episomal cDNA, and in proviral DNA in patients on suboptimal therapies. We demonstrate that during acquisition of drug resistance, wild-type episomal cDNAs are replaced by M184V-harboring episomes. Importantly, a complete replacement of wild-type episomes with M184V-containing episomes occurred while proviruses remained wild type. This indicates that episomal cDNAs are turned over by degradation rather than through death or tissue redistribution of the infected cell itself. Therefore, evolution of episomal viral cDNAs is a valid surrogate of ongoing viral replication in HIV-1-infected individuals.     

Effects of Morris water maze testing on the neuroendocrine stress response and intrahypothalamic release of vasopressin and oxytocin in the rat

Adult male Wistar rats were trained in the Morris water maze (MWM) on 3 consecutive days to find a visible platform. Concomitantly, microdialysis samples from the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei were collected in order to monitor local release of the neuropeptides vasopressin (AVP) and oxytocin (OXT), respectively, during controllable swim stress. Additionally, a separate set of animals was equipped with chronic jugular venous catheters to collect blood samples for analyzing plasma concentrations of corticotropin (ACTH) and corticosterone during training in the MWM. As measured by microdialysis, swimming in the MWM caused a significantly increased release of AVP within the PVN and of OXT within the SON on each of the 3 test sessions. In contrast to OXT in the SON, basal AVP concentrations in the PVN tended to rise from day to day. Plasma ACTH and corticosterone were found to be similarly elevated in response to MWM exposure on each of the test sessions. Taken together, these data demonstrate that testing in the MWM is not only associated with a significant activation of the hypothalamo-pituitary-adrenal axis but also with an intrahypothalamic release of AVP and OXT. If compared with findings using repeated forced swimming as an uncontrollable stressor (Wotjak, C.T., Ganster, J., Kohl, G., Holsboer, F., Landgraf, R., Engelmann, M., 1998. Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons. Neuroscience 85, 1209-1222), the present results suggest that (1) similarities in the release profiles of AVP in the PVN and plasma hormone levels are fairly independent from the controllability of the stressor and seem, thus, to primarily relate to the physical demands of the task, whereas (2) the different intra-SON OXT release profiles might be linked to the controllability of the stressor.     

Role of the fourth intracellular loop of D1-like dopaminergic receptors in conferring subtype-specific signaling properties

We investigate whether the fourth intracellular loop (IL4) of D1 and D5 dopaminergic receptors (D1R, D5R) confers D1-like subtype-specific signaling properties. Using chimeric receptors (D1R-IL4B and D5R-IL4A), we show that swapping of IL4 leads to a switch in dopamine affinity and constitutive activity of D1R and D5R. Dopamine potency was reduced for both chimeras in comparison with wild-type receptors. Moreover, dopamine-mediated maximal activation was drastically increased in cells expressing D1R-IL4B when compared with those harboring D5R-IL4A or wild-type receptors. In conclusion, IL4 plays a pivotal role in imparting subtype-specific ligand binding and activation properties to highly homologous seven-transmembrane receptors.     

A Simple Geometrical Pattern for the Branching Distribution of the Bronchial Tree, Useful to Estimate Optimality Departures

The design of the bronchial tree has largely been proposed as a model of optimal design from a physical-functional perspective. However, the distributive function of the airway may be more related to a geometrical than a physical problem. The bronchial tree must distribute a three dimensional volume of inspired air on a two dimensional alveolar surface, included in a limited volume. It is thus valid to ask whether an optimal bronchial tree from a physical perspective is also optimum from a geometrical point of view. In this paper we generate a simple geometric model for the branching pattern of the bronchial tree, deducing relationships that permit estimation of the departures from the geometrical optimum of each bifurcation. We also, for comparative purposes, estimate the departures from the physical optimum. From the geometrical assumptions: i) a symmetrical dichotomic fractal design, ii) with minimum volume and iii) maximum dispersion of the terminal points; and several simulations we suggest that the optimality is characterized by a bifurcation angle theta approximately 60 degrees and a length reduction scale gamma = (1/2)(1/3) = 0.7937. We propose distances from the physical and geometrical optimality defined as Euclidean distances from the expected optima. We show how the advanced relationships and the distances can be used to estimate departures from the optimality in bronchographs of four species. We found lower physical and geometrical departures in the distal zone than those of the proximal zones, as well as lower physical than geometrical departures from optimality.