Anomalous front broadening during spontaneous imbibition in a matrix with elongated pores

During spontaneous imbibition, a wetting liquid is drawn into a porous medium by capillary forces. In systems with comparable pore length and diameter, such as paper and sand, the front of the propagating liquid forms a continuous interface. Sections of this interface advance in a highly correlated manner due to an effective surface tension, which restricts front broadening. Here we investigate water imbibition in a nanoporous glass (Vycor) in which the pores are much longer than they are wide. In this case, no continuous liquid-vapor interface with coalesced menisci can form. Anomalously fast imbibition front roughening is experimentally observed by neutron imaging. We propose a theoretical pore-network model, whose structural details are adapted to the microscopic pore structure of Vycor glass and show that it displays the same large-scale roughening characteristics as observed in the experiment. The model predicts that menisci movements are uncorrelated, indicating that despite the connectivity of the network the smoothening effect of surface tension on the imbibition front roughening is negligible. These results suggest a new universality class of imbibition behavior, which is expected to occur in any matrix with elongated, interconnected pores of random radii.     

Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state

The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism.     

MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation?

The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.     

ITN protection, MSP1 antibody levels and malaria episodes in young children of rural Burkina Faso

Malaria blood-stage vaccines are in an early phase of clinical development with MSP1 being a major antigen candidate. There are limited data on the protective efficacy of antibodies against subunits of MSP1 in the malaria endemic areas of sub-Saharan Africa. This prospective cohort study was nested into a large insecticide-treated mosquito net (ITN) trial during which neonates were individually randomised to ITN protection from birth vs. protection from month six onwards in rural Burkina Faso. A sub sample of 120 children from three villages was followed for 10 months with six measurements of MSP1(42) antibodies (ELISA based on recombinant 42kDa fragment) and daily assessment of malaria episodes. Time to the next malaria episode was determined in relation to MSP1(42) antibody titres. MSP1(42) antibody titres were dependent on age, season, ITN-group, number of previous malaria episodes and parasitaemia. There were no significant differences in time until the next malaria episode in children with low compared to children with high MSP1(42) antibody titres at any point in time (101 vs. 97 days in May, p=0.6; 58 vs. 84 days in September, p=0.3; 144 vs. 161 days in March, p=0.5). The findings of this study support the short-lived nature of the humoral immune response in infants of malaria endemic areas. The study provides no evidence for antibodies against a subunit of MSP1 being protective against new malaria episodes in infants.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.     

Association of prion protein with cognitive functioning in humans

Objectives

Recent animal studies have suggested a key role for cellular prion protein (PrPc) in the pathological consequences of amyloid plaque formation, the hallmark of Alzheimer's disease. This epidemiological study investigated whether serum concentrations of PrPc are associated with cognitive functioning in humans.

Design, Setting, Participants

Cross-sectional study of 1,322 participants from the elderly general population in Germany, aged 65 + years at baseline (2000–2002).

Measurements

Cognitive functioning was assessed by the COGTEL phone interview 5 years after baseline. Serum PrPc was determined by a commercial immunoassay.

Results

In multiple linear regression adjusted for important confounders, subjects in higher PrPc quintiles appeared to have lower cognitive functioning scores than those in the lowest PrPc quintile. Spline regression suggested pronounced non-linearity with an inverse association between PrPc and cognitive functioning levelling off beyond median PrPc. Cognitive subdomain-specific models produced somewhat heterogeneous results.

Conclusion

The findings are suggestive of an independent association of PrPc with cognitive functioning in humans. Confirmatory and longitudinal studies are needed to elucidate the potential of PrPc for applications in early risk stratification for cognitive impairment.     

Understanding Pancreas Development for β-Cell Repair and Replacement Therapies

The lack or dysfunction of insulin-producing β-cells is the cause of all forms of diabetes. In vitro generation of β-cells from pluripotent stem cells for cell-replacement therapy or triggering endogenous mechanisms of β-cell repair have great potential in the field of regenerative medicine. Both approaches rely on a thorough understanding of β-cell development and homeostasis. Here, we briefly summarize the current knowledge of β-cell differentiation during pancreas development in the mouse. Furthermore, we describe how this knowledge is translated to instruct differentiation of both mouse and human pluripotent stem cells towards the β-cell lineage. Finally, we shortly summarize the current efforts to identify stem or progenitor cells in the adult pancreatic organ and to harness the endogenous regenerative potential. Understanding development and regeneration of β-cells already led to identification of molecular targets for therapy and informed on pathomechanisms of diabetes. In the future might lead to β-cell repair and replacement therapies.     

Comparison of revision strategies for failed C2-posterior cervical pedicle screws: a biomechanical study

Study purpose

With increasing usage within challenging biomechanical constructs, failures of C2 posterior cervical pedicle screws (C2-pCPSs) will occur. The purpose of the study was therefore to investigate the biomechanical characteristics of two revision techniques after the failure of C2-pCPSs.

Materials and methods

Twelve human C2 vertebrae were tested in vitro in a biomechanical study to compare two strategies for revision screws after failure of C2-pCPSs. C2 pedicles were instrumented using unicortical 3.5-mm CPS bilaterally (Synapse/Synthes, Switzerland). Insertion accuracy was verified by fluoroscopy. C2 vertebrae were potted and fixed in an electromechanical testing machine with the screw axis coaxial to the pullout direction. Pullout testing was conducted with load and displacement data taken continuously. The peak load to failure was measured in newtons (N) and is reported as the pullout resistance (POR). After pullout, two revision strategies were tested in each vertebra. In Group-1, revision was performed with 4.0-mm C2-pCPSs. In Group-2, revision was performed with C2-pedicle bone-plastic combined with the use of a 4-mm C2-pCPSs. For the statistical analysis, the POR between screws was compared using absolute values (N) and the POR of the revision techniques normalized to that of the primary procedures (%).

Results

The POR of primary 3.5-mm CPSs was 1,140.5 ± 539.6 N for Group-1 and 1,007.7 ± 362.5 N for Group-2; the difference was not significant. In the revision setting, the POR in Group-1 was 705.8 ± 449.1 N, representing a reduction of 38.1 ± 32.9 % compared with that of primary screw fixation. For Group-2, the POR was 875.3 ± 367.9 N, representing a reduction of 13.1 ± 23.4 %. A statistical analysis showed a significantly higher POR for Group-2 compared with Group-1 (p = 0.02). Although the statistics showed a significantly reduced POR for both revision strategies compared with primary fixation (p < 0.001/p = 0.001), the loss of POR (in %) in Group-1 was significantly higher compared with the loss in Group-2 (p = 0.04).

Conclusions

Using a larger-diameter screw combined with the application of a pedicle bone-plastic, the POR can be significantly increased compared with the use of only an increased screw diameter.