Glutamate exocytosis and MARCKS phosphorylation are enhanced by a metabotropic glutamate receptor coupled to a protein kinase C synergistically activated by diacylglycerol and arachidonic acid.
4-Aminopyridine evokes repetitive firing of synaptosomes and exocytosis of glutamate by inhibiting a dendrotoxin-sensitive K+ channel responsible for stabilizing the membrane potential. We have shown previously that activation of protein kinase C (PKC) by high concentrations of phorbol ester (4 beta-phorbol dibutyrate) can increase release by inhibiting a dendrotoxin-insensitive ion channel, whereas the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] mimics the action of 4 beta-phorbol dibutyrate, but only in the presence of 2 microM arachidonic acid (AA). In this article, we investigate the role of AA. AA plus (1S,3R)-ACPD is without effect on KCl-induced glutamate exocytosis, indicating that the regulatory pathway acts upstream of the release-coupled Ca2+ channel or Ca(2+)-secretion coupling. Diacylglycerol concentrations are greatly enhanced by (1S,3R)-ACPD alone, independently of AA, indicating that AA acts downstream of phospholipase C. Myristoylated alanine-rich C kinase substrate (MARCKS) is the major presynaptic substrate for PKC. mGluR activation by (1S,3R)-ACPD enhances phosphorylation of MARCKS, but only in the presence of AA. These results strongly suggest that AA acts on presynaptic PKC synergistically with diacylglycerol generated by the phospholipase-coupled mGluR, consistent with the known behaviour of certain purified PKC isoforms. The magnitude of the effects observed in a population of rat cerebrocortical synaptosomes suggests that this is a major mechanism regulating the release of the brain's dominant excitatory neurotransmitter and supports the concept that AA, or a related compound with a similar locus of action, may in certain circumstances play a role in synaptic plasticity.


In Vitro Anticancer Activities of Anogeissus latifolia, Terminalia bellerica, Acacia catechu and Moringa oleiferna Indian Plants.
The present study was designed to evaluate in vitro anti-proliferative potential of extracts from four Indian medicinal plants, namely Anogeissus latifolia, Terminalia bellerica, Acacia catechu and Moringa oleiferna. Their cytotoxicity was tested in nine human cancer cell lines, including cancers of lung (A549), prostate (PC-3), breast (T47D and MCF-7), colon (HCT-16 and Colo-205) and leukemia (THP-1, HL-60 and K562) by using SRB and MTT assays. The findings showed that the selected plant extracts inhibited the cell proliferation of nine human cancer cell lines in a concentration dependent manner. The extracts inhibited cell viability of leukemia HL-60 and K562 cells by blocking G0/G1 phase of the cell cycle. Interestingly, A. catechu extract at 100 μg/mL induced G2/M arrest in K562 cells. DNA fragmentation analysis displayed the appearance of a smear pattern of cell necrosis upon agarose gel electrophoresis after incubation of HL-60 cells with these extracts for 24 h.


Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs.
Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis.


Computational modelling of internally cooled wet (ICW) electrodes for radiofrequency ablation: impact of rehydration, thermal convection and electrical conductivity.
(1) To analyse rehydration, thermal convection and increased electrical conductivity as the three phenomena which distinguish the performance of internally cooled electrodes (IC) and internally cooled wet (ICW) electrodes during radiofrequency ablation (RFA), (2) Implement a RFA computer model with an ICW which includes these phenomena and (3) Assess their relative influence on the thermal and electrical tissue response and on the coagulation zone size. A 12-min RFA in liver was modelled using an ICW electrode (17 G, 3 cm tip) by an impedance-control pulsing protocol with a constant current of 1.5 A. A model of an IC electrode was used to compare the ICW electrode performance and the computational results with the experimental results. Rehydration and increased electrical conductivity were responsible for an increase in coagulation zone size and a delay (or absence) in the occurrence of abrupt increases in electrical impedance (roll-off). While the increased electrical conductivity had a remarkable effect on enlarging the coagulation zone (an increase of 0.74 cm for differences in electrical conductivity of 0.31 S/m), rehydration considerably affected the delay in roll-off, which, in fact, was absent with a sufficiently high rehydration level. In contrast, thermal convection had an insignificant effect for the flow rates considered (0.05 and 1 mL/min). Computer results suggest that rehydration and increased electrical conductivity were mainly responsible for the absence of roll-off and increased size of the coagulation zone, respectively, and in combination allow the thermal and electrical performance of ICW electrodes to be modelled during RFA.


Metabolic Adaptations in Pregnancy: A Review.
Pregnancy is a dynamic state involving multiple adaptations that are necessary in order to ensure a continuous supply of essential metabolites to support the growth and the development of the fetus. This review article is aimed to discuss important adaptations in metabolism that take place during non-complicated pregnancy. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting the importance of metabolic adaptations during a non-complicated pregnancy. The preferred language was English and the most recent reports were selected to get an updated review. It was observed clearly in the searched literature that metabolic adaptations are a crucial part of pregnancy, as they provide the mother with sufficient energy stores to meet the demands of pregnancy. These adaptions also help in preparing the mother for lactation and also help in providing proper environment for the proper growth of fetus in the womb. Moreover, multiple biomolecules including glucose, fatty acids, ketone bodies, hormones collectively contribute toward these metabolic adaptations. This review article concludes that metabolic adaptations are crucial for proper fetus development.


Effects of social status and stress on patterns of gastrointestinal parasitism in wild white-handed gibbons (Hylobates lar).
Although gibbons (family Hylobatidae) are typically monogamous, polyandrous groups occur regularly. Stress associated with elevated intragroup competition among males in polyandrous groups may increase susceptibility to infectious disease. To better understand this interplay, as well as to provide the first comprehensive assessment of parasitism in free-ranging gibbons, we characterized the richness of gastrointestinal parasites and examined their prevalence in males from 14 groups (10 pair-living, 4 multi-male) of white-handed gibbons (Hylobates lar) at Khao Yai National Park, Thailand. From September 2008 to May 2009, 324 fecal samples were collected from 23 individually recognizable male gibbons and screened for gastrointestinal helminths and protozoa after isolation via fecal floatation, sedimentation, and immunofluorescent antibody detection. A total of 10 parasite species recovered, including seven nematodes, two protozoans, and one trematode. Parasite richness and species-specific prevalence were examined relative to social organization (pair-living vs. multi-male), male status (primary vs. secondary), age (subadult, adult, senior), fecal glucocorticoid levels, and time of the year. No relationship was found between parasite richness and sociodemographic or physiological factors. Similarly, prevalence of infection with parasite species was not associated with the majority of sociodemographic factors; however, Ternidens sp. and Balantidium coli varied seasonally and Trichuris sp. decreased with increasing age. Moreover, observational data suggest that competition is low in this gibbon population, and our findings are consistent with those observations in that cooperative defense may offset stress and reduce susceptibility to infection.


Influence of lithium chloride on rabbit's EEG and behavior.
The effects of intravenous or intrahippocampal injections of lithium chloride dissolved in bidistilled water were investigated on rabbits with chronically implanted canniulas and electrodes. Bioelectric activity of the limbic structures and behavior were analyzed. Electrical activity was recorded by means of bipolar electrodes implanted chronically in the dorsal hippocampus, the gyrus cinguli, the amygdaloid complex and the medial hypothalamus, LiCl inhibited electric activity of the limbic structures and caused a reduction of spontaneous motor and exploratory activity of rabbits.


In-vivo skin respiration (CO2) measurements in the acupuncture loci.
Classical acupuncture concept is based on the vague, undefinable idea of energy. In our contemporary molecular biology, useful energy is considered to be stored in the macroerg phosphate compounds, e.g. in ATP, while (through the citrate cycle) CO2 is exhaled by the living cells of the body. In Hungary, a small and supersensitive CO2 detecting instrument was invented in 1976. Its sensitivity starts at 0.01 millionth of a gram CO2. In this study first the interrelationships between skin respiration, electrical skin resistance and skin temperature at the acupuncture point (AP) and at the adjacent skin area were investigated. The measured characteristics deviate, in spite of the distance of 1-2 centimeters. It is reasonable to suppose that in the maximum 52% the capillary CO2 tension at the AP reflects in the skin respiration data.


[Muscarinic cholinergic receptor antagonists enhanced the expression of CD(8)(+)CD(25)(+)Foxp(3)(+) regulatory T cells in stable COPD patients].
to investigate the levels of peripheral CD(8)(+)CD(25)(+)Foxp(3)(+) regulatory T cells (CD(8)(+)CD(25)(+)Treg) in stable chronic obstructive pulmonary disease (COPD) patients, and the effect of muscarinic cholinergic receptor antagonist, tiotropium bromide, on the expression of CD(8)(+)CD(25)(+)Treg. from Oct. 2007 to Mar. 2008, 23 patients with stable moderate to severe COPD received tiotropium bromide inhalation (18 microg daily) for 3 months. Before and after the use of tiotropium bromide, lung function was performed and peripheral vein blood samples were collected from the patient. Lymphocytes were isolated by three-color labeled monoclonal antibodies flow cytometry to detect the quantity and percentage of CD(8)(+)T cell, CD(8)(+)CD(25)(+) T cell, CD(8)(+)CD(25)(+)Treg, CD(4)(+)T cell, CD(4)(+)CD(25)(+) T cell and CD(4)(+)CD(25)(+)Treg, respectively. Paired t test was used for comparison between data before and after treatment. in patients with stable COPD, after tiotropium bromide treatment, the percentage of CD(4)(+) T cells was increased from (28 +/- 10)% to (36 +/- 6)%, and the difference was significant (t = 3.20, P < 0.01). CD(4)(+)CD(25)(+) was decreased from (10 +/- 7)% to (4 +/- 3)% (t = 3.78, P < 0.01), and CD(8)(+)CD(25)(+)Treg was increased from (8 +/- 8)% to (21 +/- 21)% (t = 2.72, P < 0.05). At baseline, CD(8)(+) cells, CD(8)(+)CD(25)(+) cells and CD(4)(+)CD(25)(+)Treg were detectable in the peripheral blood, but no significant changes were observed after treatment. After treatment with tiotropium bromide, the lung function was markedly improved; FEV(1), FEV(1)/Pre%, and FEV(1)/FVC were increased from (1.0 +/- 0.3) L, (35 +/- 10)% and (41 +/- 8)% to (1.1 +/- 0.3) L, (40 +/- 11)% and (45 +/- 11)%, respectively (t = 2.65, 2.56 and 2.37, respectively, all P < 0.05). By linear correlation analysis, the quantity of changes of CD(4)(+) T cells and CD(4)(+)CD(25)(+) T cells were negatively correlated with the rate of change in CD(8)(+)CD(25)(+)Treg (r = -0.61, P < 0.05 and r = -0.72, P < 0.01, respectively). in the peripheral blood of patients with stable COPD, there was expression of CD(8)(+)CD(25)(+)Treg and CD(4)(+)CD(25)(+)Treg. The muscarinic receptor antagonist tiotropium bromide, promoted the amplification of CD(4)(+), inhibited the expression of CD(25)(+), and enhanced the expression of CD(8)(+)Treg, suggesting that muscarinic receptor antagonist tiotropium bromide may possess immunomodulation function.


Shared decision making in West Africa: The forgotten area.
Up to now, little attention has been paid to West Africa when it comes to shared decision making (SDM). West African countries seem to lag behind with regard to SDM initiatives compared to many other countries in the world. There is some interest in informed decision making or informed consent, but little in a full SDM process. Few decision-making tools are available for healthcare professionals and the majority are not designed to support decision-making with patients. Furthermore, to the best of our knowledge, there are no training programs for implementing SDM in healthcare teams. Many barriers exist to implementing SDM in West Africa, including lack of options, few or poor health resources and low levels of education. However, African countries present many opportunities for SDM as well. Existing SDM innovations developed for other populations with low literacy could be explored and adapted to the West African context, and research on implementation and outcomes in West Africa could contribute to SDM worldwide. West African countries are in an excellent position to both learn from other countries and contribute to SDM development in other parts of the world. In this paper we reflect on SDM challenges and opportunities, and propose a research agenda for West Africa. We hope to awaken interest in SDM in West Africa and encourage future collaborations on SDM with various West African stakeholders, including patients, healthcare professionals, policymakers, non-government organisations (NGOs) and academic institutions.


Toward 'Computational-Rationality' Approaches to Arbitrating Models of Cognition: A Case Study Using Perceptual Metacognition.
Perceptual confidence results from a metacognitive process which evaluates how likely our percepts are to be correct. Many competing models of perceptual metacognition enjoy strong empirical support. Arbitrating these models traditionally proceeds via researchers conducting experiments and then fitting several models to the data collected. However, such a process often includes conditions or paradigms that may not best arbitrate competing models: Many models make similar predictions under typical experimental conditions. Consequently, many experiments are needed, collectively (sub-optimally) sampling the space of conditions to compare models. Here, instead, we introduce a variant of optimal experimental design which we call a computational-rationality approach to generative models of cognition, using perceptual metacognition as a case study. Instead of designing experiments and post-hoc specifying models, we began with comprehensive model comparison among four competing generative models for perceptual metacognition, drawn from literature. By simulating a simple experiment under each model, we identified conditions where these models made maximally diverging predictions for confidence. We then presented these conditions to human observers, and compared the models' capacity to predict choices and confidence. Results revealed two surprising findings: (1) two models previously reported to differently predict confidence to different degrees, with one predicting better than the other, appeared to predict confidence in a direction opposite to previous findings; and (2) two other models previously reported to equivalently predict confidence showed stark differences in the conditions tested here. Although preliminary with regards to which model is actually 'correct' for perceptual metacognition, our findings reveal the promise of this computational-rationality approach to maximizing experimental utility in model arbitration while minimizing the number of experiments necessary to reveal the winning model, both for perceptual metacognition and in other domains.


Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease.
Interstitial lung disease (ILD) is frequent complication of systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). The disease is heterogeneous, and its outcome is unpredictable. Some patients have severe and progressive deterioration of ILD, which is the leading cause of mortality. We aimed to determine whether serum levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) correlate with SSc/MCTD-associated ILD activity. We retrospectively analyzed the medical records of 40 patients with SSc/MCTD-associated ILD: 29 patients with SSc and 11 patients with MCTD. Measurement of serum KL-6 and SP-D levels, pulmonary function tests, and high-resolution computed tomography (HRCT) performed in parallel were reviewed. Serum KL-6 correlated positively with diffusing capacity of the lung for carbon monoxide (DLCO) (% predicted) and disease extent on HRCT, and the changes in serum levels of KL-6 were significantly related to the changes in forced vital capacity (FVC) in SSc/MCTD-associated ILD. On the other hand, multivariate logistic regression analyses with calculation of the area under the curve of the receiver-operating characteristic curve suggested that a higher serum level of SP-D was a significant predictor of FVC decline in SSc/MCTD-associated ILD. Our study suggests that serum KL-6 can be a useful monitoring tool of SSc/MCTD-associated ILD activity. In contrast, serum SP-D may be a significant predictor of potential FVC decline in the short term.


Hybrid holographic Maxwellian near-eye display based on spherical wave and plane wave reconstruction for augmented reality display.
The holographic Maxwellian display is a promising technique for augmented reality (AR) display because it solves the vergence-accommodation conflict while presenting a high-resolution display. However, conventional holographic Maxwellian display has the inherent trade-off between depth of field (DOF) and image quality. In this paper, two types of holographic Maxwellian displays, the spherical wave type and the plane wave type, are proposed and analyzed. The spherical wavefront and the plane wavefront are produced by a spatial light modulator (SLM) for Maxwellian display. Due to the focusing properties of different wavefronts, the two types of display have complementary DOF ranges. A hybrid approach combining the spherical wavefront and plane wavefront is proposed for a large DOF with high image quality. An optical experiment with AR display is demonstrated to verify the proposed method.


Inhibition of the Notch1 Pathway Promotes the Effects of Nucleus Pulposus Cell-Derived Exosomes on the Differentiation of Mesenchymal Stem Cells into Nucleus Pulposus-Like Cells in Rats.
Stem cell therapies for intervertebral disc degeneration have been demonstrated as a promising strategy. Previous studies have shown that human nucleus pulposus cell- (NPC-) derived exosomes can induce the differentiation of mesenchymal stem cells (MSCs) into NP-like cells in vitro. However, the mechanism of MSC differentiation into NP-like cells with the induction of NPC exosomes is still unclear. Here, we verified the induction effects of NPC exosomes on the differentiation of MSCs into NP-like cells. In addition, the Notch1 pathway was downregulated in this process. Then, DAPT and soluble Jagged1 (SJAG) were applied to inhibit or enhance the expression of the Notch1 pathway, respectively, resulting in the upregulation or downregulation of collagen II, aggrecan, and Sox9 in MSCs. Knocking down of Notch1 protein facilitated the effects of NPC exosomes on the differentiation of MSCs into NP-like cells. NPC exosomes were more effective than an indirect coculture system in terms of the differentiation of MSCs into NP-like cells. Inhibition of NPC exosome secretion with Rab27a siRNA prevented the induction effects of an indirect coculture system on the differentiation of MSCs into NP-like cells. Transwell migration assays revealed that NPC exosomes could promote the migration of MSCs. Taken together, the Notch1 pathway was negatively associated with the differentiation of MSCs into NP-like cells with the treatments of NPC exosomes. Inhibition of the Notch1 pathway facilitates NPC exosome-induced differentiation of MSCs into NP-like cells in vitro. NPC exosomes play a key role in the differentiation of MSCs into NP-like cells in an indirect coculture system of NPCs and MSCs.


Cytoplasmic actin: purification and single molecule assembly assays.
The actin cytoskeleton is essential to all eukaryotic cells. In addition to playing important structural roles, assembly of actin into filaments powers diverse cellular processes, including cell motility, cytokinesis, and endocytosis. Actin polymerization is tightly regulated by its numerous cofactors, which control spatial and temporal assembly of actin as well as the physical properties of these filaments. Development of an in vitro model of actin polymerization from purified components has allowed for great advances in determining the effects of these proteins on the actin cytoskeleton. Here we describe how to use the pyrene actin assembly assay to determine the effect of a protein on the kinetics of actin assembly, either directly or as mediated by proteins such as nucleation or capping factors. Secondly, we show how fluorescently labeled phalloidin can be used to visualize the filaments that are created in vitro to give insight into how proteins regulate actin filament structure. Finally, we describe a method for visualizing dynamic assembly and disassembly of single actin filaments and fluorescently labeled actin binding proteins using total internal reflection fluorescence (TIRF) microscopy.


Regulation and expression of progesterone receptor mRNA isoforms A and B in the male and female rat hypothalamus and pituitary following oestrogen treatment.
Progesterone receptors play a central role in neuroendocrine and behavioural regulation. To gain insight into the sex- and tissue-specific regulation of progesterone receptors, protein binding on a progesterone receptor-oestrogen response element and mRNA levels for progesterone receptor (PR)-A and PR-B were compared between female and male rats following oestradiol benzoate replacement treatment in hypothalamic and pituitary tissue. Both male and female pituitary protein extracts demonstrated an increase in nuclear protein binding activity to a progesterone receptor-oestrogen response element following oestradiol benzoate treatment. However, there was a greater difference in total binding activity seen in the female pituitary extracts compared to male pituitary protein extracts. In both cases, reflecting the binding data, oestradiol benzoate pretreatment led to an increase in pituitary PR-B messenger RNA, although this increase was significantly larger in females than in males. Oestradiol benzoate treatment also led to a significant increase in specific binding of hypothalamic nuclear proteins to the progesterone receptor oestrogen response element from both females and male hypothalamic extracts. In addition, PR-B messenger RNA was induced by oestradiol benzoate treatment in the female rat hypothalamus, under circumstances where no PR-A could be detected. The male also demonstrated an increase in PR-B messenger RNA following oestradiol benzoate treatment, with undetectable levels of PR-A, although to a lesser degree than that seen in the female. The predominance of PR-B over PR-A messenger RNA in rat hypothalamus and pituitary, and the quantitative differences between female and male rats, could both contribute to the greater responsiveness of female rats to progesterone with respect to control over luteinizing hormone release from the pituitary, and lordosis behaviour regulated by hypothalamic neurones.


Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study.
Vitamin D is believed to play an important role outside the endocrine system in the regulation of the immune system, and in cellular proliferation and differentiation. The aim of the study was to investigate the impact of vitamin D levels on innate immunity. Participants for this prospective, longitudinal study were recruited amongst otherwise healthy staff of a large hospital in Victoria, Australia. Those fulfilling the inclusion criteria, including a vitamin D level of <50 nmol/L, were supplemented. Using flow cytometry, expression of the innate immune receptors TLR2, TLR4 and CD86 was measured on peripheral blood mononuclear cells (PBMCs) collected prior to vitamin D treatment and then at 1 and 3 months. Additonally, PBMCs at each timepoint were stimulated with specific TLR ligands and resultant supernatants were assayed for the cytokines TNFα, IL-6, IFN-α and IP-10. In participants whose vitamin D level was >100 nmol/L post supplementation (n=11), TLR2 expression on PBMCs increased significantly, with no change noted in TLR4 or CD86 expression. Stimulation of vitamin D deficient samples with TLR ligands produced a number of proinflammatory cytokines, which were significantly reduced upon vitamin D normalisation. In patients whose levels returned to a deficient level at 3 months despite ongoing low-level supplementation, an increase in the pro-inflamamtory state returned. This suggests that vitamin D may play an important role in ensuring an appropriate baseline pro-inflammatory state. This ex-vivo pilot study adds clinical evidence supporting a possibly important role for vitamin D in innate immunity. If confirmed, this unique clinical study has potentially significant implications for the treatment of a variety of inflammatory conditions, where achieving optimal vitamin D levels may help reduce inflammation.


Sensing of red blood cells with decreased membrane deformability by the human spleen.
The current paradigm in the pathogenesis of several hemolytic red blood cell disorders is that reduced cellular deformability is a key determinant of splenic sequestration of affected red cells. Three distinct features regulate cellular deformability: membrane deformability, surface area-to-volume ratio (cell sphericity), and cytoplasmic viscosity. By perfusing normal human spleens ex vivo, we had previously showed that red cells with increased sphericity are rapidly sequestered by the spleen. Here, we assessed the retention kinetics of red cells with decreased membrane deformability but without marked shape changes. A controlled decrease in membrane deformability (increased membrane rigidity) was induced by treating normal red cells with increasing concentrations of diamide. Following perfusion, diamide-treated red blood cells (RBCs) were rapidly retained in the spleen with a mean clearance half-time of 5.9 minutes (range, 4.0-13.0). Splenic clearance correlated positively with increased membrane rigidity (r = 0.93; P < .0001). To determine to what extent this increased retention was related to mechanical blockade in the spleen, diamide-treated red cells were filtered through microsphere layers that mimic the mechanical sensing of red cells by the spleen. Diamide-treated red cells were retained in the microsphilters (median, 7.5%; range, 0%-38.6%), although to a lesser extent compared with the spleen (median, 44.1%; range, 7.3%-64.0%; P < .0001). Taken together, these results have implications for understanding the sensitivity of the human spleen to sequester red cells with altered cellular deformability due to various cellular alterations and for explaining clinical heterogeneity of RBC membrane disorders.


Evidence for Internal Desynchrony Caused by Circadian Clock Resetting.
Circadian disruption has been linked to markers for poor health outcomes in humans and animal models. What is it about circadian disruption that is problematic? One hypothesis is that phase resetting of the circadian system, which occurs in response to changes in environmental timing cues, leads to internal desynchrony within the organism. Internal desynchrony is understood as acute changes in phase relationships between biological rhythms from different cell groups, tissues, or organs within the body. Do we have strong evidence for internal desynchrony associated with or caused by circadian clock resetting? Here we review the literature, highlighting several key studies from measures of gene expression in laboratory rodents. We conclude that current evidence offers strong support for the premise that some protocols for light-induced resetting are associated with internal desynchrony. It is important to continue research to test whether internal desynchrony is necessary and/or sufficient for negative health impact of circadian disruption.


Thiopental-rocuronium versus ketamine-rocuronium for rapid-sequence intubation in parturients undergoing cesarean section.
We investigated the neuromuscular effects and conditions of tracheal intubation after administration of rocuronium in 40 parturients undergoing elective cesarean section. After preoxygenation, anesthesia was induced in 20 patients by thiopental 4 mg/kg and, in the other 20 patients, by ketamine 1.5 mg/kg. Rocuronium 0.6 mg/kg was then administered, and neuromuscular transmission was assessed using electromyographic response to train-of-four stimulation of the ulnar nerve at the wrist every 10 s. The time to T1/control ratio of 50% neuromuscular block (NMB) as well as the time to maximum NMB (onset time) were compared in the two groups. The time to 50% block was 45 +/- 10 s in the thiopental group and 42 +/- 14 s in the ketamine group, while the onset time was 105 +/- 35 s in the thiopental group and 101 +/- 35 s in the ketamine group. Neither the time to 50% NMB nor the onset time were significantly different between the two groups. Tracheal intubation at 50% NMB was easily performed in all patients in the ketamine-rocuronium group but was difficult in 75% of the thiopental-rocuronium group. We concluded that ketamine 1.5 mg/kg followed by rocuronium 0.6 mg/kg may be suitable for rapid-sequence induction of anesthesia in parturients undergoing cesarean section.


Involvement of Pca1 in ROS-mediated apoptotic cell death induced by alpha-thujone in the fission yeast (Schizosaccharomyces pombe).
Alpha-thujone, widely used in beverages (1-5 mg/kg), is known to have cytotoxic effects, but the mode of action and the role of potential apoptotic proteins in yeast cell death should be unraveled. In this study, we used Schizosaccharomyces pombe, which is a promising unicellular model organism in mechanistic toxicology and cell biology, to investigate the involvement of pro-apoptotic factors in alpha-thujone-induced cell death. We showed alpha-thujone-induced ROS accumulation-dependent cytotoxicity and apoptosis. In addition, we used superoxide dismutase-deficient cells (sod1 and sod2 mutants) to understand the effect of oxidative stress. Alpha-thujone caused significant cytotoxicity and apoptotic cell death, particularly in sod mutants. Moreover, two potential apoptotic factors, pca1 and pnu1 (pombe caspase-1 and pombe nuc1) were investigated to understand which factor mediates alpha-thujone-induced cell death. Pca1-deficient cells showed increased survival rates and reduced apoptosis in comparison to parental cells after chemical treatment while pnu1 mutation did not cause any significant change and the response was found identical as of parental cells. Yeast responded to alpha-thujone in caspase-dependent manner which was very similar to that for acetic acid. In conclusion, alfa-thujone-induced apoptosis and accounting mechanisms, which were mediated by ROS and driven by Pca1, were clarified in the unicellular model, S. pombe.


Over-expression of calpastatin aggravates cardiotoxicity induced by doxorubicin.
Doxorubicin causes damage to the heart, which may present as cardiomyopathy. However, the mechanisms by which doxorubicin induces cardiotoxicity remain not fully understood and no effective prevention for doxorubicin cardiomyopathy is available. Calpains, a family of calcium-dependent thiol-proteases, have been implicated in cardiovascular diseases. Their activities are tightly controlled by calpastatin. This study employed transgenic mice over-expressing calpastatin to investigate the role of calpain in doxorubicin-induced cardiotoxicity. Doxorubicin treatment decreased calpain activities in cultured neonatal mouse cardiomyocytes and in vivo mouse hearts, which correlated with down-regulation of calpain-1 and calpain-2 proteins. Over-expression of calpastatin or incubation with pharmacological calpain inhibitors enhanced apoptosis in neonatal and adult cardiomyocytes induced by doxorubicin. In contrast, over-expression of calpain-2 but not calpain-1 attenuated doxorubicin-induced apoptosis in cardiomyocytes. The pro-apoptotic effects of calpain inhibition were associated with down-regulation of protein kinase B (AKT) protein and mRNA expression, and a concomitant reduction in glycogen synthase kinase-3beta (GSK-3β) phosphorylation (Ser9) in doxorubicin-treated cardiomyocytes. Blocking AKT further increased doxorubicin-induced cardiac injuries, suggesting the effects of calpain inhibition may be mediated by inactivating the AKT signalling. In an in vivo model of doxorubicin-induced cardiotoxicity, over-expression of calpastatin exacerbated myocardial dysfunction as assessed by echocardiography and haemodynamic measurement in transgenic mice 5 days after doxorubicin injection. The 5-day mortality was higher in transgenic mice (29.16%) compared with their wild-type littermates (8%) after doxorubicin treatment. Over-expression of calpastatin enhances doxorubicin-induced cardiac injuries through calpain inhibition and thus, calpains may protect cardiomyocytes against doxorubicin-induced cardiotoxicity.


Hantavirus nucleocapsid protein coiled-coil domains.
The nucleocapsid (N) proteins of hantaviruses such as the Sin Nombre virus (SNV) bind to membranes and viral RNAs, associate with transcription and replication complexes, and oligomerize during the process of virus assembly. N proteins trimerize in vitro and in vivo, and associate via assembly domains at their amino- and carboxyl-terminal ends. Because structure prediction algorithms suggested that N protein residues 3-75 form two coiled-coil motifs separated by an intervening kink or turn sequence, we examined the properties of peptides representing SNV N protein residues 3-35, 43-75, and 3-75. Of the three peptides, N-(3-35) assembled coiled-coil oligomers only at high concentration and low temperature. In contrast, N-(43-75) efficiently trimerized at low concentration, implying that it carries a coiled-coil trigger sequence. Interestingly, while the longer peptide, N-(3-75), assembled dimers and/or trimers at high concentration, at low concentration it appeared to adopt an intramolecular helix-turn-helix conformation. These results suggest that N protein oligomerization involves the bundling of intramolecular antiparallel coils or a conformational switch from intra- to intermolecular coiled-coils.


[Allogeneic hematopoietic stem cell transplantation for treatment of refractory and relapsed acute myeloid leukemia: outcomes and prognostic factors].
Objective: To evaluate the outcomes and prognostic factors of patients with refractory and relapsed acute myeloid leukemia (AML) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The overall survival (OS) , disease free survival (DFS) , acute and chronic graft-versus-host disease (GVHD) , relapse rate (RR) , transplantation related mortality (TRM) and their related risk factors were analyzed retrospectively. Results: All the patients (median age 35 years, range 6 to 58) received myeloablative conditioning regimens. All patients had successful engraftment, and the median time of neutrophils engraftment was 14 days (range 9 to 25) . Of the patients who survived more than 100 days, the accumulative incidence of grade Ⅱ-Ⅳ acute GVHD and chronic GVHD (cGVHD) were 27.3% (95%CI 18.9%-36.3%) , 33.9% (95%CI 24.6%-43.5%) , respectively. Meanwhile, the accumulative incidence of extensive cGVHD was 9.3% (95%CI 4.5%-16.1%) . The 3-year OS, DFS, RR, and TRM was 45.0% (95%CI 34.6%-55.4%) , 45.0% (95%CI 34.8%-55.2%) , 36.6% (95%CI 26.9%-46.4%) and 19.7% (95%CI 12.4%-28.3%) respectively. Multivariate analysis revealed four independent risk factors: non remission status before transplantation[P=0.009, HR=2.21 (95%CI 1.22-4.04) ], WBC at diagnosis>50×10(9)/L[P=0.024, HR=2.11 (95%CI 1.11-4.02) ], donor age>35 years [P=0.031, HR=1.96 (95%CI 1.06-3.60) ]and without cGVHD[P=0.008, HR=0.38 (95%CI 0.18-0.78) ]. According to the risk factors before transplantation (non remission status, WBC at diagnosis>50×10(9)/L, donor age>35 years) , we then defined three subgroups with striking different OS at 3 years: no adverse factor (75.0%) ; one adverse factor (46.9%) ; two or three adverse factors (15.4%) (χ(2)=26.873, P<0.001) . Conclusion: Allo-HSCT is a promising and safe choice for patients with refractory and relapsed AML and relapse is the major cause of the transplantation failure. Disease status before transplantation, donor age, WBC at diagnosis and cGVHD are confirmed as prognostic factors for these patients who received allo-HSCT.


Three new sesquiterpenes from Pterocarpus santalinus.
Three new sesquiterpenes of canusesnol K (1), canusesnol L (2) and 12, 15-dihydroxycurcumene (3), along with five known ones (4-8), were isolated from the heartwood extract of Pterocarpus santalinus. Their structures were established by extensive analyses of 1D and 2D NMR spectroscopy, including 1H NMR, 13C NMR, HSQC, HMBC and NOESY, and HRESI-MS. The absolute configurations of the new compounds were established with Modified Mosher's method. The cytotoxic activities of all these compounds against HepG2 (human liver cancer), MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), and Hela (human cervical carcinoma) cancer cell lines were evaluated. Compound 1 exhibited moderate cytotoxic activity toward MDA-MB-231 cell lines.


https://invertebratefungi.org/: an expert-curated web-based platform for the identification and classification of invertebrate-associated fungi and fungus-like organisms.
Fungi are the major decomposers in terrestrial and aquatic ecosystems, playing essential roles in biogeochemical cycles and food webs. The Fungi kingdom encompasses a diverse array of taxa that often form intimate relationships with other organisms, including plants, insects, algae, cyanobacteria and even other fungi. Fungal parasites of insects are known as entomopathogenic fungi and are the causative agents of serious disease and/or mortality of their hosts. Entomopathogens produce distinct metabolic compounds with roles in pathogenicity, virulence and host-parasite interactions. Thus, the potential of discovering new bioactive compounds useful in biocontrol and pharmaceutical industries is high. Given the significance of entomopathogenic fungi, the rapid research advances and the increased interest, it has become necessary to organize all available and incoming data. The website https://invertebratefungi.org/ has been developed to serve this purpose by gathering and updating entomopathogenic genera/species information. Notes of entomopathogenic genera will be provided with emphasis on their taxonomic status. Information on other invertebrates, such as rotifers, will also be included. Descriptions, photographic plates, information on distribution and host (where applicable) along with molecular data and other interesting details will also be provided. The website is easily and freely accessible to users. Instructions concerning the platform architecture and functionality of the website are introduced herein. The platform is currently being expanded and will be continuously updated as part of the effort to enrich knowledge on this group of fungi. Database URL: https://invertebratefungi.org/.


Ethical issues in adolescent consent for research.
Different opinions are expressed in the literature regarding when children and adolescents can start to make decisions to participate in research and give informed consent. Nurses are frequently involved in research, either as investigators or caregivers, and must therefore have a thorough understanding of consent and related issues. In this article the issues are explored from a Canadian perspective. The argument is put forward that adolescents may be capable of a greater involvement in the research consent process than is the norm. Increasing adolescents' involvement in research has the potential to enhance their growing autonomy and capabilities. Adolescents appreciate being treated with respect and dignity by adults. This can be achieved in an environment in which protection from harm does not also mean prevention from decision making. The use of empowering processes by nurses to enhance adolescent involvement will provide benefit to adolescents in their transition to adult levels of responsibility.


Financing Approaches to Social Prescribing Programs in England and the United States.
Policy Points The number of social prescribing practices, which aim to link patients with nonmedical services and supports to address patients' social needs, is increasing in both England and the United States. Traditional health care financing mechanisms were not designed to support social prescribing practices, and flexible payment approaches may not support their widespread adoption. Policymakers in both countries are shifting toward developing explicit financing streams for social prescribing programs. Consequently, we need an evaluation of them to assess their success in supporting both the acceptance of these programs and their impacts. Investment in community-based organizations and wider public services will likely be crucial to both the long-term effectiveness and the sustainability of social prescribing.


In vivo measurements by differential pulse voltammetry of extra-cellular 5-hydroxyindoleacetic acid in the rat brain.
The use of differential pulse voltammetry, performed with electrochemically treated carbon fiber electrodes, enables us to detect in vitro or in vivo, in the striatum of anaesthetized rats, an oxidation peak (3) at a potential of + 300 mV. Electrolytic or 5-7-dihydroxytryptamine lesions of the medial forebrain bundle are followed by a decrease of 59 and 62% respectively of this peak. Biochemical measurements are significantly correlated with the measured peak (3) and decreases. Thus, peak (3) increases obtained after injection of L-tryptophan and/or Reserpine, as well as the decreases observed after injection of Clorgyline or 3-hydroxybenzylhydrazine, confirm that peak (3) is dependent upon 5-hydroxyindoleacetic acid concentration. The detection of a peak (3) in the cerebrospinal fluid and its increase after injection of Probenecid reinforce this conclusion.


Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis.
Rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis (NBM) and sham-operated rats were trained in either a simple discrimination paradigm assessing simple association learning or a negative patterning paradigm assessing configural association learning. In the simple discrimination task, rats were reinforced for responding to a light but were not reinforced for responding to a tone. In the negative patterning discrimination task, rats were reinforced for responding to either a light or a tone presented alone but were not reinforced for responding to both stimuli presented simultaneously. Simple discrimination learning was not affected, whereas acquisition of negative patterning was impaired by NBM lesions. Impaired configural association learning may reflect a loss in the ability of rats with NBM lesions to attend to multiple sensory stimuli or to cope with conflicting response strategies.


In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis.
Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis.


Structurally similar allosteric modulators of α7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects.
Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs.


Draft genome database construction from four strains (NIES-298, FCY- 26, -27, and -28) of the cyanobacterium Microcystis aeruginosa.
Microcystis aeruginosa is a cyanobacterium that can form harmful algal blooms (HABs) producing toxic secondary metabolites. We provide here draft genome information of four strains of this freshwater cyanobacterium that was obtained by the Next Generation Sequencing approach to provide a better understanding of molecular mechanisms at the physiological and ecological levels. After gene assembly, genes of each strain were identified and annotated, and a genome database and G-browser of M. aeruginosa were subsequently constructed. Such genome information resources will enable us to obtain useful information for molecular ecological studies with a better understanding of modulating mechanisms of environmental factors associated with blooming.


Multi-scale mechanical characterization of highly swollen photo-activated collagen hydrogels.
Biological hydrogels have been increasingly sought after as wound dressings or scaffolds for regenerative medicine, owing to their inherent biofunctionality in biological environments. Especially in moist wound healing, the ideal material should absorb large amounts of wound exudate while remaining mechanically competent in situ. Despite their large hydration, however, current biological hydrogels still leave much to be desired in terms of mechanical properties in physiological conditions. To address this challenge, a multi-scale approach is presented for the synthetic design of cyto-compatible collagen hydrogels with tunable mechanical properties (from the nano- up to the macro-scale), uniquely high swelling ratios and retained (more than 70%) triple helical features. Type I collagen was covalently functionalized with three different monomers, i.e. 4-vinylbenzyl chloride, glycidyl methacrylate and methacrylic anhydride, respectively. Backbone rigidity, hydrogen-bonding capability and degree of functionalization (F: 16 ± 12-91 ± 7 mol%) of introduced moieties governed the structure-property relationships in resulting collagen networks, so that the swelling ratio (SR: 707 ± 51-1996 ± 182 wt%), bulk compressive modulus (Ec: 30 ± 7-168 ± 40 kPa) and atomic force microscopy elastic modulus (EAFM: 16 ± 2-387 ± 66 kPa) were readily adjusted. Because of their remarkably high swelling and mechanical properties, these tunable collagen hydrogels may be further exploited for the design of advanced dressings for chronic wound care.


Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.
The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.


Design of tissue engineering scaffolds as delivery devices for mechanical and mechanically modulated signals.
New approaches to tissue engineering aim to exploit endogenous strategies such as those occurring in prenatal development and recapitulated during postnatal healing. Defining tissue template specifications to mimic the environment of the condensed mesenchyme during development allows for exploitation of tissue scaffolds as delivery devices for extrinsic cues, including biochemical and mechanical signals, to drive the fate of mesenchymal stem cells seeded within. Although a variety of biochemical signals that modulate stem cell fate have been identified, the mechanical signals conducive to guiding pluripotent cells toward specific lineages are less well characterized. Furthermore, not only is spatial and temporal control of mechanical stimuli to cells challenging, but also tissue template geometries vary with time due to tissue ingrowth and/or scaffold degradation. Hence, a case study was carried out to analyze flow regimes in a testbed scaffold as a first step toward optimizing scaffold architecture. A pressure gradient was applied to produce local (nm-micron) flow fields conducive to migration, adhesion, proliferation, and differentiation of cells seeded within, as well as global flow parameters (micron-mm), including flow velocity and permeability, to enhance directed cell infiltration and augment mass transport. Iterative occlusion of flow channel dimensions was carried out to predict virtually the effect of temporal geometric variation (e.g., due to tissue development and growth) on delivery of local and global mechanical signals. Thereafter, insights from the case study were generalized to present an optimization scheme for future development of scaffolds to be implemented in vitro or in vivo. Although it is likely that manufacture and testing will be required to finalize design specifications, it is expected that the use of the rational design optimization will reduce the number of iterations required to determine final prototype geometries and flow conditions. As the range of mechanical signals conducive to guiding cell fate in situ is further elucidated, these refined design criteria can be integrated into the general optimization rubric, providing a technological platform to exploit nature's endogenous tissue engineering strategies for targeted tissue generation in the lab or the clinic.


Adherence to Mediterranean diet among patients with acute cardiovascular events admitted in Cardiac Rehabilitation unit.
The Mediterranean Diet plays a critical role in the prevention of primary cardiovascular disease (CVD). Actually, there is a scarcity of evidence for secondary prevention. The current study aims to assess adherence to the Mediterranean diet (MD) in patients recently admitted to the Cardiac Rehabilitation Unit following acute cardiovascular disease. Adherence to MD was assessed in 111 patients admitted to the Cardiac Rehabilitation Unit of the Federico II Hospital in Naples. The Medi-Lite score was used to assess adherence to MD. The main determinant of reduced MD compliance was assessed using Pearson's correlation analysis and a multivariable regression model. The population had a median MD adherence score of 11 and a mean score of 10.9. The lowest possible score was 5 (indicating poor adherence), and the highest possible score was 15 (excellent adherence index). There were 3 participants with a poor score (<7), 82 with a good score (7-12), and 26 with an excellent score (³13). Lower Medi-Lite score was associated with younger age and being an active worker in a multivariate regression model (both p<0.05). Our findings show that among patients admitted to the Cardiac Rehabilitation Unit after a major CV event, young active workers have the lowest adherence to MD, requiring an individualized and multidisciplinary approach to improve their adherence to MD for secondary CV prevention.


Evolution of interferon-based therapy for chronic hepatitis C.
Since 1986, interferon-alfa (IFN-α) monotherapy has been administered for patients with chronic hepatitis C (CHC). However, sustained response rate is only about 8% to 9%. Subsequent introduction of ribavirin in combination with IFN-α was a major breakthrough in the treatment of CHC. Sustained virological responses (SVRs) rate is about 30% in hepatitis C virus genotype 1 (HCV-1) patients, and is about 65% in HCV-2 or -3 patients. After 2000, pegylated interferon (PegIFN) much improved the rates of SVR. Presently, PegIFN-α-ribavirin combination therapy has been current standard of care for patients infected with HCV. In patients with HCV-1, treatment for 48 weeks is optimal, but 24 weeks of treatment is sufficient in HCV-2 or -3 infected patients. Clinical factors have been identified as predictors for the efficacy of the IFN-based therapy. The baseline factor most strongly predictive of an SVR is the presence of HCV-2 or -3 infections. Rapid virological response (RVR) is the single best predictor of an SVR to PegIFN-ribavirin therapy. If patients can't achieve a RVR but achieve a complete early virological response (cEVR), treatment with current standard of care can provide more than 90% SVR rate. HCV-1 patients who do not achieve an EVR should discontinue the therapy. Recent advances of protease inhibitor may contribute the development of a novel triple combination therapy.


Stress Measured by Allostatic Load in Neurologically Impaired Children: The Importance of Nutritional Status.
Allostatic load (AL) is the cumulative physiological wear and tear that results from repeated efforts to adapt to stressors over time. The life stress response is modified by nutritional status. We estimated AL scores among neurologically impaired (NI) children; the association with malnutrition was also evaluated. Forty-one patients with severe disabilities were included. Data based on 15 biomarkers were used to create the AL score. A dichotomous outcome of high AL was defined for those who had ≥6 dysregulated components. Body mass index (BMI)-standard deviation score (SDS) <-2 or SDS ≥2 and biochemical markers (≥4) defined malnutrition. High AL was noted in 17/41 of the whole sample (41.47%). Malnutrition occurred in 36.6% of the subjects. A significant correlation between high AL and malnutrition was observed (p = 0.01; ar ea under the receiver operating characteristic curve, 0.7457). High AL subjects had a significantly higher BMI (p = 0.009) and lower BMI-SDS (p = 0.003) than low AL subjects. AL score correlated with fat mass (p ≤ 0.01) and negatively correlated with fat-free mass (p ≤ 0.02). In NI children, high AL was associated with malnutrition. Body composition is a better indicator than BMI of allostatic adjustments. AL estimation should be considered a measure of health risk and be used to promote quality of life in at-risk disabled populations.


Iridoid glucosides and flavones from the aerial parts of Avicennia marina.
Two new iridoid glucosides, namely, 2'-O-[(2E,4E)-5-phenylpenta-2,4-dienoyl]mussaenosidic acid (1; mussaenosidic acid = [1S-(1alpha,4aalpha,7alpha,7aalpha)]-1-(beta-D-glucopyranosyloxy)-1,4a,5,6,7,7a-hexahydro-7-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylic acid) and 2'-O-(4-methoxycinnamoyl)mussaenosidic acid (2), were isolated from the aerial parts of the mangrove plant Avicennia marina. Beside that, one known iridoid glucoside, 2'-O-coumaroylmussaenosidic acid (3) and four known flavones (flavone = 2-phenyl-4H-1-benzopyran-4-one) including 4',5-dihydroxy-3',7-dimethoxyflavone (4), 4',5-dihydroxy-3',5',7-trimethoxyflavone (5), 4',5,7-trihydroxyflavone (6), and 3',4',5-trihydroxy-7-methoxyflavone (7) were also isolated and identified. The structures of these compounds were elucidated by NMR spectroscopy and by low- and high-resolution mass spectrometry. The chemotaxonomic significance of these findings was discussed. In addition, each isolated compound was evaluated for the ability of alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical-scavenging activity.


Cardiotoxic effects of pavetamine extracted from Pavetta harborii in the rat.
Previous studies have shown that crude extracts from Pavetta harborii as well as dried plant material have cardiotoxic effects on rats and sheep that can lead to heart failure. The active component has since been isolated and identified. This substance has been named pavetamine. The aim of this study was to determine whether pavetamine has cardiotoxic effects similar to those seen in previous reports, when administered to rats intraperitoneally. Sprague Dawley rats received two doses, initially 4 mg/kg and then 3 mg/kg pavetamine respectively and were monitored for 35 days before cardiodynamic parameters were measured by inserting a fluid-filled catheter into the left ventricle via the right carotid artery. These values were compared to those of control rats that had received only saline. Pavetamine significantly reduced systolic function and body mass in the treated rats, which indicates that it has the potential to induce heart failure in this animal model.


Characterization of the chicken melanocortin 5 receptor and its potential role in regulating hepatic glucolipid metabolism.
Melanocortin receptors (MC1R-MC5R) and their accessory proteins (MRAPs) are involved in a variety of physiological processes, including pigmentation, lipolysis, adrenal steroidogenesis, and immunology. However, the physiological roles of MC5R are rarely characterized in vertebrates, particularly in birds. In this work, we cloned the full-length cDNA of chicken MC5R and identified its core promoter region. Functional studies revealed that cMC5R was more sensitive to ACTH/α-MSH than β-MSH/γ-MSH, and was coupled to the cAMP/PKA signaling pathway. We demonstrated that MRAP2 decreased MC5R sensitivity to α-MSH, whereas MRAP1 did not have a similar effect, and that both MRAPs significantly reduced MC5R expression on the cell membrane surface. Transcriptome and qPCR data showed that both MRAP1 and MC5R were highly expressed in chicken liver. Additionally, we observed that ACTH might increase hepatic glucose production and decrease lipogenesis in primary hepatocytes, and dose-dependently downregulated the expression levels of ELOVL6 and THRSPA genes. These findings indicated that ACTH may act directly on hepatocytes to regulate glucolipid metabolism, which will help to understand the function of MC5R in avian.


Genotyping of hepatitis C virus types 1, 2, 3, and 4 by a one-step LightCycler method using three different pairs of hybridization probes.
Determination of hepatitis C virus (HCV) genotypes has become increasingly important during the last years for prediction of the clinical course and the outcome of antiviral therapy. Therefore, numerous different methods have been developed to enable HCV genotyping. However, many of them are very laborious and expensive, leading to limited usage in daily routine diagnostics. We have established a method which combines the speed of the new LightCycler technology with the use of amplification products generated for diagnostic quantitative HCV RNA determination. Differentiation of HCV genotypes is performed with these amplicons in a single step by using fluorophore-labeled hybridization probes. Although currently only two different acceptor fluorophores are available for the LightCycler, types 1, 2, 3, and 4, which are by far the prevailing HCV genotypes in Europe and the United States, can be distinguished. Genotypes of specimens from 190 chronically HCV-infected patients were determined by the LightCycler method and compared with the results of nucleotide sequencing. Concordant results were obtained for all samples. This new method offers a fast and convenient possibility to determine the quantitative HCV RNA load and the genotype in large-scale settings within about 4 h.


The Sanford Lorraine Cross Award for medical innovation: Advancing a rigorous and repeatable method for recognizing translational research leaders who today are bringing emerging transformative innovations to patients.
Medical innovation awards stand out as an important means to focus public attention on what matters in medical advancement. Traditional awards typically focus on celebrating medical innovators with either a track record of proven successes in new treatments or promising basic science breakthroughs still years away from reaching patients. Perhaps one of the greatest challenges for medical innovation that is not sufficiently addressed by these traditional awards is celebrating translational research efforts on the cusp of major advancements where medical innovators are demonstrating success in bringing emerging transformative medical innovations to patients. As a part of its award process, the Sanford Lorraine Cross Award has developed a unique method to fill this gap in the landscape of medical innovation awards for ongoing translational research efforts by identifying promising medical innovations within a narrow spectrum of the research pipeline on the verge of having transformative impact for patients in the near term. The Sanford Lorraine Cross Award addresses the challenges of identifying emerging transformative medical innovations making their way through development by deploying a rigorous, analytically-based "early signals analysis" to identify emerging transformative medical innovations in its selection process independent of the medical innovators who are succeeding in bringing them forward. It also stands apart from traditional medical innovation awards in focusing on identifying award candidates that have significant roles in bringing the emerging transformative medical innovation across the finish line to patients, and their efforts in overcoming challenges, forging collaborations, and ensuring a successful outcome. The data-driven award selection process used for the Lorraine Cross award ultimately inverts the standard medical award selection paradigm - truly innovative areas of discovery and breakthrough science are identified independently of candidates and used to then focus candidate selection on the areas with the most promising transformative potential for patients. This article sets out the details of how the Sanford Award makes use of leading tools and methods in identifying transformative innovations currently in translational research to provide another important focus of what matters in medical innovation. The Sanford Lorraine Cross Award identifies the most successful application of translational research that ultimately expedited the development of a treatment or cure of a disease.


[Complications of acute otitis media].
Most cases of acute otitis media (AOM) resolve even without antibiotic treatment. In the pre-antibiotic era, AOM complications were common and could lead to deafness and neurological sequelae. With the use of antibiotics, the complications have become less frequent, but they may still evolve. The possible increase in the occurrence of complications has to be considered if we start treating AOM more conservatively and if bacterial antibiotic resistance situation becomes more problematic. These rare but possibly lethal complications should be diagnosed and treated promptly. The need for cochlear implantation has to be evaluated soon after an episode of meningitis if deafness is suspected.


Kinetic and thermodynamic study of bovine serum albumin interaction with rifampicin using surface plasmon resonance and molecular docking methods.
The interaction of bovine serum albumin (BSA) with various drugs, such as antibiotics, due to the importance of BSA in drug delivery has attracted increasing research attention at present. Therefore, the aim of this study was investigation of BSA interaction with rifampicin using surface plasmon resonance (SPR) and molecular docking methods under the imitated physiological conditions ( pH = 7.4 ). BSA immobilization on carboxymethyl dextran hydrogel chip has been carried out after activation with N-hydroxysuccinimide/N-ethyl-N-(3-diethylaminopropyl) carbodiimide. The dose-response sensorgrams of BSA upon increasing concentration of refampicin were attained in SPR analysis. The high affinity of rifampicin to BSA was demonstrated by a low equilibrium constants ( K D ) value ( 3.46 × 10 ? 5 at 40°C). The process of kinetic values changing shows that affinity of BSA to rifampicin decreased with rising temperature. The positive value of both enthalpy change ( ? H ) and entropy change ( ? S ) showed that hydrophobic force plays major role in the BSA interaction with rifampicin. The positive value of ? G was indicative of nonspontaneous and enthalpy-driven binding process. In addition, according to the molecular docking study, hydrogen binding has some contributions in the interaction of rifampicin with BSA.


Facile Preparation of a Carbon-Based Hybrid Film for Efficient Solar-Driven Interfacial Water Evaporation.
Solar-driven interfacial water evaporation is one promising technology for seawater desalination and sewage purification because it offers a feasible and sustainable strategy to relieve global water scarcity. Herein, a novel hybrid film composed of recycled carbon soot and poly(vinyl alcohol) is developed by a very simple, green, and highly scalable "salt-assisted" assembling method. The hybrid film possesses characteristics with a porous structure, superhydrophilicity, ∼100% light absorption, and low thermal conductivity, which can effectively convert light into heat under solar illumination. Consequently, the hybrid film can achieve a photothermal conversion efficiency of 91.5% under a stimulated solar irradiation of 1 kW m-2. Furthermore, the hybrid film can be applied for seawater desalination and dye wastewater purification. The findings of our work not only provide a new photothermal platform with high light-to-thermal conversion ability and good reusability but also open a new avenue for the applications of carbon soot-based hybrid films in solar-assisted water evaporation and sewage purification.


Success in the workplace: From the voice of (dis)abled to the voice of enabled.
The intention of this article is twofold; first to encourage a shift in seeing 'the disabled' not as people with disabilities but rather as people with unique abilities. Secondly, to explore ways of facilitating gainful employment for these uniquely abled people. The term disability is examined against a backdrop of definitions including the definition postulated by the International Classification of Functioning. In this article, the life experiences of a purposive sample of people with (dis)abilities who have been successful in the world of work are explored. A narrative approach gives voice to their experiences. Quotes from the participants' responses are used to illustrate the common themes that emerged relating to their experiences. These themes are resonated against a backdrop of relevant literature. If disabled people are enabled to recognize and use their unique abilities, as well as develop various self-determination skills, imagine the endless possibilities which could arise for them and society in general.


The effects of sex, parity and maternal age on birth weights in a specialist hospital setting in Nigeria.
This study looked at the combined effects of maternal age, fetal sex and parity in a specialist hospital setting and compared it with already published figures obtained from public health-care data in Nigeria. The results show a relationship exists with bivariate analysis between these variables and birth weight, but with multivariate analysis the relationship proves to be spurious. Socio-economic status and maternal health were felt to be the most important considerations within the specialist hospital setting, as patients who attend are more likely to be of high socio-economic status and therefore on a higher income and better educated. This has a beneficial impact on maternal health and a positive outcome on birth weight.


Early strategy vs. late initiation of renal replacement therapy in adult patients with acute kidney injury: an updated systematic review and meta-analysis of randomized controlled trials.
The optimal time to start renal replacement therapy (RRT) for acute kidney injury (AKI) remains controversial. We aim to compare the effects of early vs. delayed RRT initiation on clinical outcomes in adult patients with AKI. PubMed, Embase, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, ClinicalTrials.gov, and the International Clinical Trial registry platform were systematically searched from inception to 7 August 2022. The review included randomized clinical trials (RCTs) comparing early and delayed initiation of RRT in AKI patients. The selected primary outcomes were short-term and long-term mortality. Secondary outcomes included RRT dependency, intensive care unit (ICU) length of stay, hospital length of stay, mechanical ventilator-free days, vasoactive agents-free days, RRT-free days, and adverse events. Overall, 15 RCTs, including 5,625 patients, were analyzed. Early RRT showed no survival benefit when compared to the delayed therapy (28-or 30-day mortality: RR, 1.01, 95% CI: 0.94-1.08, p = 0.87; 60-day mortality: RR, 0.87, 95% CI: 0.71-1.06, p = 0.16; 90-day mortality: RR, 1.00, 95% CI: 0.88-1.13, p = 0.97; in-hospital mortality: RR, 1.05, 95% CI: 0.88-1.24, p = 0.58; ICU mortality: RR, 1.00, 95% CI: 0.91-1.10, p = 0.98). The delayed RRT did not lead to a higher risk of RRT dependency, ICU, or hospital length of stay than the early RRT. Similarly, early initiation of RRT did not lead to longer ventilator-free, vasoactive agent-free, and RRT-free days. However, early RRT initiation was associated with more adverse events. Our study suggested that early RRT initiation was not associated with survival benefits or better clinical outcomes and increased the risk of RRT-associated adverse events. Current evidence does not support the use of early RRT for AKI patients without urgent indications.


Electroencephalographic evidence of gray matter lesions among multiple sclerosis patients: A case-control study.
This study aimed to investigate evidence of gray matter brain lesions in multiple sclerosis (MS) patients by evaluating the resting state alpha rhythm of brain electrical activity.The study included 50 patients diagnosed with MS recruited from the MS clinic with 50 age and gender-matched control participants. The study investigated parameters of posterior dominant rhythm (PDR) in the electroencephalography (EEG) recordings including wave frequency and amplitude. Functional disability among the patients was evaluated according to the expanded disability status scale. Univariate statistical analysis was completed using one-way analysis of variance and t test with a P value of less than .05 to indicate statistical significance.Patients with MS had significantly lower PDR frequency and amplitude values compared to the controls (P value < .01) and 34% of the MS patients had a PDR frequency of less than 8.5 Hz. The PDR frequency was negatively associated with the level of functional disability among the patients (P value <.001) and 4% of the patients had abnormal epileptiform discharges.Background slowing of resting alpha rhythms and epileptiform discharges are suggestive of gray matter degeneration and may help in the prediction and follow-up of cortical damage and functional disabilities among MS patients. Therefore, electroencephalography monitoring of the PDR spectrum may serve as an alternative or complementary tool with other imaging techniques to detect and monitor cerebral cortical lesions.


Hypertension in black people: pathophysiology and therapeutic aspects.
Salt sensitivity is regarded as an important contributor to the higher risk of hypertension in black people as compared with whites. This finding is in agreement with a better response to diuretics than to monotherapy with angiotensin-converting enzyme (ACE) inhibitor in black subjects. It is important to remember that the hypotensive effect of ACE inhibitor is augmented in patients on a thiazide diuretic. Moreover, the antihypertensive response to a specific drug varies among black patients. Thus, ACE inhibitors should also be viewed as important options to treat hypertensive black subjects. Results from clinical trials support an emphasis on lifestyle modification and a more intensive blood pressure lowering by pharmacological interventions to reduce the large black-white gap in cardiovascular events and end-stage renal disease (ESRD) attributed to hypertension.


Neurovascular Coupling in the Dentate Gyrus Regulates Adult Hippocampal Neurogenesis.
Newborn dentate granule cells (DGCs) are continuously generated in the adult brain. The mechanism underlying how the adult brain governs hippocampal neurogenesis remains poorly understood. In this study, we investigated how coupling of pre-existing neurons to the cerebrovascular system regulates hippocampal neurogenesis. Using a new in vivo imaging method in freely moving mice, we found that hippocampus-engaged behaviors, such as exploration in a novel environment, rapidly increased microvascular blood-flow velocity in the dentate gyrus. Importantly, blocking this exploration-elevated blood flow dampened experience-induced hippocampal neurogenesis. By imaging the neurovascular niche in combination with chemogenetic manipulation, we revealed that pre-existing DGCs actively regulated microvascular blood flow. This neurovascular coupling was linked by parvalbumin-expressing interneurons, primarily through nitric-oxide signaling. Further, we showed that insulin growth factor 1 signaling participated in functional hyperemia-induced neurogenesis. Together, our findings revealed a neurovascular coupling network that regulates experience-induced neurogenesis in the adult brain.


Reparameterization of Non-Bonded Parameters for Copper Ions in Plastocyanin: An Adaptive Force Matching Study.
Molecular mechanics rely on existing experimental and theoretical inputs to confidently calculate the trajectories of molecular systems. These calculations, however, are often hindered by missing force field parameters. A notable subject of this problem is metal centers of proteins. This study parameterized, through an adaptive force matching (AFM) workflow, the copper cofactor of plastocyanin in its two oxidation states. New 12-6 Lennard-Jones (LJ) parameters and atomic partial charges were generated to complete the non-bonded description of the copper site. Our models show uniform distorted tetrahedral structures for reduced plastocyanin, Cu(I), and oxidized plastocyanin, Cu(II). These structures align with the QM/MM MD results and existing crystallography studies. TD-DFT calculations, meanwhile, showed that conformations with elongated axial Cu-SMet and shortened equatorial Cu-SCys bonds retain the experimental UV-Vis profile of blue copper (BC) proteins, thus signifying the importance of Cu-S interactions on BC proteins' unique spectroscopic properties.


Leucine Supplementation: A Novel Strategy for Modulating Lipid Metabolism and Energy Homeostasis.
Lipid metabolism is an important and complex biochemical process involved in the storage of energy and maintenance of normal biological functions. Leucine, a branched amino acid, has anti-obesity effects on glucose tolerance, lipid metabolism, and insulin sensitivity. Leucine also modulates mitochondrial dysfunction, representing a new strategy to target aging, neurodegenerative disease, obesity, diabetes, and cardiovascular disease. Although various studies have been carried out, much uncertainty still exists and further studies are required to fully elucidate the relationship between leucine and lipid metabolism. This review offers an up-to-date report on leucine, as key roles in both lipid metabolism and energy homeostasis in vivo and in vitro by acceleration of fatty acid oxidation, lipolysis, activation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)-silent information regulator of transcription 1 (SIRT1)-proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, synthesis, and/or secretion of adipokines and stability of the gut microbiota.


[Multiple meningiomas. Part I. Types. Classification. Differential Diagnosis].
Meningiomas usually are solitary tumors but they can be multiple in various conditions. True multiple meningiomas in the sense of Cushing are rare. The development of more than one meningioma in the same individual may be due to central neurofibromatosis or following external cranial irradiation. Multiple meningiomas can occur after dissemination of the tumor cells following surgery. The purpose of this review is to define and discuss the different types and the criteria of differential diagnosis for MM.


Sequential Addition of Amines to Nitrile and Carbon-Carbon Multiple Bond: A Route to 7-Amino-5H-dibenzo[c,e]azepines.
A rare earth metal-catalyzed sequential inter- and intramolecular C-N bond formation of 2-nitrile-2'-alkenyl(alkynyl)biphenyls with amines has been developed, which provides a straightforward and efficient access to a range of new functional dibenzo[c,e]azepines. This represents the first examples of direct construction of seven-membered azaheterocycle from unsaturated nitriles and amines. Such transformations have the advantages of avoiding the use of additives, easily available starting materials, step- and high atom-economy, mild reaction conditions, and high selectivity.


A highly conserved arginine in gp120 governs HIV-1 binding to both syndecans and CCR5 via sulfated motifs.
HIV-1 has maximized its utilization of syndecans. It uses them as in cis receptors to infect macrophages and as in trans receptors to infect T-lymphocytes. In this study, we investigated at a molecular level the mechanisms that control HIV-1-syndecan interactions. We found that a single conserved arginine (Arg-298) in the V3 region of gp120 governs HIV-1 binding to syndecans. We found that an amine group on the side chain of this residue is necessary for syndecan utilization by HIV-1. Furthermore, we showed that HIV-1 binds syndecans via a 6-O sulfation, demonstrating that this binding is not the result of random interactions between basic residues and negative charges, but the result of specific contacts between gp120 and a well defined sulfation in syndecans. Surprisingly, we found that Arg-298, which mediates HIV-1 binding to syndecans, also mediates HIV-1 binding to CCR5. We postulated that HIV-1 recognizes similar motifs on syndecans and CCR5. Supporting this hypothesis, we obtained several lines of evidence that suggest that the 6-O sulfation recognized by HIV-1 on syndecans mimics the sulfated tyrosines recognized by HIV-1 in the N terminus of CCR5. Our finding that CCR5 and syndecans are exploited by HIV-1 via a single determinant echoes the mechanisms by which chemokines utilize these two disparate receptors and suggests that the gp120/chemokine mimicry may represent a common strategy in microbial pathogenesis.


[Sutureless wound adaptation. Comparison between corneal and corneoscleral incision].
Fifty-four eyes with concomitant diseases, either a coagulation disorder or previous glaucoma surgery, were implanted with a folded, disc-shaped silicone intraocular lens (IOL) via a 3.5 mm three-step clear corneal tunnel; we developed this technique in 1991. IOLs of the same lens type were implanted through a 3.5 mm corneoscleral tunnel by the same surgeon in a control group consisting of 52 eyes. The final visual outcome was reached after 4 weeks in 44.7% of the patients (compared to 63.5% in the control group). The postoperative astigmatism stabilized after 3 months in 31.4% of the patients belonging to the clear corneal tunneling group and after 1 month in 32.1% of the patients belonging to the corneoscleral tunneling group. Compared to the control group, the continuously decreasing induced astigmatism was significantly greater in the clear corneal tunneling group at all times, except for 1 week postoperatively. After 1 year, the mean astigmatism was 0.91 +/- 0.50 D, compared to 0.57 +/- 0.36 D in the control group. After 18 months, the average induced astigmatism in the clear corneal tunneling group increased to 1.30 +/- 0.54 D, compared to the stable value in the control group amounting to 0.59 +/- 0.52 D. As an alternative to routine corneoscleral small incision surgery, the clear corneal technique is especially suited for patients with a coagulation disorder, with unfavorable anatomic conditions, or with glaucoma; a scleral incision should be avoided in these cases.


Grease gun injuries to the orbit and adnexa.
The grease gun injury is an uncommon injury to the orbit. However, high-pressure injection of grease, oil, or paint is frequently reported in injuries of the hand and usually affects the fingers or palm, which require complicated surgical and medical care. Two cases of grease gun injury to the orbit are reported: one, a catastrophic injury, and the other resulting in satisfactory recovery after surgical debridement and adjuvant medical treatment. Presentation, investigation, and therapy are discussed.


Estimating Heart Rate, Energy Expenditure, and Physical Performance With a Wrist Photoplethysmographic Device During Running.
Wearable sensors enable long-term monitoring of health and wellbeing indicators. An objective evaluation of sensors' accuracy is important, especially for their use in health care. The aim of this study was to use a wrist-worn optical heart rate (OHR) device to estimate heart rate (HR), energy expenditure (EE), and maximal oxygen intake capacity (VO2Max) during running and to evaluate the accuracy of the estimated parameters (HR, EE, and VO2Max) against golden reference methods. A total of 24 healthy volunteers, of whom 11 were female, with a mean age of 36.2 years (SD 8.2 years) participated in a submaximal self-paced outdoor running test and maximal voluntary exercise test in a sports laboratory. OHR was monitored with a PulseOn wrist-worn photoplethysmographic device and the running speed with a phone GPS sensor. A physiological model based on HR, running speed, and personal characteristics (age, gender, weight, and height) was used to estimate EE during the maximal voluntary exercise test and VO2Max during the submaximal outdoor running test. ECG-based HR and respiratory gas analysis based estimates were used as golden references. OHR was able to measure HR during running with a 1.9% mean absolute percentage error (MAPE). VO2Max estimated during the submaximal outdoor running test was closely similar to the sports laboratory estimate (MAPE 5.2%). The energy expenditure estimate (n=23) was quite accurate when HR was above the aerobic threshold (MAPE 6.7%), but MAPE increased to 16.5% during a lighter intensity of exercise. The results suggest that wrist-worn OHR may accurately estimate HR during running up to maximal HR. When combined with physiological modeling, wrist-worn OHR may be used for an estimation of EE, especially during higher intensity running, and VO2Max, even during submaximal self-paced outdoor recreational running.


Disposing and recycling waste printed circuit boards: disconnecting, resource recovery, and pollution control.
Over the past decades, China has been suffering from negative environmental impacts from distempered e-waste recycling activities. After a decade of effort, disassembly and raw materials recycling of environmentally friendly e-waste have been realized in specialized companies, in China, and law enforcement for illegal activities of e-waste recycling has also been made more and more strict. So up to now, the e-waste recycling in China should be developed toward more depth and refinement to promote industrial production of e-waste resource recovery. Waste printed circuit boards (WPCBs), which are the most complex, hazardous, and valuable components of e-waste, are selected as one typical example in this article that reviews the status of related regulations and technologies of WPCBs recycling, then optimizes, and integrates the proper approaches in existence, while the bottlenecks in the WPCBs recycling system are analyzed, and some preliminary experiments of pinch technologies are also conducted. Finally, in order to provide directional guidance for future development of WPCBs recycling, some key points in the WPCBs recycling system are proposed to point towards a future trend in the e-waste recycling industry.


Insurance Coverage, Access to Care, and Medical Debt Since the ACA: a Look at California, Florida, New York, and Texas.
ISSUE: The Affordable Care Act has significantly increased health insurance coverage and access to care among U.S. adults nationwide. However, the law gives states flexibility in implementing certain provisions, leading to wide variations between states in consumers' experiences. GOAL: To examine the differences in insurance coverage, access to care, and medical bill problems in the four largest states—California, Florida, New York, and Texas—all of which have made different choices in implementing the law. METHODS: Analysis of the Commonwealth Fund Biennial Health Insurance Survey, 2016. FINDINGS AND CONCLUSIONS: In 2016, uninsured rates among adults ages 19 to 64 across the four states varied from 7 percent in New York and 10 percent in California to 16 percent in Florida and 25 percent in Texas. This variation was also apparent in the proportions of residents reporting problems getting needed care because of the cost—significantly lower in California and New York than in Florida and Texas. Lower percentages of Californians and New Yorkers reported having a medical bill problem in the past 12 months or having accrued medical debt compared to Floridians and Texans. These variations might be explained by several factors: whether the state expanded Medicaid eligibility; whether it ran its own health insurance marketplace; what the uninsured rate was prior to the Affordable Care Act; differences in the cost protections provided by private health plans; and demographic differences.


A gene-derived SNP-based high resolution linkage map of carrot including the location of QTL conditioning root and leaf anthocyanin pigmentation.
Purple carrots accumulate large quantities of anthocyanins in their roots and leaves. These flavonoid pigments possess antioxidant activity and are implicated in providing health benefits. Informative, saturated linkage maps associated with well characterized populations segregating for anthocyanin pigmentation have not been developed. To investigate the genetic architecture conditioning anthocyanin pigmentation we scored root color visually, quantified root anthocyanin pigments by high performance liquid chromatography in segregating F2, F3 and F4 generations of a mapping population, mapped quantitative trait loci (QTL) onto a dense gene-derived single nucleotide polymorphism (SNP)-based linkage map, and performed comparative trait mapping with two unrelated populations. Root pigmentation, scored visually as presence or absence of purple coloration, segregated in a pattern consistent with a two gene model in an F2, and progeny testing of F3-F4 families confirmed the proposed genetic model. Purple petiole pigmentation was conditioned by a single dominant gene that co-segregates with one of the genes conditioning root pigmentation. Root total pigment estimate (RTPE) was scored as the percentage of the root with purple color.All five anthocyanin glycosides previously reported in carrot, as well as RTPE, varied quantitatively in the F2 population. For the purpose of QTL analysis, a high resolution gene-derived SNP-based linkage map of carrot was constructed with 894 markers covering 635.1 cM with a 1.3 cM map resolution. A total of 15 significant QTL for all anthocyanin pigments and for RTPE mapped to six chromosomes. Eight QTL with the largest phenotypic effects mapped to two regions of chromosome 3 with co-localized QTL for several anthocyanin glycosides and for RTPE. A single dominant gene conditioning anthocyanin acylation was identified and mapped.Comparative mapping with two other carrot populations segregating for purple color indicated that carrot anthocyanin pigmentation is controlled by at least three genes, in contrast to monogenic control reported previously. This study generated the first high resolution gene-derived SNP-based linkage map in the Apiaceae. Two regions of chromosome 3 with co-localized QTL for all anthocyanin pigments and for RTPE, largely condition anthocyanin accumulation in carrot roots and leaves. Loci controlling root and petiole anthocyanin pigmentation differ across diverse carrot genetic backgrounds.


State of the Art in Development of Heat Exchanger Geometry Optimization and Different Storage Bed Designs of a Metal Hydride Reactor.
The efficient operation of a metal hydride reactor depends on the hydrogen sorption and desorption reaction rate. In this regard, special attention is paid to heat management solutions when designing metal hydride hydrogen storage systems. One of the effective solutions for improving the heat and mass transfer effect in metal hydride beds is the use of heat exchangers. The design of modern cylindrical-shaped reactors makes it possible to optimize the number of heat exchange elements, design of fins and cooling tubes, filter arrangement and geometrical distribution of metal hydride bed elements. Thus, the development of a metal hydride reactor design with optimal weight and size characteristics, taking into account the efficiency of heat transfer and metal hydride bed design, is the relevant task. This paper discusses the influence of different configurations of heat exchangers and metal hydride bed for modern solid-state hydrogen storage systems. The main advantages and disadvantages of various configurations are considered in terms of heat transfer as well as weight and size characteristics. A comparative analysis of the heat exchangers, fins and other solutions efficiency has been performed, which makes it possible to summarize and facilitate the choice of the reactor configuration in the future.


Genome-wide identification of oil biosynthesis-related long non-coding RNAs in allopolyploid Brassica napus.
Long noncoding RNAs (lncRNAs) are transcripts longer than 200 bp that do not encode proteins but nonetheless have been shown to play important roles in various biological processes in plants. Brassica napus is an important seed oil crop worldwide and the target of many genetic improvement activities. To understand better the function of lncRNAs in regulating plant metabolic activities, we carried out a genome-wide lncRNA identification of lncRNAs in Brassica napus with a focus on lncRNAs involved in lipid metabolism. Twenty ribosomal RNA depleted strand specific RNA-seq (ssRNA-seq) datasets were generatred using RNAs isolated from B. napus seeds at four developmental stages. For comparison we also included 30 publically available RNA-seq datasets generated from poly(A) enriched mRNAs isolated from from various Brassica napus tissues in our analysis. A total of 8905 lncRNA loci were identified, including 7100 long intergenic noncoding RNA (lincRNA) loci and 1805 loci generating long noncoding natural antisense transcript (lncNAT). Many lncRNAs were identified only in the ssRNA-seq and poly(A) RNA-seq dataset, suggesting that B. napus has a large lncRNA repertoire and it is necessary to use libraries prepared from different tissues and developmental stages as well as different library preparation approaches to capture the whole spectrum of lncRNAs. Analysis of coexpression networks revealed that among the regulatory modules are networks containing lncRNAs and protein-coding genes related to oil biosynthesis indicating a possible role of lncRNAs in the control of lipid metabolism. One such example is that several lncRNAs are potential regulators of BnaC08g11970D that encodes oleosin1, a protein found in oil bodies and involved in seed lipid accumulation. We also observed that the expression levels of B. napus lncRNAs is positively correlated with their conservation levels. We demonstrated that the B. napus genome has a large number of lncRNA and that these lncRNAs are expressed broadly across many developmental times and in different tissue types. We also provide evidence indicating that specific lncRNAs appear to be important regulators of lipid biosynthesis forming regulatory networks with transcripts involved in lipid biosynthesis. We also provide evidence that these lncRNAs are conserved in other species of the Brassicaceae family.