Effect of BCNU pretreatment on diquat-induced oxidant stress and hepatotoxicity.
Diquat administration produces hepatic necrosis in male Fischer-344 rats, and minimally in male Sprague-Dawley rats, with massive oxidant stress observable in both strains as evidenced by increased biliary efflux of glutathione disulfide (GSSG). Pretreatment of both strains of rats with 80 mg/kg of 1,3-bis(2-chloroethyl)-N-nitrosourea (BCNU) inhibited hepatic glutathione reductase by 75 percent and increased dramatically the biliary efflux of GSSG produced by administration of diquat. BCNU pretreatment markedly potentiated diquat hepatotoxicity in the Fischer rats and modestly in Sprague-Dawley rats. BCNU-pretreated Fischer rats did not show an enhanced depletion of nonprotein sulfhydryls in response to diquat, in spite of the dramatic potentiation of the hepatic necrosis produced, nor were protein thiols depleted. The effects of BCNU on diquat hepatotoxicity in the Fischer rat are consistent with a critical role for reactive oxygen species in the pathogenesis of the observed hepatic necrosis and for the protective role of the glutathione peroxidase/reductase system. The data suggest that shifts in thiol-disulfide equilibria are not responsible for the cell death produced by oxidant stress in vivo, but are consistent with a role for lipid peroxidation in the pathogenesis of the lesion.


fMRI Brain Response in Patients with Depression at the Time of Control of the Severity of Positive Social Emotions and Analysis of Behavioral Factors.
The study presents functional magnetic resonance imaging (fMRI) data on the brain activity in depression and psycho-diagnostic indicators that characterize cognitive activity strategies of positive social emotion regulation. It was shown that fMRI activity of the brain during viewing of emotionally neutral and moderately positive images and searching for an optimal self-regulation strategy was associated with changes in activation in the dorsomedial prefrontal cortex. Analysis of behavioral factors showed that strategies of searching for the optimal way of emotional self-regulation were closely related to the general style of behavior, level of uncertainty tolerance, and commitment. The integration of psycho-diagnostic and neuroimaging data allows deeper understanding of the mechanisms of emotions regulation that contributes to the optimization of protocols for the diagnosis and treatment of depressive disorders.


Using benchmarked lung radiation dose constraints to predict pneumonitis risk: Developing a nomogram for patients with mediastinal lymphoma.
We identified lung dosimetric constraints to assist in predicting the radiation pneumonitis (RP) risk in patients with mediastinal lymphoma and then identified the clinical prognostic factors that were associated with the achievement of key dosimetric constraints. In 190 patients who received mediastinal intensity modulated radiation therapy, we used univariate χ2 and multivariate logistic models to identify the predictors of RP and achievement of lung dose-volume histogram (DVH) constraints and build a predictive nomogram for RP. An increased risk of RP was strongly associated with mean lung dose (MLD) > 13.5 Gy (odds ratio [OR]: 8.13; 95% confidence interval [CI], 3.01-21.93; P < .001) and the percent of lung volume receiving ≥5 Gy (V5) > 55% (OR: 7.01; 95% CI, 2.94-16.72; P < .001). Therefore, patients had low RP risk (8%) if both MLD ≤13.5 and V5 ≤55 constraints were achieved, moderate risk (24%) if only MLD was achieved, and the highest risk (48%) if MLD was not achieved. Deep-inspiration breath-hold (DIBH) technique during treatment strongly prognosticated achieving MLD and V5 DVH constraints (OR,3.88; 95% CI, 1.84-8.19; P < .001). Specifically, 86% of patients who were treated with DIBH versus 63% without DIBH achieved DVH constraints (P < .001). This translated into a "number needed to treat" with DIBH of 4 patients to enable 1 additional patient to achieve both constraints. In comparison, the clinical characteristics were marginal prognosticators: DVH constraints were more likely achieved in nonbulky disease (OR: 3.01; 95% CI, 0.89-4.53; P = .09) and patients who had not previously received salvage chemotherapy (OR, 2.44; 95% CI, 0.98-6.11; P = .06). Nomogram-predicted risks of RP ranged from 4% to 60% on the basis of MLD and V5, total radiation dose, and use of salvage chemotherapy. Achieving mean lung and V5 DVH constraints is critical to reduce RP risk in patients with lymphoma who receive mediastinal intensity modulated radiation therapy. The use of the DIBH technique is a promising risk-modifying treatment approach in patients with mediastinal lymphoma and especially in patients with a history of nonmodifiable risk factors for RP such as bulky disease and salvage chemotherapy.


Arabidopsis AtVPS15 plays essential roles in pollen germination possibly by interacting with AtVPS34.
VPS15 protein is a component of the phosphatidylinositol 3-kinase complex which plays a pivotal role in the development of yeast and mammalian cells. The knowledge about the function of its homologue in plants remains limited. Here we report that AtVPS15, a homologue of yeast VPS15p in Arabidopsis, plays an essential role in pollen germination. Homozygous T-DNA insertion mutants of AtVPS15 could not be obtained from the progenies of self-pollinated heterozygous mutants. Reciprocal crosses between atvps15 mutants and wild-type Arabidopsis revealed that the T-DNA insertion was not able to be transmitted by male gametophytes. DAPI staining, Alexander's stain and scanning electron microscopic analysis showed that atvps15 heterozygous plants produced pollen grains that were morphologically indistinguishable from wild-type pollen, whereas in vitro germination experiments revealed that germination of the pollen grains was defective. GUS staining analysis of transgenic plants expressing the GUS reporter gene driven by the AtVPS15 promoter showed that AtVPS15 was mainly expressed in pollen grains. Finally, DUALmembrane yeast two-hybrid analysis demonstrated that AtVPS15 might interact directly with AtVPS34. These results suggest that AtVPS15 is very important for pollen germination, possibly through modulation of the activity of PI3-kinase.


A Lemierre-like syndrome caused by Staphylococcus aureus: an emerging disease.
Despite its clear definition, Lemierre's syndrome is frequently used to describe any septic thrombophlebitis of the jugular vein. We report a Lemierre-like syndrome caused by Staphylococcus aureus without an oropharyngeal infection and present a systematic synthesis of reported cases to date of Lemierre-like syndrome caused by S. aureus. In addition to our case, 24 cases were found. In contrast to the classical picture, S. aureus is associated with an oropharyngeal infection in less than half of the cases. Another striking feature is the significant proportion of patients being very young and the fact that all 25 cases were published in the last 17 years. S. aureus is a rare, but emerging cause of Lemierre-like syndrome. Adequate patient care rests on a high index of suspicion, prompt initiation of antibiotic therapy and early detection and management of metastatic abscesses.BULLET POINT SUMMARYThe term Lemierre's syndrome should be reserved for the classic triad of bacteraemia caused by anaerobic pathogens (primarily Fusobacterium necrophorum), evidence of internal jugular venous thrombosis, and a history of recent oropharyngeal infection.Similar syndromes not caused by anaerobic organisms or without history of an oropharyngeal infection should be named Lemierre-like syndrome and may be a more challenging diagnosis.Staphylococcus aureus is a cause of Lemierre-like syndrome, especially in very young children (<2 years old).The Staphylococcus aureus Lemierre-like syndrome is an emerging clinical syndrome.Adequate patient care is based on a high index of suspicion, prompt initiation of broad-spectrum antibiotics and active detection and management of metastatic abscesses.


Childhood temperamental, emotional, and behavioral characteristics associated with mood and anxiety disorders in adolescence: A prospective study.
Mood and anxiety disorders account for a large share of the global burden of disability. Some studies suggest that early signs may emerge already in childhood. However, there is a lack of well-powered, prospective studies investigating how and when childhood mental traits and trajectories relate to adolescent mood and anxiety disorders. We here examine cross-sectional and longitudinal association between maternally reported temperamental traits, emotional and behavioral problems in childhood (0.5-8 years) and clinical diagnosis of mood or anxiety ("emotional") disorders in adolescence (10-18 years), using the prospective Norwegian Mother, Father and Child Cohort Study (MoBa) of 110,367 children. Logistic regression analyses showed consistent and increasing associations between childhood negative emotionality, behavioral and emotional problems and adolescent diagnosis of emotional disorders, present from 6 months of age (negative emotionality). Latent profile analysis incorporating latent growth models identified five developmental profiles of emotional and behavioral problems. A profile of early increasing behavioral and emotional problems with combined symptoms at 8 years (1.3% of sample) was the profile most strongly associated with emotional disorders in adolescence (OR vs. reference: 5.00, 95% CI: 3.70-6.30). We found a consistent and increasing association between negative emotionality, behavioral and emotional problems in early to middle childhood and mood and anxiety disorders in adolescence. A developmental profile coherent with early and increasing disruptive mood dysregulation across childhood was the profile strongest associated with adolescent emotional disorders. Our results highlight the importance of early emotional dysregulation and childhood as a formative period in the development of adolescent mood and anxiety disorders, supporting potential for prevention and early intervention initiatives.


Strategy for sodium-salt substitution: On the relationship between hypertension and dietary intake of cations.
Chronic diseases, especially cardiovascular diseases (CVD), have become one of the main causes affecting human health. Hypertension is a prominent representative of CVD. The formation and development of hypertension is closely related to people's daily diet. A large number of studies have shown that excessive intake of salt (NaCl) could increase the risk of hypertension. In recent years, more and more investigations have focused on other cations that may be contained in edible salt, exploring whether they have an effect on hypertension and the underlying mechanism. This article focuses on the relationship between four metal elements (potassium, calcium, magnesium, and zinc) and hypertension, by discussing the main metabolic pathway, the impact of diet intake on blood pressure, and especially the regulation mechanisms on blood pressure in detail. At the same time, some opinions and suggestions are put forward, combined with the current hot topics "salt reduction" and "salt substitution".


Contextual fear conditioning regulates synapse-related gene transcription in mouse microglia.
Microglia have been suggested to be involved in the underlying mechanism of conditional fear memory formation by regulating inflammatory cytokines. However, the mechanism linking microglia and neuronal activity related to fear conditioning remains unclear. This study characterized the transcription profile of microglia in a fear memory conditional mouse model. Compared with those in control mice microglia, the most significantly induced genes were synapse-related, whereas immune-related genes were reduced due to fear memory consolidation. Whilst the increased expression of synapse-related genes was reversed after fear memory extinction, that of immunological genes was not, strongly suggesting a connection between microglia, neurons, and a dysregulated immune response following contextual fear conditioning. Furthermore, in the hippocampal microglia, we found that the expression of neurotransmitter release regulators, γ-aminobutyric acid (GABA) receptor GABRB3 and synapsin 1/2, increased under fear memory consolidation and restored (decreased) after extinction. In addition, compared with the transcription profile in peripheral monocytes, few overlapping genes were not enriched in biological processes. Taken together, the identified conditional fear stress-induced changes in mouse microglial transcription profiles suggest that microglia-neuron communication mediates contextual fear conditioning.


Reactive oxygen species precede the epsilon isoform of protein kinase C in the anesthetic preconditioning signaling cascade.
Protein kinase C (PKC) and reactive oxygen species (ROS) are known to have a role in anesthetic preconditioning (APC). Cardiac preconditioning by triggers other than volatile anesthetics, such as opioids or brief ischemia, is known to be isoform selective, but the isoform required for APC is not known. The authors aimed to identify the PKC isoform that is involved in APC and to elucidate the relative positions of PKC activation and ROS formation in the APC signaling cascade. Isolated guinea pig hearts were subjected to 30 min of ischemia and 120 min of reperfusion. Before ischemia, hearts were either untreated or treated with sevoflurane (APC) in the absence or presence of the nonspecific PKC inhibitor chelerythrine, the PKC-delta inhibitor PP101, or the PKC-epsilon inhibitor PP149. Spectrofluorometry and the fluorescent probes dihydroethidium were used to measure intracellular ROS, and effluent dityrosine as used to measure extracellular ROS release. Previous sevoflurane exposure protected the heart against ischemia-reperfusion injury, as previously described. Chelerythrine or PP149 abolished protection, but PP101 did not. ROS formation was observed during sevoflurane exposure and was not altered by any of the PKC inhibitors. APC is mediated by PKC-epsilon but not by PKC-delta. Furthermore, PKC activation probably occurs downstream of ROS generation in the APC signaling cascade.


Subcellular tension fields and mechanical resistance of the lamella front related to the direction of locomotion.
Keratocytes derived from the epidermis of aquatic vertebrates are now widely used for investigation of the mechanism of cell locomotion. One of the main topics under discussion is the question of driving force development and concomitantly subcellular force distribution. Do cells move by actin polymerization-driven extension of the lamella, or is the lamella edge extended at regions of weakness by a flow of cytoplasm generated by hydrostatic pressure? Thus, elasticity changes were followed and the stiffness of the leading front of the lamella was manipulated by local application of phalloidin and cytochalasin D (CD). In scanning acoustic microscopy (SAM), elasticity is revealed from the propagation velocity of longitudinal sound waves (1 GHz). The lateral resolution of SAM is in the micrometer range. Using this method, subcellular tension fields with different stiffnesses (elasticity) can be determined. A typical pattern of subcellular stiffness distribution is related to the direction of migration. Cells forced to change their direction of movement by exposure to DC electric fields of varying polarity alter their pattern of subcellular stiffness in relationship to the new direction. The cells spread into the direction of low stiffness and retract at zones of high stiffness. The pattern of subcellular stiffness distribution reveals force distribution in migrating cells; i.e., if a cell moves exactly in a direction perpendicular to its long axis, then the contractile forces are largest along the long axis and decrease toward the short axis. Locomotion in any angle oblique to this axis requires an asymmetric stiffness distribution. Inhibition of actomyosin contractions by La3+ (2 mM), which inhibits Ca2+ influx, reduces cytoplasmic stiffness accompanied by an immediate cessation of locomotion and a change of cell shape. Local release of CD in front of a progressing lamella activates a cell to follow the CD gradient: The lamella thickens locally and is extended toward the tip of the microcapillary. Release of phalloidin stops extension of the lamella, and the cell turns away from the releasing microcapillary. The response to CD is assumed to be the result of local weakening of the cytoplasm due to severing of the actin fibrils. Phalloidin is supposed to stabilize the leading front by inhibition of F-actin depolymerization. These observations are in favor of the assumption that migration is due to an extension of the cell into the direction of minimum stiffness, and they are consistent with the hypothesis that local release of hydrostatic pressure provides the driving force for the flux of cytoplasm.


Valorization of polyhydroxyalkanoates production process by co-synthesis of value-added products.
Polyhydroxyalkanoates (PHAs) are the only polyesters that are completely synthesized biologically and possess features equivalent to petroleum-based plastics besides being biodegradable. PHA based materials may certainly prove helpful in addressing the concerns caused due to the indiscriminate use of synthetic plastics. However, the cost of producing these polymers on a large scale is still uneconomical. Various approaches have been developed to tackle this issue through usage of agro-industrial wastes, co-production of high market value products, polymer extraction using green solvents, etc. The advent of recombineering and CRISPR technologies has broadened the scope of constructing a microbe capable of synthesizing multiple products with economic feasibility. Quite a few high-market value chemicals are possible to synthesize along with the favorable accumulation of PHA. The present article attempts to review all PHA polymer co-production processes with other chemicals reported till date and discusses the opportunities for their large-scale operation in future.


Task-specific modulation of anticipatory postural adjustments in individuals with hemiparesis.
To study adaptation of anticipatory postural adjustments (APAs) in paretic and non-paretic muscles of individuals with hemiparesis to changes in the direction of the self-initiated perturbation and additional manual support. Electrical activity of leg and trunk muscles on both sides of the body and ground reaction forces were recorded in 10 patients with hemiparesis and a group of matched control subjects. Subjects released a standard load, held in the hand of the extended relatively unimpaired arm. The load was released either in front of the body or to the side, with or without the impaired arm touching an external stable surface. APAs were reduced in individuals with hemiparesis, especially on the paretic side. In paretic muscles, the modulation of APAs with the direction of the perturbation was decreased or showed atypical patterns. Also the effects of touch were decreased in patients. Center of pressure displacements shortly after load release were similar in control subjects and patients. The results suggest that the ability of individuals with hemiparesis to prepare for a self-initiated predictable perturbation is reduced and that they may use alternative strategies of postural stabilization.


Prevalence of inadequate intake of folate after mandatory fortification: results from the first National Dietary Survey in Brazil.
Our aim was to estimate the prevalence of folate inadequacy (POFI) according to life stage, socio-economic status, and geographical regions after the mandatory fortification of wheat and maize flour in Brazil. This was a population-based study. Data from two non-consecutive food records from the National Dietary Survey/Household Budget Survey 2008-2009 were used to estimate the usual dietary folate intake in µg dietary folate equivalents (DFEs). The National Cancer Institute method was used to account for within-person variance and the Estimated Average Requirement (EAR) cut-point method was used to calculate the POFI. The survey included 32,749 individuals, 15,700 males and 17,049 females, over 10 years old. Pregnant women, lactating women, and individuals with unreliable energy intake data were excluded. Overall POFI was 31.5% and mean dietary folate intake was 411.1 µg DFE. The lowest POFI occurred in the youngest age group of 10-13 years in both sexes, while the highest POFI was observed in the group ≥ 71 years. In women of childbearing age, POFI was around 32%. The lowest income strata had the highest POFI. The most developed regions (South and Southeast) had the lowest POFI compared to less developed regions. Our data show that folate inadequacy is still prevalent in Brazil mainly in low-income groups and less developed regions. Actions need to be taken to ensure that women of childbearing age, who presented a high prevalence of inadequate folate intake, achieve the recommended daily intake of 400 µg DFEs.


A systematic review evaluating health-related quality of life, work impairment, and healthcare costs and utilization in bipolar disorder.
Bipolar disorder greatly impacts health-related quality of life (HRQoL), physical and social functioning, employment, and work productivity, and greatly increases health-care utilization and costs. Our objective was to characterize how bipolar disorder impacts HRQoL, work impairment, and health-care utilization and costs. A systematic literature review was conducted to identify bipolar disorder studies of HRQoL, functioning, work impairment, and health-care utilization and costs. We searched Medline, ClinPSYC, and HealthSTAR for English-language articles published between January 1985 and November 2002 using MeSH headings and keywords. Additional articles were identified from references of relevant articles. We identified 65 HRQoL articles, 14 work-impairment articles, and 28 utilization-and-care-cost articles. For all HRQoL instruments used, bipolar disorder patients' HRQoL was rated similarly to that of unipolar depression patients, and equal to or lower compared with patients with other chronic nonmental illnesses. Current treatments have been shown to improve HRQoL and physical and social functioning; some data indicate that management may improve selfreported work impairment and absenteeism. Bipolar disorder patients have been found to utilize health-care services more than do patients with depression or chronic medical conditions. Inpatient costs are the largest cost contributor; treatment to prevent recurrence has been shown to be the most effective way to reduce costs. Bipolar disorder imposes a tremendous burden on patients and the health-care system, resulting in decreased HRQoL and increased medical and work impairment costs. Limited data suggest that appropriate management can improve HRQoL and functioning while reducing utilization and cost.


Ethical considerations in oncology: balancing the interests of patients, oncologists, and society.
Oncologists face ethical dilemmas every day in deciding about choice of treatment, continuation of treatments, events near the end of life, conflicts of interest, and risk management. Yet, many oncologists have limited training in ethics. Review of existing studies and definitions of useful terms. Case studies analyzed according to ethical principles. Individual oncology cases can be analyzed according to ethical principles with benefit to the patient, physician, and possibly society. Ethics cannot resolve many of the thorny questions about allocation of resources, justice, or possible conflict of interest. Oncology decision-making fits into formal ethical frameworks, and understanding both can help doctors and patients make difficult choices. Understanding of ethical principles can help daily practice, but does not solve current dilemmas of allocation of resources, unrealistic demands, etc. More formal collaboration between hospital ethics committees or personnel and clinical oncologists is recommended for the day-to-day decision-making process.


Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.
Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial-mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.


Antioxidative activity of the hydrolytic enzyme treated Sorbus commixta Hedl. and its inhibitory effect on matrix metalloproteinase-1 in UV irradiated human dermal fibroblasts.
Superoxide radical scavenging activity and DPPH radical scavenging activity were assessed in order to evaluate the antioxidant effect of the Sorbus commixta Hedl. extract (SCoE). SCoE was also treated with several carbohydrate-hydrolytic enzymes that significantly increased the total phenol and flavonoid composition of SCoE. The enzymatically treated SCoE was then assessed for antioxidative activity. The most efficient radical scavenging activity was observed when SCoE was treated with -glucanase. The radical scavenging activity of beta-glucanase-treated SCoE (beta-GSCoE) enhanced the viability of human dermal fibroblasts (HDFs) exposed to ultraviolet (UV) light. The intracellular reactive oxygen species (ROS) scavenging activity of beta-GSCoE was assessed using UVB (20 mJ/cm2)-irradiated HDFs. UVB irradiation increased dichlorofluorescein (DCF) fluorescence, which was measured by a 5-(6-)chloromethyl-2',7'- dichlorodihydrofluorescein diacetate (CM-H2DCFDA). DCF-fluorescence was significantly decreased in the beta-GSCoE-containing culture medium, suggesting that beta-GSCoE scavenges free radicals. The protective effect was further verified by assessing the expression of matrix metalloproteinase-1 (MMP-1) in UVA-irradiated HDFs. The treatment of UVA-irradiated HDFs with beta-GSCoE resulted in a dose-dependent decrease in the expression level of MMP-1 protein and mRNA. These results suggest that beta-GSCoE may mitigate the effects of photoaging in skin by reducing UV-induced adverse skin reactions.


The effect of torsion on the appearance of the rupture surface of the ACL of rabbits.
This study investigates how torsion affects the mechanical properties and appearance of the rupture surfaces of the anterior cruciate ligament (ACL). Rupture of the ACL is frequent among athletes and twisting of the knee during rupture is often implicated as a major factor in the injury. The problem is compounded by the ACL having limited ability to heal when ruptured. Thirty-two specimens were stretched to failure at tension--torsion rates of 10 mm/min and 1 degree/s, 10 mm/min and 40 degree/s, 500 mm/min and 1 degree/s and 500 mm/min and 40 degree/s. Results from these experiments were compared with those from pure tension tests performed at displacement rates of 10 and 500 mm/min. The changes that occurred during the rupture process were monitored by video recordings and the appearance of the rupture surfaces studied by scanning electron microscopy (SEM). We found significant differences in stiffness between tests carried out with and without torsion. The macro and microscopic appearance of the ruptures from specimens tested with torsion at different displacement rates were similar although, for the slow displacement rate, the rupture surfaces were different from those from tests carried out without torsion. The failure modes for all tests carried with torsion were similar, with all the specimens failing in the ligament substance by fibre pullout. The modes of failure for tests carried at 500 mm/min with torsion were different from those tested without torsion. Half of the specimens tested without torsion failed by tibial avulsion, whereas all specimens tested with torsion failed in the ligament substance. These results suggest that torsion affects both mechanical and structural properties of the ACL and should, therefore, be considered when designing or selecting replacements for the ACL.


Successfully developing biotech drugs in Europe--IBC biomedical conference. 19-20 November 1998, London, UK.
This conference gave an overview of developing business strategies to capitalize on opportunities in the biotech industry. Although the importance of the biotech sector is clear, it is faced with many and varied business and regulatory problems. Financing, timescales, manufacturing, drug development and drug registration, as well as analysis of the current biotech market were discussed.


[Experimental study on the functional regulation of naringin in human periodontal ligament cells].
To detect the effect of naringin on human periodontal ligament cells' (hPDLCs) proliferation,bone formation and OPG mRNA expression. hPDLCs were primarily cultured and identified in vitro through enzyme digestion combined tissue culture method. With 3-(4, 5-Dimethylthiazol-2- yl)-2, 5-diphenyltetrazolium bromide (MTT) method, enzyme linked immunosorbent assay and RT-PCR, the hPDLCs' proliferation, alkaline phosphatase (ALP) activity, expression of collagen protein-I and OPG mRNA were observed after treatment with different concentrations (100,10,1.0,0.1,0.01mg/L) of naringin at different times. SPSS16.0 software package was used for statistical analysis. Primary cultured hPDLCs had good shape; Significant promotion of proliferation,ALP activity and collagen protein-I expression of hPDLCs with naringin was found at the dose of 1.0 mg/L; and 1.0mg/L naringin regulated the expression of OPG mRNA in time-dependent manner. Naringin might significantly promote the proliferation of hPDLCs and conversion into the osteoblast.


[Modern angiological diagnostic methods].
The tasks of apparative examination methods in the angiologic diagnostics are explained. Apart from the mechanical oscillography the possibilities of registration and evaluation of the peripheral pulse wave are discussed. As quantitative examination method the plethysmography is broadly used. The most important applications of the ultrasound-Doppler-technique are described.


The (extended) achondroplasia foramen magnum score has good observer reliability.
Achondroplasia is the most common skeletal dysplasia. A significant complication is foramen magnum stenosis. When severe, compression of the spinal cord may result in sleep apnea, sudden respiratory arrest and death. To avoid complications, surgical decompression of the craniocervical junction is offered in at-risk cases. However, practice varies among centres. To standardize magnetic resonance (MR) reporting, the achondroplasia foramen magnum score was recently developed. The reliability of the score has not been assessed. To assess the interobserver reliability of the achondroplasia foramen magnum score. Base of skull imaging of children with achondroplasia under the care of Sheffield Children's Hospital was retrospectively and independently reviewed by four observers using the achondroplasia foramen magnum score. Two-way random-effects intraclass coefficient (ICC) was used to assess inter- and intra-observer reliability. Forty-nine eligible cases and five controls were included. Of these, 10 were scored normal, 17 had a median score of 1 (mild narrowing), 11 had a median score of 2 (effacement of cerebral spinal fluid), 10 had a score of 3 (compression of cord) and 6 had a median score of 4 (cord myelopathic change). Interobserver ICC was 0.72 (95% confidence interval = 0.62-0.81). Intra-observer ICC ranged from 0.60 to 0.86. Reasons for reader disagreement included flow void artefact, subtle T2 cord signal and myelopathic T2 cord change disproportionate to canal narrowing. The achondroplasia foramen magnum score has good interobserver reliability. Imaging features leading to interobserver disagreement have been identified. Further research is required to prospectively validate the score against clinical outcomes.


Rhizoma Amorphophalli inhibits TNBC cell proliferation, migration, invasion and metastasis through the PI3K/Akt/mTOR pathway.
Triple-negative breast cancer (TNBC) often presents with a high histological grade and high malignancy, which greatly contribute to patient morbidity and mortality. Rhizoma Amorphophalli exhibits many biological and pharmacological activities, but its potential as a therapeutic agent for the treatment of metastatic TNBC patients remains poorly understood. The aim of this study was to determine whether Rhizoma Amorphophalli inhibits metastasis in the human TNBC MDA-MB-231 cell line. CCK-8 and colony formation assays were adopted for the analysis of cell activity and cell proliferation, respectively. Flow cytometry was used for cell cycle analysis. Wound healing and transwell assays were performed to assess cell migration and invasion, respectively. PI3K/Akt/mTOR signaling pathways were analyzed through western blotting. Breast cancer cell metastasis to the lung in a xenograft model was evaluated by in vivo fluorescence imaging. A GC-MS analysis was performed to determine the main components of the petroleum ether fraction from the ethanol extract of Rhizoma Amorphophalli (abbreviated RhA). RhA significantly reduced breast cancer cell viability and proliferation. The flow cytometry analysis indicated that RhA induced MDA-MB-231 cell arrest at the S phase. Additionally, RhA decreased MDA-MB-231 cell migration and invasion and inhibited the PI3K/Akt/mTOR signaling pathway. In addition, mice treated with RhA exhibited a significant reduction in tumor infiltration and a decrease in breast cancer cell metastasis to the lung. The GC-MS analysis results showed that RhA contained a large number of unsaturated fatty acids, such as octadecadienoic acid (linoleic acid), octadecatrienoic acid (linolenic acid), and oleate, which might represent the anticancer components of the extract. The results of this study suggest that RhA has potential as a therapeutic candidate for metastatic TNBC treatment.


Asp577 mutations enhance the catalytic efficiency of cyclodextrin glycosyltransferase from Bacillus circulans.
The amino acid residue Asp 577 is located in calcium-binding site III (CaIII) of the cyclodextrin glycosyltransferase (EC 220.127.116.11, CGTase) from Bacillus circulans STB01. In the present study, the effects of replacing Asp577 with glycine, alanine, valine, leucine, and isoleucine on the catalytic efficiency of this CGTase were investigated. Two of these replacements, D577G and D577A, increased the β-cyclization activity of CGTase. Kinetic studies showed that the Km values of D577G and D577A were 36.1% and 18.0% lower and the kcat/Km values were 43.9% and 23.0% higher than those of the wild-type enzyme, respectively. These mutations increased both the affinity of CGTase for maltodextrin and the catalytic efficiency of the cyclization reaction. Furthermore, although D577G and D577A only slightly enhanced β-cyclodextrin production, compared with the wild-type enzyme, their higher β-cyclization activities resulted in a significant reduction in the amount of mutant protein required during the cyclodextrin production process. Thus, the two mutants are more suitable for the industrial production of β-cyclodextrin than the wild-type enzyme. The enhancement of catalytic efficiency may be due to the smaller size of the glycine and alanine side chains, which may weaken the impact of this residue on CaIII.


Application of adaptive-network-based fuzzy inference systems to the parameter optimization of a biochemical rule-based model.
In this study, the binding of allergens to antibody-receptor complexes was investigated. This process is important in understanding the allergic response. A BioNetGen model that simulates this process, combined with a novel method for encoding steric effects via the optimization of the cutoff distance and the rule binding rate, was previously developed. These parameters were optimized by fitting the model output to the output of a 3D simulation that explicitly represents molecular geometry. In this work, the parameters for the BioNetGen model were optimized using an adaptive-network-based fuzzy inference system in order to predict the rule rate and cutoff distance given a residual-sum-of-squares value or a probability distribution. The fuzzy systems were constructed using fuzzy c-means clustering with existing data from BioNetGen model parameter scans used as the training data. Fuzzy systems with various input data and number of clusters were created and tested. Their performance was analyzed with regard to the effective optimization of the rule-based model. The study found that the fuzzy system that uses a residual-sum-of-squares value as the input value performs acceptably well. However, the performance of the fuzzy systems that use probabilities as their input values performed inconsistently in the tests and need further development. This methodology could potentially be modified for use in fitting other biological models.


Management of Lower Extremity and Pelvic Tumors Using Computer Assisted Modeling (CAM) A Case Series.
Computer assisted modeling (CAM) has become an important tool in surgical oncology and reconstructive surgery. The preservation of the limb is an important consideration when approaching the treatment of lower extremity and pelvic tumors. The use of cutting guides allows for optimal conservation of disease-free bone and maintenance of function. We present a small case series that illustrates the use of CAM in patients with lower extremity and pelvic bone tumors.


Enhancement of aldehyde dehydrogenase activity in human and rat hepatocyte cultures by 3-methylcholanthrene.
Aldehyde dehydrogenase was measured in primary cultures of hepatocytes obtained with a two-step collagenase perfusion either from human hepatic tissue or from livers of Fisher rats. Basal enzyme activity declines gradually as a function of time in culture, but remains at all times higher when measured with propionaldehyde and NAD (P/NAD) than with benzaldehyde and NADP (B/NADP). Treatment of the cultures with 2 microM of 3-methylcholanthrene for four days significantly increased the B-NADP activity of human and rat hepatocytes (tenfold and eightfold respectively). In human hepatocytes 3-methylcholanthrene increases also the P/NAD activity, but to a lesser extent (twofold), compared to the B/NADP activity. Due to the significant enhancement of B/NADP activity in cultures of human and rat hepatocytes after application of 3-methylcholanthrene, the initial difference in the basal activity levels between the P/NAD and B/NADP forms diminishes or, in the case of human hepatocytes, is even inverted. These results show for the first time that aldehyde dehydrogenase activity is increased in cultured human hepatocytes. This biochemical property is preserved in human and rat hepatocyte cultures, despite the rather quick loss of the basal aldehyde dehydrogenase activity.


No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China-Myanmar border.
The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China's plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China-Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance. The therapeutic efficacy of DHA-PPQ for the treatment of uncomplicated P. falciparum was evaluated along the China-Myanmar border from 2010 to 2014. The dry blood spots samples collected in the efficacy study prior DHA-PPQ treatment and from the local hospital by passive detection were used to amplify k13 and pm2. Polymorphisms within k13 were genotyped by capillary sequencing and pm2 copy number was quantified by relative-quantitative real-time polymerase chain reaction. Treatment outcome was evaluated with the World Health Organization protocol. A linear regression model was used to estimate the association between the day 3 positive rate and k13 mutation and the relationship of the pm2 copy number variants and k13 mutations. DHA-PPQ was effective for uncomplicated P. falciparum infection in Yunnan Province with cure rates > 95%. Twelve non synonymous mutations in the k13 domain were observed among the 268 samples with the prevalence of 44.0% and the predominant mutation was F446I with a prevalence of 32.8%. Only one sample was observed with multi-copies of pm2, including parasites with and without k13 mutations. The therapeutic efficacy of DHA-PPQ was > 95% along the China-Myanmar border, consistent with the lack of amplification of pm2. DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China-Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.


Constructing POSS and viologen-linked porous cationic frameworks induced by the Zincke reaction for efficient CO2 capture and conversion.
POSS and viologen-linked porous cationic frameworks (V-PCIF-X, X = Cl, Br) are constructed via the Zincke reaction between octa(aminophenyl)silsesquioxane and viologen linkers. The typical V-PCIF-Br has a high surface area with abundant ionic sites, micro-/mesopores and Si-OH groups, serving as an efficient porous adsorbent and metal-free catalyst for simultaneous CO2 capture and conversion.


Illicit drug use and violence.
This chapter reviews evidence on the relationship between illicit drug use and violence, specifically cannabis, stimulant drugs, and opioids. It summarizes findings of systematic reviews of evidence on cannabis, stimulant drugs, and opioids. It also examines evidence from epidemiological studies of drug use among violent offenders and of violence among persons who use drugs, intervention studies, animal studies, human laboratory studies, and human neuroimaging studies. More studies have examined cannabis because of its higher prevalence of use. There is an association between cannabis use and violence, suggestive evidence of a dose-response relationship between the frequency of cannabis use and violence, and a stronger association in persons with psychoses. There is similar emerging evidence on stimulant use and violence, but evidence on opioids is very limited. There is limited and mixed evidence from intervention studies that reducing drug use reduces violence. Animal and human studies provide potential biological explanations for these associations. The association between cannabis use and violence is most consistent but limited by study heterogeneity and lack of control for potential confounders. It is unclear whether these associations are causal or reflect reverse causation or the effects of confounding.


The impact of local government competition and green technology innovation on economic low-carbon transition: new insights from China.
The government-led Chinese economic development system determines that local government competition is a significant factor affecting the economic low-carbon transition. Driving an economic development mode with green technology innovation as the core is the critical path to realizing an economic low-carbon transition. Consequently, it is of significant practical relevance to investigate the impact of local government competition and green technology innovation on the economic low-carbon transition under the government-led Chinese economic development system. This paper systematically explores the nexus between green technology innovation and economic low-carbon transition in terms of local government competition perspective using the system generalized method of moments, panel threshold model, and geographically weighted regression on the basis of a dataset of 30 provincial administrative areas in China from a period of 2006-2019. The results indicate that green technology innovation significantly promotes the economic low-carbon transition. Local government competition not only significantly dampens the economic low-carbon transition but also considerably inhibits the positive effect of green technology innovation on the economic low-carbon transition. A significant N-shaped association is evident between green technology innovation and the economic low-carbon transition when green technology innovation is applied as a threshold, while such association is insignificant when local government competition is used as a threshold. Compared with high-competition intensity areas, green technology innovation promotes economic low-carbon transition weaker in low- competition intensity areas, while local government competition inhibits economic low-carbon transition stronger. However, local government competition significantly inhibits the positive effect of green technology innovation on the economic low-carbon transition in low-competition intensity areas, while insignificant in high-competition intensity areas. The geographically weighted regression technique as a whole also verified the above results. Therefore, policymakers should not only increase research and development investment in green technologies, but also develop a regionally linked low-carbon emission reduction system to avoid ineffective competition among governments to facilitate the earlier fulfillment of the "dual carbon" goal.


Going beyond the individual: how state-level characteristics relate to HPV vaccine rates in the United States.
The human papillomavirus (HPV) vaccine is an underutilized cancer control practice in the United States. Although individual contextual factors are known to impact HPV vaccine coverage rates, the impact of macro-level elements are still unclear. The aim of this analysis was to use HPV vaccination rates to explore the underuse of an evidence-based cancer control intervention and explore broader-level correlates influencing completion rates. A comprehensive database was developed using individual-level date from the National Immunization Survey (NIS)-Teen (2016) and state-level data collected from publically available sources to analyze HPV vaccine completion. Multi-level logistic models were fit to identify significant correlates. Level-1 (individual) and level-2 (state) correlates were fitted to a random intercept model. Deviance and AIC assessed model fit and sampling weights were applied. The analysis included 20,495 adolescents from 50 U.S. states and the District of Columbia. Teen age, gender, race/ethnicity, and maternal education were significant individual predictors of HPV completion rates. Significant state-level predictors included sex education policy, religiosity, and HPV vaccine mandate. States with the lowest HPV coverage rates were found to be conservative and highly religious. Little variation in vaccine exemptions and enacted sex and abstinence education polices were observed between states with high and low HPV vaccine coverage suggesting various contextual and situational factors impact HPV vaccine completion rates. Given that gender, religiosity, political ideology, and education policies are predictors of HPV vaccine completion, the interaction and underlying mechanism of these factors can be used to address the underutilization of the HPV vaccine.


Differential pulsed amperometry coupled to microchip capillary electrophoresis.
In this work, we describe a novel electrochemical detection method, differential pulsed amperometry (DPA) on microchip capillary electrophoresis (MCE). In a pulse period, a sequential two-step sampling is executed at two different potentials (E1 and E2). Differential current signal of the duplex sampling events is recorded that functions as time domain. The performance of this detection scheme was evaluated by separating and detecting three model analytes including tyramine (Tym), tryptophan (Trp), and p-aminobenzoic acid (PABA). Multiple parameters that would affect electrochemical response and peak shape, such as sampling potential, sampling time, and electrode cleaning time, were investigated. This pulse technique exhibits better sensitivity over constant potential amperometry (CPA), nearly equal to triple pulsed amperometry (TPA). More importantly, DPA can generate more stable baseline than TPA, primarily due to the background subtraction through the two-step sampling, which is beneficial to further improve analytical sensitivity. In the optimal condition, the limits of detection for Tym, Trp and PABA, were down to 0.27μM, 0.32μM and 1.1μM, respectively. DPA detection opens up a new avenue for microchip electrochemistry, and can be virtually extended to other fluid analysis techniques.


Changes in Haemophilus influenzae capsule locus: possible emergence of novel variants in Brazil.
A total of 28 strains of Haemophilus influenzae (Hi) a and b isolated from clinical samples before and after the introduction of the Hib conjugate vaccine in Brazil were analyzed to determine variants of the capsular gene. Our results suggest the occurrence of new variants closely related to types I and II previously described elsewhere. Eleven Hib strains belonged to type I, 8 were type II, and 3 Hia strains were type II. Six strains showed negative results after polymerase chain reaction targeting capsule locus; the variable regions were sequenced and compared with types I and II. Phylogenetic analysis showed that 5 Hib strains were actually subtypes of type I (type I-A), whereas 1 Hia strain was a subtype of type II (type II-A). Types I and II strains were present in both periods of vaccination. This study suggests that a gradual change in the capsule genes of H. influenzae is probably occurring, and novel variants might be emerging among Brazilian isolates.


Trends in prescribing patterns of hormonal contraceptives for adolescents.
Little is known regarding how prescribing patterns of hormonal contraceptives to adolescents in the United States have changed over time as new formulations become available and knowledge of thrombosis risk increases. Desogestrel and high-dose estrogen-containing formulations have been associated with a higher risk of thrombosis than other methods. We used the National Ambulatory Medical Care/National Hospital Ambulatory Medical Care surveys to describe trends in contraception prescriptions for 11- to 21-year-old females between 1993 and 2004. The majority of prescriptions arose from obstetrics/gynecology clinics. The proportion of desogestrel-containing prescriptions was approximately 10% throughout the study period. Ortho Evra (transdermal norelgestromin, ethinyl estradiol) and Yasmin (oral drospirenone, ethinyl estradiol) accounted for a steadily increasing proportion of prescriptions. With regard to contraception and thrombosis risk, a significant minority of adolescents are prescribed desogestrel-containing contraceptives, and a greater number are exposed to higher levels of estrogen from transdermal contraception. Future studies are needed to evaluate the absolute risk of thrombosis in adolescents using these formulations so clinicians have accurate safety information when prescribing to this unique population.


Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents.
Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC50 values in the range of 2.9-5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50 =6.1 μM) and MV-4-11 (IC50 =11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50 =31.8-55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10-19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.


Introduction: Fertility and longevity.
The authors of this Views and Reviews outline the current understanding of the association between fertility and longevity. Natural fertility in populations that did not employ any contraception make up the model that attempts to define this relationship. Longevity seems to be increased in women with late-age conceptions and may be the result of genetic or environmental factors or both. A new concept is suggested that demonstrates the potential rejuvenating effect of pregnancy on older pregnant mothers. The link between infertility itself and conceptions at an older age with morbidity and mortality is summarized.


Automated anthropometric phenotyping with novel Kinect-based three-dimensional imaging method: comparison with a reference laser imaging system.
Anthropometry for measuring body composition, shape, surface area and volume is important for human clinical research and practice. Although training and technical skills are required for traditional tape and caliper anthropometry, a new opportunity exists for automated measurement using newly developed relatively low-cost three-dimensional (3D) imaging devices. The aim of this study was to compare results provided by a Kinect-based device to a traditional laser 3D reference system. Measurements made by the evaluated device, a hybrid of commercially purchased hardware (KX-16; TC(2), Cary, NC, USA) with our additional added software, were compared with those derived by a high-resolution laser scanner (Vitus Smart XXL; Human Solutions North America, Cary, NC, USA). Both imaging systems were compared with additional linear (stadiometer-derived height) and volumetric (total volume, air-displacement plethysmography) measurements. Subjects (n=101) were healthy children (age ≥5 years) and adults varying in body mass index. Representative linear (4), circumferential (6), volumetric (3) and surface area (1) measurements made by the Kinect-based device showed a consistent pattern relative to the laser system: high correlations (R(2)s= 0.70-0.99, all P<0.001); 1-3% differences for large linear (for example, height, X±s.d., -1.4±0.5%), circumferential (for example, waist circumference, -2.1±1.8%), volume (for example, total body, -0.8±2.2%) and surface area (whole-body, -1.7±2.0%) estimates. By contrast, mean measurement differences were substantially larger for small structures (for example, forearm volume, 31.3±31.4%). Low-cost 3D Kinect-based imaging systems have the potential for providing automated accurate anthropometric and related body measurements for relatively large components; further hardware and software developments may be able to improve system small-component resolution.


Systemic treatments in Parthenium dermatitis: A systematic review and meta-analysis.
Parthenium dermatitis is the commonest form of plant dermatitis in India, caused by the plant Parthenium hysterophorus. Systemic immunosuppressives are commonly employed in its treatment. However, there is a relative lack of comparative head-to-head trials. This study was done to assess the relative efficacy and safety of systemic treatments in Parthenium dermatitis. We systematically reviewed all the published studies investigating the safety and efficacy of systemic treatments for Parthenium dermatitis in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial registries. Treatment benefit data were tabulated based on outcome measures of scoring systems. The quality of evidence for each outcome was assessed by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria for meta-analysis. The pooled Standardized mean difference (SMD) for case series and comparative studies based on clinical severity score (CSS) for azathioprine was 4.007 (95% CI (Confidence interval): 3.141, 4.873) and 0.746 (95% CI: 0.139, 1.352), respectively. About 88.8% (95% CI: 76.8%, 100.8%, p = 0.076) of the patients had excellent or a good response to azathioprine. Our meta-analysis shows that azathioprine has the highest level of evidence in the treatment of Parthenium dermatitis.


Hepatocellular carcinoma progression is protected by miRNA-34c-5p by regulating FAM83A.
To elucidate the role of microRNA-34c-5p (miRNA-34c-5p) in the progression of hepatocellular carcinoma (HCC) and the indicated mechanism. Relative levels of miRNA-34c-5p and FAM83A in HCC tissues and cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Their influences on clinical features in HCC patients were analyzed. Kaplan-Meier method was introduced for assessing the relationship between miRNA-34c-5p and overall survival in HCC. After overexpression of miRNA-34c-5p in HepG2 and HB611 cells, we detected proliferative, migratory and invasive abilities by cell counting kit-8 (CCK-8) and transwell assay. The interaction between miRNA-34c-5p and FAM83A was explored by Dual-Luciferase reporter assay. Finally, their co-regulation on HCC cell phenotypes was examined. MiRNA-34c-5p was downregulated in HCC tissues, especially stage III+IV cases. Its level was correlated to tumor size, tumor number and TNM staging in HCC. Overexpression of miRNA-34c-5p inhibited proliferative, migratory and invasive abilities in HepG2 and HB611 cells. In addition, miRNA-34c-5p targeted on FAM83A and negatively regulated its level. Overexpression of FAM83A could reverse the inhibitory effects of miRNA-34c-5p on malignant phenotypes of HCC cells. By negatively regulating FAM83A level, miRNA-34c-5p alleviates the progression of HCC.


Central motor conduction after magnetic stimulation in diabetes.
Central motor conduction times (CMCTs), obtained by means of magnetic stimulation of the motor cortex and spinal roots, were studied in 138 patients affected by diabetes mellitus but with no signs or symptoms of central nervous system (CNS) involvement. CMCTs were significantly increased in diabetic patients (p < 0.001, t-test) with respect to normal controls, with values exceeding upper confidence limits (mean +/- 2.5 SD of controls) in about 30% of patients. There was no correlation between CMCT delay and type of diabetes (insulin-dependent or non-insulin-dependent), patient age, disease duration, degree of metabolic control compensation, presence or absence of retinopathy or nephropathy, and presence or absence of peripheral or autonomic neuropathy. CNS involvement in diabetes mellitus is discussed. Particular emphasis is given to the sensitivity and reliability of CMCTs obtained by means of magnetic stimulation as a tool in the early diagnosis of CNS functional alterations in diabetes mellitus.


Radiation-induced DNA single-strand scission and its rejoining in spermatogonia and spermatozoa of mouse.
Gamma-ray-induced DNA single-strand scissions and the ability to repair the scissions in spermatogonia from young mice and in spermatozoa from adult mice were studied quantitatively by an alkaline sucrose density-gradient centrifugation method. The average size of DNAs in non-irradiated spermatogonia was 2.6--3.0 X 10(8) daltons, similar to those of a spermatid-rich population, and the size of DNA in non-irradiated spermatozoa was 1.2 X 10(8) daltons. In spermatogonia, the radiosensitivity of DNA was 0.42 single-strand breaks/10(12) daltons of DNA/rad in oxic conditions and only 0.24 under anoxic conditions. In spermatozoa the break efficiency of DNA was 0.22 single-strand breaks/10(12) daltons of DNA/rad under oxic conditions and altered little under anoxic irradiation. The DNA scissions were efficiently repaired in spermatogonia within 10 min, whereas the breaks in spermatozoa were not rejoined at all even after two days of post-irradiation time. The radiosensitivities of DNA, repair capability and non- and/or slow-reparable DNA scissions were compared in spermatogonium-rich, spermatid-rich and spermatozoan-rich populations.


Femtosecond laser programmed artificial musculoskeletal systems.
Natural musculoskeletal systems have been widely recognized as an advanced robotic model for designing robust yet flexible microbots. However, the development of artificial musculoskeletal systems at micro-nanoscale currently remains a big challenge, since it requires precise assembly of two or more materials of distinct properties into complex 3D micro/nanostructures. In this study, we report femtosecond laser programmed artificial musculoskeletal systems for prototyping 3D microbots, using relatively stiff SU-8 as the skeleton and pH-responsive protein (bovine serum albumin, BSA) as the smart muscle. To realize the programmable integration of the two materials into a 3D configuration, a successive on-chip two-photon polymerization (TPP) strategy that enables structuring two photosensitive materials sequentially within a predesigned configuration was proposed. As a proof-of-concept, we demonstrate a pH-responsive spider microbot and a 3D smart micro-gripper that enables controllable grabbing and releasing. Our strategy provides a universal protocol for directly printing 3D microbots composed of multiple materials.


Identification of Potential PPAR γ Agonists as Hypoglycemic Agents: Molecular Docking Approach.
Peroxisome proliferator-activated receptor gamma (PPAR γ) has become an attractive molecular target for drugs that aim to treat hyperglycemia. The object of our study is to identify the required molecular descriptor and essential amino acid residues for effective PPAR γ agonistic activity. In this work, we employed Molegro Virtual Docker program in all molecular docking simulations. Accuracy of receptor-compound docking was validated on a set of 15 PPAR γ-compound complexes for which crystallographic structures were available. The reliability of the docking results was acceptable with good root-mean-square deviation value (<2 Å). A significant correlation between different data derived from docking calculations and experimental data was revealed. Our results allowed identification of compounds with potential to become drugs against hyperglycemia.


Aversive conditioning in the sociopath.
Results of two experiments on differential conditioning of the skin conductance (SCR) in sociopaths and normal control subjects are described. In the first experiment it was found that an equal number of sociopaths and control subjects were aware of the conditioning contingency. However, only the normal subjects displayed reliable differential SCR conditioning. Sociopaths showed a dissociation between verbal learning and conditioning of a physiological change. The second experiment examined the differential conditioning of normal subjects and sociopaths in partial remission. The number of aware subjects in the two groups did not differ. Aware subjects in both groups showed differential SCR conditioning. Differential conditioning in sociopaths did not persist over trials as it did in control subjects. A deficiency in ACTH 4--10 as well as neurological dysfunctions were considered possible factors in the etiology of sociopathy. Further research on the relation of neuropeptides to the etiology and treatment of sociopathy is suggested.


Evolution of surfactant protein-D levels in children with ventilator-associated pneumonia.
The pathobiology of ventilator-associated pneumonia (VAP) in children is poorly understood; investigation has been limited by lack of universally applied diagnostic criteria and reliable biomarkers for this condition. We evaluated the clinical pulmonary infection score (CPIS) in diagnosing VAP and prospectively characterized the relationship between surfactant protein-D (SP-D) metabolism and VAP. Children admitted to an Egyptian PICU requiring intubation were screened for the absence of primary pulmonary pathology. Thirty-nine children underwent two evaluations: during the first 36 hr following intubation and after 4 days of mechanical ventilation. During both, bronchoalveolar lavage fluid (BALF) was obtained for culture and SP-D assay. CPIS was computed during the second evaluation. Optimum performance of the CPIS against BALF culture occurred at a cutoff value of 6, (ROC AUC of 0.89 ± 0.05). Children who developed VAP had significantly higher SP-D levels, both preceding (129.9 ± 33.5 ng/ml at the 1st BAL)-and following positive BALF culture (249.5 ± 51.2 ng/ml at the 2nd BAL), compared to children whose BALF remained sterile (62.6 ± 18.1 ng/ml and 64.9 ± 9.4 ng/ml; P < 0.001). This increase in SP-D levels was most evident in children infected with Pseudomonas aeruginosa compared to children with Klebsiella pneumonia or S. aureus. The CPIS performed well against BALF culture. We observed a bacterial species-specific difference in SP-D levels in children who developed VAP; this change preceded detection of infection by CPIS or BALF culture.


Temporary vascular shunt for damage control of extremity vascular injury: A toolbox for trauma surgeons.
In an emergency, a general surgeon may be faced with the need to treat arterial trauma of the extremities when specialized vascular surgery is not available in their hospital setting, either because an arterial lesion was not diagnosed during pre-admission triage, or because of iatrogenic arterial injury. The need for urgent control of hemorrhage and limb ischemia may contra-indicate immediate transfer to a hospital with a specialized vascular surgery service. For a non-specialized surgeon, hemostasis and revascularization rely largely on damage control techniques and the use of temporary vascular shunts (TVS). Insertion of a TVS is indicated for vascular injuries involving the proximal portion of extremity vessels, while hemorrhage from distal arterial injuries can be treated with simple arterial ligature. Proximal and distal control of the injured vessel must be obtained, followed by proximal and distal Fogarty catheter thrombectomy and lavage with heparinized saline. The diameter of the TVS should be closely approximated to that of the artery; use of an oversized TVS may result in intimal tears. Systematic performance of decompressive fasciotomy is recommended in order to prevent compartment syndrome. In the immediate postoperative period, the need for systematic use of anticoagulant or anti-aggregant medications has not been demonstrated. The patient should be transferred to a specialized center for vascular surgery as soon as possible. The interval before definitive revascularization depends on the overall condition of the patient. The long-term limb conservation results after placement of a TVS are identical to those obtained when initial revascularization is performed.


Bi-directional Synthesis of Pre- and Post-contrast MRI via Guided Feature Disentanglement.
Magnetic resonance imaging (MRI) with gadolinium contrast is widely used for tissue enhancement and better identification of active lesions and tumors. Recent studies have shown that gadolinium deposition can accumulate in tissues including the brain, which raises safety concerns. Prior works have tried to synthesize post-contrast T1-weighted MRIs from pre-contrast MRIs to avoid the use of gadolinium. However, contrast and image representations are often entangled during the synthesis process, resulting in synthetic post-contrast MRIs with undesirable contrast enhancements. Moreover, the synthesis of pre-contrast MRIs from post-contrast MRIs which can be useful for volumetric analysis is rarely investigated in the literature. To tackle pre- and post- contrast MRI synthesis, we propose a BI-directional Contrast Enhancement Prediction and Synthesis (BICEPS) network that enables disentanglement of contrast and image representations via a bi-directional image-to-image translation(I2I)model. Our proposed model can perform both pre-to-post and post-to-pre contrast synthesis, and provides an interpretable synthesis process by predicting contrast enhancement maps from the learned contrast embedding. Extensive experiments on a multiple sclerosis dataset demonstrate the feasibility of applying our bidirectional synthesis and show that BICEPS outperforms current methods.


Microbial sialidases: does bigger always mean better?
Sialidases are a superfamily of N-acylneuraminate-releasing (sialic-acid-releasing) exoglycosidases found mainly in higher eukaryotes and in some, mostly pathogenic, viruses, bacteria and protozoans. The functions of sialidases are poorly understood and, until recently, their biochemical and evolutionary relationships were unclear. A comparative approach has demonstrated the remarkable similarities and differences between nonviral sialidases, and is providing clues about their functions.


Activation of metabotropic glutamate receptors by repetitive stimulation in auditory cortex.
To determine whether metabotropic glutamate receptors (mGluRs) contribute to the responses of neurons to repetitive stimulation in the rat auditory cortex in vitro, five stimulus pulses were delivered at 2-100 Hz which elicited five depolarizing synaptic responses, f-EPSPs: f-EPSPs(1-5). Stimulus pulses 2-5 delivered at low frequencies (2-10 Hz) elicited f-EPSPs(2-5) that were about 15% smaller than the response elicited by the first pulse (f-EPSP(1)). In the presence of the nonspecific mGluR agonist, ACPD, the amplitude of all f-EPSPs was 40% smaller than predrug responses. APV, CNQX, or bicuculline (antagonists of NMDA-, AMPA/kainate-, and GABA(A)-receptors, respectively) did not change this effect of ACPD. The mGluR antagonist, MCPG, had no effect on f-EPSPs but did reduce the effect of ACPD. High-frequency stimulation (50-100 Hz) elicited f-EPSPs that were smaller with each successive stimulus. In ACPD, f-EPSP(1) was 40% smaller than predrug, but f-EPSPs(3-5) were not changed compared to pre-ACPD f-EPSPs(3-5), indicating that ACPD occludes the effect of repetitive stimulation. MCPG increased f-EPSP(5) by 15%, indicating that a portion of the reduction of f-EPSPs during high-frequency stimulation is mediated by mGluRs. MCPG also partially blocked the effect of ACPD. In CNQX, ACPD only decreased EPSPs, but APV or bicuculline did not change the effect of ACPD. These results suggest that the successive reduction of f-EPSPs during a high-frequency train is partially a result of mGluR activation.


The effect of accessibility on rates of fruit removal from tropical shrubs: An experimental study.
In a series of field experiments using Costa Rican rain forest plants, we examined the effect of accessibility on fruit removal rates. We compared the effects of fruit placement in terminal and axillary infructescences on diurnal and nocturnal removal rates, visitation rates, and incidence of fruit damage. We used three different species of berries (Phytolacca rivinoides, Psychotria brachiata, and Psychotria pitteri) and worked in three different habitats (fallow fields, treefall gaps, and forest understory) and in two different seasons (July-September, a season of fruit abundance and December-January, a season of fruit scarcity.)We found that in oldfields especially, diurnal removal rates by birds were significantly greater from axillary than from terminal infructescences. Nocturnal removal from axillary infructescences-presumably by rodents-is also occassionally significant. From these data, from observations on climbing ability and fruit use in captive rodents, and from reports in the literature, we suggest that rodents are significant sources of fruit and seed loss in tropical shrubs. We hypothesize that placement of the infructescence on the plant affects fruit removal by both seed-dispersing birds and by the less agile, often seed-destroying rodents. The balance between the two rates is an important component of a plant's dispersal success.Diurnal fruit removal rates were higher during the season of fruit scarcity than during the season of fruit abundance and higher in old fields than in forest gaps or understory. Fruit damage rates-probably due to orthopterans-were slightly greater in gaps and understory than in old fields.


Photo-ID and telemetry highlight a global whale shark hotspot in Palawan, Philippines.
The Philippines is home to the second largest known population of whale sharks in the world. The species is listed as endangered due to continued population declines in the Indo-Pacific. Knowledge about the connectivity within Southeast Asia remains poor, and thus international management is difficult. Here, we employed pop-up archival tags, data mining and dedicated effort to understand an aggregation of whale sharks at Honda Bay, Palawan, Philippines, and its role in the species' conservation. Between Apr and Oct 2018, we conducted 159 surveys identifying 117 individual whale sharks through their unique spot patterns (96.5% male, mean 4.5 m). A further 66 individual whale sharks were identified from local operators, and data mined on social media platforms. The satellite telemetry data showed that the whale sharks moved broadly, with one individual moving to Sabah, Malaysia, before returning to the site <1 year later. Similarly, another tagged whale shark returned to the site at a similar periodicity after reaching the Malay-Filipino border. One individual whale shark first identified in East Kalimantan, Indonesia by a citizen scientist was resighted in Honda Bay ~3.5 years later. Honda Bay is a globally important site for the endangered whale shark with connectivity to two neighbouring countries, highlighting the need for international cooperation to manage the species.


[Rickets. Diagnosis and therapy].
Rickets is caused by deficient mineralization at the level of growth plate and is usually due to a decreased serum calcium/phosphate product. Although the diagnosis of rickets can usually be suspected on the basis of a clinical examination (bone deformities in legs, impaired growth), radiological examination and detailed biochemical work-up are necessary to elucidate the etiology of the underlying disease. It is important to differentiate between calcipenic/vitamin deficient and phosphopenic rickets. The former is due to vitamin D deficiency, and the ultimate cause of this usually lies in altered vitamin D supply; however, impaired synthesis of or resistance to the actions of vitamin D can also be a cause. Phosphopenic rickets is usually related to impaired phosphate reabsorption in the proximal renal tubule. Both calcipenic and phosphopenic rickets can be acquired or hereditary in origin.


Di-ammonium potassium citrate, (NH4)2KC6H5O7.
The crystal structure of di-ammonium potassium citrate, 2NH4 +·K+·C6H5O7 3-, has been solved and refined using laboratory X-ray powder diffraction data and optimized using density functional theory. The KO7 coordination polyhedra are isolated. The ammonium cations and the hydro-phobic methyl-ene sides of the citrate anions occupy the spaces between the coordination polyhedra. Each hydrogen atom of the ammonium ions acts as a donor in a charge-assisted N-H⋯O, N-H⋯(O,O) or N-H⋯(O,O,O) hydrogen bond. There is an intra-molecular O-H⋯O hydrogen bond in the citrate anion between the hydroxide group and one of the terminal carboxyl-ate groups.


Mass concentration in a nonlocal model of clonal selection.
Self-renewal is a constitutive property of stem cells. Testing the cancer stem cell hypothesis requires investigation of the impact of self-renewal on cancer expansion. To better understand this impact, we propose a mathematical model describing the dynamics of a continuum of cell clones structured by the self-renewal potential. The model is an extension of the finite multi-compartment models of interactions between normal and cancer cells in acute leukemias. It takes a form of a system of integro-differential equations with a nonlinear and nonlocal coupling which describes regulatory feedback loops of cell proliferation and differentiation. We show that this coupling leads to mass concentration in points corresponding to the maxima of the self-renewal potential and the solutions of the model tend asymptotically to Dirac measures multiplied by positive constants. Furthermore, using a Lyapunov function constructed for the finite dimensional counterpart of the model, we prove that the total mass of the solution converges to a globally stable equilibrium. Additionally, we show stability of the model in the space of positive Radon measures equipped with the flat metric (bounded Lipschitz distance). Analytical results are illustrated by numerical simulations.


[Radioprotective action of a GGS-10 gaseous hypoxic mixture on the DNA supramolecular complex of normal tissues and sarcoma 45 of rats].
Gas hypoxic mixture (GHM-10) inhaled by rats during gamma-irradiation (2 to 20 Gy) effectively protects the supramolecular complex of DNA (SC DNA) in bone marrow and spleen, but fails to protect this complex in sarcoma 45. GHM-10 itself has been shown to induce rapid and prolonged, but irreversible, decrease in SC DNA elastic viscosity in normal tissues.


Sugarcane bagasse mild alkaline/oxidative pretreatment for ethanol production by alkaline recycle process.
In order to decrease the alkali and water consumptions in the sugarcane bagasse alkaline/oxidative pretreatment for ethanol production, an alkaline recycle process was carried out. Two recycles of NaOH/H2O2 pretreatment did not decrease the pretreatment and enzymatic hydrolysis efficiencies and the consumptions of NaOH and water would be saved by 26% and 40%, respectively. A simultaneous saccharification and fermentation (SSF) culture with pretreated bagasse as substrate was developed giving 25 g ethanol l(-1) with a yield of 0.2 g g(-1) bagasse and productivity of 0.52 g l(-1) h(-1).


Rocuronium infusion requirements and plasma concentrations at constant levels of neuromuscular paralysis during three phases of liver transplantation.
To develop a rapid online test of graft liver function during liver transplantation. Prospective, observational study. University hospital transplant unit. 17 adult patients with end-stage liver disease who underwent liver transplantation surgery. Rocuronium infusion dose requirements and plasma concentrations to maintain constant levels of neuromuscular paralysis during three phases of liver transplantation and their relationship with early postoperative liver function tests were studied. Infusion dose requirements of rocuronium, assay of rocuronium plasma concentrations using gas chromatography-mass spectrometry, and intensity of neuromuscular blockade were measured. A 24% decrease in rocuronium infusion requirements was observed during the an-hepatic phase. Rocuronium requirement during the neohepatic phase was increased only modestly or remained unchanged in 14 of the 16 patients who had normal graft function in the immediate postoperative period. Rocuronium plasma concentrations for maintaining constant levels of paralysis were significantly lower during the neohepatic phase than during the paleohepatic and anhepatic phases, indicating that there is likely to be a change in pharmacodynamics during this phase. Significant reduction in rocuronium infusion requirements during the neohepatic phase was observed in the only patient who had poor graft function in the early postoperative stage, suggesting that the reduced infusion requirement to maintain a constant neuromuscular paralysis may be related to the functional state of the graft liver after reperfusion. A significant reduction in rocuronium infusion requirement during the neohepatic phase may be suggestive of impaired organ function after reperfusion of the graft liver. Rocuronium may serve as a potential online indicator of graft liver function during liver transplantation by measurement of its infusion requirements during transplantation.


Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy.
The myriad consequences of age-related muscle atrophy include reduced muscular strength, power, and mobility; increased risk of falls, disability, and metabolic disease; and compromised immune function. At its root, aging muscle atrophy results from a loss of myofibers and atrophy of the remaining type II myofibers. The purpose of this trial (NCT02442479) was to titrate the dose of resistance training (RT) in older adults in an effort to maximize muscle regrowth and gains in muscle function. A randomized, four-arm efficacy trial in which four, distinct exercise prescriptions varying in intensity, frequency, and contraction mode/rate were evaluated: (1) high-resistance concentric-eccentric training (H) 3d/week (HHH); (2) H training 2d/week (HH); (3) 3d/week mixed model consisting of H training 2d/week separated by 1 bout of low-resistance, high-velocity, concentric only (L) training (HLH); and (4) 2d/week mixed model consisting of H training 1d/week and L training 1d/week (HL). Sixty-four randomized subjects (65.5±3.6y) completed the trial. All participants completed the same 4weeks of pre-training consisting of 3d/week followed by 30weeks of randomized RT. The HLH prescription maximized gains in thigh muscle mass (TMM, primary outcome) and total body lean mass. HLH also showed the greatest gains in knee extension maximum isometric strength, and reduced cardiorespiratory demand during steady-state walking. HHH was the only prescription that led to increased muscle expression of pro-inflammatory cytokine receptors and this was associated with a lesser gain in TMM and total body lean mass compared to HLH. The HL prescription induced minimal muscle regrowth and generally lesser gains in muscle performance vs. the other prescriptions. The HLH prescription offers distinct advantages over the other doses, while the HL program is subpar. Although limited by a relatively small sample size, we conclude from this randomized dose-response trial that older adults benefit greatly from 2d/week high-intensity RT, and may further benefit from inserting an additional weekly bout of low-load, explosive RT. ClinicalTrials.govNCT02442479.


Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children.
Certain phenols and phthalates are used in many consumer products including personal care products (PCPs). We aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. Our study relied on a subsample of 90 adult-child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24h and biomarker concentrations. Benzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children.


A £30 million pledge for children's palliative care leads to a race against the clock to secure funding.
The government recently announced that up to £30 million would be made available to the children's palliative care sector in England, on the condition that the money is spent by March 2011. The challenge now is to ensure this money is spent on sustainable projects to develop children's palliative care before time runs out.


Implementing Rubric-Based Peer Review for Video Microlecture Design in Health Professions Education.
Efficient and effective instructional materials designed for asynchronous learning are increasingly important in health professions curricula. Video microlectures are an effective instructional method, but many faculty lack training in applying best-practice multimedia principles to development of their own recorded microlectures. Here we report a rubric designed for use in a peer-review process to evaluate and improve microlectures. The one-page rubric provides a framework for application of multimedia principles and cognitive load theory to microlecture design. Quality improvement of microlectures following redesign according to rubric elements is supported by increased student viewership, which coincided with higher rubric peer review scores.


Effects of monoamine oxidase inhibitors on the diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in C57BL/6 mice.
Diethyldithiocarbamate (DDC) is known to potentiate the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The aims of the present study were to provide biochemical, pathological and behavioral evidence for the degeneration of dopamine (DA) neurons in C57BL/6 strain mice treated simultaneously with DDC and MPTP, and to evaluate the effects of monoamine oxidase (MAO) inhibitors on DDC-enhanced MPTP toxicity. DDC (400 mg/kg)+ MPTP (30 mg/kg) treatment decreased significantly the levels of striatal DA and its metabolites and induced bradykinesia. In mice treated with DDC+MPTP, degenerative areas were found in striatum, substantia nigra and tuberculum olfactorium by assessment of the binding of [125I]RTI-121, a DA transporter ligand. Pretreatment with a MAO-B inhibitor selegiline prior to the administration of DDC and MPTP completely inhibited the decrease in the levels of DA and its metabolites, bradykinesia and degeneration of dopaminergic nerve terminals. In contrast, the protective action of clorgyline was not clearly observed in this model system.


Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance.
Heterochromatin is characterized by dimethylated or trimethylated histone H3 Lys9 (H3K9me2 or H3K9me3, respectively) and is found at transposable elements, satellite repeats and genes, where it ensures their transcriptional silencing. The histone methyltransferases (HMTs) that methylate H3K9 - in mammals Suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, G9A and G9A-like protein (GLP) - and the 'readers' of H3K9me2 or H3K9me3 are highly conserved and show considerable redundancy. Despite their redundancy, genetic ablation or mistargeting of an individual H3K9 methyltransferase can correlate with impaired cell differentiation, loss of tissue identity, premature aging and/or cancer. In this Review, we discuss recent advances in understanding the roles of the known H3K9-specific HMTs in ensuring transcriptional homeostasis during tissue differentiation in mammals. We examine the effects of H3K9-methylation-dependent gene repression in haematopoiesis, muscle differentiation and neurogenesis in mammals, and compare them with mechanistic insights obtained from the study of model organisms, notably Caenorhabditis elegans and Drosophila melanogaster. In all these organisms, H3K9-specific HMTs have both unique and redundant roles that ensure the maintenance of tissue integrity by restricting the binding of transcription factors to lineage-specific promoters and enhancer elements.


Characterization of protonated phospholipids as fragile ions in quadrupole ion trap mass spectrometry.
Some ions exhibit "ion fragility" in quadrupole ion trap mass spectrometry (QIT-MS) during mass analysis with resonance ejection. In many cases, different ions generated from the same compound exhibit different degrees of ion fragility, with some ions (e.g., the [M+H](+) ion) stable and other ions (e.g., the [M+Na](+) ion) fragile. The ion fragility for quadrupole ion trap (QIT) mass spectrometry (MS) for protonated and sodiated ions of three phospholipids, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, PC (16:0/16:0), 1,2-dipalmitoyl-sn-glycero-3-phophoethanolamine, PE (16:0/16:0), and N-palmitoyl-D-erythro-sphingosylphosphorylcholine, SM (d18:1/16:0), was determined using three previously developed experiments: 1) the peak width using a slow scan speed, 2) the width of the isolation window for efficient isolation, and 3) the energy required for collision-induced dissociation. In addition, ion fragility studies were designed and performed to explore a correlation between ion fragility in QIT mass analysis and ion fragility during transport between the ion source and the ion trap. These experiments were: 1) evaluating the amount of thermal-induced dissociation as a function of heated capillary temperature, and 2) determining the extent of fragmentation occurring with increasing tube lens voltage. All phospholipid species studied exhibited greater ion fragility as protonated species in ion trap mass analysis than as sodiated species. In addition, the protonated species of both SM (d18:0/16:0) and PC (16:0/16:0) exhibited greater tendencies to fragment at higher heated capillary temperatures and high tube lens voltages, whereas the PE (16:0/16:0) ions did not appear to exhibit fragility during ion transport.


Unliganded thyroid hormone receptor regulates metamorphic timing via the recruitment of histone deacetylase complexes.
Anuran metamorphosis involves a complex series of tissue transformations that change an aquatic tadpole to a terrestrial frog and resembles the postembryonic perinatal period in mammals. Thyroid hormone (TH) plays a causative role in amphibian metamorphosis and its effect is mediated by TH receptors (TRs). Molecular analyses during Xenopus development have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes and causes histone deacetylation at target genes while liganded TR leads to increased histone acetylations and altered histone methylations at target genes. Transgenic studies involving mutant TR-cofactors have shown that corepressor recruitment by unliganded TR is required to ensure proper timing of the onset of metamorphosis while coactivator levels influence the rate of metamorphic progression. In addition, a number of factors that can influence cellular free TH levels appear to contribute the timing of metamorphic transformations of different organs by regulating the levels of unliganded vs. liganded TR in an organ-specific manner. Thus, the recruitment of HDAC-containing corepressor complexes by unliganded TR likely controls both the timing of the initiation of metamorphosis and the temporal regulation of organ-specific transformations. Similar mechanisms likely mediate TR function in mammals as the maturation of many organs during postembryonic development is dependent upon TH and resembles organ metamorphosis in amphibians.


Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways.
Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine, were found to enhance neurite outgrowth induced by nerve growth factor (NGF) in PC12 cells. These drugs increased the number of cells bearing neurites, the length of primary neurites, and the size of the cell body of NGF-differentiated PC12 cells. In addition, the drugs induced sprouting of neurite-like processes in PC12 cells in the absence of NGF. Olanzapine, quetiapine, and clozapine enhanced the phosphorylation of Akt and ERK in combination with NGF, and specific inhibitors of these pathways attenuated these effects. Pretreatment of cells overnight with pertussis toxin had no effect on NGF-induced differentiation but significantly decreased the effects of the antipsychotic drugs on neurite outgrowth, suggesting that Gi/Go-coupled receptors are involved in the response to drug. A better understanding of the mechanisms underlying the effects of the second-generation drugs might suggest new therapeutic targets for enhancement of neurite outgrowth.


Multi-domain convolutional neural network (MD-CNN) for radial reconstruction of dynamic cardiac MRI.
Cardiac MR cine imaging allows accurate and reproducible assessment of cardiac function. However, its long scan time not only limits the spatial and temporal resolutions but is challenging in patients with breath-holding difficulty or non-sinus rhythms. To reduce scan time, we propose a multi-domain convolutional neural network (MD-CNN) for fast reconstruction of highly undersampled radial cine images. MD-CNN is a complex-valued network that processes MR data in k-space and image domains via k-space interpolation and image-domain subnetworks for residual artifact suppression. MD-CNN exploits spatio-temporal correlations across timeframes and multi-coil redundancies to enable high acceleration. Radial cine data were prospectively collected in 108 subjects (50 ± 17 y, 72 males) using retrospective-gated acquisition with 80%:20% split for training/testing. Images were reconstructed by MD-CNN and k-t Radial Sparse-Sense(kt-RASPS) using an undersampled dataset (14 of 196 acquired views; relative acceleration rate = 14). MD-CNN images were evaluated quantitatively using mean-squared-error (MSE) and structural similarity index (SSIM) relative to reference images, and qualitatively by three independent readers for left ventricular (LV) border sharpness and temporal fidelity using 5-point Likert-scale (1-non-diagnostic, 2-poor, 3-fair, 4-good, and 5-excellent). MD-CNN showed improved MSE and SSIM compared to kt-RASPS (0.11 ± 0.10 vs. 0.61 ± 0.51, and 0.87 ± 0.07 vs. 0.72 ± 0.07, respectively; P < .01). Qualitatively, MD-CCN significantly outperformed kt-RASPS in LV border sharpness (3.87 ± 0.66 vs. 2.71 ± 0.58 at end-diastole, and 3.57 ± 0.6 vs. 2.56 ± 0.6 at end-systole, respectively; P < .01) and temporal fidelity (3.27 ± 0.65 vs. 2.59 ± 0.59; P < .01). MD-CNN reduces the scan time of cine imaging by a factor of 23.3 and provides superior image quality compared to kt-RASPS.


Long-term epicardial ventricular pacing from endocardial bipolar pacemaker lead: perforation of right atrial wall.
One of the hazards of endocardial cardiac pacing is that the pacemaker lead may perforate the myocardial wall or interventricular septum although the incidence of such perforations is believed to be small. This paper describes what is believed to be a unique case in which a pacemaker lead perforated the atrial wall at implantation (or possibly shortly afterwards) and yet gave satisfactory right ventricular epicardial pacing for more than five years. The perforation was discovered during a routine postmortem examination but earlier lateral x-ray examinations would probably have identified the abnormal position of the electrodes. Moreover, the present implantation technique would not have allowed perforation of the atrial wall at implantation to go undetected.