Spectral properties of induced and evoked gamma oscillations in human early visual cortex to moving and stationary stimuli.
In two experiments, magnetoencephalography (MEG) was used to investigate the effects of motion on gamma oscillations in human early visual cortex. When presented centrally, but not peripherally, stationary and moving gratings elicited several evoked and induced response components in early visual cortex. Time-frequency analysis revealed two nonphase locked gamma power increases-an initial, rapidly adapting response and one sustained throughout stimulus presentation and varying in frequency across observers from 28 to 64 Hz. Stimulus motion raised the sustained gamma oscillation frequency by a mean of approximately 10 Hz. The largest motion-induced frequency increases were in those observers with the lowest gamma response frequencies for stationary stimuli, suggesting a possible saturation mechanism. Moderate gamma amplitude increases to moving versus stationary stimuli were also observed but were not correlated with the magnitude of the frequency increase. At the same site in visual cortex, sustained alpha/beta power reductions and an onset evoked response were observed, but these effects did not change significantly with the presence of motion and did not correlate with the magnitude of gamma power changes. These findings suggest that early visual areas encode moving and stationary percepts via activity at higher and lower gamma frequencies, respectively.


Novel method to detect a motif of local structures in different protein conformations.
In order to detect a motif of local structures in different protein conformations, the Delaunay tessellation is applied to protein structures represented by C(alpha) atoms only. By the Delaunay tessellation the interior space of the protein is uniquely divided up into Delaunay tetrahedra whose vertices are the C(alpha) atom positions. Some edges of the tetrahedra are virtual bonds connecting adjacent residues' C(alpha) atoms along the polypeptide chain and others indicate interactions between residues nearest neighbouring in space. The rules are proposed to assign a code, i.e., a string of digits, to each tetrahedron to characterize the local structure constructed by the vertex residues of one relevant tetrahedron and four surrounding it. Many sets comprised of the local structures with the same code are obtained from 293 proteins, each of which has relatively low sequence similarity with the others. The local structures in each set are similar enough to each other to represent a motif. Some of them are parts of secondary or supersecondary structures, and others are irregular, but definite structures. The method proposed here can find motifs of local structures in the Protein Data Bank much more easily and rapidly than other conventional methods, because they are represented by codes. The motifs detected in this method can provide more detailed information about specific interactions between residues in the local structures, because the edges of the Delaunay tetrahedra are regarded to express interactions between residues nearest neighbouring in space.


Supramolecular macrocycles reversibly assembled by Te(…)O chalcogen bonding.
Organic molecules with heavy main-group elements frequently form supramolecular links to electron-rich centres. One particular case of such interactions is halogen bonding. Most studies of this phenomenon have been concerned with either dimers or infinitely extended structures (polymers and lattices) but well-defined cyclic structures remain elusive. Here we present oligomeric aggregates of heterocycles that are linked by chalcogen-centered interactions and behave as genuine macrocyclic species. The molecules of 3-methyl-5-phenyl-1,2-tellurazole 2-oxide assemble a variety of supramolecular aggregates that includes cyclic tetramers and hexamers, as well as a helical polymer. In all these aggregates, the building blocks are connected by Te(…)O-N bridges. Nuclear magnetic resonance spectroscopic experiments demonstrate that the two types of annular aggregates are persistent in solution. These self-assembled structures form coordination complexes with transition-metal ions, act as fullerene receptors and host small molecules in a crystal.


Antibiotic Treatment Drives the Diversification of the Human Gut Resistome.
Despite the documented antibiotic-induced disruption of the gut microbiota, the impact of antibiotic intake on strain-level dynamics, evolution of resistance genes, and factors influencing resistance dissemination potential remains poorly understood. To address this gap we analyzed public metagenomic datasets from 24 antibiotic treated subjects and controls, combined with an in-depth prospective functional study with two subjects investigating the bacterial community dynamics based on cultivation-dependent and independent methods. We observed that short-term antibiotic treatment shifted and diversified the resistome composition, increased the average copy number of antibiotic resistance genes, and altered the dominant strain genotypes in an individual-specific manner. More than 30% of the resistance genes underwent strong differentiation at the single nucleotide level during antibiotic treatment. We found that the increased potential for horizontal gene transfer, due to antibiotic administration, was ∼3-fold stronger in the differentiated resistance genes than the non-differentiated ones. This study highlights how antibiotic treatment has individualized impacts on the resistome and strain level composition, and drives the adaptive evolution of the gut microbiota.


Enhanced hydrogen evolution reaction on hybrids of cobalt phosphide and molybdenum phosphide.
Production of hydrogen from water electrolysis has stimulated the search of sustainable electrocatalysts as possible alternatives. Recently, cobalt phosphide (CoP) and molybdenum phosphide (MoP) received great attention owing to their superior catalytic activity and stability towards the hydrogen evolution reaction (HER) which rivals platinum catalysts. In this study, we synthesize and study a series of catalysts based on hybrids of CoP and MoP with different Co/Mo ratio. The HER activity shows a volcano shape and reaches a maximum for Co/Mo = 1. Tafel analysis indicates a change in the dominating step of Volmer-Hyrovský mechanism. Interestingly, X-ray diffraction patterns confirmed a major ternary interstitial hexagonal CoMoP2 crystal phase is formed which enhances the electrochemical activity.


Absorption and transport of cobalamin (vitamin B12).
This review apprises the reader of recent advances in cobalamin absorption and transport since 1970. This field has been of interest to gastroenterologists, hematologists, and biochemists as well as nutritionists. Clinical conditions leading to cobalamin deficiency present especially to the first two of these specialties. Many recent advances involve biochemical definition of the specific transport proteins themselves. Full understanding of the multiple clinical conditions associated with cobalamin deficiency requires some knowledge of these proteins. We do not discuss every paper in the field, especially the early literature (see 47, 61, 150). Despite rapid strides in understanding the mechanism of absorption and transport of cobalamin both in prokaryotic and eukaryotic cells, the complete sequence of events during cellular absorption at the plasma membrane level and events in the cells that mediate intracellular movement of cobalamin have not been elucidated completely. Here we emphasize the current state of knowledge about cobalamin absorption and transport in man and other mammalian systems, particularly the physiological role and biochemical nature of proteins involved (intrinsic factor, intrinsic factor-cobalamin receptor, transcobalamins).


Targeting the Pim kinases in multiple myeloma.
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.


The effect of angiotensin-I converting enzyme inhibition on insulin action in healthy volunteers.
Acute hyperinsulinaemia, achieving insulin levels within the physiological range, induces sodium retention. At the same time an activation of the renin-angiotensin system occurs, with a rise in plasma renin activity (PRA) and angiotensin-II level but no change in plasma aldosterone. After administration of higher, pharmacological doses of insulin an increase in systolic blood pressure and heart rate can also be observed, while further increases in PRA and angiotensin-II are noted. To determine whether angiotensin-II is involved in observed insulin actions, we studied the renal and cardiovascular effects of three dosages of insulin (50 (Ins I), 300 (Ins II) and 500 (Ins III) mU kg-1 h-1) in healthy subjects after one week of treatment with the angiotensin-I converting enzyme inhibitor enalapril (10 mg twice a day), using the euglycaemic clamp technique. Control data were obtained from two previously conducted experiments in the same subjects, one with infusion of insulin and one with the insulin solvent only. The effect of insulin on fractional sodium excretion, blood pressure and heart rate was unaffected by enalapril, which precludes any involvement of the renin-angiotensin system with regard to these aspects of insulin action. Insulin sensitivity increased significantly during treatment with enalapril (with enalapril: Ins I: 11.3 +/- 3.0, Ins II: 20.0 +/- 3.4 and Ins III: 20.6 +/- 3.9 mg kg-1 min-1 glucose (mean +/- SD); without enalapril: Ins I: 8.7 +/- 2.3, Ins II: 13.7 +/- 3.0 and Ins III: 15.5 +/- 3.1 mg kg-1 min-1 glucose; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Peripheral blood manipulation significantly affects the result of dendritic cell monitoring.
It has been postulated that the plasmacytoid/myeloid dendritic cell ratio (pDC/mDC) reflects immune reactivity, and can therefore be used to monitor transplant recipients. We investigated the influence of Ficoll-Paque separation and PBMC cryopreservation on the pDC/mDC ratio and the expression of maturation markers, e.g. chemokine receptors (CKRs) CCR7, CXCR4, and CCR5, in comparison to fresh blood cells. Fractions of pDCs and mDCs, and CKR expression were measured by flow cytometry in fresh blood, in Ficoll-isolated PBMCs and in cryopreserved PBMCs from healthy individuals and kidney transplant recipients. Ficoll-isolation of PBMCs resulted in higher pDC/mDC ratios in both groups compared to fresh blood cells resulting from a relatively large increase in pDCs compared to mDCs. The pDC/mDC ratio increased further after cryopreservation of PBMCs from kidney transplant recipients. Ficoll-isolation and cryopreservation of PBMCs affected the proportion of mDCs and pDCs positive for CKRs, and their expression levels resulting in a more mature phenotype. In conclusion, the pDC/mDC ratio and pDC or mDC maturation status based on CKR expression, is dependent on manipulation of PBMCs. Therefore, fresh blood is preferable for monitoring purposes in transplant patients, as only these cells reflect the in vivo immune-status of patients accurately.


The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.
This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.


Involvement of polypyrimidine tract-binding protein (PTBP1) in maintaining breast cancer cell growth and malignant properties.
We have investigated some roles of splicing factor polypyrimidine tract-binding protein (PTBP1) in human breast cancer. We found that PTBP1 was upregulated in progressively transformed human mammary epithelial cells (HMECs), as well as in breast tumor cell lines compared with HMECs with finite growth potential and found that the level of PTBP1 correlated with the transformation state of HMECs. Knockdown of PTBP1 expression substantially inhibited tumor cell growth, colony formation in soft agar and in vitro invasiveness of breast cancer cell lines, a result similar to what we have reported in ovarian cancer. However, ectopic expression of PTBP1 (as a PTBP1-EGFP fusion protein) did not enhance the proliferation of immortalized HMEC. Rather, PTBP1 expression promoted anchorage-independent growth of an immortalized HMEC as assessed by increased colony formation in soft agar. In addition, we found that knockdown of PTBP1 expression led to upregulation of the expression of the M1 isoform of pyruvate kinase (PKM1) and increase of the ratio of PKM1 vs PKM2. PKM1 has been reported to promote oxidative phosphorylation and reduce tumorigenesis. Correspondingly, we observed increased oxygen consumption in PTBP1-knockdown breast cancer cells. Together, these results suggest that PTBP1 is associated with breast tumorigenesis and appears to be required for tumor cell growth and maintenance of transformed properties. PTBP1 exerts these effects, in part, by regulating the splicing of pyruvate kinase, and consequently alters glucose metabolism and contributes to the Warburg effect.


Photogrammetric analysis of the articular surface of the distal radius.
Three-dimensional measurements made using photogrammetry have recently gained popularity with the development of real-time detection facilities and up-to-date equipment. The modelling of human bones presents a particular challenge as the measurements required are difficult to obtain, especially from uneven surfaces. In this study, the articular surfaces of 12 radius bones were evaluated using photogrammetry to obtain three-dimensional coordinates of certain points. Morphometric characteristics of the digital topography of the articular surface were analysed using three-dimensional data from more than 200 points for each specimen. The coronal plane curve, from the tip of the styloid process to the centre of the distal radioulnar articular notch, was found to be similar to the fourth degree polynomial function. A mathematical expression representing the sagittal curve passing through scapholunate border could not be found. Close-range photogrammetry is a safe and precise technique that can provide reliable, reproducible and accurate data for evaluating complex morphological surfaces.


[Circulating endothelial cells--markers of blood vessel lesions in patients with diffuse liver disease].
The increased level of the circulating endothelial cells (CEC) is in direct dependance with a degree of an endothelial trauma. We defined CEC in blood (cells x 104/L) of 67 adults and children with acute and chronic viral hepatitis (A and B) and healthy volontiars. The author obtained reliable results of increased CEC in all groups consisting of patients with diffuse liver deseases (17,4+/-6,5 and 19,8+/-8,4) in comparison with control groups (3,8+/-1,9 and 3,8+/-1,2) thus CEC can be of practical value as a marker of microvessel lesions of the liver. Endotheliocytemia testifies to be a factor during endothelial trauma in pathogenesis of diffuse liver disease.


Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people.
The aetiology of metabolic syndrome is complex, being determined by the interplay of both genetic and environmental factors. The aim of this study was to identify genetic polymorphisms that confer susceptibility to metabolic syndrome, to allow prediction of genetic risk for this condition. The study population comprised 2417 unrelated Japanese subjects (1522 with metabolic syndrome and 895 controls). The genotypes for 44 polymorphisms of 31 candidate genes related to lipid metabolism were determined using a combination of PCR and sequence-specific oligonucleotide probes with suspension array technology. The chi(2) test and subsequent multivariate logistic regression analysis with adjustment for age, sex and smoking status found that the-3A-->G and 553G-->T (Gly185Cys) polymorphisms of APOA5, the 2052T-->C (Val653Val) and 1866C-->T (Asn591Asn) polymorphisms of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4 and the 1014T-->A polymorphism of C1QTNF5 were significantly (false discovery rate <0.05) associated with the prevalence of metabolic syndrome, with the variant alleles of APOA5 and C1QTNF5 representing risk factors for and those of LDLR and CYP3A4 being protective against this condition. Serum levels of triglycerides and high-density lipoprotein (HDL) cholesterol differed significantly (p<0.05) among APOA5 genotypes; the serum level of HDL cholesterol differed among LDLR genotypes; and the fasting plasma glucose level and body mass index differed between CYP3A4 and C1QTNF5 genotypes, respectively. APOA5, LDLR, CYP3A4 and C1QTNF5 are susceptibility loci for metabolic syndrome in Japanese people. Genotypes for these polymorphisms may prove informative for prediction of genetic risk for metabolic syndrome.


Combined Metagratings for Efficient Broad-Angle Scattering Metasurface.
Spectrally controlled diffusion and reflection of light are key operations for light management in many optical devices. Integration of this operation in complex nanophotonic devices requires a 2D interface that provides tailored spectrum and directivity control. Here, we present a metagrating superstructure that realizes a resonant light reflector with tailored angular scattering profile. Millimeter-sized metasurfaces are built from arrays of combined supercells of 20-50 μm, composed of 5-7 differently pitched metagratings that tailor at will and with large efficiency the angular response. Each supercell is composed of one or more Si Mie resonators, arranged in a periodic array above an Ag back plane and tailored to resonantly scatter light at 650 nm into only the ±1 diffraction orders with very high efficiency. By varying the pitch and supercell design, we can tailor the overall metasurface reflection profile with large flexibility, realizing a broad-angle Lambertian-type scattering metasurface, as well as a large-angle (35-75°) scattering metasurface, both with resonant optical scattering efficiencies above 70%. These ultrathin structures, fabricated using thin-film deposition, electron beam lithography, and reactive ion etching, can find applications for light trapping and spectrum splitting in solar cells and other devices.


Characterization of light chain and light chain constant region fragment mRNAs in MPC 11 mouse myeloma cells and variants.
Cultured MPC 11 mouse myeloma cells synthesize not only gamma2b heavy and kappa light chains but also a carboxyl terminal (constant region) fragment of kappa light chain. In vitro translational analysis of total cytoplasmic and microsomal RNA indicates that these cells contain RNA which directs synthesis of both a light chain precursor and a light chain fragment precursor. Variant clones which do not synthesize either heavy or light chains continue to synthesize the light chain fragment. One such "nonproducing" variant was studied in detail. It does not contain translatable mRNA for the intact light chain but does contain RNA which is translated into the light chain fragment precursor. Nucleic acid hybridization analysis with a cDNA probe specific for the constant region of kappa light chains revealed that microsomal RNA from the wild-type cell contains both 14S and a 10S species of kappa specific RNA, whereas the variant contains only the 10S species. Translational analysis of these same RNAs indicates that the 14S species codes for the light chain precursor, while the 10S RNA codes for the light chain fragment precursor.


A Retrospective Analysis of a Consolidation of Urology Practices, and the Resulting Physician Productivity in the Provision of Urologic Care.
In recent decades, the number of small medical practices has decreased, allowing for larger conglomerates to form. Although the literature includes several studies looking at physician productivity in small practices as opposed to larger groups, almost none have been performed in recent years. This study looks at a consolidated urology practice that has combined many physicians from many smaller groups, and how it is performing in terms of physician productivity. Productivity measures from each physician's initial years in the larger practice were analyzed, demonstrating that the physicians in the larger practice become significantly more productive during their time in the practice. This productivity can be attributed to a variety of factors, including strong physician leadership, a superior management team, a steadfast support staff, and well-equipped facilities.


Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines.
Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell-based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.


Cognitive adaptation to the experience of social and cultural diversity.
Diversity is a defining characteristic of modern society, yet there remains considerable debate over the benefits that it brings. The authors argue that positive psychological and behavioral outcomes will be observed only when social and cultural diversity is experienced in a way that challenges stereotypical expectations and that when this precondition is met, the experience has cognitive consequences that resonate across multiple domains. A model, rooted in social categorization theory and research, outlines the preconditions and processes through which people cognitively adapt to the experience of social and cultural diversity and the resulting cross-domain benefits that this brings. Evidence is drawn from a range of literatures to support this model, including work on biculturalism, minority influence, cognitive development, stereotype threat, work group productivity, creativity, and political ideology. The authors bring together a range of differing diversity experiences and explicitly draw parallels between programs of research that have focused on both perceiving others who are multicultural and being multicultural oneself. The findings from this integrative review suggest that experiencing diversity that challenges expectations may not only encourage greater tolerance but also have benefits beyond intergroup relations to varied aspects of psychological functioning.


Impact of less social connectedness and fear of COVID-19 test on employees task performance: A multi-mediation model.
The core objective of this study is to examine the impact of less social connectedness and testing fear on employee health. This study also investigates the mediating role of psychological strain between the relationship of less social connectedness, testing fear and employee health. Furthermore, this study also assesses the impact of employee health on employee performance. The study's target audience consisted of employees in the electronics industry in China. The convenience sample method was used in this study to collect data from respondents. Data analysis of this study was performed by using the structural equation modeling technique. The statistical software used for data analysis is Smart PLS 3. The results of this study show that less COVID-19 testing fear has a negatively significant impact on employee health, but less social connectedness has not significant direct impact on employee health. Furthermore, psychological strain was discovered to mediate the relationship between less social connectedness and employee health and testing fear and employee health. In addition, this impact of employee health on employee performance was found significant. This study provides theoretical and practical implications. In the context of practical implications, this study provides valuable insights for the organizational management to develop a healthy and positive working environment and adopt healthy behavior among their employees which ultimately foster their job performance.


Antifertility effect of calcium channel blockers on male rats: association with oxidative stress.
Calcium ions are vital in many biologic processes including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, haemostasis, bone metabolism and sperm functions. Calcium channel blockers (CCB) appear to have a reversible anti-fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis. While the effects of CCB on male reproductive function have been investigated, less information is available regarding other reproductive indices and the underlying mechanism in the pathogenesis of male reproductive dysfunction. Therefore, the involvement of oxidative mechanisms in the adverse manifestation induced by CCB on male reproductive functions is investigated in this study. For this purpose, lipid peroxidation; enzymatic antioxidants such as superoxide dismutase, catalase and glutathione reduced; epididymal sperm count, motility; histopathology of the testes, epididymis, seminal vesicle, prostate glands; and reproductive performance were determined. CCB administration in rats causes significant oxidative stress in the male reproductive milieu in term of increase in malondialdehyde (MDA) level and a concomitant decrease in catalase, superoxide dismutase and reduced glutathione enzyme activities in the testes. In addition, CCB treatment significantly decreased the sperm count, sperm motility, fertility index, implantation count, and litter size in this study. There is substantial evidence that CCB induces significant oxidative stress in the testes, which appears to be responsible for the adverse effects of decreased sperm count and motility ultimately leading to reduced fertility in rats.


Carboxymethyl mungbean starch as a new pharmaceutical gelling agent for topical preparation.
An application of carboxymethyl mungbean starch (CMMS) as a gelling agent in the topical pharmaceutical preparation was investigated. CMMS was prepared using specific conditions that yielded a high-viscosity product. Polymer gels and gel bases were prepared at 1-10% (wt/wt), and physicochemical studies were carried out in comparison with four standard gelling agents: carbopol 940 (CP), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), and sodium carboxymethyl cellulose (SCMC). Piroxicam was used as a model drug to study the drug release profile of the gel formulations. The tackless, greaseless, and transparent CMMS gels exhibited pseudoplastic behavior with thixotropy at concentrations less than 5% (wt/wt). At a concentration of 5% (wt/wt) and higher, the semisolid gels showed plastic flow characteristics. Viscosity and X-ray diffraction results indicated a good compatibility between CMMS and the acidic piroxicam. No precipitation of piroxicam or phase separation was observed during a stability test. The release rate of piroxicam from 3% (wt/wt) CMMS gel was 1,003.79 +/- 105.08 microg/cm(2), which was comparable with 947.66 +/- 133.70 microg/cm(2) obtained from a 0.5% (wt/wt) carbopol formulation. The release profiles of both formulations were consistent and remained unchanged after 2 months' storage. Viscosity played an important role in controlling the release rate of low concentration CMMS formulations by regulating the drug diffusion. At a concentration of 5% (wt/wt) CMMS and higher, the release rates of piroxicam were not significantly different. A plausible explanation based on the nature of the gelling agent was proposed. Stability and drug release profiles of CMMS and commercial gelling agents were compared. The results supported the potential use of CMMS as a new, effective gelling agent for topical gel preparation.


Triangular Ag-Pd alloy nanoprisms: rational synthesis with high-efficiency for electrocatalytic oxygen reduction.
We report the generation of triangular Ag-Pd alloy nanoprisms through a rationally designed synthetic strategy based on silver nanoprisms as sacrificial templates. The galvanic replacement between Ag nanoprisms and H2PdCl4 along with co-reduction of Ag(+)/Pd(2+) is responsible for the formation of final prismatic Ag-Pd alloy nanostructures. Significantly, these Ag-Pd alloy nanoprisms exhibited superior electrocatalytic activity for the oxygen reduction reaction (ORR) as compared with the commercial Pd/C catalyst. Such a high catalytic activity is attributed to not only the alloyed Ag-Pd composition but also the dominant {111} facets of the triangular Ag-Pd nanoprisms. This work demonstrates the rational design of bimetallic alloy nanostructures with control of selective crystal facets that are critical to achieve high catalytic activity for fuel cell systems.


A kinetic analysis of discus-throwing techniques.
The purposes of this study were to investigate (1) the relationships between official distance and selected ground reaction measures during discus throwing; and (2) the relationships between selected ground reactions and selected lower extremity joint kinetics. Three high-speed video cameras and three force plates were used to collect three-dimensional videographic and force plate data in this study. An inverse dynamic model was used to determine the lower extremity kinetics. Multiple regression analyses were conducted to determine relationships of the selected kinematic and kinetic measures with the official distance. Official distance was significantly correlated with ground reaction forces on the left foot during the first single-support phase, on the right foot during the second single-support phase and delivery phase, and on the left foot during the delivery phase. Also, the right-hip extension and internal rotation moments and left-knee extension moment during the delivery phase were significantly correlated with official distance. These results suggest that discus throwers should drive vigorously forward during the first single-support phase and increase the landing impact force on the right foot after flight. Also they should increase forward and rightward ground reaction force on the right foot and backward and vertical force on the left foot by powerful right-hip extension and internal rotation and left-knee extension during the delivery phase. These results provide critical information regarding the training of discus-throwing techniques, and the direction of future biomechanical studies on this event.


PATAN-domain regulators interact with the Type IV pilus motor to control phototactic orientation in the cyanobacterium Synechocystis.
Many prokaryotes show complex behaviors that require the intricate spatial and temporal organization of cellular protein machineries, leading to asymmetrical protein distribution and cell polarity. One such behavior is cyanobacterial phototaxis which relies on the dynamic localization of the Type IV pilus motor proteins in response to light. In the cyanobacterium Synechocystis, various signaling systems encompassing chemotaxis-related CheY- and PatA-like response regulators are critical players in switching between positive and negative phototaxis depending on the light intensity and wavelength. In this study, we show that PatA-type regulators evolved from chemosensory systems. Using fluorescence microscopy and yeast two-hybrid analysis, we demonstrate that they localize to the inner membrane, where they interact with the N-terminal cytoplasmic domain of PilC and the pilus assembly ATPase PilB1. By separately expressing the subdomains of the response regulator PixE, we confirm that only the N-terminal PATAN domain interacts with PilB1, localizes to the membrane, and is sufficient to reverse phototactic orientation. These experiments established that the PATAN domain is the principal output domain of PatA-type regulators which we presume to modulate pilus extension by binding to the pilus motor components.


Adenylyl cyclase signalling complexes - Pharmacological challenges and opportunities.
Signalling pathways involving the vital second messanger, cAMP, impact on most significant physiological processes. Unsurprisingly therefore, the activation and regulation of cAMP signalling is tightly controlled within the cell by processes including phosphorylation, the scaffolding of protein signalling complexes and sub-cellular compartmentalisation. This inherent complexity, along with the highly conserved structure of the catalytic sites among the nine membrane-bound adenylyl cyclases, presents significant challenges for efficient inhibition of cAMP signalling. Here, we will describe the biochemistry and cell biology of the family of membrane-bound adenylyl cyclases, their organisation within the cell, and the nature of the cAMP signals that they produce, as a prelude to considering how cAMP signalling might be perturbed. We describe the limitations associated with direct inhibition of adenylyl cyclase activity, and evaluate alternative strategies for more specific targeting of adenylyl cyclase signalling. The inherent complexity in the activation and organisation of adenylyl cyclase activity may actually provide unique opportunities for selectively targeting discrete adenylyl cyclase functions in disease.


The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.
To describe a framework for people making and using evidence-informed health system and public health recommendations and decisions. We developed the GRADE Evidence to Decision (EtD) framework for health system and public health decisions as part of the DECIDE project, in which we simultaneously developed frameworks for these and other types of healthcare decisions, including clinical recommendations, coverage decisions and decisions about diagnostic tests. Building on GRADE EtD tables, we used an iterative approach, including brainstorming, consultation of the literature and with stakeholders, and an international survey of policy-makers. We applied the framework to diverse examples, conducted workshops and user testing with health system and public health guideline developers and policy-makers, and observed and tested its use in real-life guideline panels. All the GRADE EtD frameworks share the same basic structure, including sections for formulating the question, making an assessment and drawing conclusions. Criteria listed in the assessment section of the health system and public health framework cover the important factors for making these types of decisions; in addition to the effects and economic impact of an option, the priority of the problem, the impact of the option on equity, and its acceptability and feasibility are important considerations that can inform both whether and how to implement an option. Because health system and public health interventions are often complex, detailed implementation considerations should be made when making a decision. The certainty of the evidence is often low or very low, but decision-makers must still act. Monitoring and evaluation are therefore often important considerations for these types of decisions. We illustrate the different components of the EtD framework for health system and public health decisions by presenting their application in a framework adapted from a real-life guideline. This framework provides a structured and transparent approach to support policy-making informed by the best available research evidence, while making the basis for decisions accessible to those whom they will affect. The health system and public health EtD framework can also be used to facilitate dissemination of recommendations and enable decision-makers to adopt, and adapt, recommendations or decisions.


Genetics of late-onset Alzheimer's disease: update from the alzgene database and analysis of shared pathways.
The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database.


In-vitro antimicrobial activity of Lawsonia inermis Linn (henna). A pilot study on the Omani henna.
To investigate the antimicrobial activity of henna's fresh and dry leaves and seeds obtained from Oman. This study was carried out at the College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman during the period January-June, 2004. Crude extracts of fresh and dry leaves and seeds were investigated for their antimicrobial activity against 3 standard bacterial strains namely: Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Eleven different bacterial strains were obtained from patients attending the Sultan Qaboos University Hospital, Muscat, Sultanate of Oman. In addition, one Candida albicans (C. albicans) species was used for testing the antifungal activity of the Omani henna sample. All fresh and dry leaves and seeds of the Omani henna demonstrated antibacterial activity against all 3 standard strains and the 11 patients' isolated strains. Henna dry leaves demonstrated the best in-vitro antimicrobial activity and in particular against Shigella sonnei. However, henna fresh and dry seeds failed to show any activity against C. albicans. Omani henna does possess, in-vitro antibacterial activity against a wide spectrum of bacterial strains and C. albicans.


Nitrous oxide accumulation in soils from riparian buffers of a coastal plain watershed carbon/nitrogen ratio control.
Riparian buffers are used throughout the world for the protection of water bodies from nonpoint-source nitrogen pollution. Few studies of riparian or treatment wetland denitrification consider the production of nitrous oxide (N2O). The objectives of this research were to ascertain the level of potential N2O production in riparian buffers and identify controlling factors for N2O accumulations within riparian soils of an agricultural watershed in the southeastern Coastal Plain of the USA. Soil samples were obtained from ten sites (site types) with different agronomic management and landscape position. Denitrification enzyme activity (DEA) was measured by the acetylene inhibition method. Nitrous oxide accumulations were measured after incubation with and without acetylene (baseline N2O production). The mean DEA (with acetylene) was 59 microg N2O-N kg(-1) soil h(-1) for all soil samples from the watershed. If no acetylene was added to block conversion of N2O to N2, only 15 microg N2O-N kg(-1) soil h(-1) were accumulated. Half of the samples accumulated no N2O. The highest level of denitrification was found in the soil surface layers and in buffers impacted by either livestock waste or nitrogen from legume production. Nitrous oxide accumulations (with acetylene inhibition) were correlated to soil nitrogen (r2=0.59). Without acetylene inhibition, correlations with soil and site characteristics were lower. Nitrous oxide accumulations were found to be essentially zero, if the soil C/N ratios>25. Soil C/N ratios may be an easily measured and widely applicable parameter for identification of potential hot spots of N2O productions from riparian buffers.


Volume regulation of natural killer cells under hypotonic stress: comparison with T and B cell subpopulations.
In response to hypotonic stress, human T and B cells vary in the ability to adjust their volume. Whereas T cells exhibit a regulatory volume decrease (RVD) under these conditions, B cells do not. We studied the ability of peripheral blood-derived natural killer (NK) cells to regulate their volume in this way. Percoll density gradient purified NK subpopulation showed variable RVD which suggested the presence of mixtures of regulatory and non-regulatory cells within these subgroups. Further purification by flow cytometry into Leu 7+ and Leu 11+ cells showed that these NK cells displayed RVD similar to thymocytes but distinct from B cells and more mature T cells. These data support the hypothesis that NK cells may be derived from T cell precursors which, upon differentiation to NK cells, retain the RVD characteristic of pre-T cells. This finding may also be useful in further characterizing neoplastic clones which display NK-like activity but phenotypic heterogeneity.


Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders.
Benzodiazepine drugs may impair breathing during sleep, leading to the development of sleep-disordered breathing or, in subjects with sleep apnoea, an increase in the severity of pre-existing apnoeas. Flumazenil is a selective benzodiazepine-antagonist. We hypothesized that endogenous ligands of benzodiazepine receptors might contribute to the pathogenesis of obstructive sleep apnoea syndrome (OSAS) and that the intensity of OSAS could, therefore, be reduced by flumazenil. Ten male patients (mean age 55 yrs, mean body mass index 42.4 kg.m-2, mean apnoea index (AI) 53.5 and mean respiratory disturbance index (RDI) 74.2) were investigated. None of the patients had been treated for OSAS prior to the study. The study design was randomized, single-blind, placebo-controlled and cross-over. On the first or second study night, patients were randomly assigned to receive i.v. flumazenil (2 mg) or placebo (0.9% NaCl) between 01:00 and 01:30 h. Comparing the polysomnographic results of the placebo night and the flumazenil night in all 10 patients, no significant differences were found regarding obstructive events or sleep architecture. Accordingly, the data concerning sleep-disordered breathing and sleep stages during the 30 min period prior to and the 30 min period following the administration of flumazenil did not differ. It is concluded that endogenous ligands of the benzodiazepine receptor play no role in the pathogenesis of obstructive sleep apnoea syndrome, since respiratory and sleep data are not altered by flumazenil. Therefore, attempts to treat obstructive sleep apnoea syndrome with flumazenil do not seem to be warranted.


The University of Toronto liver transplant program.
The University of Toronto liver transplant program began in 1985 at a time when the procedure had already evolved from an experimental form of surgery to an accepted treatment for many forms of liver failure. The program was established not only to provide clinical care for patients but also to address academically the barriers which impeded success. The program brought together experts in medicine, surgery, pathology, and the basic sciences of immunology, virology and molecular biology. Our group has had a special interest in transplantation for viral hepatitis. We demonstrated the role of HBV DNA as a prospective factor in both viral recurrence and survival. We further studied a number of agents to prevent re-infection including PGE, HBIG and more recently lamivudine. Although the short-term results of transplantation for HCV appear excellent, reinfection of the graft and development of chronic hepatitis and cirrhosis may make long-term results problematic. Therefore, we have directed attention to studies of pathogenesis and treatment of HCV in liver transplantation. Our studies have demonstrated a unique role for ribavirin as an immunomodulatory agent which can benefit the course of posttransplant HCV. Future studies will examine combination therapy in an attempt to eradicate the virus. Our group also has been interested in PNF and FHF and have demonstrated a positive effect of PGE in this setting. As we look to the future, the greatest challenges facing transplantation are the shortage of organ donors and the toxic effects of long-term immunosuppression. Our group now has established research efforts both in tolerance induction and xenotransplantation which we feel are necessary to make transplantation an effective, universal treatment for end stage organ failure.


Effort-reward imbalance at work and weight changes in a nationwide cohort of workers in Denmark.
To investigate the relation between effort-reward imbalance (ERI) at work and subsequent weight changes. We included participants from a population-based cohort of workers in Denmark (mean age = 47 years, 54% women) with two (n = 9005) or three repeated measurements (n = 5710). We investigated the association between (a) ERI (ie, the mismatch between high efforts spent and low rewards received at work) at baseline and weight changes after a 2-year follow-up (defined as ≥5% increase or decrease in body mass index (BMI) vs stable), and (b) onset and remission of ERI and subsequent changes in BMI. Using multinomial logistic regression we calculated risk ratios (RR) and 95% confidence intervals (CI), adjusted for sex, age, education, cohabitation, migration background, and follow-up time. After 2 years, 15% had an increase and 13% a decrease in BMI. Exposure to ERI at baseline yielded RRs of 1.09 (95% CI: 0.95-1.25) and 1.04 (95% CI: 0.90-1.20) for the increase and decrease in BMI, respectively. There were no differences between sex and baseline BMI in stratified analyses. The onset of ERI yielded RRs of 1.04 (95% CI: 0.82-1.31) and 1.15 (95% CI: 0.84-1.57) for subsequent increase and decrease in BMI. The RRs for the remission of ERI and subsequent increase and decrease in BMI were 0.92 (95% CI: 0.71-1.20) and 0.78 (95% CI: 0.53-1.13), respectively. Of the ERI components, high rewards were associated with a lower risk of BMI increase. ERI was not a risk factor for weight changes. Future studies may investigate whether this result is generalizable to other occupational cohorts and settings.


Maximum acceptable speed based on physiological performance for different alignments of rural roads under the influence of visibility in fog-a driving simulator study.
Objectives: The goals of this research are to: (i) investigate whether the driver's physiological performance has a significant impact on driving speed choice, considering the visibility level under fog conditions and the horizontal and vertical alignment of a rural road; (ii) quantify the relationships among these variables; (iii) calculate the maximum acceptable speed that meets the driver's physiological tolerance threshold.Methods: A driving simulator study was conducted. A total of 30 participants were recruited, and each completed 5 driving simulator trials under varying visibility levels, radii of curvature and vertical grades. A multiple linear regression model was established to measure the association between normalized heart rate, driving speed, visibility, radius of curvature and gradient.Results: The results indicated that driving speed, visibility, radius of curvature and gradient all significantly affected the normalized heart rate. For instance, an increase in driving speed and vertical grade and a reduction in the radius of curvature are related to an increase in normalized heart rate. Moreover, an acceptable speed model that considered the driver's normalized heart rate was constructed, given the visibility level and horizontal and vertical alignment.Conclusions: The study shows a significant correlation between the drivers' physiological performance and his or her driving speed choice under the influence of visibility in fog. Given visibility conditions and road alignment parameters, we can calculate the maximum acceptable speed that meets the driver's physiological requirements. Such findings should be indicative of real-time traffic management that could reduce the crash risk under inadequate visibility conditions in fog.


Maternal Factors Affecting Delivery Mode of the Previous Cesarean Delivery Mothers.
To examine delivery type of mother who have had a previous cesarean and identify maternal factors related to type of delivery. The study sample included 60,504 mothers who had delivered through cesarean section. Related variables were categorized as sociodemographic factors (age, residence, health insurance type, income level) and clinical characteristics (14 maternal factor, 4 fetal factor and pre-term). For data analysis, chi2 and multivariate logistic regression were conducted. Among the 60,504mothers, 3,075 were delivered through Vaginal Birth After C-Section (VBAC) and the VBAC rate was 5.1%. Underage 34, the VBAC rate increased according to age increases up to 3%. Mothers residing in urban areas had VBAC more frequently than mothers in rural area. Mothers in the high and middle income levels had a greater possibility of having VBAC than mothers in lower income levels. A greater likelihood of increase in repeated cesarean section were found in mothers with maternal and fetal factors. Evidence based nursing practice guidelines and education programs for previous cesarean section mothers and health policy are needed to increase VBAC.


Cellular immunity for prevention and clearance of HIV infection.
Despite the major strides that have been made in HIV therapy with the advent of potent anti-retroviral drugs, these medications are quite expensive and are still not readily available for the vast majority of infected individuals worldwide. Even when available, the long-term toxicities associated with anti-retroviral medications and the frequent emergence of drug-resistance mutations can complicate therapy, making the formulation of effective vaccines imperative. This chapter will review the current state of understanding regarding cell-mediated immune responses that are associated with control of HIV replication. This knowledge has generated sound hypotheses regarding the prospects for augmenting cell-mediated immunity through immune-based therapies. With regard to prophylactic vaccines, it is presently unclear which vaccine-induced immune responses will protect against infection. While much progress has been made in formulating vaccine constructs designed to elicit cell-mediated immune responses, sterilizing immunity is unlikely to be achieved with the current vaccines. However, the ability to control viremia and prevent disease progression in animal infection models looks promising. The ability to measure immune responses has also advanced markedly over the past few years and will allow investigators to more accurately measure the immunogenicity of vaccine constructs, and correlate the magnitude and breadth of these responses with protection.


Qualitative and Quantitative Analysis of the Corneal Endothelium With Smartphone Specular Microscopy.
We sought to demonstrate the feasibility of a lower-cost, portable method for qualitative and quantitative analysis of the corneal endothelium using a smartphone and slit-lamp biomicroscope. In this study, at a single academic center, we recruited healthy participants to undergo imaging of the corneal endothelium using both a smartphone-based method and a specular microscope. Participants first had their eyes imaged with a CellChek NSP-9900 Specular Microscope (Konan Medical, Inc, Irvine, CA). For image capture on the smartphone, a beam of light approximately 0.2 mm in diameter was directed to the center of the cornea with a slit-lamp biomicroscope to achieve specular reflection. With 40× zoom on the slit-lamp and 4K video mode set on an iPhone 7 Plus held to an ocular, the corneal endothelium was recorded until the hexagonal pattern of cells was identified and the sharpest frame from the video was selected. The videos were analyzed from 14 sets of eyes (average length 2 minutes 40 seconds). The average intraclass correlation coefficient was 0.67 (95% confidence interval, 0.43-0.82). The mean difference between smartphone endothelial cell count and specular endothelial cell count was -209 cells/mm (SD = 483 cells/mm), which did not achieve significance (P = 0.14). A Bland-Altman analysis with simple linear regression showed no proportional bias when comparing the 2 modalities (coefficient = -0.20; t-value = -0.42; P = 0.68). Smartphone specular microscopy is capable of qualitative and quantitative analysis of the corneal endothelium. Further refinement to standardize the light source and automate analysis will increase feasibility.


Regulatory effect of NK homeobox 1 (NKX2.1) on melanocortin 4 receptor (Mc4r) promoter in Mandarin fish.
The melanocortin 4 receptor (MC4R) is a G protein-coupled transporter that mediates the regulation of thyroid hormones and leptin on energy balance and food intake. However, the mechanisms of transcriptional regulation of Mc4r by thyroid hormone and leptin in fish have been rarely reported. The messenger RNA expression of Mc4r gene was significantly higher in brain than those in other tissues of mandarin fish. We analyzed the structure and function of a 2029 bp sequence of Mc4r promoter. Meanwhile, overexpression of NKX2.1 and incubation with leptin significantly increased Mc4r promoter activity, but triiodothyronine showed the opposite effect. In addition, mutations in the NKX2.1 binding site abolished not only the activation of Mc4r promoter activity by leptin but also the inhibitory effect of thyroid hormones on Mc4r promoter activity. In summary, these results suggested that thyroid hormones and leptin might regulate the transcriptional expression of Mc4r through NKX2.1.


Non-neoplastic epithelial disorders of the vulva.
Lichen sclerosus, lichen planus, and lichen simplex chronicus are three of the most common non-neoplastic epithelial disorders of the vulva. Lichen sclerosus is characterized by intense vulvar itching and can affect men and women of all ages, but it manifests most commonly in postmenopausal women. Patients with lichen sclerosus have an increased risk of developing squamous cell carcinoma, and they should be monitored for malignancy. Lichen planus is an inflammatory autoimmune disorder that can affect the vulva and the vagina; it peaks in incidence between ages 30 and 60. There are three clinical variants of lichen planus affecting the vulva: erosive, papulosquamous, and hypertrophic. Lichen simplex chronicus is caused by persistent itching and scratching of the vulvar skin, which results in a thickened, leathery appearance. It is thought to be an atopic disorder in many cases and may arise in normal skin as a result of psychological stress or environmental factors. Definitive diagnosis of non-neoplastic disorders depends on the histology of biopsied tissue. All three disorders are treated with topical corticosteroid ointments of varying potency. Lichen sclerosus and lichen planus are not routinely treated with surgery, which is necessary only in patients who have a malignancy or advanced scarring that causes dyspareunia or clitoral phimosis. Educational counseling teaches patients that even though these chronic disorders cannot be cured, they can be effectively managed.


Release Mode Dynamically Regulates the RRP Refilling Mechanism at Individual Hippocampal Synapses.
Synaptic strength and reliability are determined by the number of vesicles released per action potential and the availability of release-competent vesicles in the readily releasable pool (RRP). Compared with release of a single vesicle (univesicular release), multivesicular release (MVR) would speed up RRP depletion, yet whether the RRP is refilled differently during the two different release modes has not been investigated. Here, we address this question by quantitative optical imaging with an axon-targeting glutamate sensor, iGluSnFRpre. We found that hippocampal synapses preferentially release multiple vesicles per action potential at high extracellular calcium or by paired-pulse stimulation. When MVR prevails, the RRP is recovered very rapidly with a time constant of 430 ms. This rapid recovery is mediated by dynamin-dependent endocytosis followed by direct reuse of retrieved vesicles. Furthermore, our simulation proved that the portion of retrieved vesicles that directly refill the RRP increases dramatically (>70%) in MVR compared with that in univesicular release (<10%). These results suggest that the contribution of rapid and direct recruitment of retrieved vesicle to the RRP changes dynamically with release mode at the level of individual synapses, which suggests a form of presynaptic homeostatic plasticity for reliable synaptic transmission during various synaptic activity.SIGNIFICANCE STATEMENT The number of vesicles released in response to an action potential and the number of release competent vesicles in the readily releasable pool (RRP) are the fundamental determinants of synaptic efficacy. Despite its functional advantages, releasing multiple vesicles, especially at small synapses, can deplete the RRP after a couple of action potentials. To prevent failure of synaptic transmission, the RRP should be refilled rapidly, yet whether the RRP replenishment process is regulated by the release mode has not been investigated. Here, using quantitative optical glutamate imaging and simulation, we demonstrate that the contribution of the fast refilling mechanism changes with release mode at the level of individual synapses, suggesting a rapid form of presynaptic homeostatic plasticity during various synaptic activity.


Nucleoporin FG domains facilitate mRNP remodeling at the cytoplasmic face of the nuclear pore complex.
Directional export of messenger RNA (mRNA) protein particles (mRNPs) through nuclear pore complexes (NPCs) requires multiple factors. In Saccharomyces cerevisiae, the NPC proteins Nup159 and Nup42 are asymmetrically localized to the cytoplasmic face and have distinct functional domains: a phenylalanine-glycine (FG) repeat domain that docks mRNP transport receptors and domains that bind the DEAD-box ATPase Dbp5 and its activating cofactor Gle1, respectively. We speculated that the Nup42 and Nup159 FG domains play a role in positioning mRNPs for the terminal mRNP-remodeling steps carried out by Dbp5. Here we find that deletion (Δ) of both the Nup42 and Nup159 FG domains results in a cold-sensitive poly(A)+ mRNA export defect. The nup42ΔFG nup159ΔFG mutant also has synthetic lethal genetic interactions with dbp5 and gle1 mutants. RNA cross-linking experiments further indicate that the nup42ΔFG nup159ΔFG mutant has a reduced capacity for mRNP remodeling during export. To further analyze the role of these FG domains, we replaced the Nup159 or Nup42 FG domains with FG domains from other Nups. These FG "swaps" demonstrate that only certain FG domains are functional at the NPC cytoplasmic face. Strikingly, fusing the Nup42 FG domain to the carboxy-terminus of Gle1 bypasses the need for the endogenous Nup42 FG domain, highlighting the importance of proximal positioning for these factors. We conclude that the Nup42 and Nup159 FG domains target the mRNP to Gle1 and Dbp5 for mRNP remodeling at the NPC. Moreover, these results provide key evidence that character and context play a direct role in FG domain function and mRNA export.


Antimicrobial activity of plant extracts against Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes on fresh lettuce.
Plant extracts have been found to be effective in reducing microorganisms. This study evaluated antimicrobial activity of 12 plant extracts against Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes by using a disk diffusion assay, and Syzygium aromaticum (clove) showed the highest inhibitory effect. To investigate the efficacy of clove extract that inactivates pathogens on lettuce, inoculated lettuce with S. Typhimurium, E. coli O157:H7, and L. monocytogenes was treated with diluted clove extracts or distilled water for 0, 1, 3, 5, and 10 min. Clove extract treatment significantly reduced populations of the 3 tested pathogens from the surface of lettuce. Practical Application: This result indicated that clove extract is a useful antimicrobial agent to reduce the microbial level of foodborne pathogens on fresh lettuce. It also might be a natural antimicrobial for reducing or replacing chemical sanitizers in food preservation.


Reduced serum-stimulatory activity on prostacyclin production by cultured aortic endothelial cells in diabetes mellitus.
Reduced prostacyclin (PGI2) production by the vascular wall has been proposed as a possible cause of macro- or microangiopathy in diabetes mellitus. In the present study, we confirmed the stimulatory activity on PGI2 (PSA) production in plasma-derived serum (PDS) by cultured aortic endothelial cells. Furthermore, the abnormality of PSA was examined in diabetic PDS. PSA in PDS from non-insulin-dependent diabetics significantly decreased as compared with that in PDS from age-matched control subjects. There was no difference in PSA in PDS between diabetic patients with and without vascular complications such as retinopathy and nephropathy. In addition, after treatment with dialysis, PSA in diabetic PDS was still not restored to that in normal PDS. These findings suggest that relatively heat-stable (56 degrees C, 30 min) and nondialyzable PGI2 stimulatory substance(s) may decrease in diabetic PDS. It is concluded that a reduction in PDS-stimulated PGI2 production by the vascular wall can play an important role in the pathogenesis of vascular lesions in diabetes mellitus.


Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors.
A variety of human cancers overexpress a cell surface receptor with high affinity for the vitamin, folic acid ( K(d) approximately 10(-10)M). Covalent attachment of therapeutic agents to folic acid has been shown to allow efficient targeting of the folate-drug conjugates to folate receptor-expressing cancer cells, with little or no uptake by normal tissues except the kidneys. We report here the use of folate's ability to deliver attached molecules specifically to cancer cells to convert poorly immunogenic tumors into highly immunogenic tissue targets. By linking folic acid to a model hapten, we have been able to decorate folate receptor-expressing cancer cell surfaces with >10(6) haptens/cell in vivo. Following marking of such cells with haptens, the cells are observed to become opsonized with autologous anti-hapten antibodies, which is presumed to mediate cell removal via antibody-dependent cellular cytotoxicity (ADCC). Supplemental administration of low levels of ADCC-activating cytokines [e.g. interleukin-2 (IL-2) and interferon-alpha (IFN-alpha)] has been shown to synergize with the folate-targeted immunotherapy. Thus, using M109 syngeneic lung cancer cells injected intraperitoneally into Balb/c mice that were previously immunized against fluorescein, a significant extension of life span is observed following treatment with folate-fluorescein conjugates, and complete cures are observed upon supplementation with moderate levels of IL-2 and IFN-alpha. Because control tumor-bearing mice treated with the same cytokines but with non-targeted fluorescein show no extension of life span, we conclude that tumor-specific opsonization is an essential step in this immunotherapy. Finally, because the anti-fluorescein antibodies are unable to access the folate receptors on the apical membranes of the kidney proximal tubules, no kidney or other normal tissue cytotoxicity is observed. These data suggest that retargeting of haptens to folate receptor-expressing cancers might constitute a method for mobilizing the immune system specifically against poorly immunogenic tumors.


Performance comparison of scene matching techniques.
The problem of matching two images of the same scene, taken by different sensors under different viewing geometries, is a challenging problem in the field of image processing and pattern recognition. The scenes are usually transformed so drastically by the different viewing geometries and sensor characteristics that it is extremely difficult, if not impossible, to match the original images without the proper data processing. Geometric and intensity transformations must be performed to bring the matching elements and their intensity into a one-to-one correspondence. Objects of interest represented by subimages of one scene were located in the other using scene matching techniques with intensity difference and edge features as measurement features. Performance characteristics of the matches by these techniques are presented in terms of the probability of a match as a function of the probability of false fix.


Rapid detection of bacteriuria by laser nephelometry.
A total of 1,002 urine specimens were evaluated by laser nephelometry. This technique was compared with both colony counts, done with a calibrated loop, and serial dilutions. For urine specimens containing between 10(4) and 10(5) bacteria per ml, laser nephelometry detected 75.4% of those detected by colony count and 65.6% of those detected by serial dilution. For specimens where the concentration of bacteria was greater than 10(5) per ml, laser nephelometry detected 95.8 and 92.4% of those detected by colony count and serial dilution, respectively. The mean detection time for bacteriuria varied from 1.57 h for more than 10(5) bacteria per ml to 4.47 h for more than 10(4) bacteria per ml. To determine the number of bacteria according to the voltage growth curve, the passage time at 3 V was used as an index. The mean passage time at 3 V decreased from 5.18 h for fewer than 10(4) bacteria per ml to 1.42 h for more than 10(6) bacteria per ml. The mean passage time at 3 V differed significantly for different concentrations of bacteria. Thus, this index allowed us to predict the number of bacteria in the urine specimens. Laser nephelometry has been used for many years for the immunological determination of proteins; it can now also be considered a tool for rapid screening in bacteriology.


Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.
Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.


Ultrasonography and radiography in the diagnosis of Peyronie's disease.
In this study the authors compare ultrasonography and radiography with clinical examination in the diagnosis of Peyronie's disease. They also review its clinical presentation. In contrast to previous studies they found no correlation between plaques found on ultrasonography or radiography and those found on clinical examination. They conclude that ultrasonography and radiography are not reliable in diagnosing Peyronie's disease.


High recovery of cell-free methylated DNA based on a rapid bisulfite-treatment protocol.
Detection of cell-free methylated DNA in plasma is a promising tool for tumour diagnosis and monitoring. Due to the very low amounts of cell-free DNA in plasma, analytical sensitivity is of utmost importance. The vast majority of currently available methods for analysing DNA methylation are based on bisulfite-mediated deamination of cytosine. Cytosine is rapidly converted to uracil during bisulfite treatment, whereas 5-methylcytosine is only slowly converted. Hence, bisulfite treatment converts an epigenetic modification into a difference in sequence, amenable to analysis either by sequencing or PCR based methods. However, the recovery of bisulfite-converted DNA is very poor. Here we introduce an alternative method for the crucial steps of bisulfite treatment with high recovery. The method is based on an accelerated deamination step and alkaline desulfonation in combination with magnetic silica purification of DNA, allowing preparation of deaminated DNA from patient samples in less than 2 hours. The method presented here allows low levels of DNA to be easily and reliably analysed, a prerequisite for the clinical usefulness of cell-free methylated DNA detection in plasma.


Immunomodulatory Effects of Nontoxic Glycoprotein Fraction Isolated from Rice Bran.
Rice bran, a by-product of brown rice milling, is a rich source of dietary fiber and protein, and its usage as a functional food is expected to increase. In this study, immunomodulatory effects of glycoprotein obtained from rice bran were studied in normal mice and mouse models of cyclophosphamide-induced immunosuppression. We prepared glycoprotein from rice bran by using ammonium precipitation and anion chromatography techniques. Different doses of glycoprotein from rice bran (10, 25, and 50 mg/kg) were administered orally for 28 days. On day 21, cyclophosphamide at a dose of 100 mg/kg was administered intraperitoneally. Glycoprotein from rice bran showed a significant dose-dependent restoration of the spleen index and white blood cell count in the immunocompromised mice. Glycoprotein from rice bran affected the immunomodulatory function by inducing the proliferation of splenic lymphocytes, which produce potential T and B cells. Moreover, it prevented cyclophosphamide-induced damage of Th1-type immunomodulatory function through enhanced secretion of Th1-type cytokines (interferon-γ and interleukin-12). These results indicate that glycoprotein from rice bran significantly recovered cyclophosphamide-induced immunosuppression. Based on these data, it was concluded that glycoprotein from rice bran is a potent immunomodulator and can be developed to recover the immunity of immunocompromised individuals.


Environmental medicine, part 2 - health effects of and protection from ubiquitous airborne solvent exposure.
Chemicals known as solvents are part of a broad class of chemicals called volatile organic compounds. These compounds are used in a variety of settings, are ubiquitous, and off-gas readily into the atmosphere. Asa result of their overuse, they can be found in detectable level virtually all samples of both indoor and outdoor air. Certain of these compounds are detectable in adipose samples of all U.S. residents Once in the body they can lead to a variety of neurological, immunological, endocrinological, genitourinary, and hematopoietic problems. Some individuals also have metabolic defects that diminish the liver's clearing capacity for these compounds. Supplementation may be of benefit to help clear these compounds from the body and to prevent adverse health effects.


[Theory and practice of designing the therapeutic drugs based on the lipophilic fractions of vegetable raw materials for the prevention and treatment of inflammatory lesions of urogenital system].
Principle approaches to designing the therapeutic drugs based on the lipophilic fractions of vegetable raw-materials and meant for the prevention and treatment of inflammatory lesions of urogenital-system organs are substantiated in the paper both experimentally and theoretically. Considering the peculiarities of the mentioned pathologies, it is recommended to use the lipophilic fractions as the main components of soft drugs, in particular, of suppositories and ointments. The preliminary results of preclinical tests proved the chosen trend in creating the new therapeutic-and-preventive preparations to be promising.


Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study.
To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. ClinicalTrials.gov NCT03939624.


Eulipidemic effects of berberine administered alone or in combination with other natural cholesterol-lowering agents. A single-blind clinical investigation.
Berberine (BERB) and a combination (COMB) of berberine (CAS 2086-83-1) with policosanol (CAS 557-61-9), red yeast extract (containing monacolin, CAS 557-61-9), folic acid and astaxanthin were orally administered daily for 4 weeks to 40 subjects with moderate dyslipidemias divided in two parallel groups each of 20 subjects. Total cholesterol (TC), LDL, HDL, Non HDL, ApoB, ApoA, Lp(a) and triglycerides (TG) were measured before and at the end of treatments. BERB and COMB significantly reduced TC (respectively by 16% and 20%), LDL (by 20% and 25%), ApoB (by 15% and 29%) and TG (by 22% and 26%), and increased HDL (by 6.6% and 5.1%). Adverse events or impairments of liver transaminases or of CPK were not observed. In conclusion, food supplements containing natural products such as berberine, policosanol, red yeast extracts, folic acid and astaxanthin could be a useful support to diet and life style changes to correct dyslipidemias and to reduce cardiovascular risk in subjects with moderate mixed dyslipidemias.


4-D ultrafast shear-wave imaging.
Over the last ten years, shear wave elastography (SWE) has seen considerable development and is now routinely used in clinics to provide mechanical characterization of tissues to improve diagnosis. The most advanced technique relies on the use of an ultrafast scanner to generate and image shear waves in real time in a 2-D plane at several thousands of frames per second. We have recently introduced 3-D ultrafast ultrasound imaging to acquire with matrix probes the 3-D propagation of shear waves generated by a dedicated radiation pressure transducer in a single acquisition. In this study, we demonstrate 3-D SWE based on ultrafast volumetric imaging in a clinically applicable configuration. A 32 × 32 matrix phased array driven by a customized, programmable, 1024-channel ultrasound system was designed to perform 4-D shear-wave imaging. A matrix phased array was used to generate and control in 3-D the shear waves inside the medium using the acoustic radiation force. The same matrix array was used with 3-D coherent plane wave compounding to perform high-quality ultrafast imaging of the shear wave propagation. Volumetric ultrafast acquisitions were then beamformed in 3-D using a delay-and-sum algorithm. 3-D volumetric maps of the shear modulus were reconstructed using a time-of-flight algorithm based on local multiscale cross-correlation of shear wave profiles in the three main directions using directional filters. Results are first presented in an isotropic homogeneous and elastic breast phantom. Then, a full 3-D stiffness reconstruction of the breast was performed in vivo on healthy volunteers. This new full 3-D ultrafast ultrasound system paves the way toward real-time 3-D SWE.


Point of care and patient privacy: who is in control?
Public and patient access to medical records has been severely limited through policies limiting physical and timely access and intellectual understanding of content. New expectations of patient/public access and control have arisen accompanying the new paradigms of health care delivery and health information (computer-based patient records). Examples from these new paradigms are personalized and presented in information system contexts from bedside to community settings. Patient and family involvement in care delivery, education, assessment, and control of privacy are explored. A personalized confidentiality/security/privacy module of the computer-based patient record is suggested.


Toxicants exposures as novel zoonoses: reflections on sustainable development, food safety and veterinary public health.
The modern concept of zoonosis considers any detriment to the health and/or quality of human life resulting from relationships with (other) vertebrate or edible or toxic invertebrate animals. Whereas exposure to toxicants through foods of animal origin (a.o.) is a well-established issue, hereby we discuss it as novel zoonoses, from the standpoints of health implications as well as similarities and differences with classical zoonoses caused by biological agents. Novel toxicant-related zoonoses are linked with new issues in food safety, such as the environment-feed-food chain. In fact, the potential effect of the combined and repeated exposure to dietary toxicants is generally long-term and not readily discernible. Endocrine disrupting chemicals in staple foods of a.o. are discussed as a telling example of a food safety issue summing up critical points covered by the definition of sustainable development, also implicating health risks for generations to come. We suggest some critical points to implement the veterinary public health action in sustainable food safety, such as enhancement of Hazard Analysis and Critical Control Points systems for toxicological risk management.


Early prognosis in traumatic brain injury: from prophecies to predictions.
Traumatic brain injury (TBI) is a heterogeneous condition that encompasses a broad spectrum of disorders. Outcome can be highly variable, particularly in more severely injured patients. Despite the association of many variables with outcome, prognostic predictions are notoriously difficult to make. Multivariable analysis has identified age, clinical severity, CT abnormalities, systemic insults (hypoxia and hypotension), and laboratory variables as relevant factors to include in models to predict outcome in individual patients. Advances in statistical modelling and the availability of large datasets have facilitated the development of prognostic models that have greater performance and generalisability. Two prediction models are currently available, both of which have been developed on large datasets with state-of-the-art methods, and offer new opportunities. We see great potential for their use in clinical practice, research, and policy making, as well as for assessment of the quality of health-care delivery. Continued development, refinement, and validation is advocated, together with assessment of the clinical impact of prediction models, including treatment response.


Drug-induced hepatotoxicity: 2005.
The removal from the marketplace of several widely prescribed drugs due to hepatotoxicity has attracted considerable attention. Now under extensive review are means by which we can better identify hepatic risk prior to federal approval. Assessment of risk-to-benefit ratios regarding a novel agent with hepatotoxicity issues (especially one for a life-threatening condition) requires considerable judgment and education on the part of prescribers and patients. The spectrum of drug-induced liver injury is broad with simulation of almost all unknown liver disorders. Drug-induced liver injuries often have a somewhat characteristic signature, as regards type of injury (hepatocellular vs cholestatic) and time of onset. The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. Factors affecting susceptibility to drug-induced injury include age, sex, concomitant use of other drugs, and genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs. Drug-drug interactions present particular problems in patients, often elderly, who are receiving several drugs simultaneously. Mechanisms of drug-induced liver injury are many and varied. With many drugs, intermediary products produced during metabolism are highly reactive and toxic. In these situations, the balance between the rate of production of the metabolite and the effectiveness of the drug may determine whether or not hepatic injury occurs.


Factors associated with physician follow-up among patients with chest pain discharged from the emergency department.
Many patients with chest pain do not receive follow-up from a physician after discharge from the emergency department despite significant survival benefit associated with follow-up care. Our objective was to evaluate factors associated with physician follow-up to understand this gap in practice. We conducted an observational study involving patients at high risk who were assessed for chest pain and discharged from an emergency department in Ontario between April 2004 and March 2010. We used multivariable logistic regression to determine the association of clinical and nonclinical characteristics with physician follow-up. We identified 56 767 patients, of whom 25.1% did not receive any follow-up by a physician, 69.0% were seen by their primary care physician, and 17.3% were seen by a cardiologist within 30 days. Patients who had medical comorbidities and cardiac conditions such as myocardial infarction or heart failure were less likely to have follow-up. In contrast, a previous visit to a primary care physician was associated with the highest odds of having physician follow-up (odds ratio [OR] 6.44, 95% confidence interval [CI] 5.91-7.01). Similarly, a previous visit to a cardiologist was strongly associated with follow-up by a cardiologist (OR 3.01, 95% CI 2.85-3.17). Patients evaluated in emergency departments with the highest tertile of chest pain volume were more likely to receive follow-up from any physician (OR 1.52, 95% CI 1.31-1.77) and from a cardiologist (OR 2.04, 95% CI 1.61-2.57). Nonclinical factors are strongly associated with physician follow-up for patients with chest pain after discharge from the emergency department. However, patients with comorbidities and at higher risk for future adverse events are less likely to receive follow-up care.


STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium.
The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 +/- 58 vs. 1,028 +/- 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt(max); 4,648 +/- 309 vs. 2,737 +/- 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum -dP/dt (-dP/dt(min); -2,239 +/- 205 vs. -1,215 +/- 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt(max) (4,648 +/- 309 vs. 3,241 +/- 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and -dP/dt(min) (-2,239 +/- 205 vs. -1,323 +/- 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.


Adaptation of skeletal muscle characteristics to a high-fat diet in rats with different intra-abdominal-obesity susceptibilities.
The purpose of the present study was to investigate the relationship between intra-abdominal-obesity susceptibility and the adaptation of skeletal muscle metabolic and histochemical characteristics when fed a high-fat diet (HFD) for a short period of time. Twenty-four male Wistar rats were fed a HFD (39.7% calories of fat) for 5 wk. After the 5-wk dietary period, the rats were sacrificed and divided into intra-abdominal-obesity-prone (OP) or obesity-resistant (OR) groups according to the total intra-abdominal fat pads (epididymal, mesenteric, and perirenal) weights. A superficial portion of the Muscle (M.) gastrocnemius tissue obtained from 2 groups before and after feeding the HFD were analyzed to determine their hexokinase (HK), (beta-hydroxyacyl CoA dehydrogenase (beta-HAD), and citrate synthase (CS) activities. Muscle fiber composition and capillary density were examined in the deep portion of the M. gastrocnemius, soleus, and extensor digitorum longus (EDL) gained after the HFD. While the OP group had more intra-abdominal fat pads and a heavier final body weight than the OR group, there was no significant difference in the energy intake between the two. Due to the HFD, the OP group showed significant increases in beta-HAD and CS activities, while the OR group did not. Change of beta-HAD activity by HFD in the OP group was significantly greater than that in the OR group. The ratio of fat oxidation, expressed as beta-HAD/CS, significantly increased in the OP group, but not in the OR group. No differences were found in either the muscle fiber composition or capillarization. These results suggest that intra-abdominal-obesity-susceptive rats may have a higher adaptation degree in muscle oxidative enzyme activities as characteristic in the early stage of intra-abdominal adipose accumulation.


[The turn of the screw: complex visual hallucinations in the Henry James' novel].
The turn of the screw is one of the most celebrated stories by Henry James. It is also a top writing within the so-called fantastic literature, whose narrative strength comes from the intermittent visions suffered by the main character. The vividness and dramatic content that represent the firstly unidentified human figures, that moreover recur as brief, stereotyped and fragmentary images, are constitutive of complex visual hallucinations. These characteristics, alongside acute premonitory symptoms such as emotional changes (fear, anxiety) or altered thinking (forced, "dejà vu", "jamais vu"), and the final altered awareness or loss of consciousness, allow us to infer an epileptic nature of the ten episodes described. Postictal psychosis, that follows a lucid interval and may last up to the several weeks encompassed by the story, would account for the paranoia featured, in the setting of a temporal lobe epilepsy. The accurate descriptions prompted us to search for autobiographical, scientific or literary influences: The alcoholism and visual hallucinations suffered by his father, the knowledge on hallucinations provided by his brother Williams on his paramount and former The Principles of Psychology, and an early devotion to Poe's writings, an epileptic himself with excellent descriptions of seizures in his writings, might have enabled the author to perform his story with such a hallmark of neurological details.


Virtual Screening of the Multi-pathway and Multi-gene Regulatory Molecular Mechanism of Dachengqi Decoction in the Treatment of Stroke Based on Network Pharmacology.
Stroke is ranked second among diseases that cause mortality worldwide. Owing to its complicated pathogenesis, no satisfactory treatment strategies for stroke are available. Dachengqi decoction (DCQD), a traditional Chinese herbal medicine, has been widely used in China for a long time, as it has a good effect on stroke. However, the molecular mechanism underlying this effect of DCQD is unclear. In the present study, we aimed to reveal and explore the multi-pathway and multi-gene regulatory molecular mechanism of Dachengqi decoction in the treatment of stroke. In this study, a network pharmacology method, in combination with oral bioavailability prediction and drug-likeness evaluation, was employed to predict the active ingredients of DCQD. The target genes of the active components and the traced pathways related to these target genes were predicted. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using clusterProfiler software package on the R platform and ClueGo+CluePedia plug-ins. Finally, the key DCQD targets were verified using the Gene Expression Omnibus (GEO) dataset. According to the ADME model, 52 active components were screened from 296 active components of DCQD. After prediction and screening, 215 stroke-related targets were obtained and analyzed via GO and KEGG analyses. GO analysis showed that DCQD targets were mainly involved in the regulation of oxidative stress, lipid metabolism, inflammation, and other biological processes. KEGG pathway analysis further revealed pathways involved in stroke, such as arachidonic acid metabolic, HIF-1 signaling pathway, estrogen signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, platelet activation pathway, VEGF signaling pathway, and cAMP signaling pathway. Network analysis revealed that DCQD might be involved in the regulation of lipid metabolism, blood pressure, inflammation, angiogenesis, neuroprotection, platelet aggregation, apoptosis, and oxidation in stroke treatment. GEO dataset analysis showed that DCQD's therapeutic effects might be exerted via the bidirectional regulation principle. Based on the methods of network pharmacology and GEO analysis, it was found that, during stroke treatment, DCQD regulates and controls multiple genes and multiple pathways in a synergistic manner, providing a new strategy for stroke treatment.


Realistic and spherical head modeling for EEG forward problem solution: a comparative cortex-based analysis.
The accuracy of forward models for electroencephalography (EEG) partly depends on head tissues geometry and strongly affects the reliability of the source reconstruction process, but it is not yet clear which brain regions are more sensitive to the choice of different model geometry. In this paper we compare different spherical and realistic head modeling techniques in estimating EEG forward solutions from current dipole sources distributed on a standard cortical space reconstructed from Montreal Neurological Institute (MNI) MRI data. Computer simulations are presented for three different four-shell head models, two with realistic geometry, either surface-based (BEM) or volume-based (FDM), and the corresponding sensor-fitted spherical-shaped model. Point Spread Function (PSF) and Lead Field (LF) cross-correlation analyses were performed for 26 symmetric dipole sources to quantitatively assess models' accuracy in EEG source reconstruction. Realistic geometry turns out to be a relevant factor of improvement, particularly important when considering sources placed in the temporal or in the occipital cortex.


Optimization of Ultrasonic-Assisted Extraction of Chlorogenic Acid from Tobacco Waste.
Using tobacco waste as raw material, the ultrasonic-assisted extraction of chlorogenic acid was optimized by response surface methodology (RSM). After repeated freezing and thawing of tobacco waste twice, the effect of pH value, ethanol volume fraction, temperature and extraction time on the extraction rate of chlorogenic acid was investigated by a single factor experiment. On the basis of this, the factors affecting the yield of chlorogenic acid were further optimized by using RSM. The optimum extraction conditions for chlorogenic acid were set at pH = 4.1, ethanol volume fraction was 49.57% and extraction time was 2.06 h. Under the above conditions, the extraction rate of chlorogenic acid could reach 0.502%, which was higher than traditional extraction and unpretreated ultrasonic extraction. All these results can be used as a reference for the extraction of effective ingredients in tobacco waste.


Interactions among human papillomavirus proteins and host DNA repair factors differ during the viral life cycle and virus-induced tumorigenesis.
This review focuses on the impact of human papillomavirus (HPV) oncogenes on DNA repair pathways with a particular focus on how these relationships change as productive HPV infections transition to malignant lesions. We made specific efforts to incorporate advances in the understanding of HPV and DNA damage repair over the last 4 years. We apologize for any articles that we missed in compiling this report.