Energy Balance of Canadian Armed Forces Personnel during an Arctic-Like Field Training Exercise.
Operating in temperature extremes frequently leads to a discrepancy in energy balance. Investigating the effects of operating in extreme cold temperatures on metabolic requirements has not been well described in Canadian Armed Forces (CAF) personnel. The objective was to accurately assess energy deficits using the "gold standard" methodology for measuring energy intake (EI) and energy expenditure (EE). Nutritional intake of a convenience sample of 10 CAF Class A Reservists, completing a basic military qualification (land) course under winter weather conditions, was assessed using the daily measured food intake/food waste collections. EE was measured by the doubly-labelled water method. Average EI was 2377 ± 1144 kcal/day, which was below the EE (4917 ± 693 kcal/day), despite having ~5685 kcal available in the field rations. A significant body weight loss of 2.7% was associated with the average daily energy deficit of 2539 ± 1396 kcal. As a result, participants demonstrated voluntary anorexia. Such results may have important implications for the impairment of performance and health under longer duration operations.


The Benefits of Omega-3 Fats for Stabilizing and Remodeling Atherosclerosis.
The majority of acute coronary syndromes are caused by the rupture of plaques rendered vulnerable by oxidized lipids, inflammation, and a thin fibrous cap with reduced collagen and smooth muscle cell content.2 Thus, stabilizing and reversing vulnerable atherosclerotic plaques can help to prevent cardiovascular events. In this regard, long-chain omega-3 fatty acids have a plethora of data for stabilizing vulnerable atherosclerotic plaques as well as reversing atherosclerosis. This review paper will summarize the observational data as well as animal and human studies supporting such a role and further discuss the current controversies around omega-3 supplementation.


Inhibition of polyamine oxidase prevented cyclin-dependent kinase inhibitor-induced apoptosis in HCT 116 colon carcinoma cells.
Roscovitine and purvalanol are novel cyclin-dependent kinase (CDK) inhibitors that prevent cell proliferation and induce apoptotic cell death in various cancer cell lines. Although a number of studies have demonstrated the potential apoptotic role of roscovitine, there is limited data about the therapeutic efficiency of purvalanol on cancer cells. The natural polyamines (PAs) putrescine, spermidine, and spermine have essential roles in the regulation of cell differentiation, growth, and proliferation, and increased levels of these compounds have been associated with cancer progression. Recently, depletion of intracellular PA levels because of modulation of PA catabolic enzymes was shown to be an indicator of the efficacy of chemotherapeutic agents. In this study, our aim was to investigate the potential role of PA catabolic enzymes in CDK inhibitor-induced apoptosis in HCT 116 colon carcinoma cells. Exposure of cells to roscovitine or purvalanol decreased cell viability in a dose- and time-dependent manner. The selected concentrations of roscovitine and purvalanol inhibited cell viability by 50 % compared with control cells and induced apoptosis by activating the mitochondria-mediated pathway in a caspase-dependent manner. However, the apoptotic effect of purvalanol was stronger than that of roscovitine in HCT 116 cells. In addition, we found that CDK inhibitors decreased PA levels and significantly upregulated expression of key PA catabolic enzymes such as polyamine oxidase (PAO) and spermine oxidase (SMO). MDL-72,527, a specific inhibitor of PAO and SMO, decreased apoptotic potential of CDK inhibitors on HCT 116 cells. Moreover, transient silencing of PAO was also reduced prevented CDK inhibitor-induced apoptosis in HCT 116 cells. We conclude that the PA catabolic pathway, especially PAO, is a critical target for understanding the molecular mechanism of CDK inhibitor-induced apoptosis.


H. pylori virulence factors.
Among people infected with Helicobacter pylori, the virulence of the infecting strain is a major determinant of who develops disease. Strains producing vacuolating cytotoxin activity are more commonly isolated from people with peptic ulcers than without. The gene encoding the toxin, vacA, varies between strains, especially in its signal sequence and mid regions. vacA genotype influences cytotoxin activity, and signal sequence type correlates closely with peptic ulceration. Infection with strains possessing cagA (cytotoxin associated gene A) is more common among people with peptic ulceration or gastric adenocarcinoma than without. cagA is a marker for the cag pathogenicity island, which includes genes necessary for the enhanced inflammation induced by pathogenic strains. Serological detection of infection with cagA+ strains is at present the best practical test for virulence. However, before a strategy of screening and selective treatment can be considered, it is important to assess whether cagA- strains are entirely non-pathogenic.


Distinguishing noise from signal in patterns of genomic divergence in a highly polymorphic avian radiation.
Recently diverged taxa provide the opportunity to search for the genetic basis of the phenotypes that distinguish them. Genomic scans aim to identify loci that are diverged with respect to an otherwise weakly differentiated genetic background. These loci are candidates for being past targets of selection because they behave differently from the rest of the genome that has either not yet differentiated or that may cross species barriers through introgressive hybridization. Here we use a reduced-representation genomic approach to explore divergence among six species of southern capuchino seedeaters, a group of recently radiated sympatric passerine birds in the genus Sporophila. For the first time in these taxa, we discovered a small proportion of markers that appeared differentiated among species. However, when assessing the significance of these signatures of divergence, we found that similar patterns can also be recovered from random grouping of individuals representing different species. A detailed demographic inference indicates that genetic differences among Sporophila species could be the consequence of neutral processes, which include a very large ancestral effective population size that accentuates the effects of incomplete lineage sorting. As these neutral phenomena can generate genomic scan patterns that mimic those of markers involved in speciation and phenotypic differentiation, they highlight the need for caution when ascertaining and interpreting differentiated markers between species, especially when large numbers of markers are surveyed. Our study provides new insights into the demography of the southern capuchino radiation and proposes controls to distinguish signal from noise in similar genomic scans.


The complete iodine and nitrogen nuclear electric quadrupole coupling tensors for fluoroiodoacetonitrile determined by chirped pulse Fourier transform microwave spectroscopy.
Molecular pulsed jet, chirped-pulse Fourier transform microwave spectroscopy has been used to record 499 transitions for the title molecule. Measurements have been made in the 8-16 GHz regions. Vibrational and electronic ground state rotational constants A, B, and C have been obtained, together with centrifugal distortion terms. The complete iodine and nitrogen nuclear quadrupole coupling tensors have been determined for the first time. Quantum chemical calculations have been performed to aid with analyses and, in particular, to aid in determining the signs of the off-diagonal components of the nuclear quadrupole coupling tensors. An experimentally determined relative electronegativity scale for several polyhalomethyl groups is proposed.


Slowing DNA Transport Using Graphene-DNA Interactions.
Slowing down DNA translocation speed in a nanopore is essential to ensuring reliable resolution of individual bases. Thin membrane materials enhance spatial resolution but simultaneously reduce the temporal resolution as the molecules translocate far too quickly. In this study, the effect of exposed graphene layers on the transport dynamics of both single (ssDNA) and double-stranded DNA (dsDNA) through nanopores is examined. Nanopore devices with various combinations of graphene and Al2O3 dielectric layers in stacked membrane structures are fabricated. Slow translocations of ssDNA in nanopores drilled in membranes with layers of graphene are reported. The increased hydrophobic interactions between the ssDNA and the graphene layers could explain this phenomenon. Further confirmation of the hydrophobic origins of these interactions is obtained through reporting significantly faster translocations of dsDNA through these graphene layered membranes. Molecular dynamics simulations confirm the preferential interactions of DNA with the graphene layers as compared to the dielectric layer verifying the experimental findings. Based on our findings, we propose that the integration of multiple stacked graphene layers could slow down DNA enough to enable the identification of nucleobases.


Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis, and Alzheimer disease: new insights from accurate analysis of 10 forms.
A comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify 10 forms of vitamin D in sera from healthy adults and patients suffering from rheumatoid arthritis (RA), type 1 diabetes (T1-D), and Alzheimer disease (AD). The rapid assay, validated according to US Food and Drug Administration guidelines with Chromsystems and DEQAS samples, was applied to 36 nonhealthy sera samples (41.7% male, age range of 14-95, mean = 54.00 ± 21.98 years), consisting of individuals with RA, T1-D, and AD (n = 12 each) and was compared to samples from 32 healthy individuals (50% male, age range of 19-90, mean = 58.83 ± 22.93 years). The key findings are (1) the 23R,25-dihydroxyvitamin D3 form was quantified for the first time (healthy = 0.427 ± 0.633 nmol/L; combined disease = 0.395 ± 0.483 nmol/L), (2) the 3-epi-25-hydroxyvitamin D3 metabolite was found in all groups with significantly higher concentration in the diseased samples [healthy = 6.093 ± 6.711 nmol/L; combined disease = 22.433 ± 13.535 nmol/L, t(52.5) = -6.411; P < .001], (3) a significant difference was found for the active form (1α-25-dihydroxyvitamin D3) between health (0.027 ± 0.035 nmol/L) and disease (0.433 ± 0.870 nmol/L) [t(35.1) = -2.797, P = 0.008], and (4) there was no significant correlation between the total circulating and total active forms in either the disease or healthy group (r = -0.180 and -0.274, respectively, with no difference between the correlation coefficients, z = -0.389, P = .697). Receiver operating characteristic curve analysis showed good sensitivity and specificity for using the 3-epi-25-hydroxyvitamin D concentration to predict disease status (area under the curve = 0.880, P < .001). Discriminant function analysis using concentrations of 23R,25-dihydroxyvitamin D3, 25-hydroxyvitamin D2, and 3-epi-25-hydroxyvitamin D classified 94.4% (91.7% in cross-validation) of the cases correctly. This study reveals significant differences between health and disease with epimers having the potential to relate to disease. The potential implications of the information gleaned from measuring all forms warrant application of more comprehensive assays for future clinical studies investigating the link between vitamin D and health.


Carbon monoxide activates human intestinal smooth muscle L-type Ca2+ channels through a nitric oxide-dependent mechanism.
Carbon monoxide (CO) is increasingly recognized as a physiological messenger. CO is produced in the gastrointestinal tract with diverse functions, including regulation of gastrointestinal motility, interacting with nitric oxide (NO) to mediate neurotransmission. The aim of this study was to determine the effect of CO on the human intestinal L-type Ca(2+) channel expressed in HEK cells and in native cells using the patch-clamp technique. Extracellular solution contained 10 mM Ba(2+) as the charge carrier. Maximal peak Ba(2+) current (I(Ba)) was significantly increased by bath application of 0.2% CO to transfected HEK cells (18 +/- 3%). The NO donor S-nitroso-N-acetylpenicillamine also increased I(Ba), and CO (0.2%) increased NO production in transfected HEK cells. The CO-induced increase in I(Ba) was blocked when cells were pretreated with 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) or inhibitors of NO synthase (NOS). The PKA inhibitor KT-5720 (0.5 microM) and milrinone (3 microM), a phosphodiesterase (PDE) III inhibitor, blocked the effect of CO on I(Ba). Similar effects were seen in freshly dissociated human intestinal smooth muscle cells. The data suggest that exogenous CO can activate native and heterologously expressed intestinal L-type Ca(2+) channels through a pathway that involves activation of NOS, increased NO, and cGMP levels, but not PKG. Rather, the pathway appears to involve PKA, partly by reducing cAMP breakdown through inhibition of PDE III. CO-induced NO production may explain the apparent discrepancy between the low affinity of guanylyl cyclase for CO and the robust cGMP production evoked by CO.


Regional planning--effects on the obstetrician-gynecologist.
Both the precepts and the impact of regional planning for maternity care are often misunderstood. Here, a summary of 8 separate studies in 5 geographic regions describes the reactions of obstetrician-gynecologists to systems of regional planning, as well as their use of the system and the impact of regional planning on their practices. Overall, few physicians acquired new obstetric privileges, and closure of maternity services had limited impact on their practices. Approximately 50% of the physicians referred some patients to level 2 or 3 units, but only 25% actually transferred patients in a given year. The perceptions of a majority of physicians were of improvement in patient services and physician education as a result of regional planning activities. Recommendations are offered for additional needed studies of regional planning efforts.


DEAD-box ATPases are global regulators of phase-separated organelles.
The ability of proteins and nucleic acids to undergo liquid-liquid phase separation has recently emerged as an important molecular principle of how cells rapidly and reversibly compartmentalize their components into membrane-less organelles such as the nucleolus, processing bodies or stress granules1,2. How the assembly and turnover of these organelles are controlled, and how these biological condensates selectively recruit or release components are poorly understood. Here we show that members of the large and highly abundant family of RNA-dependent DEAD-box ATPases (DDXs)3 are regulators of RNA-containing phase-separated organelles in prokaryotes and eukaryotes. Using in vitro reconstitution and in vivo experiments, we demonstrate that DDXs promote phase separation in their ATP-bound form, whereas ATP hydrolysis induces compartment turnover and release of RNA. This mechanism of membrane-less organelle regulation reveals a principle of cellular organization that is conserved from bacteria to humans. Furthermore, we show that DDXs control RNA flux into and out of phase-separated organelles, and thus propose that a cellular network of dynamic, DDX-controlled compartments establishes biochemical reaction centres that provide cells with spatial and temporal control of various RNA-processing steps, which could regulate the composition and fate of ribonucleoprotein particles.


10th anniversary review: addressing land degradation and climate change in dryland agroecosystems through sustainable land management.
Sustainable land management (SLM) is proposed as a unifying theme for current global efforts on combating desertification, climate change and loss of biodiversity in drylands. A focus on SLM will achieve the multiple goals of the three UN Conventions (UNCCD, UNFCCC and UNCBD) and in particular will address the roots causes of poverty and vulnerability to climate change rather than a current focus on adapting to climate change. The interlinkages between land degradation, climate change and loss of biodiversity are outlined together with a proposed set of interventions to achieve multiple goals. It is argued that improved land productivity is a viable goal to reduce poverty in drylands provided it is linked to payments for environmental services and better crop and weather insurances and coupled with alternative livelihoods that are not primarily dependent on land productivity. Obstacles to the achievement of SLM are discussed and the steps necessary to overcome them are presented. It is suggested that promoting SLM would be a better focus for the UNCCD than combating desertification.


Blackspotted rockskippers (Entomacrodus striatus) avoid refuges with conspecifics.
During an escape from predators, many animals need to evaluate and choose a refuge within seconds. We investigated refuge choice in the amphibious blackspotted rockskipper, Entomacrodus striatus, in Moorea, French Polynesia. Rockskippers are small combtooth blennies that inhabit rocky beaches and jetties at the aquatic/terrestrial interface. They are conspicuous for their eponymous jumping to/from refugia among rocks when threatened. We have observed refugia with both multiple conspecifics and solitary fish in the field, and here tested whether fish choose refugia that are occupied by conspecifics in the laboratory. E. striatus chose unoccupied refugia on the opposite side of the experimental tank in 11/14 trials, a significantly greater number of times than they chose occupied refugia. In 3/14 trials, fish chose occupied refugia, indicating that refuge occupation does not prohibit their use by conspecifics. We hypothesize that chemical stress signals from the occupying fish deter most fish from choosing the same refuge.


RNAi of Complex I and V of the electron transport chain in glutamate neurons extends life span, increases sleep, and decreases locomotor activity in Drosophila melanogaster.
RNAi targeting the electron transport chain has been proven to prolong life span in many different species, and experiments specifically with Drosophila melanogaster and Caenorhabditis elegans have shown a distinct role for neurons. To determine which subset of neurons is implicated in this life span extension, we used the GAL4/UAS system to activate RNAi against genes of Complex I and Complex V. We found life span extension of 18-24% with two glutamate neuron (D42 and VGlut) GAL4 lines. We used the GAL80 system to determine if the overlapping set of glutamate neurons in these two GAL4 lines imparts the life span extension. Limiting GAL4 activity to non-VGlut glutamate neurons in the D42 background failed to extend life span, suggesting that glutamate neurons have an important role in aging. Interestingly, RNAi of the electron transport chain in D42 glutamate neurons also caused an increase in daytime and nighttime sleep and a decrease in nighttime locomotor activity. Changes to sleep patterns and prolonged life span were not accompanied by any changes in female fertility or response to starvation. Our findings demonstrate that a small subset of neurons can control life span, and further studies can look into the contributions made by glutamate neurons.


Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches.
Recent advances in nanoscience and nanotechnology radically changed the way we diagnose, treat, and prevent various diseases in all aspects of human life. Silver nanoparticles (AgNPs) are one of the most vital and fascinating nanomaterials among several metallic nanoparticles that are involved in biomedical applications. AgNPs play an important role in nanoscience and nanotechnology, particularly in nanomedicine. Although several noble metals have been used for various purposes, AgNPs have been focused on potential applications in cancer diagnosis and therapy. In this review, we discuss the synthesis of AgNPs using physical, chemical, and biological methods. We also discuss the properties of AgNPs and methods for their characterization. More importantly, we extensively discuss the multifunctional bio-applications of AgNPs; for example, as antibacterial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer agents, and the mechanism of the anti-cancer activity of AgNPs. In addition, we discuss therapeutic approaches and challenges for cancer therapy using AgNPs. Finally, we conclude by discussing the future perspective of AgNPs.


Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia.
Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone.


Volumetric contrast-enhanced ultrasound imaging of renal perfusion.
To determine whether volumetric contrast-enhanced ultrasound (US) imaging has the potential to monitor changes in renal perfusion after vascular injury. Volumetric contrast-enhanced US uses a series of planar image acquisitions, capturing the nonlinear second harmonic signal from microbubble contrast agents flowing in the vasculature. Tissue perfusion parameters (peak intensity [IPK], time to peak intensity [TPK], wash-in rate [WIR], and area under the curve [AUC]) were derived from time-intensity curve data collected during in vitro flow phantom studies and in vivo animal studies of healthy and injured kidneys. For the flow phantom studies, either the contrast agent concentration was held constant (10 μL/L) with varying volumetric flow rates (10, 20, and 30 mL/min), or the flow rate was held constant (30 mL/min) with varying contrast agent concentrations (5, 10, and 20 μL/L). Animal studies used healthy rats or those that underwent renal ischemia-reperfusion injury. Renal studies were performed with healthy rats while the transducer angle was varied for each volumetric contrast-enhanced US image acquisition (reference or 0°, 45°, and 90°) to determine whether repeated renal perfusion measures were isotropic and independent of transducer position. Blood serum biomarkers and immunohistology were used to confirm acute kidney injury. Flow phantom results revealed a linear relationship between microbubble concentrations injected into the flow system and the IPK, WIR, and AUC (R(2) > 0.56; P < .005). Furthermore, there was a linear relationship between volume flow rate changes and the TPK, WIR, and AUC (R(2) > 0.77; P < .005). No significant difference was found between the transducer angle during data acquisition and any of the perfusion measures (P > .60). After induction of renal ischemia-reperfusion injury in the rat animal model (n = 4), volumetric contrast-enhanced US imaging of the injured kidney revealed an initial reduction in renal perfusion compared to control animals, followed by progressive recovery of vascular function. Volumetric contrast-enhanced US-based renal perfusion imaging may prove clinically feasible for detecting and monitoring acute kidney injury.


In vitro quantification of melanoma tumor cell invasion.
In order to quantify the invasiveness of melanoma tumor cells in vitro, a modification of the amniotic basement membrane (BM) model, described by Liotta et al. (Cancer Letters, 11, 141, 1980), was used in combination with radiolabeled tumor cells. B16-F10 metastatic murine melanoma cells and a derived clone (B16-F10L) were prelabeled with 0.1 muCi/ml of [14C]thymidine for 20-24 h in serum-free medium at 37 degrees C. Following incubation, fetal bovine serum was added to a concentration of 5 per cent, and the cells were allowed to grow to confluency for the next 24-28 h. The labeled cells were seeded onto amniotic membranes situated in Membrane Invasion Culture System (MICS) chambers at a density of 2.5 X 10(4) per well. At various times points, radioactivity of tumor cells that completely traversed the membrane was determined using an under-the-membrane sampling method. The average percent invasion demonstrated by the B16-F10 line was 2.75 per cent, and 3.65 per cent exhibited by the B16-F10L cell line after 48-53 h in vitro. Since it was apparent that some variability in thickness existed among membrane samples, a morphological analysis was performed on five sectors of a three-inch-diameter sample from four different placentae. Differences and similarities in BM thickness within the same sector were noted by this technique and could possibly contribute to some variability observed in tumor cell invasion in this model. Another parameter examined was the proliferation of tumor cells in the upper and lower wells of the MICS chambers. By 48 h, approximately 32.1 per cent of the B16-F10 cell line as well as the clone had replicated in the upper wells associated with the BMs compared with a 32.9 per cent replication in the lower wells, which reaffirmed the viability of the tumor cells under experimental conditions and insured similarly replicating populations of cells. In order to quantify the invasiveness of radiolabeled tumor cells accurately through a biological membranous barrier, the proper concentration of cells must be used, tumor cell heterogeneity should be taken into consideration, the technique of sampling radiolabeled invasive cells should be critically analysed, and thickness of the membranous barrier should all be considered as possible important factors in the quantitative analyses.


A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause.
To compare the effects of daily ingestion of soy flour (S), ground flaxseed (F), or wheat flour (W) muffins, on quality of life and hot flash frequency and severity in postmenopausal women. This was a double-blind, randomized, controlled, intention-to-treat trial. Ninety-nine women, 1 to 8 years after menopause, ingested muffins with 25 g of flaxseed (50 mg of lignans), 25 g of soy (42 mg of isoflavones), or wheat (control) daily for 16 weeks. Subjects completed the Menopause-specific Quality of Life instrument monthly along with daily hot flash frequency and severity diaries. Compliance measures included a 3-day food diary and urinary isoflavone and lignan analyses at weeks 0 and 16 and returned muffin counts monthly. Eighty-seven women (28, ground flaxseed muffins; 31, soy flour muffins; and 28, wheat flour muffins) completed the trial. Multivariate analysis of variance of all quality-of-life domains yielded an insignificant treatment x time interaction (F46,122 = 0.92, P = 0.62) but a significant time main effect (P <.0001). Repeated-measures analyses of covariance controlling for body mass index showed no significant group x time interaction nor time nor group differences on all quality-of-life domains and hot flash measures except severity. Hot flashes were less severe with flaxseed (P = 0.001) compared to placebo; however, the group x by time interaction was not significant. Phytoestrogen excretion analysis showed treatment group exposure as allocated and no contamination. Neither dietary flaxseed nor soy flour significantly affected menopause-specific quality of life or hot flash symptoms in this study.


Diurnal variations in brain iron concentrations in BXD RI mice.
Under normal and dietary iron deficiency conditions, the BXD recombinant inbred (RI) strains of mice show large variations in regional brain iron concentration, particularly in the ventral midbrain (VMB). In a study utilizing just one of the BXD strains, diurnal changes in subregional brain iron concentration were found, which were dependent on the brain region and sex of the mice. The focus of this study was to determine if diurnal changes in VMB can be found across other BXD RI strains and whether a diurnal effect would be common to all strains or variable across strains similar to the large strain variability in iron concentrations determined during the first part of the light phase. Eight RI (BXD type) strains of mice of both sexes were selected for this study. Mice were sacrificed at postnatal day 120: half in the light phase (LP) and half in the dark phase (DP) of the light-dark cycle. Iron concentrations were determined in VMB, which was the primary region of interest, and five other brain regions. Exploratory analysis was also done on liver and spleen iron concentrations to assess for diurnal changes. Three strains showed clear diurnal variation in iron in the VMB and the others strains showed diurnal variations in other regions. These changes were not equally apparent in both sexes. Exploratory analysis also found strain×sex-dependent diurnal differences in spleen and liver iron. In conclusion, significant brain-regional-specific diurnal changes in total iron concentrations were found in a selection of BXD RI mice. Sex and strain are functional determinates of which regions will be affected and in what direction the affect will be. The study provides an animal model for future work into determining the biological and genetic basis of circadian influences on VMB iron homeostasis.


Percutaneous Kirschner wire (K-wire) fixation for humerus shaft fractures in children: A treatment concept.
Fractures of the humeral shaft are uncommon, representing less than 10 percent of all fractures in children. Humeral shaft fractures in children can be treated by immobilisation alone. A small number of fractures are unable to be reduced adequately or maintained in adequate alignment, and these should be treated surgically. In the present study, Kirschner wires (K-wire) were used to achieve a closed intramedullary fixation of humeral shaft fractures. The objective of this study was to evaluate the efficacy of intramedullary K-wires for the treatment of humeral shaft fracture in children. This prospective study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from June 2005 to June 2010. Sixty-eight children with a mean age of 7.7 years (range, 2-14 years) were recruited from Emergency and out patient department having closed fracture of humerus shaft. All patients were operated under general anaesthesia. All patients were followed for 12 months. Out of 68 patients, 64 patients underwent union in 42-70 days with a mean of 56 days. Complications found in four patients who had insignificant delayed union which were united next 3 weeks. Intramedullary K-wires were removed after an average of 5 months without any complications. The results were excellent in 94.11% and good in 5% children. This technique is simple, quick to perform, safe and reliable and avoids prolonged hospitalization with good results and is economical.


Coding and Modulation for LMDS and Analysis of the LMDS Channel.
Local Multipoint Distribution Service (LMDS) has the potential to become a viable alternative to coaxial cable, fiber and other wired and wireless technologies providing "last mile" communication services. A major obstacle, however, is the high equipment cost. While for example cable modems supporting two-way services are available for $200 to $300, LMDS modem providing similar services will cost over $1000. The major cost driver of LMDS equipment is the radio frequency (RF) unit, as Ka-band technology still is quite expensive. The modem design must minimize the overall architecture cost, and low-cost modems requiring an expensive architecture should not be used. The channel characteristics of LMDS systems are very different from those of fiber, coaxial cable, and lower frequency wireless links, major channel impairments being non-linear high power amplifier (HPA), high phase noise and high co-channel interference. Modems should therefore be developed specifically for LMDS systems. This report deals with the choice of coding and modulation schemes, the LMDS channel, and how the channel impairments should be overcome by digital signal processing algorithms.


A novel method of loading samples onto mini-gels for SDS-PAGE: increased sensitivity and Western blots using sub-microgram quantities of protein.
Commercially available mini-gels for sodium dodecyl sulphate (SDS)-PAGE and Western blotting are limited both by the number of lanes that can be loaded per gel and the minimum amount of protein per lane that must be loaded. Here we describe a method for loading protein samples onto existing commercially available mini-gels that allows loading of 50 or more lanes per gel. The enhanced sensitivity of the method allows Western blotting with sub-microgram quantities of protein. Samples are loaded onto filter paper strips mounted on a plastic backing sheet, and film-wrapped strips on a separate dummy loader interdigitate with the sample strips, creating a physical barrier to lateral diffusion. The sample loader sandwich is placed on top of the stacking gel, and is compatible with all commercially available SDS-PAGE systems. Comparison of 15-lane mini-gels with 30-lane micro-loader strips reveals up to a 10-fold increase in sensitivity with the new method. Using 50- and 66-lane micro-loaders, sub-microgram quantities of protein produce reliable and quantifiable signal by Western blotting. Manipulation of the ionic conditions within dummy loader strips provides a mechanism for enhancing lateral resolution, allowing for the possibility of further miniaturization.


Monkey alcohol tissue research resource: banking tissues for alcohol research.
An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of ethanol (EtOH) and they metabolize it more rapidly than primates. The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates, specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent per day) over long periods of time (12 to 30 months) with concomitant pathological changes in endocrine, hepatic, and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the EtOH-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. The MATRR is a unique postmortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer EtOH using a standardized experimental paradigm to the broader alcohol research community. This resource provides a translational platform from which we can better understand the disease processes associated with alcoholism.


Long-term use of occlusal appliance has impact on sleep structure.
Acrylic occlusal appliances (OAs) have been used for temporomandibular disorders and sleep bruxism, but the effects of the treatment are still insufficiently evaluated. Two all-night polysomnographic recordings were made in a sleep laboratory on 14 bruxists (9 females and 5 males with mean age of 27·5 years). The measurement included basic polysomnography with additional masseter muscle electromyogram and movement recording (static charge-sensitive bed method) using randomisation. The base night recording was followed by the second study night after 8 weeks regular use of OA. The OA was made on the occlusal surface of the teeth of the upper jaw, and it was used at night time during the study period. With the OA, rapid eye movement sleep changed from 23·3% to 19·6% (P = 0·078), and slow wave sleep increased significantly from 10·2% to 14·7% (P = 0·039). Masseter contraction (MC) episodes occurred with similar frequency (9·7 vs. 10·5 episodes per hour, P = 0·272). The intensity of the rhythmic MC bursts within an episode decreased from 5·5 to 4·4 (P = 0·027). The groups were post hoc divided into responders and non-responders using a 20% change in MC episode per hour as a cut-off point. The results indicated that 43% of bruxists increased activity (negative responders), while 36% decreased (positive responders), and in 21%, there was no change in the level. It is concluded that OA does not have significant feedback inhibition on masseter muscle motor activity during sleep. However, OA may increase slow wave sleep.


Gastric Cancer Stem Cells Effect on Th17/Treg Balance; A Bench to Beside Perspective.
Gastric cancer stem cells (GCSCs), a small population among tumor cells, are responsible for tumor initiation, development, metastasis, and recurrence. They play a crucial role in immune evasion, immunomodulation, and impairment of effector immunity and believed to be emerged to change the balance of the immune system, importantly CD4+ T cells in the chronic inflamed tumor site. However, different subtypes of innate and adaptive immune cells are involved in the formation of the immune system in the tumor microenvironment, we would look at T cells in this study. Tumor microenvironment induces differentiation of CD4+ T cells into different subsets of T cells, mainly suppressive regulatory T cells (Treg), and T helper 17 (Th17) cells, although their exact role in tumor immunity is still under debate depending on tumor types and stages. Counterbalance between Th17 and Treg cells in the gastrointestinal system result in the homeostasis and normal function of the immune system, particularly mucosal immunity. Recent data demonstrated a high infiltration of Th17 and Treg cells into the gastric tumor site and proved that tumor microenvironment might disturb the balance between Th17 and Treg. It is possible to assume an association between activation of CSCs which contribute to metastasis in late stages, and the imbalanced Th17/Treg cells observed in advanced gastric cancer patients. This review intends to clarify the importance of gastric tumor microenvironment specifically CSCs in relation to Th17/Tregs balance firstly and to highlight the relevance of imbalanced Th17/Treg subsets in determining the stages and behavior of the tumor secondly. Finally, the present study suggests a clinical approach looking at the plasticity of T cells with a focus on Th17 as a promising dedicated arm in cancer immunotherapy.


DNA-protein cross-links induced by nickel compounds in intact cultured mammalian cells.
The carcinogenic activity of crystalline NiS has been attributed to phagocytosis and intracellular dissolution of the particles to yield Ni2+ which is thought to enter the nucleus and damage DNA. In this study the extent and type of DNA damage in Chinese hamster ovary CHO cells treated with various nickel compounds was assessed by alkaline elution. Both insoluble (crystalline NiS) and soluble (NiCl2) nickel compounds induced single strand breaks and DNA protein cross-links. The single strand breaks were repaired relatively quickly but the DNA-protein cross-links were present and still accumulating 24 h after exposure to nickel. Single strand breakage occurred at both non-cytotoxic and cytotoxic concentrations of nickel, however, DNA-protein cross-linking was absent when cells were exposed to toxic nickel levels. The concentration of nickel that induced DNA-protein cross-linking correlated with those metal concentrations that reversibly inhibited cellular replication.


Comparison of Microbial and Chemical Source Tracking Markers To Identify Fecal Contamination Sources in the Humber River (Toronto, Ontario, Canada) and Associated Storm Water Outfalls.
Storm water runoff is a major source of pollution, and understanding the components of storm water discharge is essential to remediation efforts and proper assessment of risks to human and ecosystem health. In this study, culturable Escherichia coli and ampicillin-resistant E. coli levels were quantified and microbial source tracking (MST) markers (including markers for general Bacteroidales spp., human, ruminant/cow, gull, and dog) were detected in storm water outfalls and sites along the Humber River in Toronto, Ontario, Canada, and enumerated via endpoint PCR and quantitative PCR (qPCR). Additionally, chemical source tracking (CST) markers specific for human wastewater (caffeine, carbamazepine, codeine, cotinine, acetaminophen, and acesulfame) were quantified. Human and gull fecal sources were detected at all sites, although concentrations of the human fecal marker were higher, particularly in outfalls (mean outfall concentrations of 4.22 log10 copies, expressed as copy numbers [CN]/100 milliliters for human and 0.46 log10 CN/100 milliliters for gull). Higher concentrations of caffeine, acetaminophen, acesulfame, E. coli, and the human fecal marker were indicative of greater raw sewage contamination at several sites (maximum concentrations of 34,800 ng/liter, 5,120 ng/liter, 9,720 ng/liter, 5.26 log10 CFU/100 ml, and 7.65 log10 CN/100 ml, respectively). These results indicate pervasive sewage contamination at storm water outfalls and throughout the Humber River, with multiple lines of evidence identifying Black Creek and two storm water outfalls with prominent sewage cross-connection problems requiring remediation. Limited data are available on specific sources of pollution in storm water, though our results indicate the value of using both MST and CST methodologies to more reliably assess sewage contamination in impacted watersheds. Storm water runoff is one of the most prominent non-point sources of biological and chemical contaminants which can potentially degrade water quality and pose risks to human and ecosystem health. Therefore, identifying fecal contamination in storm water runoff and outfalls is essential for remediation efforts to reduce risks to public health. This study employed multiple methods of identifying levels and sources of fecal contamination in both river and storm water outfall sites, evaluating the efficacy of using culture-based enumeration of E. coli, molecular methods of determining the source(s) of contamination, and CST markers as indicators of fecal contamination. The results identified pervasive human sewage contamination in storm water outfalls and throughout an urban watershed and highlight the utility of using both MST and CST to identify raw sewage contamination.


Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment.
Cystic fibrosis (CF) affects more than 30,000 people in the United States and 80,000 people worldwide. This life-threatening genetic disorder causes a buildup of thick, viscous mucus secretions in various organ systems, most commonly the gastrointestinal, pulmonary, and genitourinary systems. This article reviews the clinical manifestations, diagnosis, and monitoring of patients with CF as well as guidelines for management and emerging pharmacologic treatments.


Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells.
Helicobacter pylori, a common pathogen that causes chronic gastritis and cancer, has evolved to establish persistent infections in the human stomach. Epidemiological evidence suggests that H. pylori with both highly active vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), the major virulence factors, has an advantage in adapting to the host environment. However, the mechanistic relationship between VacA and CagA remains obscure. Here, we report that CagA interferes with eukaryotic endocytosis, as revealed by genome-wide screening in yeast. Moreover, CagA suppresses pinocytic endocytosis and the cytotoxicity of VacA in gastric epithelial cells without affecting clathrin-dependent endocytosis. Our data suggest that H. pylori secretes VacA to attack distant host cells while injecting CagA into the gastric epithelial cells to which the bacteria are directly attached, thereby protecting these attached host cells from the cytotoxicity of VacA and creating a local ecological niche. This mechanism might allow H. pylori to balance damage to one population of host cells with the preservation of another, allowing for persistent infection.


Pharmaceutically active secondary metabolites of microorganisms.
The antibiotics have been useful in our battles against infectious bacteria and fungi for over 50 years. However, many antibiotics are used commercially, or are potentially useful, in medicine for activities other than their antibiotic action. They are used as antitumor agents, immunosuppressive agents, hypocholesterolemic agents, enzyme inhibitors, antimigraine agents, and antiparasitic agents. A number of these products were first discovered as antibiotics which failed in their development as such, or as mycotoxins. In addition to the above alternative applications, new powerful antibiotics have been discovered and commercialized in recent years and others are in clinical testing at the moment. A few successful secondary metabolites appear to have no antibiotic activity. The recently increased development of resistance to older antibacterial and antifungal drugs is being met with the use or clinical testing of older, underutilized or previously nondeveloped narrow-spectrum antibacterial products as well as powerful semisynthetic antifungal agents.


Regulation of the herpesvirus saimiri oncogene stpC, similar to that of T-cell activation genes, in growth-transformed human T lymphocytes.
Herpesvirus saimiri strain C488, a T-cell tumor virus of New World primates, transforms human T lymphocytes to stable interleukin-2-dependent growth without need for further stimulation by antigen or mitogen. The transformed cell lines show the phenotype of activated mature T cells and retain many essential features of the primary parental cells, e.g., antigen specificity. In contrast to transformed New World monkey T cells, the human lines do not support lytic growth of the virus, even after chemical stimulation. Here we show that many viral genes remain silent during episomal persistence. However, the viral oncogene stpC is predominantly transcribed and translated to a stable cytoplasmic protein of 20 kDa that is heterogeneously expressed in individual cells. This 1.7-kb mRNA is bicistronic, encoding also Tip, a viral protein interacting with the T-cell-specific tyrosine kinase Lck. stpC/tip transcripts are heavily induced upon stimulation by mitogen or phorbol ester. Block of protein synthesis does not abolish transcription: treatment with cycloheximide greatly induces stpC/tip mRNA levels. Thus, this gene complex is regulated similarly to early T-cell activation genes. Constitutive and induced expression engage different transcription start sites. The T-cell regulation of the viral genes stpC and tip may contribute to the T-cell tropism of growth transformation by herpesvirus saimiri.


Pursuing colloidal diamonds.
The endeavor to selectively fabricate a cubic diamond is challenging due to the formation of competing phases such as its hexagonal polymorph or others possessing similar free energy. The necessity to achieve this is of paramount importance since the cubic diamond is the only polymorph exhibiting a complete photonic bandgap, making it a promising candidate in view of photonic applications. Herein, we demonstrate that due to the presence of an external field and delicate manipulation of its strength we can attain selectivity in the formation of a cubic diamond in a one-component system comprised of designer tetrahedral patchy particles. The driving force of such a phenomenon is the structure of the first adlayer which is commensurate with the (110) face of the cubic diamond. Moreover, after a successful nucleation event, once the external field is turned off, the structure remains stable, paving an avenue for further post-synthetic treatment.


Pneumothorax in lung metastasis of advanced soft tissue sarcoma patients treated with oral pazopanib.
Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to evaluate those in our patients. This was a single center retrospective study of incidence of pneumothorax in patients with lung metastases in advanced STS treated with oral pazopanib between July, 2016 and December, 2020. Patients were treated with pazopanib usually from 2nd line onwards with a dose ranging from 400 mg to 800 mg once daily. Total of 34 patients with lung metastasis in a setting of advanced STS were treated with oral pazopanib during the study period. The setting of pazopanib use was 2nd line in four and 1st line in one of them. The starting dose was 600 mg once daily in three patients, 400 mg OD in one patient, and 800 mg OD in one patient. Five patients developed pneumothorax with duration on pazopanib of 6, 7, 24, 6, and 2.5 months, respectively. Three patients had symptoms and required chest tube drainage. None of them were smokers or had any other underlying lung disease. The disease response of those patients was stable disease in four and partial response in one during treatment with pazopanib. One patient had a rechallenge with further pazopanib course without any recurrence of pneumothorax. Pneumothorax is a rare pulmonary complication after pazopanib use in patients with lung metastasis. Clinicians should be aware of this rare complication as literature is scarce. Rechallenge with pazopanib is feasible after pneumothorax.


Transcriptional activation through ETS domain binding sites in the cytochrome c oxidase subunit IV gene.
A mutational analysis of the rat cytochrome c oxidase subunit IV (RCO4) promoter region revealed the presence of a major control element consisting of a tandemly repeated pair of binding sites for a nuclear factor from HeLa cells. This factor was designated NRF-2 (nuclear respiratory factor 2) because a functional recognition site was also found in the human ATP synthase beta-subunit gene. Deletion or site-directed point mutations of the NRF-2 binding sites in the RCO4 promoter resulted in substantial loss of transcriptional activity, and synthetic oligomers of the NRF-2 binding sites from both genes stimulated a heterologous promoter when cloned in cis. NRF-2 binding and transcriptional activation required a purine-rich core sequence, GGAA. This motif is characteristic of the recognition site for a family of activators referred to as ETS domain proteins because of the similarity within their DNA-binding domains to the ets-1 proto-oncogene product. NRF-2 recognized an authentic Ets-1 site within the Moloney murine sarcoma virus long terminal repeat, and this site was able to compete for NRF-2 binding to the RCO4 promoter sequence. In addition, a single polypeptide of 55 kDa was detected following cross-linking of a partially purified NRF-2 fraction to RCO4, the human ATP synthase beta subunit, or Moloney murine sarcoma virus binding sites. However, in contrast to Ets-1, which appears to be exclusive to lymphoid tissues, NRF-2 has the broad tissue distribution expected of a regulator of respiratory chain expression.


Antimicrobial agents and the central nervous system.
There is an ever-expanding number of antimicrobial agents available for the clinician to use to combat infections. We review the majority of such agents that are currently available relative to their theoretical or proven efficacy in the treatment of CNS infections. Due to the unique ability of the CNS to exclude many agents delivered via the blood stream, easily administered and efficacious therapy remains a problem. Based on the pharmacokinetics of anti-infective drugs and their antimicrobial spectrum, at present a penicillin derivative or chloramphenicol should be used whenever possible because parenteral therapy will usually achieve the desired results. In many neurosurgery-associated infections, intrathecal or intraventricular antibiotics may be required to supplement parenteral treatment and/or surgical intervention. Some of the more promising agents (such as rifampin, trimethoprim-sulfamethoxazole, and metronidazole) await further clinical trials to establish their place in the therapeutic armamentarium. Careful, randomized, prospective studies of prophylactic antibiotics must be performed in the neurosurgical setting. A group of tables are included that summarize the expected spinal fluid levels, the sensitivities of organisms commonly causing neurosurgical infections, doses of drugs given intrathecally or intraventricularly, and recommended regimens for certain infections.


Age-dependent dynamics of Theileria equi and Babesia caballi infections in southwest Mongolia based on IFAT and/or PCR prevalence data from domestic horses and ticks.
Epidemiological factors of tick-borne equine piroplasmoses, caused by Theileria equi and Babesia caballi, were investigated using logistic regression (GLM) and general additive models (GAM) based on the prevalences determined in 510 domestic horses and in ticks in S.W. Mongolia by indirect immunofluorescence antibody test (IFAT) and/or multiplex PCR. Prevalences of T. equi and B. caballi in horses were 66.5% (95% CI: 62.1-70.7) and 19.1% (15.6-22.9), respectively by PCR and 78.8% (74.9-82.3) and 65.7% (61.3-69.9) by IFAT. Of 166 ticks analysed from PCR- and IFAT-negative horses 1 was PCR positive for B. caballi and none for T. equi. GAM demonstrated non-linear increasing proportions of T. equi-PCR and -IFAT positive horses with age suggesting persistent infection. In contrast, the B. caballi-PCR prevalence decreased with age despite a concurrent increase in the proportion of IFAT-positive animals suggesting parasite elimination. The tick (Dermacentor nuttalli) burden of the horses increased with age and decreased with advancing season. Geldings were more likely to be infected with, and seroconvert to, T. equi. Neither herd affiliation, date of sample collection nor abundance of tick infestation had a significant influence on parasite prevalence.


Aesthetic microtia reconstruction with Medpor.
The complex architecture of the auricle makes it one of the most challenging structures for the reconstructive surgeon to re-create. Overlying the ear's unique cartilage framework are layers of varied soft tissues forming a three-dimensional organ, which is distinctively positioned on the head. Arguably, the most challenging auricle to reconstruct is third-degree microtia due to a near-total absence of native tissue and a need for lifelong durability of the reconstruction. Many methods of reconstruction have been studied; autogenous costal cartilage reconstruction has been one of the more traditional methods, with favorable long-term results reported by several surgeons. However, this technique requires tremendous artistic and technical skill on the part of the surgeon-sculptor to construct a realistic-appearing ear. High-density porous polyethylene (Medpor) is a stable, alloplastic implant that can integrate with host tissues, is resistant to infection, and has been successfully applied to reconstruction of the head and neck. For auricular reconstruction, Medpor--enveloped in a temporoparietal fascial flap with full-thickness skin graft coverage--is a durable and aesthetically gratifying alternative in microtic patients. This alternative surgical technique reduces surgical time and morbidity, standardizes results among surgeons, and facilitates an aesthetic, natural-appearing reconstruction of the auricle.


New tools for learning.
In the last twenty-five years more has been learned about the human brain than in the past history of mankind. Through the use of new technologies such as PET and CAT scans and functional MRI's, it is now possible to see and learn much about the human brain while it is in the process of thinking. The research of neuroscientists, such as Marian Diamond, has demonstrated that the brain changes physiologically as a result of learning and experience--for better or worse--and that plasticity can continue throughout the lifespan. It appears that there are particular kinds of environments that are most conducive to the development of good mental equipment. They are positive, nurturing, stimulating, and encourage action and interaction. Many of the most effective schools and training programs have created such high-challenge low-threat environments. It is also very clear that intelligence is not a static structure, but an open, dynamic system that can continue to develop throughout life. This understanding is being utilized not only in school systems but in the workplace, where training programs show that even at the adult level people are able to develop their intelligence more fully. Corporations such as Motorola have implemented programs in which they are training their employees, managers, and executives to think, problem-solve and create more effectively using strategies developed by such educational innovators as Reuven Feurstein, J.P. Guilford, and Edward de Bono. A most recent development is in the new kinds of technology that make it possible for people to take responsibility for their own learning as they access and process information through the internet, communicate with experts anywhere in the world, and use software that facilitate higher order thinking and problem-solving. Computers are in no way replacing teachers, but rather these new tools allow them to spend more time being facilitators, mentors, and guides. As a result, teachers and students are able more often to collaborate on creating new knowledge as well as mastering the basics. As technology becomes more ubiquitous, there is growing recognition of the importance of the arts in humanizing the curriculum. "More high-tech, more need for high-touch" is becoming the by-word of many schools. They recognize that the arts are not only culturally important and civilizing influences, but they can facilitate the learning of almost any subject. I believe that these four concepts--the plasticity of the brain, the modifiability of intelligence, the use of technology as a powerful new tool for learning, and the renaissance of the arts in education--have major implications specifically for educational systems and generally for the future of our world. In this time of rapid change, leading-edge educational systems are equipping people with the ability to learn, unlearn, and relearn continually. They are giving students meaningful opportunities to apply what they have learned in order to turn information into knowledge. And--of critical importance if any of this is to lead to a healthy future--they are helping students to learn to use knowledge responsibly, ethically, and with integrity. Furthermore, they are involving students in experiences that develop compassion and altruism in the process of their education. Our complex world urgently needs more people who have developed their fullest potential in mind, body, and spirit.


Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain.
Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.


Specific binding of RGS9-Gbeta 5L to protein anchor in photoreceptor membranes greatly enhances its catalytic activity.
The complex between the short splice variant of the ninth member of the RGS protein family and the long splice variant of type 5 G protein beta subunit (RGS9-Gbeta5L) plays a critical role in regulating the duration of the light response in vertebrate photoreceptors by activating the GTPase activity of the photoreceptor-specific G protein, transducin. RGS9-Gbeta5L is tightly associated with the membranes of photoreceptor outer segments; however, the nature of this association remains unknown. Here we demonstrate that rod outer segment membranes contain a limited number of sites for high affinity RGS9-Gbeta5L binding, which are highly sensitive to proteolysis. In membranes isolated from bovine rod outer segments, all of these sites are occupied by the endogenous RGS9-Gbeta5L, which prevents the binding of exogenous recombinant RGS9-Gbeta5L to these sites. However, treating membranes with urea or high pH buffers causes either removal or denaturation of the endogenous RGS9-Gbeta5L, allowing for high affinity binding of recombinant RGS9-Gbeta5L to these sites. This binding results in a striking approximately 70-fold increase in the RGS9-Gbeta5L ability to activate transducin GTPase. The DEP (disheveled/EGL-10/pleckstrin) domain of RGS9 plays a crucial role in the RGS9-Gbeta5L membrane attachment, as evident from the analysis of membrane-binding properties of deletion mutants lacking either N- or C-terminal parts of the RGS9 molecule. Our data indicate that specific association of RGS9-Gbeta5L with photoreceptor disc membranes serves not only as a means of targeting it to an appropriate subcellular compartment but also serves as an important determinant of its catalytic activity.


Running up and down hills: some consequences of size.
Small mammals are able to run at about the same maximum speed vertically as horizontally, but larger mammals cannot do this. During level running a mouse weighing 30 grams uses about eight times as much energy per unit of body weight as does a chimpanzee weighing 17.5 kilograms (42.6 joules per kilogram meter versus 5.17 joules per kilogram meter). The additional energy required to lift 1 kilogram of body weight 1 meter while running uphill was similar for the two species (about 15.5 joules per kilogram meter). Therefore the increment in energy expenditure for mice to run uphill compared to running horizontally is about one-eighth that for a chimpanzee. Both mice and chimpanzees were able to recover about 90 percent of the energy stored running uphill on the way down.


CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma.
To understand the role of epigenetic inactivation of tumor-related genes in the pathogenesis of thyroid cancer, we investigated the methylation profile of distinct thyroid neoplasms. We analyzed the methylation pattern of 17 gene promoters in nine thyroid cancer cell lines and in 38 primary thyroid carcinomas (13 papillary thyroid carcinoma [PTC], 10 follicular thyroid carcinoma [FTC], 9 undifferentiated thyroid carcinoma [UTC], 6 medullary thyroid carcinoma [MTC]), 12 goiters, and 10 follicular adenomas (FA) by methylation- specific polymerase chain reaction (PCR). Epigenetic inactivation was validated by expression analysis. Twelve of these genes (RASSF1A, p16(INK4A), TSHR, MGMT, DAPK, ERalpha, ERbeta, RARbeta, PTEN, CD26, SLC5A8, and UCHL1) were frequently methylated in UTC (15%-86%) and thyroid cancer cell lines (25%-100%). In the more aggressive UTC, the mean methylation index (MI = 0.44) was the highest compared to other thyroid alterations PTC (MI = 0.29, p = 0.123), FTC (MI = 0.15, p = 0.005), MTC (MI = 0.13; p = 0.017), FA (MI = 0.27; p = 0.075) and goiters (MI = 0.23; p = 0.024). Methylation of TSHR, MGMT, UCHL1, and p16 occurred preferentially in UTC and this inactivation was reverted by a demethylating agent. Our results show that hypermethylation of several tumor-related gene promoters is a frequent event in UTC. The hypermethylation status may be reversed by DNA demethylating agents. Their clinical value remains to be investigated.


DNA for crime investigation: European co-operation model.
The article presents DNA related data exchange mechanism established within the framework of the European Union for the transnational crime investigation. First of all, it provides with the comprehensive overview of legal and practical state of play, pointing out that approved legal basis seeks to ensure legality and reliability in this area by establishing information exchange purposes and competent authorities involved, setting up technical requirements for the DNA analysis and DNA data bases, laying down provisions on accreditation of forensic service providers, foreseeing at least minimum common data protection requirements. Secondly, it reveals that despite being the most exhaustive international regulation on DNA related data exchange among law enforcement and judicial authorities it misses effective data protection mechanism, does not harmonize neither backgrounds for DNA collection in criminal process in general nor storage requirements and that results the variation in categories of subjects related to the crime investigation and included in data bases of different Member States. These gaps make the use of data collected and stored in another Member State vulnerable from the perspective of different rules on evidences' legality within the criminal process. The article also reveals the model's weakness in terms of assessment of its efficiency as statistics gathered for the time being show only number of coincidences (hits) of searched DNA profiles, but not the impact on crime investigation and its results.


Connecting bulk viscosity measurements to kinetic limitations on attaining equilibrium for a model aerosol composition.
The growth, composition, and evolution of secondary organic aerosol (SOA) are governed by properties of individual compounds and ensemble mixtures that affect partitioning between the vapor and condensed phase. There has been considerable recent interest in the idea that SOA can form highly viscous particles where the diffusion of either water or semivolatile organics within the particle is sufficiently hindered to affect evaporation and growth. Despite numerous indirect inferences of viscous behavior from SOA evaporation or "bounce" within aerosol instruments, there have been no bulk measurements of the viscosity of well-constrained model aerosol systems of atmospheric significance. Here the viscous behavior of a well-defined model system of 9 dicarboxylic acids is investigated directly with complementary measurements and model predictions used to infer phase state. Results not only allow us to discuss the atmospheric implications for SOA formation through this representative mixture, but also the potential impact of current methodologies used for probing this affect in both the laboratory and from a modeling perspective. We show, quantitatively, that the physical state transformation from liquid-like to amorphous semisolid can substantially increase the importance of mass transfer limitations within particles by 7 orders of magnitude for 100 nm diameter particles. Recommendations for future research directions are given.


Vasopressin and hypertension in man.
The role of vasopressin in human hypertension was examined in a series of studies. In patients with primary hyperaldosteronism and benign essential hypertension, circulating vasopressin was generally lower than in normotensive subjects. In contrast, plasma vasopressin was increased (p less than 0.001) in patients with malignant-phase hypertension. However, compared to infused vasopressin in normal subjects, when plasma levels of up to 120 pg/ml did not affect blood pressure, the increased levels found in malignant hypertension could not account for the hypertension. The possibility that there may be an increased pressor sensitivity to vasopressin in hypertension was examined by infusing the peptide into nine patients with essential hypertension. This showed a slight increase in sensitivity compared to normotensive subjects, but again this was insufficient to account for the discrepancy between the circulating level of vasopressin and the extent of the raised blood pressure in the hypertensive patients. The effect of chronically elevated levels of vasopressin was studied in a group of patients with the syndrome of inappropriate ADH excess as a consequence of bronchogenic carcinoma. In spite of having chronically elevated levels of vasopressin, these patients had normal blood pressures for their age and sex. Our results suggest that, although vasopressin is elevated in malignant hypertension, it does not contribute significantly to the raised blood pressure, and its increase is probably a consequence of volume shrinkage through renal salt and water loss.


Perfecting DNA double-strand break repair on transcribed chromatin.
Timely repair of DNA double-strand break (DSB) entails coordination with the local higher order chromatin structure and its transaction activities, including transcription. Recent studies are uncovering how DSBs trigger transient suppression of nearby transcription to permit faithful DNA repair, failing of which leads to elevated chromosomal aberrations and cell hypersensitivity to DNA damage. Here, we summarize the molecular bases for transcriptional control during DSB metabolism, and discuss how the exquisite coordination between the two DNA-templated processes may underlie maintenance of genome stability and cell homeostasis.


Carbon-based Biradicals: Structural and Magnetic Switching.
Sterically hindered C═C double bonds often deform into a bent or twisted geometry. Thus, many overcrowded ethylenes or anthraquinodimethanes can adopt multiple conformations, such as a folded form or a twisted form, which are interconvertible under the application of external stimuli. A perpendicular form with biradical character can also be adopted when designed to incorporate a stable carbon-based radical unit, which is involved in stimuli-responsive magnetic switching accompanied by a structural change. This review focuses on recent advances in the development of such strained π-electron systems and reveals the factors that affect the mutual interconversion and switching behavior. The energy barrier for the interconversion of conformational isomers is affected by the tricyclic skeleton or bulky substituents on the C═C double bonds, whereas the relative stability of the perpendicular biradical form increases with the additional insertion of 9,10-anthrylene units into the C═C double bonds.


Risk stratification and prognostic implication of plasma biomarkers in nondiabetic patients with stable coronary artery disease: the role of high-sensitivity C-reactive protein.
To evaluate the implication of plasma biomarkers to future cardiovascular events in nondiabetic patients with stable coronary artery disease (CAD). Designs and settings: Prospective, follow-up study at a tertiary referral center. Patients and measurement: Serial plasma biomarkers including high-sensitivity C-reactive protein (hsCRP), homocysteine, soluble adhesion molecules, von Willebrand factor, and lipid profiles were determined before coronary angiograms in a series of nondiabetic CAD patients with stable angina. Among them, 75 consecutive patients who received coronary revascularization (48 coronary interventions and 27 coronary bypass surgeries) later and another 75 age- and gender-matched patients who preferred medical treatment were both enrolled. In patients of each group, major cardiovascular events including cardiac death, nonfatal myocardial infarction, new or repeated coronary revascularization, and hospitalization for unstable angina, stroke, or peripheral artery disease were prospectively followed up for at least 6 months. Patients were followed up to 40 months (median, 18 months). The incidences of major cardiovascular events were similar between the two groups. For patients with medical treatment, plasma levels of hsCRP, homocysteine, low-density lipoprotein, and the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) were significantly higher in those with cardiovascular events than those without. However, only hsCRP > 0.1 mg/dL (relative risk [RR], 2.78; 95% confidence interval [CI], 1.21 to 6.41; p = 0.016) and TC/HDL-C ratio > 4.8 (RR, 2.42; 95% CI, 1.04 to 5.65; p = 0.041) were independent predictors by multivariable analysis. For patients with revascularization, basal plasma hsCRP levels were higher in those with cardiovascular events than those without (p = 0.04). However, no biochemical markers could predict future major cardiovascular events in these patients. In nondiabetic patients with CAD, basal plasma hsCRP levels were increased with future cardiovascular events regardless of different treatment strategies. Both plasma hsCRP level and TC/HDL-C ratio independently predict future cardiovascular events, confirming the role of plasma biomarkers in clinical risk stratification especially in patients with medical treatment.


Cerebral blood flow and cognitive function in obstructive sleep apnea syndrome.
Neuropsychological deficits are among the main symptoms of obstructive sleep apnea syndrome (OSAS), which could be related to impaired cerebral blood flow (CBF). We conducted a study in 20 subjects tested in our Sleep Laboratory, to assess regional CBF and cognitive function in OSAS. Our measurements included technetium-99m hexamethylamino propylenamine oxime brain perfusion scintigraphy in wakeful state, i.e. in the morning after polysomnography and also cognitive function tests after polysomnography, in 20 patients, 16 male and 4 female, aging between 30 and 60 years. We found that apnea-hypopnea index was greater than or equal to 5 in 16 (85%) subjects, consistent with OSAS. Mean arterial oxygen saturation during sleep was correlated with CBF in all regions. Cognitive function test scores in verbal memory were positively correlated with percentage of sleep duration with less than 90% of oxygen saturation during sleep. Cerebral blood flow was not uniform in OSAS patients, and was significantly lower in the left frontal and left temporal regions as compared to that of these regions on the right hemisphere. In conclusion, our findings indicated association of CBF and verbal memory with hypoxemia during sleep and decreased perfusion after apneic episodes in the left frontal and temporal lobes in OSAS patients, which could also indicate impairment of upper airway motor control.


RNA-seq analysis of the head-kidney transcriptome response to handling-stress in the red cusk-eel (Genypterus chilensis).
Stress is a primary contributing factor of fish disease and mortality in aquaculture. We have previously reported that the red cusk-eel (Genypterus chilensis), an important farmed marine fish, demonstrates a handling-stress response that results in increased juvenile mortality, which is mainly associated with skeletal muscle atrophy and liver steatosis. To better understand the systemic effects of stress on red cusk-eel immune-related gene expression, the present study assessed the transcriptomic head-kidney response to handling-stress. The RNA sequencing generated a total of 61,655,525 paired-end reads from control and stressed conditions. De novo assembly using the CLC Genomic Workbench produced 86,840 transcripts and created a reference transcriptome with a N50 of 1426bp. Reads mapped onto the assembled reference transcriptome resulted in the identification of 569 up-regulated and 513 down-regulated transcripts. Gene ontology enrichment analysis revealed a significant up-regulation of the biological processes, like response to stress, response to biotic stimulus, and immune response. Conversely, a significant down-regulation of biological processes is associated with metabolic processes. These results were validated by RT-qPCR analysis for nine candidate genes involved in the immune response. The present data demonstrated that short term stress promotes the immune innate response in the marine teleost G. chilensis. This study is an important step towards understanding the immune adaptive response to stress in non-model teleost species.


Breast cancer in patients treated for Hodgkin's disease: clinical and pathological analysis of 76 cases in 63 patients.
In a retrospective multicentric analysis, 63 women treated between 1941 to 1988 for Hodgkin's disease (HD) subsequently developed 76 breast cancers (BC). The median age at diagnosis of HD was 26 years (range 7-67), and 22 women (35%) were 20 years old or less. Exclusive radiotherapy (RT) was used in 36 women (57%) and combined modalities with chemotherapy (CT) in 25 (39%). Breast cancer occurred after a median interval of 16 years (range 2-40) and the median age at diagnosis of the first BC was 42 years (range 25-73). TNM classification (UICC, 1978) showed 10 T0 (non-palpable lesions) (13%), 20 T1 (26%), 22 T2 (29%), 8 T3 (11%), 7 T4 (9%) and 9 Tx (12%), giving altogether a total of 76 tumours, including, respectively, 5 and 8 bilateral synchronous and metachronous lesions. Among the 68 tumours initially discovered, 53 ductal infiltrating, one lobular infiltrating and two medullary carcinomas were found. Moreover, two fibrosarcomas and 10 ductal carcinoma in situ (DCIS) were also found. Among 50 axillary dissections for invasive carcinomas, histological involvement was found in 31 cases (62%). 45 tumours were treated by mastectomy, without (n = 35) or with (n = 10) RT. 27 tumours had lumpectomy, without (n = 7) or with RT (n = 20). 2 others received RT only, and one only CT. 7 patients (11%) developed isolated local recurrence. 20 patients (32%) developed metastases and all died; 38 are in complete remission, whereas 5 died of intercurrent disease. The 5-year disease-specific survival rate by the Kaplan-Meier method was 61%. The 5-year disease-specific survival rate for pN0, pN1-3 and pN > or = 3 groups were 91%, 66% and 0%, respectively (P < 0.0001) and 100%, 88%, 64% and 23% for the T0, T1, T2 and T3T4 groups, respectively. These secondary BCs seem to be of two types: a large number of aggressive tumours with a very unfavourable prognosis (especially in the case of pN > 3 and/or T3T4); and many tumours with a 'slow development' such as DCIS and microinvasive lesions, especially in patients treated exclusively by RT. Moreover, a very unusual rate of bilateral tumours (21%) was observed. These secondary BC could be 'in field', in 'border of field' or 'out of field'. However, a complete analysis of doses delivered by supradiaphragmatic irradiation was often very difficult, due to large variations in several parameters. We conclude that young women and girls treated for HD should be carefully monitored by clinical examination, mammography and ultrasonography.


Influence of the phosphorylation state of neurofilament proteins on the interactions between purified filaments in vitro.
The extensive enzymic dephosphorylation of neurofilaments determined the progressive loss of their capacity to interconnect in vitro into a reticulated network, measured by the formation of highly viscous gels in purified preparations of neurofilaments [Leterrier & Eyer (1987) Biochem. J. 245, 93-101]. Conversely, a cyclic AMP-dependent activation of the gelation process was obtained by phosphorylation of the neurofilament proteins by the cyclic-nucleotide-dependent protein kinase added to the preparation. These findings argue for a direct relationship between the high phosphorylation level of the neurofilament subunits and the cross-bridging of the polymers in vitro. However, a transient stimulation of the neurofilament viscosity kinetics was also observed during the early steps of dephosphorylation with acid phosphatase, which, moreover, disappeared with longer incubation times before the net inhibition was obtained. In the same way, the calmodulin-dependent brain phosphatase, calcineurin, induced a permanent activation of the phenomenon, correlated with a low dephosphorylation capacity of the neurofilament molecules. Taken together, these results suggest a functional heterogeneity of the numerous phosphate groups of the neurofilament subunits and raise the hypothesis of a highly controlled regulation of the neurofilament cross-bridging by selective phosphorylation-dephosphorylation mechanisms.


Dendritic cell biocompatibility of ether-based urethane films.
The use of synthetic materials for biomedical applications is ever expanding. One of the major requirements for these materials is biocompatibility, which includes prevention of immune system responses. Due to the inherent complexity of their structural composition, the polyurethane (PU) family of polymers is being used in a variety of medical applications, from soft and hard tissue scaffolds to intricate coatings on implantable devices. Herein, we investigated whether two polymer materials, D3 and D7, induced an immune response, measured by their effects on a dendritic cell (DC) line, JAWS II. Using a lactate dehydrogenase cytotoxicity assay and Annexin V/PI staining, we found that the PU materials did not induce cytotoxicity in DC cells. Using confocal microscopy, we also showed that the materials did not induce activation or maturation, as compared to positive controls. This was confirmed by looking at various markers, CD80, CD86, MHC class I, and MHC class II, via flow cytometry. Overall, the results indicated that the investigated PU films are biocompatible in terms of immunotoxicology and immunogenicity and show great promise for use in regenerative medicine.


The effect of ranitidine on the disposition of lignocaine.
The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.


Comparison of the validity of checklist assessment in cardiac arrest simulations with an app in an academic hospital in Taiwan: a retrospective observational study.
Robust assessment is a crucial component in Advanced Cardiac Life Support (ACLS) training to determine whether participants have achieved learning objectives with little or no variation in their overall outcomes. This study aimed to evaluate resuscitation performance by real-time logs. We hypothesised that instructors may not be able to evaluate time-sensitive parameters, namely, chest compression fraction, time to initiating chest compression and time to initiating defibrillation accurately in a subjective manner. Video records and formal checklist-based test results of Megacode scenarios for the ACLS certification examination at several hospitals in Taipei were examined. For the study interest, three time-sensitive parameters were measured via video review assisted by a mobile phone application, and were used for evaluation. We evaluated if the pass/fail results made by instructors via checklists were correlated with these parameters. A total of 185 Megacode scenarios were eligible for the final analysis. Among the three parameters, good chest compression fraction was statistically significant with a higher OR of passing (OR=3.65; 95% CI 1.36 to 9.91; p=0.01). In 112 participants with one parameter that did not meet the criteria, 25 were graded as fail, making the specificity 22.3% (95% CI 15.0% to 31.2%). Visual observation of cardiopulmonary resuscitation performance is not accurate when evaluating time-sensitive parameters. Objective results should be offered for training outcome evaluation, and also for feedback to participants.


Hepatocellular localisation of biosynthesis of vitronectin. Characterisation of the primary structure of rat vitronectin.
To characterize the primary structure of rat Vn, a cDNA library constructed from freshly isolated rat hepatocytes, was screened with a human Vn cDNA probe. Comparison of the sequence of the obtained rat cDNA clone with the sequences of human, mouse and rabbit Vn cDNA's showed predominantly consensus in the somatomedin B domain, the RGD-sequence and its flanking regions, in the first hemopexin type domain and at the carboxyl terminal part of Vn, the heparin binding site. To specify the liver cell type involved in the biosynthesis of Vn, we used a competitive PCR-assay to discriminate between expression levels. We found that expression of Vn in hepatocytes is at least 1000-fold higher than in Kupffer cells and 3000-fold higher than in endothelial liver cells.


Salivary gland ultrasonography: can it be an alternative to sialography as an imaging modality for Sjogren's syndrome?
Salivary ultrasonography (US) was evaluated as an alternative imaging modality to sialography for Sjögren's syndrome (SS). Parotid sialography and parotid and submandibular US were performed in 360 patients (188 with SS and 172 non-SS) who were suspected of SS and had fulfilled the American-European criteria (AEC) for SS or had received > or =3 of the objective examinations that were considered minimal requirements for classifying non-SS and had undergone both the imaging examinations. The glands were considered positive for SS if they exhibited peripheral sialoectatic changes on sialography and/or hypoechoic areas, echogenic streaks and/or irregular gland margins on US. The images obtained were independently rated as SS-positive or SS-negative by three radiologists in a blind fashion and the final decision was made by consensus. Interobserver and intermodality agreement was evaluated using kappa values for sialography and parotid and/or submandibular US. Average kappa values for the interobserver agreement were 0.81, 0.80 and 0.82 in sialography, parotid and submandibular US, respectively, indicating very good or good agreement. The kappa value for intermodality agreement between sialography and parotid US was 0.81 and between sialography and submandibular US was 0.76, indicating very good and good agreement, respectively. The diagnostic ability of parotid US was significantly lower than that of sialography (p<0.001, McNemar test). However, the diagnostic ability of submandibular US was comparable to that of sialography (p=0.153). Submandibular US is a promising technique that can be used as a practical alternative to sialography in the classification of SS.


A comparison of cerebral vasomotor reactivity in diabetic and nondiabetic Iranian patients.
Cerebral microangiopathy is one of the most important complications in diabetes. It may interfere with cerebral vasomotor reactivity (VMR) which may lead to disability, stroke or even death. The aim of the present study was to determine and compare VMR changes in diabetic and non- diabetic patients. Fifty three diabetic and 51 non- diabetic patients (with no other vascular abnormality) were recruited. Vasomotor reactivity was evaluated with Trans- Cranial Doppler (TCD) before and after CO2 inhalation. There were 69 (66.30%) males. The mean age was 41.53 ± 17.80 years. The general average of VMR was 5.79 ± 3.00%, the figures in diabetic and nondiabetic patients were 5.31 ± 2.60% and 6.62 ± 2.00%, respectively (p = 0.02). The average of flow velocity (FV) change was 42.47± 29.00 in diabetics and 53.34 ±16.70 in non- diabetic patients (p = 0.04). It is recommended that such non- invasive method is necessary for evaluation of cerebral vasculature in diabetic patients for better prevention.


Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway.
Although alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 46 days after injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared with corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (P < 0.05) and increased cytoplasmic staining of active-β-catenin in nontumor liver sections from EtOH+DEN mice compared with PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (P < 0.05); depletion of retinol and retinoic acid stores (P < 0.05); increased expression of cytosolic and nuclear expression of β-catenin (P < 0.05) and phosphorylated-glycogen synthase kinase 3β (p-GSK3β), P < 0.05; significant upregulation in Wnt7a mRNA expression; and increased expression of several β-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathways protein (WISP1), and matrix metalloproteinase-7(MMP7), P < 0.05. These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver.


A Myocardial Infarction Following a Mild Case of COVID-19 in a 26-Year-Old Male.
A well-known complication of COVID-19 is hypercoagulability in both the venous and arterial circulation. Most cases of hypercoagulability-related complications have been described in hospitalized patients with severe diseases and multiple comorbidities. However, this report outlines a case of myocardial infarction in a young patient with no prior medical history after only a mild course of COVID-19. His symptoms resolved after a mild 12-day illness course that did not require hospitalization or supplemental oxygen. Three days after the resolution of his symptoms (15 days after testing positive), the patient presented to the emergency department with crushing chest pain and was found to have complete thrombotic occlusion of his left anterior descending artery. Hypercoagulability in COVID-19 patients is suspected to be caused by vascular endothelial injury and cytokine storm. This has been demonstrated in the arterial and venous circulation, as seen in histopathology samples as well as increased incidence of acute limb ischemia in COVID-19 patients. Additionally, COVID-19 is known to have myocardial involvement, as demonstrated by elevations in cardiac enzymes and cardiac imaging findings that may persist months after initial infection. Those affected by COVID-19 may have dangerous cardiovascular complications that persist after the resolution of the acute viral illness.


In silico analysis of the structure and interaction of COP1 protein of Arabidopsis thaliana.
Previous studies have shown that COP1 (constitutive photomorphogenic 1) protein of Arabidopsis thaliana plays a crucial role in different aspects of photomorphogenesis. Interaction of COP1 with SPA1 (suppressor of phytochrome A) and other regulatory proteins actively affect light regulatory gene expression in diverse directions. Though several studies have explained the function of COP1 protein, method of its interaction with SPA1 and cryptochromes are still not explained in detail. In this study, in silico analysis was followed to predict the tertiary structure, active site residues, functionally important regions and regular expressions of COP1 protein. Its ease of its interaction with SPA1 and seven other regulatory proteins, namely bZIP transcription factor 56 (HY5), transcription factor HY5-like (HYH), serine/threonine-protein phosphatase 7 (AtPP7), protein long hypocotyl in FAR-RED 1 (HFR1), OBP3-responsive protein 1 (OBP3), transcription factor MYC2 (MYC2/ZBF1) and Z-box binding factor 2 protein (GBF1/ZBF2) was measured using protein-protein docking. Interaction with MYC2 was found to be stronger than with others with a global energy value of -22.46. It was also found that COP1 shared three regions of regular expression with SPA1, the last expression also being present in MYC2/ZBF1 and OBP3. Taken together, the insight into structural and functional properties of COP1 protein presented in this study would be helpful in determining the role of COP1 in unknown mechanisms of photomorphogenesis.


The Drosophila cohesin subunit Rad21 is a trithorax group (trxG) protein.
The cohesin complex is a key player in regulating cell division. Cohesin proteins SMC1, SMC3, Rad21, and stromalin (SA), along with associated proteins Nipped-B, Pds5, and EcoI, maintain sister chromatid cohesion before segregation to daughter cells during anaphase. Recent chromatin immunoprecipitation (ChIP) data reveal extensive overlap of Nipped-B and cohesin components with RNA polymerase II binding at active genes in Drosophila. These and other data strongly suggest a role for cohesion in transcription; however, there is no clear evidence for any specific mechanisms by which cohesin and associated proteins regulate transcription. We report here a link between cohesin components and trithorax group (trxG) function, thus implicating these proteins in transcription activation and/or elongation. We show that the Drosophila Rad21 protein is encoded by verthandi (vtd), a member of the trxG gene family that is also involved in regulating the hedgehog (hh) gene. In addition, mutations in the associated protein Nipped-B show similar trxG activity i.e., like vtd, they act as dominant suppressors of Pc and hh(Mrt) without impairing cell division. Our results provide a framework to further investigate how cohesin and associated components might regulate transcription.


Nesticus baeticus sp. n., a new troglobitic spider species from south-west Europe (Araneae, Nesticidae).
A new troglobitic species, Nesticus baeticussp. n. (♂♀), inhabiting the karst landscapes of the high part of the Cazorla, Segura and Las Villas Natural Park (NE Jaén, Spain) where it has been found in 8 caves is diagnosed and described, its distribution and habitat are also analyzed.The new species belongs to the Iberian species group that includes Nesticus luquei, Nesticus lusitanicus and Nesticus murgis. Evolutionary relationships of the Iberian Nesticus species are discussed on the basis of morphological and molecular data (cox1 and rrnL).


Cigarette smoking shortens the duration of daily leisure time physical activity in patients with intermittent claudication.
The authors determined (1) whether peripheral arterial occlusive disease (PAOD) patients who smoke have a reduction in either the duration or intensity of daily physical activities compared with nonsmoking patients, and (2) whether group differences in the pattern of physical activity persisted after controlling for potential confounding variables. A total of 170 smokers and 201 nonsmokers who had quit smoking for at least 1 year prior to investigation were studied. Physical activity patterns were measured using the Minnesota Leisure Time Physical Activity (LTPA) questionnaire. Patients also were characterized on potential covariates such as demographics, comorbid conditions, cardiovascular risk factors, ambulatory measures, peripheral hemodynamics, and anthropometric measures. The smokers were 37% less physically active than the nonsmokers (87 +/- 90 versus 139 +/- 121 kcal/day; P = 0.027). The reduced total LTPA in the smokers was due to a 28% shorter duration of performing activities (26 +/- 7 versus 36 +/- 22 min/day; P = 0.031), and a 3% lower mean intensity of the activities (3.3 +/- 1.0 versus 3.8 +/- 0.8 kcal/min; P = 0.038). The distance score on the Walking Impairment Questionnaire and the hip circumference were significant covariates of the LTPA measures. After adjusting for these covariates, the total LTPA remained 29% lower in the smokers (P = 0.039), the mean daily duration of LTPA remained 20% lower (P = 0.043), but the mean intensity of LTPA was no longer different between the groups. Compared with their nonsmoking counterparts, claudicants who smoke have a reduced total LTPA because they engage in activities of similar intensity for a shorter duration of time.