Can imaging be the new yardstick for diagnosing peripheral neuropathy?-a comparison between high resolution ultrasound and MR neurography with an approach to diagnosis.
Peripheral neuropathies are a group of disorders which affect the peripheral nervous system which have been conventionally diagnosed using electrodiagnostic studies. This study was carried out to assess the role of imaging in diagnosing peripheral mononeuropathy as exact anatomical localisation of the pathology is possible using high-resolution ultrasound and MR neurography, the modalities assessed in this study. A hospital-based prospective analytical study was carried out in a resource-limited setting on 180 peripheral nerves in 131 patients with symptoms of peripheral mononeuropathy after taking IRB approval. Each patient underwent high-resolution ultrasound examination and MR neurography, findings of which were then compared and statistically analysed assuming electrodiagnostic findings as the gold standard. Overall, the diagnostic accuracy was highest for the proton density fat-saturated MR sequence (93.89%) followed by high-resolution ultrasound (80%). The sensitivity was highest for proton density fat-saturated sequence while the T1 MR sequence had the highest specificity. Combined diagnostic accuracy of both modalities was calculated to be 93.33% with a negative predictive value of 80%. High-resolution ultrasound and MRI equally detected the cases with nerve discontinuity, while neuromas were better identified on MRI. With the advent of higher frequency probes and improved MR field strength, imaging of peripheral nerves is possible with better accuracy. Imaging assessment of nerves allows anatomical delineation with identification of exact site of involvement. This comparative study demonstrates the role of imaging in diagnosing peripheral nerve pathologies with the accuracy of MRI as high as 93.89% which may serve as an imaging gold standard. High-resolution ultrasound, being quicker, cost effective and a comparable accuracy of 80% can serve as a reliable screening tool. This study incorporates a larger study group and compares HRUS with MRI, taking NCV as gold standard, which has not been done in the preceding studies. With this study, we conclude that these two imaging modalities are not mutually exclusive. Rather, they complement each other and can be used in conjunction as an imaging yardstick for diagnosing peripheral neuropathies.


Epigenetic modifiers exert renal toxicity through induction of p66shc.
Trichostatin A (TSA) and 5-azacytidine (5AZA) induce reactive oxygen species (ROS)-mediated injury in renal proximal tubule cells. Since TSA and 5AZA are activators of p66shc, we questioned whether p66shc may mediate renal toxicity of TSA- and 5AZA. Renal proximal tubule cells were treated with either TSA or 5AZA for 24 hours followed by treatment with 200 μM H(2)O(2). Expression of p66shc and activity of its promoter, as well as its mitochondrial and cytochrome c binding were determined. Impact of knockdown of p66shc and mutation of its cytochrome c-binding site on ROS production and cell injury was studied. TSA, and 5AZA increased expression of p66shc through induction of its promoter and also increased its mitochondrial/cytochrome c binding. Knockdown or mutation of the cytochrome c binding site of p66shc attenuated ROS production and cell injury. Therapeutic means that interfere with induction of p66shc may ameliorate renal toxicity of those epigenetic modifiers.


Things can only get better.
Research waste reduces the usefulness of research. Rachel Dean describes the problem in veterinary science and suggests a way to increase the use of research results by practitioners.


The Rise in Single-Mother Families and Children's Cognitive Development: Evidence From Three British Birth Cohorts.
This article assessed changes in the association between single motherhood and children's verbal cognitive ability at age-11 using data from three cohorts of British children, born in 1958 (n = 10,675), 1970 (n = 8,933) and 2000 (n = 9,989), and mediation analysis. Consistent with previous studies, direct effects were small and insignificant. For those born in 1958 and 1970 indirect effects, operating through reduced economic and parental resources, were associated with -.107-SD to -.156-SD lower attainment. Differences between the two cohorts, and by children's age when parents separated, were insignificant. For the 2000 cohort, effect sizes for children born to single mothers did not change significantly (-.112-SD) but attenuated for children whose parents separated in early childhood (-.076-SD) or while of school age (-.054-SD).


Druggable chemical space and enumerative combinatorics.
There is a growing body of literature describing the properties of marketed drugs, the concept of drug-likeness and the vastness of chemical space. In that context, enumerative combinatorics with simple atomic components may be useful in the conception and design of structurally novel compounds for expanding and enhancing high-throughput screening (HTS) libraries. A random combination of mono- and diatomic carbon, hydrogen, nitrogen, and oxygen containing components in the absence of molecular weight constraints but with the ability to form rings affords virtual compounds that fall in bulk physicochemical space typically associated with drugs, but whose ring assemblies fall in new or under-represented areas of chemical shape space. When compared against compounds in the ChEMBL_14, MDDR, Drug Bank and Dictionary of Natural Products, the percentage of virtual compounds with a Tanimoto index of 1.0 (ECFP_4) was found to be as high as 0.21. Depending on therapeutic target, this value may be in range of what might be expected from an experimental HTS campaign in terms of a true hit rate. Virtual compounds derived through enumerative combinatorics of simple atomic components have drug-like properties with ring assemblies that fall in new or under-represented areas of shape space. Structures derived in this manner could provide the starting point or inspiration for the design of structurally novel scaffolds in an unbiased fashion.


Subharmonic signal generation from contrast agents in simulated neovessels.
Detection and measurement of blood flow in neovessels around a tumor can yield prognostic information about the tumor. Early detection and classification may help differentiate benign and malignant tumors; thus, improving patient management. This can be accomplished by injecting ultrasonic contrast agents and measuring the backscattered signals from them. Use of the subharmonic backscattered signals from these agents may be better than fundamental or second harmonic components because of the negligible subharmonics generated by the surrounding tissue. Preliminary results on the detection and measurement of subharmonic signal components up to 12 dB (at increasing pressures) from very small tubes (200 to 300 microm diameter) are reported, demonstrating the possibility and potential application of subharmonic imaging in detecting tumor angiogenesis.


Nitroglycerin in a transdermal therapeutic system in chronic heart failure.
Nitroglycerin (NTG) in a transdermal therapeutic system (TTS) was evaluated in 16 patients with severe chronic heart failure. Eight patients were given NTG TTS with an in vivo release rate of 5 mg/24 h. No significant changes in heart rate or blood pressure were observed. Pulmonary capillary wedge (PCW) pressure was reduced significantly from a control value of 29 +/- 4 mm Hg to 17 +/- 2 mm Hg after 1 h (p less than 0.01), and significant reduction was maintained for 24 h. The system was then removed and PCW pressure rose to 27 +/- 2 mm Hg after 2 h. NTG TTS, 10 mg/24 h, was applied and PCW pressure was again reduced significantly. Significant reduction in systemic vascular resistance and increases in cardiac and stroke volume indices occurred on the first day at 4 h but were not maintained. In another eight patients, the haemodynamic effects of NTG TTS (5 mg/24 h), oral isosorbide dinitrate (20 mg), and topical NTG ointment (1 inch) were compared. Significant reductions in PCW pressure were achieved with each method of treatment, but no significant alterations in other haemodynamic measurements were observed. Haemodynamic reevaluation of 10 patients treated with NTG TTS for 3 months showed partial attenuation of the reduction in PCW pressure compared with the initial response.


Prescribed-time stabilization of semi-linear parabolic equations subject to distributed disturbance.
In this paper, we investigate the problem of prescribed-time stabilization for a class of semilinear parabolic systems subject to spatiotemporal-varying disturbance via distributed control. By employing the time-varying feedback gain and disturbance suppression method, the proposed control law is continuous and stabilizes the closed-loop system within the prescribed time, where the convergence time is independent of initial values and can be given in advance as needed. When the upper bound of disturbance is known, we use a hyperbolic tangent function to restrain disturbance. While the upper bound of disturbance is unknown, we design the prescribed-time adaptive law and a prescribed-time disturbance observer estimating the disturbance itself. Some numerical examples are provided to verify the theoretical results.


Altered T cell subsets and function in polytransfused beta-thalassemia patients: correlation with sex and age at first transfusion.
Monoclonal antibodies (OKT series) have been used to investigate possible modifications of T lymphocytes and T lymphocyte subsets in 65 multiply transfused beta-thalassemia patients. No significant difference was observed in percentage and absolute number of OKT3-, OKT4-, and OKT8-positive cells when compared to controls. A subgroup of patients (10 patients, 15.3%), however, could be selected who showed a reversal of OKT4/OKT8 ratio. These patients did not differ from the others as to age, number of transfusions, frequency of splenectomy, ferritin levels, hepatitis B markers, chronic liver disease incidence, and numbers of B lymphocytes and natural killer cells. The features distinguishing this group from the remaining patients were: decreased mitogen responsiveness; early age when first transfused; high incidence of males (90%). Immunological investigation was done in 2 occasions, 1 year apart, but no significant modification was observed in these patients. These findings suggest that in beta-thalassemia patients transfusion therapy started very early in life may be responsible for persistent immunological modifications. The susceptibility to such modifications might be greater in males.


Chronic vocal cord palsy in Thuringia, Germany: a population-based study on epidemiology and outcome.
Although surgical treatment of patients with chronic vocal cord palsy (VCP) is an integral part of clinical routine of otorhinolaryngologists, there is nearly no population-based data published on incidence and efficiency of this surgery country-wide or nation-wide. 1430 patients with chronic VCP were treated in a department of otorhinolaryngology between 2005 and 2010 in Thuringia, Germany. VCP was unilateral and bilateral in 63 and 18%, respectively. The affected side was not documented in 20%. Iatrogenic lesions of the recurrent nerve (42%) and neoplastic infiltration (27%) were the leading etiologies. 192 patients (13%) received surgical treatment. 31% of patient needed more than one surgery. The rate of surgeries was higher for bilateral VCP (p < 0.0001). Vocal cord augmentation was the most frequent surgery for unilateral VCP and posterior cordectomy for bilateral VCP. The complication rate was high (16%), but not different between unilateral and bilateral VCP (p = 0.108). The risk for tracheostomy was higher in the bilateral VCP group (p < 0.0001). Voice improvement was better after treatment of unilateral VCP (p < 0.0001). Breathing improvement was more frequent after bilateral VCP (p = 0.028). Dysphagia did not improve significantly. The rate of better voice, breathing, and swallowing function was higher in patients treated surgically than without surgery (all p < 0.0001). The rate of patients admitted for treatment of vocal fold palsy was 9.9/100,000 habitants. The surgical rate of VCP was 1.38/100,000 habitants. This population-based analysis shows that surgery for VCP is performed with higher incidence than expected effectively, but with relevant risks in daily routine of otorhinolaryngologists.


Comparison between fat intake assessed by a 3-day food record and phospholipid fatty acid composition of red blood cells: results from the Monitoring of Cardiovascular Disease-Lille Study.
We investigated the relationship between assessment of fatty acid intake by a 3-day food record and by capillary gas chromatography of erythrocyte phospholipid fatty acid. The study was performed in a sample of 244 men aged 45 to 66 years from the general population who were participating in the Monitoring of Cardiovascular Disease (MONICA)-Lille survey. The relationship between each nutrient and food item and erythrocyte phospholipid fatty acid was investigated by a regression model on proportion including each food item and nutrient as a dependent variable and percentage of fatty acid and covariables (nonalcoholic energy intake, age, alcohol intake, and smoking) as independent variables. Polyunsaturated fat and linoleic acid intake were positively correlated with linoleic acid content of erythrocytes (beta = 0.641 and 0.604, respectively, P < .001). Monounsaturated and saturated fat intake were correlated with oleic acid (beta = 0.375 and 0.373, respectively, P < .01). Fish intake correlated positively with docosahexaenoic acid (DHA) (beta = 0.383, P < .001) and negatively with arachidonic acid (beta = -0.509, P < .01). These data confirm, on a group level, a good relationship between assessment of polyunsaturated fat intake by a 3-day record and linoleic acid content of erythrocyte membranes. These data suggest that erythrocyte oleic acid content is a marker of both saturated and monounsaturated fat intake.


Poorly differentiated, neuron-specific enolase positive round cell tumor with two translocations t(11;22) and t(21;22).
The authors describe a highly malignant, disseminated round cell tumor originating in the ninth rib of a 14-year-old boy. Extensive studies by means of light and electron microscopic examination, histocytochemistry and immunocytochemistry and cytogenetic analysis revealed an undifferentiated, neuron-specific enolase positive round cell tumor with a unique karyotype: 45,XY,-21,t(11;22)(q23;q11), der(22)t(21;22)(q11.2;p11). Thus, despite the absence of definite morphologic features, such as Homer-Wright rosettes, neurosecretory granules and cytoplasmatic processes, these findings suggest a neuroectodermal origin of this bone tumor.


Removal of the preputial glands alters the individual odors of male MHC-congenic mice and the preferences of females for these odors.
Inbred mice of MHC-congenic strains prefer to mate with mice of different MHC types. Mate selection based on MHC-type occurs through the urinary odors specific to each MHC-congenic mouse strain. Both urine and preputial gland odors of male mice have been postulated to act as female attractants and the present study examined the attraction of MHC-congenic female mice (C57BL/6J and B6-AKR.H-2k) to the urine and preputial gland odors of males. Females of both strains showed a greater attraction to the urine odors of intact males of the other MHC type, but did not show a preference for the urine odors of these males after their preputial glands were removed. There was, however, a preference for the preputial fluid of males of the other MHC type. These results indicate that the MHC-specific urinary odors of mice may arise from the preputial glands, and that it is the MHC-specific preputial gland odors of MHC-conspecific males that are used for mate selection by females.


The effect of orbital decompression surgery on refraction and intraocular pressure in patients with thyroid orbitopathy.
To investigate the effect of orbital decompression surgery in thyroid orbitopathy (TO) on both refractive status and intraocular pressure (IOP). A prospective, multicentre, consecutive audit of patients undergoing thyroid decompression surgery. Indications for surgery included cosmetically unacceptable proptosis or corneal exposure. Exclusion criteria included the following: previous orbital surgery, glaucoma, corneal disease, steroid use in the preceding 12 months, or an acute optic neuropathy. Automated refraction, keratometry, pachymetry, Hertel exophthalmometry, and IOP were recorded at 1 month pre- and 3 months postoperatively. IOP using the Tono-Pen (mean of three readings) was measured in the primary, upgaze, and downgaze positions. Data were collected from 52 orbits of 33 patients (East Grinstead, New York, and Adelaide). There was no significant difference between pre- and postoperative data for sphere, cylinder, or central corneal thickness (CCT). The mean spherical equivalent was -0.43 ± 1.49 D pre-operatively and -0.28 ± 1.52 D postoperatively. The steepest meridian of corneal curvature was 93.1 degrees pre- and 94.2 degrees postoperatively, with no significant difference. Mean IOP significantly decreased when measuring by Goldmann applanation tonometry (GAT) (2.28 mm Hg, (*) P=0.001) and Tono-Pen (3.06 mm Hg, (*) P=<0.0001). IOP measured in upgaze was significantly greater than that in the primary position. Regression analysis between change in IOP and either Hertel exophthalmometry or the number of orbital walls decompressed was non-significant ((*)Student's t-test). Patients with TO undergoing orbital decompression had, on average, with-the-rule astigmatism not affected by orbital decompression surgery. IOP was significantly reduced by decompression surgery although no relationship between IOP and the degree of decompression was observed.


Morphologic evaluation of Descemet's membrane and corneal endothelium in diabetes mellitus.
Diabetes mellitus is characterized by abnormally thickened basement membranes throughout the body and the eye. In addition, abnormal corneal endothelial cell morphology has been found in eyes of diabetics. The authors examined Descemet's membrane (the basement of the corneal endothelium) and the endothelial cells in 19 diabetic corneas and 19 age-matched nondiabetic normal corneas in a masked fashion by transmission electron microscopy and specular microscopy. No statistically significant quantitative or qualitative differences were found between the two groups.


Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens.
Our objectives were to determine the content of cytochrome P450 (CYP) 3A4, CYP3A5, and P-glycoprotein and to measure CYP3A4-dependent catalytic activity in paired human small intestinal and liver specimens. Samples of duodenum or proximal jejunum and liver wedge biopsy specimens were obtained from 15 patients undergoing a gastrointestinal operation. Enterocytes were isolated from the intestinal samples. The contents of CYP3A4, CYP3A5, and P-glycoprotein and CYP3A4-mediated catalytic activities were determined in homogenized enterocyte and liver samples. The CYP3A4 protein content was about 3 times (P <.01) and the P-glycoprotein content about 7 times (P <.0001) higher in the enterocyte homogenates than in the liver homogenates. CYP3A5 protein was detected in all samples, but the levels were too low in most cases to allow quantification. The 2 cases with a quantifiable hepatic CYP3A5 content had the CYP3A5*1/*3 genotype; all other cases were homozygous for the CYP3A5*3 allele. No intraindividual correlations between the intestine and liver with respect to CYP3A4 content, P-glycoprotein content, or the measured catalytic activities were present. Values for the maximum rate of metabolism (V(max)) of verapamil N-dealkylation (formation of D-617) and N-demethylation (formation of norverapamil) activities correlated with the CYP3A4 protein content in both organs. This work demonstrated a much higher content of both CYP3A4 protein and P-glycoprotein in enterocytes isolated from human duodenal or jejunal mucosa than in paired specimens of liver tissue. These results lend support to the view that biotransformation in the gut wall substantially contributes to the overall first-pass metabolism of many CYP3A4 substrates. Furthermore, the high content of P-glycoprotein on the apical surface of enterocytes supports the theory that this efflux transporter may act in concert with CYP3A4 to limit oral drug bioavailability. Finally, these results indicate that neither CYP3A4 nor MDR1 (P-glycoprotein) is coordinately regulated in the liver and intestine.


Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent.
Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR) promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved T cell expansion and anti-tumor function. These studies illuminate the interaction between tonic CAR signaling and the chosen expression platform and identify inhibitory properties of the 4-1BB costimulatory domain that have direct implications for rational CAR design.


Tritrophic interactions between aphids (Aphis jacobaeae Schrank), ant species, Tyria jacobaeae L., and Senecio jacobaea L. lead to maintenance of genetic variation in pyrrolizidine alkaloid concentration.
We hypothesize that the tritrophic interaction between ants, the aphid Aphis jacobaeae, the moth Tyria jacobaeae, and the plant Senecio jacobaea can explain the genetic variation observed in pyrrolizidine alkaloid concentration in natural populations of S. jacobaea. The ant Lasius niger effectively defends S. jacobaea plants infested with A. jacobaeae against larvae of T. jacobaeae. S. jacobaea plants with A. jacobaeae which are defended by ants escape regular defoliation by T. jacobaeae. Plants with aphids and ants have a lower pyrrolizidine alkaloid concentration than plants without aphids and ants. When these data are fitted to an existing theoretical model for temporal variation in fitness it is shown that varying herbivore pressure by T. jacobaeae in interaction with ants defending aphid-infested plants with a low pyrrolizidine alkaloid concentration can lead to a stable polymorphism in pyrrolizidine alkaloid concentration. Costs of the production and maintenance of pyrrolizidine alkaloids are not accounted for in the model.


SRT1720 ameliorates sodium taurocholate-induced severe acute pancreatitis in rats by suppressing NF-κB signalling.
Severe acute pancreatitis (SAP) is a medical emergency that is often associated with multiple organ failure and high mortality. Although an SAP diagnosis requires prompt treatment, therapeutic options remain limited. SRT1720 is a newly formulatedSIRT1 activator that exerts multiple pharmacological activities with beneficial health effects. However, its potential as an SAP treatment has not been explored. The current study assessed the effect of SRT1720 on a rat model of sodium taurocholate-induced SAP and explored the underlying mechanism. SAP was induced in rats by retrograde injection of a 3.5% sodium taurocholate solution (1 ml/kg) in the biliopancreatic duct. SRT1720 (5 mg/kg) was administered intraperitoneally after sodium taurocholate exposure. Serum samples were analysed for inflammatory cytokine levels and select enzymatic activities using the enzyme-linked immunosorbent assay and commercial enzyme activity assay kits, respectively; protein expression levels were evaluated by western blotting; mRNA levels of biomarkers were determined by quantitative real-time PCR; histopathological changes were analysed by haematoxylin and eosin staining and immunohistochemistry.SRT1720 treatment significantly reduced serum amylase, lipase, pancreatic histological scores, proinflammatory cytokine (TNF-α and IL-6) levels, and expression of NF-κB and p65 in sodium taurocholate-induced SAP rats. Importantly, the treatment stimulated SIRT1 and IκBα levels in pancreatic tissue. Our data suggest that SRT1720 protects rats from sodium taurocholate-induced SAP by suppressing the NF-κB signalling pathway.


The KCNQ1-KCNE2 K⁺ channel is required for adequate thyroid I⁻ uptake.
The KCNQ1 α subunit and the KCNE2 β subunit form a potassium channel in thyroid epithelial cells. Genetic disruption of KCNQ1-KCNE2 causes hypothyroidism in mice, resulting in cardiac hypertrophy, dwarfism, alopecia, and prenatal mortality. Here, we investigated the mechanistic requirement for KCNQ1-KCNE2 in thyroid hormone biosynthesis, utilizing whole-animal dynamic positron emission tomography. The KCNQ1-specific antagonist (-)-[3R,4S]-chromanol 293B (C293B) significantly impaired thyroid cell I(-) uptake, which is mediated by the Na(+)/I(-) symporter (NIS), in vivo (dSUV/dt: vehicle, 0.028 ± 0.004 min(-1); 10 mg/kg C293B, 0.009 ± 0.006 min(-1)) and in vitro (EC(50): 99 ± 10 μM C293B). Na(+)-dependent nicotinate uptake by SMCT, however, was unaffected. Kcne2 deletion did not alter the balance of free vs. thyroglobulin-bound I(-) in the thyroid (distinguished using ClO(4)(-), a competitive inhibitor of NIS), indicating that KCNQ1-KCNE2 is not required for Duox/TPO-mediated I(-) organification. However, Kcne2 deletion doubled the rate of free I(-) efflux from the thyroid following ClO(4)(-) injection, a NIS-independent process. Thus, KCNQ1-KCNE2 is necessary for adequate thyroid cell I(-) uptake, the most likely explanation being that it is prerequisite for adequate NIS activity.


Enantiomerization and hydrolysis of (+/-)-7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide by stopped-flow multidimensional high-performance liquid chromatography.
A novel stopped-flow multidimensional HPLC (sf-MD-HPLC) procedure has been developed to investigate simultaneously the effect of the pH on the enantiostability and hydrolysis of (+/-)-7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide [(+/-)IDRA21]. It was possible to determinate the rate constants and free energy barriers of enantiomerization and hydrolysis rate constants of (+/-)IDRA21, by using two chiral stationary phases (CSPs) and one achiral C18 column. A classical batchwise kinetic method was used to calculate rate constants of hydrolysis at the same temperature and in the same buffers used in sf-MD-HPLC. The good agreement of the results obtained validate the sf-MD-HPLC procedure. Furthermore, hydrolysis rate constants of (+/-)IDRA21 were calculated in a series of buffers over a pH range of 1.20-10.60 at 37 degrees C in order to evaluate the influence of the pH on hydrolysis.


JMJD1A promotes tumorigenesis and forms a feedback loop with EZH2/let-7c in NSCLC cells.
Lung cancer is the most common cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for 80 to 85 % of all lung cancer. Although the standard treatment regimen has been established, long-term survival for NSCLC patients is still generally poor. The histone demethylase Jumonji domain containing 1A (JMJD1A) has been proposed as an oncogene in several types of human cancer, but its clinical significance and functional roles in NSCLC remain largely unclear. In the present study, JMJD1A was frequently upregulated in NSCLC compared with para-carcinoma tissues. JMJD1A knockdown significantly inhibited NSCLC cell growth, migration, and invasion in vitro and tumorigenesis in vivo. Further experiments demonstrated that JMJD1A knockdown could decrease the expression of EZH2, which has been shown to play a crucial role in the carcinogenesis of NSCLC and, in turn, increase the expression of anti-tumor microRNA let-7c. Also, let-7c directly targeted the 3'-untranslated regions of JMJD1A and EZH2. Taken together, JMJD1A could promote NSCLC tumorigenesis. JMJD1A/EZH2/let-7c constituted a feedback loop and might represent a promising therapeutic target for NSCLC.


Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?
Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction. Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot. After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression. Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function.


Association between tumor diameter and lymphovascular space invasion among women with early-stage endometrial cancer.
To investigate the association between tumor diameter and intratumoral risk factors that might predict the need for full surgical staging among women with endometrial cancer (EC). Data from patients with early-stage EC treated at the Istituto Nazionale dei Tumori, Milan, Italy, between January 2004 and December 2012 were retrospectively analyzed. Associations between tumor diameter and tumor grade, myometrial invasion, risk group, lymphovascular space invasion (LVSI), and lower uterine segment (LUS) involvement were assessed by bivariate and multivariate analysis. In total, 181 patients met the inclusion criteria. The tumor diameter was 2cm or less in 110 women (60%). χ(2) analysis showed that tumor grading, myometrial invasion, risk group, and LVSI were significantly associated with tumor size (P<0.001), whereas LUS involvement was marginally associated (P=0.051). By multivariate analysis, LVSI and myometrial invasion had an independent association with tumor size greater than 2cm (P<0.018). Tumor size greater than 2cm was significantly and independently associated with LVSI and myometrial invasion among patients with early-stage EC. Given the difficulty of obtaining reliable LVSI data from frozen sections, tumor size might be used as a surrogate at the time of surgery to provide additional information to triage patients for full surgical staging.


Gender differences in fascicular lengthening during eccentric contractions: the role of the patella tendon stiffness.
Elastic tendons have been suggested to attenuate fascicle lengthening during eccentric contractions; however, there is no in vivo evidence to support this hypothesis. Therefore, the aim of this study was to determine whether patella tendon stiffness modulates vastus lateralis (VL) fascicle lengthening during eccentric contractions in males and females. Vastus lateralis and patella tendon properties were measured in males and females owing to previously reported intrinsic gender differences in tendon properties. During maximal voluntary eccentric knee extensions, VL fascicle lengthening and torque were recorded at every 10° (range of motion 20-90°). A significant correlation between maximal patella tendon stiffness and change in fascicle length (r=0.476, P=0.023) was observed. Similarly, there was a significant correlation between maximal Young's modulus and change in fascicle length (r=0.470, P=0.049). As expected, patella tendon stiffness and Young's modulus were significantly higher in males compared with females (P<0.05). Interestingly, change in VL fascicle length during the eccentric contractions was significantly greater in males compared with females (P<0.05). Based on patella tendon moment arm measurements, VL muscle-tendon unit elongation was estimated to be significantly greater in males compared with females (5.24 and 4.84 cm respectively). The significant difference in fascicle lengthening during eccentric contractions may be partly explained by the significantly higher patella tendon moment arm, patella tendon stiffness and Young's modulus found in males compared with females. The current study provides in vivo evidence to support the hypothesis that the tendon acts as a 'mechanical buffer' during eccentric contractions.


Determination of the painful level in osteoporotic vertebral fractures--Retrospective comparison between plain film, bone scan, and magnetic resonance imaging.
Determining the actual painful vertebral level is difficult when evaluating osteoporotic vertebral fracture, especially when there are acute and chronic fractures simultaneously. In this study, we retrospectively evaluated and compared the findings between plain film, bone scan, and magnetic resonance imaging (MRI) in the diagnosis of new fracture in osteoporotic vertebral fractures. This is a retrospective clinical study of patients who were diagnosed with osteoporotic vertebral fractures using plain film, bone scan, and MRI within a 1-month interval between February 2008 and December 2012. The findings in plain film, the extent of increased uptake in bone scan, and signal change in MRI were compared to evaluate the actual level of pain. All patients received percutaneous vertebroplasty according to MR finding. Pain scores (visual analog scale) of the study patients were compared prior to and after the procedure. A total of 52 patients with a mean age of 79.1 years (range 59-92 years) were enrolled in this study, and were treated by vertebroplasty confirmed by MRI. It was observed that patient pain score (visual analog scale) improved from 7.6 to 2.8. Plain film examination revealed 79 vertebrae that were suspected to be compression fractures. Among the suspected vertebrae, 62 showed increased uptake in bone scan, and MRI showed bony edema change in 58 vertebrae. The consistency between bone scan and MRI was 96.9% in patients with single-level suspected fracture on plain film. There was moderate agreement (kappa was 0.56) in patients where multiple levels were noted. Fifteen vertebrae with vacuum cleft sign on plain film showed total concordance in both bone scan and MRI. For patients with single-level compression fracture, the painful level in osteoporotic vertebral fractures can be determined by plain film and bone scan testing. Vacuum cleft sign noted on plain film may be enough to localize the level of pain. However, MRI testing is further needed in multiple osteoporotic vertebral fracture patients.


A Novel circ_0104345/miR-876-3p/ZBTB20 Axis Regulates the Proliferation, Migration, Invasion, and Apoptosis of Breast Cancer Cells.
Breast cancer (BC) is one of the most common malignant tumors in women. CircRNA/miRNA/mRNA regulatory axes have been shown to be involved in the pathogenesis of BC. Here, we sought to analyze the functional mechanism of circ_0104345 in BC. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the levels of circ_0104345, miR-876-3p and zinc finger and BTB domain containing 20 (ZBTB20) mRNA. Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to test cell viability and proliferation, respectively. Cell migration was tested by wound healing assay, and cell invasion was examined by transwell assay. Tube formation ability was tested by angiogenesis assay. Flow cytometry was applied for cell apoptosis. Western blot assay was utilized to measure the protein expression. The relationship between miR-876-3p and circ_0104345 or ZBTB20 was identified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenografts in mice were conducted to analyze the effect of sh-circ_0104345 on tumor growth in vivo. Circ_0104345 and ZBTB20 were upregulated and miR-876-3p expression was decreased in BC. Circ_0104345 knockdown inhibited cell proliferation, migration, invasion, and enhanced cell apoptosis. MiR-876-3p was targeted by circ_0104345. MiR-876-3p depletion reversed the effects of circ_0104345 downregulation on the progression of BC cells. ZBTB20 was regulated by circ_0104345 through miR-876-3p. The effects of miR-876-3p on BC cell behaviors were restored by ZBTB20 increase. The results of in vivo experiments indicated that silencing of circ_0104345 blocked the growth of xenograft tumors. In this study, we demonstrated, for the first time, the crucial regulation of the new circ_0104345/miR-876-3p/ZBTB20 axis in the biological phenotypes of BC cells.


Structure, mechanical properties, corrosion behavior and cytotoxicity of biodegradable Mg-X (X=Sn, Ga, In) alloys.
As-cast Mg-Sn, Mg-Ga and Mg-In alloys containing 1-7 wt.% of alloying elements were studied in this work. Structural and chemical analysis of the alloys was performed by using light and scanning electron microscopy, energy dispersive spectrometry, x-ray diffraction, x-ray photoelectron spectroscopy and glow discharge spectrometry. Mechanical properties were determined by Vickers hardness measurements and tensile testing. Corrosion behavior in a simulated physiological solution (9 g/l NaCl) was studied by immersion tests and potentiodynamic measurements. The cytotoxicity effect of the alloys on human osteosarcoma cells (U-2 OS) was determined by an indirect contact assay. Structural investigation revealed the dendritic morphology of the as-cast alloys with the presence of secondary eutectic phases in the Mg-Sn and Mg-Ga alloys. All the alloying elements showed hardening and strengthening effects on magnesium. This effect was the most pronounced in the case of Ga. All the alloying elements at low concentrations of approximately 1 wt.% were also shown to positively affect the corrosion resistance of Mg. But at higher concentrations of Ga and Sn the corrosion resistance worsened due to galvanic effects of secondary phases. Cytotoxicity tests indicated that Ga had the lowest toxicity, followed by Sn. The most severe toxicity was observed in the case of In.


Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP-mediated mechanism.
Intrahepatic bile duct epithelial cells, or cholangiocytes, contribute to bile secretion in response to hormones, including secretin. However, the mechanism by which secretin stimulates ductular bile flow is unknown. Since recent data in nonhepatic epithelia have suggested a role for exocytosis in fluid secretion, we tested the hypothesis that secretin stimulates exocytosis by isolated cholangiocytes. Cholangiocytes were isolated from normal rat liver by a newly described method employing enzymatic digestion and mechanical disruption followed by immunomagnetic separation using specific monoclonal antibodies, and exocytosis was measured using a fluorescence unquenching assay employing acridine orange. Secretin caused a dose-dependent (10(-12)-10(-7) M) increase in acridine orange fluorescence by acridine orange-loaded cholangiocytes with a peak response at 10 min; the half-maximal concentration of secretin was 7 x 10(-9) M. The secretin effect was inhibited by preincubation of cholangiocytes with colchicine (30% inhibition, p less than 0.05) or trypsin (90% inhibition, p less than 0.001); no inhibition was seen with lumicolchicine and heat-inactivated trypsin. Cholecystokinin, insulin, and somatostatin had no effect on fluorescence of acridine orange-loaded cholangiocytes; secretin had no effect on fluorescence of acridine orange-loaded hepatocytes or hepatic endothelial cells. Exposure of isolated cholangiocytes to secretin at doses that stimulated exocytosis caused a dose-dependent increase in cyclic AMP levels (218% maximal increase, p less than 0.05); moreover, an analogue of cyclic AMP stimulated exocytosis by cholangiocytes. Secretin had no effect on intracellular calcium concentration using Fura-2-loaded cholangiocytes assessed by digitized video microscopy. Our results demonstrate, for the first time, that secretin stimulates exocytosis by rat cholangiocytes. The effect is cell- and hormone-specific, dependent on intact microtubules, on a protein(s) on the external surface of cholangiocytes, and on changes in cellular levels of cyclic AMP. The results are consistent with the hypothesis that secretin-induced changes in bile flow may involve an exocytic process.


Electrophysiological Correlates of Blast-Wave Induced Cerebellar Injury.
Understanding the mechanisms underlying traumatic neural injury and the sequelae of events in the acute phase is important for deciding on the best window of therapeutic intervention. We hypothesized that evoked potentials (EP) recorded from the cerebellar cortex can detect mild levels of neural trauma and provide a qualitative assessment tool for progression of cerebellar injury in time. The cerebellar local field potentials evoked by a mechanical tap on the hand and collected with chronically implanted micro-ECoG arrays on the rat cerebellar cortex demonstrated substantial changes both in amplitude and timing as a result of blast-wave induced injury. The results revealed that the largest EP changes occurred within the first day of injury, and partial recoveries were observed from day-1 to day-3, followed by a period of gradual improvements (day-7 to day-14). The mossy fiber (MF) and climbing fiber (CF) mediated components of the EPs were affected differentially. The behavioral tests (ladder rung walking) and immunohistological analysis (calbindin and caspase-3) did not reveal any detectable changes at these blast pressures that are typically considered as mild (100-130 kPa). The results demonstrate the sensitivity of the electrophysiological method and its use as a tool to monitor the progression of cerebellar injuries in longitudinal animal studies.


Macrophage I-A/I-E expression and macrophage-stimulating lymphokines in murine lupus.
Seeking common abnormalities in mice genetically predisposed to lupus-like autoimmune disease, we investigated (1) the ontogeny of Ia antigens (I-A/I-E) on the surfaces of resident peritoneal macrophages (rpM phi) of lupus and normal mice, (2) spontaneous and lectin-induced in vitro production of M phi-stimulating factors (interferon, IFN; M phi-activating factor, MAF; M phi-Ia-inducing/recruiting factor, MIRF), and (3) responses of rpM phi from such animals to Ia-inducing signals. Indirect immunofluorescence techniques showed that Ia+ rpM phi increased numerically during the life spans of MRL/Mp lpr/lpr, while no such increase was observed in age-matched non-lpr MRL/Mp +/+ or (MRL/Mp lpr/lpr X MRL/Mp +/+)F1 hybrid mice. However, neonatal thymectomy, which prevents lymphoproliferation and autoimmune disease in MRL/Mp lpr/lpr mice, had no effect on this enhanced M phi I-A/I-E expression. NZB mice developed a similar increase with age, whereas BXSB and (NZB X NZW)F1 lupus mice, like immunologically normal controls, had low numbers of I-A/I-E+ rpM phi. Cultured splenocytes of lupus mice, including those with high percentages of I-A/I-E+ rpM phi, did not spontaneously (in the absence of mitogens) elaborate MIRF, MAF, or IFN activity. Furthermore, concanavalin A-stimulated splenocytes from lupus mice, particularly strains with early autoimmune disease manifestations [MRL/Mp lpr/lpr, male BXSB, and female (NZB X NZW)F1] produced levels of these lymphokines that were lower than normal controls. MRL/Mp lpr/lpr and NZB rpM phi, when stimulated in vitro with the supernatant of a MIRF-producing T cell hybridoma, did not hyperrespond. Our study shows that increased I-A/I-E+ rpM phi occur in some, but not all, lupus mice and this increase does not correlate with increased spontaneous or mitogen-induced production of M phi-stimulating lymphokines nor with hyperresponsiveness to Ia-inducing signals.


Carcinoma of the laryngeal saccule: a novel biopsy technique to make a difficult diagnosis.
Tumours of the laryngeal ventricle and saccule are rare and difficult to diagnose endoscopically. We present a case in which the tumour remained confined within the saccule, and describe how the problem of obtaining a positive biopsy was overcome.


The use of reserpine for elderly hypertensive patients.
Antihypertensives are among the most commonly prescribed drugs for the elderly. Several studies have discussed the benefits of stepped-care drug therapy for hypertension in the elderly, and propranolol, methyldopa, and more recently, clonidine and prazosin have been recommended as step-two antihypertensive drugs. Recent articles omit reserpine as an alternative. A case is made for the use of reserpine by comparing factors of special importance to most elderly: cost, side-effects, frequency of dosage, number of tablets, and the effect of omitted doses.


From a glucocentric to a lipocentric approach towards metabolic syndrome.
Insulin resistance, the essential component of metabolic syndrome, has traditionally been defined from a glucocentric viewpoint, with glucotoxicity playing a lead role. However, as overabundant circulating fatty acids are now known to be overt contributors, there is a paradigm shift in the understanding of metabolic syndrome acknowledging the importance of lipotoxicity as a major perpetuator of insulin resistance. Ectopic accumulation of fat in liver, adipose, muscle and pancreatic islets, provokes insulin resistance through various mechanisms. Chronic inflammation/adipocytokine generation, endoplasmic reticulum stress and mitochondrial dysfunction/oxidative stress also contribute significantly towards insulin resistance. Targets that can act as counter regulators/master switches at the converging point of all these metabolic pathways are currently under intense development.


HLA Class I Binding of Mutant EGFR Peptides in NSCLC Is Associated With Improved Survival.
Cancer-associated mutations have the potential to generate neoantigens and elicit CD8-positive T-cell-dependent adaptive immune responses. There are currently no reports of CD8-positive T-cells with specificity for neoepitopes generated by EGFR mutations, which are driver oncogenes in a subset of patients with lung cancer. We used NETMHCpan 4.0 to identify putative protective human leukocyte antigen (HLA) class I allotypes that are predicted in silico to bind and present mutant EGFR-generated peptides on the basis of predefined criteria. We associated the presence or absence of these alleles with clinical outcomes in patients from The Cancer Genome Atlas with lung adenocarcinoma. We identified 12 HLA class I alleles that fulfilled the predefined criteria for being protective for EGFR p.L858R and six for EGFR p.E746_A750del, the two most common EGFR mutations in lung cancer. We validated the in silico predictions for peptide-HLA allele binding in vitro. A third (12 of 36) of patients with mostly early stage lung adenocarcinoma in The Cancer Genome Atlas with either EGFR p.L858R or EGFR p.E746_A750del had at least one protective allele in their host genomes. More importantly, patients with protective alleles exhibited better disease-free (hazard ratio: 0.20, 95% confidence interval: 0.05-0.78) and overall survival (hazard ratio: 0.13, 95% confidence interval: 0.02-0.64), and this effect was independent of the EGFR mutation type, stage, age, and sex. Our data revealed that clinical outcomes were improved in patients with EGFR mutation-positive lung adenocarcinoma who harbored protective HLA class I alleles. Thus, immunity with specificity for mutant EGFR is possible in a subset of patients with early stage lung cancer and portends a better prognosis.


Molecularly targeted therapy for pediatric brain tumors.
Treatment of pediatric brain tumors remains a challenge because of the toxicity associated with conventional treatment and the relative resistance of tumors at the time of recurrence. The traditional approach of administering cytotoxic agents at the maximum tolerated dose is being supplanted by the development of molecularly targeted agents aimed at critical cellular changes that are responsible for the growth and spread of cancer cells. These agents theoretically should be more specific for tumor cells and less toxic to normal cells. While the idea of targeted therapy has generated much excitement in the oncology community, the degree of benefit to patients with central nervous system (CNS) tumors remains unclear. Numerous challenges remain in the development of these agents, including identification of meaningful targets, delivery of agents in sufficient quantity at the target site, and determination of any biologic response to these agents. This article discusses the rationale behind several of these agents and their use in pediatric patients with brain tumors.


Splenic blood flow and intrasplenic platelet kinetics in relation to spleen volume.
The relationship between the splenic blood flow and the intrasplenic platelet kinetics on the one hand, i.e. the two factors which govern the size of the exchangeable splenic platelet pool, and the spleen size on the other were assessed in 21 patients afflicted with haematologic disorders and variable splenomegaly. The splenic blood flow and intrasplenic platelet kinetics were measured using 111In-labelled platelets and compartmental analysis of their equilibration between circulating blood and splenic pool; the spleen size was determined by scintigraphy using 99mTc-labelled stannous colloid. Significant correlations were recorded between the spleen size and the splenic platelet pool size (r = 0.76; P less than 0.001) and between the spleen size and the splenic blood flow (r = 0.56; P less than 0.01). Splenic perfusion decreased significantly with increasing spleen size, but there was no relationship between the spleen size and the intrasplenic platelet transit time. However, an association was present between splenic perfusion and intrasplenic platelet transit time (r = -0.44; P less than 0.05). It is concluded that the splenic blood flow is the major determinant of the size of the exchangeable splenic platelet pool in splenomegalic states, and that the determination of spleen size using 99mTc-scintigraphy gives a rough estimation of the pool size. Splenic perfusion appears to be one of the factors which determine the intrasplenic platelet transit time.


The travails of 19th-century urban youth as a precondition to the invention of modern adolescence.
One of the factors leading up to the "invention" of modern adolescence was what reformers saw as the corruption of youth by the city. It was the plight of these youth--all too visible to reformers, intellectuals, opinion makers, and trend setters--which set the stage for a child-saving movement during the last century aimed at taking youth off the streets, putting them in schools, stretching out the home-leaving age from 14 to 18, and in general, prolonging a developmental period.


Factors influencing patients' opt-in intention of exchanging health information.
Health information exchange (HIE) exhibits tremendous benefits in improving the quality of healthcare and reducing healthcare costs. However, it also poses challenges related to data security, data privacy, patient engagement, etc. This study aimed to explore the factors affecting patients' opt-in intention to HIE by using an empirical study based on the theory of planned behavior. A Web-based survey was conducted involving 501 valid participants in China (69% validity rate). Information sensitivity and perceived HIE transparency affected the patients' opt-in intention to HIE through the mediation of perceived behavior control and trust in HIE. Information sensitivity negatively influenced perceived behavior control (-0.551, P < 0.001) and trust in HIE (-0.489, P < 0.001). Perceived transparency of HIE positively influenced perceived behavior control (0.396, P < 0.001) and trust in HIE (0.471, P < 0.001). Moreover, patients' opt-in intention to HIE can be positively affected by perceived HIE transparency (0.195, P < 0.001) and trust in HIE (0.294, P < 0.001). In addition, the moderating effect of health status was positive and significant between trust in HIE and opt-in intention to HIE but not between the perceived behavior control and opt-in intention to HIE. This study contributes to the theory of planned behavior and enriches the literature on HIE efforts. HIE administrators should design personalized health services on the basis of these different health statuses to successfully achieve patients' opt-in intention to HIE.


Ecological correlates of explosive seed dispersal.
Based on the constraints of the ballistic mechanism, we suggest that plants that utilize explosive dispersal are either maximizing ballistic distances or maximizing secondary dispersal (and thus are ballistically short-distance dispersers). Explosive seed dispersal of seven plant species was investigated in terms of factors contributing to the distance that seeds are thrown. As predicted, the long distance dispersers (4 species) showed more constancy in distance that seeds were thrown relative to the ballistically short-distance dispersers (3 species). The distribution of explosively dispersed seeds in terms of a resource for post-dispersal predators was evaluated by computer simulation. The results indicated that seed predation is unlikely to contribute to maximizing seed dispersal distance. A model for explosive seed dispersal was developed, based on the constraints of such dispersal. Long-distance dispersers were expected to use small, closely-spaced patches or to use large patches in which inbreeding depression or competition selects for maximal dispersal distances. Short-distance dispersers were expected to use small, widely-spaced patches where ballistic dispersal in itself is an inadequate means to disperse seeds, or to use large patches in which there is no premium for dispersal distance. Preliminary evidence supported the model.


Adaptive fuzzy control of nutrients concentration in fed-batch culture of mammalian cells.
An adaptive fuzzy controller was developed to control the glucose and glutamine concentrations in the reactor constant at the desired level. The parameter values of the controller change during the cultivation according to the culture phase which was detected by the lactate concentration. Cultivations with different glucose and glutamine set point concentrations of a recombinant BHK anchorage-dependent cell line were performed in a fed-batch reactor on-line connected with an HPLC system. Glucose and glutamine concentrations were satisfactorily controlled at each set point during all cultivation periods. Ammonia had a determining effect on productivity since it inhibited cell growth and protein specific production. Ammonia production increased with an increase of glutamine or a decrease of glucose set point concentrations, indicating the importance of glucose to glutamine ratio for the optimization of productivity in mammalian cell cultures.


Integrative taxonomy reveals cryptic diversity in North American Lasius ants, and an overlooked introduced species.
Biological invasions are a grave threat to ecosystems. The black garden ant (Lasius niger) is a pest species in Europe. Current literature states that L. niger occupies a disjunct native distribution in the Holarctic, however, based on recent work, we re-evaluate this distribution. The native range of L. niger is reconsidered based on phylogenetic relationships (nine mitochondrial and nuclear markers, 5670 bp), DNA-barcoding (98 Holarctic specimens), morphometry (88 Holarctic specimens, 19 different measurements) and subjective assessment of phenotype. The potential spread of this species is estimated using ecological niche modeling. Lasius niger is more closely related to other Palearctic species than to the Nearctic ants known under this name. The latter are described as a distinct species, L. ponderosae sp. nov. However, DNA-barcoding discovered established populations of L. niger in metropolitan areas in Canada (Vancouver and Halifax). We describe a morphometrical method to delineate L. ponderosae sp. nov. and L. niger. MtDNA diversity and divergence is high within L. ponderosae sp. nov., but low within L. niger. More than 1,000,000 km2 are suitable as a habitat for L. niger in North America. This case emphasizes the critical role of integrative taxonomy to detect cryptic species and identify potential biological invasions in their nascent stages.


Bilateral testicular germ cell tumours in patients with initial stage I disease: prevalence and prognosis--a single centre's 30 years' experience.
Development of second testicular tumours, i.e. bilateral testicular cancer, is influenced by systemic chemotherapy for the first tumour. The prevalence of bilateral testicular cancer was studied in patients with initial stage I disease, in which no systemic treatment was given after orchidectomy. All stage I testicular cancer patients entered a surveillance study with an intensive follow-up since 1982. We hypothesised that after 1982, bilateral testicular cancer was diagnosed at an earlier stage of disease. The prevalence of bilateral testicular cancer was 4.7% (8/170) in stage I patients treated between 1967 and 1981, and 2.9% (8/275) in stage I patients treated between 1982 and 1997 (P > 0.5 chi 2-test). In the period 1967-1981, 6 patients had stage I second tumours and 2 patients had stage III second tumours. The former 6 patients are alive with no evidence of disease and the 2 patients with metastatic tumours died of disease or treatment. In the period 1982-1977, all 8 patients had stage I second tumours and all are alive with no evidence of disease. The overall prevalence of bilateral testicular cancer in stage I patients was 3.6% and has slightly decreased over the past three decades. Intensive follow-up, improvement of radiodiagnostic computed tomography techniques, availability of serum tumour markers, and patient education have resulted in earlier diagnosis and lower stage of contralateral testicular tumours, contributing to improved prognosis.


Evidence for a mu-delta opioid receptor complex in CHO cells co-expressing mu and delta opioid peptide receptors.
Based on non-competitive binding interactions we suggested that mu and delta receptors associate as a mu/delta receptor complex in rat brain. We hypothesized that the same non-competitive binding interactions observed in rat brain will be seen in CHO cells that co-express mu and delta receptors, but not in cells that express just mu or delta receptors. We used CHO cells expressing the cloned human mu receptor, cloned human delta receptor, or cloned mouse delta/human mu ("dimer cell"). Cell membranes were prepared from intact cells pretreated with 100nM SUPERFIT. [(3)H][d-Ala(2),d-Leu(5)]enkephalin binding assays followed published procedures. SUPERFIT, a delta-selective irreversible ligand, decreased [(3)H][d-Ala(2),d-Leu(5)]enkephalin binding to delta receptors by approximately 75% and to mu receptors by approximately 50% in dimer cells. SUPERFIT treatment did not decrease [(3)H][d-Ala(2),d-Leu(5)]enkephalin binding to mu cells. The IC(50) values observed in SUPERFIT-treated dimer cells were: [d-Pen(2),d-Pen(5)]enkephalin (1820nM) and morphine (171nM). Saturation binding experiments with SUPERFIT-treated dimer cells showed that [d-Pen(2),d-Pen(5)]enkephalin (5000nM) was a competitive inhibitor. In contrast, morphine (1000nM) lowered the B(max) from 1944fmol/mg to 1276fmol/mg protein (35% decrease). Both [d-Pen(2),d-Pen(5)]enkephalin and morphine competitively inhibited [(3)H][d-Ala(2),d-Leu(5)]enkephalin binding to SUPERFIT-treated mu cells. The results indicate that the mu-delta opioid receptor complex defined on the basis of non-competitive binding interactions in rat brain over 20 years ago likely occurs as a consequence of the formation of mu-delta heterodimers. SUPERFIT-treated dimer cells may provide a useful model to study the properties of mu-delta heterodimers.


Simultaneous quantification of hyperpolarized xenon-129 ventilation and gas exchange with multi-breath xenon-polarization transfer contrast (XTC) MRI.
To demonstrate the feasibility of a multi-breath xenon-polarization transfer contrast (XTC) MR imaging approach for simultaneously evaluating regional ventilation and gas exchange parameters. Imaging was performed in five healthy volunteers and six chronic obstructive pulmonary disease (COPD) patients. The multi-breath XTC protocol consisted of three repeated schemes of six wash-in breaths of a xenon mixture and four normoxic wash-out breaths, with and without selective saturation of either the tissue membrane or red blood cell (RBC) resonances. Acquisitions were performed at end-exhalation while subjects maintained tidal breathing throughout the session. The no-saturation, membrane-saturation, and RBC-saturation images were fit to a per-breath gas replacement model for extracting voxelwise tidal volume (TV), functional residual capacity (FRC), and fractional ventilation (FV), as well as tissue- and RBC-gas exchange (fMem and fRBC , respectively). The sensitivity of the derived model was also evaluated via simulations. With the exception of FRC, whole-lung averages for all metrics were decreased in the COPD subjects compared to the healthy cohort, significantly so for FV, fRBC , and fMem . Heterogeneity was higher overall in the COPD subjects, particularly for fRBC , fMem , and fRBC:Mem . The anterior-to-posterior gradient associated with the gravity-dependence of lung function in supine imaging was also evident for FV, fRBC , and fMem values in the healthy subjects, but noticeably absent in the COPD cohort. Multi-breath XTC imaging generated high-resolution, co-registered maps of ventilation and gas exchange parameters acquired during tidal breathing and with low per-breath xenon doses. Clear differences between healthy and COPD subjects were apparent and consistent with spirometry.


Interface and heterostructure design in polyelemental nanoparticles.
Nanomaterials that form as heterostructures have applications in catalysis, plasmonics, and electronics. Multielement nanoparticles can now be synthesized through a variety of routes, but how thermodynamic phases form in such structures and how specific interfaces between them can be designed and synthesized are still poorly understood. We explored how palladium-tin alloys form mixed-composition phases with metals with known but complex miscibilities. Nanoparticles with up to seven elements were synthesized, and many form triphase heterostructures consisting of either three-interface or two-interface architectures. Density functional theory calculations and experimental work were used to determine the balance between the surface and interfacial energies of the observed phases. From these observations, design rules have been established for making polyelemental systems with specific heterostructures, including tetraphase nanoparticles with as many as six junctions.


Frequency of hemorrhage after tooth extraction in patients treated with a direct oral anticoagulant: A multicenter cross-sectional study.
Few studies have compared the frequency of hemorrhages after tooth extraction between patients taking direct oral anticoagulants (DOACs) and those taking warfarin or no anticoagulants. Further, the effects of the timing of DOAC administration and tooth extraction on the frequency of post-extraction hemorrhage have not been demonstrated. Therefore, we compared the frequency of post-extraction hemorrhages in patients in these different conditions and examined the effects of the timing of DOAC administration and tooth extraction on the frequency. Prospective multicenter study. Eighty-six Japanese hospitals. In total, 182 teeth extracted from 145 individuals (119 teeth from adult males) receiving dabigatran and 88 teeth from individuals (62 teeth from adult males) receiving rivaroxaban were included. Tooth extraction was followed by a 7-day observational period between November 1, 2008 and December 31, 2015. Dabigatran was administered twice daily; rivaroxaban was administered once a day. Hemorrhage after tooth extraction. The frequency of hemorrhage after tooth extraction was 1.65%, 3.41%, and 3.63% in those treated with dabigatran, rivaroxaban, and warfarin, respectively, and 0.39% in those who did not receive anticoagulants. Hemorrhages after tooth extraction were significantly higher in the rivaroxaban group than in patients who did not receive anticoagulants (P = 0.008). These frequencies did not differ significantly in the dabigatran and rivaroxaban groups compared to the warfarin group (P = 0.221 and P = 1.000, respectively). The frequency of hemorrhaging after tooth extraction appeared to be similar in patients receiving continuous dabigatran or rivaroxaban and in those receiving continuous warfarin.


Preparation and applications of monoclonal antibodies to different collagen types.
Monoclonal antibodies have recently been developed against all of the major collagen types isolated from both human and other species. These antibodies have several potential advantages over polyclonal antibodies, and a brief survey will be made of the different antibodies that have so far been developed. In addition, various successful applications of these antibodies to biological investigations will be briefly discussed.


Impact of distillery effluent on carbohydrate metabolism of freshwater fish, Cyprinus carpio.
The impact of distillery effluent on carbohydrate metabolism of Cyprinus carpio was studied at different days during exposure (7, 14, and 21 days) in the ambient temperature of 28 +/- 1 degrees C. Oxygen consumption in fish decreased with increasing effluent concentrations as well as duration of exposure. Effluent concentrations and exposure durations (days) had a significant effect on oxygen consumption of tested fish (p < 0.0005). Total carbohydrate, glycogen content and SDH enzyme activity in muscle, liver and brain tissues of C. carpio exposed to different sublethal concentrations decreased gradually and significantly. This was also the case with exposure duration. Reduction in glycogen content was greater in liver tissue i.e., 54.1% in 0.2% effluent concentration on the 21st day of exposure. However, serum glucose and lactic acid content showed an increasing trend with increase in effluent concentration and time of exposure. Unlike SDH, LDH enzyme activity of muscle, liver and brain tissues showed an increasing trend and the enhancement of enzyme activity was more in liver tissue (71.3%). From these results, it could be inferred that respiratory processes in C. carpio under distillery effluent stress was affected resulting in a shift towards anaerobiosis at organ level during sublethal intoxication.


KMT2A (MLL) rearrangements observed in pediatric/young adult T-lymphoblastic leukemia/lymphoma: A 10-year review from a single cytogenetic laboratory.
T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T-ALL/LBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3'KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T-ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.


Clinical predictors and relationship between early and late atrial tachyarrhythmias after pulmonary vein antrum isolation.
Several studies have reported early (EAT) and late (LAT) atrial tachyarrhythmias following atrial fibrillation (AF) ablation, but the factors associated with them and their clinical significance are not well known. The purpose of this study was to investigate the predictors and the relationship between EAT and LAT after AF ablation. A total of 1298 patients with paroxysmal (54%), persistent (18%), or permanent (28%) AF underwent intracardiac echocardiography-guided pulmonary vein antrum isolation and were followed for 41 +/- 10 months. EAT and LAT were defined as an episode of AF or atrial flutter/tachycardia lasting longer than 1 minute that occurred within the first 3 months of ablation and after 3 months postablation, respectively. After a single ablation procedure, EAT developed in 514 (40%) patients and LAT in 292 (22%) patients. At a multivariable analysis, longer AF duration (odds ratio [OR] 1.03), history of hypertension (OR 1.32), left atrial enlargement (OR 1.55), permanent AF (OR 1.72), and lack of superior vena cava isolation (OR 1.60) were significantly associated with EAT. Independent predictors of LAT were longer AF duration (OR 1.03), history of hypertension (OR 1.65), persistent (OR 2.17) or permanent AF (OR 2.28), and occurrence of EAT (OR 30.62). The risk of LAT was inversely related to the time to first EAT occurrence (OR 20, 54, and 1,052 in first, second, and third month, respectively). Notably, 49% of patients with EAT did not experience LAT. EAT strongly predict LAT. However, EAT did not automatically mean ablation failure. Delaying redo procedure may be appropriate during the first 2 months after ablation. Longer AF duration, hypertension, and nonparoxysmal AF are independent predictors of EAT and LAT.


The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial.
Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.


An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer.
Colorectal cancer (CRC) is one of the life-threatening malignancies worldwide. Thus, novel potential therapeutic targets and therapeutics for the treatment of CRC need to be identified to improve the clinical outcomes of patients with CRC. In this study, we found that glucose-regulated protein 94 (GRP94) is overexpressed in CRC tissues, and its high expression is correlated with increased microvessel density. Next, through phage display technology and consecutive in vitro functional isolations, we generated a novel human monoclonal antibody that specifically targets cell surface GRP94 and shows superior internalizing activity comparable to trastuzumab. We found that this antibody specifically inhibits endothelial cell tube formation and simultaneously promotes the downregulation of GRP94 expression on the endothelial cell surface. Finally, we demonstrated that this antibody effectively suppresses tumor growth and angiogenesis of HCT116 human CRC cells without causing severe toxicity in vivo. Collectively, these findings suggest that cell surface GRP94 is a novel potential anti-angiogenic target in CRC and that antibody targeting of GRP94 on the endothelial cell surface is an effective strategy to suppress CRC tumor angiogenesis.


Determination of mercury in fish from rivers and lakes in Hungary by atomic absorption technique.
In 1975, in cooperation with 8 County Hygienic Stations, total mercury content in fish from rivers and lakes in Hungary was measured. The mercury content in fish muscle-tissue from 164 fish samples averaged 0.36 mg/kg. Average levels in different fish species ranged from 0.10 to 0.57 mg/kg. The amount of mercury in fish from rivers and lakes, with the exception of the Danube, was, in general, lower than the tolerance level (0.50 mg/kg) as adopted in many countries. Mercury levels in fish from Lake Balaton did not amount to more than 0.30 mg/kg. The circulating cold vapour atomic absorption method was used to determined the mercury content in the fish samples.


Molecular evidence for adaptive radiation of Micromeria Benth. (Lamiaceae) on the Canary Islands as inferred from chloroplast and nuclear DNA sequences and ISSR fingerprint data.
The Canary Islands have been a focus for phylogeographic studies on the colonization and diversification of endemic angiosperm taxa. Based on phylogeographic patterns, both inter island colonization and adaptive radiation seem to be the driving forces for speciation in most taxa. Here, we investigated the diversification of Micromeria on the Canary Islands and Madeira at the inter- and infraspecific level using inter simple sequence repeat PCR (ISSR), the trnK-Intron and the trnT-trnL-spacer of the cpDNA and a low copy nuclear gene. The genus Micromeria (Lamiaceae, Mentheae) includes 16 species and 13 subspecies in Macaronesia. Most taxa are restricted endemics, or grow in similar ecological conditions on two islands. An exception is M. varia, a widespread species inhabits the lowland scrub on each island of the archipelago and could represent an ancestral taxon from which radiation started on the different islands. Our analyses support a split between the "eastern" islands Fuerteventura, Lanzarote and Gran Canaria and the "western" islands Tenerife, La Palma and El Hierro. The colonization of Madeira started from the western Islands, probably from Tenerife as indicated by the sequence data. We identified two lineages of Micromeria on Gomera but all other islands appear to be colonized by a single lineage, supporting adaptive radiation as the major evolutionary force for the diversification of Micromeria. We also discuss the possible role of gene flow between lineages of different Micromeria species on one island after multiple colonizations.


Impaired anti-leukemic immune response in PKCtheta-deficient mice.
The cancer immunosurveillance hypothesis has found strong experimental support in recent years. It is believed that cytotoxic lymphocytes are important effectors in this process. PKCtheta plays an essential role in proliferation, activation and survival of these cells, but also proliferation and survival of leukemic T cells. In light of this, we tested the role of PKCtheta in T cell leukemia progression by inducing this disease in wild-type (wt) and PKCtheta-deficient mice with moloney-murine leukemia virus (M-MuLV). Leukemic PKCtheta(-/-) and wild-type (wt) mice showed the same profile of leukemic cell types, similar spleen and thymus sizes and comparable hematocrits. In contrast, disease incidence was higher and disease onset more rapid in PKCtheta(-/-) mice. Transfer of leukemic T cells from wt donors into PKCtheta-deficient and wt recipients induced leukemia in 100% and 40% of the mice, respectively. Interestingly, leukemic cells from PKCtheta(-/-) donors induced the disease in only 50% of the PKCtheta-deficient and 10% of the wt recipients. Intravenous injection of low numbers of EL4 cells induced tumors earlier in PKCtheta(-/-) mice. Taken together, our results show that PKCtheta is essential for the immune response to leukemia in mice and raise questions about the chronic treatment of humans with PKCtheta inhibitors.


Prevention, treatment and cure of HIV infection.
The development of antiretroviral therapy for the prevention and treatment of HIV infection has been marked by a series of remarkable successes. However, the efforts to develop a vaccine have largely failed, and efforts to discover a cure are only now beginning to gain traction. In this Review, we describe recent progress on all fronts - pre-exposure prophylaxis, vaccines, treatment and cure - and we discuss the unmet needs, both current and in the coming years. We describe the emerging arsenal of drugs, biologics and strategies that will hopefully address these needs. Although HIV research has largely been siloed in the past, this is changing, as the emerging research agenda is marked by multiple cross-discipline synergies and collaborations. As the limitations of antiretroviral drugs as a means to truly end the epidemic are becoming more apparent, there is a great need for continued efforts to develop an effective preventative vaccine and a scalable cure, both of which remain formidable challenges.


Insulinoma with hypoglycemia and normal immunoreactive insulin but with an insulin-like activity restricted to the portal vein.
In a 46-year old Caucasian woman, the authors report a B-cell adenoma with plasma immunoreactive insulin (IRI) ranging from 10 to 32 microunits/ml, despite severe spontaneous hypoglycemia. In a peroperative sample withdrawn from the portal vein, normal IRI (40 micromicron/ml) in the presence of high insulin-like activity (290 microunits/ml) was observed by using a biological assay performed on rat epididymal fat tissue. Furthermore, this material did not cross-react with insulin antibodies and was undetectable in systemic venous samples. Although further identification by chromatographic extraction was not performed, the substance secreted by the tumor is probably identical to the non-suppressible insulin-like activity (NSILA) isolated by Froesch and responsible for hypoglycemia in a few cases of extrapancreatic tumors. The absence of this material in systemic samples indicates an immediate removal by a single passage through the liver.


Allene as an alternative functional group for drug design: effect of C--C multiple bonds conjugated with quinazolines on the inhibition of EGFR tyrosine kinase.
A series of allenic quinazolines were synthesized as receptor tyrosine kinase inhibitors by using a simple protocol for palladium-catalyzed allene transformation. Among the compounds synthesized, two allenic 4-anilinoquinazolines selectively suppressed epidermal growth factor receptor (EGFR) tyrosine kinase activity in vitro. According to immunoblot analysis, the allenic quinazolines inhibited the EGF-mediated phosphorylation of EGFR and its downstream kinases in A431 cells. Furthermore, one of these allenic quinazolines decreased the proliferation of A431 cells through the induction of cell-cycle arrest and apoptosis.


Selective Autophagy Regulates Innate Immunity Through Cargo Receptor Network.
Autophagy, an evolutionarily conserved cargo degradation process, is responsible to remove superfluous and unwanted cytoplasmic materials and maintain cellular homeostasis. Autophagy can be highly selective and target specific cargoes by utilizing multiple cargo receptors, which bind both ubiquitinated cargoes and autophagosomes. Mounting evidence has revealed the deep involvement of selective autophagy in innate immunity upon pathogen invasion, including eliminating microbial pathogens, initiating the anti-microbe responses, and inhibiting excessive immune responses. Given the importance of selective autophagy in innate immunity, how cargo receptors deliver pathogens and intracellular host constitutes to autophagosomes during infection remains to be elucidated. In this review, we summarize current evidence for the regulation of innate immunity by selective autophagy and try to elucidate the mechanisms employed by cargo receptor network in mediating diverse innate immune responses.


Building Specific Signals from Frequency Chaos Game and Revealing Periodicities Using a Smoothed Fourier Analysis.
Investigating the roles and functions of DNA within genomes is becoming a primary focus of genomic research. Thus, the research works are moving towards cooperation between different scientific disciplines which aims at facilitating the interpretation of genetic information. In order to characterize the DNA of living organisms, signal processing tools appear to be very suitable for such study. However, a DNA sequence must be converted into a numerical sequence before processing; which defines the concept of DNA coding. In line with this, we propose a new one dimensional model based on the chaos game representation theory called Frequency Chaos Game Signal: FCGS. Then, we perform a Smoothed Fourier Transform to enhance hidden periodicities in the C.elegans DNA sequences. Through this study, we demonstrate the performance of our coding approach in highlighting characteristic periodicities. Indeed, several periodicities are shown to be involved in the 1D spectra and the 2D spectrograms of FCGSs. To investigate further about the contribution of our method in the enhancement of characteristic spectral attributes, a comparison with a range of binary indicators is established.


Social networks respond to a disease challenge in calves.
Changes in network position and behavioral interactions have been linked with infectious disease in social animals. Here, we investigate the effects of an experimental disease challenge on social network centrality of group-housed Holstein bull dairy calves. Within group-housed pens (6/group) calves were randomly assigned to either a previously developed challenge model, involving inoculation with Mannheimia haemolytia (n = 12 calves; 3 calves/group) or a control involving only saline (n = 12 calves; 3 calves/group). Continuous behavioral data were recorded from video on pre-treatment baseline day and for 24 h following inoculation to describe social lying frequency and duration and all active social contact between calves. Mixed-model analysis revealed that changes in network position were related to the challenge. Compared to controls, challenged calves had reduced centrality and connectedness, baseline to challenge day. On challenge day, challenged calves were less central in the directed social contact networks (lower degree, strength and eigenvector centrality), and initiated contact (higher out-degree) with more penmates, compared to healthy calves. This finding suggests that giving rather than receiving affiliative social contact may be more beneficial for challenged calves. This is the first study demonstrating that changes in social network position coincide with an experimental challenge of a respiratory pathogen in calves.


Daily transcriptomes of the copepod Calanus finmarchicus during the summer solstice at high Arctic latitudes.
The zooplankter Calanus finmarchicus is a member of the so-called "Calanus Complex", a group of copepods that constitutes a key element of the Arctic polar marine ecosystem, providing a crucial link between primary production and higher trophic levels. Climate change induces the shift of C. finmarchicus to higher latitudes with currently unknown impacts on its endogenous timing. Here we generated a daily transcriptome of C. finmarchicus at two high Arctic stations, during the more extreme time of Midnight Sun, the summer solstice. While the southern station (74.5 °N) was sea ice-free, the northern one (82.5 °N) was sea ice-covered. The mRNAs of the 42 samples have been sequenced with an average of 126 ± 5 million reads (mean ± SE) per sample, and aligned to the reference transcriptome. We detail the quality assessment of the datasets and the complete annotation procedure, providing the possibility to investigate daily gene expression of this ecologically important species at high Arctic latitudes, and to compare gene expression according to latitude and sea ice-coverage.


Dualityfree Methods for Stochastic Composition Optimization.
In this paper, we consider the composition optimization with two expected-value functions in the form of (1/n)∑i = 1n Fi((1/m)∑j = 1m Gj(x))+R(x) , which formulates many important problems in statistical learning and machine learning such as solving Bellman equations in reinforcement learning and nonlinear embedding. Full gradient- or classical stochastic gradient descent-based optimization algorithms are unsuitable or computationally expensive to solve this problem due to the inner expectation (1/m)∑j = 1m Gj(x) . We propose a dualityfree-based stochastic composition method that combines the variance reduction methods to address the stochastic composition problem. We apply the stochastic variance reduction gradient- and stochastic average gradient algorithm-based methods to estimate the inner function and the dualityfree method to estimate the outer function. We prove the linear convergence rate not only for the convex composition problem but also for the case that the individual outer functions are nonconvex, while the objective function is strongly convex. We also provide the results of experiments that show the effectiveness of our proposed methods.


Spatial orienting in complex audiovisual environments.
Previous studies on crossmodal spatial orienting typically used simple and stereotyped stimuli in the absence of any meaningful context. This study combined computational models, behavioural measures and functional magnetic resonance imaging to investigate audiovisual spatial interactions in naturalistic settings. We created short videos portraying everyday life situations that included a lateralised visual event and a co-occurring sound, either on the same or on the opposite side of space. Subjects viewed the videos with or without eye-movements allowed (overt or covert orienting). For each video, visual and auditory saliency maps were used to index the strength of stimulus-driven signals, and eye-movements were used as a measure of the efficacy of the audiovisual events for spatial orienting. Results showed that visual salience modulated activity in higher-order visual areas, whereas auditory salience modulated activity in the superior temporal cortex. Auditory salience modulated activity also in the posterior parietal cortex, but only when audiovisual stimuli occurred on the same side of space (multisensory spatial congruence). Orienting efficacy affected activity in the visual cortex, within the same regions modulated by visual salience. These patterns of activation were comparable in overt and covert orienting conditions. Our results demonstrate that, during viewing of complex multisensory stimuli, activity in sensory areas reflects both stimulus-driven signals and their efficacy for spatial orienting; and that the posterior parietal cortex combines spatial information about the visual and the auditory modality.


Defensive functions and potential ecological conflicts of floral stickiness.
Stickiness of vegetative tissues has evolved multiple times in different plant families but is rare and understudied in flowers. While stickiness in general is thought to function primarily as a defense against herbivores, it may compromise mutualistic interactions (such as those with pollinators) in reproductive tissues. Here, we test the hypothesis that stickiness on flower petals of the High-Andean plant, Bejaria resinosa (Ericaceae), functions as a defense against florivores. We address ecological consequences and discuss potential trade-offs associated with a repellant trait expressed in flowers that mediate mutualistic interactions. In surveys and manipulative experiments, we assess florivory and resulting fitness effects on plants with sticky and non-sticky flowers in different native populations of B. resinosa in Colombia. In addition, we analyze the volatile and non-volatile components in sticky and non-sticky flower morphs to understand the chemical information context within which stickiness is expressed. We demonstrate that fruit set is strongly affected by floral stickiness but also varies with population. While identifying floral stickiness as a major defensive function, our data also suggest that the context-dependency of chemical defense functionality likely arises from differential availability of primary pollinators and potential trade-offs between chemical defense with different modes of action.


Updating OSHA standards based on national consensus standards. final rule; confirmation of effective date.
OSHA is confirming the effective date of its direct final rule that revises a number of standards for general industry that refer to national consensus standards. The direct final rule states that it would become effective on March 13, 2008 unless OSHA receives significant adverse comment on these revisions by January 14, 2008. OSHA received no adverse comments by that date and, therefore, is confirming that the rule will become effective on March 13, 2008.


TNIP1-mediated TNF-α/NF-κB signalling cascade sustains glioma cell proliferation.
As a malignant tumour of the central nervous system, glioma exhibits high incidence and poor prognosis. Although TNIP1 and the TNF-α/NF-κB axis play key roles in immune diseases and inflammatory responses, their relationship and role in glioma remain unknown. Here, we revealed high levels of TNIP1 and TNF-α/NF-κB in glioma tissue. Glioma cell proliferation was activated with TNF-α treatment and showed extreme sensitivity to the TNF receptor antagonist. Furthermore, loss of TNIP1 disbanded the A20 complex responsible for IκB degradation and NF-κB nucleus translocation, and consequently erased TNFα-induced glioma cell proliferation. Thus, our investigation uncovered a vital function of the TNIP1-mediated TNF-α/NF-κB axis in glioma cell proliferation and provides novel insight into glioma pathology and diagnosis.


Low-field benchtop NMR spectroscopy as a potential non-stationary tool for point-of-care urinary metabolite tracking in diabetic conditions.
We describe the advantages and diagnostic/prognostic significance of low-field, near-portable benchtop NMR spectrometers for the multicomponent metabolomics analysis of targeted and untargeted urinary biomarkers (≥15) in type 2 diabetes patients. Implementation of these facilities at 'point-of-care' clinical sites may yield valuable advantages for the sequential monitoring of diabetic and prediabetic individuals.


A case of T-cell chronic lymphocytic leukemia (T-CLL) expressing a peculiar phenotype (E+, OKM1+, Leu 1+, OKT3- and IgG EA-).
A case of chronic leukemia is reported. Malignant cells had the morphology of lymphocytes and an affinity for skin. Cytochemically, they were peroxidase negative, and NaF-resistant alpha-naphthyl esterase positive. The peripheral mononuclear cells formed E-rosettes and reacted with Leu 1 and OKM1. They were unreactive with OKT3, OKT4, OKT6, OKT8, and OKIa1. The cells did not possess surface IG, C3b receptors, or IgG Fc receptors (EAIgG). They responded weakly to phytohemagglutinin, and did not respond to concanavalin A. The cells did not adhere to Petri dishes or phagocytose latex beads. It is concluded that it was a case of OKT3-, OKM1+, EAIgG- T-cell chronic lymphocytic leukemia. This suggests that OKT3 does not recognize all peripheral T-cells, and that OKM1 is not specific for the monocyte-myeloid lineage. These cells may be useful in the characterization of E+, OKM1+ subset of peripheral mononuclear cells.


Probing functional tyrosines.
Reactivity probes are small molecules that contain a reactive electrophile and a purification handle, and are used to identify hyperreactive amino acid residues within a whole proteome. In this issue of Chemistry & Biology, Gu et al. use sulfonyl fluoride derivatives for the identification of functional tyrosine residues in different classes of glutathione S-transferases.


Effects of granuloma formation at site of vasovasostomy.
Spermatic granulomas forming after vasectomy reversal have been thought to mechanically compromise the anastomosis. We have studied the physiologic effects of vasectomy and vasovasostomy in rats. Following delayed microsurgical vasovasostomy, fluid flow through the anastomosis and cauda epididymidal hydrostatic pressure are not significantly different in tracts that form, or do not form, sperm granulomas at the anastomosis. Given a properly performed microsurgical vasectomy reversal, a sperm granuloma arising from a small leak does not appear to mechanically compromise the anastomosis in the rat. Fertility after vasovasostomy is not significantly reduced in rats with granulomas.


Successful use of problem-solving methodology to reduce pharmacy chemotherapy processing time.
The primary objectives of this study were to (1) reduce pharmacy turnaround time (TAT) without compromising safety and quality and (2) reduce compounding order overload during peak hours (8:00 AM-5:00 PM). The secondary objective was to decrease patient wait time pertinent to pharmacy services. The setting was a hospital-based pharmacy. Pharmacy dispensing more than 1800 doses daily, 30% of which goes to outpatient cancer treatment. Patients usually receive multiple compounded medications; thus, compounding numbers are several folds higher than patient number. High compounded chemotherapy order volume overloaded pharmacy staff during peak hours and was a major contributor to patient wait time. Using Define Measure Analyze Improve Control Six Sigma and intelligent risk-taking strategies, a dedicated team identified root causes of problems and designed long-lasting solutions that would not compromise quality. The most effective initiative was the advanced preparation of chemotherapy for select patients (Concierge), which addressed pharmacy TAT, patient wait time, and chemotherapy order overload, all without affecting safety or quality of dispensed medications. Pharmacy TAT decreased by 77% for Concierge patients and 31% for standard patients. Comparable decreases were observed for patient wait time: 67% for Concierge and 27% for standard patients. Safety and quality were maintained for all dispensations during and after implementation of Concierge. A concurrent 8% increase in patient number was observed despite no changes in physical capacity. The implementation of Concierge initiatives: markedly reduced pharmacy TAT without compromising safety checks performed by pharmacists; decreased chemotherapy order overload during peak hours; improved distribution of assignments for pharmacy staffand statistically significant decreased wait time for all patients, especially those selected for Concierge. Effective selection of Concierge patients minimized additional costs associated with wasted premixed chemotherapy. Improving workflow for a subset of patients affected a greater patient population, allowing additional patients to be treated daily.


Imaging Invasion: Micro-CT imaging of adamantinomatous craniopharyngioma highlights cell type specific spatial relationships of tissue invasion.
Tissue invasion and infiltration by brain tumours poses a clinical challenge, with destruction of structures leading to morbidity. We assessed whether micro-CT could be used to map tumour invasion in adamantinomatous craniopharyngioma (ACP), and whether it could delineate ACPs and their intrinsic components from surrounding tissue.Three anonymised archival frozen ACP samples were fixed, iodinated and imaged using a micro-CT scanner prior to the use of standard histological processing and immunohistochemical techniques.We demonstrate that micro-CT imaging can non-destructively give detailed 3D structural information of tumours in volumes with isotropic voxel sizes of 4-6 microns, which can be correlated with traditional histology and immunohistochemistry.Such information complements classical histology by facilitating virtual slicing of the tissue in any plane and providing unique detail of the three dimensional relationships of tissue compartments.