Increased variability in Greenland Ice Sheet runoff from satellite observations.
Runoff from the Greenland Ice Sheet has increased over recent decades affecting global sea level, regional ocean circulation, and coastal marine ecosystems, and it now accounts for most of the contemporary mass imbalance. Estimates of runoff are typically derived from regional climate models because satellite records have been limited to assessments of melting extent. Here, we use CryoSat-2 satellite altimetry to produce direct measurements of Greenland's runoff variability, based on seasonal changes in the ice sheet's surface elevation. Between 2011 and 2020, Greenland's ablation zone thinned on average by 1.4 ± 0.4 m each summer and thickened by 0.9 ± 0.4 m each winter. By adjusting for the steady-state divergence of ice, we estimate that runoff was 357 ± 58 Gt/yr on average - in close agreement with regional climate model simulations (root mean square difference of 47 to 60 Gt/yr). As well as being 21 % higher between 2011 and 2020 than over the preceding three decades, runoff is now also 60 % more variable from year-to-year as a consequence of large-scale fluctuations in atmospheric circulation. Because this variability is not captured in global climate model simulations, our satellite record of runoff should help to refine them and improve confidence in their projections.


A novel cobalt and nitrogen co-doped mesoporous hollow carbon hemisphere as high-efficient electrocatalysts for oxygen reduction reaction.
Exploring a cheap catalyst with effective activity for oxygen reduction reaction (ORR) to replace precious metal electrocatalysts has gained tremendous attention for several decades. In this study, we designed and synthesized cobalt and nitrogen supported on mesoporous hollow carbon hemisphere (Co/N/HCHs) nanocomposites by a facile and economical approach. Semisphere-shaped mesoporous hollow carbon is self-generated using silica particles as template, followed by a pyrolysis-etching process; and exhibits high electrical conductivity and high specific surface. The unique porous structure of carbon provides significant number of the abundant defective sites and shortens the mass transfer pathway, leading to a greatly enhanced electrocatalytic activity with mainly 4e- reduction. Moreover, the synergistic effects of large electrochemically active areas and good electrical conductivity, resulting from the introduction of Co and N heteroatom, are the main reason for displaying outstanding ORR activity with a high half-wave potential of 0.8 V and the electron transfer numbers of 3.89. Furthermore, an excellent long-term stability (the current density retention of 87.0%) and superb methanol tolerance in alkaline medium are achieved. Undoubtedly, this demonstrates a potential way to strategically design the non-precious metal doped carbon catalysts for wider practical applications.


Parallel synthesis of 7-heteroaryl-pyrazolo[1,5-a]pyrimidine-3-carboxamides.
A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxamides was developed. The synthesis starts with transformation of commercially available 2-acetylpyridine and acetylpyrazine with [Formula: see text] [Formula: see text]-dimethylformamide dimethylacetal into the corresponding [Formula: see text]-3-(dimethylamino)-1-(heteroaryl)prop-2-en-1-ones followed by cyclisation with methyl 5-amino-1[Formula: see text]-pyrazole-4-carboxylate to give methyl 7-heteroarylpyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxylates. Hydrolysis of the ester group and subsequent amidation of the so formed carboxylic acids with 12 primary and secondary aliphatic amines furnished a library of 24 title compounds in good overall yields and purity.


The feasibility of low mechanical index contrast enhanced ultrasound (CEUS) in distinguishing malignant from benign thoracic lesions.
We proposed to assess the feasibility of low mechanical index (MI) contrast enhanced ultrasound (CEUS) in the characterisation of thoracic lesions. Fifty patients were prospectively examined by CEUS and images acquired on a low MI (0.17-0.24) setting following injection of SonoVue. From region-of-interest (ROI) generated signal intensity (SI) time curves, the maximum SI, bolus arrival time (BAT), time to peak intensity (TTP), wash-in slope and mean transit time (MTT) were calculated. Using the Wilcoxon rank test; parameters and threshold values for positive differentiation were determined. In addition, for the parameters that allowed positive differentiation between malignant and benign lesions receiver operator curves (ROC) were obtained. The wash-in slope, TTP and MTT (p = 0.0003, <0.0001, 0.02) allowed positive differentiation. The sensitivity and specificity was 93% and 78%, with 6.87 s(-1) threshold value for the wash-in slope, 78% and 89% with 11.84 s threshold for the TTP and 48% and 89% with 78.6 s threshold for the MTT. CEUS is a useful tool for differentiating malignant and benign thoracic lesions.


Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design.
We report structural models of the full-length integrase enzyme (IN) of the human immunodeficiency virus type 1 (HIV-1) and its complex with viral and human DNA. These were developed by means of molecular modeling techniques using all available experimental evidence, including X-ray crystallographic and NMR structures of portions of the full-length protein. Special emphasis was placed on obtaining a model of the enzyme's active site with the viral DNA apposed to it, based on the hypothesis that such a model would allow structure-based design of inhibitors that retain activity in vivo. This was because bound DNA might be present in vivo after 3'-processing but before strand transfer. These structural models were used to study the potential binding modes of various diketo-acid HIV-1 IN inhibitors (many of them preferentially inhibiting strand transfer) for which no experimentally derived complexed structures are available. The results indicate that the diketo-acid IN inhibitors probably chelate the metal ion in the catalytic site and also prevent the exposure of the 3'-processed end of the viral DNA to human DNA.


A computerized system for staffing, billing and productivity measurement.
Nursing administrators are developing methods to identify nursing department costs and revenue. A patient classification system driven by computerized nurses notes was developed at LDS Hospital as part of the hospital information system. This system is used to determine appropriate staffing on all nursing units and to bill patients directly for nursing care. The data is also used to measure nursing department productivity.


Quality control of 157 whole body adiposity prediction formulae in age and activity matched men.
The physiological and clinical importance of body composition is part of public health, nutrition and Sports medicine. The most popular field method for estimating total body adiposity remains anthropometry separately or in formulae. The aim of this study was to verify the suitability of an absolute maximum out of more than 600 existing anthropometry equations estimating % adipose tissue (AT) in a cross validation with dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA) and hydrodensitometry (HD) on 74 British male subjects (mean age 34.4±14.1) with different lifestyles corresponding to a maximum of populations the original formula was developed for. Pearson correlation coefficients, paired sample t-test and Bland and Altman plots where used for analyses. From the tested formulae, 19 correlated well (r≥0.70) and showed no significant difference (p>0.05) with BIA, 15 with DXA and only 12 with HD. The results show a better match of the predicted % AT by anthropometric equations with BIA then with DXA or HD. All results and conditions considered, this study suggest not to use HD nor anthropometric formulae to assess % AT in men for an individual estimation.


Radial loop and extreme vessel tortuosity in the transradial approach: advantage of hydrophilic-coated guidewires and catheters.
Between October 2000 and October 2001, all transradial cases performed by the author necessitating radial and upper arm angiography because of difficult advancement of standard guidewires or catheters were analyzed retrospectively. Fourteen of 594 (2.4%) transradial cases met the study criteria. Radial loops or stenosis and tortuosity in the subclavian or innominate artery were responsible for the difficult access. Several examples of patients with access problems are presented. A technique using a hydrophilic-coated guidewire and a new hydrophilic-coated guiding catheter is described.


Analysis of nucleotide sequence of Iranian maize mosaic virus confirms its identity as a distinct nucleorhabdovirus.
The nucleotide sequence of the Iranian maize mosaic rhabdovirus (IMMV) was obtained using a random-PCR method (rPCR) followed by PCR with specific primers. Analysis of the complete nucleotide sequence of the IMMV genes and intergenic regions comprising a total of 12,381 nucleotides (including the partial sequences of leader and trailer regions) revealed six open reading frames (ORF) on the viral complementary RNA (vcRNA). On the basis of its similarities to other rhabdovirus sequences, the IMMV genome consists of 3'-leader-N-P-3-M-G-L-5'-trailer. The intergenic regions contained a characteristic consensus sequence, 3'-AAUUCUUUUUGGGUUU/G-5'. The IMMV gene products showed a high similarity to those of maize mosaic virus and taro vein chlorosis virus and a more distant relationship to other rhabdoviruses. Together with the biological, serological and morphological features described earlier, our molecular data provide evidence that IMMV is a distinct member of the genus Nucleorhabdovirus in the family Rhabdoviridae.


Can transabdominal ultrasound estimation of postvoiding residual (PVR) replace catheterization?
In 81 outpatients the postvoiding residual urine (PVR) using real-time B-mode ultrasonography (3.5 MHz transducer) was measured. For the calculation of the bladder volume the formula for an ellipsoid (V = 4/3 pi X r1 X r2 X r3) was found to be most accurate in predicting the actual volume measured by in-and-out catheterization (r = 0.982). Other volume formulas, using only one diameter of the bladder, were found to be much less accurate. For any arbitrary value of PVR, used in determining clinical management, the incidence of misjudgment by ultrasound was negligibly low. We conclude, that sonographic measurement of the PVR as a quick, noninvasive method, should replace catheterization, if the basic equipment is available. Additional information, e.g., prostate size, bladder configuration, diverticula, etc., can be obtained during the procedure without additional costs or loss of time.


Effect of the antiretroviral agent hypericin on rat liver mitochondria.
The photosensitizing effect of hypericin (HY), an antiretroviral agent, on the functions of isolated rat liver mitochondria has been investigated. The respiratory control ratio (RCR), ADP/O and membrane potential of mitochondria were decreased by HY in a light-dependent manner. Uncoupled respiration of mitochondria in the presence of succinate was also inhibited by HY in a light-dependent manner. The ID50 of hypericin for these inhibitions was approximately 0.5 microM. These inhibitory effects of HY were not observed when photosensitization was conducted under anaerobic conditions and were not affected by desferrioxamine (DSF) or superoxide dismutase (SOD). Upon photosensitization of HY, mitochondria consumed oxygen in the absence of respiratory substrate with concomitant formation of thiobarbituric acid reactive substance (TBARS). The amount of oxygen consumed was 100-times greater than that of TBARS formed. The oxygen uptake was partially inhibited by NaN3, and formation of TBARS was inhibited by DSF. Upon photosensitization of HY in the presence of mitochondrial membranes, the electron spin resonance (ESR) signal of 2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxyl (DMPO/.OH) was increased by a mechanism which was suppressed by DSF. An ESR signal for singlet oxygen bound to 2,5-dimethylfuran, 2,2,6,6-tetramethyl-4-piperidone (TEMP) was also detected under light in the presence of mitochondria. This signal of the TEMP-N-oxyl radical (TEMPO) was decreased by azide, which physically quenches singlet oxygen, but was increased by DSF. These results indicate that HY might inhibit mitochondrial functions by a type II photodynamic mechanism but that lipid peroxidation of biological membranes through an active oxygen-mediated photodynamic mechanism is not involved.


Sensitive fluorescent assay for copper(ii) determination in aqueous solution using quercetin-cyclodextrin inclusion.
Environmentally friendly probe materials for detecting copper ions were studied in this research. Fluorescent emission of quercetin (Q) was observed in the buffer solution (pH = 7.40), and (2-hydroxypropyl)-β-cyclodextrin (CD) could enhance the fluorescence intensity of Q. The UV/Vis spectrum showed that the Q-CD system was formed. After adding copper ions into the Q-CD system, the fluorescent emission intensity of Q-CD system generated quenching, and other metal ions could not bring change, which meant the Q-CD system showed good selectivity to copper ions. The fluorescence titration spectra showed that the concentration of copper ions was inversely proportional to fluorescence intensity, and gave a good linear change in fluorescence emission intensity in response to the concentration of copper ions ranging from 5.0 × 10-8 to 8.3 × 10-6 mol L-1. The calibration curve of the relationship between the intensity and copper ions concentration was y = -9.24x + 844.51 (R 2 = 0.997). The detection limit of copper ions was measured to be 2.3 × 10-8 mol L-1. The probable mechanism was studied by UV/Vis spectrum and Job's plot method. The results indicated that Q-CD-Cu(ii) complex was formed and intramolecular charge transfer (ICT) took place. At last, the probe was successfully applied for determination of copper ions in water bodies, vegetables and fruits with good recovery. The study showed that Q-CD system could detect copper ions as a fluorescent probe with high selectivity, sensitivity and larger linearity range.


GAPDH inhibits intracellular pathways during starvation for cellular energy homeostasis.
Starvation poses a fundamental challenge to cell survival. Whereas the role of autophagy in promoting energy homeostasis in this setting has been extensively characterized1, other mechanisms are less well understood. Here we reveal that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) inhibits coat protein I (COPI) transport by targeting a GTPase-activating protein (GAP) towards ADP-ribosylation factor 1 (ARF1) to suppress COPI vesicle fission. GAPDH inhibits multiple other transport pathways, also by targeting ARF GAPs. Further characterization suggests that this broad inhibition is activated by the cell during starvation to reduce energy consumption. These findings reveal a remarkable level of coordination among the intracellular transport pathways that underlies a critical mechanism of cellular energy homeostasis.


Daily high doses of fluoxetine for weight loss and improvement in lifestyle before bariatric surgery.
The number of gastric restrictive bariatric operations is increasing each year, but about one-fifth of patients will become disappointed due to unsatisfactory weight reduction or annoying complications. We questioned whether weight reduction by taking high doses of fluoxetine improves lifestyle before surgery. 84 severely obese subjects were referred by one bariatric surgeon for medical weight reduction and dietary counseling, before bariatric surgery. Subjects were voluntarily treated with fluoxetine, 60 mg per day, and followed-up at 1, 3, 6 and 12 months. Surgery was scheduled between 6 to 12 months after subjects started to take fluoxetine. Endpoints of this study were body weight reductions, the number of individuals who decided for themselves to postpone surgery for at least 6 months, and side-effects of fluoxetine therapy. 84 severely obese subjects consisting of 28 men (group 1) and 41 women (group 2) consented to take fluoxetine for its anorectic effects, whereas 12 men and 3 women who did not want to take fluoxetine served as the control group (group 3). Weight in these 3 groups at baseline was 149+/-26, 124+/-17, and 132+/-23 (controls) (P<0.05) with BMI 46+/-3, 44+/-3, and 45+/-2 (controls) kg/m(2) (NS). Maximum weight reduction before surgery in male and female fluoxetine users occurred at 3 and 6 months, respectively. At 6 months, men had achieved a weight reduction (kg) of -8.3 (95% CI: -9.3 to -5.9), women of -13.3 (95% CI: -16.3 to -8.8), sex difference P<0.001, and controls of -1.6 (95% CI: -3.8 to -2.5) kg, group difference P<0.0001. Only 2 men stopped fluoxetine because of annoying sexual side-effects. At 6 months, 25 fluoxetine users (29.7%) and none of the controls consented to postpone the time of surgery for at least another 6 months. Fluoxetine is effective to reduce weight in severely obese men and women who originally had requested to undergo bariatric surgery. One-third of subjects who consented to take fluoxetine as an anorectic drug agreed to delay surgery for at least 6 months later than scheduled.


A fluorescence study of the binding of poly(1,N6-ethenoadenylic acid) to Escherichia coli initiation factor 3.
The binding of initiation Factor 3 (IF3) to poly (1,N6-ethenoadenylic acid) [poly(epsilon A)] was investigated by fluorescence spectroscopy. At low salt concentrations, IF3 evokes an increase in the fluorescence intensity of poly(epsilon A) due to the unstacking of the nucleotide bases. The poly(epsilon A) fluorescence enhancement titrates to an endpoint of 13 +/- 2 nucleotide residues per IF3. The maximum poly(epsilon A) fluorescence enhancement, at lattice saturation, decreases with increasing salt concentration. Even though IF3 does not produce a large fluorescence increase between 75 and 200 mM NaCl concentration, the protein still binds to poly(epsilon A) at these salt concentrations as measured by sedimentation partition chromatography; the value of Kobs for the IF3-poly(epsilon A) interaction is comparable to that of other synthetic polynucleotides. The binding of IF3 to poly(A) at 150 and 200 mM NaCl induces an increase in nucleotide base-base separation as determined by CD, yet IF3-induced disruption of base stacking of poly(epsilon A) at these same salt concentrations is not detected by fluorescence. It is likely that IF3 binds primarily to the phosphate backbone of poly(epsilon A) at low salt concentrations, producing an increase in the fluorescence intensity. But, at higher salt concentrations, the aromatic amino acids intercalate between the nucleotide bases quenching the poly(epsilon A) fluorescence.


Effect of cardiac rehabilitation on myocardial perfusion reserve in postinfarction patients.
Cardiac rehabilitation is believed to increase myocardial perfusion reserve (MPR), but this has not been adequately studied because of poor delineation of infarcted myocardium in previous studies. The purpose of this study was to determine the effect of cardiac rehabilitation on MPR in the remote and infarcted myocardium with contrast-enhanced magnetic resonance imaging; 39 postinfarction patients were recruited for this study and randomly assigned to a training group (n = 20) or a nontraining group (n = 19). Those in the training group participated in a 3-month rehabilitation training program at an exercise intensity of 55% to 70% of peak oxygen uptake (VO2); those in the nontraining group continued their usual lifestyle. Nineteen age-, weight-, and height-matched subjects without cardiovascular risk factors were selected as healthy controls. After myocardial infarction, a reduction in perfusion reserve was seen not only in the infarcted myocardium, but also in the remote myocardium. In the training group, exercise capacity increased by 15% (p <0.01), to the same level as in healthy controls. The post-training MPR increased in both remote (30%, p <0.01) and infarcted myocardium (25%, p <0.05) and reached the same level as in healthy controls. The change in exercise capacity correlated with the change in MPR in the remote myocardium (r = 0.55, p <0.001 for peak VO2). In the nontraining group, exercise capacity and MPR were unchanged. In conclusion, cardiac rehabilitation improves perfusion reserve in both infarcted and remote myocardium, with a parallel increase in exercise capacity.


The Utility of the Plastic Surgery Standardized Letter of Recommendation Form in Predicting Residency Match Outcomes.
Letters of recommendation play an important role in resident selection. While plastic surgery's Standardized Letter of Recommendation (SLOR) form most commonly serves as an adjunct to narrative letters, the SLOR provides objective data in the review process and could eventually replace narrative letters. The utility of the SLOR in predicting Match outcomes has not been studied. Applicant data from 225 first-time residency applicants in 2020-21 were collected. Logistic regression modeling was used to predict Match outcomes. This model was validated using 100 randomly selected applicants from 2019-20. Rank placement (SLOR Question 6) was the most important factor when predicting Match outcomes (p<0.0001). All other SLOR questions were not predictive and subject to notable score inflation. No SLOR score differences were noted based on race; female applicants were rated higher in two of ten domains (p<0.05). One question on the plastic surgery SLOR was highly predictive of an applicant matching. However, the remaining SLOR questions had little utility and were subject to gross score inflation. Further work should be done to optimize the utility of the SLOR in differentiating applicants. This has important implications in ensuring the selection of professional, competent residents according to the aims of the Accreditation Council of Graduate Medical Education.


Decreased FABP5 and DSG1 protein expression following PAX6 knockdown of differentiated human limbal epithelial cells.
PAX6 haploinsufficiency related aniridia is characterized by disorder of limbal epithelial cells (LECs) and aniridia related keratopathy. In the limbal epithelial cells of aniridia patients, deregulated retinoic acid (RA) signaling components were identified. We aimed to visualize differentiation marker and RA signaling component expression in LECs, combining a differentiation triggering growth condition with a small interfering RNA (siRNA) based aniridia cell model (PAX6 knock down). Primary LECs were isolated from corneoscleral rims of healthy donors and cultured in serum free low Ca2+ medium (KSFM) and in KSFM supplemented with 0.9 mmol/L Ca2+. In addition, LECs were treated with siRNA against PAX6. DSG1, PAX6, KRT12, KRT 3, ADH7, RDH10, ALDH1A1, ALDH3A1, STRA6, CYP1B1, RBP1, CRABP2, FABP5, PPARG, VEGFA and ELOVL7 expression was determined using qPCR and western blot. DSG1, FABP5, ADH7, ALDH1A1, RBP1, CRABP2 and PAX6 mRNA and FABP5 protein expression increased (p ≤ 0.03), PPARG, CYP1B1 mRNA expression decreased (p ≤ 0.0003) and DSG1 protein expression was only visible after Ca2+ supplementation. After PAX6 knock down and Ca2+ supplementation, ADH7 and ALDH1A1 mRNA and DSG1 and FABP5 protein expression decreased (p ≤ 0.04), compared to Ca2+ supplementation alone. Using our cell model, with Ca2+ supplementation and PAX6 knockdown with siRNA treatment against PAX6, we provide evidence that haploinsufficiency of the master regulatory gene PAX6 contributes to differentiation defect in the corneal epithelium through alterations of RA signalling. Upon PAX6 knockdown, DSG1 differentiation marker and FABP5 RA signaling component mRNA expression decreases. A similar effect becomes apparent at protein level though differentiation triggering Ca2+ supplementation in the siRNA-based aniridia cell model. Expression data from this cell model and from our siRNA aniridia cell model strongly indicate that FABP5 expression is PAX6 dependent. These new findings may lead to a better understanding of differentiation processes in LECs and are able to explain the insufficient cell function in AAK.


A new technique for hemodilution, preparation of autologous platelet-rich plasma and intraoperative blood salvage in cardiac surgery.
We have developed a new system for the production of autologous platelet-rich plasma and red blood cell concentrates to be used in autologous transfusion support of cardiac surgery patients. In 15 operations no homologous blood products were required. Costs were diminished since with the same harness it was possible to carry out the intraoperative blood salvage and concentrate the erythrocytes contained in the oxygenator and its lines. Indirect costs were also reduced since no infective complication was observed due to homologous blood products.


Motivational interviewing to improve self-care for patients with chronic heart failure: MITI-HF randomized controlled trial.
The purpose of this study was to test the efficacy of a tailored motivational interviewing (MI) intervention versus usual care for improving HF self-care behaviors, physical HF symptoms and quality of life. This is a single-center, randomized controlled trial. Participants were enrolled in the hospital. Immediately after discharge, those in the intervention group received a single home visit and 3-4 follow-up phone calls by a nurse over 90 days. A total of 67 participants completed the study (mean age 62±12.8 years), of which 54% were African American, 30% were female, 84% had class III/IV symptoms, and 63% were educated at a high school level or less. There were no differences between the groups in self-care maintenance, self-care confidence, physical HF symptoms, or quality of life at 90 days. Patients who received the MI intervention had significant and clinically meaningful improvements in HF self-care maintenance over 90 days that exceeded that of usual care. These data support the use of a nurse-led MI intervention for improving HF self-care. Identifying methods to improve HF self-care may lead to improved clinical outcomes.


The association of self-control, self-efficacy, and demographic characteristics with home-based E-learning behavior in nursing and midwifery undergraduates: A cross-sectional study under the COVID-19 epidemic.
During the coronavirus disease 2019 (COVID-19) pandemic, nursing and midwifery undergraduate students' time spent in home isolation and being engaged in home-based e-learning was extended. Limited research has been conducted on home-based e-learning behavior during home isolation, and the relationships between individual factors, such as self-control, self-efficacy, and other demographic characteristics, and home-based e-learning behavior are unclear. This study aimed to explore the associations between self-control, self-efficacy, and demographic information with home-based e-learning behavior among nursing and midwifery undergraduates during the COVID-19 pandemic. A cross-sectional study was employed, and an online survey was conducted with 3733 nursing and midwifery undergraduates across seven provinces and cities in mainland China. Data were collected using the Brief Self-control Scale, General Self-efficacy Scale, Undergraduate Home-based E-learning Behavior Questionnaire, and Demographic Information Questionnaire. A multiple linear regression analysis using the stepwise method was conducted to identify predictors of home-based e-learning behavior. Undergraduates achieved an overall mean score of 26.02 (SD = 4.20) for home-based e-learning behavior and an overall mean score of 42.54 (SD = 6.22) and 27.59 (SD = 3.89) for self-control and self-efficacy, respectively. Better self-control (β = 0.250, P < 0.001), higher self-efficacy (β = 0.169, P < 0.001), universities being located in non-Hainan provinces (β = 0.249, P < 0.001), being a sophomore or freshman (β = -0.255, P < 0.001), and good perceived health status (β = -0.044, P = 0.003) were identified as the predictors of better home-based e-learning behavior among nursing and midwifery undergraduates. Self-control, self-efficacy, and demographic characteristics including the province of the university, grade level, and personal perceived health status were associated with home-based e-learning behavior. Universities should help nursing and midwifery undergraduates improve self-control and enhance self-efficacy while taking measures to decrease the impact caused by demographic characteristic differences.


Immune-mediated modulation of sarcoplasmic reticulum function in human dilated cardiomyopathy.
Calcium transport by the cardiac sarcoplasmic reticulum is depressed in human dilated cardiomyopathy, but the mechanisms involved are not clear. The possible involvement of immunological mechanisms was explored by evaluating the effect of sera from 49 patients with dilated cardiomyopathy on oxalate-facilitated Ca2+ uptake. In 14 of these patients, serum or IgG induced a time- and concentration-dependent decline (29 +/- 4% at 100-fold serum dilution) in Ca2+ transport. In 14 patients, autoantibodies against the beta 1-adrenoceptor were also demonstrated by a ligand binding inhibition assay. Serum from these patients inhibited the isoproterenol-mediated stimulation of Ca2+ uptake in permeabilized cardiac myocytes, but did not prevent the effect of protein kinase A. Anti-beta-receptor antibodies were present in 50% of the sera inhibiting Ca2+ uptake compared to 20% of those without inhibitory activity, (p less than 0.01). There was a strong correlation between the inhibition of sarcoplasmic reticulum Ca2+ transport and the HLA-DR4 phenotype (78% compared to 30% in patients with no inhibitory effect). These results suggest that immunological mechanisms play an important role in modifying sarcoplasmic reticulum function in about a third of the patients with detailed cardiomyopathy.


Correction: The Relationship Between Health Management and Information Behavior Over Time: A Study of the Illness Journeys of People Living With Fibromyalgia.
[This corrects the article DOI: 10.2196/jmir.5309.].


Negative correlation between word-level surprisal and intersubject neural synchronization during narrative listening.
Word-predictability measures, such as surprisal, have been used to show that linguistic prediction is an essential neural mechanism for successful comprehension. However, the neural dynamic of this mechanism may differ across individuals listening to the same narrative, revealing possible idiosyncrasies. Therefore, in this study, we investigated the ability of the surprisal measure to address the linguistic prediction in terms of the intersubject phase synchronization (ISPS) among healthy volunteers listening to a narrative during continuous functional Magnetic Resonance Imaging (fMRI) scanning. The data of twenty-seven participants, acquired in a previous study, were re-analyzed to estimate the ISPS associated with an audiobook listening, played forward and backward. Mean ISPS differences between playing conditions were first analyzed across the whole brain. ISPS time-series during the forward condition was explained with both a lexical-only and a semantics-weighted lexical surprisal model of the narrative word series to detect correlations between ISPS and word surprisal values. Compared to the backward condition, mean ISPS was significantly higher during forward condition in a broad network encompassing frontal, temporal, and parietal areas. The lexical-only model disclosed significant negative ISPS-surprisal correlations in the angular gyrus bilaterally, precuneus, left inferior parietal lobule, left middle frontal gyrus, left cerebellum, and left inferior frontal gyrus. The semantics-weighted surprisal model disclosed significant negative ISPS-surprisal correlations in the right angular gyrus, right precuneus, and left inferior frontal gyrus. Besides engaging language-related areas, narrative processing induces significant ISPS levels beyond the language network. The negative ISPS-surprisal correlations observed would signal divergent neural dynamics among individuals, leading to lower group synchronization, when the words to be integrated are characterized by higher surprisal levels. These results provide further support to the use of language models, such as the surprisal, to explain the neural processes of narrative comprehension and additional information into how the human brain exploits predictions during language comprehension.


Infected Meme implants: salvage reconstruction with latissimus dorsi myocutaneous flaps and silicone implants.
Polyurethane-coated breast implants are used more frequently in recent years both in augmentation and reconstruction. Postoperative infection may lead to serious complications with formation of foreign body granulomas. A case is presented with such a complication that required multiple operations and wide excision of reconstructed breasts necessitating major myocutaneous flaps to salvage the breasts.


Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.
Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which can result in chronic lung disease. The sequence of events leading to lung disease is not fully understood but recent data show that the critical pathogenic event is the loss of the ability to clear bacteria due to abnormal airway surface liquid secretion (ASL). However, whether the inhalation of bacteria triggers ASL secretion and whether this is abnormal in cystic fibrosis has never been tested. Here we show, using a novel synchrotron-based in vivo imaging technique, that wild-type pigs display both a basal and a Toll-like receptor-mediated ASL secretory response to the inhalation of cystic fibrosis relevant bacteria. Both mechanisms fail in CFTR-/- swine, suggesting that cystic fibrosis airways do not respond to inhaled pathogens, thus favoring infection and inflammation that may eventually lead to tissue remodeling and respiratory disease.Cystic fibrosis is caused by mutations in the CFTR chloride channel, leading to reduced airway surface liquid secretion. Here the authors show that exposure to bacteria triggers secretion in wild-type but not in pig models of cystic fibrosis, suggesting an impaired response to pathogens contributes to infection.


Transseptal Transcatheter Mitral Valve Replacement Using Balloon-Expandable Transcatheter Heart Valves: A Step-by-Step Approach.
Transcatheter mitral valve replacement (TMVR) using balloon-expandable valves has become an alternative therapy for selected patients with mitral valve disease. Up to now, the transapical approach has been the preferred route, but the transseptal approach is becoming increasingly popular due to its reduced invasiveness and increased safety. However, transseptal TMVR procedures are technically challenging, and little is known about the screening process required before this therapy. The authors provide operators with a step-by-step approach from the screening process to follow-up care for transseptal TMVR procedures.


Pineal gland in old age; quantitative and qualitative morphological study of 168 human autopsy cases.
Age-related changes of human pineal gland were studied morphologically on 168 autopsy cases. Pineal weight in the formalin-fixed condition was 99 +/- 56 mg in males (n = 88, mean age 78 years) and 91 +/- 41 mg in females (n = 80, mean age 79 years), which showed no sexual difference (P = 0.290). There was no correlation between pineal weight and age of the patient (r = 0.0678, P = 0.191, n = 168). The pineal volume calculated as a spheroid was directly proportional to the weight (r = 0.904, n = 167, P = 0.000). A significant correlation existed between pineal weight and the degree of calcification (r = 0.231, P = 0.002, n = 156). The density of the pineals decreased with age (r = -0.164, P = 0.017, n = 167). The degree of calcification and cyst formation did not increase with age, but the grade of cyst formation was related to the pineal volume (P = 0.0002). Some pineals of the patients over 90 years old showed no calcification and appeared indistinguishable from the ones of the younger subjects. The weight and volume of the pineals of the patients with hypertension was appreciably greater than those of the non-hypertensive patients. These results indicate that human pineals do not necessarily degenerate progressively after involution.


Clinical applications of BMPs.
Bone morphogenetic proteins (BMPs) are polypeptides discovered by Marshall Urist in 1965 and later defined by his co-workers as multifunctional cytokines involved in osteoinduction. They are members of the transforming growth factor-beta superfamily with the exception of the BMP-1. Till now at least 20 BMPs have been identified and studied, but only BMP 2, 4 and 7 have been able in vitro to stimulate the entire process of stem cell differentiation into osteoblastic mature cells. After in vitro studies BMPs have been tested in preclinical and clinical studies, showing their definite potential in osteoinduction and have been approved for clinical use in open fracture of long bones, non-unions and vertebral arthrodesis. But more clinical use of these molecules is under investigation and the possibility of using gene therapy in selected pathologies seems the most appealing.


Selective urinary screening for mucopolysaccharidoses.
Two methods for analysis of urinary glycosaminoglycans (GAGs) have been modified and improved for efficient screening of mucopolysaccharidoses. Urinary excretion of GAGs was estimated by spectrophometric measurement of alcian blue complex formation and was used in conjunction with qualitative analysis by thin layer chromatography. After normal variation in GAG excretion was established using 120 urine samples, these screening methods were applied to a total of 2057 urine samples over 4 years. Six patients with abnormal urinary GAG excretion had a mean of 50.5 +/- 20.6 mg GAG/mmol creatinine compared to 3.4 +/- 2.9 for age-matched controls. Qualitative analysis by thin layer chromatography using alternating solvent systems identified the GAGs excreted in excess and facilitated selection of specific enzyme assays for final confirmation. Six cases were diagnosed prospectively and demonstrate these quantitative and qualitative methods to be economical, efficient, and suitable for clinical use.


[Transplantable experimental tumor. Morphological and ultrastructural study (author's transl].
An experimental tumor which has been induced in newborn chicken, was transplanted into inbred BALB/c mice and then studied by the means of light and electron microscopy. Sendai virus fusion between MSV-H transformed rat cells and chickembryo cells provided the tumor. Histological pattern of this neoplasia seems to be superposable, both in chicken and in mouse, to that of anaplastic fibrosarcomas and shows some differences from either Rous sarcoma or BALB/c mouse H-6668 spontaneous rabdomyosarcoma patterns. tumor malignancy was evaluated onthe basis of rapid growth


Atrial fibrillation mechanisms before and after pulmonary vein isolation characterized by noncontact charge density mapping.
The interaction of the pulmonary vein (PV) and putative nonpulmonary triggers of atrial fibrillation (AF) remains unclear and has yet to translate into patient-tailored ablation strategies. The purpose of this study was to use noncontact mapping to detail the global conduction patterns in paroxysmal and persistent AF and how they are modified during PV ablation. Forty patients during AF ablation underwent mapping using a noncontact catheter (AcQMap, Acutus Medical, Inc., Carlsbad, CA) before and after PV isolation (PVI). Propagation history maps were analyzed postprocedure for each patient to categorize conduction patterns into focal, organized reentrant, and disorganized patterns (F-Patterns, O-Patterns, and D-Patterns, respectively). Activation patterns identified by using a noncontact mapping system can be subclassified from 3 main patterns into subtypes (macroreentrant and localized reentrant [MR and LR] subtypes and disorganized 1 and disorganized 2 [D1 and D2] subtypes). Persistent AF demonstrated more D-Patterns and less O-Patterns and F-Patterns than did paroxysmal AF. In addition, patients with PAF inducible after PVI demonstrated a higher region number and higher prevalence of MR subtypes than did those noninducible. PVs remained the critical region and included almost one-third of all patterns across any AF types. PVI was effective to eliminate PV-related functional phenotypes and affected recurrence with other patterns. Activation patterns identified using AcQMap can be classified into 3 main patterns (F-Patterns, O-Patterns, and D-Patterns) as well as subtypes (MR and LR subtypes and D1 and D2 subtypes). PerAF was different from PAF in demonstrating a higher region number and higher prevalence of D-Patterns but a lower region number and lower prevalence of O-Patterns and F-Patterns.


A case study of improved cook stoves in primate conservation from Democratic Republic of Congo.
Human communities living near nonhuman primate habitats often depend on wood from forests for their energy needs. Improving the efficiency of local cook stoves is a potential "win-win" solution that is commonly promoted to protect forests and improve human health and development. Despite the popularity of improved stove projects in primate conservation, few outcomes have been formally published. As a result, it is currently unclear whether this approach is a wise investment of limited conservation funds. This paper describes a pilot study conducted by the Gorilla Rehabilitation and Conservation Education Center to evaluate the potential for using improved stoves for the conservation of an important habitat for Grauer's gorillas and chimpanzees in eastern Democratic Republic of Congo. Community surveys and observations of human forest use revealed a heavy local reliance on forest-derived wood. Wood was the main source of fuel used in households, the most highly valued forest resource, and the primary resource extracted during forest observations. It was primarily collected by women and children. The use of traditional, inefficient three-stone hearths for cooking was also widespread. A 2-year campaign using a community-based social marketing approach resulted in an increase in improved stove installations from 18% to 78% of households in one village. After stove adoption, weekly household wood consumption was reduced by half. Campaign elements that showed promise include promotion using women's networks and intensive follow-up assessment and support. We conclude that, if scaled up, improved stoves may be a useful strategy for reducing encroachment into our target protected area but that successful implementation will require a significant long-term commitment with evaluation and oversight. It is recommended that before investing in improved stoves, primate conservation projects take long-term and evaluation requirements into consideration.


Geometric uncertainties in voluntary deep inspiration breath hold radiotherapy for locally advanced lung cancer.
Deep inspiration breath hold (DIBH) increases lung volume and can potentially reduce treatment-related toxicity in locally advanced lung cancer. We estimated geometric uncertainties in visually guided voluntary DIBH and derived the appropriate treatment margins for different image-guidance strategies. Seventeen patients were included prospectively. An optical marker-based respiratory monitoring with visual guidance enabled comfortable DIBHs, adjusted to each patient's performance. All patients had three consecutive DIBH CTs at each of the treatment fractions 2, 16 and 31. DIBH reproducibility was evaluated as inter- and intra-fractional variations in lung volume, tumour position and differential motion between primary tumour and mediastinal lymph nodes. Lung volume increased by median 60% in DIBH. Inter- and intra-fractional lung volume variations were median 2.1% and 1.1%, respectively. Inter- and intra-fractional uncertainties in 3D tumour position were 4.8 ± 2.8 mm and 1.7 ± 1.4 mm (mean ± SD). Inter- and intra-fractional differential motion was 4.8 ± 3.3 mm and 0.0 ± 1.1 mm. For single targets, visually guided voluntary DIBH radiotherapy is highly reproducible provided an image-guidance strategy with tumour registration is performed. If the primary tumour is separated from the mediastinal lymph nodes, inter-fractional differential motion remains a challenge and margins must be adapted to reflect the image registration strategy.


Monoclonal antibodies reveal three types of idiotypic determinants on MOPC 173: H-L-specific private and public idiotopes, and Vh-specific public idiotope(s).
Monoclonal anti-idiotypic antibodies against the IgG2a, K myeloma protein MOPC 173 were raised with A/J- and CBA-immune B-cells. The specificity of the antibodies was studied by hemagglutination and inhibition of a radioimmunoassay (RIA). A series of myeloma proteins, their H- and L-chains, free or reassociated in various combinations, were used as inhibitors. The RIA patterns allow recognition of three types of idiotypic determinants: private conformational idiotope(s), a public conformational idiotope, and public VH-determinant(s). Strain distribution of the public determinant was studied. A tentative correlation between amino acid positions and Id determinants is discussed.


The use of mesophilic and lactic acid bacteria strains as starter cultures for improvement of coffee beans wet fermentation.
The use of starter cultures during food fermentation aims to standardize the process and to obtain a higher quality product. The objectives were to study mesophilic bacteria (MB) and lactic acid bacteria (LAB) isolated from wet coffee processing and evaluate their performance in a pulped coffee medium. Eighty-six bacteria isolates (59 MB and 27 LAB) were assessed for pectinolytic activity, metabolite production, and pH value decrease in coffee-based culture (CPM). Seven bacteria strains (3 MB and 4 LAB) were selected and used as starter cultures in the wet fermentation of pulped coffee. The MB and LAB populations varied from 4.48 to 8.43 log CFU g-1 for MB and 3.54 to 8.72 log CFU g-1 for LAB during fermentation. Organic acid concentration (ranged from 0.01 to 0.53 for succinic acid; 0.71 to 8.14 for lactic acid and 0.06 to 0.29 for acetic acid), and volatile compounds (44 compounds were detected in green beans and 98 in roasted beans) were evaluated during fermentation. The most abundant compounds found in roasted beans belong to furans [15], ketones and esters [14], pyridines [13], and pyrazines [12]). Leuconostoc mesenteroides CCMA 1105 and Lactobacillus plantarum CCMA 1065 presented volatile compounds important for coffee aroma. Isovaleric acid; 2,3-butanediol; phenethyl alcohol; β-linalool; ethyl linoleate; and ethyl 2-hydroxypropanoate could improve cupping qualities.


Immediate implants: indications and clinical decision making.
This paper is intended to describe the current concepts in timing of implant placement, and to address some of the controversies surrounding implants and bone grafting.


Boar sperm motility is modulated by CCK at a low concentration of bicarbonate under capacitation conditions.
In a previous study, our group detected the cholecystokinin (CCK) protein in the porcine oviduct. This fact, together with the involvement of CCK in the regulation of sperm protein tyrosine phosphorylation by the modulation of HCO3 - uptake (in mice and humans) suggests a role for CCK during sperm capacitation. Therefore, on the one hand, the expression of CCK receptors (CCK1R and CCK2R) on boar testes has been investigated and probed; on the other hand, boar spermatozoa (from seminal doses of 1-day and 5-day storage) were exposed to different concentrations of CCK (0-control, 25 or 50 μM) in a medium supporting capacitation supplemented with 0, 5 or 25 mmol/L of HCO3 - for 1 h at 38.5°C. Sperm motion (total and progressive motility), kinetic parameters, viability, acrosome status, and mitochondrial activity were determined. No differences between groups (0, 25 or 50 μM of CCK) were observed when HCO3 - was absent in the media (p > .05). However, the results showed that when the media was supplemented with 5 mmol/L HCO3 - in 1-day seminal dose storage, the linearity index (LIN, %), straightness index (STR, %) and oscillation index (WOB, %) (sperm kinetics parameters) increased in the presence of CCK regardless the concentration (p < .05). Nevertheless, CCK in sperm from 5-day storage only increased the WOB parameter in comparison to the control (p < .05). Furthermore, the average amplitude of the lateral displacement of the sperm head (ALH, μm) and curvilinear velocity (VCL, μm/s) decreased when CCK was present, depending on its concentration and sperm aging (1-day vs. 5-days) (p < .05). In the case of the media supporting capacitation supplemented with 25 mmol/L HCO3 - , any differences were observed except for sperm viability in the 5-day seminal doses, which increased in the 50 μM-CCK group compared to the control (p < .05). In conclusion, these data suggest an implication of CCK protein during sperm capacitation under low bicarbonate concentration increasing the sperm linear trajectory.


Injection pain: comparison of three mandibular block techniques and modulation by nitrous oxide:oxygen.
The authors conducted this study to compare the pain on injection of the three mandibular block techniques and to determine the effect that the delivery of nitrous oxide:oxygen, or N2O:O2, had on this pain. Based on sample size calculation, the authors randomly assigned 60 subjects to receive either local anesthetic alone or local anesthetic with N2O:O2 titrated to effect. Each subject received two mandibular block injections bilaterally from three possible pairings: Gow-Gates/standard block, standard block/Vazirani-Akinosi or Gow-Gates/ Vazirani-Akinosi. Subjects scored their pain using a 100-millimeter visual analog scale immediately after each injection. The authors analyzed data using analysis of variance, Student t tests and multiple regression analyses. There were no significant differences in pain on injection among the three injection techniques. The subjects in the group that received N2O:O2 and the local anesthetic demonstrated a statistically significant reduction in pain on injection compared with subjects in the group that received the local anesthetic only (P < .05). When N2O:O2 was used, there was a statistically significant decrease in pain with the first injection (P < .0005), an effect not seen with the second injection. There was no significant difference in pain among the three mandibular block techniques. N2O:O2 can reduce pain on the first injection given, but this effect is not seen subsequently. The decision to select one of the three mandibular block techniques should be based on factors other than pain on injection. N2O:O2 reduces pain on the first injection only.


Probing the microenvironmental conditions for induction of superficial zone protein expression.
To determine the in vitro conditions which promote expression of superficial zone protein (SZP). Chondrocytes from 6-month-old calves were expanded in monolayer culture and the expression of SZP in alginate bead and monolayer culture was quantified with quantitative real time-polymerase chain reaction (qRT-PCR) and immunostaining. The effect of oxygen tension on SZP expression was determined by qRT-PRC analysis of cells cultured in two dimension (2D) and three dimension (3D) under hypoxic (1% pO2) or normoxic (21% pO2) conditions. Finally, to examine the effect of cyclic tensile strain on expression of SZP in 2D and 3D cultures, chondrocytes encapsulated in alginate beams or seeded on type I collagen coated polydimethylsiloxane (PDMS) chambers were subjected to 5% strain at 1 Hz, 2 h/day for 4 days or 2 h at the fourth day of culture and mRNA levels were quantified. Bovine chondrocytes in monolayer showed a drastic decrease in SZP expression, similar in trend to the commonly reported downregulation of type II collagen (Col2). Chondrocytes embedded in alginate beads for 4 days re-expressed SZP but not Col2. SZP expression was higher under normoxic conditions whereas Col2 was upregulated only in alginate beads under hypoxic conditions. Cyclic mechanical strain showed a tendency to upregulate mRNA levels of SZP. A microenvironment encompassing a soft encapsulation material and 21% oxygen is sufficient for fibroblastic chondrocytes to re-express SZP. These results serve as a guideline for the design of stratified engineered articular cartilage and suggest that microenvironmental cues (oxygen tension level) strongly influence the pattern of SZP expression in vivo.


Arthroscopic Posterior Labral Repair in Active-Duty Military Patients: A Reliable Solution for an At-Risk Population, Regardless of Anchor Type.
Active-duty servicemembers are a population at risk for the development of posterior shoulder instability. While short-term outcomes after arthroscopic posterior labral repair for posterior shoulder instability are promising, there is a paucity of longer term follow-up data for this procedure. The primary purpose was to report midterm outcomes after arthroscopic posterior labral repair in active-duty military patients for posterior shoulder instability without bone loss. The secondary purpose was to determine if outcomes varied between anchor types used. Cohort study; Level of evidence, 3. Preoperative and postoperative outcomes, with a minimum 3-year follow-up, for a visual analog scale for pain, the Single Assessment Numeric Evaluation (SANE), the American Shoulder and Elbow Surgeons (ASES) score, and the Rowe score were collected and analyzed. A separate subgroup analysis was performed comparing the outcomes of patients who underwent repair with biocomposite anchors versus those who underwent repair with all-suture anchors. A total of 73 patients with a mean follow-up of 82.55 ± 24.20 months met the inclusion criteria and were available for analysis. As a whole, the cohort demonstrated statistically and clinically significant improvements in outcome scores at final follow-up. Preoperative and postoperative range of motion did not vary significantly. While the difference in final outcome scores between the 2 anchor types did not reach statistical significance, a statistically significantly larger proportion of patients who underwent repair with all-suture anchors versus those who underwent repair with biocomposite anchors met the Patient Acceptable Symptom State for the SANE (97.14% vs 78.95%, respectively; P = .0180) and the ASES score (88.57% vs 68.42%, respectively; P = .0171). The proportion of patients who achieved the substantial clinical benefit or surpassed the minimal clinically important difference, however, did not vary by anchor type. Overall, 70 patients (95.89%) remained on active duty and were able to return to preinjury work and recreational activity levels. There were 3 patients (4.11%) who had recurrent posterior instability. This population of active-duty servicemembers undergoing posterior labral repair for posterior labral instability without bone loss demonstrated a statistically and clinically significant improvement in midterm outcomes, a low recurrence rate, and a rate of return to active duty of 95.89%, regardless of the anchor type used.


Cellular schwannoma: report of a case diagnosed intraoperatively with the aid of cytologic imprints.
The diagnosis of cellular schwannoma in intraoperative consultation is difficult because of the hypercellularity and deep location, which may lead to errors. The recognition of cytologic features together with the histological appearance are of great importance to make the correct diagnosis. An accurate diagnosis of this variant of schwannoma is important because other spindle cell tumors display differences in treatment and clinical behavior. We report a demonstrative case of cellular schwannoma arising in retroperitoneum of a 52-yr-old woman in which the cytologic imprints were useful to make an accurate diagnosis intraoperatively. Briefly, the differential diagnosis is discussed.


The neurogenetics and evolution of food-related behaviour.
All organisms must acquire nutrients from the ambient environment to survive. In animals, the need to eat has driven the evolution of a rich array of complex food-related behaviours that ensure appropriate nutrient intake in diverse niches. Here, we review some of the neural and genetic components that contribute to the regulation of food-related behaviour in invertebrates, with emphasis on mechanisms that are conserved throughout various taxa and activities. We focus on synthesizing neurobiological and genetic approaches into a neurogenetic framework that explains food-related behaviour as the product of interactions between neural substrates, genes and internal and external environments.


Unravelling secretion in Cryptococcus neoformans: more than one way to skin a cat.
Secretion pathways in fungi are essential for the maintenance of cell wall architecture and for the export of a number of virulence factors. In the fungal pathogen, Cryptococcus neoformans, much evidence supports the existence of more than one route taken by secreted molecules to reach the cell periphery and extracellular space, and a significant degree of crosstalk between conventional and non-conventional secretion routes. The need for such complexity may be due to differences in the nature of the exported cargo, the spatial and temporal requirements for constitutive and non-constitutive protein secretion, and/or as a means of compensating for the extra burden on the secretion machinery imposed by the elaboration of the polysaccharide capsule. This review focuses on the role of specific components of the C. neoformans secretion machinery in protein and/or polysaccharide export, including Sec4, Sec6, Sec14, Golgi reassembly and stacking protein and extracellular exosome-like vesicles. We also address what is known about traffic of the lipid, glucosylceramide, a target of therapeutic antibodies and an important regulator of C. neoformans pathogenicity, and the role of signalling pathways in the regulation of secretion.


Trpm1: Novel function at the intersection of light and pain response in the iris.
In mammals, the retina is the photosensitive tissue that is responsible for the capture of light and the transduction of the light-initiated signals to the brain. These visual signals help to drive image and non-image forming behaviors. The pupillary light reflex (PLR) is an involuntary non-image forming behavior which involves the constriction of the iris muscle tissue in response to ambient light intensity. A subset of photosensitive retinal ganglion cells provides the principal pathway for all light input to the olivary pretectal nucleus which directs the neuronal input to drive iris constriction. Transient receptor potential melastatin 1 (Trpm1) knockout mice have a severe defect in PLR, but it remains unclear how the Trpm1 channel contributes to this behavior. We have demonstrated that the reduced PLR in Trpm1-/- mice at scotopic and photopic intensities is due to a functional loss of Trpm1 in the retina as well as the iris sphincter muscle. We have also tested constriction in isolated eyes and have shown that light-driven constriction independent of signaling from the brain also requires Trpm1 expression. In both the in vivo PLR and the iris photomechanical response, melanopsin is required for the light-dependent activation. Finally, pharmacological experiments using capsaicin to activate pain afferents in the eye demonstrate that Trpm1 expression is required for all sensory driven iris constriction. Our results demonstrate for the first time that Trpm1 has a novel and necessary role in iridial cells and is required for all sensory-driven constriction in the iris.


Role of external oversight in quality activities: accreditation, credentialing, licensure, and deemed status.
There currently exist a number of organizations which provide quality oversight to the ESRD program in the United States. The state surveyors confirm that dialysis facilities comply with Medicare's conditions of coverage, but surveyor activities have traditionally followed a quality assurance rather than a continuous quality improvement (CQI) model. State surveyors focus primarily on nursing homes, so their content knowledge of ESRD quality issues may be limited. The ESRD Networks have CQI expertise on their staffs, and their quality agenda is driven by their medical review boards, whose members bring scientific and technical expertise from the provider community. The success of the Networks in achieving quality goals has been hampered by personnel and resource limitations and by inconsistent direction by the Health Care Financing Administration (HCFA). Texas has developed a dialysis facility licensure program that partners its ESRD Network and its Medicare state surveyors in quality oversight activities. This collaboration has led to improved patient outcomes and may prove to be a model for other states. Non-Medicare payers may contract with dialysis providers based on performance specifications that exceed those of Medicare's conditions of coverage. A private credentialing mechanism for dialysis facilities that satisfies the performance specifications of all payers has been proposed but, in the absence of deemed status for Medicare survey and certification activities, is unlikely to achieve widespread acceptance.


Alteration of a brain network with stable and strong functional connections in subjects with schizophrenia.
It is widely accepted that there are some common network patterns in the human brain. However, the existence of stable and strong functional connections in the human brain and whether they change in schizophrenia is still a question. By setting 1% connections with the smallest coefficient of variation, we found a widespread brain functional network (frame network) in healthy people(n = 380, two datasets from public databases). We then explored the alterations in a medicated group (60 subjects with schizophrenia vs 71 matched controls) and a drug-naive first-episode group (68 subjects with schizophrenia vs 45 matched controls). A linear support vector classifier (SVC) was constructed to distinguish patients and controls using the medicated patients' frame network. We found most frame connections of healthy people had high strength, which were symmetrical and connected the left and right hemispheres. Conversely, significant differences in frame connections were observed in both patient groups, which were positively correlated with negative symptoms (mainly language dysfunction). Additionally, patients' frame network were more left-lateralized, concentrating on the left frontal lobe, and was quite accurate at distinguishing medicated patients from controls (classifier accuracy was 78.63%, sensitivity was 86.67%, specificity was 76.06%, and the area under the curve (AUC) was 0.83). Furthermore, the results were repeated in the drug-naive set (accuracy was 84.96%, sensitivity was 85.29%, specificity was 88.89%, and AUC was 0.93). These findings indicate that the abnormal pattern of frame network in subjects with schizophrenia might provide new insights into the dysconnectivity in schizophrenia.


Identification of transferrin as the main binding site for protactinium in rat blood serum.
The distribution of 233Pa in rat serum at periods between 5 and 50 min after i.v. injection of a solution of protactinium chloride was studied by gel chromatography. Sequential analysis of sera on Sephacryl S-300 and DEAE-Sephadex showed that 233Pa was associated only with the transferrin fraction of the serum proteins. This finding was confirmed by iso-electric focusing electrophoresis. In the cytosol fractions prepared from the liver and kidneys of the 233Pa injected rats the nuclide was also shown to be protein bound.


Examining moment to moment affective determinants of smoking rate following a quit attempt among homeless daily smokers.
Cigarette smoking disproportionately affects homeless individuals, who have a higher smoking prevalence, fewer resources, and increased stressors compared to domiciled smokers. Little is known about how to facilitate smoking cessation among this population although some findings support focusing efforts on affective variables as well as alternate outcomes in order to optimize interventions for this group. Participants were homeless adults recruited from a Dallas, TX, shelter (N = 57, 61.4% male, Mage = 48.8 ± 9.0) to participate in tobacco cessation classes using an American Cancer Society-based therapy and support group with nicotine replacement therapy. Moment-to-moment changes in affect [e.g., negative affect (NA), positive affect (PA), and stress] were recorded via Ecological Momentary Assessments to assess whether they were associated with concurrent changes in cigarettes smoked per day (CPD) following a specific quit attempt. Separate generalized linear models (GLM) were evaluated for each predictor to examine the associations between affective variables and CPD in covariate-adjusted analyses. Significant interaction effects of time and affect were found for all variables (NA: p = 0.0011, PA: p = 0.0006, stress: p = 0.0259), whereby the association of affect and CPD were significant in the early part of the week but the effects faded as time progressed. With regard to main effects, only increases in PA during the post-quit week significantly predicted fewer CPD (adjusted incidence rate ratio = 0.924, SE = 0.027, p = 0.0032). Homeless smokers may be more likely to decrease their cigarette consumption during periods of greater PA throughout the post-quit week. Relationship between positive affect and reduction in CPD suggest focus on affective variables with homeless smokers may be an effective avenue for change in smoking behaviors, particularly in the days immediately following a quit attempt. Time effects should be further investigated to determine when these interventions might best be implemented.


Biological fate of methenamine in man. Absorption, renal excretion and passage to umbilical cord blood, amniotic fluid and breast milk.
Methenamine hippurate was administered orally as tablets or granules to healthy volunteers. Plasma concentrations of methenamine reached a maximum 1--2 hours after a single dose and then declined with a half-life of about 4 hours. The apparent distribution volume was similar to that of total body water. Renal clearance of methenamine was somewhat lower than that of creatinine. In cross-over experiments over six days, methenamine recovered in the urine corresponded to about 80 per cent of the dose given per 12 hours, slightly lower values being obtained from granules than from tablets. The efficient renal elimination of methenamine was confirmed in similar studies on patients post-operatively. Methenamine hippurate was also given to healthy pregnant women during labor, a few hours before expected delivery. Methenamine was found to pass the placental barrier. The concentration of methenamine in umbilical cord plasma was low but reached the level in maternal plasma after about 4 hours. In amniotic fluid the methenamine con centration was low and varying. No correlation was obtained to the maternal or umbilical cord plasma levels. The methenamine concentration in breast milk was of the same magnitude as in maternal plasma. It is concluded that methenamine may be safely given to pregnant and lactating women with respect to the ellbeing of the child.


Sequential Electrodeposition of Bifunctional Catalytically Active Structures in MoO3 /Ni-NiO Composite Electrocatalysts for Selective Hydrogen and Oxygen Evolution.
Exploring earth-abundant and highly efficient electrocatalysts is critical for further development of water electrolyzer systems. Integrating bifunctional catalytically active sites into one multi-component might greatly improve the overall water-splitting performance. In this work, amorphous NiO nanosheets coupled with ultrafine Ni and MoO3 nanoparticles (MoO3 /Ni-NiO), which contains two heterostructures (i.e., Ni-NiO and MoO3 -NiO), is fabricated via a novel sequential electrodeposition strategy. The as-synthesized MoO3 /Ni-NiO composite exhibits superior electrocatalytic properties, affording low overpotentials of 62 mV at 10 mA cm-2 and 347 mV at 100 mA cm-2 for catalyzing the hydrogen and the oxygen evolution reaction (HER/OER), respectively. Moreover, the MoO3 /Ni-NiO hybrid enables the overall alkaline water-splitting at a low cell voltage of 1.55 V to achieve 10 mA cm-2 with outstanding catalytic durability, significantly outperforming the noble-metal catalysts and many materials previously reported. Experimental and theoretical investigations collectively demonstrate the generated Ni-NiO and MoO3 -NiO heterostructures significantly reduce the energetic barrier and act as catalytically active centers for selective HER and OER, synergistically accelerating the overall water-splitting process. This work helps to fundamentally understand the heterostructure-dependent mechanism, providing guidance for the rational design and oriented construction of hybrid nanomaterials for diverse catalytic processes.


A complex rearrangement, including a deleted 8q, in a case of Langer-Giedion syndrome.
A 10-month-old infant with failure to thrive, delayed development, mild dysmorphia, cardiac anomalies, and cryptorchidism was referred for cytogenetic evaluation. Routine GTG-banded analysis revealed a modal number of 46 chromosomes, which contained an obvious complex rearrangement involving chromosomes 1, 8, and 14. Parental chromosomes were normal. Following high resolution techniques, this de novo rearrangement demonstrated an intraband deletion and was designated as [46,XY,t(1;8;14)(1pter----1p13.1::14q12----14pter++ +;1qter----1p13.1::8q24.13----8qter; 14qter----14q12::8p23.3----8q24.11:)]. Although deletions have been implicated as possibly responsible for abnormal phenotypes in patients with de novo "balanced rearrangements", in most cases, they could not be demonstrated. The present case is only the second instance documenting a subtle intraband deletion in association with a complex translocation. Fourteen of the reported 18 patients with an 8q deletion (including this infant) have Langer-Giedion syndrome, suggesting an etiologic relationship. However, the same deletion is not present in all cases.


Sesquiterpene lactone potentiates the immunomodulatory, antiparasitic and cardioprotective effects on anti-Trypanosoma cruzi specific chemotherapy.
We investigated the immunomodulatory, antiparasitic and cardioprotective effects of a sesquiterpene lactone (SL) administered alone or combined with benznidazole (Bz), in a murine model of Chagas' disease by in vitro and in vivo assays. Antiparasitic and cytotoxic potential of tagitinin C (SL) and Bz were tested in vitro against T. cruzi epimastigotes and cardiomyocytes. Swiss mice challenged with T. cruzi were also treated for 20 days with tagitinin C (10 mg/kg) alone and combined with Bz (100 mg/kg). Tagitinin C exhibited a higher antiparasitic (IC50: 1.15 µM) and cytotoxic (CC50 at 6.54 µM) potential than Bz (IC50: 35.81 µM and CC50: 713.5 µM, respectively). When combined, these drugs presented an addictive interaction, determining complete suppression of parasitemia and parasitological cure in all infected mice (100%) compared to those receiving Bz alone (70%). Anti-T. cruzi immunoglobulin G, and pro-inflammatory cytokines IFN-γ and TNF-α levels were reduced in animals treated with tagitinin C combined with Bz, while IL-10 production was unaffected. Heart inflammation was undetectable in 90% of the animals receiving this combination, while only 50% of the animals receiving Bz alone showed no evidence of myocarditis. Together, our findings indicated that the combination of tagitinin C and Bz exerts potent antiparasitic, immunomodulatory and cardioprotective effects. Due to the remarkable suppression of parasitemia and high parasitological cure, this combination was superior to Bz monotherapy, indicating a high potential for the treatment of Chagas's disease.


Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice.
Frontotemporal dementia (FTD) is a heterogeneous group of early onset and progressive neurodegenerative disorders, characterized by degeneration in the frontal and temporal lobes, which causes deterioration in cognition, personality, social behavior and language. Around 45% of the cases are characterized by the presence of aggregates of the RNA-binding protein TDP-43. In this study, we have used a murine model of FTD that overexpresses this protein exclusively in the forebrain (under the control of the CaMKIIα promoter) for several biochemical, histological and pharmacological studies focused on the endocannabinoid system. These mice exhibited at postnatal day 90 (PND90) important cognitive deficits, signs of emotional impairment and disinhibited social behaviour, which were, in most of cases, maintained during the first year of life of these animals. Motor activity was apparently normal, but FTD mice exhibited higher mortality. Their MRI imaging analysis and their ex-vivo histopathological evaluation proved changes compatible with atrophy (loss of specific groups of pyramidal neurons: Ctip2- and NeuN-positive cells) and inflammatory events (astroglial and microglial reactivities) in both cortical (medial prefrontal cortex) and subcortical (hippocampus) structures at PND90 and also at PND365. The analysis of the endocannabinoid system in these mice proved a decrease in the hydrolysing enzyme FAAH in the prefrontal cortex and the hippocampus, with an increase in the synthesizing enzyme NAPE-PLD only in the hippocampus, responses that were accompanied by modest elevations in anandamide and related N-acylethanolamines. The potentiation of these elevated levels of anandamide after the pharmacological inactivation of FAAH with URB597 resulted in a general improvement in behaviour, in particular in cognitive deterioration, associated with the preservation of pyramidal neurons of the medial prefrontal cortex and the CA1 layer of the hippocampus, and with the reduction of gliosis in both structures. Our data confirmed the potential of elevating the endocannabinoid tone as a therapy against TDP-43-induced neuropathology in FTD, limiting glial reactivity, preserving neuronal integrity and improving cognitive, emotional and social deficits.


Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance.
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered critical components in the development of insulin resistance and Type 2 diabetes. However, understanding the molecular mechanisms underlying these individual disorders and how they are linked has been challenging. Here, we provide evidence that elevated levels of cytosolic free Ca(2+) due to mitochondrial dysfunction and concomitant activation of p38 mitogen activated protein kinase (MAPK) induce ER stress response in human liver sk-HepI cells. Blocking Ca(2+) release from mitochondria or ER using ruthenium red or ryanodine ameliorated the increase in expression of gluconeogenic enzymes due to mitochondrial dysfunction. Disturbance in mitochondrial function results in the activation of p38 MAPK and related transcription factors that are directly responsible for increased phosphoenolpyruvate carboxykinase (PEPCK) expression. In addition, abnormal activation of c-Jun N-terminal kinase (JNK) influences the PEPCK expression by affecting insulin signaling and Forkhead box O (Foxo) 1 activity. Alleviation of ER stress response using a chemical chaperone reduces p38 MAPK activation, as well as PEPCK overexpression, indicating that ER stress response strengthens mitochondrial stress-induced abnormalities. Our results demonstrate that mitochondrial dysfunction is directly linked to the ER stress response, and together, cause aberrant insulin signaling and an abnormal increase of hepatic gluconeogenesis.


LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling.
Lung cancer is the leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer development and progression, and as promising biomarkers for the diagnosis and prognosis of cancer. In this study, we identified a new lncRNA (LINC02159) that was upregulated in the tumor tissues and serum of non-small cell lung cancer (NSCLC) patients. We demonstrated that knockdown of LINC02159 inhibited NSCLC cell proliferation, migration, and invasion, but induced cell apoptosis and cell cycle arrest in vitro and retarded tumor growth in vivo, while overexpression of LINC02159 led to the opposite effect. We discovered that LINC02159 was highly correlated with cancer growth and metastasis-related pathways by using transcriptomic analysis and that YAP1 was a potential target gene of LINC02159. Mechanistically, LINC02159 bound to the Aly/REF export factor (ALYREF) to enhance the stability of YAP1 messenger RNA (mRNA) via m5C modification, which led to the overexpression of YAP1 and the activation of the Hippo and β-catenin signaling pathways in NSCLC cells. Rescue experiments showed that LINC01259 promoted NSCLC progression in a YAP1- and ALYREF-dependent manner. In conclusion, LINC02159 plays an oncogenic role in NSCLC progression by regulating ALYREF/YAP1 signaling, and it has the potential to be utilized as a diagnostic marker and therapeutic target for NSCLC.


The pathogenesis of COPD and IPF: distinct horns of the same devil?
New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases, despite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a "double hit" pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence of pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing factors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise the regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF, mesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling pathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal tissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases (irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD).


A CLINICAL CASE OF COEXISTENT PARASITIC LIVER AND GASTRIC LESIONS CAUSED BY CLONORCHIASIS.
Clonorchiasis is a parasitic disease caused by Clonorchis sinensis. Parasite colonies can develop not only in the bile and pancreatic ducts but also in the gastric wall. This is confirmed by the described clinical case of perforated gastric ulcer, the morphological study of which revealed parasite colonies in the wall of the organ.


The ubiquitin E3 ligase Nedd4-2 relieves mechanical allodynia through the ubiquitination of TRPA1 channel in db/db mice.
Neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) is a member of the E3 ubiquitin ligase family that is highly expressed in sensory neurons and involved in pain modulation via downregulation of ion channels in excitable membranes. Ubiquitination involving Nedd4-2 is regulated by adenosine monophosphate-activated protein kinase (AMPK), which is impaired in the dorsal root ganglion (DRG) neurons of db/db mice. AMPK negatively regulates the expression of transient receptor potential ankyrin 1 (TRPA1), a recognised pain sensor expressed on the membrane of DRG neurons, consequently relieving mechanical allodynia in db/db mice. Herein, we studied the involvement of Nedd4-2 in painful diabetic neuropathy and observed that Nedd4-2 negatively regulated diabetic mechanical allodynia. Nedd4-2 was co-expressed with TRPA1 in mouse DRG neurons. Nedd4-2 was involved in TRPA1 ubiquitination, this ubiquitination, as well as Nedd4-2-TRPA1 interaction, was decreased in db/db mice. Moreover, Nedd4-2 levels were decreased in db/db mice, while an abnormal intracellular distribution was observed in short-term high glucose-cultured DRG neurons. AMPK activators not only restored Nedd4-2 distribution but also increased Nedd4-2 expression. These findings demonstrate that Nedd4-2 is a potent regulator of TRPA1 and that the abnormal expression of Nedd4-2 in DRG neurons contributes to diabetic neuropathic pain.


Neuroinformatics analyses reveal GABAt and SSADH as major proteins involved in anticonvulsant activity of valproic acid.
The unequivocal hypotheses about anticonvulsant activity of valproic acid (VPA) have always been a basic hurdle in designing next generation neurotherapeutics, particularly the anti-epileptic drugs. The present study reports about a comprehensive in-silico investigation into qualitative and quantitative binding of VPA and corresponding natural ligands of four major enzymes involved in neurotransmissions, namely-GABA transaminase (GABAt), α-keto glutarate dehydrogenase (α-KGDH), Succinate Semialdehyde dehydrogenase (SSADH) and Glutamate Decarboxylase (GAD), respectively. The molecular docking analyses revealed that VPA inhibits GABAt and α-KGDH through allosteric while SSADH through competitive mode of binding. There is an observed elevation in binding of glutamate over GAD in the presence of VPA. The docking inhibition constant (Ki) of VPA to all the studied enzymatic receptors were observed to be well below the therapeutic concentration of VPA in blood, except for α-KGDH, thus favouring GABAergic over glutamatergic mode of anticonvulsant activity of VPA. The report is probably the first comprehensive in-silico molecular study about VPA action.


Gastrointestinal Stromal Tumors: Our Ten-Year Experience of a Single-Center Tertiary Hospital.
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal neoplasms of the gastrointestinal tract. They have variable clinical presentation, prognosis, and molecular characteristics. Here, we present the results of our retrospective study including patients operated on for GIST during the last decade. All the patients who underwent GIST resection during the decade 2008-2018 were included in the study. The diagnosis was based on the pathology report. All the data were collected and analyzed statistically using the Statistical Package for Social Science v25.0. Finally, after having applied the proper search terms, a comprehensive review of articles published in the Medline database was held. Thirty-two patients (sixteen women) were included in the study with a mean age of 69.6 years old (SD = 13.9). Twenty-one patients had a GIST in the stomach, eight in the small intestine, and three had an extra GIST. Of the 29 patients contacted, 21 were alive with a mean survival time of 74.3 months (SD = 49.6 months, min: 3.0 months, max: 161.0 months), whereas eight patients passed away. Finally, 13 patients were treated with tyrosine kinase inhibitors (TKIs) of whom only one died, while 9 patients passed away from those treated with surgery alone (p = 0.031). Our results were in concordance with the existing data in the literature. GISTs require patient-based therapeutical management depending on the histology of the tumors. Gastric tumors present a better prognosis than those localized in the intestine, while the use of TKIs has led to an improvement in patient survival rate.


Short-term hypoxic preconditioning improved survival following cardiac arrest and resuscitation in rats.
Cardiac arrest and resuscitation produces delayed mortality and hippocampal neuronal death in rats. Hypoxic preconditioning has been to shown to protect the brain from ischemic insults. We have previously reported that with chronic hypobaric hypoxia, the accumulation of hypoxic-inducible factor-1 alpha (HIF-1α) and its target genes was increased for the first several days of hypoxic exposure, and returned to baseline level by 3 weeks when angiogenesis is completed. In this study, we investigated the effect of short-term (3 days) and long-term (21 days) hypoxic preconditioning on recovery from cardiac arrest and resuscitation in rats. Our data showed that the overall survival rate was considerably improved in the short-term hypoxic preconditioning group compared to the non-preconditioned controls (86 %, 6/7 vs. 54 %, 7/13); however, the survival rate in the long-term hypoxic preconditioning group was decreased. Our data suggest that hypoxic preconditioning provides protection after cardiac arrest and resuscitation more likely through increased accumulation of HIF-1α and its target genes rather than through successful vascular adaptation as a result of hypoxia-induced angiogenesis.


Non-kin selection enhances complexity in cooperation: A unified quantitative law.
How cooperation evolves in the presence of selfishness is a core problem in evolutionary biology. Selfish individuals tend to benefit themselves, which makes it harder to maintain cooperation between unrelated individuals and for living systems to evolve towards complex organizations. The general evolutionary model presented here identifies that non-kin selection is the root cause for cooperation between unrelated individuals and can enable and maintain higher complexity of biological organizations (the coexistence of more individuals of different types). The maintained number of genotypes within a cooperation organization is shown to follow a universal exponential law as a quantitative function of the population size and non-kin selection strength, showing a gene-pool-size invariance. Our results highlight that non-kin selection may be a hallmark of biological evolution, and play an important role in shaping life's potentials.


Effect of Different Filler Wires on Mechanical Property and Conductivity of Aluminum-Copper Joints.
The 1060 aluminum and T2 copper were joined by the pulsed double electrode gas metal arc welding (DE-GMAW) brazing method by using four types of filler wires, namely pure aluminum (Al) ER1100, aluminum-magnesium (Al-Mg) ER5356, aluminum-silicon (Al-Si) ER4043, and Al-Si ER4047, respectively. The effects of different types of filler wires on intermetallic compounds, microhardness tensile strength, and conductivity of joints were investigated. The results showed that a lot of brittle intermetallic compounds laying in the copper side brazing interface zone were generated using pure Al, Al-Mg, and Al-Si filler wires, which caused the change of microhardness, tensile strength, and the conductivity of joints. Meanwhile, with the increase in Si elements contents for Al-Sifiller wires, the thickness of the intermetallic compound layers decreased obviously, which was only up to 3 µm and the conductivity of the joints decreased. In addition, the microhardness, tensile strength, and the conductivity of the joints, when using Al-Sifiller wires, was higher than that using pure Al and Al-Mg filler wires. Hence, in comparison to the pure filler wires and Al-Mg filler wires, the Al-Si filler wires were more suitable for Al-Cu joints by DE-GMAW as Si element content was lower.


Specific oligonucleotide primers for detection of endoglucanase positive Bacillus subtilis by PCR.
A polymerase chain reaction (PCR) assay was developed for discrimination of Bacillus subtilis from other members of B. subtilis group as well as rapid identification from environmental samples. Primers ENIF and EN1R from endoglucanase gene were used to amplify a1311 bp DNA fragment. The specificity of the primers was tested with seven reference strains and 28 locally isolated strains of endoglucanase positive Bacillus species. The PCR product was only produced from B. subtilis. The results demonstrated high specificity of two oligonucleotides for B. subtilis. This species-specific PCR method provides a quick, simple, powerful and reliable alternative to conventional methods in the detection and identification of B. subtilis. To our knowledge this is the first report of a B. subtilis specific primer set.


Hypobaric hypoxia induces dendritic plasticity in cortical and hippocampal pyramidal neurons in rat brain.
Hypobaric hypoxia (HH), a predisposing environmental condition at high altitude (HA) encountered by many mountaineers jeopardizes their normal physiology like motor coordination and cognitive functions. Our previous studies revealed that the HH induces oxidative stress and neurodegeneration, which is associated with spatial memory impairment in rats. However, the dendritic changes after exposure to different duration of HH remain largely unknown. The aim of the present study was to investigate the duration-dependent dendritic changes in CA1, CA3 and entorhinal cortex (EC) of hippocampus and layer II of prefrontal cortex (PFC) with spatial memory functions in rats on exposure to different duration of HH. The rats were exposed to simulated HA of 6100 m for 3, 7, 14 and 21 days and the spatial reference memory was investigated using Morris water maze (MWM) and the morphological alteration of CA1, CA3, EC and layer II of PFC were investigated. There was a significant decrease in dendritic arborization and spine number along with increased number of damaged neurons, after 3, 7 and 14 days of HH but after 21 days of HH exposure the structural recovery was noted in all the regions. There was impairment of spatial memory after 3 and 7 days of exposure, but slight improvement of spatial memory was noted after 14 and 21 days of exposure. Our studies suggested that HH induces dendritic plasticity of PFC and hippocampal pyramidal neurons of rat brain, which might be associated with improvement of spatial memory function after 21 days of HH exposure.


Design, synthesis, evaluation of new 3-acetylisoxazolines and their hybrid analogous as anticancer agents: In vitro and in silico analysis.
3-Acetylisoxazolines were synthesized by the reaction of natural (R)-limonene and (R)-carvone with acetone in the presence of iron (III) nitrate. The reaction showed to be highly peri- and regioselective. Next, using a 1,3-dipolar cycloaddition reaction, the mono-3-acylisoxazolines derived from these monoterpenes were evaluated for their reactivity with nitrilimines. Only the enone of carvone-isoxazoline was regioselectively reactive, providing a new fused isoxazoline-carvone-pyrazolines. The structure of all the newly synthesized mono-cycloadducts (3 & 5) and bis-cycloadducts (4 & 7a-c) were fully identified based on their HRMS and NMR spectral data. They have also been screened for their cytotoxic activity against four human cancer cell lines: fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast (MCF-7 and MDA-MB-231) cell lines. The obtained results showed that compound 4 was a potent cytotoxic agent against all selected cells. The possible mechanism of apoptosis induction by compound 4 was investigated using Annexin-V binding assay, caspase-3/7 activity and analysis cell cycle progression. The compound 4 induced the early apoptosis of both MCF-7 and MDA-MB-231 through caspase-3/7 activation, and the compound 4 have elicited S and G2/M phase arrest in MCF-7and MDA-MB-231 cancer cells, respectively. For further target investigations, a molecular docking study was employed and it showed that compound 4 has an inhibitory activity against Pim-1 protein kinase. Molecular dynamics study showed that compound 4/Pim-1 complex was stable during the simulation run at different time intervals. In-Silico ADMET predicted that compound 4 has good pharmacokinetic properties with high estimated oral bioavailability.


[Therapeutic strategies in advanced ALK positive non-small cell lung cancer].
Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically targetable oncogenic driver found in 5% of patients with non-small-cell lung cancer (NSCLC). The objective of this paper is to synthesise current knowledge on ALK rearrangement and its impact on the management of advanced NSCLC. Several inhibitors of the tyrosine kinase of ALK (crizotinib, ceritinib, alectinib) have been approved as first line therapies in patients with advanced ALK positive NSCLC, which are associated with a better median progression-free survival than conventional chemotherapy. Unfortunately, the emergence of drug resistance leads to tumor progression. In patients with oligoprogressive disease if local ablative therapy can be effected, continuing with the same ALK tyrosine kinase inhibitor is one option. In patients with progression, clinicians may consider switching to another therapy. Rebiopsy of the tumor or liquid biopsy could be attempted to identify the mechanisms of resistance and to customize ALK-target therapy. The emergence of crizotinib drug resistance has prompted the development of next generation drugs including ceritinb, alectinib, brigatinib and lorlatinib. The ability to quickly develop targeted therapies against specific oncogenic drivers will require close co-operation between pathologists, pulmonologists and oncologists in the future to keep pace with drug discoveries and to define optimal therapeutic strategies.


Activities of asymmetric dimethylarginine-related enzymes in white adipose tissue are associated with circulating lipid biomarkers.
Asymmetric NG,NG-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is regulated by the enzymatic participants of synthetic and metabolic processes, i.e., type I protein N-arginine methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH). Previous reports have demonstrated that circulating ADMA levels can vary in patients with type 1 and type 2 diabetes mellitus (T2DM). White adipose tissue expresses the full enzymatic machinery necessary for ADMA production and metabolism; however, modulation of the activities of adipose ADMA-related enzymes in T2DM remains to be determined. A rodent model of T2DM using 11- and 20-week old Goto-Kakizaki (GK) rats was used. The expression and catalytic activity of PRMT1 and DDAH1 and 2 in the white adipose tissues (periepididymal, visceral and subcutaneous fats) and femur skeletal muscle tissue were determined by immunoblotting, in vitro methyltransferase and in vitro citrulline assays. Non-obese diabetic GK rats showed low expression and activity of adipose PRMT1 compared to age-matched Wistar controls. Adipose tissues from the periepididymal, visceral and subcutaneous fats of GK rats had high DDAH1 expression and total DDAH activity, whereas the DDAH2 expression was lowered below the control value. This dynamic of ADMA-related enzymes in white adipose tissues was distinct from that of skeletal muscle tissue. GK rats had lower levels of serum non-esterified fatty acids (NEFA) and triglycerides (TG) than the control rats. In all subjects the adipose PRMT1 and DDAH activities were statistically correlated with the levels of serum NEFA and TG. Activities of PRMT1 and DDAH in white adipose tissues were altered in diabetic GK rats in an organ-specific manner, which was reflected in the serum levels of NEFA and TG. Changes in adipose ADMA-related enzymes might play a part in the function of white adipose tissue.


Effects of interferon-alpha in patients with AIDS-associated Kaposi's sarcoma are related to blood interferon levels and dose.
Definition of improved therapeutic regimens of interferon-alpha (IFN-alpha) for the treatment of Kaposi's sarcoma (KS) would be useful since currently recommended doses are sometimes associated with unacceptable toxicity. IFN concentrations were measured in serum samples from men with AIDS-associated KS who were enrolled in a trial of IFN-alpha alone (16 patients) or a trial of IFN-alpha combined with zidovudine (25 patients). Analyses were done to examine the relationship between the dose of IFN-alpha, blood level of IFN, and the patient's clinical response to treatment. There was no correlation between dose of zidovudine given and response. As expected, there was a high correlation between dose of IFN-alpha and blood level in both studies (p less than 0.001). Furthermore, we found relationships between clinical response and both dose of IFN-alpha and blood level achieved. In the two studies combined, among men with greater than 200 CD4+ cells/mm3 of blood at baseline on average daily doses of greater than or equal to 10 million international units (MIU) of IFN-alpha, 13/19 (68%) responded compared to 6/17 (35%) on less than MIU (p = 0.05). Similarly, of men with IFN blood levels greater than or equal to 100 IU/mL 12/16 (75%) responded compared to 7/20 (35%) of those with blood levels less than 100 IU/mL (p = 0.02). The dose and blood levels of IFN achieved and maintained may be important factors in determining responses of KS. Additional clinical trials of IFN-alpha treatment of KS at doses about 10 MIU/day appear warranted.


Efficacy of two insecticides for protecting loblolly pines (Pinus taeda L.) from subcortical beetles (Coleoptera: Curculionidae and Cerambycidae).
Tests were conducted on two insecticides (carbaryl and bifenthrin) for excluding subcortical beetles (Coleoptera: Curculionidae and Cerambycidae) from loblolly pine trees (Pinus taeda L.). Two trap designs (single- and double-pane windows) and two trapping heights (1.5 and 4 m) were also evaluated for maximizing beetle catches. In July 2009, 15 loblolly pine trees were double girdled and were either left unsprayed or sprayed with carbaryl or bifenthrin. A total of 28 473 bark beetles were caught in window traps, including Ips avulsus Eichoff, I. grandicollis (Eichhoff), I. calligraphus (Germar) and Dendroctonus terebrans (Olivier). Both insecticides significantly reduced colonization of the trees by bark and woodboring beetles by 300-400%, with no differences in efficacy observed between the two insecticides. About 59% more I. avulsus were caught in double- than in single-pane window traps, with no differences for any other species. Traps at 4 m caught more I. avulsus and I. grandicollis (290 and 153% respectively), while traps at 1.5 m caught more D. terebrans (215%). Either bifenthrin or carbaryl can be used to exclude subcortical beetles from loblolly pine trees. Trapping data reflect known vertical partitioning on the bole by these insects. Double-pane traps were slightly more effective than single-pane traps in catching subcortical beetles.