Comprehensive Scrna-Seq Analysis and Identification of CD8_+T Cell related Gene Markers for Predicting Prognosis and Drug Resistance of Hepatocellular Carcinoma.
Tumor heterogeneity of immune infiltration of cells plays a decisive role in hepatocellular carcinoma (HCC) therapy response and prognosis. This study investigated the effect of different subtypes of CD8+T cells on the HCC tumor microenvironment about its prognosis. Single-cell RNA sequencing, transcriptome, and single-nucleotide variant data from LUAD patients were obtained based on the GEO, TCGA, and HCCD18 databases. CD8+ T cells-associated subtypes were identified by consensus clustering analysis, and genes with the highest correlation with prognostic CD8+ T cell subtypes were identified using WGCNA. The ssGSEA and ESTIMATE algorithms were used to calculate pathway enrichment scores and immune cell infiltration levels between different subtypes. Finally, the TIDE algorithm, CYT score, and tumor responsiveness score were utilized to predict patient response to immunotherapy. We defined 3 CD8+T cell clusters (CD8_0, CD8_1, CD8_2) based on the scRNA- seq dataset (GSE149614). Among, CD8_2 was prognosis-related risk factor with HCC. We screened 30 prognosis genes from CD8_2, and identified 3 molecular subtypes (clust1, clust2, clust3). Clust1 had better survival outcomes, higher gene mutation, and enhanced immune infiltration. Furthermore, we identified a 12 genes signature (including CYP7A1, SPP1, MSC, CXCL8, CXCL1, GCNT3, TMEM45A, SPP2, ME1, TSPAN13, S100A9, and NQO1) with excellent prediction performance for HCC prognosis. In addition, High-score patients with higher immune infiltration benefited less from immunotherapy. The sensitivity of low-score patients to multiple drugs including Parthenolide and Shikonin was significantly higher than that of high-score patients. Moreover, high-score patients had increased oxidative stress pathways scores, and the RiskScore was closely associated with oxidative stress pathways scores. And the nomogram had good clinical utility. To predict the survival outcome and immunotherapy response for HCC, we developed a 12-gene signature based on the heterogeneity of the CD8+ T cells.


Relocation of annexin V to platelet membranes is a phosphorylation-dependent process.
Annexins are a family of calcium-binding proteins that have been implicated in a wide range of intracellular processes. We have previously reported that stimulation of platelets with agents that increase intracellular [Ca2+] induces the relocation of annexin V to membranes, and that this annexin V may be binding to a 50 kDa protein located within platelet membranes. We report here, using an in vitro reconstitution system, that the relocation of annexin V to membranes is enhanced by ATP. We also demonstrate that when adenosine 5'-[gamma-thio]-triphosphate, which can replace ATP in phosphorylation reactions, is substituted for ATP, the amount of annexin V that binds to membranes is further increased. In separate experiments using intact cells, we show that the protein phosphatase inhibitor okadaic acid mimics the action of the physiological agonist thrombin, in that it induces annexin V to bind to membranes and that the addition of the protein kinase inhibitor staurosporine inhibits A23187-induced relocation of annexin V. In addition, alkaline phosphatase, when added to isolated membranes, was found to remove endogenous annexin V from the membranes. Furthermore, immunoprecipitation of 33P-labelled proteins indicated that annexin V may form a multi-protein complex including phosphoproteins of 25, 50 and 83 kDa. Taken together these observations suggest that, following physiological activation, the phosphorylation of one or more proteins is responsible for the tight association of annexin V with platelet membranes and the subsequent regulation of membrane localized processes.


Genetic and environmental influences on schizotypy: a community-based twin study.
This study investigated the factor structure and etiology of four self-report schizotypy questionnaires during young adulthood (age 18-27) in 98 monozygotic and 59 same-sex dizygotic twin pairs from the community. A single phenotypic factor was identified that was primarily associated with Perceptual Aberration, Magical Ideation, and the Rust Inventory of Schizotypal Cognitions scales, and less so with Social Anhedonia. Univariate etiologic models suggested that in addition to nonshared environmental influences, Perceptual Aberration and Social Anhedonia were significantly influenced by either genes or shared family environment, whereas Magical Ideation and the Rust Inventory were influenced by shared family environment, but not genes. Multivariate twin analyses detected a common schizotypy factor, primarily defined by Perceptual Aberration, Magical Ideation, and the Rust Inventory scales, that was influenced by genes or shared environment as well as nonshared environment. Contrary to expectations, these results suggest that, at least in community-based samples, these "positive" schizotypy questionnaires are not strongly genetically influenced.


Cationic Ordering and Its Influence on the Magnetic Properties of Co-Rich Cobalt Ferrite Thin Films Prepared by Reactive Solid Phase Epitaxy on Nb-Doped SrTiO3(001).
Here, we present the (element-specific) magnetic properties and cation ordering for ultrathin Co-rich cobalt ferrite films. Two Co-rich CoxFe3-xO4 films with different stoichiometry (x=1.1 and x=1.4) have been formed by reactive solid phase epitaxy due to post-deposition annealing from epitaxial CoO/Fe3O4 bilayers deposited before on Nb-doped SrTiO3(001). The electronic structure, stoichiometry and homogeneity of the cation distribution of the resulting cobalt ferrite films were verified by angle-resolved hard X-ray photoelectron spectroscopy. From X-ray magnetic circular dichroism measurements, the occupancies of the different sublattices were determined using charge-transfer multiplet calculations. For both ferrite films, a partially inverse spinel structure is found with increased amount of Co3+ cations in the low-spin state on octahedral sites for the Co1.4Fe1.6O4 film. These findings concur with the results obtained by superconducting quantum interference device measurements. Further, the latter measurements revealed the presence of an additional soft magnetic phase probably due to cobalt ferrite islands emerging from the surface, as suggested by atomic force microscope measurements.


New amyloid beta-disaggregating agents: synthesis, pharmacological evaluation, crystal structure and molecular docking of N-(4-((7-chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines.
In the journey towards the development of potent multi-targeted ligands for the treatment of Alzheimer's disease, a series of Aβ aggregation inhibitors having quinoline scaffold were designed utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations via ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aβ self-aggregation inhibition. Molecules 5g and 5a showed the highest inhibitory potential, 53.73% and 53.63% at 50 μM respectively; higher than the standard Aβ disaggregating agent, curcumin. Molecules 5g and 5a disaggregated AChE-induced (58.26%, 47.36%) Aβ aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu2+-induced Aβ aggregation. A docking study significantly showed their interaction with key residues of Aβ and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (5a, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (ii)-5a and Cu(ii)-5g complexes were found by Job's method (0.5 : 1 for 5a and 0.8 : 1 for 5g). In silico ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aβ aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.


Sialylation of lactosyl lipids in membrane microdomains by T. cruzi trans-sialidase.
A synthetic perfluoroalkyl-tagged lactosyl glycolipid has been shown to form lipid microdomains in fluid phospholipid bilayers. When embedded in the membranes of phospholipid vesicles, this glycolipid was trans-sialylated by soluble T. cruzi trans-sialidase (TcTS) to give a perfluoroalkyl-tagged glycolipid that displayed the ganglioside GM3 epitope, with up to 35% trans-sialylation from fetuin after 18 h. Following sialylation, vesicles bearing this Neu5Ac(α2-3)Gal(β1-4)Glc sequence in their "glycocalyx" were recognised and agglomerated by the lectin M. amurensis leukoagglutinin. Monitoring TcTS-mediated trans-sialylation by HPLC over the first 6 h revealed that enzymatic transformation of bilayer-embedded substrate was much slower than that of a soluble lactosyl substrate. Furthermore, clustering of the lactose-capped glycolipid into "acceptor" microdomains did not increase the rate of sialic acid transfer from fetuin by soluble TcTS, instead producing slight inhibition.


Rabbit skeletal muscle glycogen synthase. I. Relationship between phosphorylation state and kinetic properties.
Nine samples of purified rabbit skeletal muscle glycogen synthase (UDP-glucose:glycogen 4-alpha-glucosyltransferase, EC 22.214.171.124) were obtained with alkali-labile phosphate contents ranging from 0.27 to 3.49 residues per 85,000 molecular weight subunit. The enzyme samples appeared essentially homogeneous when analyzed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and had relatively constant specific activity under standard conditions with saturating UDP-glucose and glucose-l-P concentrations (37.1 +/- 1.0 mumol of glucose incorporated/mg/min). When the UDP-glucose concentration was varied, deviations from Michaelis-Menten kinetics were observed for all samples (Hill slopes of 0.79 +/- 0.02), but these deviations were virtually abolished by the presence of 5 mM glucose-6-P. Glucose-6-P decreased the S0.5 (concentration required for half-maximal rate) for UDP-glucose. The plots of activity increase caused by glucose-6-P versus glucose-6-P concentration became progressively more sigmoid in shape with enzyme samples of higher phosphate content. Both the S0.5 for UDP-glucose and the M0.5 for glucose-6-P (concentration for half-maximal activation) were sensitive functions of the alkali-labile phosphate content of glycogen synthase. The M0.5 increased from 3.3 muM at 0.27 phosphate/subunit to 2.7 mM at 3.5 phosphates/subunit, and the S0.5 varied from 0.75 mM (0.27 phosphate/subunit) to at least 61 mM (2.3 phosphates/subunit). Both parameters increased continuously with phosphate content, with the greatest absolute changes occurring at values greater than 2 residues of phosphates/subunit. The effects of both phosphorylation and activation by glucose-6-P appeared to be mediated primarily through alteration of the apparent affinity for UDP-glucose. With the phosphorylating conditions used, the results suggested that phosphate could not be introduced into the glycogen synthase molecule without altering its kinetic properties. Further, either the different phosphorylation sites were not equivalent, or else identical sites interacted in determining the kinetic properties of glycogen synthase.


Case Study: Competition Nutrition Intakes During the Open Water Swimming Grand Prix Races in Elite Female Swimmer.
The nutritional intake of elite open water swimmers during competition is not well established, and therefore this case study aims to provide new insights by describing the feeding strategies adopted by an elite female swimmer (28 yrs; height; 1.71 m; body mass: 60 kg; body fat: 16.0%) in the FINA open water Grand Prix 2014.Seven events of varying distances (15-88 km) and durations (3-12 hrs) were included. In all events, except one, feeds were provided from support boats. Swimmer and support staff were instructed to track in detail all foods and beverages consumed during the events. Nutritional information was gathered from the packaging and dietary supplements labels and analyzed by nutrition software. Mean carbohydrate (CHO) and protein intake reached 83 ± 5 g·h-1 and 12 ± 8 g·h-1, respectively. Fat intake was neglected (~1 g·h-1). Mean in-race energy intake reached 394 ± 26 kcal·h-1. Dietary supplements in the form of sport beverages and gels, containing multitransportable CHO, provided 40 ± 4 and 49 ± 6% of all CHO energy, respectively. Caffeine (3.6 ± 1.8 mg·kg-1 per event) and sodium (423 ± 16 mg·h-1) were additionally supplemented in all events. It was established that continuous intake of high doses of CHO and sodium and moderate dose of caffeine were an essential part of the feeding strategy for elite-level high intensity ultra-endurance open-water swimming races. A well scheduled and well-prepared nutrition strategy is believed to have ensured optimal individual performance during Grand Prix events.


GOTrapper: a tool to navigate through branches of gene ontology hierarchy.
Gene Ontology (GO) is a useful resource of controlled vocabulary that provides information about annotated genes. Based on such resource, finding the biological function is useful for biologists to come up with different hypotheses and help further investigations of an experiment. The biological function for desired genes and gene associations is picked up from a randomly chosen list or through the analysis of differential gene expression. Many tools have been developed to utilize GO knowledge and cluster genes according to relevant biological functions. The retrieved GO terms include both specific and non-specific terms, which is not user-friendly in terms of data analysis. Thus one approach is still missing, which allows navigating through different levels of GO hierarchy manually. We developed a tool, GOTrapper, which allows moving up or down to the very bottom of the GO hierarchy. This is performed manually by the user, based on an assigned threshold. This tool grabs the shared terms by the desired set of input genes of Homo sapiens. Here, two inputs are possible. "Within" is to find associated terms within one gene list, and "Between" is to find associated terms between two lists. The tool also provides the option to return the terms with the pre-selected evidence codes. GOTrapper is a user-friendly Java tool that helps the user move up and down the ontology tree, which leads to new hypotheses and devising new association of the input genes. It also allows returning terms of associated genes based on selected evidence codes. This tool can be accessed and is freely available at https://github.com/BioGeneTools/GOTrapper .


Spatially optimized data-level fusion of texture and shape for face recognition.
Data-level fusion is believed to have the potential for enhancing human face recognition. However, due to a number of challenges, current techniques have failed to achieve its full potential. We propose spatially optimized data/pixel-level fusion of 3-D shape and texture for face recognition. Fusion functions are objectively optimized to model expression and illumination variations in linear subspaces for invariant face recognition. Parameters of adjacent functions are constrained to smoothly vary for effective numerical regularization. In addition to spatial optimization, multiple nonlinear fusion models are combined to enhance their learning capabilities. Experiments on the FRGC v2 data set show that spatial optimization, higher order fusion functions, and the combination of multiple such functions systematically improve performance, which is, for the first time, higher than score-level fusion in a similar experimental setup.


Computational identification of protein-coding sequences by comparative analysis.
Gene prediction is an essential step in understanding the genome of a species once it has been sequenced. For that, a promising direction in current research on gene finding is a comparative genomics approach. In this paper, we present a novel approach to identifying evolutionarily conserved protein-coding sequences in genomes. The method takes advantage of the specific substitution pattern of coding sequences together with the consistency of reading frames. It has been implemented in a software called PROTEA. Large-scale experimentation shows good results. PROTEA is intended to be a useful complement to existing tools based on homology search or statistical properties of the sequences.


Should we cross the valve: the risk of retrograde catheterization of the left ventricle in patients with aortic stenosis.
A 67-year-old man is referred to your cardiology clinic complaining of worsening angina and dyspnea on exertion. Physical examination reveals a harsh grade IV/VI late-peaking crescendo-decresendo systolic murmur, loudest at the upper sternal border. The aortic closure sound is diminished. Echocardiography demonstrates left ventricular hypertrophy, an ejection fraction of 50%, no evidence of mitral regurgitation, and severe aortic stenosis (AS) with a peak aortic gradient of 4.8 m/s (92 mm Hg) and a mean aortic gradient of 55 mm Hg. You schedule him for coronary angiography but wonder whether you should reevaluate his aortic valve gradient invasively. Combining the keywords "aortic valve stenosis" and "heart catheterization/adverse effects," you find 72 articles. From these you choose the following: Omran H, Schmidt H, Hackenbroch M, et al. Silent and apparent cerebral embolism after retrograde catheterization of the aortic valve in valvular stenosis: a prospective randomized study. Lancet 2003;361:1241-6. What is the stroke risk of retrograde catheterization of the aortic valve in patients with AS? The study was prospective and randomized; unblinded treatment but with blinded assessment of outcomes. The study was conducted at a single center in Bonn, Germany. A total of 152 patients with known or suspected AS undergoing cardiac catheterization were randomized to catheterization with or without retrograde passage of the aortic valve in a 2:1 randomization format. Patients underwent brain magnetic resonance imaging (MRI) the day before and within 48 hours after cardiac catheterization. Patients with unclear echo findings or contraindications to MRI or transesophageal echocardiography were excluded. There were no significant baseline differences between the 2 groups: mean age 70.5 years, left ventricular ejection fraction 62%, and mean aortic valve gradient 51 mm Hg. All patients were evaluated in the groups to which they had been randomized and, other than the experimental intervention, the 2 groups were treated similarly (with the exception of the administration of 5000 units of intravenous heparin to the group receiving retrograde aortic catheterization). A control group of 32 patients without aortic valvular stenosis was evaluated as well. The intervention consisted of retrograde passage of the aortic valve for the purpose of obtaining an invasive aortic valve pressure gradient. The main outcome measures were acute cerebral embolic events, defined by MRI findings within 48 hours after catheterization (as compared to precatheterization MRI) and by clinical examination. Twenty-two of 101 patients (22%) assigned to retrograde catheterization developed new focal MRI abnormalities consistent with acute cerebral embolic events. Three of these patients (3%) demonstrated clinically apparent neurologic deficits. None of the patients who did not undergo retrograde catheterization--and none of the control patients--had MRI or clinical evidence of cerebral embolism.


Synovial chondromatosis: Report of a rare surgical problem of the temporomandibular joint.
Synovial chondromatosis of the joint is a rare benign condition characterized by the formation of metaplastic cartilage in the synovium of the joint resulting in numerous attached and unattached osteocartilagenous bodies. It may recur after surgical intervention. For this reason removal of the synovium and the bodies is advocated. This is a report of a case which occurred in the temporomandibular joint which had numerous loose bodies and exhibited features of degenerative joint disease as well. The loose bodies were removed, a high condylar shave performed and the synovium left intact. The patient is still free from joint problems five years later.


The histopathologic diagnosis of leprosy.
The objective of this paper is to encourage histopathologists to recognize and diagnose leprosy so that it can be treated effectively at the earliest stage possible, before irreversible deformities result. Recognition of the earliest form of leprosy-indeterminate-is emphasized. Histopathologic descriptions are made and illustrated for the principal types of leprosy. Emphasis is placed on (1) the need for dependable acid-fast staining of leprosy bacillus, (2) the non-specific infiltrate in indeterminate leprosy, and (3) the involvement of nerves in all types of leprosy.


Large ulcerated cecal lipoma mimicking malignancy.
Colonic lipomas are relatively uncommon tumors of mesenchymal origin, composed of well-differentiated adipose tissue supported by fibrous tissue, that usually occur in cecum and ascending colon. Colonic lipomas rarely cause symptoms and are usually detected incidentally. However, if the lesion is large, it may produce symptoms, such as abdominal pain, rectal bleeding, obstruction, intussusception, and even weight loss. Large colonic lipomas can be mistaken for malignancy, which may result in extensive surgical operations. We report a large broad-based ulcerated cecal lipoma in a 68-year-old woman, who presented with abdominal pain and weight loss. The ulcerated lesion was highly suspicious for malignancy radiologically and endoscopically. The patient underwent laparoscopic right-hemicolectomy, and the lesion was diagnosed as a cecal submucosal lipoma. The surgical approach remains the treatment of choice for large and complicated cases.


Effects of a brief pilot sexual harassment prevention workshop on employees' knowledge.
Administrators from three workplaces were interested in conducting evidence-based sexual harassment prevention training for their employees, but they could devote little time during the workday to the training. A pilot program to evaluate the use of a 1-hour workshop that followed best practice recommendations and adult learning principles using job-related scenarios was designed. Participants' overall sexual harassment prevention knowledge scores significantly increased from before to after the workshop and were significantly higher after the workshop than those of a control group. The majority of participants also perceived that their workplaces were committed to employees understanding the sexual harassment policy, and that the workplace would seriously investigate claims and take corrective action. Even a brief workshop covering essential content using adult learning principles can be effective in sexual harassment prevention knowledge acquisition.


Relationship between arterial stiffness and chronic kidney disease in patients with primary hypertension.
To investigate the association of noninvasive indices of arterial stiffness with chronic kidney disease (CKD) in patients with primary hypertension, 547 (mean age 60 years, 63% males) hypertensive hospital inpatients were recruited, comprising 337 hypertensives without CKD and 210 hypertensives with CKD. Noninvasive arterial stiffness indices were obtained, including central arterial haemodynamics derived from the radial artery waveform using SphygmoCor V8.0 system, carotid-femoral pulse wave velocity (cfPWV), large and small artery elasticity indices (C1, C2 respectively). Intima-media thickness (IMT) was evaluated by ultrasonography. The diagnosis of CKD was assessed by the estimated glomerular filtration rate (eGFR) or urinary albumin creatinine ratio (ACR). Compared with hypertension without CKD, hypertensive patients with CKD were older, had higher central systolic blood pressure, cfPWV, and IMT (all P < 0.01). With decreasing eGFR, cfPWV and augmentation index adjusted to heart rate of 75 bpm increased progressively whereas C2 decreased (P < 0.05) in subjects with CKD. In the overall population, cfPWV showed a significant trend of a negative association with eGFR (P = 0.04) after adjusting for age, gender, and brachial systolic blood pressure. Multiple logistic analysis showed that 1 SD (3 m/s) increase in cfPWV entailed a 1.35 (95% Cl: 1.018-1.790) times higher likelihood of the presence of CKD even after adjustment for confounding factors. The association of arterial stiffness and CKD suggests that cfPWV may be a potential hemodynamic index to evaluate cardiovascular risk in CKD patients with primary hypertension.


Chronic administration of catechin decreases depression and anxiety-like behaviors in a rat model using chronic corticosterone injections.
Previous studies have demonstrated that repeated administration of the exogenous stress hormone corticosterone (CORT) induces dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis and results in depression and anxiety. The current study sought to verify the impact of catechin (CTN) administration on chronic CORT-induced behavioral alterations using the forced swimming test (FST) and the elevated plus maze (EPM) test. Additionally, the effects of CTN on central noradrenergic systems were examined by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity in rat brains. Male rats received 10, 20, or 40 mg/kg CTN (i.p.) 1 h prior to a daily injection of CORT for 21 consecutive days. The activation of the HPA axis in response to the repeated CORT injections was confirmed by measuring serum levels of CORT and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Daily CTN administration significantly decreased immobility in the FST, increased open-arm exploration in the EPM test, and significantly blocked increases of TH expression in the locus coeruleus (LC). It also significantly enhanced the total number of line crossing in the open-field test (OFT), while individual differences in locomotor activities between experimental groups were not observed in the OFT. Taken together, these findings indicate that the administration of CTN prior to high-dose exogenous CORT significantly improves helpless behaviors, possibly by modulating the central noradrenergic system in rats. Therefore, CTN may be a useful agent for the treatment or alleviation of the complex symptoms associated with depression and anxiety disorders.


Thymidine kinase deletion mutants of herpes simplex virus type 1.
Deletions in the cloned thymidine kinase (TK) gene of herpes simplex virus type 1 (HSV-1), strain 17 syn+, were produced by two methods. Removal of a 506 base pair fragment from between the unique SstI and Bg/II restriction endonuclease sites of pTK1 (HSV-1 BamHI p cloned in pAT153) and subsequent transformation of Escherichia coli resulted in the isolation of 50 deleted plasmids. Sequential digestion of pTK1 with Bg/II and nuclease BAL 31 followed by ligation and recleavage with Bg/II resulted in the isolation of 31 deleted plasmids. Three clones, pTK2, pTK3 and pTK4, obtained following Bg/II and SstI treatment of pTK1 were recombined with wild-type (wt) HSV-1 (17) syn+ DNA in baby hamster kidney (BHK) cells to produce TK- deletion mutants HSV-1 (17) TK 1301, HSV-1 (17) TK 1302 and HSV-1 (17) TK 1303 respectively. 5-Bromo-2'-deoxyuridine, 5-bromo-2'-deoxycytidine and 9-(2-hydroxyethoxymethyl)guanine were used to reduce the background of TK+ virus in heterogeneous recombinant stocks analysed for the presence of TK- recombinants. All recombinant clones isolated produced a small syncytial plaque morphology in BHK cells. The mutants HSV-1 (17) TK 1301 and HSV-1 (17) TK 1302 were TK-, failed to produce polypeptides of molecular weights 43000 and 19000 found in wt-infected cells and demonstrated one-step growth curves different from wt virus and the TK- mutant HSV-1 (17) dPyk-7. Superinfection studies with HSV-1 (17) TK 1301, HSV-1 (17) TK 1302, HSV-1 (MDK) and HSV-1 (17) dPyk-7 indicated that all TK- mutants except dPyK-7 produce a trans-acting gene product which can switch on the transforming HSV-1 TK gene.


Enhancement of immune function in mice fed high doses of soy daidzein.
High soy consumption leading to high exposures of soy isoflavones has been associated with a reduced risk of cancers at many sites. As part of a study focusing on the chemopreventive mechanisms, we have investigated the modulating effects of daidzein, a prominent and more bioavailable isoflavone in soy foods, on murine immune function. Swiss mice were fed daidzein at various doses daily for seven consecutive days. At high doses (20 and 40 mg/kg), daidzein exerted a stimulatory effect on nonspecific immunity, as shown by increases in the phagocytic response of peritoneal macrophages and thymus weight, in a dose-dependent manner. Augmentation of spleen immunoglobulin M-producing cells against sheep red blood cells demonstrated an-activation of humoral immunity. Enhanced cell-mediated immunity was also observed as increases in lymphocyte proportion of peripheral blood. However, no significant immunoregulatory effect was found when mice were fed 10 mg/kg daidzein. These results demonstrate for the first time that daidzein at high doses enhances several immunologic functions and suggest a novel approach to understanding the mechanism(s) by which soy foods may contribute to observed cancer prevention.


Variation of shell shape in the clonal snail Melanoides tuberculata and its consequences for the interpretation of fossil series.
Interpreting paleontological data is difficult because the genetic nature of observed morphological variation is generally unknown. Indeed, it is hardly possible to distinguish among several sources of morphological variation including phenotypic plasticity, sexual dimorphism, within-species genetic variation or differences among species. This can be addressed using fossil organisms with recent representatives. The freshwater snail Melanoides tuberculata ranks in this category. A fossil series of this and other species have been studied in the Turkana Basin (Kenya) and is presented as one of the best examples illustrating the punctuated pattern of evolution by the tenants of this theory. Melanoides tuberculata today occupies most of the tropics. We studied variation of shell shape in natural populations of this parthenogenetic snail using Raup's model of shell coiling. We considered different sources of variation on estimates of three relevant parameters of Raup's model: (1) variation in shell shape was detected among clones, and had both genetic and environmental bases; (2) sexual dimorphism, in those clones in which males occur, appeared as an additional source of shell variation; and (3) ecophenotypic variation was detected by comparing samples from different sites and years within two clones. We then tested the performance of discriminant function analyses, a classical tool in paleontological studies, using several datasets. Although the three sources of variation cited above contributed significantly to the observed morphological variance, they could not be detected without a priori knowledge of the biological entities studied. However, it was possible to distinguish between M. tuberculata and a related thiarid species using these analyses. Overall, this suggests that the tools classically used in paleontological studies are poorly efficient when distinguishing between important sources of within-species variation. Our study also gives some empirical bases to the doubts cast on the interpretation of the molluscan series of the Turkana Basin.


Peak Annotation and Verification Engine for Untargeted LC-MS Metabolomics.
Untargeted metabolomics can detect more than 10 000 peaks in a single LC-MS run. The correspondence between these peaks and metabolites, however, remains unclear. Here, we introduce a Peak Annotation and Verification Engine (PAVE) for annotating untargeted microbial metabolomics data. The workflow involves growing cells in 13C and 15N isotope-labeled media to identify peaks from biological compounds and their carbon and nitrogen atom counts. Improved deisotoping and deadducting are enabled by algorithms that integrate positive mode, negative mode, and labeling data. To distinguish metabolites and their fragments, PAVE experimentally measures the response of each peak to weak in-source collision induced dissociation, which increases the peak intensity for fragments while decreasing it for their parent ions. The molecular formulas of the putative metabolites are then assigned based on database searching using both m/ z and C/N atom counts. Application of this procedure to Saccharomyces cerevisiae and Escherichia coli revealed that more than 80% of peaks do not label, i.e., are environmental contaminants. More than 70% of the biological peaks are isotopic variants, adducts, fragments, or mass spectrometry artifacts yielding ∼2000 apparent metabolites across the two organisms. About 650 match to a known metabolite formula based on m/ z and C/N atom counts, with 220 assigned structures based on MS/MS and/or retention time to match to authenticated standards. Thus, PAVE enables systematic annotation of LC-MS metabolomics data with only ∼4% of peaks annotated as apparent metabolites.


Integrated analysis reveals key genes with prognostic value in lung adenocarcinoma.
Lung cancer is one of the most common malignant tumors. Despite advances in lung cancer therapies, prognosis of non-small-cell lung cancer is still unfavorable. The aim of this study was to identify the prognostic value of key genes in lung tumorigenesis. Differentially expressed genes (DEGs) were screened out by GEO2R from three Gene Expression Omnibus cohorts. Common DEGs were selected for Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology enrichment analysis. Protein- protein interaction networks were constructed by the STRING database and visualized by Cytoscape software. Hub genes, filtered from the CytoHubba, were validated using the Gene Expression Profiling Interactive Analysis database, and their genomic alterations were identified by performing the cBioportal. Finally, overall survival analysis of hub genes was performed using Kaplan-Meier Plotter. From three datasets, 169 DEGs (70 upregulated and 99 downregulated) were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that upregulated DEGs were significantly enriched in cell cycle, p53 pathway, and extracellular matrix-receptor interactions; the downregulated DEGs were significantly enriched in PPAR pathway and tyrosine metabolism. The protein-protein interaction network consisted of 71 nodes and 305 edges, including 49 upregulated and 22 downregulated genes. The hub genes, including AURKB, BUB1B, KIF2C, HMMR, CENPF, and CENPU, were overexpressed compared with the normal group by Gene Expression Profiling Interactive Analysis analysis, and associated with reduced overall survival in lung cancer patients. In the genomic alterations analysis, two hotspot mutations (S2021C/F and E314K/V) were identified in Pfam protein domains. DEGs, including AURKB, BUB1B, KIF2C, HMMR, CENPF, and CENPU, might be potential biomarkers for the prognosis and treatment of lung adenocarcinoma.


Single-strand conformational polymorphism analysis: basic principles and routine practice.
Single-strand conformational polymorphism (SSCP) analysis is a simple and sensitive technique for mutation detection and genotyping. The principle of SSCP analysis is based on the fact that single-stranded DNA has a defined conformation. Altered conformation due to a single base change in the sequence can cause single-stranded DNA to migrate differently under nondenaturing electrophoresis conditions. Therefore wild-type and mutant DNA samples display different band patterns. SSCP analysis involves the following four steps: (1) polymerase chain reaction (PCR) amplification of DNA sequence of interest; (2) denaturation of double-stranded PCR products; (3) cooling of the denatured DNA (single-stranded) to maximize self-annealing; (4) detection of mobility difference of the single-stranded DNAs by electrophoresis under non-denaturing conditions. Several methods have been developed to visualize the SSCP mobility shifts. These include the incorporation of radioisotope labeling, silver staining, fluorescent dye-labeled PCR primers, and more recently, capillary-based electrophoresis. Silver staining is simple, rapid, and cost-effective, and can be routinely performed in clinical laboratories. The use of SSCP analysis to discover and genotype single-nucleotide polymorphisms (SNPs) has been widely applied to the genetics of hypertension, including both monogenic (e.g., Liddle's syndrome) and polygenic disorders (e.g., essential hypertension).


Candida albicans Pde1p and Gpa2p comprise a regulatory module mediating agonist-induced cAMP signalling and environmental adaptation.
Deletion of PDE2, but not of PDE1 has been shown to reduce invasion and virulence. However simultaneous deletion of PDE2 and PDE1 abolishes these processes completely, suggesting that although Pde1 has a secondary role it also contributes to virulence in Candida albicans. In the present study the roles of the two phosphodiesterases, as well as that of Gpa2, in agonist-induced cAMP signalling, growth, morphogenesis and response to some stresses have been investigated. Our biochemical evidence shows that Gpa2 stimulates cAMP signalling in response to intracellular acidification and that Pde1, but not Pde2, is responsible for down-regulation of cAMP signalling induced by glucose addition or intracellular acidification. Furthermore, the genetic interactions of PDE1 and in some cases PDE2, with GPA2 caused synthetic defects in growth, morphogenesis and responses to some stresses, suggesting that Gpa2 mediates its effects on these processes in a cAMP pathway-independent manner. Remarkably, the synthetic interactions involving PDE1, PDE2 and GPA2 are not observed in Saccharomyces cerevisiae suggesting that conserved components of the cAMP pathway are used for different purposes in different yeast species. We suggest that cAMP phosphodiesterases have species-specific differential roles, which make them attractive antifungal targets, for combinatorial treatment.


TBP-TAF complex SL1 directs RNA polymerase I pre-initiation complex formation and stabilizes upstream binding factor at the rDNA promoter.
Knowledge of the role of components of the RNA polymerase I transcription machinery is paramount to understanding regulation of rDNA expression. We describe key findings for the roles of essential transcription factor SL1 and activator upstream binding factor (UBF). We demonstrate that human SL1 can direct accurate Pol I transcription in the absence of UBF and can interact with the rDNA promoter independently and stably, consistent with studies of rodent SL1 but contrary to previous reports of human SL1. UBF itself does not bind stably to rDNA but rapidly associates and dissociates. We show that SL1 significantly reduces the rate of dissociation of UBF from the rDNA promoter. Our findings challenge the idea that UBF activates transcription through recruitment of SL1 at the rDNA promoter and suggest that the rate of pre-initiation complex (PIC) formation is primarily determined by the rate of association of SL1, rather than UBF, with the promoter. Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells.


Loss of integration is associated with reduced resistance to oxidative stress.
One cellular mechanism thought to be particularly important as a constraint on lifespan and life-history strategies is oxidative stress. Susceptibility to oxidative stress is influenced by a number of antioxidant defences, whose effectiveness depends on the synergistic and competitive interactions among them (biochemical integration). It is generally assumed that exposure to oxidative stress is detrimental, but it is also possible that low level oxidative stress has a positive effect on integration, and therefore carries some benefits. Using three experimental groups of zebra finches (control, mild and high flight activity), we tested whether exercise-induced oxidative stress altered the integration of the pro-oxidant/antioxidant system by manipulating levels of flight activity, known to generate oxidative stress in birds. We show for the first time that a short-term high level of physical activity leads to a reduction in integration among components of the blood antioxidant defences, associated with a reduced resistance to oxidative stress. We found no evidence of improved integration in the antioxidant defences at low levels of oxidative stress exposure, suggesting that improved integration is not the route whereby any benefits of low level stress exposure occur. These findings point to a reduction in biochemical integration as a potential mechanism explaining a reduced resistance to oxidative stress induced by short-term stressors.


Collapsing glomerulopathy, the Saudi Arabian scenario. A study of 31 cases and a review of literature.
To compare the clinico-pathological features of collapsing glomerulopathy (CG) at a tertiary hospital in Saudi Arabia with the world literature. Methods: In a retrospective study, all biopsy-diagnosed cases of CG between 2004-2015 were identified and analyzed, at King Khalid University Hospital, King Saud University, Riyadh. The clinico-pathological findings along with prognosis were reviewed and compared with the reported literature. Results: Thirty-one CG patients were identified, most were adult males. All the CG cases were idiopathic, all Arabs, none HIV positive, none of African descent, and none with a history of drug abuse. The number of glomeruli with collapsing lesions per biopsy ranged from 1 to 9. Other types of FSGS lesions (not otherwise specified and perihilar) were also noted. There was extensive podocyte effacement. Upon treatment, remission (complete/partial) was noted in almost half the patients; around one fourth did not respond to treatment; and one fourth progressed to end stage kidney disease (ESKD). The median time taken to develop ESKD from the time of biopsy diagnosis was 23 months. Conclusion: The clinico-pathological and prognostic correlates of CG in Saudi Arabia are comparable with that of the world literature. The management protocol at our center is the same as that practiced in different parts of the world, and the prognosis is overall poor.


Role of DBP in the circadian oscillatory mechanism.
Transcript levels of DBP, a member of the PAR leucine zipper transcription factor family, exhibit a robust rhythm in suprachiasmatic nuclei, the mammalian circadian center. Here we report that DBP is able to activate the promoter of a putative clock oscillating gene, mPer1, by directly binding to the mPer1 promoter. The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, dbp transcription is activated by CLOCK-BMAL1 through E-boxes and inhibited by the mPER and mCRY proteins, as is the case for mPer1. Thus, a clock-controlled dbp gene may play an important role in central clock oscillation.


Bayesian survival analysis with BUGS.
Survival analysis is one of the most important fields of statistics in medicine and biological sciences. In addition, the computational advances in the last decades have favored the use of Bayesian methods in this context, providing a flexible and powerful alternative to the traditional frequentist approach. The objective of this article is to summarize some of the most popular Bayesian survival models, such as accelerated failure time, proportional hazards, mixture cure, competing risks, multi-state, frailty, and joint models of longitudinal and survival data. Moreover, an implementation of each presented model is provided using a BUGS syntax that can be run with JAGS from the R programming language. Reference to other Bayesian R-packages is also discussed.


Protease-activated receptor 2: activation, signalling and function.
PARs (protease-activated receptors) are a family of four G-protein-coupled receptors for proteases from the circulation, inflammatory cells and epithelial tissues. This report focuses on PAR(2), which plays an important role in inflammation and pain. Pancreatic (trypsin I and II) and extrapancreatic (trypsin IV) trypsins, mast cell tryptase and coagulation factors VIIa and Xa cleave and activate PAR(2). Proteases cleave PAR(2) to expose a tethered ligand that binds to the cleaved receptor. Despite this irreversible activation, PAR(2) signalling is attenuated by beta-arrestin-mediated desensitization and endocytosis, and by lysosomal targeting and degradation, which requires ubiquitination of PAR(2). beta-Arrestins also act as scaffolds for the assembly of multi-protein signalling complexes that determine the location and function of activated mitogen-activated protein kinases. Observations of PAR(2)-deficient mice support a role for PAR(2) in inflammation, and many of the effects of PAR(2) activators promote inflammation. Inflammation is mediated in part by activation of PAR(2) in the peripheral nervous system, which results in neurogenic inflammation and hyperalgesia.


Removal of coin from upper esophageal tract in children with Magill's forceps under propofol sedation.
Foreign body ingestion is a common emergency problem in children. Coins are the most common foreign bodies lodged in the esophagus. This is a retrospective study where we reviewed 21 consecutive paediatric cases of coins impacted in the upper esophagus. These children were attended at the BP Koirala Institute of Health Sciences, Dharan, from March 2007 to March 2008. In this study, Mc-Intosh laryngoscopes were inserted into the pharynx to elevate the larynx and to expose the esophageal entrance. Then Magill's forceps were advanced into the esophagus and opened in order to see and extract the coin from the esophagus under propofol sedation. Coins were successfully removed by Magill forceps without any complications from all 21 children. Amongst these children, 14 (66.7%) were male and 7 (33.3%) were female. The mean age of the children was 3.79 (+/- 3.02) years. The coin was grasped and extracted on the first attempt in all 21 patients. The mean time for the removal of the coin (i.e. initiation of laryngoscope to removal of coin) was 51.48 (+/- 24.17) seconds. During direct laryngoscopy, 15 (71.4%) coins were visualized clearly, whereas 6 (28.6%) were not. However all coins were successfully removed. The most commonly ingested coin is a one rupee Nepali coin (42.9%) followed by a two rupee coin (19.0%) and an Indian one rupee coin. Thus it can be seen that the coin impacted at the cricopharynx and upper oesophagus can be safely, easily and quickly removed by direct laryngoscopy and Magill's forceps under propofol sedation.


Organoleptic properties, ease of use, and perceived health effects are determinants of acceptability of micronutrient supplements among poor Mexican women.
We assessed the acceptability of 3 micronutrient supplements for pregnant and lactating women: micronutrient powder (Sprinkles), a fortified food (Nutrivida), and tablets. Pregnant or lactating beneficiaries of the Oportunidades program participating in a cluster randomized supplementation trial in urban Mexico were surveyed about the acceptability of 1 of 3 supplements (n = 268). Semistructured interviews (n = 40) were also conducted with a subset of women in the trial and from adjacent rural areas. Acceptability of the supplements was evaluated based on women's perceptions and experiences with organoleptic qualities, ease of use, and perceived health effects (positive and negative). The median Likert scale ranking of organoleptic and use qualities for all 3 supplements was "I liked it" (2 on a scale of 1-5). However, responses to open-ended survey questions and semistructured interviews indicated decided preferences. Tablets and Sprinkles were strongly preferred over Nutrivida. In interviews, women expressed dislike of the smell, taste, and texture of Nutrivida; they found it cumbersome to store and prepare and reported the most negative effects with it. Between tablets and Sprinkles, tablets were preferred because of the absence of perceptible taste or smell and the simplicity of use. This study provides valuable insights into our currently limited understanding of women's perceptions and preferences among supplements by broadening the concept of acceptability beyond organoleptic properties. Such an analytical approach is useful for identifying both appropriate nutritional supplements within a given sociocultural context as well as the information that should be included in nutrition education to improve adherence.


Generation of halothane-induced immune response in a guinea pig model of halothane hepatitis.
A guinea pig model of halothane hepatitis was used to explore the humoral immune response induced by multiple halothane exposures and the potential role this response might play in contributing to liver damage. Three different strains of guinea pigs (Strain 2, Amana, and Hartley) were exposed to 1% halothane under either 21 or 80% oxygen for 4 hr at 2-week intervals. In each strain, halothane induced the appearance of an antibody cross-reactive with trifluoroacetylated guinea pig serum albumin (TFA-GSA). Three of six Strain 2 guinea pigs demonstrated an association between antibody titer and serum glutamate pyruvate transaminase levels. However, the possible cause and effect relationship between these two factors requires more investigation. Hartley guinea pigs had a 4- to 11-fold higher level of anti-TFA antibody than the other two strains because of either a "higher responder" genetic background or exposure conditions that favored oxidative metabolism of halothane. Immunization of Amana guinea pigs with TFA-GSA evoked a specific anti-TFA antibody response. However, the presence of this antibody before halothane exposure did not potentiate the transient liver damage induced by exposure. Thus, these results demonstrate that in guinea pigs multiple exposures to halothane induce the formation of an antibody that recognizes a reactive intermediate of halothane formed during the anesthetic's metabolism.


Two classes of single-input X-cells in cat lateral geniculate nucleus. I. Receptive-field properties and classification of cells.
Cells in the cat's dorsal lateral geniculate nucleus (LGN) were studied by presentation of visual stimuli and also by simultaneous recording of their ganglion cell inputs in the retina. This paper describes receptive-field properties and a new system of classification for LGN X-cells that appear to receive essentially only one excitatory retinal input. These X-cells were of two distinct classes. The visual responses of one class of cell (XS, single) replicated the basic form of the responses of a retinal X-cell. The other class of cell (XL, lagged) had responses with two remarkable features: their firing lagged 40-80 ms behind that of XS-cells or ganglion cells at response onset, and they fired anomalously at times when XS-cells or ganglion cells would not be firing. Thus, for a flashing spot, XL-cells were inhibited from firing after stimulus onset, during the time when XS-cells or retinal X-cells had an initial transient peak in firing; XL-cells generally had an anomalous peak in firing after stimulus offset, after XS-cells or retinal X-cells had stopped firing. For a moving bar, XS-cells or retinal X-cells responded primarily while the bar was in the receptive-field center, whereas most of a typical XL-cell's response occurred after the bar had left the receptive-field center. The latencies of various features in the visual responses were analyzed. For several visual response latencies, the distribution was clearly bimodal, thus objectively demonstrating the existence of two cell classes. Using only the latencies from spot and bar responses, over 90% of these single-input cells could be reliably identified as belonging to one of the two classes. The remaining cells (7 of 128) were intermediate between the two classes in some but not all respects; because they had some properties in common, these cells were kept in a separate group (XPL, partially lagged). The axons of both XS- and XL-cells could be antidromically activated from visual cortex. Cortical latencies were typically 0.7-2.0 ms for XS-cells but much longer, typically 2.4-5.0 ms, for XL-cells. It is possible that XL-cells have not previously been recognized as a separate class because cells with such long latencies have been recorded infrequently in the past. Responses to central flashing spots were more transient than those of retinal X-cells for most XS-cells and more sustained for most XL-cells.(ABSTRACT TRUNCATED AT 400 WORDS)


Using confidence intervals to evaluate the focus alignment of spectrograph detector arrays.
High-resolution spectrographs extract detailed spectral information of a sample and are frequently used in astronomy, laser-induced breakdown spectroscopy, and Raman spectroscopy. These instruments employ dispersive elements such as prisms and diffraction gratings to spatially separate different wavelengths of light, which are then detected by a charge-coupled device (CCD) or complementary metal-oxide-semiconductor (CMOS) detector array. Precise alignment along the optical axis (focus position) of the detector array is critical to maximize the instrumental resolution; however, traditional approaches of scanning the detector through focus lack a quantitative measure of precision, limiting the repeatability and relying on one's experience. Here we propose a method to evaluate the focus alignment of spectrograph detector arrays by establishing confidence intervals to measure the alignment precision. We show that propagation of uncertainty can be used to estimate the variance in an alignment, thus providing a quantitative and repeatable means to evaluate the precision and confidence of an alignment. We test the approach by aligning the detector array of a prototype miniature echelle spectrograph. The results indicate that the procedure effectively quantifies alignment precision, enabling one to objectively determine when an alignment has reached an acceptable level. This quantitative approach also provides a foundation for further optimization, including automated alignment. Furthermore, the procedure introduced here can be extended to other alignment techniques that rely on numerically fitting data to a model, providing a general framework for evaluating the precision of alignment methods.


Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.
Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded. Severity of signal sequence mutations correlated with increased proximity of Ago2 to nascent chain and mRNA degradation. Ago2 knockdown inhibited degradation of the mutant mRNA, while overexpression of Ago2 or knockdown of SRP54 promoted degradation of secretory protein mRNA. The results reveal a previously unappreciated general mechanism of translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP).


Relative quantitative assay of the biological activity of interferon messenger ribonucleic acid.
RNA extracted from cells previously stimulated to synthesize the antiviral protein, interferon, causes species-specific interferon synthesis when added to heterospecific cell cultures. Our results confirm the report of De Maeyer-Geugnard, De Maeyer & Montagnier (1972). We have used this observation to obtain a relative quantitative assay for the interferon messenger RNA activity. At appropriate RNA concentrations, the yield of interferon is proportional to the concentration of RNA adsorbed to recipient cell cultures.


Systemic treatment of early breast cancer--a biological perspective.
Breast cancer is the most common non-skin cancer affecting women worldwide. In the United States, over 90% of tumors are diagnosed as either in situ or localized to the breast or regional lymph nodes. Surgical treatment and adjuvant radiotherapy play an important role in loco-regional treatment of early stage breast cancer. Systemic adjuvant therapy is targeted towards isolated circulating and/or disseminated tumor cells to prevent systemic recurrence. This review will describe the diverse tumor biology of human breast cancer and how it influences decisions with regard to the use of adjuvant therapies.


Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice.
D-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-amino acids including D-serine, a full agonist at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral D-serine, plasma D-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although D-serine levels were rapidly diminished in wild-type mice (t(½) = 1.2 h), sustained drug levels over the course of 4 h (t(½) > 10 h) were observed in mice lacking DAAO. Coadministration of D-serine with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma D-serine levels, although CBIO seems to have only temporary effects on the plasma D-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of D-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma D-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia.


Breast Augmentation with Microtextured Anatomical Implants in 653 Women: Indications and Risk of Rotation.
Anatomical implants provide a wide range of options in terms of implant dimensions for breast augmentation. Nevertheless, many surgeons choose not to use anatomical implants due to the risk of rotation malposition and because their advantages over round implants are not clearly defined. A retrospective review of medical records was performed on all women who underwent breast augmentation or implant exchange with microtextured anatomical implants from 2012 to 2019 in a single private clinic. The authors focused on the outcomes of a subgroup of women with glandular ptosis and nipple placement below the inframammary fold who underwent breast augmentation with anatomical implants. Furthermore, the incidence and risk factors for implant rotation were analyzed. In total, 653 women underwent primary breast augmentation (n = 529) or implant exchange (n = 124) with anatomical implants. The median follow-up period was 2.7 years (interquartile range, 1.6 to 3.9 years). The incidence of implant rotation was 14 (2.6 percent) in the primary augmentation group and four (3.2 percent) in the implant exchange group. Implant rotation was not associated with type of surgery (p = 0.76), implant projection (p = 0.23), or implant height (p = 0.48). The authors successfully used anatomical implants to elevate the nipple in 92.9 percent of the women with glandular ptosis without using a mastopexy. The study results indicate that the rotation risk with microtextured implants is similar to that with macrotextured implants. Furthermore, the authors found that high-projection anatomical implants can be used as an alternative to augmentation-mastopexy in women with glandular ptosis. Therapeutic, III.


Lipid metabolism, cerebral metabolic rate, and some related enzyme activities after brain infarction in rats.
Multiple infarcts were produced in cerebral hemispheres of rats by injecting calibrated 50-micron microspheres into the left internal carotid artery, and alterations in lipid and energy metabolism were evaluated 24 hours later in the embolized hemisphere. Total phospholipid content was decreased by 26%, but the different classes of phospholipids were not equally affected. Phosphatidylinositol and phosphatidylserine levels were decreased by about 40% and phosphatidylcholine and phosphatidylethanolamine by 25%, while sphingomyelin level remained unchanged. There was a 3.2-fold increase in total free fatty acid content with a relatively larger rise in polyunsaturated free fatty acids 20:4 and 22:6 (20-fold increase). Determination of enzyme activities showed decreases in Na+,K+-ATPase (-21%) and hexokinase (-14%) but no changes in phosphofructokinase and pyruvate kinase. Study of energy metabolism using the closed system method of Lowry et al showed a significant depression (-36%) of the cerebral metabolic rate. Taken together, these data suggest a relation between lipid alterations and dysfunction of energy metabolism. Phospholipid degradation with subsequent free fatty acid release and alteration in membrane-bound enzymes may have a direct effect on metabolic machinery and may slow cerebral metabolic rate.


Differential binding of immunoglobulin A and immunoglobulin G1 immune complexes to primate erythrocytes in vivo. Immunoglobulin A immune complexes bind less well to erythrocytes and are preferentially deposited in glomeruli.
Primate erythrocytes appear to play a role in the clearance of potentially pathogenic immune complexes (IC) from the circulation. This study was undertaken to compare the clearance from the circulation and tissue uptake of two monoclonal IC probes: one of which, IgG1-IC, was bound well by erythrocytes, the other of which, IgA-IC, was bound relatively poorly by erythrocytes. The IC probes were labeled with different iodine isotopes and infused either concomitantly or sequentially into the arterial circulation. The results indicate that, compared with IgG1-IC, IgA-IC bind less well to primate erythrocytes, are cleared from the circulation more quickly despite their smaller size, and show increased uptake in kidney and lung but decreased uptake in liver and spleen. Evidence is presented which suggests that this pattern of clearance from the circulation and systemic uptake of IgA-IC is the result of decreased binding of IgA-IC to circulating erythrocytes. These findings support the hypothesis that the primate erythrocyte-IC clearing mechanism may be critically important for the safe removal of IC from the circulation.


Human factors in the health care facility.
Previous articles in this series have investigated the role of human factors engineering (HFE) in the design and development of medical devices and instrumentation. This article turns its focus to HFE within health care facilities--hospitals, clinics, nursing homes, HMOs, etc. The objective of HFE for the device manufacturer is to produce effective and safe systems. The health care facility is concerned with maintaining the safety of patients and staff, enhancing the cost efficiency of its operations, and controlling liability. Human factors engineering can be effective in realizing all of these goals. Proactive measures include (1) evaluation of currently employed systems for efficiency and error potential, (2) evaluation of systems prior to purchase, (3) evaluation and enhancement of facilities, and (4) design and evaluation of procedures. Retroactively, HFE participation in accident/incident investigations can carry such investigations beyond the placing of blame to determining what made a human error possible or even inevitable.


[Caudal regional anesthesia: a safe anesthetic procedure for abdominal and inguinal surgery in newborns and toddlers].
Caudal anesthesia is a safe and effective technique in children. Some surgical procedures, such as abdominal or inguinal surgeries, could be performed avoiding general anesthesia in newborns and babies, reducing the risk of respiratory depression and neurotoxicity. Our objective is to analyze the experience in a tertial referral center. We carried a retrospective study in patients under 1 year of age who underwent abdominal or inguinal procedures under caudal regional anesthesia, between 2016 and 2018. Demographics, diagnosis, comorbidity, surgical procedure, operation time, oral intake, perioperative complications and hospital stay were recorded. We included 87 patients under 1 year of age. In 56 patients (23 males, 33 females) surgery was performed under caudal anesthesia (37 scheduled, 19 urgent). Mean age was 2 months (0-11). Comorbidity: 25 associated prematurity, 3 severe tracheomalacia, 1 apnea and 8 bronchopulmonary dysplasia. Surgical procedures: 34 inguinal hernia repair, 9 incarcerated inguinal hernias, 5 neonatal testicular torsions, 8 pyloromyotomies. Mean operation time was 35 min (15-80) and mean anesthetic time 30 min (20-60). Oral intake started 2 h after surgery in 55 patients. Discharge was given in 24 h (12-36). Complications were not noticed. Any patient needed conversion to general anesthesia. Caudal anesthesia should be the anesthetic technique of choice in newborns and babies who undergo abdominal or inguinal surgeries, especially in those with comorbidity. This procedure could be performed safely, avoiding respiratory or neurological complications, with a fast recovery of patients and short hospital stay.


TSH measurement is not an appropriate screening test for autonomous functioning thyroid nodules: a retrospective study of 368 patients.
Based on the assumption that normal TSH concentration rules out the presence of autonomous functioning thyroid nodules (AFTNs), clinical guidelines on the management of thyroid nodules only recommend a thyroid scan if TSH concentration is subnormal. However, the proportion of AFTN presenting with a normal TSH is unknown. Our objective is therefore to determine the proportion of AFTNs with a normal TSH level to ascertain whether a normal TSH really rules out an AFTN. Retrospective study on 368 patients with an AFTN. Thyroid scans with a diagnosis of AFTN were reviewed retrospectively by one of us (R Moreno-Reyes), blinded to the clinical data. The diagnosis of solitary AFTN was confirmed in 368 patients. Among them, we selected 217 patients based on the absence of another thyroid nodule >10 mm, the absence of medical conditions able to interfere with thyroid function, and the completeness of the data. The proportion of AFTNs with normal TSH was 49%. This proportion increased to 71% in patients for whom thyroid scan was performed in the workup of a thyroid nodule. Our data suggest that serum TSH is not an effective screening tool to diagnose AFTNs. Using 'TSH-only' screening, as recommended by the majority of guidelines, the diagnosis of AFTN would have been missed in 71% of our patients in the workup of a thyroid nodule. Thyroid scan remains the gold standard for detecting AFTN and should be considered before performing fine-needle aspiration cytology (FNAC), as the reliability of FNAC in an unsuspected AFTN remains unclear.


Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils.
Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents. The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells. The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway. Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.


Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway.
Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.


Acute streptococcal necrotising fasciitis.
Two cases of acute streptococcal necrotising fasciitis are reported. Both patients were taking nonsteroidal antiinflammatory drugs when they developed this infection. Urgent surgical debridement was undertaken and resulted in a successful outcome in both patients. The clinical and histopathological features of this condition are reviewed.


Effect of Total Alkali in Leonuri Herba on rat ear acne model of serum IL-6 level, Thymus and Spleen Tissue Morphology.
To investigate the effect of Total Alkali in Leonuri Herba (TALH) on rat ear acne model of serum IL-6 level, Thymus and Spleen Tissue Morphology. The rats were divided into the TALH group at high, medium and low doses (200 mg kg-1, 100 mg·kg-1, 50 mg·kg-1), the tanshinone group (360 mg·kg-1), model group and the blank group. All the rats were administrated once a day for 14 days. At the same time on the first day, the rats in the blank group were injected normal saline in the stomach and also had intradermal injection of sterile saline in the auricle. The rats in other groups (model group were lavaged with physiological saline) were injected intradermally auricle spare Staphylococcus epidermidis bacteria liquid. After the injection, the rat ear swelling rate was calculated for 5 consecutive days in terms of rat auricle thickness measurement. 1 h after the last administration, the eyeball blood was removed, centrifuged to separate serum, and measured to be at serum IL-6 level; The tissue sections of thymus and spleen were observed according to morphology criteria. Compared with the blank group, the level of IL-6 in serum of the rats in the model group was remarkably higher, and those in the thymus and spleen groups were remarkably lower, indicating the rat ear acne model is successful. Compared with the model group, the rats in the TALH group can remarkably make serum IL-6 level decrease, causing significant thymus cortical thickening and increased spleen sections, and remarkably increasing the lymphocytes of thymus and spleen. The effect of large dose in the TALH group is the best and increases with the increase of the dose and curative effect. The TALH treatment of acne may be related to the reduction of serum IL-6 levels and the resistance of the atrophy of the thymus and spleen on the rat ear acne model.


[Characterization of Triticum aestivum-Dasypyrum villosum germplasms Shannong05078].
A germplasm line Shannong05078 was developed from the progenies of Am3 x Triticum aestivum-Dasypyrum villosum amphidiploid, the purpose of this study is to ascertain the genome composition of Shannong05078 and then supply wheat breeding with reference. The results showed that Shannong05078 was stable in morphology characters and presenting favorable agronomic traits, it was resistant to powdery mildew and rust. Its protein content was higher, and the HWM-GS of it was 7+8, 5+10. The chromosome number of Shannong05078 was 2n=28, and the chromosome configuration was 2n=14 II at the PMC MI. SSR analysis showed that Shannong05078 contained the whole A and B genomes, and had little genetic materials from D genome. A specific primer of Dasypyrum villosum (phv29) was used to identify the genetic materials form Dasypyrum villosum in Shannong05078, and specific band of Dasypyrum villosum appeared in it. It can be deduced that the genomic composition of Shannong05078 is 2n=AABB=28, and genetic materials of D genome and Dasypyrum villosum were translated into Shannong05078.


Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord.
With advancing age, the incidence of neuronal atrophy and dystrophy increases and, in parallel, behavioural sensorimotor impairment becomes overt. Activated microglia has been implicated in cytotoxic and inflammatory processes in neurodegenerative diseases as well as during aging. Here we have used immunohistochemistry and in situ hybridization to examine the expression of OX42, ED1, ED2, GFAP and clusterin in CNS of young adult and behaviourally tested aged rats (30-month-old), to study the occurrence of activated microglia/ED1 positive macrophages in senescence and to what extent this correlates with astrogliosis and signs of sensorimotor impairment among the individuals. The results show a massive region-specific increase in activated microglia and ED1 expressing cell profiles in aged rats. The infiltration was most prominent in the spinal cord dorsal columns, including their sensory relay nuclei, and the outer portions of the lateral and ventral columns. At such sites the occurrence of macrophages coincided with increased levels of GFAP and positive correlations were evident between the labeling for, on the one hand, OX42 and, on the other, GFAP and ED1. Also, the ventral and dorsal roots were heavily infiltrated by ED1 positive cells. The signs of gliosis were most pronounced among aged rats with advanced sensorimotor impairment. In contrast, the grey matter of aged rats showed very few activated microglia/ED1 labeled cells despite signs of focal astrogliosis. ED2 expression was confined to perivascular cells and leptominges with a similar labeling pattern in young and aged rats. In aged rats increased expression of clusterin was observed in GFAP-immunoreactive profiles of the white matter only. It is suggested that this increase may reflect a response to degenerative/inflammatory processes.


Seeking connection, autonomy, and emotional feedback: A self-determination theory of self-regulation in attention-deficit hyperactivity disorder.
Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent and highly debated diagnosis for mental disorder in practice today. Two decades of research have substantially contributed to evolving conceptualizations and understanding of the condition. However, this evolution has not been extended to theoretical research. Current cognitive behavioral-based theories aim to identify the etiology of ADHD and experience challenges in accommodating the full spectrum of both neurobiological and behavioral research evidence. Characterizations historically associated with mental illness have generated public stigma, influencing low self-esteem, negative self-concept, and identity development in ADHD individuals. Neurodiversity research and activism recognize a diversity of nonnormative development and highlight the need for alternatives to deficit models of functioning. Recent research in psychology recommends developing approaches beyond symptom control and seeking to develop positive psychological factors and well-being. We propose that the perspective presented by self-determination theory (SDT) on human motivation, self-regulation, and self-determination offers a new understanding of ADHD research evidence and symptomology. According to this theory, humans have a natural tendency toward growth and self-actualization. We propose a framework grounded in SDT that provides an alternative understanding of ADHD neural processing, motivation and engagement, self-regulation, and a potential foundation for treatment approaches with self-determination and positive identity outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Effects of 1% Lidocaine Instillation on Overactive Bladder Induced by Bladder Outlet Obstruction in Rats.
Lidocaine is a common local anesthetic and antiarrhythmic drug that acts via the local anesthetic effect of blocking voltage-gated sodium channels in peripheral neurons. To evaluate lidocaine as a therapeutic agent, we investigated optimal concentrations and effects of intravesical lidocaine instillation in a bladder outlet obstruction (BOO)-induced rat model of overactive bladder (OAB). To determine the therapeutic dosage of lidocaine, 16 female Sprague-Dawley (SD) rats (mean weight = 200 ± 20 g) were divided into four treatment groups: those receiving saline, 0.5% lidocaine, 1% lidocaine, and 2% lidocaine (n = 4 per group). Twenty-four additional SD rats were divided into two groups to investigate the effect of 1% lidocaine treatment in rats with BOO and normal rats (n = 12 per group). Cystometry was performed by infusing physiological saline and lidocaine into the bladder at a slow infusion rate (0.04 mL/min). Cystometric parameters were analyzed using PowerLab®. The expression of c-Fos, a protein expressed by C-fibers in the spinal cord (L6), was investigated via western blotting. Among the test lidocaine doses, only 1% lidocaine increased the intercontraction interval (ICI) (control mean = 500.56 ± 24.4 s; treatment mean = 641.0 ± 49.3 s; p < .01) without changes in threshold pressure and basal pressure. In the BOO-induced OAB group, the ICI increased significantly after instillation of 1% lidocaine (control mean = 135.8 ± 12.87 s; OAB-group mean = 274.2 ± 33.21 s; p < .01). Detrusor overactivity and non-voiding contraction were observed in the control group but not in rats with BOO after lidocaine instillation. The expression of c-Fos in C-fibers in the spinal cord (L6) decreased significantly after 1% lidocaine treatment in rats with BOO. Intravesical instillation of 1% lidocaine improves cystometric parameters without deterioration of contractility by blocking excessive C-fiber activity in the rat model of BOO-induced OAB. Therefore, instillation of 1% lidocaine has minimal effects on normal nerves while blocking nerves that contribute to OAB. Our findings suggest that intravesical instillation of 1% lidocaine is a useful treatment for OAB.


Clinical Evaluation of the Articulinx Intercarpometacarpal Cushion for the First CMC Joint: A Feasibility Study.
Background The Intercarpometacarpal Cushion (ICMC; Articulinx, Cupertino, CA, USA) is an implantable spacer designed as a less invasive surgical treatment for osteoarthritis (OA) of the first carpometacarpal joint (CMC-1). Description of Technique Following local anesthesia and exposure of the joint capsule the ICMC, attached to a needle and suture tethers, is guided into the joint space under fluoroscopic visualization through a dorsal approach. The needle is pulled through the thenar eminence to the opposite side of the hand and, once proper device placement is confirmed, cut free and the joint capsule closed. Patients and Methods Eight female patients (median age 56 years; range, 42-83) were treated and followed for 6 to 24 months. Safety of the implant procedure was evaluated intraoperatively. Pain, joint function, and strength were evaluated at 6 weeks, 3, 6, 12 and 24 months with a Visual Analog Scale (VAS) for pain, the QuickDASH inventory, Canadian Occupational Performance Measure (COPM), and pinch and grip strength measurements. Results At 2 years (n = 6), mean VAS pain scores decreased from 6.3 (± 1.5) to 2.2 (± 1.1) (p < 0.001), mean QuickDASH scores improved from 47 (± 15) to 31 (± 11) (p < 0.10), mean COPM performance scores improved from 5.0 (± 1.2) to 5.5 ( ± 1.3) (p = NS). Mean pinch and grip strength measurements also improved compared with baseline. No serious adverse events occurred. Two device removals occurred, associated with a traumatic event and Stage IV OA with device displacement, at 6 and 9 months respectively. Conclusion The ICMC can be implanted safely. Effectiveness needs to be confirmed in future studies.


The hardwiring of development: organization and function of genomic regulatory systems.
The gene regulatory apparatus that directs development is encoded in the DNA, in the form of organized arrays of transcription factor target sites. Genes are regulated by interactions with multiple transcription factors and the target sites for the transcription factors required for the control of each gene constitute its cis-regulatory system. These systems are remarkably complex. Their hardwired internal organization enables them to behave as genomic information processing systems. Developmental gene regulatory networks consist of the cis-regulatory systems of all the relevant genes and the regulatory linkages amongst them. Though there is yet little explicit information, some general properties of genomic regulatory networks have become apparent. The key to understanding how genomic regulatory networks are organized, and how they work, lies in experimental analysis of cis-regulatory systems at all levels of the regulatory network.


[Genetic tau-variants in patients with frontotemporal dementia].
[corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects. Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups. The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5). In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.


Feasibility, Process, and Outcomes of Cardiovascular Clinical Trial Data Sharing: A Reproduction Analysis of the SMART-AF Trial.
Data sharing is as an expanding initiative for enhancing trust in the clinical research enterprise. To evaluate the feasibility, process, and outcomes of a reproduction analysis of the THERMOCOOL SMARTTOUCH Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (SMART-AF) trial using shared clinical trial data. A reproduction analysis of the SMART-AF trial was performed using the data sets, data dictionary, case report file, and statistical analysis plan from the original trial accessed through the Yale Open Data Access Project using the SAS Clinical Trials Data Transparency platform. SMART-AF was a multicenter, single-arm trial evaluating the effectiveness and safety of an irrigated, contact force-sensing catheter for ablation of drug refractory, symptomatic paroxysmal atrial fibrillation in 172 participants recruited from 21 sites between June 2011 and December 2011. Analysis of the data was conducted between December 2016 and April 2017. Effectiveness outcomes included freedom from atrial arrhythmias after ablation and proportion of participants without any arrhythmia recurrence over the 12 months of follow-up after a 3-month blanking period. Safety outcomes included major adverse device- or procedure-related events. The SMART AF trial participants' mean age was 58.7 (10.8) years, and 72% were men. The time from initial proposal submission to final analysis was 11 months. Freedom from atrial arrhythmias at 12 months postprocedure was similar compared with the primary study report (74.0%; 95% CI, 66.0-82.0 vs 76.4%; 95% CI, 68.7-84.1). The reproduction analysis success rate was higher than the primary study report (65.8%; 95% CI 56.5-74.2 vs 75.6%; 95% CI, 67.2-82.5). Adverse events were minimal and similar between the 2 analyses, but contact force range or regression models could not be reproduced. The feasibility of a reproduction analysis of the SMART-AF trial was demonstrated through an academic data-sharing platform. Data sharing can be facilitated through incentivizing collaboration, sharing statistical code, and creating more decentralized data sharing platforms with fewer restrictions to data access.


Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.
Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.


Clinical, Biochemical, and Radiological Presentation of RT-PCR-Positive vs RT-PCR-Negative SARS-CoV-2 Pneumonia Requiring ICU Care: An Observational, Cross-Sectional, Single-Center Study in Kalaburagi, Kalyana Karnataka.
Introduction Studies have reported similar clinical, biochemical, and radiological features between real-time polymerase chain reaction (RT-PCR)-positive and RT-PCR-negative patients. Therefore, the present study aims to assess differences in RT-PCR-positive versus RT-PCR-negative patients' characteristics. Methods We prospectively included 70 consecutive patients with typical coronavirus disease 2019 (COVID-19)-like clinical features who were either RT-PCR-positive or negative, requiring admission to the intensive care unit. The patients were classified into positive and negative RT-PCR groups and evaluated for clinical features, comorbidities, laboratory findings, and radiologic features. Results Fifty-seven point one percent (57.1%; 40/70) were RT-PCR positive, and 42.9% (30/70) were RT-PCR negative patients. The respiratory rate was higher among negative patients (P = 0.02), whereas the mean duration of fever was longer (3.34 vs 2.5; P = 0.022) among positive patients. At presentation, RT-PCR-negative patients had lower saturation of peripheral oxygen (SpO2) (near significant P = 0.058). Evaluation of co-morbidities revealed no differences. The neutrophil/lymphocyte ratio (NLR) (4.57 vs 6.52; P = 0.048), C-reactive protein (CRP) (9.97 vs 22.7; P = 0.007), and serum ferritin (158 vs 248.52; P = 0.010) were higher in patients who tested negative for RT-PCR. Thrombocytopenia (2.42 vs 1.76; P = 0.009), D-dimer levels (408.91 vs 123.06; P = 0.03), and interleukin (IL-6) levels (219.3 vs 80.81; P = 0.04) were significantly elevated among RT-PCR positive patients. The percentage of lung involvement in negative cases was 42.29+/-22.78 vs 36.21+/-21.8 in positive cases (P=0.23). The CT severity score was similar in both cohorts. Conclusion Both RT-PCR-positive and negative patients have similar clinical, biochemical, and radiological features. Considering that we are amidst a pandemic, it is advisable to have a similar approach irrespective of the RT-PCR report and triage and isolate accordingly. We recommend an RT-PCR-negative intensive care unit (ICU) ward and that the treating physician take a call on the management with a holistic approach driven clinically by the laboratory findings and helped by radiological findings. Stressing only on the RT-PCR report for management can be counterproductive.


Demystifying spasticity in primary care.
To raise awareness of spasticity in primary care and clarify how to identify, diagnose, and manage it effectively and efficiently in patients with pre-existing neurologic conditions. PubMed was searched for articles published from 1970 to May 2018 using the terms spasticity, spasticity in physical disability, spasticity in mobility impairment, and spasticity with family medicine or primary care. Other relevant guidelines and resources were reviewed and used. Spasticity is a common secondary complication in conditions such as spinal cord injury, multiple sclerosis, stroke, cerebral palsy, and other neuromuscular physical disabilities and can have a negative effect on health and quality of life. Factors such as inconsistent definition, poorly understood mechanism, and relatively low prevalence make spasticity seem like a daunting condition to manage. Furthermore, its variable presentation and effect on a patient's quality of life, and its range of treatments with varying levels of evidence, can make treatment challenging in primary care and in other clinical settings. Family physicians play an important role in recognizing and inquiring about spasticity and its changes, triggers, and effects on function. Ruling out reversible causes is important. Many management strategies can be instituted by family physicians. Managing spasticity might be unfamiliar to many practitioners. It is important for physicians to understand spasticity and the potential treatment options available to improve quality of life. The current review provides concise information on the clinical relevance of spasticity in primary care and how to assess and manage it effectively and efficiently in those with chronic neurologic conditions.


Exploring the working mechanism of graphene patterning by magnetic-assisted UV ozonation.
When assisted with an inhomogenous vertical magnetic field, ultraviolet (UV) ozonation turns directional and is testified to be applicable to graphene patterning. Using a more cost-effective low-pressure mercury lamp, we further explore the underlying working mechanism by changing oxygen content, introducing reactive ozone or inert nitrogen molecules, and study the lateral under-oxidation impeded Dirac point shifts for a graphene field-effect transistor under UV irradiation. The paramagnetic oxygen molecule X3Σ accelerates toward graphene with the magnetic moment aligned parallel to the magnetic field. The O(3P) atoms, stemming from such a directional oxygen molecule, have a high initial velocity before being further accelerated, and therefore enhance the oxidation capability compared with those from weak diamagnetic ozone molecules. Intermolecular or atomic-molecular collisions between the high-speed oxygen molecules/atoms and the randomly moved weak diamagnetic molecules, including nitrogen and ozone, appear crucial in deteriorating graphene patterning by increasing the lateral under-oxidation. This study may shed light on our understanding of graphene patterning by magnetic-assisted UV ozonation.


Mmp2 Deficiency Leads to Defective Parturition and High Dystocia Rates in Mice.
Parturition is the final and essential step for mammalian reproduction. While the uterus is quiescent during pregnancy, fundamental changes arise in the myometrial contractility, inducing fetal expulsion. Extracellular matrix (ECM) remodeling is fundamental for these events. The gelatinases subgroup of matrix metalloproteinases (MMPs), MMP2 and MMP9, participate in uterine ECM remodeling throughout pregnancy and parturition. However, their loss-of-function effect is unknown. Here, we determined the result of eliminating Mmp2 and/or Mmp9 on parturition in vivo, using single- and double-knockout (dKO) mice. The dystocia rates were measured in each genotype, and uterine tissue was collected from nulliparous synchronized females at the ages of 2, 4, 9 and 12 months. Very high percentages of dystocia (40-55%) were found in the Mmp2-/- and dKO females, contrary to the Mmp9-/- and wild-type females. The histological analysis of the uterus and cervix revealed that Mmp2-/- tissues undergo marked structural alterations, including highly enlarged myometrial, endometrial and luminal cavity. Increased collagen deposition was also demonstrated, suggesting a mechanism of extensive fibrosis in the Mmp2-/- myometrium, which may result in dystocia. Overall, this study describes a new role for MMP2 in myometrium remodeling during mammalian parturition process, highlighting a novel cause for dystocia due to a loss in MMP2 activity in the uterine tissue.


Marine Fish Proteins and Peptides for Cosmeceuticals: A Review.
Marine fish provide a rich source of bioactive compounds such as proteins and peptides. The bioactive proteins and peptides derived from marine fish have gained enormous interest in nutraceutical, pharmaceutical, and cosmeceutical industries due to their broad spectrum of bioactivities, including antioxidant, antimicrobial, and anti-aging activities. Recently, the development of cosmeceuticals using marine fish-derived proteins and peptides obtained from chemical or enzymatical hydrolysis of fish processing by-products has increased rapidly owing to their activities in antioxidation and tissue regeneration. Marine fish-derived collagen has been utilized for the development of cosmeceutical products due to its abilities in skin repair and tissue regeneration. Marine fish-derived peptides have also been utilized for various cosmeceutical applications due to their antioxidant, antimicrobial, and matrix metalloproteinase inhibitory activities. In addition, marine fish-derived proteins and hydrolysates demonstrated efficient anti-photoaging activity. The present review highlights and presents an overview of the current status of the isolation and applications of marine fish-derived proteins and peptides. This review also demonstrates that marine fish-derived proteins and peptides have high potential for biocompatible and effective cosmeceuticals.


Improving Descriptive Terminology using a Descriptive Algorithm as an Educational Intervention to Improve Referral Accuracy.
The accuracy of clinical communication in referrals to Dermatology has not been fully explored. Baseline analysis of inpatient ward referral to a Dermatology service, revealed only 37% of referrals used accurate descriptive terminology. Theme analysis of individual descriptive terms used was performed to assess knowledge deficits and develop a novel intervention to improve descriptive accuracy. A descriptive algorithm was developed to act as a scaffolding resource for the use of descriptive terms. The Belfast Dermatology Descriptive Algorithm was developed as a tool to determine primary and secondary morphological features of eruptions, and highlight common clinical pitfalls. It was designed to adhere to principles of adult learning. Assessment was completed following the introduction of the algorithm. The accuracy of descriptions used was increased to 70% with introduction of the resource. This outcome reflects how educational interventions, in the format of an accessible resource tool, can be utilised as a unique intervention to improve education in clinical practice.