Homocysteine threshold value based on cystathionine beta synthase and paraoxonase 1 activities in mice.
Hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Among the determinants which predispose to premature thromboembolic and atherothrombotic events, serum activity of paraoxonase 1, mainly synthesized in the liver, has been shown to be a predictor of cardiovascular disease and to be negatively correlated with serum homocysteine levels in human. Even though treatments of hyperhomocysteinaemic patients ongoing cardiovascular complications are commonly used, it still remains unclear above which homocysteine level a preventive therapy should be started. In order to establish a threshold of plasma homocysteine concentration we have analyzed the hepatic cystathionine beta synthase and paraoxonase 1 activities in a moderate to intermediate murine model of hyperhomocysteinaemia. Using wild type and heterozygous cystathionine beta synthase deficient mice fed a methionine enriched diet or a control diet, we first studied the link between cystathionine beta synthase and paraoxonase 1 activities and plasma homocysteine concentration. Among the animals used in this study, we observed a negative correlation between plasma homocysteine level and cystathionine beta synthase activity (rho=-0.52, P=0.0008) or paraoxonase 1 activity (rho=-0.49, P=0.002). Starting from these results, a homocysteine cut-off value of 15 microm has been found for both cystathionine beta synthase (P=0.0003) and paraoxonase 1 (P=0.0007) activities. Our results suggest that both cystathionine beta synthase and paraoxonase 1 activities are significantly decreased in mice with a plasma homocysteine value greater than 15 microm. In an attempt to set up preventive treatment for cardiovascular disease our results indicate that treatments should be started from 15 microm of plasma homocysteine.


Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID-19) in India.
Healthcare workers (HCWs) and frontline workers were recommended hydroxychloroquine (HCQ) 400 mg twice a day on day 1, followed by 400 mg once weekly for the next 7 weeks, as prophylaxis against COVID-19. There was limited information on the population pharmacokinetics (popPK) of HCQ in an Indian setting when administered for prophylaxis against COVID-19, and hence this study was proposed. It was a multicentric prospective study conducted at 3 sites in India wherein HCWs who were already on HCQ prophylaxis, who were about to start prophylaxis or who had stopped the prophylaxis for any reason were enrolled. Each participant gave 2 to 6 blood samples at different time points and whole-blood HCQ concentrations were assayed using liquid chromatography with tandem mass spectrometry (LC MS/MS). popPK analysis was performed using PUMAS 1.1.0. A total of N = 338 blood samples from N = 121 participants were included in the popPK analysis. A 2-compartment structural model with linear elimination was able to explain the observed data. Body weight was found to be a significant covariate influencing drug clearance. The final model was assessed using goodness-of-fit plots, a visual predictive check and a bootstrap, all of which confirmed that the model was appropriate. Simulations based on the current regimen showed that trough values were below the half-maximal effective concentration (EC50) of 0.7 μmol against COVID-19. A new weight-based dosage regimen was proposed to maintain the trough concentration above the EC50 threshold.


Response localization of the pharmacological agents histamine and salbutamol along the respiratory system by forced oscillations in asthmatic subjects.
The bronchodilating effect of 1 mg and 0.4 mg salbutamol on the impedance of the respiratory system was studied in 25 asthmatic subjects after histamine-induced bronchoconstriction. Histamine caused an increase of respiratory resistance (Rrs) at lower frequencies and a frequency dependence of Rrs. Respiratory reactance (Xrs) decreased at all frequencies after histamine challenge. These changes can be explained by peripheral airway obstruction. Impedance measurements performed 5 min after inhalation of 1 mg and 0.4 mg salbutamol showed a decrease of Rrs values at lower frequencies, a disappearance of the frequency dependence of Rrs, and a significant increase of Xrs values. No significant differences in absolute changes of Rrs and Xrs are observed between the salbutamol regimens. These changes after inhalation of salbutamol can be explained by supposing a predominant action on the peripheral airways.


Hypoxic cell sensitization to radiation damage by a new radiosensitizer: cis-dichloro-bis(1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3)platinum(II) (flap).
A new, stable platinum coordination complex (FLAP) containing the 5-nitroimidazole, metronidazole, has been prepared and characterized. The square-planar platinum(II) complex has two metronidazole molecules and two chlorine atoms in the cis configuration. The properties of FLAP differ significantly from metronidazole alone or other platinum complexes tested in the same system. It has a low toxicity towards Chinese hamster ovary cells and is a very effective radiosensitizer toward hypoxic cells in vitro: a one-h pretreatment with a non-toxic dose of 50 microM gave an enhancement ratio of 2.4. No potentiation of aerated cells to X-irradiation damage was observed after a similar schedule of pretreatment at the higher dose of 100 microM FLAP.


Selective etching of silicon nitride over silicon oxide using ClF3/H2 remote plasma.
Precise and selective removal of silicon nitride (SiNx) over silicon oxide (SiOy) in a oxide/nitride stack is crucial for a current three dimensional NOT-AND type flash memory fabrication process. In this study, fast and selective isotropic etching of SiNx over SiOy has been investigated using a ClF3/H2 remote plasma in an inductively coupled plasma system. The SiNx etch rate over 80 nm/min with the etch selectivity (SiNx over SiOy) of ~ 130 was observed under a ClF3 remote plasma at a room temperature. Furthermore, the addition of H2 to the ClF3 resulted in an increase of etching selectivity over 200 while lowering the etch rate of both oxide and nitride due to the reduction of F radicals in the plasma. The time dependent-etch characteristics of ClF3, ClF3 & H2 remote plasma showed little loading effect during the etching of silicon nitride on oxide/nitride stack wafer with similar etch rate with that of blank nitride wafer.


An experimental study of enhanced cell killing by hyperthermia and bleomycin.
In vitro cell killing effects from heating and/or bleomycin have been investigated using the KK-47 cell line derived from a human bladder carcinoma and the colony-forming assay system. Percent survivals of the asynchronous cells heated to 40 degrees, 41 degrees, 42 degrees and 43 degrees C for 30 min were 96.6%, 93.3%, 91.4% and 71.2%, respectively, and those at 43 degrees C for 2h were 80.6%, 75.5%, 46.0% and 1.4%, respectively. The survival percentages of the cells treated with bleomycin at the concentrations of 1, 3, 6 and 10 micrograms per ml at 37 degrees C for 30 min were 66.0%, 40.4%, 21.9% and 11.9%, respectively. When hyperthermia at 43 degrees C was combined with bleomycin, a greatly enhanced cell killing effect was obtained by preheating and simultaneous heating as compared with the effect of post-heating.


Adenoma detection rate and the quality of colonoscopy: the sword has two edges.
With the increasing demand for colonoscopy for colorectal cancer screening and surveillance of colorectal adenomas and carcinomas, there has been an increasing emphasis on the quality of colonoscopy. Few publications have considered the full implications of pushing the adenoma detection rate as a prime quality indicator. In this article, some of the potential problems with this course are discussed and an alternative approach is suggested. Although defining and measuring quality in colonoscopy is important, further work needs to be done to arrive at a practical, clinically meaningful way of quality assessment.


Care-seeking behavior of women with reproductive health problems from low-income areas of Beirut.
To examine the patterns of care-seeking behavior and provider choice of women with self-reported reproductive health problems from 3 urban communities in Beirut. The study was based on a sample of 1869 completed questionnaires from 2051 eligible women (married or had been married, and between 15 and 59 years) obtained during the Urban Health Survey. Associations between community of residence, other background characteristics, and two outcome measures (health care usage and choice of provider) were assessed using logistic regression. Of the 1869 women assessed, 439 (23.5%) reported reproductive health problems; of these, 273 (62%) women sought care for their problems, with the majority (52.5%) using private providers. Younger age, health insurance, and severity and duration of problems were associated with use. Women with higher parity and those with financial problems were significantly more likely to use public and subsidized services. The private health sector needs to be more involved in planning, implementing, and offering reproductive health care in low-income communities.


Influence of saccades on manual reactions--a reaction time and VEP study.
Experiments were performed to investigate the retardation of motor reactions, triggered immediately after saccadic eye movements, by comparing VEP latencies and manual reaction times. As visual stimuli grating patterns of different spatial frequencies were used. They were presented during continuous fixation ("resting eye" condition) as well as shortly after a saccade ("saccadic" condition) with different onset delays (25, 50, 100, 150 msec), in order to determine the influence of saccades on VEP latencies and on manual reaction times. Compared with the reaction times in the "resting eye" condition, the postsaccadic reaction times were much prolonged whereas the respective VEP latencies are almost unchanged. Thus an inhibitory interaction of different motor responses (i.e. saccadic eye movements and manual reactions in this study) at higher levels of the afferent system or at the motor control site is postulated. This result has been confirmed for stimuli of different spatial frequencies.


An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice.
The aim of this study was to investigate the effect of modification processes on physical properties and explain the mechanism of sustained drug release from modified rice (MR). Various types of Vietnamese rice were introduced in the study as the matrices of sustained release dosage form. Rice was thermally modified in water for a determined temperature at different times with a simple process. Then tablets containing MR and isradipine, the model drug, were prepared to investigate the capability of sustained drug release. Scanning electron microscopy (SEM) was used to determine different morphologies between MR formulations. Flow property of MR was analyzed by Hausner ratio and Carr's indices. The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH 1.2 and pH6.8 at 37±0.5°C. The matrix tablet containing MR showed a sustained release as compared to the control. The SEM analyses and swelling/erosion studies indicated that the morphology as well as swelling/erosion rate of MR were modulated by modification time, drying method and incubation. It was found that the modification process was crucial because it could highly affect the granule morphologies and hence, leading to the change of flowability and swelling/erosion capacity for sustained release of drug.


Improved exopolysaccharide production from Bacillus licheniformis MS3: Optimization and structural/functional characterization.
Exopolysaccharides (EPS) are microbially-originated, complex biosynthetic polymers, mainly carbohydrates in nature. They have gained attention of modern researches due to their novel physicochemical characteristics. However, the development of cost-effective strategies to improve the EPS yield, remains a challenge. In this study, cost-effective EPS production was carried out from B. licheniformis in solid state fermentation of mango peels substrate with waste-to-value theme. Initially, B. licheniformis was exposed to ultraviolet (UV) radiations of short wavelength which significantly improved the EPS yield (from 3.4 to 4.6 g/L). The highest EPS producing mutant strain (B. licheniformis MS3) was further proceeded for yield optimization using RSM-CCD approach. Optimization improved the yield >3.2-folds (from 4.6 to 15.6 g/L). The optimally yielded fraction was characterized using HPLC, FT-IR and SEM analyses. HPLC revealed the hetero-polymeric nature of EPS containing mannose (20.60%), glucose (46.80%), and fructose (32.58%) subunits. FT-IR spectroscopy revealed the presence of hydroxyl and carboxyl functional groups, and glycosidic linkages among monosaccharides. SEM microstructure showed that EPS comprise smoother surface with less porosity. Studies on functional characteristics revealed the presence of hydrophilic moieties among EPS with moderate water (105.3%) and oil (86.3%) uptake capacity. The EPS exhibited excellent emulsifying properties showed good stability against all hydrocarbons/oils tested. In conclusion, the cost-effective EPS production with multifunctional properties, this study may be valuable for various biochemical and biotechnological sectors.


The core minimum dataset for measuring pain outcomes in pain services across Scotland. Developing and testing a brief multi-dimensional questionnaire.
There is currently no agreed minimum dataset to inform specialist chronic pain service provision. We aimed to develop a Core Minimum Dataset (CMD) for pain services in Scotland and perform preliminary analysis to evaluate its psychometric properties in adults with chronic pain. The questionnaire was developed following a review of existing relevant data collection instruments and national consultation. The CMD questionnaire was completed alongside a routine pre-clinic questionnaire by patients attending two pain services over 3 months. Concurrent validity was tested by comparing scores between the CMD and pre-existing questionnaires. Reliability was assessed by test-retest and discriminative validity via receiver operating characteristic (ROC) curves. The final CMD questionnaire consisted of five questions on four domains: pain severity (Chronic Pain Grade [CPG] Q1); pain interference (CPG Q5); emotional impact (Patient Health Questionnaire-2 [PHQ-2], two questions); and quality of life (Short Form Health Survey-36 [SF-36] Q1). 530 patients completed the questionnaire. Strong correlation was found with the Hospital Anxiety and Depression Scale (rs = 0.753, p < 0.001). Moderate correlations were found with the Brief Pain Inventory for pain interference (rs = 0.585, p < 0.001) and pain severity (rs = 0.644, p < 0.001). Moderate to good reliability was demonstrated (Intra-class Correlation Coefficient = 0.572-0.845). All items indicated good discrimination for relevant health states. The findings represent initial steps towards developing an accurate questionnaire that is feasible for assessing chronic pain in adults attending specialist pain clinics and measuring service improvements in Scotland. Further validation testing, in clinical settings, is now required.


The respiratory chain of Paramecium tetraurelia in wild type and the mutant Cl1. I. Spectral properties and redox potentials.
1. Purified mitochondria have been prepared from wild type Paramecium tetraurelia and from the mutant Cl1 which lacks cytochrome aa3. Both mitochondrial preparations are characterized by cyanide insensitivity. Their spectral properties and their redox potentials have been studied. 2. Difference spectra (dithionite reduced minus oxidized) of mitochondria from wild type P. tetraurelia at 77 K revealed the alpha peaks of b-type cytochrome (s) at 553 and 557 nm, of c-type cytochrome at 549 nm and a-type cytochrome at 608 nm. Two alpha peaks at 549 and 545 nm could be distinguished in the isolated cytochrome c at 77 K. After cytochrome c extraction from wild type mitochondria, a new peak at 551 nm was unmasked, probably belonging to cytochdrome c1. The a-type cytochrome was characterized by a split Soret band with maxima at 441 and 450 nm. The mitochondria of the mutant Cl1 in exponential phase of growth differed from the wild type mitochondria in that cytochrome aa3 was absent while twice the quantity of cytochrome b was present. In stationary phase, mitochondria of the mutant were characterized by a new absorption peak at 590 nm. 3. Cytochrome aa3 was present at a concentration of 0.3 nmol/mg protein in wild type mitochondria and ubiquinone at a concentration of 8 nmol/mg protein both in mitochondria of the wild type and the mutant Cl1. Cytochrome aa3 was more susceptible to heat than cytochromes b and c,c1.


Short chain fatty acids in plasma and brain: quantitative determination by gas chromatography.
A reliable and practicable method for the determination of short chain fatty acids in plasma and brain tissue is presented. The sample preparation by partition chromatography on silicic acid allows subsequently a quantitation of short chain fatty acids without interference by methylmalonic acid, or other more polar compounds. With the gas-chromatographic system 2-methylbutyrate is separated from isovalerate. Reference values are given for plasma. The system is also useful in combination with mass spectrometry.


Production of beauvericin byFusarium proliferatum from maize in Italy.
Beauvericin (BEA), a toxic cyclodepsipeptide, was purified from corn kernel cultures of a toxigenic strain ofFusarium proliferatum, Isolated from corn ear rot in northern Italy (45 mg/kg dry culture). The strain, designed ITEM-1503, also produced fumonisin B, (2,250 mg/kg dry culture), and moniliformin (150 mg/kg dry culture). Thin-layer chromatography, high-performance thin layer chromatography, high-performance liquid chromatography, low-resolution electronic impact mass spectrometry and 1H, 13C nuclear magnetic resonance spectroscopy were used for BEA Isolation and confirmation. This is the first report on the production of BEA byF. proliferatum.


Effects of sex, size and substrate on growth and mortality of trees in tropical wet forest.
Females and males of three tree species did not differ in growth or mortality over an interval of 9.5 years. Comparing between sexes and across species, there was no consistent pattern of effects of short-term (1 year) growth and fecundity on longer-term gorwth or mortality. Effects of size were significant (but minor) for growth in one species, and were significant for mortality in two species. Soil type affected mortality in one species, but affected growth in all three species. Sex and size are not consistently strong bases for predicting the performance of adult trees.


Physico-chemical characteristics of superoxide dismutase in Ascaris suum.
1. Three SOD isoenzymes obtained from purified extracts of Ascaris suum were characterized. 2. The physico-chemical characteristics studied were: optimum pH, methods of preservation of enzymatic activity, molecular weight, and the u.v. and visible light absorption spectra. 3. The optimum pH for the Cu, Zn SOD I and II was 10.2 and 10.1 for the Mn SOD. 4. The extracts retained their levels of activity longer at -70 degrees C, and after lyophilization. The Mn SOD was more labile than the Cu, Zn SOD I and II. 5. The molecular weights obtained by filtration through Sephadex G-75 were: 73,000 for Mn SOD; 42,600 for Cu, Zn SOD I; and 39,800 for the Cu, Zn SOD II. 6. Both the u.v. and visible light spectra were similar to other dismutases from other sources.


Harnessing the cooperation between DNA-PK and cGAS in cancer therapies: The cooperation between DNA-PK and cGAS shapes tumour immunogenicity.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is central for the initiation of anti-tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS-STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA-dependent protein kinase (DNA-PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA-PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non-canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.


A Comparison of the Initial Cost Associated With Resection Versus Laparoscopic Radiofrequency Ablation of Small Solitary Colorectal Liver Metastasis.
The aim of this report was to perform a cost-comparison between liver resection (LR) and radiofrequency ablation (RFA). Patients with colorectal liver metastasis (CRLM)≤3 cm, who underwent LR or laparoscopic RFA between 2006 and 2015 were included in the study. Using a prospectively maintained CRLM database, clinical, oncologic, and financial parameters were compared. Sixty-three patients underwent open or laparoscopic LR, and 25 patients underwent laparoscopic RFA. No significant difference was noted in postoperative complications, readmission rate, and local recurrence rate. With a median follow-up of 40 months for RFA, and 36 months for LR (P=0.61), mean cancer-specific overall survival was 51 months for RFA and 63 months for LR (P=0.64). The median disease-free survival was 14 months for RFA, and 21 months for LR (P=0.59). The mean operating room and hospital costs were 51% and 55% higher in the LR (P<0.001, each). The results of the study suggest that in selected patients with small solitary CRLM, laparoscopic tumor ablation might offer opportunities for cost-savings compared with resection as the primary treatment. This model may suggest possible equivalent oncologic outcomes between the 2 modalities.


Predictive accuracy of partial coherence interferometry and swept-source optical coherence tomography for intraocular lens power calculation.
The purpose of this study is to compare the predictive accuracy of intraocular lens (IOL) calculations made with partial coherence interferometry (PCI, IOLMaster, version 5) and swept-source optical coherence tomography (SS-OCT, Argos). Axial length (AL), mean keratometry value (K), and anterior chamber depth (ACD) were obtained using PCI and SS-OCT optical biometers. Intraocular lens (IOL) power calculations were made using the Barret-Universal II, Haigis, Hoffer Q, SRK/T, and T2 formulas and compared the predictive accuracy between biometers. In 153 eyes (153 patients), axial length measurements made with PCI (24.65 ± 2.35 mm) and SS-OCT (24.62 ± 2.29 mm) were significantly different (P < 0.001). Corneal power (P = 0.97) and anterior chamber depth (P = 0.51) were not significantly different between biometer. The mean absolute error was not significantly different between the five IOL power calculation formulas for either PCI or SS-OCT measurements. When AL was 24.5-26.0 mm, mean absolute error derived from SS-OCT was smaller than mean absolute error derived from PCI for all five IOL power calculation formulas (all P < 0.05). In conclusion, predictive accuracy of PCI and SS-OCT were nearly the same. However, in medium-long eyes, the predictive accuracy of SS-OCT for IOL calculations was higher.


Equilibrium and local stability in a logistic matrix model for age-structured populations.
A logistic matrix model for age-structured population dynamics is constructed. This model discretizes a continuous, density-dependent model with age structure, i.e. it is an extension of the logistic model to the case of age-dependence. We prove the existence and uniqueness of its equilibrium and give a necessary and sufficient condition for the local stability of the equilibrium.


Homoeopathic versus conventional treatment of children with eczema: a comparative cohort study.
To assess, over a period of 12 months, whether homoeopathic treatment could influence eczema signs/symptoms and quality of life (QoL) compared with conventional treatment. Prospective multi-centre cohort study. Children with eczema aged 1-16 years were recruited from primary care practices. Conventional versus homoeopathic treatment. Patients (or parents) assessed eczema symptoms by numerical rating scales as well as disease-specific Atopie Lebensqualitaets-Fragebogen (ALF) and general quality of life (KINDL, KITA) at 0, 6 and 12 months. A total of 118 children were included: 54 from homoeopathic (mean age+/-S.D. was 5.1+/-3.3 years; 56% boys) and 64 from conventional practices (6.2+/-3.8 years; 61% boys). Eczema symptoms (assessed by patients or their parents) improved from 0 to 12 months for both treatment options, but did not differ between the two groups: 3.5-2.5 versus 3.4-2.1; p=0.447 (adjusted). Disease-related quality of life improved in both groups similarly. In the subgroup of children aged 8-16 years the general quality of life showed a better trend for conventional treatment compared with homoeopathic treatment (p=0.030). This observational study is the first long-term prospective investigation to compare homoeopathic and conventional treatment of eczema in children. Over a period of 12 months, both therapy groups improved similarly regarding perception of eczema symptoms (assessed by patients or parents) and disease-related quality of life.


Evaluation of the microcrystallinity of a drug substance, indomethacin, in a pharmaceutical model tablet by chemometric FT-Raman spectroscopy.
To establish a chemometric method for the precise evaluation of the microcrystallinity of indomethacin (IMC) in a pharmaceutical model tablet, based on FT-Raman spectroscopy. Standard sample powders of homogeneous mixtures of amorphous and crystalline IMC were prepared in various proportions. A calibration model for the crystallinity of IMC was constructed by partial least-square (PLS) analysis based on the multiplicative scatter correction (MSC)+second-derivative transformed Raman spectra. A calibration model for the crystallinity of IMC in a model pharmaceutical product (IMC/mannitol=1:9 wt/wt) was also constructed using homogeneous standard sample powders of various degrees of crystallinity of IMC. This technique was validated to detect to 2% an amorphous or crystalline material in IMC contained in the model product (0.2% of the total mass of the tablet). Using this technique, not only pressure-induced amorphization but also the difference in microcrystallinity of IMC at the surface and interior of a model product tablet was elucidated after compaction of the tablet. The established technique is ideally suited for precise quantification of microanalysis of drug substances and drug products, particularly at the surface and interior of the tablet.


Ratiometric fluorescent sensor with large pseudo-Stokes shifts for precise sensing and imaging of pH without interferential background fluorescence.
Endowing fluorescent pH sensors with large Stokes shifts promises to resolve interferential background fluorescence in practice, and yet few such method has been reported, owing to lack of luminescent materials with large Stokes shifts used in fluorescent sensors. Herein, we elaborately designed NaGdF4:Ce@NaGdF4:Nd@NaYF4:Eu core-double shells (CDS) lanthanide-doped fluoride nanoparticles (LFNPs), employing Gd3+-mediated energy migration and interfacial energy transfer to realize intense red and NIR emissions under 254 nm irradiation, and pseudo-Stokes shifts of which reached up to striking 361 nm and 610 nm, respectively. The CDS LFNPs collaborated with absorption-based pH indicator bromocresol green to from a novel fluorescent sensor film, and employing low-cost dual chip RGB-NIR camera to precisely record luminescence signals. On the basis of inner-filter effects, this senor system enabled accurate ratiometric read-out of pH value ranging from 5 to 6 (pKa ± 0.5), according to intensity ratios of pH-sensitive red emissions and referenced NIR emissions, avoiding common errors (e.g., fluctuant light sources). Notably, the large pseudo-Stokes shifts allowed red and NIR emissions far from the interfering background fluorescence possessing relatively small Stokes shifts, ensuring elevated signal-to-noise ratio and accurate pH determination. Therefore, the devised pH sensor system based on the CDS LFNPs exhibited sufficient accuracy in autofluorescent real samples (e.g., algae, serum), revealing a novel way of employing large pseudo-Stokes shifts to realize the background-free pH measurement and 2D imaging.


Characterization of major elements of insulin signaling cascade in chicken adipose tissue: apparent insulin refractoriness.
The role of insulin in chicken adipose tissue appears weak or questionable. In a first study, proximal and distal components of the insulin signaling cascade were characterized in abdominal adipose tissue of fasted or fed chickens for the first time. Similar measurements were performed on epididymal adipose tissue from fasted or fed rats for comparison. Tyrosine phosphorylation of IR beta subunit, IRS-1 and Shc and phosphorylation of downstream components (Akt and MAPK ERK1/2) were significantly reduced as expected by fasting in rat, but not in chicken. Phosphorylation of MAPK P38 was increased by fasting in chicken but not in rat. Phosphorylation of AMPK was not affected in the conditions investigated in either species. Whatever the nutritional state, the protein levels of IR and IRS-1 were lower in chicken than in rat, whereas those of Shc, Akt, AMPK, MAPK ERK2 and MAPK P38 were similar in both species. In fed state, PI3K activity was higher in chicken than in rat. Insulin sensitivity of insulin cascade was further investigated in chicken adipose tissue following in vivo insulin neutralization for 1 or 5h in fed chickens. Insulin privation did not alter early insulin signaling steps (IRβ, IRS-1 and Shc) or downstream elements (Akt, P70S6K, S6 ribosomal protein, AMPK, MAPK ERK2 and MAPK P38). Finally, phosphorylation of the transcription factor Creb was increased by 2-fold by 5h fasting or 5h insulin privation, most likely in response to an increase in plasma glucagon levels. Thus, insulin signaling is markedly different in chicken abdominal adipose tissue from that operating in mammals making chicken an interesting model of insulin resistance or refractoriness.


Mutalomycin, a new polyether antibiotic taxonomy, fermentation, isolation and characterization.
Mutalomycin is a new metal-complexing polyether antibiotic produced by a strain of Streptomyces mutabilis NRRL 8088. The metabolite, a monocarboxylic acid, was isolated as the sodium salt C41H69NaO12. The structure of this polyether was established by X-ray analysis of its potassium salt C41H69KO12. Mutalomycin contains six heterocyclic rings and is structurally related to nigericin. The metabolite is active against gram-positive bacteria and Eimeria tenella (chicken coccidiosis).


Photodynamic therapy in superficial bladder cancer: past, present and future.
For many reasons, such as toxicity and lack of selectivity of photosensitisers, as well as complexity of technical procedures and inconstant therapeutic results, photodynamic therapy of highly recurrent superficial bladder cancer never gained wide acceptance in the urological community. However, the 25 years of experience combined with the recent discovery of new photosensitisers, such as protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (ALA) or ALA-derivatives or hypericin open new, very interesting perspectives in this therapeutic field.


Smart Lenses with Electrically Tuneable Astigmatism.
The holy grail of reconfigurable optics for microscopy, machine vision and other imaging technologies is a compact, in-line, low cost, refractive device that could dynamically tune optical aberrations within a range of about 2-5 wavelengths. This paper presents the first electrically reconfigurable, fully elastomeric, tuneable optical lenses with motor-less electrical controllability of astigmatism in the visible range. By applying different voltage combinations to thin dielectric elastomer actuator segments surrounding a soft silicone lens, we show that the latter can be electrically deformed either radially or along selectable directions, so as to tune defocus or astigmatism, up to about 3 wavelengths. By mounting the new lenses on a commercial camera, we demonstrate their functionality, showing how electrically reconfiguring their shape can be used to dynamically control directional blurring while taking images of different targets, so as to emphasize directional features having orthogonal spatial orientations. Results suggest that the possibility of electrically controlling aberrations inherent to these smart lenses holds promise to develop highly versatile new components for adaptive optics.


Fine structure of human chorionic membrane. Ultrastructural and histochemical examinations.
Normal human term chorionic membrane was examined by electron microscopy and histochemistry. In comparison with previous studies of the human chorion, our findings showed the following new morphological aspects: (1) The cellular junctions between adjacent trophoblastic cells were made up not only of desmosomes but also of gap junctions and occasional tight junctions. (2) The epithelial basement membrane was stratified and discontinuous. (3) Besides the fibroblasts and macrophages (Hofbauer cells), the connective tissue of the human chorion also contained myofibroblasts. Histochemically, the surface coat of the plasma membrane of the chorionic epithelial cells, the microfibrils, and the proteoglycans associated with the collagen fibrils showed a positive reaction to ruthenium red. This was not so for the basement membrane of the chorionic epithelium. Since the tight junctions are seldom present in the chorionic membrane, they are apparently not significant for the paracellular protein transfer. Similar to the amnion epithelium, it is assumed that the intercellular spaces and the discontinous basement membrane of the chorionic epithelium represent a paracellular route for non-placental protein transfer. As the myofibroblasts in human amnion, we suggest that the myofibroblasts in the chorionic membrane may contribute to the protection of the fetal membranes from overdistension.


Nippostrongylus brasiliensis: histochemical changes in the composition of mucins in goblet cells during infection in rats.
Changes in the quality of mucins in jejunal goblet cells were investigated during an infection with Nippostrongylus brasiliensis in rats. At 10 days after infection, when proliferative activity in the crypts is excessive and both crypts and villi are characterized by hyperplasia of goblet cells, the histochemical composition of the population of goblet cells in comparison with controls shows a marked increase in crypt and villous goblet cells containing neutral mucins. At 15 days after infection both crypts and villi display a significant increase in goblet cells containing acid mucin and decrease in goblet cells containing neutral mucin. The acid mucins in crypt and villous goblet cells on day 15 appear to be sulphomucins predominantly, whereas in controls sialomucin-containing goblet cells dominate both in the crypts and on the villi. These experiments establish that the explusion of N. brasiliensis from the intestine of the rat coincides not only with quantitative, but also with remarkable qualitative changes in the histochemical composition of mucins in goblet cells.


Accessibility and Digital Mental Health: Considerations for More Accessible and Equitable Mental Health Apps.
Digital mental health is often touted as a solution to issues of access to mental health care. However, there has been little research done to understand the accessibility of digital mental health, especially for those with disabilities. In this piece, we define accessibility as it relates to mental health apps, describe the current state of accessibility in the digital world broadly and in mental health apps more specifically, outline why accessibility matters in mental health apps, and identify future steps to better incorporate accessibility into research and development of mental health apps.


Comparisons of different treatment outcomes in IVF/ET patients with hydrosalpinx: a retrospective study.
To explore suggestions for clinicians on the most effective treatment for hydrosalpinx undergoing IVF-ET. We reviewed 936 women with hydrosalpinx and 6715 tubal infertile women without hydrosalpinx who underwent IVF/ICSI between January 2014 and August 2019 in our center. Hydrosalpinx patients received different treatments including laparoscopic surgery (only salpingectomy and proximal tubal occlusion/ligation were included), ultrasonic-guided aspiration and hysteroscopic tubal occlusion. Outcomes were analyzed by One-way ANOVA, Chi-Square test and logistic regression. The live birth rate (LBR) of laparoscopic surgery was significantly higher compared with hydrosalpinx aspiration (48.3% vs 39.6%, p = .024). The cumulative live birth rate (CLBR) of subsequent laparoscopic surgery was significantly higher compared with subsequent hysteroscopic occlusion (65.1% vs 34.1%, p = .001) and no subsequent treatment (65.1% vs 44.9%, p < .005). Subsequent laparoscopic surgery significantly improved the CLBR of hydrosalpinx patients who received ultrasonic-guided aspiration and didn't get clinical pregnancy in fresh cycles (Odds Ratio (OR) =1.875; 95%CI = 1.041-3.378, p = .036). Laparoscopic surgery leads to significantly higher LBR than ultrasonic-guided aspiration and significantly higher CLBR than hysteroscopic occlusion and no treatment.


Impacts of the biocide chlorothalonil on biomarkers of oxidative stress, genotoxicity, and sperm quality in guppy Poecilia vivipara.
Chlorothalonil is a fungicide present in antifouling paints and other formulations used in agriculture, although studies have shown this chemical to be toxic to fish species. To clarify the deleterious effects of chlorothalonil for these non-target organisms, the present study evaluated the toxic effects of this biocide for the estuarine guppy Poecilia vivipara in terms of an acute mortality test (96 h) and the analysis of biomarkers of oxidative stress, genotoxicity, and sperm quality. The LC50 calculated for P. vivipara was 40.8 μg/L of chlorothalonil. For the analysis of biomarkers, fish were exposed (96 h) to 1 and 10 μg/L of chlorothalonil. It was observed that chlorothalonil alters the levels of pro- and antioxidants towards oxidative stress. In the gills, a negative effect on total antioxidant capacity (ACAP) was detected, while there was a reduction in the activity of glutathione S-transferase (GST) in the liver. However, levels of glutathione (GSH) and the activity and glutamate-cysteine-ligase (GCL) increased in both tissues, as a possible detoxification response. Following chlorothalonil exposure, oxidative damage measured by lipoperoxidation (LPO) significantly increased at the cellular level only (red blood cells (RBCs) and sperm cells). An increase in fluidity of membranes, reactive oxygen species concentration and micronuclei (MNs) incidence were also seen in RBCs. In sperm cells, LPO increased, while membrane and mitochondrial functionality as well as sperm motility decreased. Based on these results, chlorothalonil can be considered as a toxic compound for fish, causing genotoxicity and affecting the RBCs physiology and the fertility of males of P. vivipara.


Quick weight loss: sorting fad from fact.
This article reviews popular diets for their ability to produce effective weight loss. Most of the "evidence" for fad diets is based on anecdotal findings, theories and testimonials of short term results. The most prominent elements of fad diets are those of ritual and sacrifice. These diets offer quick and painless weight loss while allowing consumption of favourite or tasty foods, but place severe restrictions on certain other foods or food categories. Fad diets often work in the short term because they are low-kilojoule diets in disguise; that is, energy intake as a result of the diet is lower than the person's requirements. Successful long term weight loss depends on the consumption over a long period of time of less energy than is expended. The ideal approach is to increase physical activity while modifying eating behaviour to achieve a nutritionally balanced intake.


Integrating baseline MR imaging biomarkers into BCLC and CLIP improves overall survival prediction of patients with hepatocellular carcinoma (HCC).
We aimed to evaluate the independent predictive role of baseline imaging biomarkers for overall survival (OS) and transplant-free survival (TFS) in patients with HCC and assess the incremental value of these biomarkers to current staging systems. In this retrospective IRB approved study, the clinical, laboratory, and imaging parameters of 304 HCC patients were collected. Cox regression model was utilized to identify the potential predictors of survival. Recursive partitioning test was utilized to identify the optimal ADC cutoff for stratifying patients' OS. Patients were stratified based on Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP). Binary ADC value (above vs. below the cutoff) and tumor margin (well- vs. ill-defined) were integrated into BCLC and CLIP. OS and TFS was compared for patients based on standard criteria with and without imaging biomarkers. At baseline, patients with low tumor ADC and well-defined tumor margin (favorable imaging biomarkers) had longer survival, as compared to those with high ADC and ill-defined tumor margin (unfavorable imaging biomarkers) (median OS of 43 months vs. 7 months, respectively) (p < 0.001). Tumor ADC and tumor margin remained strong independent predictors of survival after adjustment for demographics, BCLC and CLIP staging, and tumor burden. Incorporating ADC and tumor margin improved performance of OS prediction by 9% in BCLC group and 6% in CLIP group. Incorporating ADC and tumor margin to current staging systems for HCC significantly improve prediction of OS and TFS of these criteria. • ADC and tumor margin are predictors of overall survival in HCC patients, independent of clinical, laboratory, and other imaging variables. • Adding ADC and tumor margin improved the prognostic value of BCLC and CLIP criteria by 9% and 6%, respectively. • High ADC and ill-defined tumor margin at baseline predicted poor survival, regardless of patient's liver function and general health status.


Comparative Scanning Electron Microscopic Study of the Marginal Adaptation of Four Root-End Filling Materials in Presence and Absence of Blood.
The aim of this study was to evaluate marginal adaptation of mineral trioxide aggregate (MTA), calcium enriched mixture (CEM) cement, Biodentine and BioAggregate in presence of normal saline and human blood. In this in-vitro experimental study, 80 extracted single-rooted human teeth were instrumented and filled with gutta-percha. After resecting the root-end, apical cavity preparation was done and the teeth were randomly divided into 4 groups (N=20)(a total of 8 subgroups). Root-end filling materials were placed in 3mm root-end cavities prepared ultrasonically. Half the specimens in each group were exposed to normal saline and the other half to fresh whole human blood. After 4 days, epoxy resin replicas of the apical portion of samples were fabricated and scanning electron microscopy (SEM) analysis was performed to find gaps in the adaptation of the root-end filling materials at their interface with dentin. The Kruskal-Wallis and Mann-Whitney tests were used for statistical analysis of data with P<0.05 as the limit of significance. There were no significant differences in marginal adaptation of the 8 tested groups (P>0.05). Based on the results, blood contamination does not affect the marginal adaptation of MTA, CEM cement, Biodentine or BioAggregate.


Label-free and ratiometric detection of nuclei acids based on graphene quantum dots utilizing cascade amplification by nicking endonuclease and catalytic G-quadruplex DNAzyme.
Herein, we report a ratiometric fluorescence assay based on graphene quantum dots (GQDs) for the ultrasensitive DNA detection by coupling the nicking endonuclease assisted target recycling and the G-quadruplex/hemin DNAzyme biocatalysis for cascade signal amplifications. With o-phenylenediamine acted as the substrate of G-quadruplex/hemin DNAzyme, whose oxidization product (that is, 2,3-diaminophenazine, DAP) quenched the fluorescence intensity of GQDs (at 460nm) obviously, accompanied with the emergence of a new emission of DAP (at 564nm). The ratiometric signal variations at the emission wavelengths of 564 and 460nm (I564/I460) were utilized for label-free, sensitive, and selective detection of target DNA. Utilizing the nicking endonuclease assisted target recycling and the G-quadruplex/hemin DNAzyme biocatalysis for amplified cascade generation of DAP, the proposed bioassay exhibited high sensitivity toward target DNA with a detection limit of 30fM. The method also had additional advantages such as facile preparation and easy operation.


Endoscopic management of chronic pancreatitis.
Endoscopic management of CP is generally safe, minimally invasive, and often effective for years, does not hinder further surgery, and can be repeated. It should be applied as a first-line approach to improving the clinical condition of patients with this chronic disease. The best results are obtained when endoscopic treatment is performed early in the course of CP. Proper patient selection, adequate expertise, and a supporting multidisciplinary infrastructure are essential. New technologies will continue to be developed and to extend the scope of therapeutic pancreatic endoscopy.


McIndoe procedure for vaginal agenesis: results and complications.
During the 10-year interval from 1976 through 1985, 50 patients with congenital absence of the vagina underwent McIndoe vaginoplasty at our institution. The medical records of these patients were retrospectively reviewed, and additional information was obtained through a survey of the patients. The mean duration of follow-up was 6.5 years. Two rectovaginal fistulas and one graft failure were among the complications that occurred. Five patients required additional reconstructive vaginal operations. Operative vaginoplasty was considered functionally successful by 40 of the 47 patients (85%) who responded to the survey, yet only 36 of these 40 (90%) had remained coitally active by the time of the survey. Recognizing the potential for complications, the need for long-term follow-up and care of the neovagina, and the less-than-perfect results achieved, we continue to consider the McIndoe operation as the procedure of choice for most patients with vaginal agenesis.


Equine complement activation as a mechanism for equine neutrophil migration in Onchocerca cervicalis infections.
Extracts of Onchocerca cervicalis, an equine parasite, were incubated with radiolabeled equine neutrophils and neutrophil migration was assessed for factors derived from the parasite itself or for host-derived factors after incubation of these same parasite extracts with equine serum. No stimulus for cell migration was observed in saline extracts of adult worms, uterine microfilariae, or skin microfilariae at any dosage tested. However, after incubation of saline extracts with fresh normal equine sera a marked stimulus for neutrophil migration was observed. Ablation of this biologic activity was noted if equine serum had been pretreated with 10 mM EDTA or heated at 50 and 56 degrees C for 30 min. However, if equine serum was treated with 10 mM EGTA, made 10 mM with respect to Mg2+ ions, no reduction in neutrophil migration was noted, thereby suggesting that the equine alternative complement pathway was the means of generating the serum-derived neutrophil migration stimulus. Preliminary gel filtration of the activated equine serum suggested that although there was a neutrophil stimulus associated with a C5a-like molecule, other complement or serum components could be involved.


Draft Genome Sequence of Shiga Toxin-Negative Escherichia coli O157:H7 Strain C1-057, Isolated from Feedlot Cattle.
Escherichia coli O157:H7 is one of the major foodborne pathogens in the United States. We isolated a variant Shiga toxin-negative E. coli O157:H7 strain from feedlot cattle. We report here the draft genome sequence of this isolate, consisting of a chromosome of ~4.8 Mb and two plasmids of ~96 kb and ~14 kb.


Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease.
The aim of this study was to determine the clinical features and frequencies of genetic subtypes in a series of patients with Charcot-Marie-Tooth (CMT) disease from Eastern China. Patients were divided into three subtypes, CMT1, CMT2 and hereditary neuropathy with liability to pressure palsy (HNPP), according to their electrophysiological manifestations. Multiplex ligation-dependent probe analysis (MLPA) was performed to detect duplications/deletions in the PMP22 gene. The coding regions and splice sites of the GJB1, MPZ, MFN2 and GDAP-1 genes were determined by direct sequencing. Among the 148 patients in the study, 37.2% of the cases had mutations in genes assessed. The mutation detection rate was higher in patients with family histories than in spontaneous cases. PMP22 duplication (13.5%) was predominant in this group of patients, followed by PMP22 deletion (11.5%), and point mutations in GJB1 (8.8%), MPZ (2.0%) and MFN2 (0.7%). Three novel mutations (c.151T>C and c.310 A>G in GJB1 and c.1516 C>G in MFN2) were detected. A small deletion in PMP22 exon 4 was detected in a patient with severe CMT1. Genetic tests have great value in CMT patients with family histories. The frequency of PMP22 duplications was lower in Asian patients than in others. We suggest that genetic testing strategies in CMT patients should be primarily based on electromyography data.


RETRACTED: The interplay between reactive oxygen and nitrogen species contributes in the regulatory mechanism of the nitro-oxidative stress induced by cadmium in Arabidopsis.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor, after consultation with the corresponding author Dr. Shiliang Liu due to image issues. The article reused several images from the author's paper published in Environmental Pollution 239 (2018) 53-68 (which has been retracted due to image issues): Figures 1c, 1d, 2a, 2b, 2c, 4a, 9a and 9b. The article also plagiarized part of a paper from other authors that had appeared in Plant Physiology, 150, 229-243 (2009). The images that were reused were Fig 5 a, 5c, 5e and 5 g. This was brought to the editors' attention via a letter to the editor. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.


Psychosocial functioning in adolescents with perinatal HIV infection receiving highly active antiretroviral therapy.
With effective highly active antiretroviral therapy (HAART), perinatally HIV-infected children are living longer through adolescence. We conducted a cross-sectional study of perinatally HIV-infected adolescents, aged 11 to 18 years. Demographically matched controls were also enrolled. The adolescents completed the Youth Self-Report (YSR), while the caregivers filled out the Child Behavior Checklist (CBCL), to determine emotional and behavioral problems. The sample included 50 HIV-infected adolescents and 56 controls. The internalizing problem scores from the YSR were significantly higher in the HIV-infected group than those in the control group (13.76 versus 9.95, P = .02). The total competence scores, from both the self-report and the caregiver report in the HIV-infected group, were significantly lower than those of the control group (P = .005 and .001). Although HAART has prolonged the survival of HIV-infected children, they remain at increased risk of psychosocial problems as well as impaired social functioning.


Notch-dependent DNA cis-regulatory elements and their dose-dependent control of C. elegans stem cell self-renewal.
A long-standing biological question is how DNA cis-regulatory elements shape transcriptional patterns during metazoan development. Reporter constructs, cell culture assays and computational modeling have made major contributions to answering this question, but analysis of elements in their natural context is an important complement. Here, we mutate Notch-dependent LAG-1 binding sites (LBSs) in the endogenous Caenorhabditis elegans sygl-1 gene, which encodes a key stem cell regulator, and analyze the consequences on sygl-1 expression (nascent transcripts, mRNA, protein) and stem cell maintenance. Mutation of one LBS in a three-element cluster approximately halved both expression and stem cell pool size, whereas mutation of two LBSs essentially abolished them. Heterozygous LBS mutant clusters provided intermediate values. Our results lead to two major conclusions. First, both LBS number and configuration impact cluster activity: LBSs act additively in trans and synergistically in cis. Second, the SYGL-1 gradient promotes self-renewal above its functional threshold and triggers differentiation below the threshold. Our approach of coupling CRISPR/Cas9 LBS mutations with effects on both molecular and biological readouts establishes a powerful model for in vivo analyses of DNA cis-regulatory elements.


Primary total knee arthroplasty using the Genesis I total knee prosthesis: a 5- to 10-year follow-up study.
This study analyzed the data from 82 primary total knee arthroplasties performed in 74 patients using the Genesis Total Knee Arthroplasty System. Ten men and 64 women with a mean age of 78 years were evaluated at a mean follow-up of 7 years. Seventy procedures used cemented femoral and tibial components, and 12 used cementless femoral and tibial components. The preoperative mean HSS score was 39. At the most recent follow-up, the mean HSS score increased to 92. The mean preoperative range of motion was 82 degrees and increased to 108 at the most recent follow-up. Clinically, there were 63 excellent (77%), 14 good (17%), 4 fair (5%), and 1 poor (1%) result.


A cost-benefit analysis for use of large SNP panels and high throughput typing for forensic investigative genetic genealogy.
Next-generation sequencing (NGS), also known as massively sequencing, enables large dense SNP panel analyses which generate the genetic component of forensic investigative genetic genealogy (FIGG). While the costs of implementing large SNP panel analyses into the laboratory system may seem high and daunting, the benefits of the technology may more than justify the investment. To determine if an infrastructural investment in public laboratories and using large SNP panel analyses would reap substantial benefits to society, a cost-benefit analysis (CBA) was performed. This CBA applied the logic that an increase of DNA profile uploads to a DNA database due to a sheer increase in number of markers and a greater sensitivity of detection afforded with NGS and a higher hit/association rate due to large SNP/kinship resolution and genealogy will increase investigative leads, will be more effective for identifying recidivists which in turn reduces future victims of crime, and will bring greater safety and security to communities. Analyses were performed for worst case/best case scenarios as well as by simulation sampling the range spaces with multiple input values simultaneously to generate best estimate summary statistics. This study shows that the benefits, both tangible and intangible, over the lifetime of an advanced database system would be huge and can be projected to be for less than $1 billion per year (over a 10-year period) investment can reap on average > $4.8 billion in tangible and intangible cost-benefits per year. More importantly, on average > 50,000 individuals need not become victims if FIGG were employed, assuming investigative associations generated were acted upon. The benefit to society is immense making the laboratory investment a nominal cost. The benefits likely are underestimated herein. There is latitude in the estimated costs, and even if they were doubled or tripled, there would still be substantial benefits gained with a FIGG-based approach. While the data used in this CBA are US centric (primarily because data were readily accessible), the model is generalizable and could be used by other jurisdictions to perform relevant and representative CBAs.


Multisensory temporal integration: task and stimulus dependencies.
The ability of human sensory systems to integrate information across the different modalities provides a wide range of behavioral and perceptual benefits. This integration process is dependent upon the temporal relationship of the different sensory signals, with stimuli occurring close together in time typically resulting in the largest behavior changes. The range of temporal intervals over which such benefits are seen is typically referred to as the temporal binding window (TBW). Given the importance of temporal factors in multisensory integration under both normal and atypical circumstances such as autism and dyslexia, the TBW has been measured with a variety of experimental protocols that differ according to criterion, task, and stimulus type, making comparisons across experiments difficult. In the current study, we attempt to elucidate the role that these various factors play in the measurement of this important construct. The results show a strong effect of stimulus type, with the TBW assessed with speech stimuli being both larger and more symmetrical than that seen using simple and complex non-speech stimuli. These effects are robust across task and statistical criteria and are highly consistent within individuals, suggesting substantial overlap in the neural and cognitive operations that govern multisensory temporal processes.


Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer.
Clinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer. The validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5-10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan-Meier curves were used with associated 10-year DR risks (%). 2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78-2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32-2.56)). The 10-year DR risks were 2.9% (1.9-4.5), 7.2% (5.3-9.9), and 12.9% (10.0-16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2-6.7), 6.9% (4.4-10.8), and 11.1% (7.4-16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded. The CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.


Effect of treatment of transverse maxillary deficiency using rapid palatal expansion on oral health-related quality of life in children: A randomized controlled trial.
This trial aimed to longitudinally evaluate the effect of the treatment of transverse maxillary deficiency using rapid palatal expansion (RPE) on self-perceived oral health-related quality of life (OHRQOL) in children. Eighty participants aged 8-10 years with transverse maxillary deficiency and bilateral posterior crossbite were randomly assigned to 2 groups (n = 40 each): a group treated with RPE using hyrax-type appliances and a nontreated control group. OHRQOL was assessed by using the Child Perceptions Questionnaire for 8-10-year-olds at 4 times: before RPE, during RPE (T1), at the end of RPE (T2), and 1 month after the appliance removal (T3). Generalized mixed models were used for data analysis (α = 0.05). Both groups exhibited similar demographic characteristics and OHRQOL scores at baseline. All participants completed the study. RPE had a time-dependent effect on OHRQOL. At T1 and T2, this therapy is expected to increase the overall OHRQOL scores by 1.17 times (ie, ∼17% increase; T1 95% confidence interval [CI], 1.08-1.26; T2 95% CI, 1.09-1.27; P = 0.001). In contrast, the overall OHRQOL scores at T3 are expected to be 0.28 times the baseline scores (ie, ∼72% reduction; T3 95% CI, 0.26-0.31; P = 0.001). All individual domains of the OHRQOL evidenced a positive impact of treatment at T3 (P = 0.001). Only the oral symptoms and social well-being domains showed a significantly negative impact of the treatment at T1 and T2. Correction of the transverse maxillary deficiency by RPE in children aged 8-10 years improves OHRQOL. There is a temporary worsening of OHRQOL during the treatment of this condition using RPE. This trial was not registered. The protocol was not published before trial commencement. This study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil, Financing Code 001.


Synthesis of axially Schiff base new substituted silicon phthalocyanines and investigation of photochemical and sono-photochemical properties.
Sono-photodynamic therapy, which show a very high therapeutic effect compared to photodynamic therapy, is a newer method for anticancer treatments. However, unlike Photodynamic therapy (PDT), the number of studies measuring the efficiency of singlet oxygen for the Sono-photodynamic therapy (SPDT) method is quite insufficient in the literature. Therefore, this study aimed to synthesis novel axially substituted silicon (IV) phthalocyanines containing imine groups with improved photochemical properties and then reported the efficiency of singlet oxygen by both of photochemical and sono-photochemical studies. According to the results, the substituent group increased the singlet oxygen yield of silicon (IV) phthalocyanine dichloride and the sono-photochemical effect increased the singlet oxygen yields (ΦΔ=0.35 for 2a, 0.69 for 2b in photochemical study, 0.78 for 2a, 0.97 for 2b in sono-photochemical study).This article may pave the way to achieve high singlet oxygen efficiency.


Bilirubin: its role in cytoprotection against oxidative stress.
Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, in the last 10 years, in vitro and in vivo studies, have demonstrated that bilirubin exhibits potent anti-oxidant properties preventing the oxidative damage triggered by a wide range of oxidant-related stimuli. Therefore, the idea of a beneficial and physiological role for bilirubin in cytoprotection against short and long-lasting oxidant-mediated cell injury is highlighted here.


Clinicopathologic significance of combined hepatocellular-cholangiocarcinoma with stem cell subtype components with reference to the expression of putative stem cell markers.
To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-like 1 homolog (DLK1), as well as putative stem cell markers, such as NCAM/CD56 and CD133. In this study we examined the expression of stem cell markers using immunohistochemistry. Thirty-six cases of combined HC-CC were subclassified into 24 cases, with more than 5% stem cell features (group B) and 12 cases with less than 5% stem cell areas (group A). The postoperative overall survival rate was worse for group B than for group A. DLK1 was frequently expressed in group B cases compared with group A, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma cases. The 2010 WHO classification seems important for elucidating the pathogenesis of stem cell-related liver cancers.


Regulated Gene Therapy.
Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.


Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment.
Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.


Impact of economic recessions on healthcare workers and their crises' responses: study protocol for a systematic review of the qualitative and quantitative evidence for the development of an evidence-based conceptual framework.
During economic recessions, health professionals face reduced income and labour opportunities, hard conditions often exacerbated by governments' policy responses to crises. Growing evidence points to non-negligible effects on national health workforces and health systems-decrease in motivation, burnout, migration-arising from the combination of crisis-related factors. However, no theoretical conceptualisation currently exists framing the impacts recessions have on human resources for health (HRH), or on their reactions. This paper lays out a protocol for a systematic review of the existing qualitative, quantitative and mixed-method evidence on the economic recessions and HRH; results from the review will be used to develop a conceptual framework linking existing theories on recessions, austerity measures, health systems and population health, with a view of informing future health policies. Eight relevant databases within the health, health systems, multidisciplinary and economic literature will be searched, complemented by secondary searches and experts' input. Eligible studies will present primary quantitative or qualitative evidence on HRH impacts, or original secondary analyses. We will cover the 1970-2019 period-the modern age of global economic recessions-and full texts in English, Spanish, Italian, French, Portuguese or Greek. Two reviewers will independently assess, perform data extraction and conduct quality appraisal of the texts identified. A 'best-fit' framework synthesis will be applied to summarise the findings, using an a priori, theoretically driven framework. That preliminary framework was built by the research team to inform the searches, and will be appraised by external experts. In addition to peer-reviewed publications, the new framework will be presented in global health systems research conferences and inform regional policy dialogue workshops in Latin America on economic recessions and health systems. CRD42019134165.


Reversible end-of-life indicator leading to erroneous pacemaker replacement-pitfalls of telemetry.
In several modern pacemakers, end-of-life (EOL) is indicated by a single-step rate drop, which is initiated by a voltage-sensitive electronic switch. This switch may also be activated by other causes, such as very short voltage drops, low temperatures, and electrocautery. We report a case in which a Cordis 233 F Sequicor II pulse generator was operating at 51.6 bpm in VOO mode at the time of implantation. As telemetry seemed to indicate that back-up pacing (the EOL indicator in this model) was "off," it was erroneously assumed that the pacemaker was not working properly. The unit was replaced by another impulse generator. At laboratory testing, the pacemaker was within specifications, when back-up pacing was separately programmed off. In conclusion, physicians should be aware of the new phenomenon of reversible EOL indicators, and that they may not rely on telemetry in this respect. Future pacemakers should incorporate a telemetry message which prevents similar misunderstandings.


Analysis of dinitro- and amino-nitro-toluenesulfonic acids in groundwater by solid-phase extraction and liquid chromatography-mass spectrometry.
A reversed-phase LC-MS method with quadrupole-time of flight (QTOF) detection has been developed for the determination of four dinitro-toluenesulfonic acids and two amino-nitro-toluenesulfonic acids in groundwater. The analytes were separated by HPLC with 0.1% ( v/ v) formic acid as mobile phase modifier compatible with mass spectrometric detection. QTOF-MS analysis with negative ion electrospray ionization afforded good selectivity and sensitivity for analysis of the dinitro- and amino-nitro-toluenesulfonic acids. Structure elucidation and confirmation were accomplished by tandem mass spectrometry. Characteristic ions resulting from the loss of NO, NO(2), and SO(2) from the [M-H](-) ions were detected. An intense fragment ion at m/ z 80 representing the [SO(3)](-) ion was detected for all dinitro- and amino-nitro-toluenesulfonic acids. Solid-phase extraction using a co-polymer cartridge was developed for preconcentration of the analytes from water. Good recovery (>85%) was achieved when 0.1% formic acid was added into the water samples before extraction. Method detection limits ranged from 10 to 76 ng L(-1) for the targeted compounds when 10 mL water was analyzed. Groundwater samples collected from wells close to a former ammunition plant in Stadtallendorf, Germany, were analyzed for the dinitro- and amino-nitro-toluenesulfonic acids.


Adsorption and desorption of phthalic acid esters on graphene oxide and reduced graphene oxide as affected by humic acid.
The implications of humic acid (HA) regarding surface properties of graphene materials and their interactions with phthalic acid esters (PAEs) are not vivid. We report the role of HA on graphene oxide (GO) and reduced graphene oxide (RGO) for sorption-desorption behavior of PAEs. Besides higher surface area and pore volume, the hydrophobic π-conjugated carbon atoms on RGO ensured prominent adsorption capacity towards PAEs in comparison to hydrophilic GO, highlighting the hydrophobic effect. After adjusting for the hydrophobic effect by calculating the hexadecane-water partition coefficient (KHW) normalized adsorption coefficient (Kd/KHW), the dimethyl phthalate (DMP) molecule portrayed a higher adsorption affinity towards RGO by π-π electron donor-acceptor (EDA) interaction for active sites on graphene interface via sieving effect. In contrast to RGO, the weak π-π EDA interactions and H-bonding was observed between the carbonyl groups of PAEs and oxygen containing functional groups on GO. There was no obvious change in morphologies of GO and RGO before and desorption as revealed by SEM and TEM images, as desorption hysteresis did not occur in all conditions. The presence of HA also resulted in shielding effect thereby decreasing the adsorption rate and capacity of diethyl phthalate (DEP) on GO and RGO, while it had little effect on DMP, probably due to the adsorbed HA as new active sites. The desorption of DMP and DEP on RGO in presence of HA was quick and enhanced. These results should be important for evaluating the fate and health risk of graphene materials and PAEs in the environment.


Small mucus-granule-containing ciliated cells in the human gastric mucosa: a transitional form to metaplastic ciliated cells.
Ciliated cells were found in the gastric mucosa in close association with intestinal metaplasia, mainly in the pyloric mucosa, of Japanese patients. The occurrence of ciliated cells is believed to be an acquired phenomenon and is considered to be a type of metaplasia; the term "ciliated metaplasia" is used to describe this phenomenon. Ciliated cells are found in the basal part of the glands among normal-looking mucous cells, mucous neck cells and neuroendocrine cells, but never on the surface or in foveolar epithelium. In ciliated cell-containing glands, mitoses were noted in the neck region and the ultrastructural features of these cells were identical to those of undifferentiated neck cells. However, cell metaplasia from undifferentiated cells to metaplastic ciliated cells has never been demonstrated previously. The small mucus-granule-containing ciliated cells found in our present study may arise subsequent to division of undifferentiated neck cells into mucous cells with some daughter cells then exhibiting differentiation characteristics specific to ciliated cells. Thus they contain a mixture of both small mucus granules and numerous basal bodies and cilia, at the same time as a transitional form.


Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea-pig.
1. Neuropeptide Y (NPY) is one of the most potent stimulants of food intake. It has been debated which receptor subtype mediates this response. Initially Y(1) was proposed, but later Y(5) was announced as a 'feeding' receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea-pig. When infused intracerebroventricularly, NPY dose-dependently increased food intake. 2. PYY, (Leu(31),Pro(34))NPY and NPY(2 - 36) stimulated feeding, whereas NPY(13 - 36) had no effect. These data suggest that either Y(1) or Y(5) receptors or both may mediate NPY induced food intake in guinea-pigs. 3. The Y(1) receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar affinity for the Y(1) receptor (K(i) values 1.1+/-0.2 nM and 5.6+/-0.9 nM, respectively), but low affinity for the Y(2) or Y(5) receptors. When guinea-pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited. 4. The Y(5) antagonist, CGP 71683A had high affinity for the Y(5) receptor (K(i) 1.3+/-0.05 nM) without having any significant activities at the Y(1) and Y(2) receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated. 5. The present study shows that NPY stimulates feeding in guinea-pigs through Y(1) and Y(5) receptors. As the guinea-pig is very distantly related to the rat and mouse, this suggests that both Y(1) and Y(5) receptors may mediate NPY-induced hyperphagia also in other orders of mammals.


"It's a preventable type of harm": Evidence-based strategies to prevent sexual abuse in schools.
The last two decades have seen global public recognition of the scale and impact of adult-perpetrated institutional child sexual abuse. A sizeable body of knowledge about generalized safeguarding measures has since been generated to inform organizations' prevention efforts. Apparent in the extant literature, however, is a notable lack of evidence-based and context-specific prevention strategies targeting perpetration in distinct institutional environments. This absence extends to educational settings where most reported contemporary cases occur or originate. The recommendations outlined in this article contribute to this gap. Derived from empirical findings establishing the role of context-specific rather than person-specific factors, a range of prevention strategies framed by Situational Crime Prevention are proposed for secondary educational settings. These recommendations are supplemented by the unique insights of interviewed experts with specialist professional knowledge. Recommendations center around targeting features of the environment such as high-risk locations, available guardians, and intimacy-promoting situations available in educational contexts. Taken together, this robust prevention and control agenda can create conditions for safer educational environments.


The expression of prepulse inhibition of the acoustic startle reflex as a function of three pulse stimulus intensities, three prepulse stimulus intensities, and three levels of startle responsiveness in C57BL6/J mice.
Using the acoustic startle reflex, prepulse inhibition (PPI) is typically demonstrated by the interaction between two auditory stimuli presented in close temporal proximity. When a startle-eliciting pulse stimulus is shortly preceded by a weak prepulse stimulus, the reaction to the former is attenuated in comparison to when the pulse stimulus is presented alone. The present experiment evaluated the influence of different prepulse and pulse intensities upon the expression of PPI by additionally taking into account individual differences in startle reactivity. To this end, we subdivided a cohort of 102 mice into three subsets of equal size differing in startle responsiveness, and evaluated PPI using three levels of prepulse stimulus in combination with three intensities of pulse stimulus. Our results revealed additive as well as complex interactive effects amongst individual's reactivity, pulse intensity and prepulse intensity. At the same time, additional issues concerning the quantification of PPI are highlighted, especially when startle reactivity differs considerably between comparison groups. We concluded that the variation in pulse intensity represents a valuable addition to PPI assessment in general, and especially in genetically modified mice.


Reports of two cases of autoimmune thyroiditis while receiving anticonvulsant therapy.
Two cases, one a 15-year-old girl and the other a 12-year-old girl, with goitrous hypothyroidism associated with elevated anti-DNA and antithyroid antibodies are reported. Abnormalities were noticed 1 year and 3 months and 5 years after the start of anticonvulsant therapy in case 1 and case 2, respectively. Alternation of drug (Valproate from ethosuximide) in case 1 resulted in disappearance of the goitre, and the thyroid function tests became normal. The titers of the antithyroglobulin and the antimicrosomal antibodies were reduced (below 1:100) from 1:400 and 1:1600, respectively. Discontinuance of anticonvulsant therapy and replacement therapy with desiccated thyroid in case 2 resulted in clinical improvement, reduction of antithyroglobulin antibody from 1:6400 to 1:400 and of antimicrosomal antibody from 1:409,600 to 1:25,600, and the thyroid function tests becoming normal. The present observations suggest that the anticonvulsants may induce or exacerbate autoimmune mechanisms in certain thyroid diseases.


Transcriptome-wide analysis of basic helix-loop-helix transcription factors in Isatis indigotica and their methyl jasmonate responsive expression profiling.
Jasmonates (JAs) act as conserved elicitors of plant secondary metabolism. JAs perception triggers extensive transcriptional reprogramming leading to activation of the entire metabolic pathways. The family of basic helix-loop-helix (bHLH) transcription factors (TFs) has essential roles in JA signaling; however, little is known about their roles in regulation of secondary metabolites in Isatis indigotica. In this study, we identified 78 putative IibHLH sequences using the annotation of I. indigotica transcriptome. The identified proteins were characterized based on phylogenetic and conserved motif analyses. Using RNA sequencing, 16 IibHLHs showed significant positive response to MeJA (methyl jasmonate) at 1h, indicating their roles as early signaling events of JA-mediated transcriptional reprogramming. Ten IibHLHs presented co-expression pattern with biosynthetic pathway genes, suggesting their regulating role in secondary metabolite synthesis. These gene expression profiling data indicate that bHLHs can be used as candidate genes in molecular breeding programs to improve metabolite production in I. indigotica.


Characterization of novel cytochrome P450 2E1 knockout rat model generated by CRISPR/Cas9.
A bacterial CRISPR-associated protein-9 nuclease (CRISPR/Cas9) from Streptococcus pyogenes has generated considerable excitement as a new tool to edit the targeted genome. Cytochrome P450 (CYP) 2E1 not only plays an important role in the xenobiotic metabolism and chemical toxicity, but also is involved in many kinds of diseases, such as alcoholic liver diseases and diabetes. Despite its importance, few animal models are used to predict CYP2E1 properties in physiology, pathology, as well as carcinogen activation. To establish a novel model for investigating the functions of CYP2E1 in vivo, this study has successfully generated the Cyp2e1 knockout (KO) rat model without detectable off-target effects using CRISPR/Cas9 system. The Cyp2e1 KO rats were viable and fertile and did not display any obvious physiological abnormities. The absent expression of CYP2E1 in KO rats also resulted in inactive behaviors in the metabolism of CYP2E1 substrates. The Cyp2e1 KO rats as a novel and available rodent animal model provide a powerful tool for the study of CYP2E1 in the chemical metabolism, toxicity, carcinogenicity, and its core factor in drug-drug interactions.


Initial results of a first-in-human study on the PlasmaWire™ System, a new radiofrequency wire for recanalization of chronic total occlusions.
To examine the safety, efficacy, and efficiency of the PlasmaWireTM System to recanalize coronary chronic total occlusions (CTO) using controlled ablation inside the CTO. The PlasmaWireTM System is a new bipolar radiofrequency (RF) wire system utilizing plasma-mediated ablation to facilitate wire crossing in CTOs. Two independent PlasmaWireTM wires are used in tandem for channel creation by applying RF energy between the tips so as to localize the ablation. Prospective, nonrandomized, single-arm, multicenter study in seven patients with CTOs indicated for percutaneous coronary intervention (PCI). In this study, both wires were antegradely delivered to the distal end of CTO for antegrade re-entry in two cases and bidirectionally (antegrade and retrograde) delivered to the CTO for retrograde re-entry in five cases. In all cases, channel creation was achieved within a few seconds and was confirmed on angiogram or intravascular ultrasound (IVUS) and CTO recanalization was successfully achieved without any major adverse cardiac and cerebrovascular events (MACCE) or other minor complications. The clinical follow-up showed no clinical event at 1 month. The PlasmaWireTM System was shown to be safe and effective in obtaining CTO recanalization through a re-entry channel utilizing plasma-mediated ablation while reducing procedure time. The PlasmaWire™ System is a new bi-polar RF wire system utilizing plasma-mediated ablation for channel creation to facilitate CTO recanalization. This first-in-human study in which seven patients were enrolled was conducted to demonstrate the safety, efficacy, and efficiency of this system for CTO recanalization. Channels through the CTOs were successfully created within a few seconds by applying RF energy between the tips of two independent PlasmaWireTM wires and recanalization was achieved in all cases without any complication. The PlasmaWireTM System may safely facilitate CTO recanalization with less vessel injury and improve initial results of CTO PCI while reducing procedure time.


Identification and isolation of core histones from Schizosaccharomyces pombe.
Core histones have been isolated from Schizosaccharomyces pombe and compared electrophoretically to core histones from Saccharomyces cerevisiae and rat liver. The molecular masses of all cognate histones examined were found to be very similar as determined by SDS gel electrophoresis. Histones H3, H2A and H2B from Sch. pombe migrated almost identically to their respective counterparts from S. cerevisiae as determined by acid/urea gel electrophoresis. Two-dimensional gel electrophoresis with a Triton X-100 acid/urea gel in the first dimension followed by an SDS gel in the second dimension was used to separate Sch. pombe histones from contaminating ribosomal proteins.


HILPDA-mediated lipidomic remodelling promotes radiotherapy resistance in nasopharyngeal carcinoma by accelerating mitophagy.
Radiotherapy resistance is a major obstacle to nasopharyngeal carcinoma (NPC) therapy and contributes to tumour recurrence and metastasis. Lipid metabolism is a key regulatory mechanism in cancer biology; however, its role in NPC radiotherapy resistance remains unclear. In this study, we identified hypoxia-inducible lipid droplet-associated protein (HILPDA) as a newly discovered regulator of radioresistance that induces not only lipid droplet (LD) formation but also intracellular lipid remodelling, notably changing mitochondrial cardiolipin (CL) levels. Additionally, we found that the upregulation of CL promotes mitophagy in response to irradiation exposure. Mechanistically, HILPDA inhibits PINK1-mediated CLS1 ubiquitination and degradation. The combination of a mitophagy inhibitor and irradiation significantly increases the radiosensitivity of NPC cells. Human cancer-derived data confirmed that the HILPDA-CLS1 pathway promotes NPC radioresistance. Collectively, these findings suggest that HILPDA plays a critical role in promoting NPC radioresistance and might be targeted to overcome radiotherapeutic resistance in NPC patients in the clinic.


Percutaneous gallbladder drainage as a bridge to concomitant coronary artery bypass grafting and laparoscopic cholecystectomy.
A 74-year-old woman with left main and three-vessel coronary artery disease was scheduled for off-pump coronary artery bypass grafting and developed acute severe cholecystitis preoperatively. Percutaneous gallbladder drainage was placed to achieve gallbladder decompression and infection control. Two weeks later, CABG and laparoscopic cholecystectomy were successfully performed at the same time.


Structural investigation of deleterious non-synonymous SNPs of EGFR gene.
Epidermal Growth Factor Receptor (EGFR), a member of the receptor tyrosine kinase family has shown to be implicated in the development and progression of various cancers due to mutations in the tyrosine kinase domain (TKD). It is important to understand the functional significance of amino acid variation occurring within TKD due to non-synonymous Single Nucleotide Polymorphism (nsSNPs). Therefore, we have evaluated the influence of nsSNPs on the structure of EGFR-TKD using computational methods. Out of 2,493 SNPs in the EGFR gene, only 41 were found to be non-synonymous. In silico evaluation of these nsSNPs using a sequence based SIFT tool and structure based PolyPhen algorithm revealed that 13 nsSNPs disrupted the conformation of EGFR-TKD. Protein stability analysis using CUPSAT, I-mutant2.0 and iPTree-STAB identified 6 mutants that are less stable than the wild structure. Thereafter, to evaluate the structural impact of 5 mutants (G719A, P733L, V742A, S768I and H773R) the molecular dynamics (MD) simulation for 2 ns was performed. The MD trajectories showed that the native EGFR was stabilized after 0.9 ns while the stability of mutants was achieved after longer simulation. The RMSF profile of P-loop and A-loop shows an increased flexibility for all the mutants. We also observed that the 3 mutants (V742A, P733L and H773R) showed large root mean square deviation (2.075, 2.59 and 2.752 Å respectively) compared to the native EGFR. Further docking studies indicate that gefitinib can be administered for combating cancer occurring due to presence of these mutations.


Mercuric chloride induces increases in both cytoplasmic and nuclear free calcium ions through a protein phosphorylation-linked mechanism.
The mechanism of the lymphocyte stimulatory action of sulfhydryl group-reactive mercuric ions was studied with respect to its potential ability to induce a protein tyrosine phosphorylation-linked signal for mobilization of free Ca2+ into cytoplasm and nucleus of the cell. Exposure of human leukamic T cell line (Jurkat) cells to high (1 mM) and low (0.01 mM) concentrations of HgCl2 induced tyrosine phosphorylation of multiple proteins in a concentration-dependent manner. Confocal microscopy directly visualized the time course localization of Ca2+ inside the cells after exposure to HgCl2. The onset and level of Ca2+ mobilization following HgCl2 exposure were in parallel to those of protein tyrosine phosphorylation. Interestingly, by either concentration of HgCl2, Ca2+ was mobilized in both cytoplasm and nucleus almost simultaneously, and the level of Ca2+ mobilization in the nucleus was more than that in the cytoplasm. All the HgCl2-mediated Ca2+ mobilization was prevented by addition of protein kinase inhibitor staurosporin prior to HgCl2. These results suggest that heavy metal stress triggers a protein tyrosine phosphorylation-linked signal that leads to a nuclear event-dominant Ca2+ mobilization.


Optimized lepton universality tests in B → V ℓ ν ¯ decays.
We propose improved lepton flavor universality (LFU) ratios in semileptonic P → V ℓ ν ¯ decays, when comparing μ and τ modes, that minimize the theoretical form-factor uncertainties. These optimized ratios are obtained with simple cuts or reweighting of the dilepton mass distributions, which imply a minimum loss of signal on the rare tauonic modes while maximizing the cancellation of theoretical uncertainties among the two modes. We illustrate the usefulness of these observables in B c → J / ψ , B c → ψ ( 2 S ) , B → D ∗ and B s → D s ∗ transitions, showing that in all cases we can reach O ( 1 % ) uncertainties on the SM predictions of the improved LFU ratios employing conservative form-factor uncertainties.


Perceptions of women on the impact of menorrhagia on their health using multi-attribute utility assessment.
To assess patient preferences regarding the treatment of menorrhagia using the multi-attribute utility methodologies, to produce a clinically applicable scale, and to assess health outcomes following treatment of menorrhagia. Women referred to the gynaecology department for the treatment of menorrhagia were interviewed regarding the effects of menorrhagia on different aspects of their life. Their concerns were categorised into main components of health (domains). The relative importance of each domain was rated by the women using importance points which were distributed to represent the perceived importance of each domain. A series of statements (intra-domain statements) was developed for each domain, which described various possible conditions of that component of health. These were also rated using a one metre visual analogue scale with numerical anchor points at zero (worst) and 100 (best). The components of health considered most important were, in order of impact, family life, followed by physical health, work life, psychological health, practical difficulties and social life. The scores for the intra-domain statements were combined into a scale to allow the calculation of a final health state utility for a particular outcome based upon the statements the patient chooses within each domain. In planning treatment for menorrhagia clinicians can assess a woman's current perception of their health, using a simple to administer clinical scale.


Principles of sequence-dependent flexure of DNA.
The curvature of a bent rod may be defined in several different, but equivalent ways. The best way of describing the curvature of double-helical DNA is by an angle of turning per base step. Curvature comes mainly from the angle of roll between successive base-pairs, and this is defined as positive when the angle opens up on the minor groove side of the bases. DNA forms a plane curve if the roll angle values along the molecule alternate periodically between positive and negative, with a complete period equal to the helical repeat. It is known from studies of crystallized oligomers that the roll angles for particular dinucleotide steps have preferred values, or lie in preferred ranges of values. Therefore the formation of a plane curve will be easier with some base sequences of DNA than with others. We set up a computer algorithm for determining the ease with which DNA of given sequence will adopt a curved form. The algorithm has two different sets of constants: in model 1 the base step parameters come from an inspection of crystallized oligomers, and in model 2 data from a statistical survey of the incidence of dinucleotide steps in a large number of samples of chicken erythrocyte core DNA is incorporated. Both forms of the algorithm successfully locate the dyad of the nucleosome sequence (modulo 10) in a frog gene, and suggest strongly that sequence-dependent flexural properties of DNA play a part in the recognition of binding sites by nucleosome cores.


Visual receptive thalamopetal neurons in the optic tectum of teleosts (Holocentridae).
Tectal neurons previously known to receive retinofugal input were herein shown to project to the nucleus prethalamicus. Following HRP injections into the nucleus prethalamicus, pyriform neurons in the stratum periventriculare and stratum album centrale, and fusiform neurons in the stratum griseum centrale, were retrogradely labeled. Because the labeled types of neurons have been characterized as the main visual receptive neurons of the optic tectum, and because the nucleus prethalamicus of teleosts projects to the telencephalon, this nucleus can now be considered homologous to the nucleus rotundus of reptiles and birds and to the nucleus lateralis posterior-pulvinar complex of mammals, that is, it provides a relay for retinotectal visual input to the telencephalon. Orthogradely labeled terminals as well as retrogradely labeled neurons were also found in the dorsal area of the telencephalon. The tecto-prethalamotelencephalic projections are only ipsilateral.


Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS).
Cerebrospinal fluid (CSF) is a promising source of biomarkers in amyotrophic lateral sclerosis (ALS). Using the two-dimensional difference in gel electrophoresis (2-D-DIGE), we compared CSF samples from patients with ALS (n = 14) with those from normal controls (n = 14). Protein spots that showed significant differences between patients and controls were selected for further analysis by MALDI-TOF mass spectrometry. For validation of identified spots western blot analysis and ELISA was performed. We identified 2 proteins that were upregulated and 3 proteins that were down-regulated in CSF in ALS. Of these, two proteins (Zn-alpha-2-glycoprotein and ceruloplasmin precursor protein) have not been reported in CSF of patients with ALS so far. In contrast, several other proteins (transferrin, alpha-1-antitrypsin precursor and beta-2-microglobulin) seem to be unspecifically affected in different neurological diseases and may therefore be of limited value as disease-related biochemical markers in ALS. Further evaluation of the candidate proteins identified here is necessary.