Pharmacophore modeling for COX-1 and -2 inhibitors with LigandScout in comparison to Discovery Studio.
Pharmacophore modeling has become an integrated tool in drug discovery. However, no prospective study compares the performance of the available software. The two widely used pharmacophore modeling and screening software programs Discovery Studio and LigandScout were used to generate, validate, and prospectively apply COX-1 and -2 models. Selected virtual hits were tested in cell-free enzymatic assays. The correct retrieval of active compounds was compared. In the enzymatic testing, 10.5% of the tested hits for COX-2 and 6.6% of the predicted compounds for COX-1 were active. To directly compare the two models, both based on the same PDB entry, were selected for virtual screening. The two programs yielded vastly different hit lists, but both predicted active compounds. To obtain a comprehensive selection of active compounds, more than one program should be used for modeling.


Predictors of Consanguinity Marriage Decision in Saudi Arabia: A Pilot Study.
Consanguineous marriages are common in Saudi Arabia, increasing the risk of genetic blood disorders in offspring. This pilot study assessed the knowledge and perceived threats regarding genetic blood disorders, norms, and premarital screening for consanguineous marriage among unmarried university students in Saudi Arabia as a predictor of marriage decisions. A cross-sectional study was conducted from 22 January through 22 April 2022. In total, 400 unmarried students at Saudi Arabian universities were recruited using the non-probability convenience sampling technique. The data were analyzed using descriptive statistics and multinomial logistic regression. The results showed that the majority of participants had poor knowledge of genetic blood disorders. Most of the participants had a favorable attitude toward consanguineous marriage, while perceived threats towards genetic blood disorders were perceived as neutral by the participants. Moreover, their norms regarding consanguineous marriage also showed neutral results. A multinomial regression shows that participants with poor attitudes were significantly 22.3 times more likely to have poor marriage decisions (95% CI: 4.9-101.7, p < 0.001). However, participants with good and neutral norms regarding consanguinity marriage were significantly protective factors against poor marriage decisions with an RRR ratio of 0.165 (95% CI:0.030-0.918, p = 0.04) and 0.238 (95% CI: 0.071-0.797, p = 0.02), respectively. To mitigate the risk of genetic blood disorders in future generations, there is a need for targeted awareness campaigns about genetic blood disorders and the risks of consanguineous marriages by integrating this education into university curricula, and premarital counseling. It is also important to address societal norms, promoting informed decision-making, and provide premarital consultation to couples who carry the same mutated genes and are at risk of transmitting the disease to their offspring. Furthermore, there is a need for further research to assess the effectiveness of campaigns in this regard.


Short-term effects of canagliflozin on glucose and insulin responses in insulin dysregulated horses: A randomized, placebo-controlled, double-blind, study.
Decreasing hyperinsulinemia is crucial in preventing laminitis in insulin dysregulated (ID) horses. Complementary pharmacological treatments that efficiently decrease postprandial hyperinsulinemia in ID horses are needed. Compare short-term effects of canagliflozin vs placebo on glucose and insulin responses to an oral sugar test (OST) as well as the effects on body weight and triglyceride concentrations in horses with ID. Sixteen privately-owned ID horses. A single-center, randomized, double-blind, placebo-controlled, parallel design study. The horses were randomized (ratio 1:1) to either once daily PO treatment with 0.6 mg/kg canagliflozin or placebo. The study consisted of an initial 3-day period for obtaining baseline data, a 3-week double-blind treatment period at home, and a 3-day follow-up period similar to the initial baseline period but with continued double-blind treatment. Horses were subjected to an 8-sample OST in the morning of the third day on both visits. Maximal geometric least square (LS) mean insulin concentration (95% confidence interval [CI]) during the OST decreased after 3 weeks of canagliflozin treatment compared with placebo (83.2; 55.4-125.0 vs 215.2; 143.2-323.2 μIU/mL). The geometric LS mean insulin response (insulin AUC0-180 ) for canagliflozin-treated horses was >66% lower compared with placebo. Least square mean body weight decreased by 11.1 (4-18.1) kg and LS mean triglyceride concentrations increased by 0.99 (0.47-1.5) mmol/L with canagliflozin treatment. Canagliflozin is a promising drug for treatment of ID horses that requires future studies.


Socioeconomic and intraoral polarization of untreated caries and tooth loss among male adolescents.
The aim of this study was to investigate the intraoral distribution of untreated caries and tooth loss and estimate the impact of different socioeconomic factors on the occurrence of these outcomes. A cross-sectional study was conducted with 652 18-year-old male adolescents from the city of Sapucaia do Sul, Brazil, who conscripted for military service. The participants answered a questionnaire addressing sociodemographic variables. Two trained and calibrated examiners performed the clinical examinations for the diagnosis of dental caries using the criteria of the World Health Organization. Tooth group and adolescent were the units of analysis for the primary outcomes of the study. Poisson regression analysis with robust variance was performed, with the calculation of crude and adjusted prevalence ratios (PR) and 95% confidence intervals (CI). The prevalence of caries experience and untreated caries was 70.2% and 39.3%, respectively, and 9.4% of the adolescents had missing teeth. Sixty-seven percent of the untreated caries and 98.8% of missing teeth were in first molars. The probability of dental caries and tooth loss was significantly higher among adolescents with less schooling (PR = 2.56; 95%CI: 1.97-3.32 and PR = 3.28; 95%CI: 1.61-6.65, respectively) and those whose mothers had less schooling (PR = 1.31; 95%CI: 1.03-1.67 and PR = 2.30; 95%CI: 1.18-4.50, respectively). In conclusion, the occurrence of untreated dental caries and tooth loss was concentrated in the first molars of adolescents. Moreover, the prevalence of both conditions was higher among adolescents with low schooling and whose mothers had low schooling, reflecting the strong intraoral and socioeconomic polarization of these outcomes.


Epigallocatechin gallate (EGCG) alleviates the inflammatory response and recovers oral microbiota in acetic acid-induced oral inflammation mice.
The oral microbiota, the second largest microbiome in the human body, plays an integral role in maintaining both the local oral and systemic health of the host. Oral microecological imbalances have been identified as a potential risk factor for numerous oral and systemic diseases. As a representative component of tea, epigallocatechin gallate (EGCG) has demonstrated inhibitory effects on most pathogens in single-microbial models. In this study, the regulatory effect of EGCG on more complex oral microbial systems was further explored through a mouse model of acetic acid-induced oral inflammation. Acetic acid induces histological damage in the cheek pouch, tongue, and throat, such as broken mucosa, submucosal edema, and muscular disorders. These detrimental effects were ameliorated significantly following EGCG treatment. Additionally, EGCG reduced the levels of the inflammatory cytokines interleukin-6 and tumor necrosis factor-α to alleviate the inflammation of the tongue, cheek pouch, and throat. According to the 16S rDNA gene sequencing data, EGCG treatment contributed to increased diversity of the oral microbiota and the reversal of oral microecological disorder. This study demonstrates the regulatory effect of EGCG on dysregulated oral microbiota, providing a potential option for the prevention and treatment of oral-microbiota-associated diseases.


Contribution of nitropyrene to the mutagenic activity of coal fly ash.
Stack-collected coal fly ash from western low-sulfur coal was extracted with 60:40 benzene/methanol. This extract was fractionated by preparative-scale high performance liquid chromatography (HPLC) and the mutagenic activity of 14 fractions was evaluated by microbial assay with Salmonella typhimurium TA1538. A widespread distribution of direct-acting mutagens, which probably includes both mono- and dinitroaromatics, was detected. HPLC methods were also used to isolate 1-nitropyrene from the total benzene/methanol extract. The identification of 1-nitropyrene was based on gas chromatographic and HPLC retention measurements and mass spectral data. The concentration of 1-nitropyrene in the ash extract was determined by quantitative HPLC analyses. Mutagenicity assays of the total extract and an authentic 1-nitropyrene standard with Salmonella strains TA1538, TA100, and TA98 indicated that the 1-nitropyrene accounts for approximately 0.03-0.16% of the total mutagenic activity of the extract.


Psychosocial factors as risk indicators of periodontitis.
Cross-sectional investigation of associations between psychosocial and periodontal parameters. One hundred and ten patients 18-76 years of age were examined clinically and 57 radiographically at the Department of Conservative Dentistry of the University Hospital of Heidelberg: probing depths (PDs) and attachment level (PAL-V) were obtained at six sites per tooth. Inter-proximal bone loss was assessed in 57 patients on panoramic radiographs. Further chemical and general environmental sensitivity, somatization, and smoking status were assessed by several questionnaires. Significant correlations between severe bone loss and age (r=0.38, p=0.004) were observed. PAL-V and PD also correlated with age (r=0.45, p<0.001; r=0.37, p<0.001) and pack years (r=0.21, p=0.031; r=0.3, p=0.002). After adjustment for age, smoking, and sex a negative correlation between chemical odour sensitivity and bone loss, PD=4 mm as well as PAL-V=4 mm was observed. Further, a negative correlation was observed between gastrointestinal sensitivity and PAL-V=4 mm. Psychological stress correlated positively with bone loss. The results give evidence for associations of psychosocial factors and periodontal disease. Some environmental traits seem to be related to more favourable periodontal status.


Improvement of Chicken Primordial Germ Cell Maintenance In Vitro by Blockade of the Aryl Hydrocarbon Receptor Endogenous Activity.
Primordial germ cells (PGCs) are the undifferentiated progenitors of gametes. Germline competent PGCs can be developed as a cell-based system for genetic modification in chickens, which provides a valuable tool for transgenic technology with both research and industrial applications. This implies manipulation of PGCs, which, in recent years, encouraged a lot of research focused on the study of PGCs and the way of improving their culture. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that besides mediating toxic responses to environmental contaminants plays pivotal physiological roles in various biological processes. Since a novel compound that acts as an antagonist of this receptor has been reported to promote expansion of hematopoietic stem cells, we conducted the present study with the aim of determining whether addition of an established AHR antagonist to the standard culture medium used nowadays for in vitro chicken PGCs culture improves ex vivo expansion. We have found that addition of α-naphthoflavone in culture medium promotes the amplification of undifferentiated cells and that this effect is exerted by the blockade of AHR action. Our results constitute the first report of the successful use of a readily available AHR antagonist to improve avian PGCs expansion, and they further extend the knowledge of the effects of AHR modulation in undifferentiated cells.


Influence of dietary conjugated linoleic acid isomers on early inflammatory responses in male broiler chickens.
1. The influence of dietary conjugated linoleic acid isomer (CLA, 0 and 10 g/kg) on the metabolic and physiological responses to immune stimulation induced by a single injection of Salmonella enteritidis lipopolysaccharide (LPS) or repeated injections of LPS and Sephadex G-50 was determined in male broiler chicks. 2. In experiment 1, 10-d-old chicks were fed on experimental diets for 14 d and half of the birds fed on each diet were injected intraperitoneally with LPS (1.5 mg/kg body weight). In experiment 2,7-d-old chicks were fed on experimental diets for 18 d. Immune stimulation was started at 19 d old and continued for 5 d. Half of the birds fed on each diet were injected intraperitoneally with 0.25 mg/kg body weight of LPS at 19, 21 and 23 d of age, and with 250 mg/kg body weight of Sephadex at 20 and 22 d of age to stimulate the immune system. 3. In experiment 1, giving CLA prevented an increase in blood heterophil to lymphocyte ratio 7 h after a single injection of LPS, and increases in plasma ceruloplasmin and alpha 1 acid glycoprotein (AGP) 24 h after the injection, but not 7 h after the injection. CLA also prevented a decrease in food intake for 24 h after LPS injection. 4. In experiment 2, the CLA diet partially prevented reductions in body weight gain and weight gain to feed intake ratio caused by repeated injections of LPS and Sephadex. Feeding CLA prevented increases in plasma ceruloplasmin and AGP at 24 d of age caused by repeated injections of LPS and Sephadex, but not at 20 d of age. 5. These results suggest that feeding CLA alleviates some undesirable metabolic and physiological changes induced by immunological stimulation in male broiler chicks.


Optical behavior of substituted 4-(2'-hydroxyphenyl)imidazoles.
A set of tetraarylimidazoles bearing a 2-hydroxyphenyl substituent at position 4, as well as their models lacking intramolecular hydrogen bonds, was efficiently synthesized. Structural investigations proved that the hydrogen bond strength for 4-(2'-hydroxyphenyl)imidazoles is weaker than that for analogous 2-(2'-hydroxyphenyl)imidazoles as estimated from dihedral angles and bond distances. Photophysical investigations revealed that these compounds have other properties than those observed for imidazoles bearing a 2-hydroxyphenyl substituent at position 2. They exhibit a negligible fluorescence quantum yield regardless of the solvent polarity. Additionally, dual fluorescence is observed in nonpolar solvents. Plausibly, although a hydrogen bond is present within their chemical structure in the solid state, it is not clear if excited-state intramolecular proton transfer occurs. The presence of OH groups triggers the radiationless deactivation channel if compared with model imidazole possessing a 2-methoxyphenyl group.


Delay-encoded transmission and image reconstruction method in synthetic transmit aperture imaging.
Synthetic transmit aperture (STA) imaging systems usually have a lower SNR compared with conventional Bmode ultrasound systems because only one or a small number of elements are selected for each transmission in STA. Here we propose delay-encoded synthetic transmit aperture (DE-STA) imaging to encode all the transmission elements to increase the SNR of the pre-beamformed RF signals. The encoding scheme is similar to the Hadamard encoding. However, in each transmission of DE-STA imaging, selected transmitting elements are delayed by a half period of the ultrasound wave relative to the rest transmitting elements, rather than using a pulse inversion as in the Hadamard encoding sequence. After all the transmission events, a decoding process in the temporal frequency domain is applied to the acquired RF signals to recover the equivalent traditional STA signals with a better SNR. The proposed protocol is tested with simulated data (using Field II) and experimental data acquired with a commercial linear array imaging system (Ultrasonix RP). The results from both the simulations and the experiments demonstrate increased SNR of pre-beamformed RF signals and improved image quality in terms of peak signal-to-noise ratio (PSNR), resolution and contrast-to-noise ratio compared with traditional STA. The lateral resolution (as assessed by a wire target) of DESTA imaging is improved by 28% and the PSNR of the wire is increased by 7 dB, respectively, compared with traditional STA imaging. The proposed image reconstruction framework can also be extended to other transmission protocols.


Oral terbinafine-induced bullous pemphigoid.
To report a case of drug-induced bullous pemphigoid (BP) in an otherwise healthy elderly patient after taking terbinafine for 20 days. A 78-year-old man presented with distal subungual onychomycosis of the toenails. Oral terbinafine 250 mg/d was started for treatment. Twenty days after the beginning of the treatment, the patient presented with widespread pruritic blistering eruption, more severe on the extremities. He had not received terbinafine before and was not receiving any other drug. The diagnosis of BP was confirmed with histopathologic examination. The patient was treated successfully with oral steroids. Drug-induced BP is a well-known complication of many drugs and represents a spectrum from an acute and self-limited condition to a chronic disease. Terbinafine is frequently used in the elderly. It is known to have less drug interactions and adverse effects compared with the other antifungal agents. Use of the Naranjo probability scale indicated a probable relationship between BP and terbinafine treatment in this patient. To the best of our knowledge, this is the first report in the English-language literature of BP in a patient taking terbinafine. As with any other medication, oral terbinafine has the potential for severe adverse reactions. Healthcare professionals should be aware of this possibility.


Stereocontrolled Synthesis of Left Halves of Halichondrins.
A stereocontrolled synthesis of the left halves of halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions was used to construct the [6,6]-spiroketal in a stereocontrolled manner. With this approach, the left halves of halichondrins, homohalichondrins, and norhalichondrins were synthesized.


[Serial deletions of tandem reverse CTCF sites reveal balanced HOXD regulatory landscape of enhancers].
The genome architectural protein CTCF (CCCTC-binding factor) not only mediates long-distance chromatin interactions between distal enhancers and target promoters, but also functions as an important insulator-binding factor to block improper enhancer activation of non-target promoters, and is thus of great significance to transcriptional regulation of developmental genes. The Hox (Homeobox) gene family plays an important role in the development of the brain, bones, and limbs. The spatiotemporal colinear expression of the HOXD cluster along the proximal-distal axis of limbs is regulated by two clusters of enhancers known as super-enhancers located in the flanking regulatory regions. We focused on the HOXD cluster to explore the architectural role of CTCF in transcriptional regulation of developmental genes. The HOXD cluster contains 9 paralogous genes intermixed with a series of CBS (CTCF-binding site) elements. Using the CRISPR DNA-fragment editing system, we generated a series of single-cell HEK293T clones with deletion of increasing numbers of reverse CBS elements. RNA-seq experiments revealed decreased levels of HOXD gene expression. In addition, chromosome conformation capture experiments revealed increased long-distance chromatin interactions between HOXD and the upstream enhancer cluster and corresponding decreased interactions between HOXD and the downstream enhancer cluster. Thus, tandem reverse CTCF sites function as insulators to maintain HOXD regulatory balance between the upstream and downstream enhancer clusters. This study has interesting implications on the precise gene expression control of the Hox family during animal development.


Reciprocal Abuse: Elder Neglect and Abuse by Primary Caregivers and Caregiver Burden and Abuse in Turkey.
The aim of the study was to determine the relationship between the neglect and abuse that older people were exposed to by their primary caregivers and the experiences of caregivers' burden and abuse by their charges. This descriptive, cross-sectional and correlational study was conducted with 186 individuals over the age of 65 and 136 caregivers. The data were collected using questionnaires to determine neglect and abuse experienced by both older people and caregivers, and the Zarit Burden Scale. Abuse rate of the older people and their caregivers is both high and similar. This study is to make psychiatric nursing professionals aware of the problem of elder abuse and neglect. For researchers, educators, practitioners, and policymakers in the fields of aging, health, and mental health this study provides important data about elder abuse and neglect.


Oocyte provision as a (quasi) social market: Insights from Spain.
The provision of oocytes plays an important role in human fertility treatments. Spain alone performs half of oocyte provision cycles in the European Union whilst all other European countries face an oocyte shortage. How do Spanish fertility clinics manage to match the increasing domestic and foreign demand for female oocytes? Adopting a weak performativity approach and drawing insights from interviews carried out with 20 fertility clinic representatives, this study suggests that Spanish clinics are successful thanks to an egg provision system designed as a (quasi) social market. In the absence of traditional market mechanisms based on price fluctuations, the combination of fixed monetary compensation for providers and altruistic framing of oocyte provision as an act of donation, are used to mobilize relatively high numbers of women. Fertility clinics optimize this supply through a set of supplementary strategies to ensure oocyte supply always meets oocyte demand. Though successful, this market design reinforces gender stereotypes and relies on manipulative notions of altruism. A clear but unacknowledged appropriation of women's bodies and reproductive labour are also operated, which reinforces and reproduces racial and social stratifications. Therefore, we ask whether alternative mechanisms to promote female solidarity across different generations, to raise awareness of the risks of advanced maternal age, and to explore alternative market designs should be considered.


Use of locally delivered conventional drug therapies.
Coronary artery restenosis remains the major limitation of balloon angioplasty and occurs in 30-50% of initially successful procedures. Our current understanding of pathophysiology of restenosis suggests that it involves three inter-related phases; (1) acute effects of thrombosis, (2) neointimal proliferation, and (3) acute recoil and chronic remodelling. In an attempt to prevent vessel restenosis both systemic and site-specific pharmacotherapy have been investigated. Although successful in animal models, systemically administered pharmacological agents for the prevention of restenosis in humans have not been effective. The local administration of compounds such as heparin, anti-thrombin agents, colchicine, angiopeptin, antineoplastic agents, calcium antagonists, nitrates, forskolin, cytochalasin B, protein kinase inhibitors and dexamethasone have been shown to reduce neointimal formation in animal models of restenosis. Clinical trials have demonstrated the feasibility of the local administration of heparin using both InfusaSleeve and Dispatch drug delivery catheters. Preliminary results on long-term prevention of restenosis by heparin appear promising using the Dispatch delivery device. In addition, a multicentre trial investigating the effectiveness of cytochalasin B delivered using the Microporous Infusion Catheter for the prevention of restenosis is currently underway. Rapid progress in our understanding of the complex pathophysiology of restenosis and the development of more effective pharmacological agents and atraumatic site specific delivery modalities ensure a promising future for local delivery strategies.


The effects of antilymphocyte sera on bone marrow allograft rejection.
Prior sensitization can be a problem in successful graft take in bone marrow therapy. Spleen weight and femoral marrow cellularity have been used as indices of successful graft take in lethally irradiated mice receiving bone marrow allografts. Recovery if poor in mice sensitized, at least 6 days before irradiation and bone marrow therapy, to an intraperitoneal injection of allogenic bone marrow cells. Rabbit anti-mouse lymphocyte serum, normal rabbit serum and pig anti-mouse lymphocyte serum but not normal pig serum partially ablate tis immunity when administered 8 and 10 days after sensitization. Normal rabbit serum is, however, ineffective when administratered 26 and 28 days after sensitization whereas rabbit anti-mouse lymphocyte serum completely ablates this immunity. These findings demonstrate the marked radioresistance of the secondary response to bone marrow allografts and further show the effectiveness of antilymphocyte sera in ablating this immunity.


App-guided exposure and response prevention for obsessive compulsive disorder: an open pilot trial.
Although effective treatments for obsessive-compulsive disorder (OCD) exist, there are significant barriers to receiving evidence-based care. Mobile health applications (Apps) offer a promising way of overcoming these barriers by increasing access to treatment. The current study investigated the feasibility, acceptability, and preliminary efficacy of LiveOCDFree, an App designed to help OCD patients conduct exposure and response prevention (ERP). Twenty-one participants with mild to moderate symptoms of OCD were enrolled in a 12-week open trial of App-guided self-help ERP. Self-report assessments of OCD, depression, anxiety, and quality of life were completed at baseline, mid-treatment, and post-treatment. App-guided ERP was a feasible and acceptable self-help intervention for individuals with OCD, with high rates of retention and satisfaction. Participants reported significant improvement in OCD and anxiety symptoms pre- to post-treatment. Findings suggest that LiveOCDFree is a feasible and acceptable self-help intervention for OCD. Preliminary efficacy results are encouraging and point to the potential utility of mobile Apps in expanding the reach of existing empirically supported treatments.


Beyond the operatory: from patients to population.
There is a shortage of dental public health specialists in the United States, and the number of dentists entering the field is declining. A number of disincentives and barriers to pursuing training and a career in dental public health have been identified. This article gives a personal account of one dentist's transition from private practice to public health dentistry.


Esterification of pseudoephedrine hydrochloride by citric acid in a solid dose pharmaceutical preparation.
Esterification of pseudoephedrine hydrochloride (PSE) by citric acid was observed in a solid dose pharmaceutical preparation at room temperature and accelerated stability condition (40°C/75% relative humidity). The esterification of PSE with citric acid was confirmed by a solid-state binary reaction in the presence of minor level of water at elevated temperature to generate three isomeric esters. The structures of the pseudoephedrine citric acid esters were elucidated using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). Occurrence of esterification in solid state, instead of amidation which is generally more favorable than esterification, is likely due to remaining HCl salt form of solid pseudoephedrine hydrochloride to protect its amino group from amidation with citric acid. In contrast, the esterification was not observed from solution reaction between PSE and citric acid.


Relationship between structural remodeling and reactivity in pulmonary resistance arteries from hypertensive piglets.
In neonatal pulmonary hypertension, the pulmonary arteries fail to adapt to extrauterine life and remain thick walled. In a previous study on normal neonatal resistance arteries, perfusion myography and confocal microscopy showed that responses to agonist stimulation were related to wall structure. We hypothesized that in hypertensive resistance pulmonary arteries, an enhanced response to contractile and relaxant agonist stimulation would be associated with an increased wall thickness and abnormal postnatal cytoskeletal remodeling of smooth muscle cells (SMC). Pulmonary arteries (110-140 microm external diameter) from normal piglets and those exposed to chronic hypobaric hypoxia from birth or from 3 d of age were mounted on a perfusion myograph. Lumen diameter and SMC nuclear positions were tracked after addition of KCl, the thromboxane mimetic U46619, and bradykinin. After fixation in situ, SMC dimensions were measured using confocal and electron microscopy. In all hypertensive animals, wall thickness and SMC density were increased and SMC length/width ratio decreased. After hypoxic exposure for 3 d, arteries from animals exposed from birth showed a greater and faster contractile response than controls, but arteries from piglets first exposed at 3 d of age did not, though both showed similar structural appearance. Increase of exposure to 11 d elicited an enhanced response and further cytoskeletal remodeling. All vessels relaxed fully to bradykinin. SMC remodeling and reactivity appear to be influenced by the age at onset and the duration of the hypoxic insult.


Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin against Staphylococcus aureus Isolates with Different Resistance Phenotypes in Models of Cultured Phagocytic Cells.
Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examined in vitro its activity against intracellular Staphylococcus aureus (involved in the persistent character of skin and skin structure infections) by use of a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (the apparent bacteriostatic concentration [Cs ] was reached at an extracellular concentration about 0.7× its MIC and was not affected by mechanisms of resistance to the comparators) and (ii) caused a maximal reduction of the intracellular burden (maximum effect) of about -1.6 log10 CFU (which was better than that caused by linezolid, macrolides, and daptomycin and similar to that caused by moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100× their MIC, the intracellular persisting fraction was <0.1% with moxifloxacin, 0.5% with gepotidacin, and >1% with the other drugs. The accumulation and efflux of gepotidacin in phagocytes were very fast (kin and kout, ∼0.3 min-1; the plateau was reached within 15 min) but modest (intracellular concentration-to-extracellular concentration ratio, ∼1.6). In cell fractionation studies, about 40 to 60% of the drug was recovered in the soluble fraction and ∼40% was associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.


The Douglas Hospital Longitudinal Study of Normal and Pathological Aging: summary of findings.
In 1988, our group initiated the Douglas Hospital Longitudinal Study of Normal and Pathological Aging to assess the association between secretion of the stress hormone cortisol and cognitive performance in a group of 51 older adults. In this paper, we summarize the data obtained in this study to date. We have found that long-term exposure to high endogenous levels of cortisol is associated with both memory impairments and a 14; smaller volume of the hippocampus. We also report on studies showing that in older adults with moderate levels of cortisol over time, memory performance can be acutely modulated by pharmacologic manipulations of cortisol. We describe one participant who was included in the group of older adults presenting with increased cortisol levels over time, memory impairments and reduced hippocampal volume and in whom major depression, followed by Alzheimer's disease, developed during the course of the study. Together, the results of the Douglas Hospital Longitudinal Study of Normal and Pathological Aging show that increased secretion of cortisol in the older human population is significantly associated with impairment of cognitive function during aging.


Effect of Trifolium pratense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index.
Since current clinical evidence indicates that conventional estrogen hormone therapy (HT) increases cardiovascular risk, alternatives to estrogens are growing in popularity, especially among high-risk populations. To determine the effect of Trifolium pratense-derived isoflavone supplementation on the lipid profile of postmenopausal women with increased body mass index (BMI). Sixty postmenopausal women aged > 40 years, HT non-users, were randomly assigned to one of two groups: either two capsules of T. pratense (80 mg red clover isoflavones) daily for a 90-day period or placebo of equal design. After a 7-day washout period, medication was crossed-over for another 90 days. Total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C) and lipoprotein A (LpA) levels were assessed at baseline, 90 and 180 days. Women were divided into two groups: those with increased BMI (>or=25 kg/m(2)) and those with BMI < 25 kg/m(2). Fifty-three women (88.3%) completed the trial. T. pratense isoflavone supplementation had a positive effect on the lipid profile of women with increased BMI, evidenced by a significant decrease in TC, LDL-C and LpA levels. Isoflavones derived from T. pratense are an attractive alternative therapeutic option for high-risk populations such as postmenopausal women with increased BMI and abnormal lipid profile.


The role of the septal reset in creating a youthful eyelid-cheek complex in facial rejuvenation.
Resetting of the septum orbitale over the orbital rim, or "septal reset," is the latest step in achieving periorbital rejuvenation in composite rhytidectomy. The first significant step was the addition of orbicularis repositioning to conventional lateral vector deep plane rhytidectomy, followed by orbital fat preservation using the arcus marginalis release and fat transposition over the orbital rim. Those early procedures have been further refined to include the zygomaticus muscles with the orbicularis oculi in the composite flap, or zygorbicular cheek flap, and a septal reset. The septum orbitale reset has distinct advantages over transposition of orbital fat alone, as it creates a firmer undersurface for the lower eyelid. This maneuver will create a truly youthful lower eyelid-cheek complex, as the normal concave aging skeletonization of the periorbit is transformed to a convex contour of youth. The effectiveness of this operation can be demonstrated in most variations of human anatomy, whether congenital or iatrogenic, allowing the plastic surgeon to utilize the septal reset in virtually every patient undergoing and desiring a harmonious facial rejuvenation.


Bounded synchronization for uncertain master-slave neural networks: An adaptive impulsive control approach.
This paper investigates the bounded synchronization of the discrete-time master-slave neural networks (MSNNs) with uncertainty. To deal with the unknown parameter in the MSNNs, a parameter adaptive law combined with the impulsive mechanism is proposed to improve the estimation efficiency. Meanwhile, the impulsive method also is applied to the controller design for saving the energy. In addition, a novel time-varying Lyapunov functional candidate is employed to depict the impulsive dynamical characteristic of the MSNNs, wherein a convex function related to the impulsive interval is used to obtain a sufficient condition for bounded synchronization of the MSNNs. Based on the above condition, the controller gain is calculated utilizing an unitary matrix. An algorithm is proposed to reduce the boundary of the synchronization error by optimizing its parameters. Finally, a numerical example is provided to illustrate the correctness and the superiority of the developed results.


Preparation of rotenone derivatives and in vitro analysis of their antimalarial, antileishmanial and selective cytotoxic activities.
Six derivatives of the known biopesticide rotenone were prepared by several chemical transformations. Rotenone and its derivatives showed differential in vitro antiparasitic activity and selective cytotoxicity. In general, compounds were more active against Plasmodium falciparum than Leishmania panamensis. Rotenone had an EC50 of 19.0 µM against P. falciparum, and 127.2 µM against L. panamensis. Although chemical transformation does not improve its biological profile against P. falciparum, three of its derivatives showed a significant level of action within an adequate range of activity with EC50 values < 50.0 µM. This antiplasmodial activity was not due to red blood cell hemolysis, since LC50 was >>400 µM. On the other hand, all derivatives displayed a non-specific cytotoxicity on several cell lines and primary human cell cultures.


Extracting cancer quality indicators from electronic medical records: evaluation of an ontology-based virtual medical record approach.
Measuring quality in clinical care is a time-consuming manual task. The vast amounts of clinical data collected through electronic medical records (EMRs) create an opportunity to develop tools that automatically assess quality indicators; however, the diversity of EMR implementations limits the ability to implement general, reusable methods. We evaluate an ontology-based virtual medical record (VMR) approach as a standardized, sharable methodology for defining data abstractions needed for quality of care assessment. Using a set of cancer quality indicators, we conducted a requirements analysis for modeling these abstractions with an OWL-based VMR. We found that the VMR approach needs to be extended to support population-based aggregations of clinical events, models of intended versus completed actions, and models of workflow and delivery systems. Incorporating the patient perspective on quality also requires additional extension of the VMR. We are using these results to create a virtual quality record based on EMR data.


Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm.
The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC. In addition, considerable research has been reviewed, that has identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, epithelial cell adhesion molecule, LY6A, ALDH1 and side population (SP)), which are enriched for tumour initiating cells (TICs). While many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the identification of universal markers defining a CSC. The assay that forms the basis of quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is essential that some of the potential limitations be examined in this review. Highlighting such limitations or weaknesses is required to properly evaluate data and broaden our interpretation of potential mechanisms that might be contributing to the pathogenesis of ovarian cancer.


Immunization with a peptide having both T cell and conformationally restricted B cell epitopes elicits neutralizing antisera against a snake neurotoxin.
We have synthesized a free peptide capable of eliciting antibodies that neutralize toxin alpha from Naja nigricollis, a protein that binds specifically to the acetylcholine nicotinic receptor. Of the five tested fragments that encompassed the whole toxin sequence, only fragment 24-41 stimulated T cells from BALB/c mice primed with the whole toxin and conversely, only T cells from mice primed with fragment 24-41 could be stimulated by both the toxin and priming peptide. No other peptides had such properties, indicating that only fragment 24-41 possessed T determinant(s) in BALB/c mice (H-2d haplotype). In agreement with the current view that B cell proliferation requires specific T cell stimulation, only fragment 24-41 elicited an antibody response. However, the antipeptide antisera failed to bind to the native toxin and thereby to neutralize it. Instead, it recognized an unfolded form of the toxin. The peptide 24-41 was then made cyclic. A circular dichroism analysis revealed that, in organic solvent, this peptide had a tendency to adopt a beta-sheet structure, as in the folded toxin, whereas the linear peptide adopted an helical structure. The cyclic peptide not only remained T stimulating but elicited antisera that recognized and neutralized the native toxin. Furthermore, the antisera cross-reacted with several toxin variants. Our data show, therefore, that it is possible to give an appropriate B cell specificity directly to a T cell-stimulating peptide, an approach that may be of value for the design of synthetic vaccines.


Evaluation of Renal Function in Pregnant Women with Malaria: A Case-Control Study in a Mesoendemic Area.
Background. Malaria is known to have devastating effects on mortality in tropical and subtropical regions with the effect being magnified in people with weakened immunity such as those in pregnancy. We assessed the effect of malaria on renal function of pregnant women receiving antenatal care in a mesoendemic area of Ghana. Methodology. A case-control study that enrolled a total of 100 pregnant women (50 with confirmed gestational malaria as cases and 50 without malaria as controls). Sociodemographic characteristics, obstetric history (obtained with a questionnaire), urea, creatinine, sodium, and potassium were analyzed using a chemistry automated analyzer. Results. Plasma urea and creatinine were significantly increased (P = 0.0003 and P < 0.0001, resp.) among cases compared to the controls. Also the levels of urea (P = 0.033), creatinine (P = 0.032), and parasitaemia (0.016) were significantly increased with increasing gestational age. Conclusion. Malaria has a significant impact on renal function (most importantly, urea and creatinine) and is also significantly associated with increasing gestational age among our study participants.


Safe tracheostomy for patients with severe acute respiratory syndrome.
Severe acute respiratory syndrome (SARS) caused by coronavirus has become an epidemic affecting many regions worldwide. Fourteen percent to 20% of patients require endotracheal intubation and ventilator support. Some of these patients may require tracheostomy subsequently. This procedure, when performed without protection, may lead to infection of the medical and nursing staff taking care of the patient. Based on clinical information of three patients. The authors carried out an emergency tracheostomy and changed the tracheostomy tube for one patient and performed elective tracheostomy in another two patients. No medical or nursing staff member was infected after carrying out the procedure while taking all the precautions and wearing the appropriate protective apparel. The authors have prepared guidelines for performing a safe tracheostomy under both elective and emergency conditions. Surgeons who might be involved in performing the tracheostomy should become familiar with these guidelines and the appropriate protective apparel.


Making decisions with unknown sensory reliability.
To make fast and accurate behavioral choices, we need to integrate noisy sensory input, take prior knowledge into account, and adjust our decision criteria. It was shown previously that in two-alternative-forced-choice tasks, optimal decision making can be formalized in the framework of a sequential probability ratio test and is then equivalent to a diffusion model. However, this analogy hides a "chicken and egg" problem: to know how quickly we should integrate the sensory input and set the optimal decision threshold, the reliability of the sensory observations must be known in advance. Most of the time, we cannot know this reliability without first observing the decision outcome. We consider here a Bayesian decision model that simultaneously infers the probability of two different choices and at the same time estimates the reliability of the sensory information on which this choice is based. We show that this can be achieved within a single trial, based on the noisy responses of sensory spiking neurons. The resulting model is a non-linear diffusion to bound where the weight of the sensory inputs and the decision threshold are both dynamically changing over time. In difficult decision trials, early sensory inputs have a stronger impact on the decision, and the threshold collapses such that choices are made faster but with low accuracy. The reverse is true in easy trials: the sensory weight and the threshold increase over time, leading to slower decisions but at much higher accuracy. In contrast to standard diffusion models, adaptive sensory weights construct an accurate representation for the probability of each choice. This information can then be combined appropriately with other unreliable cues, such as priors. We show that this model can account for recent findings in a motion discrimination task, and can be implemented in a neural architecture using fast Hebbian learning.


Involvement of the Golgi apparatus in sorting of materials to opposite ends of frog rod retinal photoreceptors.
We have studied the rod cells of retinas of Rana pipiens by phosphatase cytochemistry and immunocytochemistry. We find that the Golgi apparatus of these cells, although different in its intracellular distribution from that of other neurons, has a cis-trans organization like that of other neurons as regards morphological features and the distribution of phosphatase activities. Antibodies against opsin bind to several sacs of the rod Golgi apparatus, especially those at the trans side of the Golgi stack. This suggests that Golgi involvement in the packaging of opsin for eventual delivery to the photoreceptive outer segments of the cell involves passage through trans Golgi systems. Proteins destined for the opposite end of the cell--the presynaptic terminal--also seem to pass through trans Golgi systems, as is indicated both by immunocytochemical localization of the synaptic vesicle protein p38 (synaptophysin) and by the presence of thiamine pyrophosphatase activity in some of the synaptic vesicles. Our findings suggest that sorting of membrane proteins destined for opposite ends of the photoreceptor takes place in systems at or near the trans Golgi face.


Detainment and health: the case of the Lebanese hostages of war.
The purpose of the current research was to compare former detainees of Khiam prison to a comparison group regarding depression, anxiety, presence of chronic diseases, smoking, and alcohol drinking. The sample consisted of 118 ex-detainees and 90 community controls. The Beck Depression Inventory, the Hamilton Anxiety Scale, the Clinician-Administered Post-Traumatic Stress Disorder Scale, and the Harvard Trauma Questionnaire were used. The ex-detainees suffered from an increased level of depression, high anxiety scores, increased chronic diseases, smoked more, and consumed more alcohol than their comparison group. Regression analyses showed that detainment independently predicted depression and anxiety.


Conotrachelus dimidiatus Champion, 1904 (Coleoptera: Curculionidae: Molytinae): morphological re-description of the immature stages, keys, tribal comparisons and biology.
The mature larva and pupa of Conotrachelus dimidiatus Champion, 1904 (Curculionidae: Molytinae) are morphologically re-described, keyed and, for the first time, compared with known larvae and pupae of other Conotrachelus species. The chaetotaxy of the larval and pupal body in the genus Conotrachelus is probably strictly uniform. The immature stages of described species are also compared with available data on the immature stages of genera from several tribes in the subfamily Molytinae. All larvae of Conotrachelus have a distinct endocranial line of a different size and a frons with only three setae. The states of these two distinct characteristics in larvae of the eight known Conotrachelus species are constant and unique compared to other tribes in the subfamily Molytinae. In Central Mexico, overwintering Conotrachelus beetles emerge in July and then feed and mate on host plants. Larvae are endophagous within the fruits. In September and October, the larvae pupate in the soil. This new information will be very useful in the application of pesticides to the fight against this well-known pest in Mexico.


The influence of calcium and reactive oxygen species on influenza virus-induced apoptosis.
In previous studies we observed that influenza A and B viruses induce apoptosis in Madin-Darby canine kidney (MDCK) cells and that this apoptosis is blocked by expression of bcl-2. Using a well-characterized, highly virulent, avian influenza virus, A/Turkey/Ontario/7732/66 (H5N9) (Ty/Ont), we sought to better understand this system. We investigated the influence of two cellular factors that are known to function in other models of apoptosis inhibited by bcl-2, calcium (Ca(2+)) and reactive oxygen species (ROS). Although Ca(2+) chelators generally inhibit apoptosis, treatment of MDCK cells with either an extracellular chelator, EGTA, or an intracellular chelator, BAPTAAM, induced apoptosis instead and enhanced Ty/Ont-induced apoptosis. Conversely, treatment with an ionophore, ionomycin, blocked the viral-induced apoptosis. In terms of ROS, neither treatment with antioxidants, N(2) flushing to induce hypoxia, nor nigericin (a compound which, like bcl-2, stabilizes the mitochondrial membrane potential against the effects of ROS and subsequent Ca(2+) dysregulation) were able to block Ty/Ont-induced apoptosis. Therefore, it is likely that ROS play little, if any, role in influenza-induced apoptosis in MDCK cells and the influence of Ca(2+) appears to be opposite to that in the majority of other more classical models of apoptosis.


Stigmatodiscus pruni, a new dothideomycete with hysteriform ascomata.
Stigmatodiscus pruni (Stigmatodiscaceae, Stigmatodiscales) is described and illustrated from corticated dead twigs of Prunus spinosa collected in Austria and France. It is characterised by hysteriform ascomata with two lateral black lips, which are erumpent through the periderm of the host, and a black disc in combination with two-celled, asymmetric brown verruculose ascospores with a distinct sheath. Phylogenetic analyses of a multigene matrix containing a representative selection of Dothideomycetes from four genes (nuc 18S rDNA, nuc 28S rDNA, rpb2 and tef1) revealed a highly supported placement within Stigmatodiscales as sister species to Stigmatodiscus enigmaticus. Micromorphology of the sexual and asexual morph matches the genus Stigmatodiscus, except for the hysteriform shape of the ascomata and the two-celled ascospores.


The pattern and control of isoprenoid quinone and tocopherol metabolism in the germinating grain of wheat (Triticum vulgare).
1. The syntheses of ubiquinone-9 and plastoquinone-9 were used as parameters respectively of mitochondrial and proplastid development in the germinating wheat grain. 2. The changes in the amounts of the tocopherols were also studied and the possible biological significance of these changes is discussed. During germination, the dimethyl tocopherols of the resting grain are probably not utilized for the synthesis of alpha-tocopherol. 3. It was demonstrated that ubiquinone synthesis, and hence probably mitochondrial development, in the aleurone cells during germination, is independent of control by gibberellic acid from the embryo. 4. The influence of light on the syntheses of the isoprenoid quinones in the etiolated wheat shoot was investigated. In particular, illumination did not stimulate the synthesis of either alpha-tocopherol or alpha-tocopherolquinone.


The efficacy of prazosin HCl in the treatment of urinary flow obstruction due to prostatic hypertrophy.
Prazosin HCl was administered to 20 patients with urinary obstructions associated with prostatic hypertrophy. Significant reductions were recorded in the nighttime and the mean 24-hour urination frequencies. Patient-assessed symptoms diminished significantly, and uroflowmetry revealed significant increases in average and maximum urine flow rates. Residual urine volume decreased, the residual urine ratio declined, and bladder compliance tended to increase. The prazosin HCl therapy produced no significant effects on blood pressure or pulse rate, and no side effects appeared. The therapy was judged to be 'extremely beneficial' in 10%, 'beneficial' or better in 50%, and 'marginally beneficial' or better in 85% of all the patients.


[Effects of er-long-zuo-ci-wan on the spontaneous activities of auditory central nucleus in rat model of tinnitus induced by salicylate acid].
Observe the effects of er-long-zuo-ci-wan (EIZCW, a compound of Chinese Traditional Medicine) on the spontaneous discharge of external cortex of inferior colliculus (ICx) and secondary auditory cortex (AII) of chronic tinnitus model rats induced by salicylate acid, to explore the neural mechanisms underlying ELZCW preventing tinnitus. 30 adult SD rats were involved and divided into three groups, normal control group, chronic tinnitus model group and ELZCW prevention group. Extracellular recording techniques and stereotaxic method were used. The spontaneous spikes were recorded and analyzed from ICx and all in different group rats. The average rate of spontaneous discharge and the interspike interval histogram of spontaneous activities were used as indexes. (1) Compared with normal control group, the average rate of spontaneous discharge recorded from the ICx in the chronic tinnitus model group increased significantly (4.57 +/- 0.54 Hz vs. 3.14 +/- 0.40 Hz, P < 0.05). Furthermore analysis showed that the discharge rate of short spike interval from the ICx in the chronic tinnitus model group increased than that of the normal group (0-40 ms: 58% vs. 40%; 0-4 ms: 9% vs. 5%). And there was an increasing tendency of the average rate of spontaneous discharge recorded from the AII in the chronic tinnitus model group compared with that in the normal group. (2) Compared with the chronic tinnitus model group, the average rate of spontaneous discharge recorded from the ICx and AII in the ELZCW prevention group significantly decreased than that in the chronic tinnitus model group (ICx: 2.41 +/- 0.21 Hz vs. 4.57 +/- 0.54 Hz, P < 0.01. AII: 2.24 +/- 0.24 Hz vs. 4.57 +/- 0.54 Hz , P < 0.01). And the discharge rate of short spike interval from the ICx and AII in the chronic tinnitus model group decreased than that in the normal control group (ICx: 0-40 ms 50% vs. 58%, 0-4 ms 4% vs. 9%. All: 0-22 ms: 24% vs. 31%, 0-8 ms 19% vs. 16%). If the increasing of the spontaneous activities of ICx and AII in chronic tinnitus rats means tinnitus, the use of ELZCW could decrease this kind of changes.


Caregiver Perspectives Regarding Special Education Service Changes Amid COVID-19.
School instruction and service delivery changed dramatically amid disruptions caused by the COVID-19 pandemic. Children receiving special education services were especially vulnerable to the impact of reduced or eliminated school services as part of their Individualized Education Programs. Caregiver perspectives regarding the changes in school service delivery amid the pandemic were evaluated using qualitative methods. Caregivers reported reduced or eliminated services, inconsistencies in service delivery, challenges with distance learning, increased stress and advocacy efforts, and varying perceptions of student engagement and teacher efforts. The implications of school services changes are discussed.


Treadmill ECG test combined with myocardial perfusion imaging for evaluation of coronary artery disease: analysis of 340 cases.
Using Coronary arteriogram as the gold standard, stress ECG (Treadmill Test - TMT) has a sensitivity of 68% and specificity (77%) for the detection of coronary artery disease (CAD). Stress myocardial perfusion imaging (MPI) with Tc-99m Sestamibi gated SPECT has a sensitivity of 85% and specificity of 90%. The aim of the study was to ascertain if the combined use of the two physiologic tests will raise the predictive value for the presence or absence of physiologically significant CAD to 100%. Three hundred and fourty patients (200 with suspected and 140 proved CAD) were studied with the same day rest and stress protocol. A rest MPI image was acquired with 8 mCi Tc-99m Sestamibi, followed by TMT; at the peak exercise 20 mCi tracer was injected and post-stress MPI image was acquired after 1 hour. 12-lead ECG at rest and during stress and recovery period was analyzed. Out of 200 patients with a prior probability of CAD 40-50% (151 with pain in chest, 81 with shortness of breath on exertion and 68 asymptomatic high risk for CAD--more than 5/9 risk factors), a normal stress MPI result in 150 patients excluded the probability of physiologically significant CAD. Fifty patients with abnormal stress MPI were refered for coronary arteriography. Stress ECG had 17% "false negative" and 23% "false positive" compared to stress MPI. In this group out of 140 known CAD, (56 post-infarct, 52 post-CABG and 32 post-PTCA), all sent for evaluation of ischemic symptoms, MPI documented 101 infarcts (fixed defects with no wall motion and thickening), 20 of them were "silent" (with no history of previous infarct) ECG did not help in picking them up. 58/101 infarcts had only fixed defects while 43/101 were accompanied by reversible ischaemia in same or other vascular territories. Thirty nine patients showed only reversible ischaemia without any infarct. Risk stratification was possible based on the extent and severity of the perfusion defects and number of territories in which defects were seen, rest LVEF, size of LV and transient dilation Combined stress ECG and stress MPI perform "gate keeper" function for referral for angiography, as well as for risk stratification of those who already have coronary angiograms. Decisions for revascularization should be based on combined evaluation--a shift from stenosis- based to ischaemic--based evaluation. Success or failure of revascularization was also documented by this evaluation.


Low 25(OH)D3 levels are associated with total adiposity, metabolic syndrome, and hypertension in Caucasian children and adolescents.
Evidence of the association between vitamin D and cardiovascular risk factors in the young is limited. We therefore assessed the relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and metabolic syndrome (MetS), its components, and early atherosclerotic changes in 452 (304 overweight/obese and 148 healthy, normal weight) Caucasian children. We determined serum 25(OH)D(3) concentrations in relation to MetS, its components (central obesity, hypertension, low high-density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment, and/or insulin resistance (IR)), and impairment of flow-mediated vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) - two markers of subclinical atherosclerosis. Higher 25(OH)D(3) was significantly associated with a reduced presence of MetS. Obesity, central obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated with increased odds of having low 25(OH)D(3) levels, after adjustment for age, sex, and Tanner stage. After additional adjustment for SDS-body mass index, elevated blood pressure (BP) and MetS remained significantly associated with low vitamin D status. The adjusted odds ratio (95% confidence interval) for those in the lowest (<17 ng/ml) compared with the highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02-2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association between 25(OH)D(3), high BP, and MetS was observed when models were adjusted for waist circumference. No correlation was found between 25(OH)D(3) concentrations and either FMD or cIMT. Low 25(OH)D(3) levels in Caucasian children are inversely related to total adiposity, MetS, and hypertension.


Molecular identification of Fusarium species isolated from transgenic insect-resistant cotton plants in Mexicali valley, Baja California.
Cotton production in the Mexicali valley is adversely affected by wilt and root rot disease associated with Fusarium species. In the present study, we sought to isolate and identify the Fusarium species in the rhizosphere of transgenic insect-resistant cotton plants grown in the Mexicali valley. Our analyses isolated four native fungi from the rhizosphere of cotton plants, namely, T-ICA01, T-ICA03, T-ICA04, and T-ICA08. These fungal isolates were categorized as belonging to Fusarium solani using their phenotypic characteristics and ITS region sequence data. Examination of the infection index showed that T-ICA03 and T-ICA04 caused systemic colonization (90%) of seeds followed by the occurrence of radicle and coleoptile decay. In contrast, T-ICA08 strain was less pathogenic against seed tissues (40%) in comparison to the other strains isolated. Our study showed that in transgenic insect-resistant cotton the disease "Fusarium wilt" is caused by the fungus, F. solani. Future studies are necessary to characterize the F. solani populations to determine whether phenological stages might influence the genetic diversity of the fungal populations present.


Cancer in the gastric remnant in China--a review of 33 cases in China.
A review of 33 cases of cancer in the gastric remnant (CGR) including 6 cases in Xian is presented. The detection rate of CGR consisting of different interval groups was 3.16%. The average age was 52.4 years, and Male: female ratio was 10:1. The average interval from the previous operation to the detection was 13.9 years. The interval of the subgroup over 30 years of age at the first operation was shorter than that of the subgroup below 30 years. The highest incidence was found in anastomotic stoma (58.1%) and cardia (32.3%). Borrmann I was the most common pathological type. Confirmed diagnostic rate with fibergastroscope was 81.8%. It is imperative that physician should follow up the patients with stomach remnant. No matter what the results of gastrointestinal barium study may be, the patients should undergo fibergastroscopic examination. The pathogenesis of CGR is also discussed.


Calcium channels and prostate cancer.
Calcium channels significantly contribute to many cellular processes, including such critical ones as proliferation, differentiation, and apoptosis. In prostate cancer, the influence of calcium channels has been known for over 30 years, with the first observations that calcium channel blockers affect the progression of cancer towards more aggressive phase. Later research identified additional classes of channel proteins having an important regulatory role and affecting malignant transformation. This review discusses the accumulated scientific knowledge focused on calcium channel involvement in regulation of cell fate in prostate tissues as well as recent developments in patents targeted at prostate cancer treatments and involving calcium channel modulators.


Correlations between pathologic changes in the stapes and conductive hearing loss in otosclerosis.
The goal of this temporal bone study was to quantify the relationship between specific histologic changes at the stapes footplate and the magnitude of the air-bone gap in otosclerosis. The study material comprised 26 specimens with otosclerosis and 37 age-matched controls. Detailed anatomic measurements were made on each histologic section through the stapes footplate in each bone, resulting in 30 different measurement parameters for each bone. For frequencies 250 to 2,000 Hz, the conductive hearing loss correlated highly with (p < .01) and appeared to be caused primarily by narrowing and loss of the annular ligament, especially at the posterior stapediovestibular joint space. The size of the air-bone gap appeared to be determined by the extent and degree of this pathologic change. Schuknecht's hypothesis that bony ankylosis of the footplate would be associated with an air-bone gap of >30 dB was supported by our data. However, the degree and extent of bony footplate ankylosis could not be reliably predicted by the size of the air-bone gap.


Assessment of the doses received by the Cuban population from 40K contained in the body: modelling based on a neural network.
Potassium-40 constitutes the main natural source of potassium present in the body, which influences the effective dose received by people. With the aim of assessing the contribution of this component to the doses received by the Cuban population, a study intended to assess the doses was developed. For this purpose, a representative sample of the Cuban population was selected according to age and sex. The measurements were made using the whole-body counter (WBC) of the Center for Radiation Protection and Hygiene (CPHR). For dose estimations, a uniform distribution of potassium for the whole body was assumed. The methodology used was the one recommended by the ICRP. The values of annual effective dose range between 93 and 209 microSv for females and between 123 and 212 microSv for males. The annual average effective dose for members of the public was estimated as 150 +/- 40 microSv, taking into account the experimental data and the specific features of the Cuban population. With the dose values obtained, it was possible to model dose estimates by means of a neural network, which was trained with the results obtained and using as starting data the sex, age, height and corporal weight of people studied. The modelobtained allows consideration of the anatomical features of each person in the estimation of doses.


Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.
Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. clinicaltrials.gov Identifier: NCT00534287.


In vivo kinematics of the salto total ankle prosthesis.
Recent technological advancements in total ankle arthroplasty (TAA) have included the introduction of the mobile bearing concept. This bearing has several advantages, but researchers have questioned whether or not increased mobility sacrifices joint stability or durability of the implant. The present study evaluated the kinematics of this type of prosthesis implanted in patients. Fluoroscopy and 3D-to-2D registration techniques were used to determine the in vivo kinematics for 20 TAA subjects performing two activities: gait and step-up. The motion of the prostheses was described in terms of clinical rotations and as rotation about the helical (screw) axis. Then, the anterior-posterior translation and axial rotation of the mobile bearing insert were determined. Among the clinical rotations, the dorsi-/plantarflexion was the most dominant, revealing the greatest pattern change and the largest magnitude. During gait, the orientation of the prosthetic components changed smoothly from plantarflexion to dorsiflexion. The average range of this motion was 9.2 degrees. For step-up activity, the range was 8.0 degrees. However, between 33% and 66% of stance phase, the talar component's orientation changed from dorsiflexion to plantarflexion. The average absolute range of anterior-posterior translation of the mobile bearing insert was 1.5 mm and 2.3 mm for gait and step-up, respectively. These measured translations were relatively small and may suggest that the rotational portion of the motion was more dominant than translational and provided sufficient mobility.


Prescription drug benefit design: the building blocks and their impact on cost.
Before changing plan design to address the problem of rising prescription drug benefit cost, employers must understand and periodically revisit the pharmacy benefit building blocks. Ultimately, aligning all aspects of the pharmacy benefit is the best and only way to help control drug benefit costs and, at the same time, promote greater employee satisfaction. This article describes how the pharmacy benefit building blocks of delivery (dispensing), provider contracting, drug products and benefit design all have to work together to produce a more effective pharmacy benefit program.


Sources of neostriatal cholecystokinin in the cat.
The objective of this study was to determine the sources of cholecystokinin within the neostriatum of the cat. Cholecystokinin-immunoreactive cells and fibers were detected by means of the peroxidase antiperoxidase immunohistochemical technique. This method was combined with intrastriatal injections of the retrograde marker horseradish peroxidase conjugated with wheat-germ agglutinin to survey the possible afferent sources of cholecystokinin to the feline neostriatum. Intrinsic, apparently aspiny cholecystokinin-immunoreactive neurons organized in a pericapsular pattern were found within both the caudate and putamen of the cat. In addition, both thalamostriatal and mesostriatal projections containing cholecystokinin were observed. These results indicate that cholecystokinin within the neostriatum of the cat arises from both intrinsic and extrinsic sites.


Legacy effects of anthropogenic disturbances modulate dynamics in the world's coral reefs.
Rapidly changing conditions alter disturbance patterns, highlighting the need to better understand how the transition from pulse disturbances to more persistent stress will impact ecosystem dynamics. We conducted a global analysis of the impacts of 11 types of disturbances on reef integrity using the rate of change of coral cover as a measure of damage. Then, we evaluated how the magnitude of the damage due to thermal stress, cyclones, and diseases varied among tropical Atlantic and Indo-Pacific reefs and whether the cumulative impact of thermal stress and cyclones was able to modulate the responses of reefs to future events. We found that reef damage largely depends on the condition of a reef before a disturbance, disturbance intensity, and biogeographic region, regardless of the type of disturbance. Changes in coral cover after thermal stress events were largely influenced by the cumulative stress of past disturbances and did not depend on disturbance intensity or initial coral cover, which suggests that an ecological memory is present within coral communities. In contrast, the effect of cyclones (and likely other physical impacts) was primarily modulated by the initial reef condition and did not appear to be influenced by previous impacts. Our findings also underscore that coral reefs can recover if stressful conditions decrease, yet the lack of action to reduce anthropogenic impacts and greenhouse gas emissions continues to trigger reef degradation. We uphold that evidence-based strategies can guide managers to make better decisions to prepare for future disturbances.


Polymers and biopolymers at interfaces.
This review updates recent progress in the understanding of the behaviour of polymers at surfaces and interfaces, highlighting examples in the areas of wetting, dewetting, crystallization, and 'smart' materials. Recent developments in analysis tools have yielded a large increase in the study of biological systems, and some of these will also be discussed, focussing on areas where surfaces are important. These areas include molecular binding events and protein adsorption as well as the mapping of the surfaces of cells. Important techniques commonly used for the analysis of surfaces and interfaces are discussed separately to aid the understanding of their application.


A nonribosomal peptide synthetase mediates siderophore production and virulence in the citrus fungal pathogen Alternaria alternata.
Alternaria species produce and excrete dimethyl coprogen siderophores to acquire iron. The Alternaria alternata gene AaNPS6, encoding a polypeptide analogous to fungal nonribosomal peptide synthetases, was found to be required for the production of siderophores and virulence on citrus. Siderophores purified from culture filtrates of the wild-type strain did not induce any phytotoxicity on the leaves of citrus. Fungal strains lacking AaNPS6 produced little or no detectable extracellular siderophores and displayed an increased sensitivity to H₂O₂, superoxide-generating compounds (KO₂ and menadione) and iron depletion. Δnps6 mutants were also defective for the production of melanin and conidia. The introduction of a wild-type AaNPS6 under the control of its endogenous promoter to a Δnps6 null mutant at least partially restored siderophore production and virulence to citrus, demonstrating a functional link between iron uptake and fungal pathogenesis. Elevated sensitivity to H₂O₂, seen for the Δnps6 null strain could be relieved by exogenous application of ferric iron. The expression of the AaNPS6 gene was highly up-regulated under low-iron conditions and apparently controlled by the redox-responsive yeast transcriptional regulator YAP1. Hence, the maintenance of iron homeostasis via siderophore-mediated iron uptake also plays an important role in resistance to toxic reactive oxygen species (ROS). Our results demonstrate further the critical role of ROS detoxification for the pathogenicity of A. alternata in citrus.


A Population Health Approach to Clinical Social Work with Complex Patients in Primary Care.
Chronic diseases disproportionately occur among people from disadvantaged backgrounds. These backgrounds correlate with poor health in adulthood. Capacity for patients' to collaborate in their care tends to be lower than among other patients, leading to inefficient uses in medical services and higher risk of adverse events. In the course of this study, social workers engaged patients with increased inpatient and emergency department (ED) use and barriers to self-management, and evaluated them for lifetime exposure to material disadvantage and violence. Intervention focused on creating a primary care team that improved patients' self-efficacy, increased locus of control, and improved capacity for engagement. Results include a 49 percent decrease in admissions and a 5 percent decrease in ED utilization with significant cost savings. Authors recommend further study to analyze social, clinical, and financial risk in a larger sample, which may yield information about a health care provider's most at-risk patients for early targeted intervention.


[American pulmonary histoplasmosis. Prospective study with 232 soldiers after a 2-year assignment in Guiana].
The purpose of this report is to describe the results of a prospective study on pulmonary histoplasmosis in French Guiana. Chest radiographs were performed in 232 French legionnaires returning from a two-year assignment in French Guiana. Further examinations were performed in a total of 8 subjects in whom chest radiographs demonstrated the presence of nodules in the lungs. No evidence of cancer or tuberculosis was found. Findings confirmed histoplasmomas in two cases and demonstrated probable histoplasmosis nodules in 6 cases including three involving calcified lesions. Five of these eight patients had been in high-risk rain forest environments. Pulmonary histoplasmosis should be considered as a possible diagnosis in subjects returning from endemic zones. Confirmation depends on a spectrum of findings. Calcified nodules require only radiographic surveillance with follow-up at six months. Non-calcified nodules require further investigation including CT-scan, bronchoscopy, and serological tests. Surgical biopsy may be necessary to achieve exact histological and mycological identification of the lesion and is recommended in smokers.


Construction of the Pyrrolo[2,3-d]carbazole Core of Spiroindoline Alkaloids by Gold-Catalyzed Cascade Cyclization of Ynamide.
We achieved direct construction of the common pyrrolo[2,3-d]carbazole core of aspidosperma and malagasy alkaloids by a gold-catalyzed cascade cyclization of ynamide. This reaction involves intramolecular cyclization from indole to ynamide followed by trapping of the resulting iminium intermediate. Through the use of chiral gold complexes, an enantiomerically enriched pyrrolo[2,3-d]carbazole was obtained in up to 74% ee. This methodology was successfully applied to the asymmetric formal synthesis of vindorosine.


Environmentally friendly polychlorinated naphthalenes (PCNs) derivatives designed using 3D-QSAR and screened using molecular docking, density functional theory and health-based risk assessment.
A complete design and screening system for environmental-friendly polychlorinated naphthalene (PCN) derivatives was established through three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, density functional theory (DFT) methods and health-based risk assessment based on dynamic multimedia fugacity model. Two types of 3D-QSAR models were established for PCNs using the experimental biological toxicity (logEC50) of 14 PCNs to carry out a modification to lower the logEC50 of CN-70. Consequently, 67 new monosubstituted and disubstituted derivatives with a lower biological toxicity than CN-70 were designed. Furthermore, 21 new CN-70 derivatives were selected through the evaluation of their persistent organic pollutant properties (biological toxicity, bio-concentration, long-range transport potential, biodegradability) and practicability (stability, insulativity, flame retardancy) using 3D-QSAR, molecular docking and DFT methods. Finally, the non-carcinogenic and carcinogenic risks of 19 new CN-70 derivatives in different exposure pathways were reduced, and 5 derivatives with a significant decrease both in biological toxicity (amplitude reduction: 12.73%-32.51%) and risk (amplitude reduction: 32.18%-59.19%) were selected as environmental-friendly PCN derivatives, which had been screened using the health-based risk assessment system associated with dynamic multimedia fugacity model. This study provides a theoretical basis for the design of environmental-friendly flame retardants and insulating materials.


An extended evaluation of an in vivo teratology screen utilizing postnatal growth and viability in the mouse.
A teratology test system proposed by Chernoff and Kavlock utilizes growth and viability for 3 days after birth to prioritize chemicals for standard teratology testing. The present study is an extended observation of the growth and viability of Chernoff and Kavlock's animals from 41 treatments for 250 days to determine if neonatal weight reductions persisted throughout life, if mortality occurred later in life or, if other serious abnormalities developed that could not be anticipated from the neonatal data. One chemical which was positive in the present study would be a false negative in the standard teratology test and the Chernoff/Kavlock Assay (CKA). Congo red did not cause frank malformations or mortality but it specifically altered reproductive function in the offspring. Two chemicals produced a variety of unusual abnormalities that were not apparent in the neonates, indicating that postnatal testing is necessary to determine the full teratogenic potential of some compounds. Mice exposed prenatally to cytosine arabinoside became hydrocephalic and 30% of them lacked lower incisors. Nitrofen caused hydrocephaly, the age of eye-opening was delayed, a few of the mice had no eyes, and most of the mice lacked Harderian glands. Eighteen of the 41 treatments caused mortality of 15%, or greater, by day 3, and four of these treatments resulted in additional mortality past the neonatal period. No compound caused a decrease in viability after the neonatal period without also reducing days 1 or 3 litter sizes, validating the use of this measurement in the CKA. Cytosine arabinoside was administered later in gestation than the CKA dosing regime and caused a marginally significant increase in mortality near birth but killed over 50% of the pups after weaning. Altering the duration or period of exposure in the CKA may necessitate a longer postnatal evaluation than presently recommended. Neonatal weight, the second parameter used in the CKA to prioritize chemicals for additional testing, appears to be less useful than viability. It was a poor predictor of subsequent growth, some early weight effects persisted, while most of those concurrent with maternal weight reductions were transient. A correlation analysis of the parameters measured in the CKA and in the present study, excluding the compounds that produce frank malformations, indicated that compounds that reduced maternal weight gain during dosing had fewer live pups and growth was transiently retarded.(ABSTRACT TRUNCATED AT 400 WORDS)


On a minimal model for hemodynamics and metabolism of lactate: application to low grade glioma and therapeutic strategies.
WHO II low grade glioma evolves inevitably to anaplastic transformation. Magnetic resonance imaging is a good non-invasive way to watch it, by hemodynamic and metabolic modifications, thanks to multinuclear spectroscopy (1)H/(31)P. In this work we study a multi-scale minimal model of hemodynamics and metabolism applied to the study of gliomas. This mathematical analysis leads us to a fast-slow system. The control of the position of the stationary point brings to the concept of domain of viability. Starting from this system, the equations bring to light the parameters that push glioma cells out of their domain of viability. Four fundamental factors are highlighted. The first two are cerebral blood flow and the rate of lactate transport through monocarboxylate transporters, which must be reduced in order to push glioma out of its domain of viability. Another factor is the intra arterial lactate, which must be increased. The last factor is pH, indeed a decrease of intra cellular pH could interfere with glioma growth. These reflections suggest that these four parameters could lead to new therapeutic strategies for the management of low grade gliomas.


Enhanced Glycolytic Metabolism Contributes to Cardiac Dysfunction in Polymicrobial Sepsis.
Cardiac dysfunction is present in >40% of sepsis patients and is associated with mortality rates of up to 70%. Recent evidence suggests that glycolytic metabolism plays a critical role in host defense and inflammation. Activation of Toll-like receptors on immune cells can enhance glycolytic metabolism. This study investigated whether modulation of glycolysis by inhibition of hexokinase will be beneficial to septic cardiomyopathy. Male C57B6/J mice were treated with a hexokinase inhibitor (2-deoxy-d-glucose [2-DG], 0.25-2 g/kg, n = 6-8) before cecal ligation and puncture (CLP) induced sepsis. Untreated septic mice served as control. Sham surgically operated mice treated with or without the 2-DG inhibitor served as sham controls. Cardiac function was assessed 6 hours after CLP sepsis by echocardiography. Serum was harvested for measurement of inflammatory cytokines and lactate. Sepsis-induced cardiac dysfunction was significantly attenuated by administration of 2-DG. Ejection fraction and fractional shortening in 2-DG-treated septic mice were significantly (P < .05) greater than in untreated CLP mice. 2-DG administration also significantly improved survival outcome, reduced kidney and liver injury, attenuated sepsis-increased serum levels of tumor necrosis factor α and interleukin 1β as well as lactate, and enhanced the expression of Sirt1 and Sirt3 in the myocardium, which play an important role in mitochondrial function and metabolism. In addition, 2-DG administration suppresses sepsis-increased expression of apoptotic inducers Bak and Bax as well as JNK phosphorylation in the myocardium. Glycolytic metabolism plays an important role in mediating sepsis-induced septic cardiomyopathy. The mechanisms may involve regulation of inflammatory response and apoptotic signaling.


[Sonographic assessment of vascular bypasses in vitro].
13 bypasses and 8 patches were examined by ultrasound in vitro with a 3.5 MHz and a 10 MHz probe. Whereas only 6 bypasses were assessable by sonography, all patches could be demonstrated in vitro. In these cases, sonography could be accomplished with either of the two frequencies used. The 10 MHz probe was superior for imaging structural details. Immediate postoperative sonography of such grafts, which cannot be demonstrated accurately in vitro, is not reliable.


Sulfotransferase 1A1 (SULT1A1) gene expression is regulated by members of the NFI transcription factors in human breast cancer cells.
Sulfotransferase 1A1 (SULT1A1) gene expression is tissue specific, with little to no expression in normal breast epithelia. Expression in breast tumors has been documented, but the transcriptional regulation of SULT1A1 in human breast tissue is poorly understood. We identified Nuclear Factor I (NFI) as a transcription factor family involved in the regulation of SULT1A1 expression. Transcription Factor Activation Profiling Plate Array assay was used to identify the possible transcription factors that regulate the gene expression of SULT1A1in normal breast MCF-10A cells and breast cancer ZR-75-1 cells. Expression levels of NFI-C and SULT1A1 were determined by real-time RT-PCR using total RNA isolated from 84 human liver samples. Expression levels of SULT1A1, NFI-A, NFI-B, NFI-C, and NFI-X were also determined in different human breast cancer cell lines (MCF-7, T-47D, ZR-75-1, and MDA-MB-231), in the transformed human epithelial cell line MCF-10A, and in ZR-75-1 cells that were transfected with siRNAs directed against NFI-A, NFI-B, NFI-C, or NFI-X for 48 h. The copy numbers of SULT1A1 in cell lines ZR-75-1, MCF-7, T-47D, MDA-MB-231, and MCF-10A were determined using a pre-designed Custom Plus TaqMan® Copy Number kit from Life Technologies. In normal human liver samples, SULT1A1 mRNA level was positively associated with NFI-C. In different human breast cancer and normal epithelial cell lines, SULT1A1 expression was positively correlated with NFI-B and NFI-C. SULT1A1 expression was decreased 41% and 61% in ZR-75-1 cells treated with siRNAs against NFI-A and NFI-C respectively. SULT1A1 gene expression was higher in cells containing more than one SULT1A1 copy numbers. Our data suggests that SULT1A1 expression is regulated by NFI, as well as SULT1A1 copy number variation in human breast cancer cell lines. These data provide a mechanistic basis for the differential expression of SULT1A1 in different tissues and different physiological states of disease.


Photo-CIDNP MAS NMR in intact cells of Rhodobacter sphaeroides R26: molecular and atomic resolution at nanomolar concentration.
Photochemically induced dynamic nuclear polarization (photo-CIDNP) is observed in photosynthetic reaction centers of the carotenoid-less strain R26 of the purple bacterium Rhodobacter sphaeroides by (13)C solid-state NMR at three different magnetic fields (4.7, 9.4, and 17.6 T). The signals of the donor appear enhanced absorptive (positive) and of the acceptor emissive (negative). This spectral feature is in contrast to photo-CIDNP data of reactions centers of Rhodobacter sphaeroides wildtype reported previously (Prakash, S.; Alia; Gast, P.; de Groot, H. J. M.; Jeschke, G.; Matysik, J. J. Am. Chem. Soc. 2005, 127, 14290-14298) in which all signals appear emissive. The difference is due to an additional mechanism occurring in RCs of R26 in the long-living triplet state of the donor, allowing for spectral editing by different enhancement mechanisms. The overall shape of the spectra remains independent of the magnetic field. The strongest enhancement is observed at 4.7 T, enabling the observation of photo-CIDNP enhanced NMR signals from reaction center cofactors in entire bacterial cells allowing for detection of subtle changes in the electronic structure at nanomolar concentration of the donor cofactor. Therefore, we establish in this paper photo-CIDNP MAS NMR as a method to study the electronic structure of photosynthetic cofactors at the molecular and atomic resolution as well as at cellular concentrations.


Delayed appearance of tracer lead in facial hair.
Three adult men were fed 204 Pb - a rare, stable isotope of lead - daily for about 100 days. Simultaneous blood and facial hair measurements of this tracer and of total lead concentrations were made by mass spectrometric isotope dilution analysis. Although the blood showed an immediate response to the intake of the tracer, the facial hair showed a more gradual response and a delay of approximately 35 days. Since the pattern of appearance of lead in hair does not appear to represent a simple time delay of blood lead concentration, the existence of a physiological pool of lead fed by the blood and giving rise to the content in hair is suggested. Hair lead values should, therefore, be interpreted as the integral of the blood lead values over the mean life of this intermediate pool - about 100 days.


Electronic Structure of Superoxidized Radical Cationic Dodecaborate-Based Clusters.
The expanding field of boron clusters has attracted continuous theoretical efforts to understand their diverse structures and unique bonding. We recently discovered a new reversible redox event of B12(O-3-methylbutyl)12 in which the superoxidized radical cationic form [B12(O-3-methylbutyl)12]•+ was identified and isolated for the first time. Herein, comprehensive (TD-)DFT studies in tandem with electrochemical experiments were employed to demonstrate the generality of the reported behavior across perfunctionalized B12(OR)12 clusters (R = aryl or alkyl). While the spin density of radical cationic clusters is delocalized in the core region, the oxidation brings about notable gains of positive partial charges on the supporting groups whose electronics can readily tune the redox potential of the 0/•+ couple. The underlying changes of frontier orbitals were elucidated, and the resulting [B12(OR)12]•+ species manifest a general diagnostic absorption as a consequence of mixed local/charge-transfer excitations.


Intrinsic limitations in mainstream methods of identifying network motifs in biology.
Network motifs are connectivity structures that occur with significantly higher frequency than chance, and are thought to play important roles in complex biological networks, for example in gene regulation, interactomes, and metabolomes. Network motifs may also become pivotal in the rational design and engineering of complex biological systems underpinning the field of synthetic biology. Distinguishing true motifs from arbitrary substructures, however, remains a challenge. Here we demonstrate both theoretically and empirically that implicit assumptions present in mainstream methods for motif identification do not necessarily hold, with the ramification that motif studies using these mainstream methods are less able to effectively differentiate between spurious results and events of true statistical significance than is often presented. We show that these difficulties cannot be overcome without revising the methods of statistical analysis used to identify motifs. Present-day methods for the discovery of network motifs, and, indeed, even the methods for defining what they are, are critically reliant on a set of incorrect assumptions, casting a doubt on the scientific validity of motif-driven discoveries. The implications of these findings are therefore far-reaching across diverse areas of biology.


Scoparone attenuates glioma progression and improves the toxicity of temozolomide by suppressing RhoA/ROCK1 signaling.
Glioma, a type of malignant brain tumor, has become a challenging health issue globally in recent years. In this study, we investigated the potential therapeutic role of scoparone in glioma and the underlying mechanism. Initially, transcriptome sequencing was conducted to identify genes that exhibited differential expression in glioma cells treated with scoparone compared to untreated cells. Subsequently, the impact of scoparone on the proliferation, migration, and invasion of glioma cells was assessed in vitro using a range of assays including cell viability, colony formation, wound healing, and transwell assays. Moreover, the apoptotic effects of scoparone on glioma cells were evaluated through flow cytometry and western blot analysis. Furthermore, we established a glioma xenograft mouse model to assess the in vivo antitumor activity of scoparone. Lastly, by integrating transcriptome analysis, we endeavored to unravel the molecular mechanisms underlying the observed antitumor effects of scoparone by examining the expression levels of RhoA/ROCK1 signaling pathway components using western blot analysis and qRT-PCR. Our transcriptome sequencing results revealed that scoparone significantly downregulated RhoA/ROCK1 signaling in glioma cells. Furthermore, scoparone treatment inhibited glioma cell proliferation, migration, and invasion, and promoted cell apoptosis in vitro. Moreover, scoparone reduced tumor growth and prolonged survival in a glioma xenograft mouse model, and improved the toxicity of temozolomide. Finally, our results showed that the antitumor effects of scoparone were mediated by the suppression of RhoA/ROCK1 signaling. Scoparone could be a promising therapeutic agent for glioma by suppressing RhoA/ROCK1 signaling. These findings pave the way for future research endeavors aimed at the development and optimization of scoparone-based therapeutic strategies.


Synchronization of complex networks through local adaptive coupling.
Two local adaptive strategies for the synchronization of complex networks are discussed in this paper. One, termed as vertex-based, uses local adaptive coupling gains at each node in the network. The other, named edge-based, associates to each edge in the network an adaptive coupling gain, determined solely on the basis of local information. The global asymptotic stability of the synchronous evolution is proven for both strategies using appropriate Lyapunov-based techniques. The effectiveness of the adaptive methodologies presented in the paper is shown via two representative examples: adaptive consensus and the adaptive synchronization of a network on N coupled Chua's circuits.