Survival outcomes in glioblastoma multiforme, including the impact of adjuvant chemotherapy.
Glioblastoma is an uncommon cancer, but one that is disproportionately represented in mortality rates. Recent developments in adjuvant chemotherapy have regenerated enthusiasm for the treatment of this tumor. Ongoing translational and clinical research has led to a greater understanding of the biologic and molecular behavior and heterogeneity of this tumor. Recent shifts in treatment standards, as well as further selective individualizing of therapies based on molecular information, promise progress for this difficult-to-treat neoplasm.


Genetic analysis of the liverwort Marchantia polymorpha reveals that R2R3MYB activation of flavonoid production in response to abiotic stress is an ancient character in land plants.
The flavonoid pathway is hypothesized to have evolved during land colonization by plants c. 450 Myr ago for protection against abiotic stresses. In angiosperms, R2R3MYB transcription factors are key for environmental regulation of flavonoid production. However, angiosperm R2R3MYB gene families are larger than those of basal plants, and it is not known whether the regulatory system is conserved across land plants. We examined whether R2R3MYBs regulate the flavonoid pathway in liverworts, one of the earliest diverging land plant lineages. We characterized MpMyb14 from the liverwort Marchantia polymorpha using genetic mutagenesis, transgenic overexpression, gene promoter analysis, and transcriptomic and chemical analysis. MpMyb14 is phylogenetically basal to characterized angiosperm R2R3MYB flavonoid regulators. Mpmyb14 knockout lines lost all red pigmentation from the flavonoid riccionidin A, whereas overexpression conferred production of large amounts of flavones and riccionidin A, activation of associated biosynthetic genes, and constitutive red pigmentation. MpMyb14 expression and flavonoid pigmentation were induced by light- and nutrient-deprivation stress in M. polymorpha as for anthocyanins in angiosperms. MpMyb14 regulates stress-induced flavonoid production in M. polymorpha, and is essential for red pigmentation. This suggests that R2R3MYB regulated flavonoid production is a conserved character across land plants which arose early during land colonization.


Optimizing treatment of epilepsy during pregnancy.
Freedom from seizures is the ultimate goal in treatment of patients with epilepsy. At the same time, the side effects of antiepileptic drugs (AEDs) should not outweigh the benefits of treatment. This is particularly important in women with epilepsy who wish to become pregnant. These women and their partners should be made aware of the risks associated with uncontrolled seizures as well as the teratogenicity of some AEDs. Recent studies have indicated a higher risk for birth defects and possibly also adverse cognitive effects associated with exposure to valproate compared with carbamazepine. Although further studies are needed, it appears reasonable to use valproate with caution in women with epilepsy who are planning to become pregnant and to consider whether other equally effective and safer AEDs are available. However, women who need valproate to control their seizures should continue the drug and not be discouraged from pregnancy, provided that they receive counseling with the best available knowledge. With proper management before conception, during pregnancy, and after birth, the vast majority of pregnancies in women with active epilepsy will have a favorable outcome.


Interactions of aromatic radicals with water.
The interactions of the benzyl radical (1), the anilinyl radical (2), and the phenoxyl radical (3) with water are investigated using density functional theory (DFT). In addition, we report dispersion-corrected DFT-D molecular dynamics simulations on these three systems and a matrix isolation study on 1-water. The radicals 1-3 form an interesting series with the number of lone pairs increasing from none to two. The anilinyl and benzyl radicals can act as Lewis base through their unpaired electrons, the lone pairs of the heteroatoms, or the doubly occupied π orbitals of the aromatic system. Matrix isolation experiments provide evidence for the formation of a π complex between 1 and water. By combining computational and experimental techniques we identify the possible interactions between the aromatic radicals 1-3 and water, predict the structure and vibrational spectra of the resulting complexes, and analyze the effects of substitution and temperature.


Internet addiction, loneliness, and academic burnout among Chinese college students: a mediation model.
The dynamics of education and student life have changed since the COVID-19 pandemic. Our society, especially the education system, has become largely dependent on the Internet. This paradigm shifts largely took place in the last few decades. As such, there are various ways in which we cannot comprehend the impact that the Internet can have on student psychology, and how multiple other factors could influence that. Internet addiction and its relationship with academic burnout, along with the impact of loneliness, are all essential factors that must be discussed candidly in the post-COVID-19 era. Hence, the objective of this study was, therefore, to explore the relationship between Internet addiction, loneliness, and academic burnout among Chinese college students as well as the mediating role of loneliness. We conducted a cross-sectional questionnaire survey at a Chinese university from October to November 2022. In total, 810 valid respondents were selected via random cluster sampling using the well-established Internet Addiction, Loneliness, and Academic Burnout Scale. The primary approach of mediation analysis and structural equation modeling testing examined the relationships among the three components. Internet addiction could be responsible for academic burnout among college students. Loneliness partially mediates the relationship between Internet addiction and academic burnout. In a mediated way, different types of loneliness contribute to different types of academic burnout. Psychological interventions for loneliness, especially emotional loneliness prevention, are the critical aspects of the problem of Internet addiction accompanied with academic burnout. The causal relationship between Internet addiction and academic burnout, possibly of a two-way nature, needs to be further explored in the next future.


An exceptional salt-tolerant antimicrobial peptide derived from a novel gene family of haemocytes of the marine invertebrate Ciona intestinalis.
A novel gene family coding for putative antimicrobial peptides was identified in the EST (expressed sequence tag) database of the sea squirt Ciona intestinalis, and one of these genes was molecularly cloned from the Northern European Ciona subspecies. In situ hybridization and immunocytochemical analysis revealed that the natural peptide is synthesized and stored in a distinct haemocyte type, the univacuolar non-refractile granulocytes. By semiquantitative RT-PCR (reverse transcription-PCR) analysis, it was shown that the expression of the gene is markedly up-regulated in haemocytes after immune challenge. To evaluate the antimicrobial potency of the putative defence protein, we synthesized a peptide corresponding to its cationic core region. The peptide was highly effective against Gram-negative and Gram-positive bacteria including several human and marine pathogens as well as the yeast Candida albicans. Notably, the antibacterial activity of the peptide was retained at salt concentrations of up to 450 mM NaCl. Using two different methods we demonstrated that the peptide kills Gram-negative and Gram-positive bacteria by permeabilizing their cytoplasmic membranes. CD spectroscopy revealed that, in the presence of liposomes composed of negatively charged phospholipids, the peptide undergoes a conformational change and adopts an alpha-helical structure. Moreover, the peptide was virtually non-cytolytic for mammalian erythrocytes. Hence, the designed salt-tolerant antimicrobial peptide may represent a valuable template for the development of novel antibiotics.


Dynamic Surface Wrinkles for In Situ Light-Driven Dynamic Gratings.
Dynamic diffraction gratings (DDGs) are considered as one of the most promising technologies for application in smart optical devices because of their in situ dynamic regulation of light propagation on demand; however, it is still a challenge to fabricate dynamic periodic micro/nanostructures due to limited materials and processes. Here, a facile and feasible strategy to construct a near-infrared (NIR) radiation-driven DDG is developed based on a double-sided surface pattern, which is fabricated by dynamic wrinkles and/or soft-imprinted static wrinkles. Poly(dimethylsiloxane) (PDMS) containing carbon nanotubes (CNTs) serves as the substrate, and wrinkles are formed on both sides. The resulting double-sided wrinkle pattern can be used as a DDG to generate various adjustable two-dimensional (2D) diffraction patterns driven by NIR light. Furthermore, with various combinations of wrinkles, we demonstrated a single-sided responsive DDG and a double-sided responsive DDG to realize the evolution of diffraction patterns from 2D to one-dimensional (1D) and 2D to zero-dimensional (0D), respectively. The results provide an alternative for DDGs that will have wide applications in smart display, sensing, and imaging systems.


Sulfonation in pharmacology and toxicology.
Sulfonation has a major function in modulating the biological activities of a wide number of endogenous and foreign chemicals, including: drugs, toxic chemicals, hormones, and neurotransmitters. The activation as well as inactivation of many xenobiotics and endogenous compounds occurs via sulfonation. The process is catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily consisting of at least ten functional genes in humans. The reaction in intact cells may be reversed by arylsulafatase present in the endoplasmic reticulum. Under physiological conditions, sulfonation is regulated, in part, by the supply of the co-substrate/donor molecule 3'-phosphadensoine-5-phosphosulfate (PAPS), and transport mechanisms by which sulfonated conjugates enter and leave cells. Variation in the response of individuals to certain drugs and toxic chemicals may be related to genetic polymorphisms documented to occur in each of the above pathways. Sulfonation has a major function in regulating the endocrine status of an individual by modulating the receptor activity of estrogens and androgens, steroid biosynthesis, and the metabolism of catecholamines and iodothyronines Sulfonation is a key reaction in the body's defense against injurious chemicals and may have a major function during early development since SULTs are highly expressed in the human fetus. As with many Phase I and Phase II reactions, sulfonation may also serve as the terminal step in activating certain dietary and environmental agents to very reactive toxic intermediates implicated in carcinogenesis.


Iron(II)-Catalyzed Heck-Type Coupling of Vinylarenes with Alkyl Iodides.
An iron(II)-catalyzed radical alkyl Heck-type reaction of alkyl iodides with vinylarenes under mild conditions has been reported. t-Butyl peroxybenzoate (TBPB) behaves simultaneously as a radical relay initiator, a precursor for the generation of alkyl radical from alkyl iodides, and an oxidant to recycle iron(II)/iron(III). Unactivated primary, secondary, and tertiary alkyl iodides are compatible with the reaction conditions. The mechanistic studies suggest that a radical-polar-crossover pathway might be involved in the catalytic cycle.


Human Rights and the Political Economy of Universal Health Care: Designing Equitable Financing.
Health system financing is a critical factor in securing universal health care and achieving equity in access and payment. The human rights framework offers valuable guidance for designing a financing strategy that meets these goals. This article presents a rights-based approach to health care financing developed by the human right to health care movement in the United States. Grounded in a human rights analysis of private, market-based health insurance, advocates make the case for public financing through progressive taxation. Financing mechanisms are measured against the twin goals of guaranteeing access to care and advancing economic equity. The added focus on the redistributive potential of health care financing recasts health reform as an economic policy intervention that can help fulfill broader economic and social rights obligations. Based on a review of recent universal health care reform efforts in the state of Vermont, this article reports on a rights-based public financing plan and model, which includes a new business tax directed against wage disparities. The modeling results suggest that a health system financed through equitable taxation could produce significant redistributive effects, thus increasing economic equity while generating sufficient funds to provide comprehensive health care as a universal public good.


Stress during pregnancy affects general intellectual and language functioning in human toddlers.
Prenatal maternal stress has been shown to impair functioning in nonhuman primate offspring. Little is known about the effects of prenatal stress on intellectual and language development in humans because it is difficult to identify sufficiently large samples of pregnant women who have been exposed to an independent stressor. We took advantage of a natural disaster (January 1998 ice storm in Québec, Canada) to determine the effect of the objective severity of pregnant women's stress exposure on general intellectual and language development of their children. Bayley Mental Development Index (MDI) scores and parent-reported language abilities of 58 toddlers of mothers who were exposed to varying levels of prenatal stress were obtained at 2 y of age. The hierarchical multiple regression analyses indicated that the toddlers' birth weight and age at testing accounted for 12.0% and 14.8% of the variance in the Bayley MDI scores and in productive language abilities, respectively. More importantly, the level of prenatal stress exposure accounted for an additional 11.4% and 12.1% of the variance in the toddlers' Bayley MDI and productive language abilities and uniquely accounted for 17.3% of the variance of their receptive language abilities. The more severe the level of prenatal stress exposure, the poorer the toddlers' abilities. The level of prenatal stress exposure accounted for a significant proportion of the variance in the three dependent variables above and beyond that already accounted for by non-ice storm-related factors. We suspect that high levels of prenatal stress exposure, particularly early in the pregnancy, may negatively affect the brain development of the fetus, reflected in the lower general intellectual and language abilities in the toddlers.


Detection and Isolation of Circulating Tumor Cells from Breast Cancer Patients Using CUB Domain-Containing Protein 1.
In cancer metastasis, single circulating tumor cells (CTCs) in the blood and disseminated tumor cells (DTCs) in the bone marrow mediate cancer metastasis. Because suitable biomarker proteins are lacking, CTCs and DTCs with mesenchymal attributes are difficult to isolate from the bulk of normal blood cells. To establish a procedure allowing the isolation of such cells, we analyzed the cell line BC-M1 established from DTCs in the bone marrow of a breast cancer patient by stable isotope labeling by amino acids in cell culture (SILAC) and mass spectrometry. We found high levels of the transmembrane protein CUB domain-containing protein 1 (CDCP1) in breast cancer cell lines with mesenchymal attributes. Peripheral blood mononuclear cells were virtually negative for CDCP1. Confirmation in vivo by CellSearch revealed CDCP1-positive CTCs in 8 of 30 analyzed breast cancer patients. Only EpCam-positive CTCs were enriched by CellSearch. Using the extracellular domain of CDCP1, we established a magnetic-activated cell sorting (MACS) approach enabling also the enrichment of EpCam-negative CTCs. Thus, our approach is particularly suited for the isolation of mesenchymal CTCs with downregulated epithelial cancer that occur, for example, in triple-negative breast cancer patients who are prone to therapy failure.


Risk factors and attributable mortality associated with superinfections in neutropenic patients with cancer.
To identify the risk factors and attributable mortality associated with superinfections in febrile neutropenic patients with hematologic malignancies, we prospectively evaluated 333 episodes of fever and neutropenia by means of univariate and multivariate analyses. Superinfection was defined as any infection either occurring during antibiotic therapy or developing within 1 week after discontinuation of antibiotic therapy. Of 333 episodes, 46 (13.8%) were defined as superinfection; these episodes occurred in 46 patients. The risk factors for superinfection in the multivariate analysis were longer duration of profound neutropenia (P < .0001), lack of use of quinolones as prophylaxis (P < .0001), presence of a central venous catheter (P = .02), and persistence of fever after 3 days of antibiotic therapy (P = .02). The crude mortality rate among patients with superinfection was 48%, and the attributable mortality rate was 24% (95% confidence interval, 3%-45%). Identifying risk factors for superinfections in neutropenic patients might allow clinical practices to reduce the negative impact of this complication.


Titanium elastic nailing in femoral diaphyseal fractures of children in 6-16 years of age.
Management of femoral diaphyseal fractures in the age group of 6-16 years is controversial. There has been a resurgence worldwide for operative fixation. Twenty-two children (18 boys, 4 girls) aged 6-16 years with recent (> 3 days) femoral diaphyseal fractures (20 closed, 2 open) were stabilized with Titanium Elastic Nail (TEN). These fractures were in proximal third (n=3), middle third (n=15) and in the distal third (n=4) 17 patients underwent surgery within seven days of their injury. The results were evaluated using Flynn's scoring criteria. Statistical analysis was done using Fischer's exact test. All 22 patients were available for evaluation after a mean of 26 months (14-36 months) of followup. Radiological union in all cases were achieved in a mean time of 8.7 weeks. Full weight bearing was possible in a mean time of 8.8 weeks. Mean duration of hospital stay was 9.8 days. The results were excellent in 13 patients (59.0%), successful in six (27.2%) and poor in three patients (13.6%). All patients had early return to school. Intramedullary fixation titanium elastic nailing is an effective treatment of diaphyseal fractures of the femur in properly selected patients of the 6-16 years age group.


Molecular evolutionary analyses of tooth genes support sequential loss of enamel and teeth in baleen whales (Mysticeti).
The loss of teeth and evolution of baleen racks in Mysticeti was a profound transformation that permitted baleen whales to radiate and diversify into a previously underutilized ecological niche of bulk filter-feeding on zooplankton and other small prey. Ancestral state reconstructions suggest that postnatal teeth were lost in the common ancestor of crown Mysticeti. Genomic studies provide some support for this hypothesis and suggest that the genetic toolkit for enamel production was inactivated in the common ancestor of living baleen whales. However, molecular studies to date have not provided direct evidence for the complete loss of teeth, including their dentin component, on the stem mysticete branch. Given these results, several questions remain unanswered: (1) Were teeth lost in a single step or did enamel loss precede dentin loss? (2) Was enamel lost early or late on the stem mysticete branch? (3) If enamel and dentin/tooth loss were decoupled in the ancestry of baleen whales, did dentin loss occur on the stem mysticete branch or independently in different crown mysticete lineages? To address these outstanding questions, we compiled and analyzed complete protein-coding sequences for nine tooth-related genes from cetaceans with available genome data. Seven of these genes are associated with enamel formation (ACP4, AMBN, AMELX, AMTN, ENAM, KLK4, MMP20) whereas two other genes are either dentin-specific (DSPP) or tooth-specific (ODAPH) but not enamel-specific. Molecular evolutionary analyses indicate that all seven enamel-specific genes have inactivating mutations that are scattered across branches of the mysticete tree. Three of the enamel genes (ACP4, KLK4, MMP20) have inactivating mutations that are shared by all mysticetes. The two genes that are dentin-specific (DSPP) or tooth-specific (ODAPH) do not have any inactivating mutations that are shared by all mysticetes, but there are shared mutations in Balaenidae as well as in Plicogulae (Neobalaenidae + Balaenopteroidea). These shared mutations suggest that teeth were lost at most two times. Shared inactivating mutations and dN/dS analyses, in combination with cetacean divergence times, were used to estimate inactivation times of genes and by proxy enamel and tooth phenotypes at ancestral nodes. The results of these analyses are most compatible with a two-step model for the loss of teeth in the ancestry of living baleen whales: enamel was lost very early on the stem Mysticeti branch followed by the independent loss of dentin (and teeth) in the common ancestors of Balaenidae and Plicogulae, respectively. These results imply that some stem mysticetes, and even early crown mysticetes, may have had vestigial teeth comprised of dentin with no enamel. Our results also demonstrate that all odontocete species (in our study) with absent or degenerative enamel have inactivating mutations in one or more of their enamel genes.


Gas phase vibrational spectroscopy of mass-selected vanadium oxide anions.
The vibrational spectra of vanadium oxide anions ranging from V(2)O(6)(-) to V(8)O(20)(-) are studied in the region from 555 to 1670 cm(-1) by infrared multiple photon photodissociation (IRMPD) spectroscopy. The cluster structures are assigned and structural trends identified by comparison of the experimental IRMPD spectra with simulated linear IR absorption spectra derived from density functional calculations, aided by energy calculations at higher levels of theory. Overall, the IR absorption of the V(m)O(n)(-) clusters can be grouped in three spectral regions. The transitions of (i) superoxo, (ii) vanadyl and (iii) V-O-V and V-O single bond modes are found at approximately 1100 cm(-1), 1020 to 870 cm(-1), and 950 to 580 cm(-1), respectively. A structural transition from open structures, including at least one vanadium atom forming two vanadyl bonds, to caged structures, with only one vanadyl bond per vanadium atom, is observed in-between tri- and tetravanadium oxide anions. Both the closed shell (V(2)O(5))(2,3)VO(3)(-) and open shell (V(2)O(5))(2-4)(-) anions prefer cage-like structures. The (V(2)O(5))(3,4)(-) anions have symmetry-broken minimum energy structures (C(s)) connected by low-energy transition structures of C(2v) symmetry. These double well potentials for V-O-V modes lead to IR transitions substantially red-shifted from their harmonic values. For the oxygen rich clusters, the IRMPD spectra prove the presence of a superoxo group in V(2)O(7)(-), but the absence of the expected peroxo group in V(4)O(11)(-). For V(4)O(11)(-), use of a genetic algorithm was necessary for finding a non-intuitive energy minimum structure with sufficient agreement between experiment and theory.


Traversable Region Detection and Tracking for a Sparse 3D Laser Scanner for Off-Road Environments Using Range Images.
This study proposes a method for detecting and tracking traversable regions in off-road conditions for unmanned ground vehicles (UGVs). Off-road conditions, such as rough terrain or fields, present significant challenges for UGV navigation, and detecting and tracking traversable regions is essential to ensure safe and efficient operation. Using a 3D laser scanner and range-image-based approach, a method is proposed for detecting traversable regions under off-road conditions; this is followed by a Bayesian fusion algorithm for tracking the traversable regions in consecutive frames. Our range-image-based traversable-region-detection approach enables efficient processing of point cloud data from a 3D laser scanner, allowing the identification of traversable areas that are safe for the unmanned ground vehicle to drive on. The effectiveness of the proposed method was demonstrated using real-world data collected during UGV operations on rough terrain, highlighting its potential as a solution for improving UGV navigation capabilities in challenging environments.


The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development.
The majority of patients with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) have deletions of chromosomal region 22q11.2. The abnormalities observed in these patients include conotruncal cardiac defects, thymic hypoplasia or aplasia, hypocalcemia, and characteristic facial features. To understand the genetic basis of these disorders, we have characterized genes within the region that is most consistently deleted in patients with DGS/VCFS, the minimal DiGeorge critical region (MDGCR). In this report, we present the identification and characterization of a novel gene, GSCL, in the MDGCR, with homology to the homeodomain family of transcription factors. Further, we provide evidence that this gene is expressed in a limited number of adult tissues as well as in early human development. The identification of GSCL required a genomic sequence-based approach because of its restricted expression and high GC content. The early expression, together with the known role of homeobox-containing proteins in development, make GSCL an outstanding candidate for some of the abnormalities seen in DGS/VCFS.


Liver fibrosis and protection mechanisms action of medicinal plants targeting apoptosis of hepatocytes and hepatic stellate cells.
Following chronic liver injury, hepatocytes undergo apoptosis leading to activation of hepatic stellate cells (HSC). Consequently, activated HSC proliferate and produce excessive extracellular matrix, responsible for the scar formation. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Treatment strategies should take into account the versatility of its pathogenesis and act on all the cell lines involved to reduce liver fibrosis. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. This review will describe the role of hepatocytes and HSC in the pathogenesis of liver fibrosis and detail the mechanisms of modulation of apoptosis of both cell lines by twelve known hepatoprotective plants in order to reduce liver fibrosis.


The urinary melanogen cysteinyldopa in melanoma and in suntanning: Australian experience.
Determination of urine cysteinyldopa excretion is the most sensitive chemical test for the detection of melanoma metastases and has been successfully applied during the Scandinavian winter, when sun irradiation is low. The value of this determination, under Australian conditions of greater sun irradiation, has been assessed by comparing the cysteinyldopa excretion of patients with that of normal subjects exposed to sunlight. Cysteinyldopa is an intermediate in the biosynthesis of the red-brown phaeomelanin. Of 20 patients without known secondary melanoma, the cysteinyldopa concentration of "spot" urines ranged from 0 to 190 (mean 48) microgram/ml; of six known to have local metastases, 0 to 80 (mean 19) microgram/ml; and of four known to have extensive metastases 80 to 1350 (mean 330) microgram/ml. The effect of sun irradiation alone was assessed in nine healthy subjects followed one to 11 weeks before and after recorded periods of sun exposure. The cysteinyldopa concentrations of 24-hour urines ranged from 40 to 3100 microgram/ml. Increases occurred three to 10 days following sun exposure and were greatest following multiple small exposures in an individual with "Celtic" complexion. It is concluded that measurement of cysteinyldopa concentration would be of value in the follow-up of melanoma patients in Australia only if patients could be persuaded to live under conditions free of all direct sun-irradiation.


Clinical Features, Risk Factors, and Treatments of Microsporidial Epithelial Keratitis.
To report the clinical manifestations, risk factors, and treatments of microsporidial epithelial keratitis in Thailand. Twenty eyes of 19 patients were diagnosed and the clinical presentations, risk factors, and management were analyzed. Of 19 patients, six patients (32%) had no apparent risk factors. Predisposing factors included soil exposure (6/19, 32%), water contamination (6/19, 32%), and eye liner (1/19, 4%). Twelve cases (63%) were detected in the rainy season. All cases presented with disseminated, punctated, elevated, epithelial keratitis. Corneal scrapings with Gram-chromotrope staining were positive in all patients. Moxifloxacin 0.5% eye drops were given and all 16 patients experienced complete resolution. Three recurrent cases were resolved with only topical moxifloxacin without corneal scraping or swabbing. Predisposing factors were not found in some patients; thus, corneal scraping with staining should be considered in cases having a high index of suspicion. The incidence is increased during the rainy season; therefore, clinicians should have more awareness during these times. Debridement with topical moxifloxacin eye drops, without any systemic medication, may be an effective treatment. Corneal scraping or swabbing may not be required in recurrences.


Lactobionic acid in a natural alkylpolyglucoside-based vehicle: assessing safety and efficacy aspects in comparison to glycolic acid.
Lactobionic acid (LA) is a newer cosmeceutical active belonging to the class of alpha-hydroxyacids (AHAs), showing advantages over them. The aim of part I of this study was to compare efficacy and irritation potential of LA vs. glycolic acid (GA) from two types of vehicles - gel and emulsion. In part II, effects of LA-containing emulsions based on a new, natural emulsifier of alkylpolyglucoside (APG) type were evaluated. Skin bioengineering was used on 77 healthy volunteers to assess: color as erythema and melanin (MI) index, transepidermal water loss, electrical capacitance and pH of the skin. In part I of the study, the parameters were measured after occlusion and periodically during 2 weeks of test samples application; in part II parameters were measured periodically during 4 weeks. LA-containing samples has produced better skin performance when compared with corresponding GA-containing ones, particularly the lack of both skin irritation and skin barrier impairment. When used in vehicles based on a new APG-emulsifier, LA and GA have shown better efficacy, emphasizing the importance of vehicle on the effects of topical actives. LA (6%) in the emulsion based on APGs could be proposed as an alternative to low-molecular AHAs in cosmeceuticals.


Evaluation of General and Musculoskeletal Health Literacy Disparities in Pediatric Sports Injury Patient and Guardian Populations.
Increased participation of adolescents in organized sports has led to an increase in pediatric sports injury. Limited health literacy puts patients at risk for worse outcomes through decreased compliance. We aim to evaluate the extent of health literacy disparities in pediatric sports medicine populations. Patients aged 10 to 17 years and their consenting guardians visiting clinic for treatment of a sports-related injury completed a unique questionnaire including self-reported health literacy measures and direct assessment of knowledge regarding care for musculoskeletal injuries. Statistical analysis based on socioeconomic factors and demographics was performed using t tests. A total of 268 patient surveys (14.37±1.94 y) and 251 guardian surveys (43.62±9.08 y) were collected. In self-reported general health literacy scores for guardians, all categories except ethnicity played a statistically significant role, with higher health literacy scores associated with higher education, use of English as the primary language at home, private insurance, and female guardians (P<0.001, <0.001, <0.001, 0.011). In contrast, age was the only factor affecting scores in the patient population (P=0.015). Among self-reported musculoskeletal health literacy and directly measured musculoskeletal literacy scores, there were significant differences in groups by age, primary language, and level of education (P=0.020, 0.003). Significant disparities in general and musculoskeletal health literacy exist within pediatric sports medicine populations, most notably between guardian groups. Improving disparities in health literacy for these populations may best be aimed at guardians, using medical education through verbal/written instruction in multiple languages. Level IV.


High-Throughput Prediction and Design of Novel Conopeptides for Biomedical Research and Development.
Cone snail venoms have been considered a valuable treasure for international scientists and businessmen, mainly due to their pharmacological applications in development of marine drugs for treatment of various human diseases. To date, around 800 Conus species are recorded, and each of them produces over 1,000 venom peptides (termed as conopeptides or conotoxins). This reflects the high diversity and complexity of cone snails, although most of their venoms are still uncharacterized. Advanced multiomics (such as genomics, transcriptomics, and proteomics) approaches have been recently developed to mine diverse Conus venom samples, with the main aim to predict and identify potentially interesting conopeptides in an efficient way. Some bioinformatics techniques have been applied to predict and design novel conopeptide sequences, related targets, and their binding modes. This review provides an overview of current knowledge on the high diversity of conopeptides and multiomics advances in high-throughput prediction of novel conopeptide sequences, as well as molecular modeling and design of potential drugs based on the predicted or validated interactions between these toxins and their molecular targets.


Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.
The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.


Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data.
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation. The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space. We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds. Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets.


The molecular biology of the low-temperature response in plants.
Plants growing in temperate regions are able to survive freezing temperatures from -5 degrees to -30 degrees C, depending on the species, through a process known as cold acclimation. In the last decade much work has been done on the molecular mechanisms of low temperature (LT) signal transduction and cold acclimation. Mutant studies and microarray analyses have revealed C-Repeat binding factor (CBF) -dependent and -independent signaling pathways in plants. Experimental evidence suggests the existence of 'potential LT sensors' but as yet there is no direct proof. A number of signal transducers such as various kinases/phosphatases have been demonstrated but the signal transduction pathways have not been elucidated. An understanding of the molecular basis of the signaling process, however, is of potential practical application. Designing new strategies to improve cold tolerance in crop varieties could increase the plant productivity and also expand the area under cultivation.


Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease.
Cystinuria is a common inherited disorder of defective renal reabsorption of cystine and dibasic amino acids. Recently, 2 responsible genes have been identified: mutations in the SLC3AI gene encoding the glycoprotein rBAT cause cystinuria type I, while variants in the SLC7A9 gene have been demonstrated in non-type I cystinuria; its gene product b(0)+AT is the light chain of the renal cystine transport system rBAT/b(0),+-AT. To estimate the role of both genes in the etiology of cystinuria, we searched for sequence alterations in SLC7A9 and SLC3AI: 30 unclassified cystinurics were investigated. In 50% of patients (15/30), point mutations in SLC3A1 were detected. Screening of the SLC7A9 gene revealed 10 mutations in 8 patients corresponding to a frequency of 27%. In addition to previously published mutations in the SLC7A9 gene, we detected 2 new mutations (F 140S, c747delG). An overall detection rate of 73% (22/30) in unclassified patients is delineated for mutations in both genes. In 33% (10/30), 2 mutations were detected, in 40% (12/30) 1 mutation. Furthermore, 5 new polymorphic sites were identified in SLC7A9. While the base pair variation in intron 9 is homogeneously distributed in patients and control individuals, the allelic and genotypic distributions of the polymorphisms in 3 exons of SLC7A9--exons 2, 5 and 6--and intron 3 differ significantly between both groups. Our results suggest that some haplotypes defined through the exons 2, 5 and 6 and intron 3 might be markers of a functional variant in the SLC7A9 gene. Evidently, since the mutation detection rates in the 2 so far known cystinuria genes never reach 100%, further genes and modulating factors should influence the phenotype in a subset of patients. However, the presented data show that testing for mutations in the 2 currently known cystinuria genes is already a meaningful approach to the molecular diagnostics of the disease.


Analysis of the performance of contractualization primary health care indicators in the period 2009-2015 in Lisbon and Tagus Valley.
Reforms started in 1996 intended that Regional Health Administrations (ARS) should play a relevant role in the process of transforming an integrated model towards a contractual health care model. The essential tool of this transformation would be the Contractualization Agency, established in each ARS. Its role in the new contractualization culture was to negotiate prospective budgets with health care institutions, which included Primary Health Care (PHC). This paper is a longitudinal analysis of the development of a set of nine PHC contractualization indicators in three Health Center Clusters (ACeS) of the Regional Health Administration of Lisbon and Tagus Valley (ARSLVT). We have noticed that the setting of goals, in terms of external contractualization and its monitoring and follow-up are decisive and help health professionals to define trajectories and performance goals. We also recognize the need to revise baseline indicators by developing them into outcome indicators.


Factor XIII: enzymatic and clinical aspects.
The present knowledge about clotting F XIII is roughly displayed. It is explained why F XIII is not a clotting factor in the strict sense of the word and that its biological function more general is the crosslinking of proteins via a transamidase reaction, the reduction of the permeability of the microvasculature, the stimulation of connective tissue cells, and finally the steering of connective tissue processes involved in wound healing. These effects are demonstrated as well in cell culture studies, animal experiments as by clinical results. Concerning the clinical results with F XIII, its effects on sclerodermia, subarachnoidal hemorrhage, inflammatory bowel diseases, Purpura Schönlein Henoch, and the wound healing are described in more detail.


Malignancy in relatives of patients with coeliac disease.
A survey of 1329 relatives of 139 patients with coeliac disease demonstrated an overall increase of cancer deaths particularly in women, but this did not quite reach 5 percent significance in men. Evidence is insufficient to determine whether this was due to the occurrence of cancer in relatives with undetected coeliac disease or to the operation of independent factors.


Clinicopathological characteristics of 8697 patients with COVID-19 in China: a meta-analysis.
Our study aims to present a summary of the clinicopathological characteristics of patients affected by the coronavirus disease 2019 (COVID-19) that can be used as a reference for further research and clinical decisions. Studies were included in the meta-analysis if they had cohort, case-control or case series designs and provided sufficient details on clinical symptoms, laboratory outcomes and asymptomatic patients. PubMed, Embase, Chinese Biomedical Literature Database, Wanfang, China Science and Technology Journal Database and China National Knowledge Infrastructure databases were electronically searched to identify related studies published between 1 January 2020 and 16 March 2020. Three reviewers independently examined the literature, extracted relevant data and assessed the risk of publication bias before including the studies in the meta-analysis. The confirmed cases of COVID-19. A total of 55 unique retrospective studies involving 8697 patients with COVID-19 were identified. Meta-analysis showed that a higher proportion of infected patients were male (53.3%), and the two major symptoms observed were fever (78.4%) and cough (58.3%). Other common symptoms included fatigue (34%), myalgia (21.9%), expectoration (23.7%), anorexia (22.9%), chest tightness (22.9%) and dyspnoea (20.6%). Minor symptoms included nausea and vomiting (6.6%), diarrhoea (8.2%), headache (11.3%), pharyngalgia (11.6%), shivering (15.2%) and rhinorrhea (7.3%). About 5.4% of the patients were asymptomatic. Most patients showed normal leucocyte counts (64.7%) and elevated C reactive protein levels (65.9%). Lymphopaenia was observed in about 47.6% of the infected patients, along with abnormal levels of myocardial enzymes (49.4%) and liver function (26.4%). Other findings included leucopenia (23.5%), elevated D-dimer (20.4%), elevated erythrocyte sedimentation rate (20.4%), leucocytosis (9.9%), elevated procalcitonin (16.7%) and abnormal renal function (10.9%). The most commonly experienced symptoms of patients with COVID-19 were fever and cough. Myalgia, anorexia, chest tightness and dyspnoea were found in some patients. A relatively small percentage of patients were asymptomatic and could act as carriers of the disease. Most patients showed normal leucocyte counts, elevated levels of C reactive protein and lymphopaenia, confirming the viral origin of the disease.


Unraveling the Ion Uptake Capacitive Deionization of Sea- and Highly Saline-Water by Sulfur and Nitrogen Co-Doped Porous Carbon Modified with Molybdenum Sulfide.
In parallel to the depletion of potable water reservoirs, novel technologies have been developed for seawater softening, as it is the most abundant source for generating deionized water. Although salt removal at subosmotic pressures and ambient temperatures by applying low-operating potentials with high energy efficiency made capacitive deionization (CDI) an advantageous water-softening process, its practical application is limited by insufficient ion removal capacity and low concentration influent. The performance of a CDI system is in progress with engineering the electrode active materials, also facilitating the advance design in highly saline- and seawater study. Herein, an innovative strategy was developed to provide high-performance CDI systems based on efficient and electrochemical ion-uptake active materials with a simple initial preparation. Nitrogen-doped porous carbons (N-pCs) received benefits from a high specific surface area and good surface wettability. The N-pCs were modified with molybdenum oxide/sulfide intercalative array and developed as CDI electrode active materials for desalination of both low/medium saline- and seawater. The MoS2/S,N-pC electrode materials exhibited perfect optimized salt adsorption capacity (SACs) of 47.9 mg g-1 when compared to N-pC (37.9 mg g-1) and MoO3/N-pC (39.6 mg g-1) counterparts at 1.4 V in a 750 ppm NaCl solution. In addition, the assembled CDI cells exhibited reasonable cycle stability and retained 96.7% of their initial SAC in continuous CDI cycles for 128,000 s. The fabricated CDI cell rendered an excellent salt removal efficiency (SRE, %) of 13.34% from the real seawater sample at 1.2 V. In detail, the SRE % of the NaCl, KCl, MgCl2, and CaCl2 soluble salts with respect to seawater sample exhibited a remarkable SRE % of 30.8%, 36%, 32.6%, and 19.3%, respectively. These SRE % values (>13.34%) provide convincing evidence on the reasonable ion uptake capability of the fabricated CDI cells for removing Na+, K+, Mg2+, and Ca2+ ions compared to other soluble component. The advanced cell design parallel to the promising outcomes provided herein makes these CDI systems immensely propitious for efficient water softening.


Nasopharyngeal abscess causing inspiratory dyspnoea in a domestic cat.
An 11-month-old female domestic shorthair cat presented with a 24 h history of inspiratory dyspnoea, abnormal upper respiratory tract sounds, gagging, retching and making exaggerated swallowing motions. Retroflexed nasopharyngoscopy revealed a large, right-sided nasopharyngeal mass that was seen to exude purulent material and a possible small foreign body when pressure was applied with forceps. Thorough expression of the mass alleviated clinical signs. Cytology revealed septic neutrophilic inflammation, and a Pasteurella species with no noted antimicrobial resistance was cultured. The cat was discharged with oral antibiotics and analgesia and made a full recovery, with no recurrence of clinical signs at the 6-month follow-up. Abscess formation in the nasopharyngeal region has not been previously reported in cats, to the authors' knowledge. The cause of the abscess was suspected to be a foreign body, but other aetiologies could not be fully excluded. This case demonstrates that nasopharyngeal abscesses are a rare but potentially significant differential diagnosis for upper respiratory tract obstruction in cats.


Electrostatic field effects of coenzymes on ligand binding to catalytic zinc in liver alcohol dehydrogenase.
The synergism between coenzyme and anion binding to liver alcohol dehydrogenase has been examined by equilibrium measurements and transient-state kinetic methods to characterize electrostatic interactions of coenzymes with ligands which are bound to the catalytic zinc ion of the enzyme subunit. Inorganic anions typically exhibit an at least 200-fold higher affinity for the general anion-binding site than for catalytic zinc on complex formation with free enzyme. Acetate and SCN- interact more strongly with catalytic zinc in the enzyme X NAD+ complex than with the general anion-binding site in free enzyme. CN- shows no significant affinity for the general anion-binding site, but combines to catalytic zinc in the absence as well as the presence of coenzymes. Coordination of CN- to catalytic zinc weakens the binding of NADH by a factor of 50, and tightens the binding of NAD+ to approximately the same extent through interactions which do not include any contributions from covalent adduct formation between CN- and NAD+. These observations provide unambiguous information about the magnitude of electrostatic field effects of coenzymes on anion (e.g. hydroxyl ion) binding to catalytic zinc. They lead to the important inference that coenzyme binding must be strongly affected by ionization of zinc-bound water irrespective of the actual acidity of the latter group. It is concluded on such grounds that the much debated pH dependence of coenzyme binding to liver alcohol dehydrogenase must derive from ionization of zinc-bound water. The assumption that such is not the case leads to the inference that there is no detectable effect of ionization of zinc-bound water on coenzyme binding over the pH range 6-12, a possibility which is definitely excluded by the present results.


Mothers' experiences of emotional abuse from an intimate partner and its associations with children's developmental outcomes at 5 years.
Intimate partner violence (IPV) is associated with an increased risk of poorer child development. Existing research has focused on physical abuse with less known about the associations with emotional IPV. To describe the period prevalence of mother's experiences of emotional IPV during children's preschool years and associations with child mental, physical, social, and cognitive development. Secondary analysis of control group data (n = 194) from an Australian randomised trial (right@home), which recruited pregnant women experiencing social adversity from antenatal clinics in 2013-14. Women reported emotional abuse (Composite Abuse Scale) at child ages 3-5 years. Measures of child development at 5 years included: Strengths and Difficulties Questionnaire, Social Skills Improvement System, Pediatric Quality of Life Inventory, Clinical Evaluation of Language Fundamentals, School Entry Alphabetic and Phonological Awareness Readiness Test, NIH executive function subtests, sleep and health. The prevalence of emotional IPV from 3 to 5 years was estimated. Regression models compared developmental outcomes according to emotional IPV exposure, adjusted for child age, child gender, and maternal education. Missing data were accounted for using multiple imputation. From 3-5 years, emotional IPV was experienced by 57% of women. Emotional IPV exposure was consistently associated with poorer child developmental outcomes. Differences were most apparent for SDQ internalising (mean difference 1.2, 95% CI 0.2 to 2.1) and externalising difficulties (1.2, 95% CI -0.1 to 2.4). Emotional IPV was highly prevalent amongst families experiencing social adversity. Developing acceptable and effective identification processes and interventions that prioritise families experiencing co-occurring social adversities should be a public health priority.


pH-Dependent conformational changes and topology of a herpesvirus translocating peptide in a membrane-mimetic environment.
Pol peptide, an oligopeptide corresponding to the 27 C-terminal amino acids of DNA polymerase from herpes simplex virus type 1, has recently been suggested to translocate from endosomal compartments into the cytosol after being intracellularly delivered via a protein carrier. While an acidic environment was thought to be important for Pol peptide membrane translocation, the mechanism of translocation remains unclear. To investigate the influence of an acidic environment on the conformational properties of the peptide and on its propensity to interact with lipid bilayers, we characterized the structure of Pol peptide at different pH values by both circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. The influence of detergent micelles, which mimic biological lipid membranes, on the peptide secondary structure was also studied. Our CD results indicate that the peptide is in a random conformation in aqueous solution at both acidic and basic pH, whereas in the presence of dodecylphosphocholine (DPC) micelles, it assumes a partial alpha-helical structure which is significantly pH-dependent. An NMR study confirmed that, in the presence of DPC micelles, a short C-terminal alpha-helix is present at pH 6.5, whereas almost two-thirds of the peptide (residues 10-26) fold into an extended amphipathic alpha-helix at pH 4.0. The orientation of Pol peptide relative to the DPC micelle was investigated using paramagnetic probes at both pH 4.0 and 6.5. These studies show that the peptide inserts deeply into the micelle at pH 4.0, whereas it is more exposed to the aqueous environment at pH 6.5. On the basis of these results, a model which might explain the mechanism of translocation of Pol peptide from acidic endosomes to the cytosol is discussed.


U.S. Policies Addressing Ultraprocessed Foods, 1980-2022.
Ultraprocessed foods are industrial formulations manufactured from substances derived from foods and industrially-produced ingredients and additives. Few countries' policies directly regulate ultraprocessed food, but several countries' dietary guidelines suggest eating less ultraprocessed food. The U.S. Dietary Guidelines for Americans do not mention the ultraprocessed food category, but the 2025-2030 Advisory Committee is tasked with evaluating research related to ultraprocessed food consumption. The U.S. Dietary Guidelines for Americans are used for U.S. food and nutrition policies. It is unknown the extent that federal and state policymakers have already proposed or passed policies addressing ultraprocessed foods. Research was conducted using Lexis+ into federal and state statutes, bills, resolutions, regulations, and proposed rules, and Congressional Research Services reports to identify policymaking related to highly processed and ultraprocessed food from January 1980 through February 2023. This research identified 25 policy actions (8 federal, 17 state) proposed or passed between 1983 and 2022 (22 of them, 2011-2022). The most common topic area related to children's nutrition (n=14), and a prevalent theme related to food prices. Only 1 policy defined ultraprocessed food, and 3 policies sought to address the broader food environment by providing incentives to small retailers to stock healthy foods. Addressing ultraprocessed food in U.S. policy activity is quite recent, with few policies directly targeting ultraprocessed foods but rather discussing them as contrary to healthy diets. Internationally, ultraprocessed foods have been directly integrated into national dietary guidelines and school food programs. These policies are consistent with emerging U.S. policy activity and may provide information for future policymaking in the U.S.


Subcutaneous immunoglobulin replacement therapy in a heart transplant recipient with severe recurrent infections.
Intravenous immunoglobulin has been shown to decrease the risk of post-transplant infections in heart recipients with IgG hypogammaglobulinemia, however the use of subcutaneous immunoglobulin has not been reported. We report on immune reconstitution, clinical efficacy and tolerability of subcutaneous immunoglobulin replacement therapy in a heart transplant recipient with secondary antibody deficiency. Maintenance of IgG levels, specific antibodies and control of infections were observed after change from intravenous immunoglobulin to subcutaneous immunoglobulin due to poor intravenous access. Recurrences of severe infections were observed when subcutaneous immunoglobulin infusions were stopped. Our observations suggest that subcutaneous immunoglobulin replacement therapy might be effective and well tolerated in selected heart recipients.


The study of polar emerging contaminants in seawater by passive sampling: A review.
Emerging Contaminants (ECs) in marine waters include different classes of compounds, such as pharmaceuticals and personal care products, showing "emerging concern" related to the environment and human health. Their measurement in seawater is challenging mainly due to the low concentration levels and the possible matrix interferences. Mass spectrometry combined with chromatographic techniques represents the method of choice to study seawater ECs, due to its sensitivity and versatility. Nevertheless, these instrumental techniques have to be preceded by suitable sample collection and pre-treatment: passive sampling represents a powerful approach in this regard. The present review compiles the existing occurrence studies on passive sampling coupled to mass spectrometry for the monitoring of polar ECs in seawater and discusses the availability of calibration data that enabled quantitative estimations. A vast majority of the published studies carried out during the last two decades describe the use of integrative samplers, while applications of equilibrium samplers represent approximately 10%. The polar Chemcatcher was the first applied to marine waters, while the more sensitive Polar Organic Chemical Integrative Sampler rapidly became the most widely employed passive sampler. The organic Diffusive Gradients in Thin film technology is a recently introduced and promising device, due to its more reliable sampling rates. The best passive sampler selection for the monitoring of ECs in the marine environment as well as future research and development needs in this area are further discussed. On the instrumental side, combining passive sampling with high resolution mass spectrometry to better assess polar ECs is strongly advocated, despite the current challenges associated.


Matrigel: a useful tool to study endothelial differentiation.
Matrigel is a matrix of a mouse basement membrane neoplasm. It represents a complex mixture of basement membrane proteins including laminin, type IV collagen, entactin/nitrogen and proteoheparan sulfate, but it also contains growth factors. Matrigel induces endothelial cells to differentiate as evidenced by both the morphologic changes and by the reduction in proliferation and, therefore, offers a convenient model to study biochemical and molecular events associated with angiogenesis. Further, Matrigel permits to study the roles of the extracellular matrix in angiogenesis.


Hepatocyte growth factor increases osteopontin expression in human osteoblasts through PI3K, Akt, c-Src, and AP-1 signaling pathway.
Hepatocyte growth factor (HGF) has been demonstrated to stimulate osteoblast proliferation and participated bone remodeling. Osteopontin (OPN) is a secreted phosphoglycoprotein that belongs to the SIBLING family and is present during bone mineralization. However, the effects of HGF on OPN expression in human osteoblasts are large unknown. Here we found that HGF induced OPN expression in human osteoblasts dose-dependently. HGF-mediated OPN production was attenuated by c-Met inhibitor and siRNA. Pretreatment of osteoblasts with PI3K inhibitor (Ly294002), Akt inhibitor, c-Src inhibitor (PP2), or AP-1 inhibitor (curcumin) blocked the potentiating action of HGF. Stimulation of osteoblasts with HGF enhanced PI3K, Akt, and c-Src activation. In addition, incubation of cells with HGF also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the OPN promoter. HGF-mediated AP-1-luciferase activity and c-Jun binding to the AP-1 element was reduced by c-Met inhibitor, Ly294002, Akt inhibitor, and PP2. Our results suggest that the interaction between HGF and c-Met increases OPN expression in human osteoblasts via the PI3K, Akt, c-Src, c-Jun, and AP-1 signaling pathway.


[Electrophysiologic analysis of the antiamnestic effect of activation of the dopaminergic and noradrenergic systems].
On a model of a defensive conditioned reflex with a short delay it was shown in acute experiments in cats that the suppression of noradrenaline (NA) synthesis by diethyldithiocarbamate led to a disturbance of retrieval of electrographic correlates of memory trace, i.e. of conditioned evoked potentials in the hippocampus and central gray matter and of motor component of the conditioned reaction, i.e. conditioned neurographic response of the radial nerve. Simultaneous suppression of both dopamine (DA) and NA syntheses by alpha-methyl-para- thyrosine led to a regional expansion of the disturbances mentioned involving the hippocampus, central gray matter, reticular formation, amygdalar complex, zona, incerta and auditory cortex. Activation of postsynaptic NA-receptors by clonidine and that of post-synaptic DA-receptors by apomorphine produced an antiamnestic effect on the conditioned evoked potential in the amygdalar complex and central gray matter.


The ns and nd Rydberg states of O2 described by Hund's case (e).
Using Hund's case (e) representation, we have obtained a simulation of the 5s Rydberg states of O(2) for J=2 by fitting the experimental data obtained recently by Sheard et al. [J. Chem. Phys. 118, 8781 (2003)]. Our analysis permits us to include evidence of not only the mixing of Hund's case (a) states by spin-orbit interaction, but also by L and S uncouplings. This mixing is even more important for the nd Rydberg states. For the 3d Rydberg state, J=2, we have been able to suggest for the first time an assignment for both the 3d sigma (1)Pi(g) and the 3d delta (1)Pi(g) states.


Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms.
Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.


Location and flexibility of the unique C-terminal tail of Aquifex aeolicus co-chaperonin protein 10 as derived by cryo-electron microscopy and biophysical techniques.
Co-chaperonin protein 10 (cpn10, GroES in Escherichia coli) is a ring-shaped heptameric protein that facilitates substrate folding when in complex with cpn60 (GroEL in E. coli). The cpn10 from the hyperthermophilic, ancient bacterium Aquifex aeolicus (Aacpn10) has a 25-residue C-terminal extension in each monomer not found in any other cpn10 protein. Earlier in vitro work has shown that this tail is not needed for heptamer assembly or protein function. Without the tail, however, the heptamers (Aacpn10del-25) readily aggregate into fibrillar stacked rings. To explain this phenomenon, we performed binding experiments with a peptide construct of the tail to establish its specificity for Aacpn10del-25 and used cryo-electron microscopy to determine the three-dimensional (3D) structure of the GroEL-Aacpn10-ADP complex at an 8-A resolution. We found that the GroEL-Aacpn10 structure is similar to the GroEL-GroES structure at this resolution, suggesting that Aacpn10 has molecular interactions with cpn60 similar to other cpn10s. The cryo-electron microscopy density map does not directly reveal the density of the Aacpn10 25-residue tail. However, the 3D statistical variance coefficient map computed from multiple 3D reconstructions with randomly selected particle images suggests that the tail is located at the Aacpn10 monomer-monomer interface and extends toward the cis-ring apical domain of GroEL. The tail at this location does not block the formation of a functional co-chaperonin/chaperonin complex but limits self-aggregation into linear fibrils at high temperatures. In addition, the 3D variance coefficient map identifies several regions inside the GroEL-Aacpn10 complex that have flexible conformations. This observation is in full agreement with the structural properties of an effective chaperonin.


Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation.
Autosomal dominant episodic ataxia type 2 (EA2) results from mutations of the CACNA1A gene. We describe EA2 with unusual features in a father and daughter with a novel CACNA1A mutation coding for Y248C. Both patients showed severe cerebellar atrophy in MRI and clinical signs of progressive spinocerebellar atrophy type 6. Most disabling were the very frequent episodes of ataxia with migraine (with aura in the father and without aura in the daughter) and nystagmus in our patients. Additionally, they suffered from ictal hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder. Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake, the typical treatment for EA2. The significance of these findings is discussed and the phenotype correlated to previously reported cases.


WRN conditioned media is sufficient for in vitro propagation of intestinal organoids from large farm and small companion animals.
Recent years have seen significant developments in the ability to continuously propagate organoids derived from intestinal crypts. These advancements have been applied to mouse and human samples providing models for gastrointestinal tissue development and disease. We adapt these methods for the propagation of intestinal organoids (enteroids) from various large farm and small companion (LF/SC) animals, including cat, dog, cow, horse, pig, sheep and chicken. We show that LF/SC enteroids propagate and expand in L-WRN conditioned media containing signaling factors Wnt3a, R-spondin-3, and Noggin (WRN). Multiple successful isolations were achieved for each species, and the growth of LF/SC enteroids was maintained to high passage number. LF/SC enteroids expressed crypt stem cell marker LGR5 and low levels of mesenchymal marker VIM. Labeling with EdU also showed distinct regions of cell proliferation within the enteroids marking crypt-like regions. The ability to grow and maintain LF/SC enteroid cell lines provides additional models for the study of gastrointestinal developmental biology as well as platforms for the study of host-pathogen interactions between intestinal cells and zoonotic enteric pathogens of medical importance.


Physical activity or fitness and the metabolic syndrome.
The metabolic syndrome is highly prevalent in populations around the world, regardless of the definition used. Physical inactivity and obesity are two of the major modifiable risk factors for the metabolic syndrome. Cross-sectional and prospective studies have generally found that levels of physical activity and fitness are inversely related to the prevalence of this syndrome. More recent research has also suggested that sedentary behaviors, such as excessive time spent watching television or using a computer, are significantly associated with an increased risk for this syndrome. Separate but complementary approaches that encourage increased participation in physical activity and discourage sedentary behaviors, both at the individual and population level, may prove useful in reducing the prevalence of this syndrome.


Insertions generating the 5'RUNX1/3'CBFA2T1 gene in acute myeloid leukemia cases show variable breakpoints.
Translocation t(8;21)(q22;q22) is a common karyotypic abnormality detected in about 15% of acute myeloid leukemia (AML) cases. The rearrangement results in fusion of the RUNX1 (also known as AML1) and CBFA2T1 (also known as ETO) genes, generating a 5'RUNX1/3'CBFA2T1 transcriptionally active fusion gene on derivative chromosome 8, but some cases with ins(21;8) and ins(8;21) have been observed. However, a detailed breakpoint characterization of the insertion events has never been reported. In the present article, we describe six insertion events among 82 (7.3%) AML cases characterized by the RUNX1/CBFA2T1 fusion. Using FISH experiments with appropriate bacterial artificial chromosome (BAC) and P1 artificial chromosome (PAC) probes, we were able to perform a detailed molecular cytogenetic characterization of one case with ins(8;21) and five with ins(21;8). Our analysis revealed that insertions generating the 5'RUNX1/3'CBFA2T1 gene showed variable breakpoints; the size of the inserted elements ranged from 2.4 to 44 Mb.


Anti-HIV agents II. Synthesis and in vitro anti-HIV activity of novel 1H,3H-thiazolo[3,4-a]benzimidazoles.
A series of 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles was synthesized starting from o-phenylenediamine, disubstituted aromatic aldehydes and 2-mercaptoacetic acid. Their antiviral activity against human immunodeficiency virus (HIV) was explored: the 1-(2',6'-dichlorophenyl) (4c), 1-(2',6'-difluorophenyl) (4i), 1-(2'-chloro,6'-fluorophenyl) (4K) and 1-(2'-chloro,5'-nitrophenyl) (4m) derivatives significantly inhibit in vitro the viral cytopathic effect in HIV-infected CEM cells. Compound 4i was selected by NCI's Review Committee for initial preclinical development studies.


Cellular functions of ascorbic acid: a means to determine vitamin C requirements.
Optimal ascorbic acid (vitamin C) requirements in humans are unknown. In situ kinetics is a biochemical approach to determine requirements for vitamin C and other vitamins. In situ kinetics requires that cellular functions of ascorbic acid are characterized. Vitamin-C-dependent cellular reactions are directly related to vitamin C concentrations inside and outside cells. By coupling intracellular and extracellular functions of ascorbic acid to vitamin concentration, in situ kinetics provides a novel approach to determining vitamin C requirements.


The participation of prostaglandins in the action of kinins on the central dopaminergic system in the rat. II. Participation of PGF2 alpha in the action of kinins on the central dopaminergic system.
Administration of prostaglandin F2 alpha (PGF2 alpha) in the presence of kinins did not change or potentiated the action of amphetamine (AMPH). Depending on the dose, PGF2 alpha could antagonize or potentiate the effect of kinins on the apomorphine (APO)-induced stereotypy. A combined treatment with PGF2 alpha and kinins did not affect or potentiate the haloperidol (HAL)-induced catalepsy. Bradykinin (BRS) and PGF2 alpha given separately or in combination did not change the levels of dopamine (DA), homovanillic acid (HVA) and noradrenaline (NA) after administration of AMPH, but given in combination elevated the striatal level of DA after treatment with APO. PGF2 alpha given in combination with BRS to rats receiving alpha-methyl-p-tyrosine (alpha-MT) increased the DA turnover in the striatum, while combined treatment with PGF2 alpha BRS, APO and alpha-MT depressed the turnover rate.


Homology, limbs, and genitalia.
Similarities in genetic control between the main body axis and its appendages have been generally explained in terms of genetic co-option. In particular, arthropod and vertebrate appendages have been explained to invoke a common ancestor already provided with patterned body outgrowths or independent recruitment in limb patterning of genes or genetic cassettes originally used for purposes other than axis patterning. An alternative explanation is that body appendages, including genitalia, are evolutionarily divergent duplicates (paramorphs) of the main body axis. However, are all metazoan limbs and genitalia homologous? The concept of body appendages as paramorphs of the main body axis eliminates the requirement for the last common ancestor of limb-bearing animals to have been provided with limbs. Moreover, the possibility for an animal to express complex organs ectopically demonstrates that positional and special homology may be ontogenetically and evolutionarily uncoupled. To assess the homology of animal genitalia, we need to take into account three different sets of mechanisms, all contributing to their positional and/or special homology and respectively involved (1) in the patterning of themain body axis, (2) in axis duplication, followed by limb patterning mechanisms diverging away from those still patterning the main body axis (axis paramorphism), and (3) in controlling the specification of sexual/genital features, which often, but not necessarily, come into play by modifying already developed and patterned body appendages. This analysis demonstrates that a combinatorial approach to homology helps disentangling phylogenetic and ontogenetic layers of homology.


Shiftwork in the hot environment.
The study examined the risks of heat induced workplace accidents (textile industry, N = 4125) and the heat tolerability of the rotating day (morning and afternoon, N = 16) and permanent night shift workers (N = 13) in hot-dry and hot-humid environment (34 to 49 degrees C, 50-80% RH; 31 to 42 degrees C ET, Basic). Accident prevalence was significantly high in the summer months (May-June) when the ambient temperature ranged between 42 and 48 degrees C (hot-dry). The influence of hot climate in accident causation was evident from the shift-wise variations in the occurrence of accidents. The longitudinal study showed that the night workers were more vulnerable and less tolerant to heat, the tolerance time being less by about 15% (31 degrees C ET) to 40% (39 degrees C ET), compared to the rotating day workers. The relationship of the segmental and compartmental temperatures (segmental triggering response) played a critical role in heat dissipation/accumulation mechanism, and reflected in the heat tolerability of the day and night workers.


Influence of formation path on the CH2BrCl2+ dissociation dynamics.
To get further insight into the CH2BrCl site-selective fragmentation previously observed upon inner-shell ionization, we have performed high-resolution Br 3d and Cl 2p Auger and spin-orbit resolved Br 3d Auger spectra, and studied the dissociation properties of the CH2BrCl2+ dication formed at threshold by means of threshold electron pair-ion coincidence measurements. The key point is that the origin of site-specific bond breaking is found in the Auger decay itself, as it preferentially populates selected dication states. Whereas the predominance of the C-Br bond breaking is observed in both threshold and inner-shell studies, no signature of selective C-Cl rupture is reported for the dication formed at threshold.


Catch-and-Release of Target Cells Using Aptamer-Conjugated Electroactive Zwitterionic Oligopeptide SAM.
Nucleic acid aptamers possess attractive features such as specific molecular recognition, high-affinity binding, and rapid acquisition and replication, which could be feasible components for separating specific cells from other cell types. This study demonstrates that aptamers conjugated to an oligopeptide self-assembled monolayer (SAM) can be used to selectively trap human hepatic cancer cells from cell mixtures containing normal human hepatocytes or human fibroblasts. Molecular dynamics calculations have been performed to understand how the configurations of the aptamers are related to the experimental results of selective cell capture. We further demonstrate that the captured hepatic cancer cells can be detached and collected along with electrochemical desorption of the oligopeptide SAM, and by repeating these catch-and-release processes, target cells can be enriched. This combination of capture with aptamers and detachment with electrochemical reactions is a promising tool in various research fields ranging from basic cancer research to tissue engineering applications.


Chronic exposure to ozone causes tolerance to airway hyperresponsiveness in guinea pigs: lack of SOD role.
Tolerance to respiratory effects of O3 has been demonstrated for anatomic and functional changes, but information about tolerance to O3-induced airway hyperresponsiveness (AHR) is scarce. In guinea pigs exposed to air or O3 (0.3 parts/million, 4 h/day, for 1, 3, 6, 12, 24, or 48 days, studied 16-18 h later), pulmonary insufflation pressure changes induced by intravenous substance P (SP, 0.032-3.2 micro ug/kg) were measured, then the animals were subjected to bronchoalveolar lavage (BAL). Bronchial rings with or without phosphoramidon were also evaluated 3 h after air or a single O3 exposure. O3 caused in vivo AHR (increased sensitivity) to SP after 1, 3, 6, 12, and 24 days of exposure compared with control. However, after 48 days of exposure, O3 no longer caused AHR. Total cell, macrophage, neutrophil, and eosinophil counts in BAL were increased in most O3-exposed groups. When data from all animals were pooled, we found a highly significant correlation between degree of airway responsiveness and total cells (r = 0.55), macrophages (r = 0.54), neutrophils (r = 0.47), and eosinophils (r = 0.53), suggesting that airway inflammation is involved in development of AHR to SP. Superoxide dismutase (SOD) levels in BAL fluids were increased (P < 0.05) after 1, 3, 6, and 12 days of O3 exposure and returned to basal levels after 24 and 48 days of exposure. O3 failed to induce hyperresponsiveness to SP in bronchial rings, and phosphoramidon increased responses to SP in air- and O3-exposed groups, suggesting that neutral endopeptidase inactivation was not involved in O3-induced AHR to SP in vivo. We conclude that chronic exposure to 0. 3 ppm O3, a concentration found in highly polluted cities, resulted in tolerance to AHR to SP in guinea pigs by an SOD-independent mechanism.


[Hypotension followed the first dose of angiotensin-converting enzyme inhibitor in patients with heart failure (a multicenter clinical trial)].
To study the hypotensive effect of the first dose in administration of perindopril and enalapril in patients with chronic cardiac failure (CCF). The trial enrolled 213 patients with CCF of functional class II-III (mean age 57 +/- 1.4 years, 155 males and 58 females). The patients were randomized into 2 groups. Group 1 received perindopril in a dose 2 mg, group 2 received enalapril. Arterial pressure was measured for 10 hours with a 30-min interval, in the last 3 hours--once an hour. First dose hypotension was stated if systolic pressure was < 90 mmHg, diastolic under 60 mmHg, mean pressure < 75 mmHg after the first intake of the drug. Significant differences in the baseline pressure between the groups were absent. None of the patients demanded therapy of arterial hypotension. Side effects of hypotension were absent. In group 1 systolic pressure fell under 90 mmHg in 8(7.7%) patients, in group 2--in 24(22.0%) patients (p = 0.004), diastolic pressure fell under 60 mmHg in 47(45.2%) and 60(55.1%) patients, respectively (p = 0.151). Mean arterial pressure was < 75 mmHg in 42(40.4%) and 62(56.9%) patients, respectively, (p = 0.016). Multivariate correlation analysis has revealed a direct correlation between the first dose hypotension and age (r = 0.159, p < 0.01) and age > 70 years (r = 0.258, p < 0.01), acute myocardial infarction (r = 0.244, p < 0.01) and inverse correlation with the initial arterial pressure (r = -0.208, p < 0.01).


Anticancer Activity of Atractylodes lancea (Thunb.) DC in a Hamster Model and Application of PET-CT for Early Detection and Monitoring Progression of Cholangiocarcinoma.
Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is an important cancer in the Great Mekong region, particularly in Thailand. Limitations of treatment options and the lack of an effective diagnostic tool for early detection of CCA are major concerns for the control of this type of cancer. The aim of the study was to investigate anti-CCA activity of the ethanolic extract of Atractylodes lancea (Thunb.) DC., and the applicability of positron emission tomography-computed tomography (PET-CT) as a tool for detection and monitoring the progression of CCA in Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN)-induced CCA hamsters. Male Syrian hamsters were used for toxicity tests and anti-CCA activity evaluation. Development of CCA was induced by initial feeding of 50 metacercariae of OV, followed by drinking water containing 12.5 ppm of DMN in hamsters. The ethanolic extract of A. lancea (Thunb.) DC. was administered orally for 30 days. PET-CT was performed every 4 weeks after initiation of CCA using 18F-fluorodeoxyglucose (18F-FDG). Results from the present study suggest that the ethanolic extract of A. lancea (Thunb.) DC. rhizome exhibited promising anti-CCA activity and safety profile in the OV/DMN-induced hamster model. To successfully apply PET-CT as a tool for early detection of tumor development and progression, modification of radiolabeling approach is required to improve its specificity for CCA cells.


Protective effect of curcumin in fructose-induced metabolic syndrome and in streptozotocin-induced diabetes in rats.
The aim of this study was to investigate the effect of pre-treatment with curcumin on metabolic changes induced by two different pathophysiological mechanisms in rats (fructose diet and streptozotocin (STZ)-induced diabetes mellitus). Five groups with 10 rats per group were investigated: control group (healthy rats), fructose diet groups without any pre-treatment (FD), fructose diet groups with curcumin pre-treatment (FDC), STZ-induced diabetes mellitus without any pre-treatment (SID) and STZ-induced diabetes mellitus with curcumin pre-treatment (SIDC). Systolic blood pressure, and several metabolic and oxidative stress parameters were assessed. Systolic blood pressure significantly increased in all groups compared with control group (P<0.001), with significantly lower values on groups with curcumin pre-treatment compared with the group without any pre-treatment and same inducement (FDS vs. FD P<0.0001, SIDC vs. SID P<0.0001). High-density lipoprotein (HDL)-cholesterol was significantly lower in all groups compared with control group (P<0.05) while triglycerides (P<0.05), aspartate aminotransferase (AST, P<0.0001) and alanine aminotransferase (ALT, P<0.0001) were significantly higher. Within the group with same induction, curcumin pre-treatment significantly improved metabolic (total cholesterol, glycaemia, triglycerides, AST, ALT; P<0.05) and oxidative stress parameters (total oxidative status (NOx), Thiol, and malondialdehyde (MDA), P<0.02) compared to untreated groups. The pre-treatment with curcumin in our experimental models significantly improved metabolic (total cholesterol, triglycerides, AST and ALT) as well as oxidative stress parameters (MDA, NOx, and Thiol) in both fructose diet and in STZ-induced diabetes in rats. These properties of curcumin may serve to improve the metabolic and oxidative stress conditions in patients with these pathological features.


Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population.
The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to Graves' disease (GD) in Caucasians. The objective of this study was to investigate whether PTPN22 gene polymorphisms confer susceptibility to GD and Graves' ophthalmopathy (GO) in a Japanese population. We performed a case-control study of PTPN22 gene polymorphisms in Japanese GD patients (n = 414) and healthy control subjects with no antithyroid autoantibodies or family history of autoimmune disorders (n = 231). The G-1123C polymorphism (rs2488457) in the promoter region, Arg620Trp (C1858T) polymorphism (rs2476601) in exon 14, IMS-JST146695 polymorphism (rs3789607) in intron 19, and SNP37 (rs3789604) downstream of the PTPN22 gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism using restriction enzymes and direct PCR sequencing methods. None of the GD patients or control subjects had the 1858T allele of the PTPN22 gene polymorphism. The AA-genotype and A-allele frequencies of SNP37 were significantly higher in GD patients than in control subjects (A-allele frequency: p = 0.0085, odds ratio = 1.45). The genotype frequencies and allele frequencies of the G-1123C and IMS-JST146695 polymorphisms did not differ between GD patients and control subjects. The -1123G/1858C/JST146695T/SNP37C haplotype frequency was significantly lower in GD patients than in control subjects. There were no associations between PTPN22 gene polymorphisms and GO. The results suggest that SNP37 of the PTPN22 gene is associated with susceptibility to GD in a Japanese population. Further studies including functional analyses are required.


Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.
Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225Ac-E4G10. We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma.


Interindividual differences in gray and white matter properties are associated with early complex motor skill acquisition.
Brain circuits mediate but also constrain experience-induced plasticity and corresponding behavioral changes. Here we tested whether interindividual behavioral differences in learning a challenging new motor skill correlate with variations in brain anatomy. Young, healthy participants were scanned using structural magnetic resonance imaging (T1-weighted MPRAGE, n = 75 and/or diffusion-weighted MRI, n = 59) and practiced a complex whole-body balancing task on a seesaw-like platform. Using conjunction tests based on the nonparametric combination (NPC) methodology, we found that gray matter volume (GMV) in the right orbitrofrontal cortex was positively related to the subjects' initial level of proficiency and their ability to improve performance during practice. Similarly, we obtained a strong trend toward a positive correlation between baseline fractional anisotropy (FA) in commissural prefrontal fiber pathways and later motor learning. FA results were influenced more strongly by radial than axial diffusivity. However, we did not find unique anatomical correlates of initial performance and learning to rate. Our findings reveal structural predispositions for successful motor skill performance and acquisition in frontal brain structures and underlying frontal white matter tracts. Together with previous results, these findings support the view that structural constraints imposed by the brain determine subsequent behavioral success and underline the importance of structural brain network constitution before learning starts.


Zinc Intake Is Associated with Lower Cadmium Burden in U.S. Adults.
Cadmium is a toxic transition metal whose absorption and accumulation might depend on zinc intake. We sought to determine whether zinc intake and serum zinc would be inversely associated with cadmium exposure. This study used data from NHANES 2003-2012, from which there were 6678 and 6488 participants with urinary and blood cadmium data, respectively, and 1195 participants with serum zinc data. Mean blood and urinary cadmium were reported by quintiles of zinc intake and by the dose and duration of zinc supplement use. The associations between zinc intake from diet and supplements, serum zinc, and blood and urinary cadmium were determined using multiple regression. Analyses were adjusted for age, body mass index, race/ethnicity, gender, income-to-poverty ratio, education, smoking status, and mean intakes of energy, calcium, and iron. Urinary cadmium concentrations were 0.04 μg/g creatinine lower among participants in the highest compared with lowest quintile of total zinc intake (P-trend = 0.0041). Zinc supplement dose and duration were inversely associated with blood cadmium (P = 0.0372) and serum zinc (P-trend = 0.0017), respectively. In adjusted regression models, a 10% increase in total zinc intake corresponded to a predicted decrease in blood cadmium of 0.42% (95% CI: -0.79%, -0.06%; P = 0.0260) and in urinary cadmium of 0.42% (95% CI: -0.81%, -0.04%; P = 0.0340). A 10% increase in serum zinc was associated with a predicted 1.99% (95% CI: -3.17%, -0.81%; P = 0.0012) decrease in blood cadmium and a predicted 4.09% (95% CI: 2.14%, 6.04%, P = 0.0001) increase in urinary cadmium. Dietary and serum zinc in US adults are associated with cadmium exposure, presumably by influencing the absorption and accumulation of cadmium. Whether the degree of reduction in cadmium exposure from greater zinc intake and status is causal or relevant from a public health perspective needs further investigation.


Dimeric and tetrameric forms of muscle fructose-1,6-bisphosphatase play different roles in the cell.
Muscle fructose 1,6-bisphosphatase (FBP2), besides being a regulatory enzyme of glyconeogenesis also protects mitochondria against calcium stress and plays a key role in regulation of the cell cycle, promoting cardiomyocytes survival. However, in cancer cells, FBP2 acts as an anti-oncogenic/anti-proliferative protein. Here, we show that the physiological function of FBP2 depends both on its level of expression in a cell as well as its oligomerization state. Animal fructose-1,6-bisphosphatases are thought to function as tetramers. We present evidence that FBP2 exists in an equilibrium between tetramers and dimers. The dimeric form is fully active and insensitive to AMP, the main allosteric inhibitor of FBP2. Tetramerization induces the sensitivity of the protein to AMP, but it requires the presence of a hydrophobic central region in which leucine 190 plays a crucial role. Only the tetrameric form of FBP2 is retained in cardiomyocyte cell nucleus whereas only the dimeric form associates with mitochondria and protects them against stress stimuli, such as elevated calcium and H2O2 level. Remarkably, in hypoxic conditions, which are typical for many cancers, FBP2 ceases to interact with mitochondria and loses its pro-survival potential. Our results throw new light on the basis of the diverse role of FBP2 in cells.


Current status of radiofrequency ablation of hepatocellular carcinoma.
Loco-regional treatments for hepatocellular carcinoma (HCC) are important alternatives to curative transplantation or resection. Among them, radiofrequency ablation (RFA) is accepted as the most popular technique showing excellent local tumor control and acceptable morbidity. The current role of RFA is well documented in the evidence-based practice guidelines of European Association of Study of Liver, American Association of Study of the Liver Disease and Japanese academic societies. Several randomized controlled trials have confirmed that RFA is superior to percutaneous ethanol injections in terms of local tumor control and survival. The overall survival after RFA is comparable to after surgical resection in a selected group of patients with smaller (< 3 cm) tumors. Currently, the clinical benefits of combined RFA with transarterial chemoembolization for intermediate stage HCC are increasingly being explored. Here we review the ongoing technical advancements of RFA and future potential.


The role of the proteasome in apoptosis induced by anthracycline anticancer agents.
To elucidate the involvement of proteasome inhibition in apoptosis induced by anthracycline anticancer agents, we investigated the interaction between the proteasome and anthracycline anticancer agents, and the function of the proteasome in apoptosis. Exposure of L1210 mouse lymphocytic leukemia cells to adriamycin (ADM) or 4'-O-tetrahydropyranyladriamycin (THP) resulted in apoptosis in a dose-dependent manner: 5 microM ADM and 0.5 microM THP induced apoptosis efficiently, but the effects of 10 microM ADM and 5 microM THP were markedly decreased or completely absent. Carbobenzoxy-leucyl-leucyl-leucinal (Z-LLLal), a specific proteasome inhibitor, also induced dose-dependent apoptosis of the cells. The inhibitory effect of THP on chymotrypsin-like protease activity of proteasomes purified from the cytosol of L1210 cells was stronger than that of ADM. Both of these agents showed reversible non-competitive inhibitory effects. The intracellular content of ubiquitinated protein increased in ADM-, THP- or Z-LLLal-treated L1210 cells during apoptosis. These results suggested that anthracycline anticancer agents induce apoptosis by interacting, at least in part, with proteasomes.


Active galactic nucleus feedback in clusters of galaxies.
Observations made during the last ten years with the Chandra X-ray Observatory have shed much light on the cooling gas in the centers of clusters of galaxies and the role of active galactic nucleus (AGN) heating. Cooling of the hot intracluster medium in cluster centers can feed the supermassive black holes found in the nuclei of the dominant cluster galaxies leading to AGN outbursts which can reheat the gas, suppressing cooling and large amounts of star formation. AGN heating can come in the form of shocks, buoyantly rising bubbles that have been inflated by radio lobes, and the dissipation of sound waves.


Story Goodness in Adolescents With Autism Spectrum Disorder (ASD) and in Optimal Outcomes From ASD.
This study examined narrative quality of adolescents with autism spectrum disorder (ASD) using a well-studied "story goodness" coding system. Narrative samples were analyzed for distinct aspects of story goodness and rated by naïve readers on dimensions of story goodness, accuracy, cohesiveness, and oddness. Adolescents with high-functioning ASD were compared with adolescents with typical development (TD; n = 15 per group). A second study compared narratives from adolescents across three groups: ASD, TD, and youths with "optimal outcomes," who were diagnosed with ASD early in development but no longer meet criteria for ASD and have typical behavioral functioning. In both studies, the ASD group's narratives had lower composite quality scores compared with peers with typical development. In Study 2, narratives from the optimal outcomes group were intermediate in scores and did not differ significantly from those of either other group. However, naïve raters were able to detect qualitative narrative differences across groups. Findings indicate that pragmatic deficits in ASD are salient and could have clinical relevance. Furthermore, results indicate subtle differences in pragmatic language skills for individuals with optimal outcomes despite otherwise typical language skills in other domains. These results highlight the need for clinical interventions tailored to the specific deficits of these populations.