Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia.
Wayne Fenton was a major driving force behind the establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) project mechanisms. These projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified 3 drug mechanisms of particular interest: cholinergic, dopaminergic, and glutamatergic. The TURNS project is designed to select potential cognitive-enhancing agents and evaluate their potential efficacy in the context of proof of concept or clinical efficacy trials. This article reviews the rationale for these 3 approaches and provides an update on the development of therapeutic agents, which act through one of these 3 mechanisms.


Syntheses of alpha-fluoro-alpha,beta-unsaturated thioamides and thiazolines from a fluorophosphonodithioacetate.
A high-yielding synthesis of methyl fluoro(diethoxyphosphono)dithioacetate starting from its difluorinated analogue is reported. Fluorophosphonothioacetamides and -methylthiazolines, prepared from this new dithioester, have been successfully transformed into highly functionalized fluoroalkenes. Good stereoselectivity in favor of the E isomer was observed from the fluorophosphonomethylthiazolines. The potential of these new fluorinated olefinating reagents for the synthesis of modified peptides and glycosides is also disclosed.


Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography.
To prospectively predict the effectiveness of a clinically used nanochemotherapeutic agent by detecting and measuring the intratumoral uptake of an x-ray contrast agent nanoprobe by using digital mammography. All animal procedures were approved by the institutional animal care and use committee. A long-circulating 100-nm-scale injectable liposomal probe encapsulating 155 mg/mL iodine was developed. Preliminary studies were performed to identify the agent dose that would result in adequate tumor enhancement without enhancement of the normal vasculature in rats. This dose was used to image a rat breast tumor (n = 14) intermittently for 3 days by using a digital mammography system; subsequently, the animals were treated with liposomal doxorubicin. The predictive capability of the probe was characterized by creating good- and bad-prognosis subgroups, on the basis of tumor enhancement found during imaging, and analyzing the tumor growth after treatment of the animals in these two subgroups. A dose of 455 mg of iodine per kilogram of body weight was found to produce an undetectable signal from the blood while achieving enough intratumoral accumulation of the probe to produce adequate signal for detection. The good- and bad-prognosis subgroups demonstrated differential tumor growth rates (P < .003). An inverse linear relationship between the contrast enhancement rate constant during imaging and the tumor growth rate constant during treatment was found (slope = -0.576, R(2) = 0.838). In this animal model, quantitative measurement of vascular permeability enabled prediction of therapeutic responsiveness of tumors to liposomal doxorubicin.


Variable light environments induce plastic spectral tuning by regional opsin coexpression in the African cichlid fish, Metriaclima zebra.
Critical behaviours such as predation and mate choice often depend on vision. Visual systems are sensitive to the spectrum of light in their environment, which can vary extensively both within and among habitats. Evolutionary changes in spectral sensitivity contribute to divergence and speciation. Spectral sensitivity of the retina is primarily determined by visual pigments, which are opsin proteins bound to a chromophore. We recently discovered that photoreceptors in different regions of the retina, which view objects against distinct environmental backgrounds, coexpress different pairs of opsins in an African cichlid fish, Metriaclima zebra. This coexpression tunes the sensitivity of the retinal regions to the corresponding backgrounds and may aid in detection of dark objects, such as predators. Although intraretinal regionalization of spectral sensitivity in many animals correlates with their light environments, it is unknown whether variation in the light environment induces developmentally plastic alterations of intraretinal sensitivity regions. Here, we demonstrate with fluorescent in situ hybridization and qPCR that the spectrum and angle of environmental light both influence the development of spectral sensitivity regions by altering the distribution and level of opsins across the retina. Normally, M. zebra coexpresses LWS opsin with RH2Aα opsin in double cones of the ventral but not the dorsal retina. However, when illuminated from below throughout development, adult M. zebra coexpressed LWS and RH2Aα in double cones both dorsally and ventrally. Thus, environmental background spectra alter the spectral sensitivity pattern that develops across the retina, potentially influencing behaviours and related evolutionary processes such as courtship and speciation.


Efficient skin interactions of graphene derivatives: challenge, opportunity or both?
Interactions between graphene, with its wide deployment in consumer products, and skin, the body's largest organ and first barrier, are highly relevant with respect to toxicology and dermal delivery. In this work, interaction of polyglycerol-functionalized graphene sheets, with 200 nm average lateral size and different surface charges, and human skin was studied and their potential as topical delivery systems were investigated. While neutral graphene sheets showed no significant skin interaction, their positively and negatively charged counterparts interacted with the skin, remaining in the stratum corneum. This efficient skin interaction bears a warning but also suggests a new topical drug delivery strategy based on the sheets' high loading capacity and photothermal property. Therefore, the immunosuppressive drug tacrolimus was loaded onto positively and negatively charged graphene sheets, and its release measured with and without laser irradiation using liquid chromatography tandem-mass spectrometry. Laser irradiation accelerated the release of tacrolimus, due to the photothermal property of graphene sheets. In addition, graphene sheets with positive and negative surface charges were loaded with Nile red, and their ability to deliver this cargo through the skin was investigated. Graphene sheets with positive surface charge were more efficient than the negatively charged ones in enhancing Nile red penetration into the skin.


QUANTUM COMPUTING: Quantum Entangled Bits Step Closer to IT.
In contrast to today's computers, quantum computers and information technologies may in future be able to store and transmit information not only in the state "0" or "1," but also in superpositions of the two; information will then be stored and transmitted in entangled quantum states. Zeilinger discusses recent advances toward using this principle for quantum cryptography and highlights studies into the entanglement (or controlled superposition) of several photons, atoms, or ions.


Specific mechanics for abutment uprighting.
General practitioners can use adjunctive orthodontics in preparation for complex comprehensive dental restorative procedures. Two orthodontic educators from opposite sides of the world explain and illustrate the biomechanics of controlled abutment uprighting. Solutions to the common mechanical and clinical problems are discussed.


Forearm Deformities in Birth Brachial Plexus Palsy - Patient Profile and Management Algorithm.
Forearm deformities are often seen in children with severe birth brachial plexus palsy (BBPP). They may be either a supination or a pronation deformity and both hinder normal use of the hand and parents often request for corrective surgery. However, the correction of these deformities can be challenging due to a paucity of options. Also, there is less information in literature on the management of forearm deformities in BBPP compared to the information with regard to nerve surgery or correction of shoulder deformities. This article presents a synopsis of incidence, pathogenesis, clinical presentation and parental concerns related to these deformities. The decision-making considerations, management strategies and outcome expectations are also discussed. Patient selection is very crucial, and the treatment plan must be individualised depending on the disability, parental expectations and existing motor power in the involved limb. Correction of both the deformities have different considerations; however, effective correction of these deformities is immensely satisfactory to the patient/parents in terms of improved function and appearance of the limb. Level of Evidence: Level V (Therapeutic).


Specific nutrient patterns are associated with higher structural brain integrity in dementia-free older adults.
Optimal nutrition may play a beneficial role in maintaining a healthy brain. However, the relationship between nutrient intake and brain integrity is largely unknown. We investigated the association of specific nutrient dietary patterns with structural characteristics of the brain. Within the population-based Swedish National study on Aging and Care-Kungsholmen (SNAC-K), a cross-sectional study of 417 dementia-free participants aged ≥60 years who underwent structural magnetic resonance imaging (MRI) scans during 2001-2003, was carried-out. Data on dietary intake were collected using a food frequency questionnaire, from which intake of 21 nutrients was estimated. By principal component analysis, five nutrient patterns were extracted: (1) NP1 was characterized by fiber, vitamin C, E, β-carotene, and folate [Fiber&Antioxidants], (2) NP2 by eicosapentaenoic (EPA, 20:5 ω-3) and docosahexaenoic (DHA, 22:6 ω-3) polyunsaturated fatty acids (PUFAs), proteins, cholesterol, vitamin B3, B12, and D [long chain (LC) ω-3PUFAs&Proteins], (3) NP3 by α-linoleic (18:2 ω-6) and α-linolenic (18:3 ω-3) PUFAs, monounsaturated fatty acids (MUFAs), and vitamin E [MUFAs&ω-3,6PUFAs], (4) NP4 by saturated fatty acids (SFAs), trans fats, MUFAs, and cholesterol [SFAs&Trans fats], (5) NP5 by B-vitamins, retinol, and proteins [B-Vitamins&Retinol]. Nutrient patterns scores were tertiled with the lowest tertile as reference, and were related to total brain volume (TBV) and white matter hyperintensities volume (WMHV) using linear regression models adjusting for potential confounders. In the multi-adjusted model, compared to the lowest intake for each pattern, the highest intake of NP1 (β = 11.11, P = 0.009), NP2 (β = 7.47, P = 0.052), and NP3 (β = 10.54, P = 0.005) was associated with larger TBV whereas NP5 was related to smaller TBV (β = -12.82, P = 0.001). The highest intake of NP1 was associated with lower WMHV (β = -0.32, P = 0.049), whereas NP4 was associated with greater WMHV (β = 0.31, P = 0.036). In sum, our results suggest that the identified brain-health specific nutrient combinations characterized by higher intake of fruit, vegetables, legumes, olive and seed oils, fish, lean red meat, poultry and low in milk and dairy products, cream, butter, processed meat and offal, were strongly associated with greater brain integrity among older adults.


Direct and hydrogen peroxide-induced chromium(V) oxidation of deoxyribose in single-stranded and double-stranded calf thymus DNA.
Oxidative DNA damage by a model Cr(V) complex, [CrO(ehba)2]-, with and without added H2O2, was investigated for the formation of base and sugar products derived from C1', C4', and C5' hydrogen atom abstraction mechanisms. EPR studies with 5,5-dimethylpyrroline N-oxide (DMPO) have shown that Cr(V)-ehba alone can oxidize the spin trap via a direct chromium pathway, whereas reactions of Cr(V)-ehba in the presence of H2O2 generated the hydroxyl radical. Direct (or metal-centered) Cr(V)-ehba oxidation of single-stranded (ss) and double-stranded (ds) calf thymus DNA demonstrated the formation of thiobarbituric acid-reactive species (TBARS) and glycolic acid in an O2-dependent manner, consistent with abstraction of the C4' H atom. A minor C1' H atom abstraction mechanism was also observed for direct Cr(V) oxidation of DNA, but no C5' H atom abstraction product was observed. Direct Cr(V) oxidation of ss- and ds-DNA also caused the release of all four nucleic acid bases with a preference for the pyrimidines cytosine and thymine in ds-DNA, but no base release preference was observed in ss-DNA. This base release was O2-independent and could not be accounted for by the H atom abstraction mechanisms in this study. Reaction of Cr(V)-ehba with H2O2 and DNA yielded products consistent with all three DNA oxidation pathways measured, namely, C1', C4', and C5' H atom abstractions. Cr(V)-ehba and H2O2 also mediated a nonpreferential release of DNA bases with the exception of the oxidatively sensitive purine, guanine. Direct and H2O2-induced Cr(V) DNA oxidation had opposing substrate preferences, with direct Cr(V) oxidation favoring ss-DNA while H2O2-induced Cr(V) oxidative damage favored ds-DNA. These results may help explain the carcinogenic mechanism of chromium(VI) and serve to highlight the differences and similarities in DNA oxidation between high-valent chromium and oxygen-based radicals.


Drosophila motor neuron retraction during metamorphosis is mediated by inputs from TGF-β/BMP signaling and orphan nuclear receptors.
Larval motor neurons remodel during Drosophila neuro-muscular junction dismantling at metamorphosis. In this study, we describe the motor neuron retraction as opposed to degeneration based on the early disappearance of β-Spectrin and the continuing presence of Tubulin. By blocking cell dynamics with a dominant-negative form of Dynamin, we show that phagocytes have a key role in this process. Importantly, we show the presence of peripheral glial cells close to the neuro-muscular junction that retracts before the motor neuron. We show also that in muscle, expression of EcR-B1 encoding the steroid hormone receptor required for postsynaptic dismantling, is under the control of the ftz-f1/Hr39 orphan nuclear receptor pathway but not the TGF-β signaling pathway. In the motor neuron, activation of EcR-B1 expression by the two parallel pathways (TGF-β signaling and nuclear receptor) triggers axon retraction. We propose that a signal from a TGF-β family ligand is produced by the dismantling muscle (postsynapse compartment) and received by the motor neuron (presynaptic compartment) resulting in motor neuron retraction. The requirement of the two pathways in the motor neuron provides a molecular explanation for the instructive role of the postsynapse degradation on motor neuron retraction. This mechanism insures the temporality of the two processes and prevents motor neuron pruning before postsynaptic degradation.


Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacologic inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and to prevent metastasis. Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment.


Acute viral hepatitis in the United States-Mexico border region: data from the Border Infectious Disease Surveillance (BIDS) Project, 2000-2009.
Little is known about the characteristics of acute viral hepatitis cases in the United States (US)-Mexico border region. We analyzed characteristics of acute viral hepatitis cases collected from the Border Infectious Disease Surveillance Project from January 2000-December 2009. Over the study period, 1,437 acute hepatitis A, 311 acute hepatitis B, and 362 acute hepatitis C cases were reported from 5 Mexico and 2 US sites. Mexican hepatitis A cases most frequently reported close personal contact with a known case, whereas, US cases most often reported cross-border travel. Injection drug use was common among Mexican and US acute hepatitis B and C cases. Cross-border travel during the incubation period was common among acute viral hepatitis cases in both countries. Assiduous adherence to vaccination and prevention guidelines in the US is needed and strategic implementation of hepatitis vaccination and prevention programs south of the border should be considered.


Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis.
Factors responsible for the progression of non-alcoholic fatty liver disease (NAFLD) to more severe liver injury are poorly understood. In the present study, we investigated the association between immune reactions triggered by oxidative stress and stage of NAFLD. Titres of IgG against human serum albumin adducted with malondialdehyde (MDA-HSA) or arachidonic acid hydroperoxide (AAHP) and against oxidised cardiolipin (Ox-CL) were measured in 167 NAFLD patients with steatosis only (n = 79), steatohepatitis (n = 74), or steatosis plus cirrhosis (n = 14), and in 59 age and sex matched controls. Circulating IgG against lipid peroxidation products was significantly higher (p<0.001) in NAFLD patients than in controls. Oxidative stress dependent immune responses were not associated with obesity, type 2 diabetes, or with serum cholesterol, ferritin, or aminotransferase levels. Titres of lipid peroxidation related antibodies were also independent of the extent of steatosis and were similarly distributed in patients with and without necroinflammation. In contrast, the same antibodies were significantly increased in patients with advanced fibrosis or cirrhosis. Logistic regression analysis confirmed that anti-MDA antibodies were independently associated with progression of NALFD and that NAFLD patients with titres of anti-MDA-HSA antibodies above the control threshold value had a threefold (relative risk 2.82 (95% confidence interval 1.35-5.90); p = 0.007) higher risk of having advanced fibrosis/cirrhosis than patients whose antibody titres were within the control range. These results indicate that the presence of immune reactions triggered by oxidative stress can be an independent predictor of progression of NAFLD to advanced fibrosis.


Treatment evaluation for a data-driven subgroup in adaptive enrichment designs of clinical trials.
Adaptive enrichment designs (AEDs) of clinical trials allow investigators to restrict enrollment to a promising subgroup based on an interim analysis. Most of the existing AEDs deal with a small number of predefined subgroups, which are often unknown at the design stage. The newly developed Simon design offers a great deal of flexibility in subgroup selection (without requiring pre-defined subgroups) but does not provide a procedure for estimating and testing treatment efficacy for the selected subgroup. This article proposes a 2-stage AED which does not require predefined subgroups but requires a prespecified algorithm for choosing a subgroup on the basis of baseline covariate information. Having a prespecified algorithm for subgroup selection makes it possible to use cross-validation and bootstrap methods to correct for the resubstitution bias in estimating treatment efficacy for the selected subgroup. The methods are evaluated and compared in a simulation study mimicking actual clinical trials of human immunodeficiency virus infection.


Polymorphism of p53 gene in Jordanian population and possible associations with breast cancer and lung adenocarcinoma.
To determine the prevalence of 3 polymorphisms in p53 gene in 3 healthy Jordanian groups and 2 cancer patient groups. Genomic DNA was extracted from blood samples obtained from 84 cancer patients (breast and lung adenocarcinoma) and 136 healthy subjects (representing Jordanian general population, Bedouins and Charkas). Samples were collected from Al-Amal Hospital for Cancer, Amman and from health centers located in different regions of Jordan from March 2002 to October 2002. Polymerase chain reaction (PCR) was used to amplify intron 3, exon 4 and intron 6 and PCR products were analyzed using gel electrophoresis and BstUI and MspI analysis. Allele frequencies (A1) were estimated for the 3 polymorphisms and Chi-square (chi2) test was used to determine the significance of differences from the Hardy-Weinberg equilibrium. Differences in allele frequencies for all 3 polymorphisms were observed among the various groups. Analysis based on haplotype frequencies showed that MspI A2 allele linked to BstUI allele was associated with lung adenocarcinoma, whereas the loss of the 16-bp duplication allele in combination with MspI A2 allele was associated with breast cancer. In the cancer patients, the most frequent extended haplotype was the absence of the 16-bp duplication in combination with the presence of the BstUI A2 and MspI restriction sites. No significant difference was found with respect to the BstUI polymorphism between cancer patients and healthy groups. However, a significant difference was found with respect to the MspI polymorphism between lung adenocarcinoma patients and healthy Jordanian general population. Charkas have a higher cancer risk than Jordanian general population based on the (16bp A1-MspI A2) for breast cancer and (MspI A2-BstUI A2) for lung adenocarcinoma.


Adverse drug reactions in Singaporean children.
Allergic reactions to drugs are considered rare in the paediatric population. Host genetic and environmental factors influence the reported incidence and characteristics of adverse drug reactions (ADRs), and cause significant variation according to the population described and case definition used. We aimed to define the prevalence and characteristics of reported drug allergies in hospitalised children in Singapore. A retrospective case control study was performed through the hospital's inpatient electronic medical record (EMR) for the period of August 2002 to December 2002. The EMR was used to identify children with a previously reported ADR. The control group was randomly selected from patients hospitalised during the same period. Of the 8437 patients hospitalised during the study period, reports of previous ADRs were found in the records of 222 patients. The mean age of the patients was 7.4 years, range 2 months to 17 years (95 percent confidence interval [CI] 6.3 - 8.4). There were 146 males and 160 Chinese. The most commonly-involved medications were betalactam antibiotics (45 percent) and non steroidal anti-inflammatory drug (18.5 percent). Compared to the control group, children with a reported ADR were more likely to be older, with a mean age of 7.4 years versus 4.6 years (p-value less than 0.001), male (odds ratio [OR] 1.7, 95 percent CI 1.2-2.4), of Chinese descent (OR 1.8, 95 percent CI 1.5-5), have an associated chronic illness (OR 3.5, 95 percent CI 2.5-5), and a diagnosis of asthma (OR 2.7, 95 percent CI 1.7-4.5). In our paediatric inpatient population, the risk of reported ADRs increases with age, male gender, Chinese descent and the presence of chronic disease. The major drugs involved are betalactam antibiotics and non-steroidal anti inflammatory drugs.


Deriving a provisional tolerable intake for intravenous exposure to silver nanoparticles released from medical devices.
Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL05) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 μg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general.


Chinese herbal medicine for resistant hypertension: a systematic review.
This study aimed to summarise the current evidence from randomised control trials (RCTs) concerning treatment of patients with resistant hypertension with Chinese herbal medicine (CHM). Seven databases, including the Cochrane Library, PubMed, EMBASE, CNKI, VIP, CBM and Wanfang, were systematically searched from their inception to March 2014 for RCTs investigating treatment of resistant hypertension in which CHM was used either as a monotherapy or in combination with conventional medicine versus placebo, no intervention or conventional medicine. Five trials containing 446 hypertensive patients were identified. The methodological quality of most trials was evaluated as generally low. All included trials compared CHM plus antihypertensive drugs with antihypertensive drugs alone for resistant hypertension. Formulations of CHM included tablet, decoction and injection. It was found that, compared with antihypertensive drugs alone, CHM (tablet) plus antihypertensive drugs resulted in clinically, but not statistically, significant reductions in systolic blood pressure (SBP; weighted mean difference (WMD)=-10.32 mm Hg; 95% CI -21.10 to 0.46; p=0.06) and diastolic blood pressure (DBP; WMD=-3.30 mm Hg; 95% CI -7.66 to 1.06; p=0.14). CHM (decoction) plus antihypertensive drugs also produced a clinically meaningful, but not statistically significant, reduction in SBP (WMD=-12.56 mm Hg; 95% CI -26.83 to 1.71; p=0.08), and did significantly decrease DBP (WMD=-7.89 mm Hg; 95% CI -11.74 to -4.04; p<0.0001). There were no significant differences in SBP (WMD=-3.50 mm Hg; 95% CI -8.95 to 1.95; p=0.21) and DBP (WMD=1.00 mm Hg; 95% CI -1.39 to 3.39; p=0.41) between CHM (injection) plus the antihypertensive drugs group and antihypertensive drugs alone. The safety of CHM remained uncertain. No definite conclusions about the effectiveness and safety of CHM for resistant hypertension could be drawn. More rigorously designed trials are warranted.


Implications of pharmacogenetics for individualizing drug treatment and for study design.
Adverse drug reactions and ineffective drug treatment are responsible for a large health care burden. Considerable variability in drug response makes the prediction of the individual reaction difficult. Pharmacogenetics can help to individualize drug treatment in accordance with the genetic make-up of the patient. Drug response is best understood as a complex interplay between pharmacokinetics, pharmacodynamics, and other disease-associated factors. There are a large number of genetic variants in the enzymes of phase I and phase II drug metabolism, in drug transporters, and drug targets, all of which account for differences in drug response. The polymorphisms in the cytochrome P450 enzyme system have been investigated most extensively. Genotype-based dose adjustment which should ensure "bioequivalent" drug concentrations in all patients has been derived from pharmacokinetic parameters, but this approach will have to be verified in prospective studies. Drug transport has recently been recognized as a further crucial determinant in pharmacokinetics. The effect of genetics on disease susceptibility and drug treatment has been studied quite extensively; however, hardly any of this progress is at present reflected in routine health care. The integration of pharmacogenetic factors in clinical trials requires novel considerations for study design and data interpretation. It is to be hoped that the new science bioinformatics will (a) help us identify the contribution of genetics to disease and treatment response and will (b) create data-processing devices which help the physician in the face of the enormously expanding scientific knowledge in selecting the best individually adapted treatment for the patient.


Energy function-based approaches to graph coloring.
We describe an approach to optimization based on a multiple-restart quasi-Hopfield network where the only problem-specific knowledge is embedded in the energy function that the algorithm tries to minimize. We apply this method to three different variants of the graph coloring problem: the minimum coloring problem, the spanning subgraph k-coloring problem, and the induced subgraph k-coloring problem. Though Hopfield networks have been applied in the past to the minimum coloring problem, our encoding is more natural and compact than almost all previous ones. In particular, we use k-state neurons while almost all previous approaches use binary neurons. This reduces the number of connections in the network from (Nk)(2) to N(2) asymptotically and also circumvents a problem in earlier approaches, that of multiple colors being assigned to a single vertex. Experimental results show that our approach compares favorably with other algorithms, even nonneural ones specifically developed for the graph coloring problem.


Fluid management and deresuscitation practices: A survey of critical care physicians.
Accumulation of a positive fluid balance is common in critically ill patients, and is associated with adverse outcomes, including mortality. However, there are few randomised clinical trials to guide clinicians as to the most appropriate fluid strategy following initial resuscitation and on the use of deresuscitation (removal of accumulated fluid using diuretics and/or renal replacement therapy). To inform the design of randomised trials, we surveyed critical care physicians with regard to perceptions of fluid overload in critical care, self-reported practice, acceptability of a variety of approaches to deresuscitation, appropriate safety parameters, and overall acceptability of a randomised trial of deresuscitation. Of 524 critical care specialists completing the survey, the majority practiced in mixed medical/surgical intensive care units in the United Kingdom. Most (309 of 363 respondents, 85%) believed fluid overload to be a modifiable source of morbidity; there was strong support (395 of 457, 86%) for a randomised trial of deresuscitation in critical illness. Marked practice variability was evident among respondents. In a given clinical scenario, self-reported practice ranged from the administration of fluid (N = 59, 14%) to the administration of a diuretic (N = 285, 67%). The majority (95%) considered it appropriate to administer diuretics for fluid overload in the setting of noradrenaline infusion and to continue to administer diuretics despite mild dysnatraemias, hypotension, metabolic alkalosis, and hypokalaemia. The majority of critical care physicians view fluid overload as a common and modifiable source of morbidity; deresuscitation is widely practiced, and there is widespread support for randomised trials of deresuscitation in critical illness.


Two zebrafish alcohol dehydrogenases share common ancestry with mammalian class I, II, IV, and V alcohol dehydrogenase genes but have distinct functional characteristics.
Ethanol is teratogenic to many vertebrates. We are utilizing zebrafish as a model system to determine whether there is an association between ethanol metabolism and ethanol-mediated developmental toxicity. Here we report the isolation and characterization of two cDNAs encoding zebrafish alcohol dehydrogenases (ADHs). Phylogenetic analysis of these zebrafish ADHs indicates that they share a common ancestor with mammalian class I, II, IV, and V ADHs. The genes encoding these zebrafish ADHs have been named Adh8a and Adh8b by the nomenclature committee. Both genes were genetically mapped to chromosome 13. The 1450-bp Adh8a is 82, 73, 72, and 72% similar at the amino acid level to the Baltic cod ADH8 (previously named ADH1), the human ADH1B2, the mouse ADH1, and the rat ADH1, respectively. Also, the 1484-bp Adh8b is 77, 68, 67, and 66% similar at the amino acid level to the Baltic cod ADH8, the human ADH1B2, the mouse ADH1, and the rat ADH1, respectively. ADH8A and ADH8B share 86% amino acid similarity. To characterize the functional properties of ADH8A and ADH8B, recombinant proteins were purified from SF-9 insect cells. Kinetic studies demonstrate that ADH8A metabolizes ethanol, with a V(max) of 13.4 nmol/min/mg protein, whereas ADH8B does not metabolize ethanol. The ADH8A K(m) for ethanol as a substrate is 0.7 mm. 4-Methyl pyrazole, a classical competitive inhibitor of class I ADH, failed to inhibit ADH8A. ADH8B has the capacity to efficiently biotransform longer chain primary alcohols (>/=5 carbons) and S-hydroxymethlyglutathione, whereas ADH8A does not efficiently metabolize these substrates. Finally, mRNA expression studies indicate that both ADH8A and ADH8B mRNA are expressed during early development and in the adult brain, fin, gill, heart, kidney, muscle, and liver. Together these results indicate that class I-like ADH is conserved in zebrafish, albeit with mixed functional properties.


Stability of antibacterial self-assembled monolayers on hydroxyapatite.
Open fractures are common in battlefields, motor vehicle accidents, gunshot wounds, sports injuries, and high-energy falls. Such fractures are treated using hydroxyapatite (HA)-based bone graft substitutes. However, open fracture wounds are highly susceptible to bacterial infections. Hence, this study was focused on incorporating antibacterial properties to HA using silver (Ag) carrying self-assembled monolayers (SAMs). Also, the stability of Ag carrying SAMs on HA was investigated under sterilization and physiological conditions. Initially, the -COOH terminated phosphonic acid SAMs of two different chain lengths (11 carbon atoms - shorter chain and 16 carbon atoms - longer chain) were deposited on HA. Antibacterial SAMs (ASAMs) were prepared by chemically attaching Ag to shorter and longer chain SAMs coated HA. X-ray photoelectron spectroscopy, atomic force microscopy, and contact angle goniometry collectively confirmed the attachment of Ag onto SAMs coated HA. The bacterial adhesion study showed that the adherence of Staphylococcus aureus was significantly reduced on ASAMs coated HA when compared to control-HA. The stability studies showed that gas plasma, dry heat and autoclave degraded most of the ASAMs on HA. UV irradiation did not damage the shorter chain ASAMs as vigorously as other treatments, while it degraded the longer chain ASAMs completely. Ethylene oxide treatment did not degrade the longer chain ASAMs unlike all other treatments but it severely damaged the shorter chain ASAMs. Both shorter and longer chain ASAMs significantly desorbed from the HA surfaces under physiological conditions although longer chain ASAMs exhibited better stability than shorter chain ASAMs. This study demonstrated the potential for using ASAMs to provide antibacterial properties to HA and the need for developing techniques to improve stability of SAMs under sterilization and physiological conditions.


A Comparative Study of Conservative Functional Treatment versus Acute Ligamentous Repair in Simple Dislocation of the Elbow in Adults.
Elbow dislocation is the second most frequent type of large joint dislocations in adults. Standard treatment of simple elbow dislocation (SED) without manifestation of instability includes closed reduction, short-term immobilization of the elbow followed by functional aftercare. This study evaluates SED treatment, comparing outcomes of conservative functional treatment and surgical therapy. 54 adult patients with SED without manifest instability treated in tertiary hospital between January 2008 and June 2015 were analyzed in this retrospective study. 28 patients were treated conservatively. Closed elbow reduction was followed by short-term plaster splint and active rehabilitation. Twenty six patients underwent closed elbow reduction and subsequent reconstruction of torn collateral ligaments. Postoperatively, plaster splint was applied followed by rehabilitation. Patients who were treated conservatively reached statistically significant better scores in Quick Disability Arm Shoulder Hand, Oxford Elbow Score, and Mayo Elbow Performance Score. Functional conservative treatment resulted in a higher range of motion. The complication rate was higher in the group of surgically treated patients. Careful examination of elbow stability after closed reduction of SED is crucial for further therapy. Patients with stable SED should be treated with functional conservative therapy. Surgical collateral ligaments revision and reconstruction are indicated only for patients with manifestation of elbow instability.


The SIgA system and hypersensitivity in patients with cystic fibrosis.
A number of investigations have been used for the first time to examine the secretory IgA (SIgA) system in different body fluids from patients with cystic fibrosis (CF). Free J-chain was detected in all the sputum specimens examined. The isolated free secretory component (SC) from CF sputum differed in electrophoretic mobility from the SC isolated from normal human colostrum. In addition the free SC from some CF saliva formed precipitin lines of partial identity with normal human saliva or colostrum. A higher proportion of CF sera (33%) than of normal sera (10%) contained free SC. These investigations suggest that there may be some defect in the synthesis and/or the assembly of the SIgA immunoglobulins, which if confirmed, may help to explain the impaired Type I and Type III allergic manifestations in patients with CF.


"Just something that happened?": Mental health impact of disclosure and framing of sexual violence in older victims.
Despite the important impact of sexual violence (SV) on mental health, few victims disclose their experiences. Although research in adult victims suggests that SV disclosure could protect against long-term mental health problems, studies in older adults are lacking. To establish the prevalence of depression, anxiety, posttraumatic stress disorder (PTSD), suicide attempts, and self-harm, their association with SV disclosure, and the moderating effect of sociodemographic characteristics and SV framing in the relation between SV disclosure and the different mental health outcomes in older SV victims. Data on sexual victimisation, mental health, SV framing, and disclosure were collected through structured face-to-face interviews with 171 randomly selected sexually victimised adults of 70 years and older living in Belgium. SV was measured using behaviourally specific questions based on a broad definition. Mental health outcomes were measured using validated scales. Depression, anxiety and PTSD were reported by 34%, 33% and 9% of participants respectively, 5% had attempted suicide and 1% reported self-harm during lifetime. SV framing was associated with the kind of help victims consulted. SV disclosure was not linked with depression and anxiety, but was associated with an increase of PTSD symptoms in older victims with care dependency (p = 0.004) or a chronic illness and/or disability (p = 0.025). SV disclosure in itself does not protect against adverse mental health outcomes in old age. Capacity building of professionals trough training and development of clinical guidelines and care procedures may increase appropriate response to SV disclosure by older victims.


On the primary nature of fluorescence yield changes associated with photosynthesis.
Absorbance changes of C-550 and cytochrome b(559), and fluorescence-yield changes were measured during irradiation of chloroplasts at -196 degrees . The photo-reduction of C-550 proceeded more rapidly than the photo-oxidation of cytochrome b(559), and the fluorescence-yield change had similar kinetics to the cytochrome b(559) change. The fluorescence yield of chloroplasts exposed to a 16-musec flash at -196 degrees did not increase during the flash, but increased in the dark after the flash. Both of these experiments indicate that the fluorescence yield follows the dark reduction of the primary electron donor of Photosystem II, not the photoreduction of the acceptor. This explanation would also account for the recent results of Mauzerall [Proc. Nat. Acad. Sci. USA (1972) 69, 1358-1362] showing that the fluorescence yield of chloroplasts at room temperature requires about 20 musec to reach a maximum after a very brief flash.


Large effects of preparative techniques on lymphocyte cyclic AMP content.
When a cell suspension is formed by disruption of a pig lymph node into medium, large and transient increases in intracellular cyclic AMP occur. Similar effects are observed when pig lymphocytes are centrifuged and the cell pellets resuspended, or when the cells are subjected to rapid temperature changes. These observations define the conditions required to manipulate the cells while maintaining a stable cyclic AMP concentration. Under these conditions, neither concanavalin A nor ionophore A23187 at mitogenic concentrations have any early effect on cyclic AMP in pig lymphocytes, but small increases in cyclic AMP (less than 2-fold) were observed at supramitogenic concentrations of concanavalin A (50 microgram/ml) or A23187 (500nM). Mouse thymocytes show qualitatively similar but much smaller changes in cyclic AMP concentration in response to experimental manipulations, and no response to mitogenic or supramitogenic concentrations of concanavalin A below the cytotoxic value.


Mother's experience of the support from a bereavement follow-up intervention after the death of a child.
To describe the mothers' experience of the support they received in a bereavement follow-up intervention after the death of a child and their experiences of the intervention programme. The intervention included three complementary components: (1) a support package, (2) peer supporters' contact with mothers and (3) health professionals' contact with mothers. Although several types of intervention have been targeted at grieving parents or mothers, there exists a lack of knowledge of what kind of intervention is supportive and enhances the coping of parents after the death of a child. An intervention was implemented in two university-level hospitals in Southern Finland. The study participants were grieving mothers (n=86) whose child had died at the age of three or younger. The data were collected by using a structured questionnaire within six months of the death of a child. The data were analysed with descriptive statistical methods. The mothers felt that the support they received helped them in coping with the situation. Among the different forms of received support, the mothers felt they received the most emotional support from peer supporters and health professionals. The mothers considered the support intervention to be useful. The collaborative support intervention between health professionals and peer supporters enabled versatile, immediate and long-term support that helped the mothers cope after the death of a child. Health professionals should collaborate systematically with the third sector to provide support for mothers after the death of their child. In addition to the support given in hospital, health professionals should arrange more contacts and meetings with bereaved mothers on a long-term basis, after the mothers have left the hospital.


Advantages and disadvantages of conditional systems for characterization of essential genes in Toxoplasma gondii.
The dissection of apicomplexan biology has been highly influenced by the genetic tools available for manipulation of parasite DNA. Here, we describe different techniques available for the generation of conditional mutants. Comparison of the advantages and disadvantages of the three most commonly used regulation systems: the tetracycline inducible system, the regulation of protein stability and site-specific recombination are discussed. Using some previously described examples we explore some of the pitfalls involved in gene-function analysis using these systems that can lead to wrong or over-interpretation of phenotypes. We will also mention different options to standardize the application of these techniques for the characterization of gene function in high-throughput.


Inhibition of contralateral premotor cortex delays visually guided reaching movements in men but not in women.
The premotor-parietal network for preparation of visually guided reaching demonstrates activity mainly contralateral to the reaching arm in men but bilaterally in women. These sex differences are most prominent in the dorsal premotor cortex (PMd); however, the functional implications of these differences remain unclear. Therefore, in the experiments described here, we used continuous theta burst stimulation (cTBS) to test hypotheses regarding the roles of PMd both contralateral and ipsilateral to the reaching arm in men and in women. Inhibitory cTBS of the ipsilateral PMd did not have a significant effect on reaction time in either men or women. However, cTBS of the contralateral PMd resulted in a slowed mean reaction time in men but not in women. Movement times were unaffected by stimulation applied to either hemisphere. These results suggest the presence of sex differences in processing within the left PMd during visually guided reaching movements using the right arm. Further, when taken together, the results suggest that ipsilateral PMd activity in women may not be functionally necessary for reaching movements. Rather, this ipsilateral activity may provide a protective redundancy that can compensate for decreased activity from the contralateral PMd. The observation of sex differences in reaction times but not in movement times following cTBS to the contralateral hemisphere suggests that these sex differences are more strongly associated with movement planning than with motor execution.


A Pilot Study Examining the Relationship Between Patients' Complaints and Scores on the Hirschfeld Mood Disorder Questionnaire.
INTRODUCTION: The incidence of bipolar disorder in the general population has been estimated at approximately 5%. The purpose of this study was to establish a relationship between patients' complaints on arrival to a primary care clinic and their subsequent scores on the Hirschfeld Mood Disorder Questionnaire (MDQ). METHOD: After reviewing data obtained from 178 consecutive patients, 171 were found adequate for study inclusion. The inclusion criteria for this study were presentation to a family practice office for care regardless of complaint and age of 18 years or older. Study participants were asked to complete a historical/demographic questionnaire, which gathered data on primary and secondary complaints and medication history, and the MDQ. RESULTS: Thirty patients (17.5%) tested positive on the MDQ for bipolar symptoms; all were aged 65 years or under. Of those who tested positive, 20% (N = 6) presented with a primary complaint of anxiety or depression. Somatic primary complaints of pain and headache carried a high likelihood of secondary complaints of anxiety or depression. CONCLUSION: Patients with complicated or multiple somatic complaints in primary care may also have concomitant undiagnosed bipolar disorder. Clinicians should use a high index of suspicion for the diagnosis of bipolar disorder when treating patients with these assessment characteristics. Further research is necessary to determine if these trends are applicable in a larger population.


The Effect of Prestressing and Temperature on Tensile Strength of Basalt Fiber-Reinforced Plywood.
The reinforcement of plywood is demonstrated by laminating pretensioned basalt fibers between veneer sheets, to fabricate so-called prestressed plywood. Belt type basalt fibers bearing a specific adhesion promoting silane sizing were aligned between veneer sheets with 20 mm spacing and were pretensioned at 150 N. Three-layer plywood samples were prepared and tested for tensile strength at room temperature and at 150 °C. The room temperature tensile tests revealed a 35% increase in tensile strength for prestressed plywood compared to that of the conventional specimen. The reinforcement effect deteriorated at 150 °C but was restored upon cooling to room temperature. The deterioration is attributed to the weakening of bonding between the basalt fibers and phenolic resin matrix at elevated temperatures due to the softening of the resin.


A 60Mb/s -64dBm Body Channel Communication Transceiver Utilizing Manchester Code.
Body channel communication (BCC) which uses the human body as the communication channel has shown better energy efficiency and security compared with air channel communication. This article presents a simple, stable, and high transfer rate BCC technique using Manchester encoding, capacitive termination, and digital signal transfer operation. Manchester encoding is used to realize the spectrum migration of the baseband signal, and digital signal transmission simplifies system design and improves signal stability. The chip is fabricated in 65-nm technology. The experimental results show that the proposed transceiver achieved the highest data rates of 60 Mbps and the measured RX sensitivity is -64dBm. And the chip is also used to set up a multi-sensor nodes communication system to realize the data interaction between one hub and eight slave sensors utilizing the human body as the communication medium.


Gonadotropin beta subunits determine the rate of assembly and the oligosaccharide processing of hormone dimer in transfected cells.
The glycoprotein hormones lutropin (LH) and chorionic gonadotropin (CG) share a common structure consisting of an identical alpha subunit noncovalently linked to a hormone-specific beta subunit. While LH is produced in the anterior pituitary, CG is synthesized in placenta. To compare the assembly, processing, and secretion of human LH and CG in the same cell type, we have expressed their subunits, individually and together, in mouse C-127 mammary tumor cells. Analysis of transfected clones revealed an unexpected difference in the secretion of individually expressed subunits. Whereas alpha and CG beta subunits were rapidly and quantitatively secreted, only 10% of newly synthesized LH beta subunit reached the medium. The remaining subunit was found in an intracellular, endoglycosidase H (endo H)-sensitive pool that had a turnover rate of approximately 8 h. Coexpression with alpha subunit resulted in "rescue" of LH beta subunit by formation of LH dimer, which was efficiently secreted. However, combination of LH beta with alpha was slow, with an overall efficiency of only 50% despite the presence of excess alpha. In contrast, CG beta was rapidly assembled with the alpha subunit after synthesis. The two beta subunits also differed in their influence on the N-linked oligosaccharide processing of combined alpha. The oligosaccharides of LH dimer were endo H resistant, while those of CG dimer remained partially endo H sensitive. Thus, despite a high degree of homology between LH beta and CG beta, the two subunits differ in their secretion as free subunits, their rate of assembly with alpha subunit, and in their effect on the N-linked oligosaccharide processing of combined alpha.


Quantum phase transition in an antiferromagnetic spinor Bose-Einstein condensate.
We have experimentally observed the dynamics of an antiferromagnetic sodium Bose-Einstein condensate quenched through a quantum phase transition. Using an off-resonant microwave field coupling the F = 1 and F = 2 atomic hyperfine levels, we rapidly switched the quadratic energy shift q from positive to negative values. At q = 0, the system undergoes a transition from a polar to antiferromagnetic phase. We measured the dynamical evolution of the population in the F = 1, mF = 0 state in the vicinity of this transition point and observed a mixed state of all 3 hyperfine components for q < 0. We also observed the coarsening dynamics of the instability for q < 0, as it nucleated small domains that grew to the axial size of the cloud.


[Inositoltriphosphate receptors and ryanodine receptors in regulation of cholinosensitivity of Helix lucorum neurones by Na,K-pump during habituation].
Influence of ouabain, the inhibitor of Na,K-pump, on habituation of Helix to tactile stimulation was identical to the ouabain-induced modification of cholinosensitivity reduction in command neurones of defensive behaviour of Helix lucorum in cellular model of habituation. Effects of intracellularly injected ligands of two types of Ca2+ -depot receptors, inositoltrisphosphate (IP3) and ryanodine receptors, on ouabain-induced changes were studied in cellular model of habituation. The antagonist of IP3 receptors heparin (0.1 mM), their agonist IP3 (0.1 mM) and inhibitor of ryanodine-dependent Ca2+ mobilization dantrolen (0.1 mM) prevented the depression of acetylcholine-induced current from the ouabain-evoked modification. The agonist/antagonist of ryanodine receptors ryanodine at two tested concentrations (0.1 mM and 1 mM) did not change the ouabain effect. It is concluded that Ca2+ released from intracellular Ca2+ -depots via IP3 receptors is involved into neuronal mechanism of Na,K-pump regulation of habituation in Helix lucorum to tactile stimulation.


Surgical and Survival Outcomes Following Pelvic Exenteration for Locally Advanced Primary Rectal Cancer: Results From an International Collaboration.
The aim of the study was to analyze data from an international collaboration, and ascertain prognostic indicators that inform clinical decision-making and practices regarding the role of pelvic exenteration for locally advanced primary rectal cancer (LARC). With improved national screening programs fewer patients present with LARC. Despite this, select cohorts of patients require pelvic exenteration. To date, the majority of outcome data are from single-center series. Anonymized data from 14 countries on patients who had pelvic exenteration for LARC between 2004 and 2014 were accumulated. The primary endpoint was overall survival. The impact of resection margin, nodal status, bone resection, and use of neoadjuvant therapy (before exenteration) on survival was evaluated using multivariable analysis. Of 1291 patients, 778 (60.3%) were male with a median (range) age of 63 (18-90) years; 78.1% received neoadjuvant therapy. Bone resection en bloc was performed in 8.2% of patients (n = 106), and 22.6% (n = 292) had resection combined with flap reconstruction. Negative resection margin (R0 resection) was achieved in 79.9%. The 30-day postoperative mortality was 1.5%.The median overall survival following R0, R1, and R2 resection was 43, 21, and 10 months (P < 0.001) with a 3-year survival of 56.4%, 29.6%, and 8.1%, respectively (P < 0.001); 37.8% of patients experienced one or more major complication. Neoadjuvant therapy increased the risk of 30-day morbidity (P < 0.012). Multivariable analysis identified resection margin and nodal status as significant determinants of overall survival (other than advanced age). Attainment of negative resection margins (R0) is the key to survival. Neoadjuvant therapy may improve survival; however, it does so at the increased risk of postoperative morbidity.


The attitudes of British surgical trainees about the treatment of HIV-infected patients.
As the incidence of HIV increases, the occupational risk of human immuno deficiency virus (HIV) infection also increases, leading to heightened anxiety within surgical practice. This study assessed the attitudes of surgeons treating HIV-infected patients. Seventy surgical trainees working in two district general hospitals were requested to complete a survey assessing their attitudes regarding the surgical management of HIV-infected patients. A needle-stick injury was reported by 64% of the trainees. Fifty-four percent of trainees were concerned about acquiring HIV from patients when performing a surgical procedure. There was a significant difference between the number of trainees worried about treating a patient with HIV and the number of trainees wearing eye protection when performing invasive procedures (p < 0.002). Eighty-six percent of trainees were confident they could treat HIV patients safely, but only 63% were aware of the hospital protocol for needle-stick injuries. There appears to be increasing concern among surgical trainees about carrying out surgical procedures on HIV-infected patients. Despite equipment being fully available, many trainees are not considering the full use of protective theatre garments to minimize the risk of HIV contamination. Further education and training is required to stress the importance of the increasing HIV prevalence and the need for safety during surgical practice.


Condition-dependent survival and movement behavior in an endangered endemic damselfly.
Movement is essential for the maintenance of populations in their natural habitats, particularly for threatened species living in fluctuating environments. Empirical evidence suggests that the probability and distance of movement in territorial species are context-dependent, often depending on population density and sex. Here, we investigate the movement behavior of the spring cohort of an endangered endemic damselfly Calopteryx exul in a lotic habitat of Northeast Algeria using capture-mark-recapture (CMR) of adults. By sampling 10 gridded river stretches across a 2 km section of the watercourse, we were able to estimate the distance of movement throughout individual lifespans and estimate movement probability for both males and females. We used multistate models to examine whether individual density and sex ratio influence survival and movement probability. We found that males and females had similar movement kernels with most individuals moving short distances (83% performing movements of < 100 m and only 1% > 1000 m). Of the 547 marked individuals, 63% were residents, and 37% were movers (moved at least 50 m from one sampling occasion to another). Survival probability showed higher estimates for females and was slightly density-dependent (i.e., lower survival probabilities were associated with high male densities). Survival probability did not show a marked difference between residents and movers. Movement probability and distances were positively correlated with individual density, but were not or slightly correlated with sex ratio, respectively. These results are not in line with the hypotheses of sex-biased movement and survival costs of movement. Our results suggest that the species performs mostly short-distance movements that are dependent on intraspecific interactions.


Membrane currents of pawn mutants of the pwA group in Paramecium tetraurelia.
Membrane currents were recorded from the wild type and two pawn mutants of the pwA complementation group in Paramecium tetraurelia under a voltage clamp. Most currents are not changed by the mutations. Transient inward currents of a leaky mutant, pwA132, upon step depolarizations are less than those in the wild type. The inward transient is completely lacking in a non-leaky mutant, pwA500. The time course of the residual inward currents in the leaky mutant is not significantly different from that of wild type. The voltage sensitivity of the Ca channels in the leaky mutant is also similar to that of wild type. The inward currents upon membrane hyperpolarizations in the mutants show normal characteristics in the presence or absence of external K+. With sufficiently large, prolonged depolarization, outward currents progressively develop in the wild type but decay in the mutants. The simplest conclusion we can draw is that the pwA mutations reduce the number of functional Ca channels but do not change the channel characteristics. From the conductance measurements, 45% of the Ca channels remain in the leaky mutant pwA132, and none remain in the non-leaky mutant pwA500. By subtracting the outward currents of pwA500 from the slow and prolonged outward currents of the wild type, we have tentatively separated a Ca-induced K+ current from the voltage-dependent K+ current. The time courses of these two currents differ by two orders of magnitude.


The alkaloid brachycerine is induced by ultraviolet radiation and is a singlet oxygen quencher.
The effects of ultraviolet (UV) radiation on chlorophyll content and accumulation of the anti-inflammatory monoterpene-indole alkaloid brachycerine in plants and calli of Psychotria brachyceras (Rubiaceae) were investigated. In this study, we also investigated a protective role for brachycerine against stress conditions. Calli and tip cuttings incubated in nutrient media were daily supplemented with 4 or 16 h of UV. High-performance liquid chromatography analyses of methanolic extracts showed only traces of brachycerine in irradiated aseptic cultures, with no alkaloid being observed in control calli. In cuttings, a 10-fold increase in brachycerine content was seen after exposure for 16 h to UV-C, whereas a 4 h daily supplementation doubled the amount of the alkaloid in leaves. Exposure to a UV-B source also doubled the alkaloid yield. In vitro brachycerine was able to quench singlet oxygen. The data indicate a potential protective role for brachycerine against UV radiation, acting as a UV filter (absorption peaks are within the UV range) and a reactive oxygen species scavenger. In addition, UV radiation may be used to increase yields of this compound of pharmaceutical interest.


Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression.
A fall in circulating levels of cardiac survival factor insulin-like growth factor 1 (IGF-1) contributes to cardiac aging. To better understand the role of IGF-1 in cardiac aging, we examined the influence of cardiac IGF-1 overexpression on lifespan, cardiomyocyte intracellular Ca2+ homeostasis, protein damage, apoptosis and expression of pro- and anti-apoptotic proteins in young and old mice. Mouse survival rate was constructed by the Kaplan-Meier curve. Intracellular Ca2+ was evaluated by fura-2 fluorescence. Protein damage was determined by protein carbonyl formation. Apoptosis was assessed by caspase-8 expression, caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay. Pro- and anti-apoptotic proteins including Bax, p53, pp53, Bcl2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC) and X-linked inhibitor of apoptosis protein (XIAP) were assessed by Western blot. Aging decreased plasma in IGF-1 levels, elevated myocyte resting intracellular Ca2+ levels, reduced electrically stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ decay associated with enhanced protein carbonyl formation, caspase-8 expression and caspase-3 activity in FVB mice, all of which with the exception of elevated resting intracellular Ca2+ were attenuated by IGF-1. Aging up-regulated expression of Bax, Bcl2 and ARC, down-regulated XIAP expression and did not affect p53, pp53 and Omi/HtrA2. The IGF-1 transgene attenuated or nullified aging-induced changes in Bax, Bcl2 and XIAP. Our data suggest a beneficial role for IGF-1 in aging-induced survival, cardiac intracellular Ca2+ homeostasis, protein damage and apoptosis possibly related to pro- and anti-apoptotic proteins.


Venomous Loxosceles Species (Araneae, Haplogynae, Sicariidae) from Brazil: 2n♂ = 23 and X1X2Y Sex Chromosome System as Shared Characteristics.
The family Sicariidae comprises the genera Hexophthalma, Sicarius and Loxosceles. This latter is subdivided in eight monophyletic groups based on genitalia morphology and molecular analyses: amazonica, gaucho, laeta, and spadicea (South America); reclusa (North America); rufescens (Mediterranean); spinulosa and vonwredei (Africa). In Brazil, the genus Loxosceles is represented by 50 species. The mitotic and meiotic characteristics of eight Loxosceles species were analyzed in order to discuss the chromosome evolution, as well as the correspondence between cytogenetic data and morphological/molecular data for the delimitation of the South American groups of species belonging to this genus. All species studied in this work showed 2n♂ = 23, including a X1X2Y sex chromosome system (SCS). Despite the similarity of diploid number and SCS, the species studied here differed regarding the chromosome morphology of some autosomal pairs, presence of secondary constrictions, size of X chromosomes and localization of Ag-NOR/rDNA sites. Based on all these chromosomal data, we verified a close relationship between Loxosceles species belonging to the amazonica and gaucho groups. Transmission electron microscopy (TEM) analysis of spread pachytene cells of L. gaucho showed regular synapsis between homologous autosomal chromosomes, but asynaptic behavior of the sex chromosomes. The axial elements of the sex chromosomes undergo conspicuous morphological modifications resulting in shortening of their length.


DR-region of Na+/K+-ATPase is a target to ameliorate hepatic insulin resistance in obese diabetic mice.
Reduced hepatic Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of metabolism diseases. The present study was designed to investigate the potential roles of NKAα1 in hepatic gluconeogenesis and glycogenesis in both hepatocytes and obese diabetic mice. Methods: Insulin resistance was mimicked by glucosamine (GlcN) in either human hepatocellular carcinoma (HepG2) cells or primary mouse primary hepatocytes. Obese diabetic mice were induced by high-fat diet (HFD) feeding for 12 weeks. Results: We found that both NKA activity and NKAα1 protein level were downregulated in GlcN-treated hepatocytes and in the livers of obese diabetic mice. Pharmacological inhibition of NKA with ouabain worsened, while activation of NKAα1 with an antibody against an extracellular DR region of NKAα1 subunit (DR-Ab) prevented GlcN-induced increase in gluconeogenesis and decrease in glycogenesis. Likewise, the above results were also corroborated by the opposite effects of genetic knockout/overexpression of NKAα1 on both gluconeogenesis and glycogenesis. In obese diabetic mice, hepatic activation or overexpression of NKAα1 stimulated the PI3K/Akt pathway to suppress hyperglycemia and improve insulin resistance. More importantly, loss of NKA activities in NKAα1+/- mice was associated with more susceptibility to insulin resistance following HFD feeding. Conclusions: Our findings suggest that NKAα1 is a physiological regulator of glucose homoeostasis and its DR-region is a novel target to treat hepatic insulin resistance.


Increased nerve growth factor by zinc supplementation with concurrent vitamin A deficiency does not improve memory performance in mice.
We investigated the effects of dietary supplementation of zinc (Zn) with or without vitamin A (Vit. A), to elucidate any cross activity between the two micronutrients, on memory and nerve growth factor (NGF) production in ddY male mice depleted for the two elements. After 3 mo-feeding with a Zn and Vit. A deficient (VAD) diet, mice were divided into three groups and replenished with normal Zn with VAD diet (NZ-VAD), high Zn with VAD diet (HZ-VAD) or normal Zn + normal Vit. A (NZ-NVA) for additional 2 mo. One more group was made and given the normal diet for the same period (Control group). Levels of NGF were measured from extracts of hippocampus, cerebellum and cortex at the end of the 3rd and 5th month. In addition, a radial arm maze task was performed at the end of the 5th month. The two Zn supplemented groups (NZ-VAD and HZ-VAD) tended to show high NGF concentration but memory was not improved. However, improved memory was observed in the NZ-NVA group. From these results we concluded that Zn may increase NGF; however, memory was improved only when Vit. A was sufficient.


Dairy ruminant exposure to persistent organic pollutants and excretion to milk.
Human activities produce polluting compounds such as persistent organic pollutants (POPs), which may interact with agriculture. These molecules have raised concern about the risk of transfer through the food chain via the animal product. POPs are characterised by a strong persistence in the environment, a high volatility and a lipophilicity, which lead to their accumulation in fat tissues. These compounds are listed in international conventions to organise the information about their potential toxicity for humans and the environment. The aim of this paper is to synthesise current information on dairy ruminant exposure to POPs and the risk of their transfer to milk. Three major groups of POPs have been considered: the polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), the polychlorobiphenyls (PCBs) and the polycyclic aromatic hydrocarbons (PAHs). The results show that contamination of fodder and soil by these compounds is observed when they are exposed to emission sources (steelworks, cementworks, waste incinerators or motorways) compared with remote areas. In general, soil contamination is considered higher than plant contamination. Highest concentrations of POPs in soil may be close to 1000 ng/kg dry matter (DM) for PCDD/Fs, to 10 000 mg/kg DM for PAHs and 100 μg/kg DM for PCBs. The contamination of milk by POPs depends on environmental factors, factors related to the rearing system (fodder and potentially contaminated soil, stage of lactation, medical state of the herd) and of the characteristics of the contaminants. Transfer rates to milk have been established: for PCBs the rate of transfer varies from 5% to 90%, for PCDD/Fs from 1% to 40% and for PAHs from 0.5% to 8%. The differential transfer of the compounds towards milk is related to the hydrophobicity of the pollutants as well as to the metabolic susceptibility of the compounds.


[Correlation between cytopathology and histopathology of the skin, lymph node and spleen in 500 dogs and cats].
The results of 382 cytological examinations in dogs and 118 in cats were retrospectively compared with the correlating histological results.The histological diagnosis represented the gold standard. The investigation comprised skin, lymph node and spleen samples. The aim was to estimate the diagnostic value and the limits of cytological examinations in relation to the type of the changes. The cases were grouped in six categories: Corresponding diagnoses were formulated in 201 cases. In lymph node samples, they were reached almost twice as frequently than in skin and spleen samples. Round cell neoplasias (mast cell tumours, canine cutaneous histiocytomas and malignant lymphomas) were most often subclassified. Cytological diagnoses lacking subclassification were reached in 98 cases. The lesions were cytologically less precisely characterized than histologically. Provisional cytological diagnosis or differential diagnosis were formulated in 112 cases. Most commonly, the distinction between neoplastic and non-neoplastic character of a lesion was not possible (especially in mesenchymal spindle-cell proliferations). In 53 cases, the cytological diagnosis could not be established. In 22 cases, the relevant lesion was diagnosed only histologically whereas the cytological picture revealed another, usually secondary tissue reaction. Cytologically incorrect diagnoses were formulated in 14 cases.


Treatment of delusions in Alzheimer's disease--response to pharmacotherapy.
Delusions are commonly encountered symptoms in patients with Alzheimer's disease and may lead to significant morbidity. The purpose of this article is to review all clinical trials to date focusing on the management of delusions in patients with Alzheimer's disease to determine the level of evidence for treatment. To achieve this objective, Medline was searched using the key words delusions, dementia, Alzheimer's disease and psychosis. Three main categories of treatment were identified: atypical antipsychotics, cholinesterase inhibitors, and other miscellaneous treatments. It was concluded that all forms of treatment were effective although the greatest burden of evidence existed for risperidone and donepezil. Side effects were noted in all forms of treatment and included somnolence and extrapyramidal effects for antipsychotic medications, whereas gastrointestinal effects were more prevalent in studies involving cholinesterase inhibitors. Further large scale, double-blind, randomized, controlled studies are required before a definitive conclusion can be reached. To our knowledge this is the only systematic review of this area.


Prevalence of diabetic peripheral neuropathy in Africa: a systematic review and meta-analysis.
Diabetes mellitus (DM) is a global health care problem that can impose a substantial economic burden. Diabetic peripheral neuropathy (DPN) is a common microvascular complication of DM that increases the potential for morbidity and disability due to ulceration and amputation. Though there is a significant amount of variation in the primary studies on DM regarding the prevalence of DPN in Africa. Hence, this study was aimed to estimate the overall prevalence of DPN in DM patients in Africa. PubMed, Scopus, Google Scholar, African Journals OnLine, WHO African Library, and the Cochrane Review were systematically searched online to retrieve related articles. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines was followed. Heterogeneity across the included studies was evaluated by the inconsistency index (I2). Publication bias was examined by funnel plot and Egger's regression test. The random-effect model was fitted to estimate the pooled prevalence of diabetic peripheral neuropathy among patients in Africa. The meta-analysis was performed using the STATA™ Version 14 software. Twenty-three studies which includes 269,691 participants were included in the meta-analysis. The overall pooled prevalence of diabetic peripheral neuropathy was 46% (95% CI:36.21-55.78%). Based on the subgroup analysis, the highest prevalence of diabetic peripheral neuropathy in DM patients was reported in West Africa at 49.4% (95% CI: 32.74, 66.06). This study revealed that the overall prevalence of diabetic peripheral neuropathy is relatively high in Africa. Hence, DPN needs situation-based interventions and preventive strategies, which are specific to the country. Further meta-analysis is needed to identify associated factors for the occurrence of diabetic peripheral neuropathy.


Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age.
The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.


HIV infection among young black men who have sex with men--Jackson, Mississippi, 2006-2008.
In the United States, black men who have sex with men (MSM) account for a disproportionate number of new cases of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). From 2001 to 2006, the number of HIV/AIDS cases among black MSM aged 13--24 years in 33 states increased 93%. In 2006, more new AIDS cases among black MSM were diagnosed in the South than in all other U.S. census regions combined. In November 2007, the Mississippi State Department of Health (MSDH) reported to CDC an increase in the number of young black MSM who received diagnoses of HIV infection at a sexually transmitted disease (STD) clinic in Jackson, Mississippi. MSDH and CDC conducted a survey of 29 young black MSM in the three-county Jackson area who received diagnoses of HIV infection during January 2006--April 2008 to characterize risk behavior and HIV testing behavior. This report summarizes the results of that survey, which found that, during the 12 months before receiving their HIV infection diagnosis, 20 (69%) of the 29 participants had unprotected anal intercourse, but only three (10%) of the 29 thought they were likely or very likely to acquire HIV infection in their lifetimes. Additional investigations are needed to determine whether this sample is illustrative of other groups of black MSM at high risk for HIV infection, especially in the South. Targeted interventions that decrease HIV risk behaviors among black MSM should be developed, implemented, and evaluated to reduce HIV transmission.


PbZr0.4Ti0.6O3 and Ba0.9Sr0.1TiO3 reflectors derived from chemical solutions containing polymers.
Ba(0.9)Sr(0.1)TiO3 (BST)-based and PbZr(0.4)Ti(0.6)O(3)-based quasi-periodic multilayers consisting of dense and porous ferroelectric layers have been fabricated by solgel technique using chemical solutions containing polyethylene glycol (PEG) or polyvinylpyrrolidone k30 (PVP). All multilayers exhibit good performance as dielectric mirrors. For each multilayer, the maximum peak reflectivity is over 90% and the photonic stopband width is no less than 30 nm at room temperature. The reflection-band position can be easily tuned by varying the thickness of the bilayer. With the same processing conditions and number of periods, the Bragg reflection performance is almost the same for quasi-periodic PZT multilayers derived from two precursors containing different polymers. The BST multilayers deposited by using a PVP-containing precursor are superior in optical properties, including peak reflectivities and stop-band width, to those deposited by using the PEG-containing solution.


Transfer of regulatory knowledge from human to mouse for functional genomics analysis.
Transcriptome profiling followed by differential gene expression analysis often leads to lists of genes that are hard to analyze and interpret. Functional genomics tools are powerful approaches for downstream analysis, as they summarize the large and noisy gene expression space into a smaller number of biological meaningful features. In particular, methods that estimate the activity of processes by mapping transcripts level to process members are popular. However, footprints of either a pathway or transcription factor (TF) on gene expression show superior performance over mapping-based gene sets. These footprints are largely developed for humans and their usability in the broadly-used model organism Mus musculus is uncertain. Evolutionary conservation of the gene regulatory system suggests that footprints of human pathways and TFs can functionally characterize mice data. In this paper we analyze this hypothesis. We perform a comprehensive benchmark study exploiting two state-of-the-art footprint methods, DoRothEA and an extended version of PROGENy. These methods infer TF and pathway activity, respectively. Our results show that both can recover mouse perturbations, confirming our hypothesis that footprints are conserved between mice and humans. Subsequently, we illustrate the usability of PROGENy and DoRothEA by recovering pathway/TF-disease associations from newly generated disease sets. Additionally, we provide pathway and TF activity scores for a large collection of human and mouse perturbation and disease experiments (2374). We believe that this resource, available for interactive exploration and download (https://saezlab.shinyapps.io/footprint_scores/), can have broad applications including the study of diseases and therapeutics.


Hepatitis C and pregnancy outcomes: a systematic review protocol.
Many women living with hepatitis C (HCV) are of childbearing age. While the risk of vertical HCV transmission has been well established, the impact of HCV on pregnancy outcomes are equivocal, with some studies reporting risks of preterm birth, low gestational weight, gestational diabetes and hypertension, while other studies report no such risks. With the shift of the HCV treatment landscape to more effective, tolerable and shorter medications, understanding pregnancy outcomes of women living with HCV are an important consideration in order to provide a baseline from which to consider the usefulness and safety of HCV treatment for this population. The objective of this systematic review will be to investigate pregnancy outcomes associated with maternal HCV infection. This systematic review will incorporate articles relevant to pregnancy outcomes among women living with HCV (eg, gestational diabetes and caesarean delivery). Articles will be retrieved from academic databases including MEDLINE, EMBASE, CINAHL, clinicaltrial.gov and the Cochrane Library and hand searching of conference proceedings and reference lists. A database search will not be restricted by date, and conference abstract will be restricted to the past 2 years. The Newcastle-Ottawa Quality Assessment Scale will be used to assess the quality of the retrieved studies. Data will be extracted and scored independently by two authors. A narrative account will synthesise the findings to answer the objectives of this review. This systematic review will synthesise the literature on the pregnancy outcomes of women living with HCV. Results from this review will be disseminated to clinical audiences, community groups and policy-makers, and may support clinicians and decision-makers in developing guidelines to promote best outcomes for this population.


Spectroscopic detection of endovesiculation by large unilamellar phosphatidylcholine vesicles: effects of chlorpromazine, dibucaine, and safingol.
Endovesiculation by large unilamellar vesicles (LUVs) induced by cationic amphiphiles is described in this work. A recent procedure to monitor phagocytosis of vesicles by macrophages by determining the amount of the simultaneously internalized water_soluble fluorescent dye HPTS with external quencher was adapted to LUVs (Daleke, D. L.; Hong, K.; Papahadjopoulos, D. Biochim. Biophys. Acta 1990, 1024, 352). Compared to dibucaine and safingol, the local anesthetic chlorpromazine (CPZ) was found to be the most efficient inducer of HPTS-internalization by LUVs. Control experiments using LUVs with entrapped HPTS indicated that the observed dye-internalization does not originate from transient lysis. A strong increase in activity above the critical micelle concentration of CPZ implies the importance of CPZ-micelles for endovesiculation. The significantly less efficient CPZ-induced HPTS-internalization by LUVs with 68 nm compared to 176 nm diameter further diminishes the likelihood of a micelle/bilayer fusion mechanism and supports the presence of 'zipper-type' endovesiculation by LUVs with diameters as small as 68 nm.


Collaboration between neuropsychologists and speech-language pathologists in rehabilitation settings.
The purpose of this study was to understand the barriers and facilitators of communication and collaboration between speech-language pathologists (SLPs) and neuropsychologists (NPs) in rehabilitation settings. Focus groups were held at 3 rehabilitation hospitals. Participants were a convenience sample and were considered representatives of acquired brain injury rehabilitation teams that include SLPs and NPs. There were a total of 28 SLPs and 10 NPs in the sample. The study used a semistructured interview guide for the focus group discussions, using questions centered on major areas known to be related to interdisciplinary collaboration. Written notes and audio recordings were analyzed for recurring and strongly stated themes. Consistent themes emerged across focus groups, which included (1) structure of collaboration, (2) perceived roles of NPs and SLPs in assessment and intervention, (3) similarities and differences in training and philosophic perspectives, (4) barriers to successful collaboration, and (5) facilitators of collaboration. The SLPs and NPs valued the contributions of both professions in the management of patients with acquired brain injuries. Effective collaboration appeared to be influenced by several factors and is discussed. It was evident that effective communication was a key and powerful element in successful collaboration.


Structure and functionality in flavivirus NS-proteins: perspectives for drug design.
Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads.


Effect of Cr-doping on the electronic structure and work function of α-Fe2O3 thin films.
We investigate the effect of Cr-doping on the properties of α-Fe2O3(001) thin films with Fe termination using the local density approximation plus a Hubbard U correction. We find that both the doping site and concentration of Cr atoms dramatically affect the electronic structure and work function (WF) of α-Fe2O3 films. The results demonstrate that it is most energetically favorable for Cr atoms to substitute the Fe atoms in the sub-surface of α-Fe2O3 thin films. The doping of Cr atoms in the sub-surface not only lowers the band gap of the film but also greatly enhances the work function by 0.9 eV with respect to the pure α-Fe2O3 film. The increase of WF correlates with the reduction of occupied O px/py states at the top valence band which leads to a decrease of the Fermi energy. As the Cr concentration changes from 4.2% to 16.7%, the WF firstly increases, and then drops. The WF reaches a maximum of 6.61 eV for the Cr concentration of 8.3%. These results suggest that doping Cr atoms in a α-Fe2O3(001) thin film can increase the corrosion potential and benefits the protection of steel from corrosion.


Regulation of growth saturation and development of necrosis in EMT6/Ro multicellular spheroids by the glucose and oxygen supply.
To investigate the effects of glucose and oxygen on spheroid growth, EMT6/Ro mouse mammary carcinoma cell spheroids were cultured in suspension in either 0.28 mM (20%) or 0.07 mM (5%) oxygen and 16.5, 5.5, 1.7, and 0.8 mM glucose. The spheroids initially grew at the same exponential rate in all culture conditions, with spheroid volume and cell number doubling times of 20-24 h. The growth rates slowed as the spheroids grew, and the maximum volume and cell number attained at growth saturation were proportional to the oxygen and glucose concentrations in the medium. There was a 500-fold difference in saturation sizes comparing spheroids cultured in the highest oxygen and glucose concentrations to those grown in the lowest. The thickness of the viable cell rims was also positively correlated with the oxygen and glucose concentrations in the medium. Comparison of the growth saturation and viable cell rim data showed an excellent correlation between the onset of central necrosis and the cessation of spheroid growth. A model is presented to explain the observed spheroid growth characteristics by proposing a competition between externally supplied growth and viability-promoting factors and internally generated inhibitory factors produced by the process of necrosis. This model has critical implications for the use of spheroids as models of cellular growth in tumors.


Prediction of Photosynthetic, Biophysical, and Biochemical Traits in Wheat Canopies to Reduce the Phenotyping Bottleneck.
To achieve food security, it is necessary to increase crop radiation use efficiency (RUE) and yield through the enhancement of canopy photosynthesis to increase the availability of assimilates for the grain, but its study in the field is constrained by low throughput and the lack of integrative measurements at canopy level. In this study, partial least squares regression (PLSR) was used with high-throughput phenotyping (HTP) data in spring wheat to build predictive models of photosynthetic, biophysical, and biochemical traits for the top, middle, and bottom layers of wheat canopies. The combined layer model predictions performed better than individual layer predictions with a significance as follows for photosynthesis R 2 = 0.48, RMSE = 5.24 μmol m-2 s-1 and stomatal conductance: R 2 = 0.36, RMSE = 0.14 mol m-2 s-1. The predictions of these traits from PLSR models upscaled to canopy level compared to field observations were statistically significant at initiation of booting (R 2 = 0.3, p < 0.05; R 2 = 0.29, p < 0.05) and at 7 days after anthesis (R 2 = 0.15, p < 0.05; R 2 = 0.65, p < 0.001). Using HTP allowed us to increase phenotyping capacity 30-fold compared to conventional phenotyping methods. This approach can be adapted to screen breeding progeny and genetic resources for RUE and to improve our understanding of wheat physiology by adding different layers of the canopy to physiological modeling.


Psychiatric healthcare resource utilization following initiation of aripiprazole once-monthly: a retrospective real-world study.
This observational retrospective real-world study examined changes in healthcare resource utilization (HCRU) pre- and post-initiation of aripiprazole once-monthly (AOM 400) in patients with schizophrenia or bipolar I disorder. Electronic health record-derived, de-identified data from the NeuroBlu Database (2013-2020) were used to identify patients ≥18 years with schizophrenia (n = 222) or bipolar I disorder (n = 129) who were prescribed AOM 400, and had visit data within 3, 6, 9, or 12 months pre- and post-initial AOM 400 prescription. Rates of inpatient hospitalization, emergency department visits, inpatient readmissions, and average length of stay were examined and compared over 3, 6, 9, and 12 months pre-/post-AOM 400 using a McNemar test. Statistically significant differences were seen in both schizophrenia and bipolar I disorder patient cohorts pre- and post-AOM 400 in inpatient hospitalization rates (p < .001 all time points, both cohorts) and 30-day readmission per patient rates (p < .001 all time points, both cohorts). Statistically significant improvement in mean length of stay was observed in both cohorts at all time points, except for at six months in patients with schizophrenia. Emergency department visit rates were significantly lower after AOM 400 initiation for both cohorts at all time points (p < .001). A reduction in the rate of hospitalizations, emergency department visits, 30-day readmissions, and average length-of-stay was observed for patients diagnosed with either schizophrenia or bipolar I disorder, which suggests a positive effect of AOM 400 treatment on HCRU outcomes and is supportive of earlier analyses from different data sources.


SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.
Dysregulation of tissue development pathways can contribute to cancer initiation and progression. In murine embryonic prostate epithelia, the transcription factor SOX9 is required for proper prostate development. In this study, we examined a role for SOX9 in prostate cancer in mouse and human. In Pten and Nkx3.1 mutant mice, cells with increased levels of SOX9 appeared within prostate epithelia at early stages of neoplasia, and higher expression correlated with progression at all stages of disease. In transgenic mice, SOX9 overexpression in prostate epithelia increased cell proliferation without inducing hyperplasia. In transgenic mice that were also heterozygous for mutant Pten, SOX9 overexpression quickened the induction of high-grade prostate intraepithelial neoplasia. In contrast, Sox9 attenuation led to a decrease proliferating prostate epithelia cells in normal and homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression was associated with increasing Gleason grades and higher Ki67 staining. Our findings identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation.


Sequence-based analysis uncovers an abundance of non-coding RNA in the total transcriptome of Mycobacterium tuberculosis.
RNA sequencing provides a new perspective on the genome of Mycobacterium tuberculosis by revealing an extensive presence of non-coding RNA, including long 5' and 3' untranslated regions, antisense transcripts, and intergenic small RNA (sRNA) molecules. More than a quarter of all sequence reads mapping outside of ribosomal RNA genes represent non-coding RNA, and the density of reads mapping to intergenic regions was more than two-fold higher than that mapping to annotated coding sequences. Selected sRNAs were found at increased abundance in stationary phase cultures and accumulated to remarkably high levels in the lungs of chronically infected mice, indicating a potential contribution to pathogenesis. The ability of tubercle bacilli to adapt to changing environments within the host is critical to their ability to cause disease and to persist during drug treatment; it is likely that novel post-transcriptional regulatory networks will play an important role in these adaptive responses.


Structural basis for NKG2A/CD94 recognition of HLA-E.
The NKG2x/CD94 (x = A, C, E) natural killer-cell receptors perform an important role in immunosurveillance by binding to HLA-E complexes that exclusively present peptides derived from MHC class I leader sequences, thereby monitoring MHC class I expression. We have determined the crystal structure of the NKG2A/CD94/HLA-E complex at 4.4-A resolution, revealing two critical aspects of this interaction. First, the C-terminal region of the peptide, which displays the most variability among class I leader sequences, interacts entirely with CD94, the invariant component of these receptors. Second, residues 167-170 of NKG2A/C account for the approximately 6-fold-higher affinity of the inhibitory NKG2A/CD94 receptor compared to its activating NKG2C/CD94 counterpart. These residues do not contact HLA-E or peptide directly but instead form part of the heterodimer interface with CD94. An evolutionary analysis across primates reveals that whereas CD94 is evolving under purifying selection, both NKG2A and NKG2C are evolving under positive selection. Specifically, residues at the CD94 interface have evolved under positive selection, suggesting that the evolution of these genes is driven by an interaction with pathogen-derived ligands. Consistent with this possibility, we show that NKG2C/CD94, but not NKG2A/CD94, weakly but specifically binds to the CMV MHC-homologue UL18. Thus, the evolution of the NKG2x/CD94 family of receptors has likely been shaped both by the need to bind the invariant HLA-E ligand and the need to avoid subversion by pathogen-derived decoys.