Transparent photoactuators based on localized-surface-plasmon-resonant semiconductor nanocrystals: a platform for camouflage soft robots.
Among the various kinds of actuators, photoactuators with the advantages of wireless and remote manipulation have attracted the interest of many researchers. However, it is challenging to develop transparent photoactuators for camouflage soft robots, because most of the current photoactuators use colored or even black light-absorbing agents. Here, we fabricate a series of transparent actuators by employing localized-surface-plasmon-resonant semiconductor nanocrystals, which mainly respond to infrared light. In this way, we introduce the advantages of wireless and remote manipulation into the camouflage soft robots. Three semiconductor nanocrystals (In2O3:Sn, W18O49 and CuS nanocrystals) are fabricated as the photothermal conversion agents to construct the photoactuators. Owing to the weak absorption of visible light, the fabricated actuators exhibit high transparency (maximum transmittance >72% at 600 nm). Meanwhile, they demonstrate remarkable deformations upon near infrared light irradiation (bending curvature up to 0.66 cm-1). Finally, a worm-like crawling robot, a glasswing butterfly robot and a two-finger robot hand are constructed to demonstrate the ability of remote manipulation and inconspicuousness in both the robot appearance and the driving signal, attaining excellent passive camouflage function. These results provide a promising platform for remote-controlled camouflage soft robots and biomimic applications, which will be of significance in the field of soft robotics.


Outcome of selective non-operative management of penetrating abdominal injuries from the North American National Trauma Database.
The aim of this study was to investigate trends in the practice of selective non-operative management (SNOM) for penetrating abdominal injury (PAI) and to determine factors associated with its failure. The National Trauma Data Bank for 2002-2008 was reviewed. Patients with PAI were categorized as those who underwent successful SNOM (operative management not required) and those who failed SNOM (surgery required more than 4 h after admission). Yearly rates of SNOM versus non-therapeutic laparotomy (NTL) were plotted. Multivariable regression analysis was performed to identify factors associated with failed SNOM and mortality. A total of 12 707 patients with abdominal gunshot and 13 030 with stab wounds were identified. Rates of SNOM were 22.2 per cent for gunshot and 33.9 per cent for stab wounds, and increased with time (P < 0.001). There was a strong correlation between the rise in SNOM and the decline in NTL (r = - 0.70). SNOM failed in 20.8 and 15.2 per cent of patients with gunshot and stab wounds respectively. Factors predicting failure included the need for blood transfusion (odds ratio (OR) 1.96, 95 per cent confidence interval 1.11 to 3.46) and a higher injury score. Failed SNOM was independently associated with mortality in both the gunshot (OR 4.48, 2.07 to 9.70) and stab (OR 9.83, 3.44 to 28.00) wound groups. The practice of SNOM is increasing, with an associated decrease in the rate of NTL for PAI. In most instances SNOM is successful; however, its failure is associated with increased mortality. Careful patient selection and adherence to protocols designed to decrease the failure rate of SNOM are recommended.


High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis.
Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.


Fish provision in a changing environment: The buffering effect of regional trade networks.
Local and regional trade networks in small-scale fisheries are important for food security and livelihoods across the world. Such networks consist of both economic flows and social relationships, which connect different production regions to different types of fish demand. The structure of such trade networks, and the actions that take place within them (e.g., people fishing, buying, selling), can influence the capacity of small-scale fisheries to provide sufficient fish in a changing social and ecological context. In this study, we aim to understand the importance of networks between different types of traders that access spatially-distinct fish stocks for the availability and variability of fish provision. We deployed a mixed-methods approach, combining agent-based modelling, network analysis and qualitative data from a small-scale fishery in Baja California Sur, Mexico. The empirical data allowed us to investigate the trade processes that occur within trade networks; and the generation of distinct, empirically-informed network structures. Formalized in an agent-based model, these network structures enable analysis of how different trade networks affect the dynamics of fish provision and the exploitation level of fish stocks. Model results reveal how trade strategies based on social relationships and species diversification can lead to spillover effects between fish species and fishing regions. We found that the proportion of different trader types and their spatial connectivity have the potential to increase fish provision. However, they can also increase overexploitation depending on the specific connectivity patterns and trader types. Moreover, increasing connectivity generally leads to positive outcomes for some individual traders, but this does not necessarily imply better outcomes at the system level. Overall, our model provides an empirically-grounded, stylized representation of a fisheries trading system, and reveals important trade-offs that should be considered when evaluating the potential effect of future changes in regional trade networks.


Supporting the shift to digital with student-centered learning analytics.
This paper is in response to the manuscript entitled "Student perceptions of privacy principles for learning analytics" (Ifenthaler and Schumacher, Student perceptions of privacy principles for learning analytics. Educational Technology Research and Development, 64(5), 923-938, 2016) from a practice perspective. Learning analytics (the use of data science methods to generate actionable educational insights) have great potential to impact learning practices during the shift to digital. In particular, they can help fill a critical information gap for students created by an absence of classroom-based cues and the need for increased self-regulation in the online environment, However the adoption of learning analytics in effective, ethical and responsible ways is non-trivial. Ifenthaler and Schumacher (2016) present important findings about students' perceptions of learning analytics' usefulness and privacy, signaling the need for a student-centered paradigm, but stop short of addressing its implications for the creation and adoption of learning analytics tools. In this paper we address this limitation by describing the three specific shifts needed in current learning analytics practice for analytics to be accepted by and effective for students: (1) involve students in the creation of analytic tools meant to serve them; (2) develop analytics that are contextualized, explainable and configurable; and (3) empower students' agency in using analytic tools as part of their larger process of learning. These shifts are currently in different stages of maturity and adoption in mainstream learning analytics practice. The primary implication of this work is a call to action for researchers and practitioners to rethink and reshape how students participate in the creation, interpretation and impact of learning analytics.


In-cell Western™ detection of organic cation transporters in bronchial epithelial cell layers cultured at an air-liquid interface on Transwell(®) inserts.
Organic cation transporters (OCT) have been shown to mediate the transport of inhaled drugs in bronchial epithelial cells and might have important physiological functions in the airway epithelium. However, a quantitative method to evaluate OCT protein expression in physiologically relevant airway epithelial cell culture models is currently lacking. In-cell Western™ (ICW) techniques might fill that gap but to date, have only been performed on cells grown on 96 or 384-well microplates. An ICW assay was designed for measuring levels of the different OCT subtypes in intact layers of the human bronchial epithelial Calu-3 cell line cultured at an air-liquid interface on Transwell(®) inserts. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the internal standard for normalisation of cell number between the layers. The protocol was subsequently validated by exposing cell layers to compounds known to cause variations in OCT expression. Antibody signals above the background fluorescence were detected for OCT1, OCT3, OCTN1 and OCTN2 but not for OCT2 in 21day old Calu-3 layers, in agreement with previous studies which had reported OCT2 was absent in the Calu-3 cell line. Furthermore, increases in the fluorescence signal associated with OCT1, OCTN1 and OCTN2 were obtained following treatment of the layers with, respectively, the nitric oxide inducer sodium nitroprusside, the peroxisome proliferator activated receptor α (PPARα) agonist fenofibrate or the PPARγ agonist rosiglitazone, confirming the reliability of the ICW method developed. However, a suitable positive control for OCT3 could not be identified. This novel ICW assay can be exploited to quantify basal OCT protein expression as well as changes in transporter levels following external stimuli in various in vitro models. It can also be easily adapted to probe any protein in epithelial layers maintained on permeable filters.


Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: the effect of water and timing of meal intake on oral delivery of Salmon Calcitonin.
To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT). The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration. Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (Cmax and AUC0-4) of plasma sCT but comparable time to reach maximum concentration (Tmax). The sCT AUC0-4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing. 0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.


GRMD cardiac and skeletal muscle metabolism gene profiles are distinct.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction. To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47-93 months) GRMD dogs, were assessed. GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a "metabolic crisis" seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction. These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.


Fractional carbon dioxide laser for facial rejuvenation: A prospective study to evaluate the efficacy and the safety.
The aim of this study was to evaluate the efficacy and safety of the fractional ablative carbon dioxide laser for facial rejuvenation. Twenty-nine female who have the complaint of facial aging were recruited for the study. Participants received a maximum of three laser treatment sessions with one-month intervals and were scored using a 5-point scale on seven categories for facial aging before and after the treatment by the physicians. Self-assessments by participants were done at the last month of follow-up period and 3 years after the last session. Mean facial aging score before the treatment was 11,24 ± 4,30 and after the treatment was 10,51 ± 3,86 (p = 0.003). The decrease in the score was mild in 18 (62,1%) participants, whereas it was moderate in only 1 (3,4%) participant. None of the participants had significant or perfect improvement. When the seven categories were analyzed seperately, the only statistically significant alteration in the score was found in the skin tone category (p = 0.0001). Results show that rejuvenation with the fractional ablative carbon dioxide laser decreases mildly the symptoms of facial aging in more than half of the patients.


Direct and Indirect Effects-An Information Theoretic Perspective.
Information theoretic (IT) approaches to quantifying causal influences have experienced some popularity in the literature, in both theoretical and applied (e.g., neuroscience and climate science) domains. While these causal measures are desirable in that they are model agnostic and can capture non-linear interactions, they are fundamentally different from common statistical notions of causal influence in that they (1) compare distributions over the effect rather than values of the effect and (2) are defined with respect to random variables representing a cause rather than specific values of a cause. We here present IT measures of direct, indirect, and total causal effects. The proposed measures are unlike existing IT techniques in that they enable measuring causal effects that are defined with respect to specific values of a cause while still offering the flexibility and general applicability of IT techniques. We provide an identifiability result and demonstrate application of the proposed measures in estimating the causal effect of the El Niño-Southern Oscillation on temperature anomalies in the North American Pacific Northwest.


Dynamics of functional heterochromatic domains in the plant interphase nucleus.
Biologists have been fascinated for more than 2 centuries about how the nucleus in eukaryotes is organised. Certain of the component parts are well known, but the overall picture is blurred and often confusing. Small genome species have chromosomes in their interphase nuclei disposed in diffuse chromosome territories, without any Rabl arrangement, while in large genomes the chromosomes run string-like through the nucleus with a Rabl orientation following through the cell cycle. What happens in genomes of intermediate size is either a bit of both, depending on the tissue being studied, or still remains to be determined. The centromeres are the most dynamic and least well understood part of the nucleus, subject to rapid evolutionary change and with an epigenetic mark based on a special form of histone CENH3. Nonetheless, the centromere epigenetic mark has been inherited for millions of years by a process that is a complete mystery. Centromeres are involved with the dynamic interactions between chromosomes and other parts of the nuclear environment, such as the nuclear matrix and inner nuclear membrane, and they also engage with the spindle when the order within the nucleus changes during its division. The nucleolus organizer regions have likewise posed tantalising problems about their massive amplification of rDNA sequences, and how they are regulated and expressed. Some of these issues are now becoming clearer with advances in the science and the ongoing development of new molecular tools. These developments are discussed in this contribution, with particular reference to the centromere and the nucleolus organizer.


PathogenMip assay: a multiplex pathogen detection assay.
The Molecular Inversion Probe (MIP) assay has been previously applied to a large-scale human SNP detection. Here we describe the PathogenMip Assay, a complete protocol for probe production and applied approaches to pathogen detection. We have demonstrated the utility of this assay with an initial set of 24 probes targeting the most clinically relevant HPV genotypes associated with cervical cancer progression. Probe construction was based on a novel, cost-effective, ligase-based protocol. The assay was validated by performing pyrosequencing and Microarray chip detection in parallel experiments. HPV plasmids were used to validate sensitivity and selectivity of the assay. In addition, 20 genomic DNA extracts from primary tumors were genotyped with the PathogenMip Assay results and were in 100% agreement with conventional sequencing using an L1-based HPV genotyping protocol. The PathogenMip Assay is a widely accessible protocol for producing and using highly discriminating probes, with experimentally validated results in pathogen genotyping, which could potentially be applied to the detection and characterization of any microbe.


A time for everything and everything in its time - exploring the mechanisms underlying seasonality of COPD exacerbations.
Across Europe, COPD affects 23 million people leading to annual health care costs of ~€25.1 billion. This burden is particularly severe during winter months in association with the peak incidence of exacerbation events. Seasonal variation in the health status of patients with COPD places additional and often critical pressure on already strained health care resources. COPD exacerbations are characterized by worsening day-to-day symptoms of an individual and often triggered by respiratory infections, but the process by which this occurs in a seasonal fashion is likely to be multifactorial. In this review, we discuss recent population studies that highlight the impact of seasonality in COPD and review the proposed biological mechanisms underlying this. An appraisal of the role of the host susceptibility and response, environmental triggers and the biology of respiratory pathogens is detailed. The impact of each aspect is considered, and an integrated model of the context for the whole individual and society in general is explored.


Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial.
Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.


Silent infarcts in patients with ischemic stroke are related to age and size of the left atrium.
Possible specific risk factors for silent infarcts remain unknown. The aim of this study was to investigate whether risk factors for silent infarcts differ from those for symptomatic infarcts in stroke patients. Silent infarcts were defined as asymptomatic infarcts detected on computed tomographic scan in patients free of history of stroke and unrelated to the symptoms and signs of the index stroke. Of 595 consecutive patients with stroke or transient ischemic attacks, 116 (19%) had at least one silent infarct on the first computed tomographic scan performed within 24 hours after onset. They were compared with the 479 remaining patients for cerebrovascular risk factors and for presumed mechanism of stroke by means of the odds ratio method. A discriminant analysis was then performed in the subgroup of 216 patients with ischemic stroke who underwent an exhaustive cardiac and vascular workup. One hundred forty-one silent infarcts (99% confidence interval [CI], 29% to 41%) and 265 symptomatic infarcts (99% CI, 59% to 71%) were subcortical infarcts smaller than 15 mm. Univariate analysis showed that patients with silent infarcts were more likely to be older than 65 years (odds ratio [99% CI], 1.11 to 3.49) and to have left atrial enlargement on echocardiogram (odds ratio [99% CI], 1.02 to 26.70) and leukoaraiosis (odds ratio [99% CI], 1.39 to 4.21). Discriminant analysis found only two independent risk factors for silent infarcts: left atrial enlargement (P = .007) and age older than 65 years (P = .03); leukoaraiosis was not found to be an independent risk factor (P = .86). Age and left atrial enlargement are the main risk factors for silent infarcts in patients with ischemic stroke or transient ischemic attacks.


Dark kinase annotation, mining, and visualization using the Protein Kinase Ontology.
The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human and machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns and drug interactions. Furthermore, we have developed a completely new browser from the ground up to render the knowledge graph visible and interactive on the web. We have enriched ProKinO with new classes and relationships that capture information on kinase ligand binding sites, expression patterns, and functional features. These additions extend ProKinO's capabilities as a discovery tool, enabling it to uncover novel insights about understudied members of the protein kinase family. We next demonstrate the application of ProKinO. Specifically, through graph mining and aggregate SPARQL queries, we identify the p21-activated protein kinase 5 (PAK5) as one of the most frequently mutated dark kinases in human cancers with abnormal expression in multiple cancers, including a previously unappreciated role in acute myeloid leukemia. We have identified recurrent oncogenic mutations in the PAK5 activation loop predicted to alter substrate binding and phosphorylation. Additionally, we have identified common ligand/drug binding residues in PAK family kinases, underscoring ProKinO's potential application in drug discovery. The updated ontology browser and the addition of a web component, ProtVista, which enables interactive mining of kinase sequence annotations in 3D structures and Alphafold models, provide a valuable resource for the signaling community. The updated ProKinO database is accessible at https://prokino.uga.edu.


Identification of smallholder farmers and pastoralists' preferences for sheep breeding traits: choice model approach.
Identification of breeding objective traits pertinent to specific production environments with the involvement of target beneficiaries is crucial to the success of a breed improvement program. A choice experiment was conducted in four locations representing different production systems and agro-ecologies that are habitat to four indigenous sheep breeds (Afar, Bonga, Horro and Menz) of Ethiopia with the objective of identifying farmers'/pastoralists' preferences for sheep breeding traits. Following a synthesis of secondary information and diagnostic surveys, two communities per location consisting of 60 households each having at least four breeding ewes were identified. Producers' priority attributes used in the choice sets were identified through in-depth production system studies conducted from December 2007 to March 2008. On the basis of prior information, four to seven attributes were used to design choice sets with different profiles in order to capture results that mimic real life of the different communities. The attributes and levels chosen for the sheep profile were as follows: body size (large/small), coat color (brown/white/black), tail type (good/bad) for both rams and ewes; horn (polled/horned) and libido (active/poor) for rams; and lambing interval (three lambings in 2 years/two lambings in 2 years time), mothering ability (good mother/bad mother), twinning rate (twin bearer/single bearer) and milk yield (two cups per milking/one cup per milking) for ewes. A fractional factorial design was implemented to construct the alternatives included in the choice sets. The design resulted in a randomized selection of 48 sheep profiles (24 sets) for both sexes, which were grouped into four blocks with six choice sets each. An individual respondent was presented with one of the four blocks to make his/her choices. Results indicate that producers' trait preferences were heterogeneous except for body size in rams and mothering ability in ewes where nearly homogeneous preferences were investigated. In the pastoral production system, attention was given to coat color of both breeding rams and ewes, favoring brown and white colors over black. Ram libido influenced producers' decisions in Bonga, Horro and Menz areas. The influence of milk yield and twinning on respondents' decision making was high in Afar and Horro, respectively. Breeders in all areas attempt to combine production and reproduction traits as well as they can in order to maximize benefits from their sheep. The elicited measurable objective traits were used to design alternative community-based sheep breeding plans for the four indigenous sheep breeds in their production environments that have been implemented since.


Rural veterinarian's perception and practices in terms of biosecurity across three European countries.
The implementation of biosecurity measures in the animal health and production context is quite broad and aims at limiting the risk of introduction and spread of diseases. Veterinarians play a major role in biosecurity as key informants on the subject for cattle holders, key players in terms of disease prevention/control and eradication programs, as well as key risk factor in terms of disease dissemination. Many biosecurity studies have highlighted professional visitors such as veterinary practitioners as representing a high-risk factor in terms of disease introduction in animal facilities but, to date, very few studies have focused on the implementation level of biosecurity measures by veterinarians. An online survey was implemented in three European countries (Belgium, France and Spain) to assess the behaviour of rural veterinarians towards biosecurity, as well as their implementation level of the biosecurity measures. A descriptive analysis of data and a scoring system were applied to assess the implementation level of measures. The influence of different factors on the implementation level of biosecurity measures was investigated through a negative binomial regression model. The study identified different strengths, weaknesses, possible constraints and solutions in terms of veterinary perspectives. Veterinarians are considered as key informants by the farmers and could therefore play a more active role in terms of guidance and improvement of biosecurity at farm level. Based on the survey outcomes, two factors seemed to influence significantly the implementation level of measures: the country where he/she practices and the veterinarian's perception level of biosecurity. The biosecurity stages with the lowest application level, therefore representing the biggest threats, were bio-exclusion (increasing the risk of disease introduction) and biocontainment (increasing the risk of inter-herd transmission).


Observability and synchronization of neuron models.
Observability is the property that enables recovering the state of a dynamical system from a reduced number of measured variables. In high-dimensional systems, it is therefore important to make sure that the variable recorded to perform the analysis conveys good observability of the system dynamics. The observability of a network of neuron models depends nontrivially on the observability of the node dynamics and on the topology of the network. The aim of this paper is twofold. First, to perform a study of observability using four well-known neuron models by computing three different observability coefficients. This not only clarifies observability properties of the models but also shows the limitations of applicability of each type of coefficients in the context of such models. Second, to study the emergence of phase synchronization in networks composed of neuron models. This is done performing multivariate singular spectrum analysis which, to the best of the authors' knowledge, has not been used in the context of networks of neuron models. It is shown that it is possible to detect phase synchronization: (i) without having to measure all the state variables, but only one (that provides greatest observability) from each node and (ii) without having to estimate the phase.


Factors associated with focal lamina cribrosa defects in glaucoma.
To assess factors associated with focal lamina cribrosa (LC) defects in glaucoma. Serial enhanced depth imaging (EDI) optical coherence tomography (OCT) B-scans of the optic nerve head were obtained from glaucoma patients. EDI OCT scans were reviewed for focal LC defects (laminar holes or disinsertions). Evaluated clinical factors included age, central corneal thickness, visual field (VF) mean deviation (MD), exfoliation syndrome, normal-tension glaucoma (NTG), disc hemorrhage, and intraocular pressure (IOP) during past follow-up. One hundred forty-eight glaucomatous eyes (148 patients; mean age, 68 ± 12 years; mean VF MD, -11.63 ± 6.96 dB) were included. Sixty-seven (45%) eyes had focal LC defects and 81 (55%) did not. Eyes with focal LC defects had a higher prevalence of both disc hemorrhage (25% vs. 6%) and NTG (33% vs. 9%) and worse VF MD (-14.12 vs. -9.58 dB) than those without focal LC defects (P = 0.002, P < 0.001, and P < 0.001, respectively). In the multivariate logistic regression analysis, higher frequency of disc hemorrhage detection (odds ratio [OR], 3.63; P = 0.032), a diagnosis of NTG (OR, 4.23; P = 0.005), and worse VF MD (OR, 1.11; P < 0.001) were significant factors associated with the presence of focal LC defects. Disc hemorrhage developed in the same half of the disc as the largest or the second largest focal LC defect in 15 of 17 eyes (88.2%). Disc hemorrhage, a diagnosis of NTG, and more advanced glaucoma status are associated with focal LC defects. Future studies are needed to elucidate the cause-and-effect relationships between focal LC defects and these factors.


Rice yield formation under high day and night temperatures-A prerequisite to ensure future food security.
Increasing temperatures resulting from climate change dramatically impact rice crop production in Asia. Depending on the specific stage of rice development, heat stress reduces tiller/panicle number, decreases grain number per plant and lower grain weight, thus negatively impacting yield formation. Hence improving rice crop tolerance to heat stress in terms of sustaining yield stability under high day temperature (HDT), high night temperature (HNT), or combined high day and night temperature (HDNT) will bolster future food security. In this review article, we highlight the phenological alterations caused by heat and the underlying molecular-physiological and genetic mechanisms operating under different types of heat conditions (HDT, HNT, and HDNT) to understand heat tolerance. Based on our synthesis of HDT, HNT, and HDNT effects on rice yield components, we outline future breeding strategies to contribute to sustained food security under climate change.


Monitoring the Circulation of SARS-CoV-2 Variants by Genomic Analysis of Wastewater in Marseille, South-East France.
The monitoring of SARS-CoV-2 RNA in sewage has been proposed as a simple and unbiased means of assessing epidemic evolution and the efficiency of the COVID-19 control measures. The past year has been marked by the emergence of variants that have led to a succession of epidemic waves. It thus appears that monitoring the presence of SARS-CoV-2 in wastewater alone is insufficient, and it may be important in the future to also monitor the evolution of these variants. We used a real-time RT-PCR screening test for variants in the wastewater of our city to assess the effectiveness of direct SARS-CoV-2 sequencing from the same wastewater. We compared the genome sequencing results obtained over the large RS network and the smaller B7 network with the different distributions of the variants observed by RT-PCR screening. The prevalence of the "UK variant" in the RS and B7 networks was estimated to be 70% and 8% using RT-PCR screening compared to 95% and 64% using genome sequencing, respectively. The latter values were close to the epidemiology observed in patients of the corresponding area, which were 91% and 58%, respectively. Genome sequencing in sewage identified SARS-CoV-2 of lineage B.1.525 in B7 at 27% (37% in patients), whereas it was completely missed by RT-PCR. We thus determined that direct sequencing makes it possible to observe, in wastewater, a distribution of the variants comparable to that revealed by genomic monitoring in patients and that this method is more accurate than RT-PCR. It also shows that, rather than a single large sample, it would be preferable to analyse several targeted samples if we want to more appropriately assess the geographical distribution of the different variants. In conclusion, this work supports the wider surveillance of SARS-CoV-2 variants in wastewater by genome sequencing and targeting small areas on the condition of having a sequencing capacity and, when this is not the case, to developing more precise screening tests based on the multiplexed detection of the mutations of interest.


Evaluation of Potential Pharmacokinetic Drug-Drug Interaction between Armodafinil and Aripiprazole in Healthy Adults.
Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as adjunctive therapy to maintenance medications for major depressive episodes associated with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder. Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed. Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-∞, -34%) and dehydro-aripiprazole, which is both formed and eliminated in part via CYP3A4 (Cmax, - 10%; AUC0-∞, - 32%). Adverse events were generally consistent with known safety profiles of each agent. Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced following armodafinil pretreatment. The combination was generally well tolerated under the conditions studied.


Hypoxia and fungal pathogenesis: to air or not to air?
Over the last 3 decades, the frequency of life-threatening human fungal infections has increased as advances in medical therapies, solid-organ and hematopoietic stem cell transplantations, an increasing geriatric population, and HIV infections have resulted in significant rises in susceptible patient populations. Although significant advances have been made in understanding how fungi cause disease, the dynamic microenvironments encountered by fungi during infection and the mechanisms by which they adapt to these microenvironments are not fully understood. As inhibiting and preventing in vivo fungal growth are main goals of antifungal therapies, understanding in vivo fungal metabolism in these host microenvironments is critical for the improvement of existing therapies or the design of new approaches. In this minireview, we focus on the emerging appreciation that pathogenic fungi like Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are exposed to oxygen-limited or hypoxic microenvironments during fungal pathogenesis. The implications of these in vivo hypoxic microenvironments for fungal metabolism and pathogenesis are discussed with an aim toward understanding the potential impact of hypoxia on invasive fungal infection outcomes.


Design, synthesis, and enzymatic evaluation of N1-acyloxyalkyl- and N1-oxazolidin-2,4-dion-5-yl-substituted beta-lactams as novel inhibitors of human leukocyte elastase.
Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5'S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.


Multiple chemical sensitivity in the clinical setting.
Multiple chemical sensitivity (MCS) is a condition in which people experience a broad array of symptoms in reaction to exposure to trace amounts of common chemicals. Symptoms are most often triggered by odors, typically affect many systems, and can range from a runny nose to difficulty breathing and heart palpitations. The cause of this condition is unclear and there is no universal consensus on how to diagnose or treat it. MCS afflicts millions of Americans, although its prevalence is difficult to establish reliably. Theories of causation include both the physical and the psychogenic. This article begins with a case study, describes the current research on MCS, and offers recommendations to guide nurses when treating these patients in the hospital.


Iron allocation in leaves of Fe-deficient cucumber plants fed with natural Fe complexes.
Iron (Fe) sources available for plants in the rhizospheric solution are mainly a mixture of complexes between Fe and organic ligands, including phytosiderophores (PS) and water-extractable humic substances (WEHS). In comparison with the other Fe sources, Fe-WEHS are more efficiently used by plants, and experimental evidences show that Fe translocation contributes to this better response. On the other hand, very little is known on the mechanisms involved in Fe allocation in leaves. In this work, physiological and molecular processes involved in Fe distribution in leaves of Fe-deficient Cucumis sativus supplied with Fe-PS or Fe-WEHS up to 5 days were studied combining different techniques, such as radiochemical experiments, synchrotron micro X-ray fluorescence, real-time reverse transcription polymerase chain reaction and in situ hybridization. In Fe-WEHS-fed plants, Fe was rapidly (1 day) allocated into the leaf veins, and after 5 days, Fe was completely transferred into interveinal cells; moreover, the amount of accumulated Fe was much higher than with Fe-PS. This redistribution in Fe-WEHS plants was associated with an upregulation of genes encoding a ferric(III) -chelate reductase (FRO), a Fe(2+) transporter (IRT1) and a natural resistance-associated macrophage protein (NRAMP). The localization of FRO and IRT1 transcripts next to the midveins, beside that of NRAMP in the interveinal area, may suggest a rapid and efficient response induced by the presence of Fe-WEHS in the extra-radical solution for the allocation in leaves of high amounts of Fe. In conclusion, Fe is more efficiently used when chelated to WEHS than PS and seems to involve Fe distribution and gene regulation of Fe acquisition mechanisms operating in leaves.


Trends in Alabama teen driving death and injury.
Motor vehicle crashes (MVCs) are a leading cause of morbidity and mortality in teens. Alabama has been in the Top 5 states for MVC fatality rate among teens in the United States for several years. Twelve years of teen MVC deaths and injuries were evaluated. Our hypothesis is that the teen driving motor vehicle-related deaths and injuries have decreased related to legislative and community awareness activities. A retrospective analysis of Alabama teen MVC deaths and injury for the years 2000 to 2011 was conducted. MVC data were obtained from a Fatality Analysis Reporting System data set managed by the Center for Advanced Public Safety at the University of Alabama. A Lowess regression-scattergram analysis was used to identify period specific changes in deaths and injury over time. Statistical analysis was conducted using True Epistat 5.0 software. When the Lowess regression was applied, there was an obvious change in the trend line in 2007. To test that observation, we then compared medians in the pre-2007 and post-2007 periods, which validated our observation. Moreover, it provided a near-even number of observations for comparison. The Spearman rank correlation was used to test for correlation of deaths and injury over time. The Mann-Whitney U-test was used to evaluate median differences in deaths and injury comparing pre-2007 and post-2007 data. Alabama teen MVC deaths and injury demonstrated a significant negative correlation over the 12-year period (Rs for deaths and injury, -0.87 [p < 0.001] and -0.92 [p < 0.001], respectively). Lowess regression identified a notable decline in deaths and injury after the year 2006. Median deaths and injury for the pre-2007 period were significantly higher than the post-2007 period, (U = 35.0, p = 0.003). Alabama teen driver deaths and injury have decreased during the 12-year study period, most notably after 2006. Factors that may have contributed to this trend may include stricter laws for teen drivers (enacted in 2002 and updated in 2010), less teen driving because of a nationwide economic downturn, delayed licensing in teens, steady improvements in overall seat belt use, and heightened public awareness of risky behaviors in teen driving.


Unilateral Holmes tremor, clearly responsive to cerebrospinal fluid release, in a patient with an ischemic midbrain lesion and associated chronic hydrocephalic ventricle enlargement. Case report.
The authors describe a 58-year-old man with sudden onset of a unilateral tremor caused by a midbrain lesion that affected the substantia nigra and the cerebellothalamic pathway. There were also clinical and neuroimaging signs of a communicating chronic hydrocephalus. The patient was severely handicapped by this tremor, which was a typical Holmes tremor with rest, posture, and intention components. Parkinson disease or multiple-system atrophy as causes for the tremor could be ruled out by DaTSCAN and 123I iodobenzamide and single-photon emission computerized tomography (SPECT), respectively. The tremor was completely supressed by temporary and permanent cerebrospinal fluid release after ventriculoperitoneal shunt placement, without any additional medication, for a period of 6 months. Afterward, the tremor returned, and the patient had to be treated by a stereotactic electrode implantation in the contralateral ventralis intermedius nucleus, which led to complete tremor suppression during the 1.5-year follow-up period. In this case report, the authors present the clinical description and the electrophysiological, SPECT, and magnetic resonance imaging data of a rare combination of symptoms and their surgical treatment.


Involvement of chymase-mediated angiotensin II generation in blood pressure regulation.
Angiotensin I-converting enzyme (ACE) inhibitors are thought to lower blood pressure in hypertensive patients, mainly by decreasing angiotensin II (Ang II) formation. Chymase, a human mast cell protease, has recently been proposed to play a role in blood pressure regulation because of its Ang II-forming activity. Here we show that the predominant chymase mRNA species in the mouse aorta are those for types 4 and 5 isoforms, and that both are efficient Ang II-forming enzymes. Evaluation of ACE-dependent and ACE-independent Ang II-forming pathways in mast cell-deficient (Kit(w)/Kit(w-v)) mice and their mast cell-sufficient littermate (MC(+/+)) controls revealed that, in contrast to the latter, Kit(w)/Kit(w-v) mice fail to express chymase mRNAs in the vasculature and have almost no ACE-independent Ang II-forming activity in either isolated blood vessels or homogenates. Moreover, in MC(+/+) but not in Kit(w)/Kit(w-v) mice, a contribution of ACE-independent Ang II generation to blood pressure regulation was evident by a 1.6-fold greater maximal reduction in mean arterial pressure with acute ACE inhibition plus AT(1) receptor blockade than with ACE inhibition alone. Thus, mast cells are the source of the vascular ACE-independent pathway, and the antihypertensive benefit of combining ACE inhibitor therapy with AT(1) receptor antagonist therapy is most likely due to negation of chymase-catalyzed Ang II generation.


The adenovirus type 12 early-region 1B 58,000-Mr gene product is required for viral DNA synthesis and for initiation of cell transformation.
An E1B 58K mutant of adenovirus type 12 (Ad12), dl207, was constructed by the deletion of 852 base pairs in the E1B 58K coding region. The mutant could grow efficiently in 293E1 cells but not in HeLa, KB, or human embryo kidney (HEK) cells. Viral DNA replication of dl207 was not detected in HeLa and KB cells and was seldom detected in HEK cells. Analysis of viral DNA synthesis in vitro showed that the Ad12-DNA-protein complex replicated by using the nuclear extract from Ad12 wild-type (WT)-infected HeLa cells but not by using the nuclear extract from dl207-infected cells. In dl207-infected HeLa and KB cells, early mRNAs were detected, but late mRNAs were not detected. The mutant induced fewer transformed foci than the WT in rat 3Y1 cells. Cells transformed by dl207 could grow efficiently in fluid medium, form colonies in soft agar culture, and induce tumors in rats transplanted with the transformed cells at the same efficiency as WT-transformed cells. Tumors were induced in hamsters injected with WT virions but were not induced in hamsters injected with dl207 virions. The results indicate that the E1B 58K protein is required both for viral DNA replication in productive infection and for initiation of cell transformation, but not for maintenance of the transformed phenotype.


Affinity reagents for cross-linking hemoglobin: bis(phenoxycarbonylethyl)phosphinic acid (BPCEP) and bis(3-nitrophenoxycarbonylethyl)phosphinic acid (BNCEP).
Synthesis and properties of two new macrobiomolecular cross-linking reagents, bis(phenoxycarbonylethyl) phosphinic acid (BPCEP) and bis(3-nitrophenoxycarbonylethyl)phosphinic acid (BNCEP), have been reported. The reagents were successfully employed to cross-link human hemoglobin under oxygenated conditions. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), high performance liquid chromatography (HPLC), and fast protein liquid chromatography (FPLC) analyses of the reaction products indicated that the cross-link was intramolecular in nature, and that it was between the two beta subunits of hemoglobin in each case. The products were purified by DEAE-cellulose chromatography, and the purified material was employed for oxygen-binding assessments. The oxygen equilibrium curve of the cross-linked material, in each case, was right-shifted toward lower oxygen affinity as desired. The sigmoidal shapes of oxygen curves, in each case, suggested retainment of oxygen-binding cooperativity, although considerably lower than that of the native hemoglobin


Standardization of Reading Charts: A Review of Recent Developments.
This review gives an overview of the current status of standardization by statistical evaluation of reading charts. First begun only 20 years ago, the statistical evaluation of reading charts now reflects an increasing clinical and scientific interest in standardized, comparable, and reproducible reading charts.For clinical or research purposes in human subjects, standardization of psychophysical tests and their test items by statistical evaluation is mandatory because it provides experimental control. Initial attempts at reading chart standardization were made by characterizing the test items, either in terms of a selection of unrelated words or in terms of sentences representing a constant number of characters, including spaces. As initiated by the RADNER Reading Charts, standardization of reading charts (and test items) by statistical evaluation has gained increasing clinical and scientific interest in the last two decades and has later also been applied to some of the other modern reading charts. A literature search was performed with respect to reading charts that (a) have been produced in accordance with the recommendations of the International Council of Ophthalmology (geometrical print size progression), (b) have been statistically analyzed, and/or (c) use clearly characterized test items (conceptually and statistically). These reading charts are as follows: the Bailey-Lovie Word Reading Charts, the Colenbrander Cards, the RADNER Reading Charts, the MNREAD Acuity Charts, the Smith-Kettlewell Reading Test (SKread Test), the C-Read Charts, and the Balsam Alabdulkader-Leat (BAL) Chart. The test items of these charts have been characterized either empirically or by statistical analysis and selection. The extent of the statistical evaluation of the reading charts varies. Despite their different methodological approaches, these reading charts represent an advancement that has made possible the useful comparison and reproducible evaluation of near visual performance.


Impact of resveratrol supplementation on inflammatory, antioxidant, and periodontal markers in type 2 diabetic patients with chronic periodontitis.
Diabetes mellitus and periodontal disease are two common and chronic diseases with bidirectional relationship influence public health and quality of life. The aims of this study was to study the impact of resveratrol supplementation in adjunct with non-surgical periodontal therapy on inflammatory, antioxidant, and periodontal markers in patients with type 2 diabetes with periodontal disease. In this randomized clinical trial, 43 patients with diabetes and chronic periodontitis were randomly allocated into two intervention and control groups receiving either resveratrol supplements or placebo for 4 weeks. Serum levels of interleukin 6 (IL6), tumor necrosis factor α (TNFα), total antioxidant capacity (TAC) and clinical attachment loss (CAL) as the main index of periodontal marker were measured pre-intervention and post-intervention. In the intervention group, the mean serum level of IL6 was reduced significantly (P = 0.039) post-intervention (2.19 ± 1.09 and 1.58 ± 1.06). No significant differences were seen in the mean levels of IL6, TNFα, TAC and CAL between two groups post-intervention. It is suggested that daily consumption of resveratrol supplement may not change TNFα, TAC and CAL, but it would be beneficial in reducing serum levels of IL6. Therefore, further studies are suggested to investigate the effects of resveratrol supplementation along with NST on periodontal status.


Percutaneous "K-wireless" pedicle screw fixation technique: an evaluation of the initial experience of 100 screws with assessment of accuracy, radiation exposure, and procedure time.
Percutaneous pedicle screws are used to provide rigid internal fixation in minimally invasive spinal procedures and generally require the use of Kirchner wires (or K-wires) as a guide for screw insertion. K-wires can bend, break, advance, or pull out during the steps of pedicle preparation and screw insertion. This can lead to increased fluoroscopic and surgical times and potentially cause neurological, vascular, or visceral injury. The authors present their experience with a novel "K-wireless" percutaneous pedicle screw system that eliminates the inherent risks of K-wire use. A total of 100 screws were placed in 28 patients using the K-wireless percutaneous screw system. Postoperative dedicated spinal CT scans were performed in 25 patients to assess the accuracy of screw placement. Screw placement was graded A through D by 2 independent radiologists: A = within pedicle, B = breach < 2 mm, C = breach of 2-4 mm, and D = breach > 4 mm. Screw insertion and fluoroscopy times were also recorded in each case. Clinical complications associated with screw insertion were documented. A total of 100 K-wireless percutaneous pedicle screws were placed into the lumbosacral spine in 28 patients. Postoperative CT was performed in 25 patients, thus the placement of only 90 screws was assessed. Eighty-seven screws were placed within the pedicle confines (Grade A), and 3 violated the pedicle (2 Grade B [1 lateral, 1 medial] and 1 Grade D [medial]) for an overall accuracy rate of 96.7%. One patient required reoperation for screw repositioning due to a postoperative L-5 radiculopathy secondary to a Grade D medial breach at L-5. This patient experienced improvement of the radiculopathy after reoperation. Average screw insertion and fluoroscopy times were 6.92 minutes and 22.7 seconds per screw, respectively. The results of this study demonstrate that the placement of K-wireless percutaneous pedicle screws is technically feasible and can be performed accurately and safely with short procedure and fluoroscopy times.


R plasmids conferring multiple drug resistance from shigella isolated in Korea.
The majority (85%) of shigella isolated in 1980 and 1981 in Korea were Shigella flexneri, the others were Sh. sonnei (14%) with only a small number of Sh. dysenteriae. Only 14 of the 459 strains of shigella isolated were susceptible to all 12 drugs tested, and 445 were resistant to three or more drugs. Strains multiply resistant to the six drugs, chloramphenicol (Cm), tetracycline (Tc), streptomycin (Sm), sulfisomidine (Su), ampicillin (Ap) and trimethoprim (Tp) were most frequently encountered, followed by those resistant to Cm, Tc, Sm, Su and Tp. The complete patterns of resistance to drugs except nalidixic acid and rifampin in approximately 73% of drug-resistant strains were co-transferred to Escherichia coli by conjugation, indicating that the resistance was R plasmid-mediated. Randomly selected R plasmids conferring various patterns of resistance markers were tested for the incompatibility groups, and almost all of them were classified into Inc FII. Two of three R plasmids conferring resistance to Cm, Tc, Sm and Su were classified into Inc B and one to Inc FII. Two R types with resistance markers of Cm, Tc, Sm and Ap were not classified with our standard plasmids used.


Transmembrane segment 6 of the Glut1 glucose transporter is an outer helix and contains amino acid side chains essential for transport activity.
Experimental data and homology modeling suggest a structure for the exofacial configuration of the Glut1 glucose transporter in which 8 transmembrane helices form an aqueous cavity in the bilayer that is stabilized by four outer helices. The role of transmembrane segment 6, predicted to be an outer helix in this model, was examined by cysteine-scanning mutagenesis and the substituted cysteine accessibility method using the membrane-impermeant, sulfhydryl-specific reagent, p-chloromercuribenzene-sulfonate (pCMBS). A fully functional Glut1 molecule lacking all 6 native cysteine residues was used as a template to produce a series of 21 Glut1 point mutants in which each residue along helix 6 was individually changed to cysteine. These mutants were expressed in Xenopus oocytes, and their expression levels, functional activities, and sensitivities to inhibition by pCMBS were determined. Cysteine substitutions at Leu(204) and Pro(205) abolished transport activity, whereas substitutions at Ile(192), Pro(196), Gln(200), and Gly(201) resulted in inhibition of activity that ranged from approximately 35 to approximately 80%. Cysteine substitutions at Leu(188), Ser(191), and Leu(199) moderately augmented specific transport activity relative to the control. These results were dramatically different from those previously reported for helix 12, the structural cognate of helix 6 in the pseudo-symmetrical structural model, for which none of the 21 single-cysteine mutants exhibited reduced activity. Only the substitution at Leu(188) conferred inhibition by pCMBS, suggesting that most of helix 6 is not exposed to the external solvent, consistent with its proposed role as an outer helix. These data suggest that helix 6 contains amino acid side chains that are critical for transport activity and that structurally analogous outer helices may play distinct roles in the function of membrane transporters.


Shear deformation response of a holographic sensor based on elastic poly(MMA-co-LMA) photopolymer.
A holographic sensor based on camphorquinon doped poly (methyl methacrylate-co-lauryl methacrylate) (poly (MMA-co-LMA)) elastic photopolymer is developed for characterizing the shear deformation of material. A shear angle and its transverse displacement, which are induced by a couple of shear stresses, are analyzed using a diffraction spectrum of a transmission holographic sensor. The dependence of the peak wavelength shift on the shear deformation presents a good linear relationship which provides a quantitative characterization means. The detectable maximum of the shear angle exceeds 26.1 deg, and the peak wavelength shift closes to 4.0 nm. The available sensitivity is better than 3.33 deg/0.5 nm (shear angle/wavelength shift) using a commercial spectrometer with 0.5 nm of resolution. Finally, the reversibility response of shear deformation further confirmed the practical applicability of the elastic polymer-based shear deformation sensor. The spectrum measurement of shear deformation provides a novel measurement means for the mechanical deformation of materials and expands the application of a holographic sensor.


Cell-specific expression of tryptophan decarboxylase and 10-hydroxygeraniol oxidoreductase, key genes involved in camptothecin biosynthesis in Camptotheca acuminata Decne (Nyssaceae).
Camptotheca acuminata is a major natural source of the terpenoid indole alkaloid camptothecin (CPT). At present, little is known about the cellular distribution of the biosynthesis of CPT, which would be useful knowledge for developing new strategies and technologies for improving alkaloid production. The pattern of CPT accumulation was compared with the expression pattern of some genes involved in CPT biosynthesis in C. acuminata [i.e., Ca-TDC1 and Ca-TDC2 (encoding for tryptophan decarboxylase) and Ca-HGO (encoding for 10-hydroxygeraniol oxidoreductase)]. Both CPT accumulation and gene expression were investigated in plants at different degrees of development and in plantlets subjected to drought-stress. In all organs, CPT accumulation was detected in epidermal idioblasts, in some glandular trichomes, and in groups of idioblast cells localized in parenchyma tissues. Drought-stress caused an increase in CPT accumulation and in the number of glandular trichomes containing CPT, whereas no increase in epidermal or parenchymatous idioblasts was observed. In the leaf, Ca-TDC1 expression was detected in some epidermal cells and in groups of mesophyll cells but not in glandular trichomes; in the stem, it was observed in parenchyma cells of the vascular tissue; in the root, no expression was detected. Ca-TDC2 expression was observed exclusively in leaves of plantlets subjected to drought-stress, in the same sites described for Ca-TDC1. In the leaf, Ca-HGO was detected in all chlorenchyma cells; in the stem, it was observed in the same sites described for Ca-TDC1; in the root, no expression was detected. The finding that the sites of CPT accumulation are not consistently the same as those in which the studied genes are expressed demonstrates an organ-to-organ and cell-to-cell translocation of CPT or its precursors.


Accelerated memory decline in Alzheimer's disease with apolipoprotein epsilon4 allele.
To investigate a possible effect of the apolipoprotein (APOE) epsilon4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE epsilon3/3, epsilon3/4, or epsilon4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE epsilon4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE epsilon4 allele is related to an accelerated memory decline in AD.


Detection of Axitinib Using Multiwalled Carbon Nanotube-Fe2O3/Chitosan Nanocomposite-Based Electrochemical Sensor and Modeling with Density Functional Theory.
In this study, axitinib (AXI), a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase and used as a second-generation targeted drug, was investigated electrochemically under optimized conditions using multiwalled carbon nanotubes/iron(III) oxide nanoparticle-chitosan nanocomposite (MWCNT/Fe2O3@chitosan NC) modified on the glassy carbon electrode (GCE) surface. Characterization of the modified electrode was performed using scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). The adsorptive stripping differential pulse voltammetric (AdSDPV) technique was used for the sensitive, rapid, and precise detection of AXI. The current peak obtained with the MWCNT/Fe2O3@chitosan NC modified electrode was 23 times higher compared to the bare electrode. The developed modified electrode showed excellent electrocatalytic activity in AXI oxidation. Under optimized conditions, the effect of supporting electrolyte and pH was investigated, and 0.1 M H2SO4 was chosen as the electrolyte with the highest peak current for the target analyte. In the concentration range of MWCNT/Fe2O3@chitosan NC/GCE, 6 × 10-9 and 1 × 10-6 M, the limit of detection (LOD) and limit of quantification (LOQ) values were calculated to be 0.904 and 0.0301 pM, respectively. Tablet and serum samples were used for the applicability of the developed sensor, relative standard deviation (RSD) values for all samples were below 2%, and the recovery results were 99.23 and 101.84%, respectively. The MWCNT/Fe2O3@chitosan NC/GCE designed to determine AXI demonstrated the applicability, selectivity, precision, and accuracy of the sensor. The mechanism of electron transfer from the modified GCE surface to the analyte solution is studied via modeling the modified GCE surface by the density functional theory (DFT) method at B3LYP/6-311+g(d,p) and M062X/6-31g(d,p) levels. We observed that the iron oxide nanoparticles play an important role in channeling electron flow from the analyte solution to the MWCNT-coated GCE electrode surface. Adsorption of the nanocomposite material onto the GCE surface occurs via strong electrostatic interactions, including ionic and hydrogen bond formations. During the adsorption-controlled oxidation process of the axitinib, the electrons are transferred via the highest occupied molecular orbital (HOMO) localized on the iron oxide moiety to the lowest unoccupied molecular orbital (LUMO) of the MWCNT/GCE surface.


Intranasal lidocaine 8% spray for second-division trigeminal neuralgia.
Trigeminal nerve block has been widely used for trigeminal neuralgia. This may induce paraesthesia. The second division of the trigeminal nerve passes through the sphenopalatine ganglion, which is located posterior to the middle turbinate and is covered by a mucous membrane. We examined the effectiveness of intranasal lidocaine 8% spray on paroxysmal pain in second-division trigeminal neuralgia. Twenty-five patients with second-division trigeminal neuralgia were randomized to receive two sprays (0.2 ml) of either lidocaine 8% or saline placebo in the affected nostril using a metered-dose spray. After a 7 day period, patients were crossed over to receive the alternative treatment. The paroxysmal pain triggered by touching or moving face was assessed with a 10 cm visual analogue scale (VAS) before and 15 min after treatment. Patients used a descriptive scale to grade pain outcome, and were asked to note whether the pain returned and how long after therapy it recurred. Intranasal lidocaine 8% spray significantly decreased VAS [baseline: 8.0 (2.0) cm, 15 min postspray: 1.5 (1.9) cm, mean (SD)], whereas the placebo spray did not [7.9 (2.0) cm, 7.6 (2.0) cm]. Moreover, pain was described as moderate or better by 23 patients of the lidocaine spray and 1 of the placebo group. The effect of treatment persisted for 4.3 h (range 0.5-24 h). Intranasal lidocaine 8% administered by a metered-dose spray produced prompt but temporary analgesia without serious adverse reactions in patients with second-division trigeminal neuralgia.


Primary care physicians' perceptions of barriers and facilitators to management of chronic kidney disease: A mixed methods study.
Given the high prevalence of chronic kidney disease (CKD), primary care physicians (PCPs) frequently manage early stage CKD. Nonetheless, there are challenges in providing optimal CKD care in the primary care setting. This study sought to understand PCPs' perceptions of barriers and facilitators to the optimal management of CKD. Mixed methods study. Community-based PCPs in four US cities: Baltimore, MD; St. Louis, MO; Raleigh, NC and San Francisco, CA. We used a self-administered questionnaire and conducted 4 focus groups of PCPs (n = 8 PCPs/focus group) in each city to identify key barriers and facilitators to management of patients with CKD in primary care. We conducted descriptive analyses of the survey data. Major themes were identified from audio-recorded interviews that were transcribed and coded by the research team. Of 32 participating PCPs, 31 (97%) had been in practice for >10 years, and 29 (91%) practiced in a non-academic setting. PCPs identified multiple barriers to managing CKD in primary care including at the level of the patient (e.g., low awareness of CKD, poor adherence to treatment recommendations), the provider (e.g., staying current with CKD guidelines), and the health care system (e.g., inflexible electronic medical record, limited time and resources). PCPs desired electronic prompts and lab decision support, concise guidelines, and healthcare financing reform to improve CKD care. PCPs face substantial but modifiable barriers in providing care to patients with CKD. Interventions that address these barriers and promote facilitative tools may improve PCPs' effectiveness and capacity to care for patients with CKD.


Recovery of mycobacteria from blood in mycobacteria growth indicator tube and Lowenstein-Jensen slant after lysis-centrifugation.
Five hundred five blood samples for culture were processed in the Isolator lysis-centrifugation system and were then inoculated into a Mycobacteria Growth Indicator Tube (MGIT) and onto a Lowenstein-Jensen (L-J) slant. Forty-nine isolates of Mycobacterium avium complex and three isolates of Mycobacterium tuberculosis were recovered from 50 of the blood culture specimens. Forty-five isolates from 43 specimens were recovered in the MGIT, with a mean time to detection of 21 days. Forty-one isolates from 40 specimens were recovered in the L-J slants, and the mean time to detection was 36 days. Nine specimens were positive in the MGIT alone, while seven specimens were positive only in L-J medium.


Risk of kidney stones with surgical intervention in living kidney donors.
A kidney stone in a person with a solitary kidney requires urgent attention, which may result in surgical and/or hospital attention. We conducted a matched retrospective cohort study to determine if living kidney donors compared to healthy nondonors have a higher risk of: (i) kidney stones with surgical intervention, and (ii) hospital encounters for kidney stones. We reviewed all predonation charts for living kidney donations from 1992 to 2009 at five major transplant centers in Ontario, Canada, and linked this information to healthcare databases. We selected nondonors from the healthiest segment of the general population and matched 10 nondonors to every donor. Of the 2019 donors and 20 190 nondonors, none had evidence of kidney stones prior to cohort entry. Median follow-up time was 8.4 years (maximum 19.7 years; loss to follow-up <7%). There was no difference in the rate of kidney stones with surgical intervention in donors compared to nondonors (8.3 vs. 9.7 events/10 000 person-years; rate ratio 0.85; 95% confidence interval [CI] 0.47-1.53). Similarly there was no difference in the rate of hospital encounters for kidney stones (12.1 vs. 16.1 events/10 000 person-years; rate ratio 0.75; 95% CI 0.45-1.24). These interim results are reassuring for the safety of living kidney donation.


Which lumbar interbody fusion technique is better in terms of level for the treatment of unstable isthmic spondylolisthesis?
The purpose of this study was to investigate and compare clinical and radiographic outcomes of 2 kinds of lumbar interbody fusion (LIF) for the treatment of adult low-grade isthmic spondylolisthesis at L4-5 and L5-S1 levels. The medical records and radiographs of 86 patients who underwent anterior LIF (ALIF) (L4-5, 42 patients; L5-S1, 44 patients) and 42 patients who underwent transforaminal LIF (TLIF) (L4-5, 22 patients; L5-S1, 20 patients) between 2001 and 2004 were retrospectively reviewed. Clinical results were investigated using the visual analog scale (VAS) and Oswestry Disability Index (ODI) scores, and using radiographic measurements, including disc height (DH), degree of spondylolisthesis, segmental lordosis, whole lumbar lordosis (WL), sacral slope (SS), and pelvic tilt; the L-1 axis S-1 distance (LASD) and pelvic incidence were also obtained. In both groups, VAS and ODI scores had significantly improved at both treatment levels. Statistical analysis showed no significant difference in postoperative VAS scores between groups at the L4-5 level and in postoperative VAS/ODI scores at the L5-S1 level. However, ODI scores were better in the TLIF than in the ALIF group at the L4-5 level. In terms of radiological changes, there were no significant differences between the 2 groups at the L4-5 level; however, at the L5-S1 level, radiographic results indicated that ALIF was superior to TLIF in its capacity to restore DH, WL, SS, and LASD. The radiological evidence of fusion shows no intergroup difference and no interlevel difference. Considering the clinical and radiological outcomes in both groups, the authors recommend that instrumented mini-TLIF is preferable at the L4-5 level, whereas instrumented mini-ALIF might be preferable at the L5-S1 level for the treatment of unstable isthmic spondylolisthesis.


Perception of global image contrast involves transparent spatial filtering and the integration and suppression of local contrasts (not RMS contrast).
When adjusting the contrast setting on a television set, we experience a perceptual change in the global image contrast. But how is that statistic computed? We addressed this using a contrast-matching task for checkerboard configurations of micro-patterns in which the contrasts and spatial spreads of two interdigitated components were controlled independently. When the patterns differed greatly in contrast, the higher contrast determined the perceived global contrast. Crucially, however, low contrast additions of one pattern to intermediate contrasts of the other caused a paradoxical reduction in the perceived global contrast. None of the following metrics/models predicted this: max, linear sum, average, energy, root mean squared (RMS), Legge and Foley. However, a nonlinear gain control model, derived from contrast detection and discrimination experiments, incorporating wide-field summation and suppression, did predict the results with no free parameters, but only when spatial filtering was removed. We conclude that our model describes fundamental processes in human contrast vision (the pattern of results was the same for expert and naive observers), but that above threshold-when contrast pedestals are clearly visible-vision's spatial filtering characteristics become transparent, tending towards those of a delta function prior to spatial summation. The global contrast statistic from our model is as easily derived as the RMS contrast of an image, and since it more closely relates to human perception, we suggest it be used as an image contrast metric in practical applications.


Synaptic plasticity and the Warburg effect.
Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes.


A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes.
The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated on primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n = 150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.


Bisphenol S negatively affects the meotic maturation of pig oocytes.
Bisphenol A (BPA), a chemical component of plastics, is a widely distributed environmental pollutant and contaminant of water, air, and food that negatively impacts human health. Concerns regarding BPA have led to the use of BPA-free alternatives, one of which is bisphenol S (BPS). However, the effects of BPS are not well characterized, and its specific effects on reproduction and fertility remain unknown. It is therefore necessary to evaluate any effects of BPS on mammalian oocytes. The present study is the first to demonstrate the markedly negative effects of BPS on pig oocyte maturation in vitro, even at doses lower than those humans are exposed to in the environment. Our results demonstrate (1) an effect of BPS on the course of the meiotic cell cycle; (2) the failure of tubulin fibre formation, which controls proper chromosome movement; (3) changes in the supply of maternal mRNA; (4) changes in the protein amounts and distribution of oestrogen receptors α and β and of aromatase; and (5) disrupted cumulus cell expansion. Thus, these results confirm that BPS is an example of regrettable substitution because this substance exerts similar or even worse negative effects than those of the material it replaced.


De novo sequences of Haloquadratum walsbyi from Lake Tyrrell, Australia, reveal a variable genomic landscape.
Hypersaline systems near salt saturation levels represent an extreme environment, in which organisms grow and survive near the limits of life. One of the abundant members of the microbial communities in hypersaline systems is the square archaeon, Haloquadratum walsbyi. Utilizing a short-read metagenome from Lake Tyrrell, a hypersaline ecosystem in Victoria, Australia, we performed a comparative genomic analysis of H. walsbyi to better understand the extent of variation between strains/subspecies. Results revealed that previously isolated strains/subspecies do not fully describe the complete repertoire of the genomic landscape present in H. walsbyi. Rearrangements, insertions, and deletions were observed for the Lake Tyrrell derived Haloquadratum genomes and were supported by environmental de novo sequences, including shifts in the dominant genomic landscape of the two most abundant strains. Analysis pertaining to halomucins indicated that homologs for this large protein are not a feature common for all species of Haloquadratum. Further, we analyzed ATP-binding cassette transporters (ABC-type transporters) for evidence of niche partitioning between different strains/subspecies. We were able to identify unique and variable transporter subunits from all five genomes analyzed and the de novo environmental sequences, suggesting that differences in nutrient and carbon source acquisition may play a role in maintaining distinct strains/subspecies.


Ectopic production of intact parathyroid hormone by a squamous cell lung carcinoma in vivo and in vitro.
Ectopic tumoral production of intact parathyroid hormone (PTH) is rare. The PTH-related protein is the common cause of hypercalcemia in most solid tumors, particularly squamous and renal carcinomas. We report the case of a 71-yr-old man with a PTH-producing squamous cell lung carcinoma. Immunocytochemical analysis of the tumor tissue as well as of cultured tumor cells revealed PTH positive staining. Cultured tumor cells released PTH and were calcium sensitive, producing 122 +/- 16 pg/microgram DNA of intact PTH (mean +/- SEM) at 0.5 mmol/L calcium compared with 26 +/- 2 pg/microgram DNA at 3.0 mmol/L calcium. Somatostatin analogues have been used in the treatment of humoral hypercalcemia of malignancy (HHM). However, we found that somatostatin (0.1 microgram/L) in cultured tumor cells increased the release of intact PTH (123 +/- 19 versus 82 +/- 1 pg/microgram DNA, P < 0.05) and thus might have a negative effect on the HHM. This report is the first to describe a true ectopic PTH-producing squamous cell lung carcinoma associated with HHM.


The significance of some observations on African ocular onchocerciasis described by Jean Hissette (1888-1965).
One of the most significant contributions to tropical medicine and ophthalmology was made by Jean Hissette: African ocular onchocerciasis. During his extensive investigations in the Babindi country, he found numerous adults with river blindness. Their eye disease was caused by the filaria Onchocerca volvulus Leuckart. He noticed the signs of interstitial keratitis and band keratopathy, faint iritis or iridocyclitis, posterior synechiae and often a downward distortion of the pupil. He was the first to describe chorioretinal scarring of the fundus, what became known as the Hissette-Ridley fundus. People reported to him their entoptic phenomena which he unequivocally interpreted to be the images of microfilariae in the patient's own eye. During his stay in Belgium in 1932, he elucidated the pathogenesis of blindness since he was able to provide histological proof of the presence of microfilariae in various ocular tissues of an enucleated eye from a patient living near the Sankuru river. Like other serious health impairments, the severe inflammatory lesions in the eye occurred only after the microfilariae had died. Hence he realized that dying microfilariae play a key role in the mechanisms leading to blindness. Hissette's precise descriptions were the logical fruit of his outstanding observational abilities and enabled him as a man of great intuition to speculate about causal relationships. He evidently benefited from the fact that he took the native Africans seriously and asked them their opinion. In 1933, his friend and teacher Dr. De Mets in Antwerp already wrote on Hissette's discovery in the Belgian Congo: "This study is of exceptional value to specialists which is not only a tribute to its author, but to our common native country (Belgium)."


SPICE: Semantic Pseudo-Labeling for Image Clustering.
The similarity among samples and the discrepancy among clusters are two crucial aspects of image clustering. However, current deep clustering methods suffer from inaccurate estimation of either feature similarity or semantic discrepancy. In this paper, we present a Semantic Pseudo-labeling-based Image ClustEring (SPICE) framework, which divides the clustering network into a feature model for measuring the instance-level similarity and a clustering head for identifying the cluster-level discrepancy. We design two semantics-aware pseudo-labeling algorithms, prototype pseudo-labeling and reliable pseudo-labeling, which enable accurate and reliable self-supervision over clustering. Without using any ground-truth label, we optimize the clustering network in three stages: 1) train the feature model through contrastive learning to measure the instance similarity; 2) train the clustering head with the prototype pseudo-labeling algorithm to identify cluster semantics; and 3) jointly train the feature model and clustering head with the reliable pseudo-labeling algorithm to improve the clustering performance. Extensive experimental results demonstrate that SPICE achieves significant improvements (~10%) over existing methods and establishes the new state-of-the-art clustering results on six balanced benchmark datasets in terms of three popular metrics. Importantly, SPICE significantly reduces the gap between unsupervised and fully-supervised classification; e.g. there is only 2% (91.8% vs 93.8%) accuracy difference on CIFAR-10. Our code is made publicly available at https://github.com/niuchuangnn/SPICE.


Eukaryotic diversity in late Pleistocene marine sediments around a shallow methane hydrate deposit in the Japan Sea.
Marine sediments contain eukaryotic DNA deposited from overlying water columns. However, a large proportion of deposited eukaryotic DNA is aerobically biodegraded in shallow marine sediments. Cold seep sediments are often anaerobic near the sediment-water interface, so eukaryotic DNA in such sediments is expected to be preserved. We investigated deeply buried marine sediments in the Japan Sea, where a methane hydrate deposit is associated with cold seeps. Quantitative PCR analysis revealed the reproducible recovery of eukaryotic DNA in marine sediments at depths up to 31.0 m in the vicinity of the methane hydrate deposit. In contrast, the reproducible recovery of eukaryotic DNA was limited to a shallow depth (8.3 m) in marine sediments not adjacent to the methane hydrate deposit in the same area. Pyrosequencing of an 18S rRNA gene variable region generated 1,276-3,307 reads per sample, which was sufficient to cover the biodiversity based on rarefaction curves. Phylogenetic analysis revealed that most of the eukaryotic DNA originated from radiolarian genera of the class Chaunacanthida, which have SrSO4 skeletons, the sea grass genus Zostera, and the seaweed genus Sargassum. Eukaryotic DNA originating from other planktonic fauna and land plants was also detected. Diatom sequences closely related to Thalassiosira spp., indicative of cold climates, were obtained from sediments deposited during the last glacial period (MIS-2). Plant sequences of the genera Alnus, Micromonas, and Ulmus were found in sediments deposited during the warm interstadial period (MIS-3). These results suggest the long-term persistence of eukaryotic DNA from terrestrial and aquatic sources in marine sediments associated with cold seeps, and that the genetic information from eukaryotic DNA from deeply buried marine sediments associated with cold seeps can be used to reconstruct environments and ecosystems from the past.


The contribution of patients' presurgery perceptions of surgeon attributes to the experience of trust and pain during third molar surgery.
Patients' feeling of trust in their surgeon may modulate the experience of pain during surgery. However, factors that contribute to patients' experience of trust during surgery remain underexamined. The current study examined the contribution of patients' impressions of surgeons' warmth and competence to their experience of trust and pain during wisdom tooth extractions. Patients (N = 135, 47% female) scheduled for a wisdom tooth extraction reported their current distress and impressions of their surgeon's warmth and competence after a brief introduction to their surgeon immediately before surgery. Immediately after their surgery, patients reported their experience of trust (feeling safe and in good hands) and pain during surgery. Path analyses modeled perceptions of surgeon warmth, competence, and their interaction as predictors of patients' experiences of trust and pain during surgery. Higher perceived surgeon competence, but not warmth, predicted the experience of higher trust and lower pain during surgery. Perceived competence interacted with perceived warmth such that the competence-trust relationship was only significant at moderate to high levels of perceived surgeon warmth and failed to reach significance at lower levels of perceived surgeon warmth. These results indicate that patients feel greater trust in surgeons who are perceived as higher in competence and warmth, underscoring the importance of impression management in surgical care.


Sarcoidosis - a multisystem disease.
Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways.


Effect of running exercise on hematological changes, hematopoietic progenitor cells (CFU-GM) and fibrinolytic system in humans.
In order to study the effect of running exercise on hematological changes, hematopoietic progenitor cells (CFU-GM) and the fibrinolytic system in humans, a running exercise protocol was developed. The volunteers ran as fast as possible for a distance of 3.8 kilometers. Immediately after exercise, there were significant increases in hematocrit, absolute numbers of total white blood cell count, platelet count and CFU-GM, total protein and plasma fibrinogen, but all values returned to baseline within 15 minutes except hematocrit, platelet and total protein which returned to baseline value in 30, 30 and 60 minutes after exercise, respectively. The fibrinolytic reactivity increased immediately after exercise and returned to baseline level 15 minutes later. The changes in all parameters were transient and the increase in hematopoietic progenitor cells were not useful for stem cell harvesting by hemapheresis.


The Perceived Social Burden in Celiac Disease.
In the present paper, we discuss the change in celiac disease (CD) awareness and perception through patients' concerns and the most recent literature. Nowadays CD has moved in the public awareness (both doctors and population) from a rare disease to a common one and the gluten free diet (GFD) is no longer the exclusive therapy for CD patients but is becoming a popular health choice for everybody. Gluten-free food, once hard to find and requiring home preparation, is now available at restaurants and grocery stores. However, the quality of life of those affected by CD seems to be still compromised and this is particularly true for those who find it difficult to adhere to a GFD and those who were asymptomatic at the time of diagnosis. Intervention at diagnosis and follow-up to improve the patients' adaptation to the condition and its limitations should be implemented.


Chemical Denaturants Smoothen Ruggedness on the Free Energy Landscape of Protein Folding.
To characterize experimentally the ruggedness of the free energy landscape of protein folding is challenging, because the distributed small free energy barriers are usually dominated by one, or a few, large activation free energy barriers. This study delineates changes in the roughness of the free energy landscape by making use of the observation that a decrease in ruggedness is accompanied invariably by an increase in folding cooperativity. Hydrogen exchange (HX) coupled to mass spectrometry was used to detect transient sampling of local energy minima and the global unfolded state on the free energy landscape of the small protein single-chain monellin. Under native conditions, local noncooperative openings result in interconversions between Boltzmann-distributed intermediate states, populated on an extremely rugged "uphill" energy landscape. The cooperativity of these interconversions was increased by selectively destabilizing the native state via mutations, and further by the addition of a chemical denaturant. The perturbation of stability alone resulted in seven backbone amide sites exchanging cooperatively. The size of the cooperatively exchanging and/or unfolding unit did not depend on the extent of protein destabilization. Only upon the addition of a denaturant to a destabilized mutant variant did seven additional backbone amide sites exchange cooperatively. Segmentwise analysis of the HX kinetics of the mutant variants further confirmed that the observed increase in cooperativity was due to the smoothing of the ruggedness of the free energy landscape of folding of the protein by the chemical denaturant.


Binding affinity of pyridines with AmIII/CmIII elucidated by density functional theory calculations.
In recent decades, N-heterocyclic ligands have been extensively used in the separation of lanthanides/actinides, whereas the selective extraction of amercium or curium has been very challenging. Using density functional theory calculations, this study is devoted to the investigation of the binding affinity of a series of modelling pyridine ligands with AmIII and CmIII. The structure-property correlations between the amercium and curium systems and the binding affinity were obtained, and promising strategies for efficient separation of AmIII/CmIII were proposed.


Genetics of dothistromin biosynthesis of Dothistroma septosporum: an update.
Dothistroma needle blight is one of the most devastating fungal pine diseases worldwide. The disease is characterized by accumulation in pine needles of a red toxin, dothistromin, that is chemically related to aflatoxin (AF) and sterigmatocystin (ST). This review updates current knowledge of the genetics of dothistromin biosynthesis by the Dothistroma septosporum pathogen and highlights differences in gene organization and regulation that have been discovered between the dothistromin and AF/ST systems. Some previously reported genes are promoted or demoted as 'dothistromin genes' based on recent research. A new dothistromin gene, norB, is reported, and evidence of dothistromin gene homologs in other Dothideomycete fungi is presented. A hypothesis for the biological role of dothistromin is outlined. Finally, the impact that the availability of the D. septosporum genome sequence will have on dothistromin research is discussed.


Research in nursing informatics 2014.
This article reflects the work done in the third year of the Nursing Informatics Year in Review project. This project seeks to search and analyze articles written by nurses as first author on the subject of nursing informatics, published August 2013-August 2014. Each year we also seek recommended articles from our American Medical Informatics Association-Nursing Informatics Work Group (AMIA-NIWG) members that meet the same criteria as the search and most influenced their thinking and scholarship. Twenty-seven articles emerged from the literature review, and our AMIA-NIWG members recommended 32 articles. We analyzed the articles by journal of publication, country of first author, source of funding, research method, research setting, and area of focus. The purpose of this article was to present the results of this project for 2014.