Water electrolysis: from textbook knowledge to the latest scientific strategies and industrial developments.
Replacing fossil fuels with energy sources and carriers that are sustainable, environmentally benign, and affordable is amongst the most pressing challenges for future socio-economic development. To that goal, hydrogen is presumed to be the most promising energy carrier. Electrocatalytic water splitting, if driven by green electricity, would provide hydrogen with minimal CO2 footprint. The viability of water electrolysis still hinges on the availability of durable earth-abundant electrocatalyst materials and the overall process efficiency. This review spans from the fundamentals of electrocatalytically initiated water splitting to the very latest scientific findings from university and institutional research, also covering specifications and special features of the current industrial processes and those processes currently being tested in large-scale applications. Recently developed strategies are described for the optimisation and discovery of active and durable materials for electrodes that ever-increasingly harness first-principles calculations and machine learning. In addition, a technoeconomic analysis of water electrolysis is included that allows an assessment of the extent to which a large-scale implementation of water splitting can help to combat climate change. This review article is intended to cross-pollinate and strengthen efforts from fundamental understanding to technical implementation and to improve the 'junctions' between the field's physical chemists, materials scientists and engineers, as well as stimulate much-needed exchange among these groups on challenges encountered in the different domains.


A Comparative Study of Functional Connectivity Measures for Brain Network Analysis in the Context of AD Detection with EEG.
This work addresses brain network analysis considering different clinical severity stages of cognitive dysfunction, based on resting-state electroencephalography (EEG). We use a cohort acquired in real-life clinical conditions, which contains EEG data of subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients, and Alzheimer's disease (AD) patients. We propose to exploit an epoch-based entropy measure to quantify the connectivity links in the networks. This entropy measure relies on a refined statistical modeling of EEG signals with Hidden Markov Models, which allow a better estimation of the spatiotemporal characteristics of EEG signals. We also propose to conduct a comparative study by considering three other measures largely used in the literature: phase lag index, coherence, and mutual information. We calculated such measures at different frequency bands and computed different local graph parameters considering different proportional threshold values for a binary network analysis. After applying a feature selection procedure to determine the most relevant features for classification performance with a linear Support Vector Machine algorithm, our study demonstrates the effectiveness of the statistical entropy measure for analyzing the brain network in patients with different stages of cognitive dysfunction.


Prevalence of anti-Taenia solium antibodies in sera from outpatients in an Andean region of Ecuador.
Sera from 9,254 individuals that presented at one of three outpatient clinics in Quito, Ecuador were assayed by indirect hemagglutination for the presence of antibodies reactive with antigens from Taenia solium cysts. Immunoblot analysis of 81 selected sera with IHA titers ranging from 0 to 1,028 showed that a titer of > or = 32 was suggestive of exposure to the parasite. Nine percent (9%) of the 9,254 patients had titers of 32 or greater. Of 3,503 sera from one clinic, which included sera from food handlers undergoing yearly physicals, 390 (11%) were positive. In addition, a correlation with age was seen in some, but not all, populations. In situations where age-related effects were noted, the highest incidence was seen in the youngest (0-20 years) and in the oldest (51-60 years) group. Thus, a resurgence of infection after a period of lower prevalence may be developing. Overall, this study shows that cysticercosis is relatively common and potentially a serious health problem in this region.


Emotional responding in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio-emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age-matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.


Technetium-99m polyphosphate bone image for early detection of skeletal metastasis. Correlation with other diagnostic parameters.
Technetium 99m-polyphosphate bone images are correlated with bone roentgenography, and serum calcium, phosphorus and alkaline phosphatase in 91 patients with suspected bone metastasis. Technetium polyphosphate bone images are the most sensitive and serum level of calcium and phosphorus are the least sensitive indicator of bone lesions. Bone roentgenography is not as sensitive as technetium polyphosphate images. Abnormal bone images with normal or abnormal bone roentenography associated with increased alkaline phosphatase in the absence of liver metastasis are highly suggestive of metastatic bone disease. Abnormal bone images adjoining the joints, associated with normal serum alkaline phosphatase and abnormal joint roentgenography suggest arthritis. It is recommended that technetium 99m-labelled phosphate bone images are considered to be the diagnostic procedure of choice to detect skeletal lesions. Polyphosphate bone images are highly sensitive, with the combination of elevated alkaline phosphatase they become relatively more specific for a metastatic bone disease.


Neuroplasticity to a single-episode traumatic stress revealed by resting-state fMRI in awake rats.
Substantial evidence has suggested that the brain structures of the medial prefrontal cortex (mPFC) and amygdala (AMYG) are implicated in the pathophysiology of stress-related disorders. However, little is known with respect to the system-level adaptation of their neural circuitries to the perturbations of traumatic stressors. By utilizing behavioral tests and an awake animal imaging approach, in the present study we non-invasively investigated the impact of single-episode predator odor exposure in an inescapable environment on behaviors and neural circuits in rodents. We found that predator odor exposure significantly increased the freezing behavior. In addition, animals exhibited heightened anxiety levels seven days after the exposure. Intriguingly, we also found that the intrinsic functional connectivity within the AMYG-mPFC circuit was considerably compromised seven days after the traumatic event. Our data provide neuroimaging evidence suggesting that prolonged neuroadaptation induced by a single episode of traumatic stress can be non-invasively detected in rodents. These results also support the face validity and construction validity of using the paradigm of single trauma exposure in an inescapable environment as an animal model for post-traumatic stress disorder. Taken together, the present study has opened a new avenue to investigating animal models of stress-related mental disorders by going beyond static neuroanatomy, and ultimately bridging the gap between basic biomedical and human imaging research.


Serine palmitoyltransferase, the first step enzyme in sphingolipid biosynthesis, is involved in nonhost resistance.
An overexpression screen of Nicotiana benthamiana cDNAs identified a gene for the LCB2 subunit of serine palmitoyltransferase (SPT) as a potent inducer of hypersensitive response-like cell death. The pyridoxal 5'-phosphate binding site of NbLCB2 is required for its function as a cell death inducer. NbLCB2 mRNA is accumulated after infection by nonhost pathogen Pseudomonas cichorii. Resistance of N. benthamiana against P. cichorii was compromised by treatment with an SPT inhibitor and in NbLCB2- and NbLCB1-silenced plants. These results suggest that biosynthesis of sphingolipids is necessary for the nonhost resistance of N. benthamiana against P. cichorii.


Correlates of Frailty among Aging Residents of Upper Selška Valley Villages under Ratitovec Mountain.
Frailty, multi-system dysregulation following multiple life stressors, is associated with age and vulnerability to negative health. Our model posits that variables such as age and sex affect biocultural changes resulting from lifestyle and alter frailty. We assessed frailty with a four-factor index. We expand understanding of frailty by examining associations with demographic, health, and lifestyle factors in a Slovenian sample. Between 2008 and 2009, 40 residents of the Selska Valley, Slovenia aged 55 to 85 years (X = 72, SD = 7.24) participated in physical assessments, responded to the SF-36, and self-reported their own and family history of non-communicable diseases. Participants included 26 women (age 59-86) and 14 men (age 57-82). We used linear regression and t-tests to assess associations of these factors with frailty. Frailty was significantly positively associated with age, sex, length of residence in the village, and multiple self-reported health factors. Conversely, frailty was significantly negatively associated with height and showed a borderline significant association with diastolic blood pressure. Controlling for age and sex, significant associations remained between frailty and self-reports of health, along with painful and reduced activity levels. Frailty also interacts with lifestyle factors. Results suggest the model proposed by Walston and colleagues (2005) is a valid cross-cultural measure of frailty.


Control of synchronization patterns in neural-like Boolean networks.
We study experimentally the synchronization patterns in time-delayed directed Boolean networks of excitable systems. We observe a transition in the network dynamics when the refractory time of the individual systems is adjusted. When the refractory time is on the same order of magnitude as the mean link time delays or the heterogeneities of the link time delays, cluster synchronization patterns change, or are suppressed entirely, respectively. We also show that these transitions occur when we change the properties of only a small number of driver nodes identified by their larger in degree; hence, the synchronization patterns can be controlled locally by these nodes. Our findings have implications for synchronization in biological neural networks.


A probabilistic approach for a cost-benefit analysis of oil spill management under uncertainty: A Bayesian network model for the Gulf of Finland.
Large-scale oil accidents can inflict substantial costs to the society, as they typically result in expensive oil combating and waste treatment operations and have negative impacts on recreational and environmental values. Cost-benefit analysis (CBA) offers a way to assess the economic efficiency of management measures capable of mitigating the adverse effects. However, the irregular occurrence of spills combined with uncertainties related to the possible effects makes the analysis a challenging task. We develop a probabilistic modeling approach for a CBA of oil spill management and apply it in the Gulf of Finland, the Baltic Sea. The model has a causal structure, and it covers a large number of factors relevant to the realistic description of oil spills, as well as the costs of oil combating operations at open sea, shoreline clean-up, and waste treatment activities. Further, to describe the effects on environmental benefits, we use data from a contingent valuation survey. The results encourage seeking for cost-effective preventive measures, and emphasize the importance of the inclusion of the costs related to waste treatment and environmental values in the analysis. Although the model is developed for a specific area, the methodology is applicable also to other areas facing the risk of oil spills as well as to other fields that need to cope with the challenging combination of low probabilities, high losses and major uncertainties.


Analysis of Y-chromosome STRs in Chile confirms an extensive introgression of European male lineages in urban populations.
We analyzed the Y chromosome haplotypes (Yfiler) of 978 non-related Chilean males grouped in five sampling regions (Iquique, Santiago de Chile, Concepción, Temuco and Punta Arenas) covering main geo-political regions. Overall, 803 different haplotypes and 688 singletons were observed. Molecular diversity was moderately lower than in other neighboring countries (e.g. Argentina); and AMOVA analysis on Y-STR haplotypes showed that among variation within Chile accounted for only 0.25% of the total variation. Punta Arenas, in the southern cone, showed the lowest haplotype diversity, and discrimination capacity, and also the highest matching probability of the five Chilean samples, probably reflecting its more marked geographic isolation compared to the other regions. Multidimensional scaling (MDS) analysis based on RST genetic distances suggested a close proximity of Chilean Y-chromosome profiles to European ones. Consistently, haplogroups inferred from Y-STR profiles revealed that the Native American component constituted only 8% of all the haplotypes, and this component ranged from 5% in the Centre of the country to 9-10% in the South and 13% in the North, which is in good agreement with the distribution of Native American communities in these regions. AMOVA computed on inferred haplogroups confirmed the very low among variation observed in Chilean populations. The present project provides the first Chilean dataset to the international Y-chromosome STR Haplotype Reference Database (YHRD) and it is also the first reference database for Y-chromosome forensic casework of the country.


Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.


Barriers to sustainable tuberculosis control in the Russian Federation health system.
The Russian Federation has the eleventh highest tuberculosis burden in the world in terms of the total estimated number of new cases that occur each year. In 2003, 26% of the population was covered by the internationally recommended control strategy known as directly observed treatment (DOT) compared to an overall average of 61% among the 22 countries with the highest burden of tuberculosis. The Director-General of WHO has identified two necessary starting points for the scaling-up of interventions to control emerging infectious diseases. These are a comprehensive engagement with the health system and a strengthening of the health system. The success of programmes aimed at controlling infectious diseases is often determined by constraints posed by the health system. We analyse and evaluate the impact of the arrangements for delivering tuberculosis services in the Russian Federation, drawing on detailed analyses of barriers and incentives created by the organizational structures, and financing and provider-payment systems. We demonstrate that the systems offer few incentives to improve the efficiency of services or the effectiveness of tuberculosis control. Instead, the system encourages prolonged supervision through specialized outpatient departments in hospitals (known as dispensaries), multiple admissions to hospital and lengthy hospitalization. The implementation, and expansion and sustainability of WHO-approved methods of tuberculosis control in the Russian Federation are unlikely to be realized under the prevailing system of service delivery. This is because implementation does not take into account the wider context of the health system. In order for the control programme to be sustainable, the health system will need to be changed to enable services to be reconfigured so that incentives are created to reward improvements in efficiency and outcomes.


Simultaneous Whole Mitochondrial Genome Sequencing with Short Overlapping Amplicons Suitable for Degraded DNA Using the Ion Torrent Personal Genome Machine.
Whole mitochondrial (mt) genome analysis enables a considerable increase in analysis throughput, and improves the discriminatory power to the maximum possible phylogenetic resolution. Most established protocols on the different massively parallel sequencing (MPS) platforms, however, invariably involve the PCR amplification of large fragments, typically several kilobases in size, which may fail due to mtDNA fragmentation in the available degraded materials. We introduce a MPS tiling approach for simultaneous whole human mt genome sequencing using 161 short overlapping amplicons (average 200 bp) with the Ion Torrent Personal Genome Machine. We illustrate the performance of this new method by sequencing 20 DNA samples belonging to different worldwide mtDNA haplogroups. Additional quality control, particularly regarding the potential detection of nuclear insertions of mtDNA (NUMTs), was performed by comparative MPS analysis using the conventional long-range amplification method. Preliminary sensitivity testing revealed that detailed haplogroup inference was feasible with 100 pg genomic input DNA. Complete mt genome coverage was achieved from DNA samples experimentally degraded down to genomic fragment sizes of about 220 bp, and up to 90% coverage from naturally degraded samples. Overall, we introduce a new approach for whole mt genome MPS analysis from degraded and nondegraded materials relevant to resolve and infer maternal genetic ancestry at complete resolution in anthropological, evolutionary, medical, and forensic applications.


Why Is Reverse Takotsubo "Reverse"?
Takotsubo cardiomyopathy (TTC) is an acute cardiac syndrome simulating myocardial infarction that is characterized by transient wall motion abnormalities in the absence of coronary artery obstruction. Reverse TTC (rTTC) is a recently described variant of TTC. This review defines and compares both forms of TTC, stating their resemblances and differences. We conducted a search of the MEDLINE database. Forty-one cases of rTTC met our eligibility criteria and were summarized in a synthesis of the demographic features, clinical characteristics, and laboratory studies. Of the 41 patients studied, 73% were women. Patients' ages ranged from 19 to 69 years and the mean age was 43. The predominant electrocardiogram finding was ST-segment depression, whereas ST-segment elevation was present in only 6 patients (14.5%). Troponin levels were raised in 92.6% of the patients, with a mean troponin I of 7.7 ng/mL. All of the patients had wall motion abnormalities on echocardiography and the mean ejection fraction was 29.3%. Of the 27 patients (66%) who had a documented angiography, 22 (81.5%) had normal coronaries and 5 (18.5%) had minor or mild obstructive coronary artery disease. Of the 41 patients, 9 (22%) died, and the mean recovery time of the ejection fraction in the survivors was 16 days. rTTC is a distinct presentation from the classic TTC. Remarkable differences exist between both forms in terms of mean age, sex, electrocardiogram presentation, troponin levels, and mortality.


Infanticide secrets: qualitative study on postpartum depression.
To explore thoughts of infanticide that did not lead to the act among mothers with postpartum depression. A phenomenologic hermeneutic study in which women were invited to share their experiences of having thoughts of infanticide. Community setting in a large metropolitan city, Brisbane, Australia. Fifteen women who had been diagnosed as clinically depressed with postpartum onset whose babies were 12 months of age or younger. Audiotaped, in-depth interviews were transcribed verbatim. Thematic analysis commenced immediately after the first interview, and data collection continued until saturation was achieved. A questioning approach that reflected hermeneutics was facilitated by use of journals by the researchers. Six themes emerged from the data: imagined acts of infanticide, the experience of horror, distorted sense of responsibility, consuming negativity, keeping secrets, and managing the crisis. Women who experienced nonpsychotic depression preferred not to disclose their thoughts of infanticide to health professionals, including trusted general practitioners or psychiatrists. These women were more likely to mention their suicidal thoughts than their infanticidal thoughts in order to obtain health care. General practitioners and other health professionals should directly ask about whether a woman has been experiencing thoughts of harming herself or her baby, regardless of the reason why she has presented.


Does spending on refugees make a difference? A cross-sectional study of the association between refugee program spending and health outcomes in 70 sites in 17 countries.
Numerous simultaneous complex humanitarian emergencies strain the ability of local governments and the international community to respond, underscoring the importance of cost-effective use of limited resources. At the end of 2011, 42.5 million people were forcibly displaced, including 10.4 million refugees under the mandate of the United Nations High Commissioner for Refugees (UNHCR). UNHCR spent US$1.65 billion on refugee programs in 2011. We analyze the impact of aggregate-level UNHCR spending on mortality of refugee populations. Using 2011 budget data, we calculated purchasing power parity adjusted spending, disaggregated by population planning groups (PPGs) and UNHCR Results Framework objectives. Monthly mortality reported to UNHCR's Health Information System from 2011 to 2012 was used to calculate crude (CMR) and under-5 (U5MR) mortality rates, and expressed as ratios to country of asylum mortality. Log-linear regressions were performed to assess correlation between spending and mortality. Mortality data for 70 refugee sites representing 1.6 million refugees in 17 countries were matched to 20 PPGs. Median 2011 spending was $623.27 per person (constant 2011 US$). Median CMR was 2.4 deaths per 1,000 persons per year; median U5MR was 18.1 under-5 deaths per 1,000 live births per year. CMR was negatively correlated with total spending (p = 0.027), and spending for fair protection processes and documentation (p = 0.005), external relations (p = 0.034), logistics and operations support (p = 0.007), and for healthcare (p = 0.046). U5MR ratio was negatively correlated with total spending (p = 0.015), and spending for favorable protection environment (p = 0.024), fair protection processes and documentation (p = 0.003), basic needs and essential services (p = 0.027), and within basic needs, for healthcare services (p = 0.007). Increased UNHCR spending on refugee populations is correlated with lower mortality, likely reflecting unique refugee vulnerabilities and dependence on aid. Future analyses using more granular data can further elucidate the health impact of humanitarian sector spending, thereby guiding policy choices.


Improved postprandial response and feeling of satiety after consumption of low-calorie muffins with maltitol and high-amylose corn starch.
The aim of this study was to determine the postprandial glucose (GR), insulin (IR), and triglyceride response as well as the satiety response (SR) to low-calorie muffins (LCMs) and to compare them to those of conventional plain muffins (PMs) and bread. The LCMs had a lower fat content, their sugar was replaced by maltitol, and wheat flour was partially replaced by high-amylose corn starch. We used bread as a reference to calculate glycemic (GI), insulinemic (II), and satiety indices (SI). Seven men and 7 women (33 +/- 7.8 y; body mass index = 25.8 +/- 2.9) were studied in a randomized crossover design and were given either bread, an LCM, or a PM during 3 different occasions. Plasma glucose, insulin, and triglyceride concentrations were periodically measured for 2 h after consumption. We used the same design in a separate assay to evaluate SR by means a subjective questionnaire. The results show that LCMs reduced the IR by 30% (P= 0.03) and lipemic response by 50% (P < 0.001) compared to PMs. GR was only found to be significantly different between bread and LCMs (52% lower in LCM; P= 0.03), with PMs in an intermediate position. The SR of LCMs is similar to bread and higher than PMs (191%; P= 0.02). We concluded that LCMs are a product with a very low GI with better postprandial and SRs than PMs. These metabolic properties are useful in normal and overweight persons. However, further research is needed on the effects of this type of products in individuals with impaired glucose tolerance.


Correlation of diffusion MRI with the Ki-67 index in non-small cell lung cancer.
The primary objective of the study was to evaluate the association between the minimum apparent diffusion coefficient (ADCmin) and Ki-67, an index for cellular proliferation, in non-small cell lung cancers. Also, we aimed to assess whether ADCmin values differ between tumour subtypes and tissue sampling method. The patients who had diffusion weighted magnetic resonance imaging (DW-MRI) were enrolled retrospectively. The correlation between ADCmin and the Ki-67 index was evaluated. Ninety three patients, with a mean age 65 ± 11 years, with histopathologically proven adenocarcinoma and squamous cell carcinoma of the lungs and had technically successful DW-MRI were included in the study. The numbers of tumour subtypes were 47 for adenocarcinoma and 46 for squamous cell carcinoma. There was a good negative correlation between ADCmin values and the Ki-67 proliferation index (r = -0.837, p < 0.001). The mean ADCmin value was higher and the mean Ki-67 index was lower in adenocarcinomas compared to squamous cell carcinoma (p < 0.0001). There was no statistical difference between tissue sampling methods. Because ADCmin shows a good but negative correlation with Ki-67 index, it provides an opportunity to evaluate tumours and their aggressiveness and may be helpful in the differentiation of subtypes non-invasively.


Pareto Optimal Design for Synthetic Biology.
Recent advances in synthetic biology call for robust, flexible and efficient in silico optimization methodologies. We present a Pareto design approach for the bi-level optimization problem associated to the overproduction of specific metabolites in Escherichia coli. Our method efficiently explores the high dimensional genetic manipulation space, finding a number of trade-offs between synthetic and biological objectives, hence furnishing a deeper biological insight to the addressed problem and important results for industrial purposes. We demonstrate the computational capabilities of our Pareto-oriented approach comparing it with state-of-the-art heuristics in the overproduction problems of i) 1,4-butanediol, ii) myristoyl-CoA, i ii) malonyl-CoA , iv) acetate and v) succinate. We show that our algorithms are able to gracefully adapt and scale to more complex models and more biologically-relevant simulations of the genetic manipulations allowed. The Results obtained for 1,4-butanediol overproduction significantly outperform results previously obtained, in terms of 1,4-butanediol to biomass formation ratio and knock-out costs. In particular overproduction percentage is of +662.7%, from 1.425 mmolh⁻¹gDW⁻¹ (wild type) to 10.869 mmolh⁻¹gDW⁻¹, with a knockout cost of 6. Whereas, Pareto-optimal designs we have found in fatty acid optimizations strictly dominate the ones obtained by the other methodologies, e.g., biomass and myristoyl-CoA exportation improvement of +21.43% (0.17 h⁻¹) and +5.19% (1.62 mmolh⁻¹gDW⁻¹), respectively. Furthermore CPU time required by our heuristic approach is more than halved. Finally we implement pathway oriented sensitivity analysis, epsilon-dominance analysis and robustness analysis to enhance our biological understanding of the problem and to improve the optimization algorithm capabilities.


Genetics of diabetic nephropathy.
The increasing prevalence of diabetes mellitus has led to a growing number of chronic complications including diabetic nephropathy (DN). In addition to its high prevalence, DN is associated with high morbidity and mortality especially due to cardiovascular diseases. It is well established that genetic factors play a role in the pathogenesis of DN and genetically susceptible individuals can develop it after being exposed to environmental factors. DN is probably a complex, polygenic disease. Two main strategies have been used to identify genes associated to DN: analysis of candidate genes, and more recently genome-wide scan. Great efforts have been made to identify these main genes, but results are still inconsistent with different genes associated to a small effect in specific populations. The identification of the main genes would allow the detection of those individuals at high risk for DN and better understanding of its pathophysiology as well.


A reconceptualization of learning disabilities via a self-organizing systems paradigm.
A dilemma exists regarding the interpretation of learning disabilities. A self-organizing systems (SOS) paradigm suggests widespread, diffuse outcomes, whereas a specific learning disability concept suggests more localized dysfunction. There may be very good reason to doubt the veridicality of the concept of a specific learning disability, not because the construct of learning disabilities itself is a frivolous concept, as some have held, but because the biological or neurological events that underlie a learning disability do not remain focal and constrained only to specific dysfunction. It is important to know whether an identified learning disability remains contained or whether processing disorders might be found in other areas. The assessment profiles of school-age children identified with nonverbal learning disabilities (NLD), assumed to have primarily right-hemispheric brain dysfunctions, and children with language-based learning disabilities (LLD), assumed to have primarily left-hemispheric brain dysfunctions, were examined to explore learning disabilities using an SOS paradigm. The pilot study reported here is used as an exemplar of how a self-organizing systems paradigm is conceptualized. Although a more comprehensive study is needed to confirm the data, this exemplar suggests that overflow into areas not typically associated with each disability subtype may occur. Concerns regarding ways of determining discrepancy for diagnostic purposes are noted, and remediation strategies designed for specific disabilities are questioned.


A descriptive study of a specialized worker's psychological trauma program.
Psychological trauma in the workplace is gaining recognition as an important cause of workplace disability but little is known about the workers who are affected. The Psychological Trauma Program (PTP) in Toronto (Canada) is a specialized provincial worker's compensation board assessment program for workers with psychological sequelae of workplace trauma. To characterize workers presenting to the PTP in terms of demographic, occupational, traumatic exposure and diagnostic variables. A retrospective secondary analysis of all workers referred to the PTP for assessment within 1 year of traumatic event between 1999 and 2006. Five hundred and thiry-one referred workers were included in the study. Most workers were working-age male (76%), married (65%) and labourers (43%). Nearly half were born outside Canada. Post-traumatic stress disorder was the primary diagnosis in 44%. Fifty-eight percent had one or more secondary diagnoses. For just over half of the workers, the traumatic event resulted in a permanent physical impairment. Specialist referral may be indicated for workers experiencing prolonged recovery following workplace trauma. Male workers and those with co-morbidities or permanent injuries may be more likely to require referral. Individualized treatment approaches are likely important; however, more research is needed to guide future interventions.


Renoprotective Effects of Metformin.
It has become clear that metformin exerts pleiotropic actions beyond its glucose-lowering agent effect. In this review, we summarise the state of the art concerning the potential renoprotective effects of metformin in vitro, animal models and clinical nephrology. A literature search was performed in PUBMED, ScienceDirect, between January 1957 and March 2017 using the following keywords: "metformin," "nephroprotection," "renoprotection," "survival," "renal failure," "chronic kidney diseases," "fibrosis," "polycystic kidney disease" and "microalbuminuria." A recent review of 17 observational studies concluded that metformin use appeared associated with reduced all-cause mortality in patients with CKD. Metformin has been shown to exert positive effects on the kidney in vitro and animal models representing different types of renal diseases, from acute kidney injury to chronic kidney disease. A retrospective cohort study from the Scientific Registry of Transplant Recipients indicated that metformin was associated with lower adjusted hazards for living donor and deceased donor allograft survival at 3 years posttransplant, and with lower mortality. Based on experimental evidence and some relevant clinical observations, metformin seems to be a promising drug in the treatment of progressive renal damage. RCT studies are the next essential step.


Cone-beam computed tomography evaluation of curved root canals prepared using reciprocal rotary files and rotational rotary files.
The aim of this study is to compare curved root canal preparation between reciprocal rotary files and rotational rotary files in extracted teeth using cone-beam computed tomography (CBCT). The independent variable was the file type (reciprocal vs. rotary), and the primary outcome variable was the centering ratio of distance change after canal preparation. Secondary outcomes were canal transportation in extension and direction and the preparation time. Forty mesial root canals from extracted permanent molars with curvatures ranging between 25° and 45° were randomly divided into 4 groups. Canals were prepared with two types of reciprocal rotary files (WaveOne and Reciproc) and two types of rotational rotary files (ProTaper and Mtwo), ten canals in each group. The root canals were scanned before and after preparation using CBCT. Group differences in outcome variables were tested using ANOVA and 5% type I error probability. At the middle third of canals, reciprocal rotary files yielded the least amount of deviation from the center in inner-outer furcal direction (P < 0.001). Transportation was shown from the original canal shape in all directions in four groups. The reciprocal rotary files took the least amount of preparation time as well (P < 0.001). Reciprocal files result in less transportation and working time than the rotational files.


Fractional Transport in Strongly Turbulent Plasmas.
We analyze statistically the energization of particles in a large scale environment of strong turbulence that is fragmented into a large number of distributed current filaments. The turbulent environment is generated through strongly perturbed, 3D, resistive magnetohydrodynamics simulations, and it emerges naturally from the nonlinear evolution, without a specific reconnection geometry being set up. Based on test-particle simulations, we estimate the transport coefficients in energy space for use in the classical Fokker-Planck (FP) equation, and we show that the latter fails to reproduce the simulation results. The reason is that transport in energy space is highly anomalous (strange), the particles perform Levy flights, and the energy distributions show extended power-law tails. Newly then, we motivate the use and derive the specific form of a fractional transport equation (FTE), we determine its parameters and the order of the fractional derivatives from the simulation data, and we show that the FTE is able to reproduce the high energy part of the simulation data very well. The procedure for determining the FTE parameters also makes clear that it is the analysis of the simulation data that allows us to make the decision whether a classical FP equation or a FTE is appropriate.


Cerebral blood volume and blood flow responses to hyperventilation in brain tumors during isoflurane or propofol anesthesia.
Using computerized tomography, we measured absolute cerebral blood flow (CBF) and cerebral blood volume (CBV) in tumor, peri-tumor, and contralateral normal regions, at normocapnia and hypocapnia, in 16 rabbits with brain tumors (VX2 carcinoma), under isoflurane or propofol anesthesia. In both anesthetic groups, CBV and CBF were highest in the tumor region and lowest in the contralateral normal tissue. For isoflurane, a significant decrease in both CBV and CBF was observed in all tissue regions with hyperventilation (P < 0.05), but without accompanying changes in intracranial pressure. However, the percent reduction in regional CBF with hypocapnia was two times larger than that observed in the CBV response (P < 0.01). In contrast, there were no significant changes in CBV and CBF in the Propofol group with hyperventilation for all regions (P > 0.10). In addition, there were no differences between CBV values for isoflurane at hypocapnia when compared with CBV values for propofol at normo- or hypocapnia (P > 0.34 and P > 0.35, respectively, in the tumor regions). Our results indicate that propofol increases cerebral vascular tone in both neoplastic and normal tissue vessels compared with isoflurane. CBV and CBF during normocapnia were significantly greater in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol. CBV and CBF remained responsive to hyperventilation only with isoflurane. In rabbits with brain tumors, brain blood flow and volume were significantly larger in all regions (tumor, peri-tumor, and contralateral normal tissue) with isoflurane than with propofol during normocapnia, and remained responsive to a reduction in PaCO(2). Consequently, during hypocapnia, brain blood flow and volume values with isoflurane were similar to values with propofol.


Comparison of microtensile bond strength of a resin composite to enamel conditioned by acid etching and Er,Cr:YSGG laser in human primary teeth.
This study was designed to compare the bond strength of composite resin restorations on the buccal surface of primary human canine after conditioning by conventional acid etching and Er,Cr:YSGG laser. Twenty sound primary canines were cut buccolingually into two halves and each half was randomly placed in Er,Cr:YSGG laser or acid etch group. The samples in the acid etch group were etched with 37% phosphoric acid for 30 s. The samples in the laser group were prepared by Er,Cr:YSGG laser. The G6-Tips and 600 µm diameter were used with a 1.5 W of power output, pulse duration of 140 µs and repetition rate of 20 Hz. The bonding agent was applied on the buccal surface of each sample and layers of resin composite were placed. The samples' bond strengths were evaluated by a microtensile test instrument. The mean of microtensile bond strength was 18.55±6.41 in the laser group and 24.62±5.56 in acid etch group. Microtensile bond strength achieved by laser conditioning was significantly lower than microtensile bond strength achieved by the conventional acid etching. Statistics To compare the results between the acid etch and laser group, the paired t test was performed (p value<0.001). Conditioning enamel in primary teeth by Er,Cr:YSGG laser, cannot be used as an alternative method for acid etching and cannot substitute this conventional method.


Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus.
Little is known about the physiological roles of aquaporin-4 (AQP4) in the central nervous system. AQP4 water channels are concentrated in endfeet membranes of astrocytes but also localize to the fine astrocytic processes that abut central synapses. Based on its pattern of expression, we predicted that AQP4 could be involved in controlling water fluxes and changes in extracellular space (ECS) volume that are associated with activation of excitatory pathways. Here, we show that deletion of Aqp4 accentuated the shrinkage of the ECS that occurred in the mouse hippocampal CA1 region during activation of Schaffer collateral/commissural fibers. This effect was found in the stratum radiatum (where perisynaptic astrocytic processes abound) but not in the pyramidal cell layer (where astrocytic processes constitute but a minor volume fraction). For both genotypes the ECS shrinkage was most pronounced in the pyramidal cell layer. Our data attribute a physiological role to AQP4 and indicate that this water channel regulates extracellular volume dynamics in the mammalian brain.


Integrated Care for Older Adults: A Struggle for Sustained Implementation in Northern Netherlands.
Integrated care has been suggested as a promising solution to the disparities in access and sustained high quality long-term care emerging in Europe's ageing population. We aim to gain a better understanding of context-specific barriers to and facilitators of implementation of integrated care by doing a retrospective assessment of seven years of Embrace. This Dutch integrated person-centred health service for older adults was based on two evidence-based models (the Chronic Care Model and the Kaiser Permanente Triangle). Despite successful deployment the programme ended in 2018. In this case study we assess the impact of the programme based on past evaluations, reflect on why it ended, lessons learned and ideas to take forward. The majority of health outcomes were positive and the perceived quality of care improved, albeit no clear-cut savings were observed, and the costs were not balanced across stakeholders. The Embrace payment model did not support the integration of health services, despite reforms in long-term care in 2015. Enabling policy and funding are crucial to the sustained implementation of integrated person-centred health services. The payment model should incentivize the integration of care before the necessary changes can be made at organizational and clinical levels towards providing proactive and preventive health services.


5-Formylcytosine landscapes of human preimplantation embryos at single-cell resolution.
Epigenetic dynamics, such as DNA methylation and chromatin accessibility, have been extensively explored in human preimplantation embryos. However, the active demethylation process during this crucial period remains largely unexplored. In this study, we use single-cell chemical-labeling-enabled C-to-T conversion sequencing (CLEVER-seq) to quantify the DNA 5-formylcytosine (5fC) levels of human preimplantation embryos. We find that 5-formylcytosine phosphate guanine (5fCpG) exhibits genomic element-specific distribution features and is enriched in L1 and endogenous retrovirus-K (ERVK), the subfamilies of repeat elements long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs), respectively. Unlike in mice, paired pronuclei in the same zygote present variable difference of 5fCpG levels, although the male pronuclei experience stronger global demethylation. The nucleosome-occupied regions show a higher 5fCpG level compared with nucleosome-depleted ones, suggesting the role of 5fC in organizing nucleosome position. Collectively, our work offers a valuable resource for ten-eleven translocation protein family (TET)-dependent active demethylation-related study during human early embryonic development.


Hepatic dysfunction during hyperalimentation.
Liver biopsy specimens were studied in 26 patients in whom liver function abnormalities developed during intravenous hyperalimentation (IVH). The clinical manifestations and duration of IVH were evaluated in relation to the morphological changes seen in the liver. Early hepatic changes consisted of fatty metamorphosis, and progressive intrahepatic cholestasis developed as IVH was continued. Essential fatty acid deficiency, amino acid imbalance, caloric excess, and toxic manifestations of certain amino acids are postulated as causative factors. The hepatic steatosis secondary to IVH may be treated by lowering the dextrose concentration of the infusion or by administering dextrose-free amino acid solutions. The clinical importance of this common complication of IVH is the difficulty in distinguishing it from other causes of cholestasis in seriously ill patients.


Myocardial Geometry and Dysfunction in Morbidly Obese Adolescents (BMI 35-40 kg/m2).
This study evaluated the preclinical effect of obesity on the ventricular remodeling in adolescents with morbid obesity, and determined if subjects labelled as metabolically healthy obesity (MHO) presented better heart index than those with metabolically unhealthy obesity (MUO). Prospective case-control research of 45 adolescents (14-year-old) with morbid obesity and 25 normal weight adolescents' gender- and age-matched with Tanner stage 4-5. Left ventricle (LV) was evaluated by conventional Doppler echocardiography, tissue Doppler imaging and two-dimensional speckle tracking echocardiography. Compared to normal-weight subjects, adolescents with morbid obesity presented a high percentage of pathological LV geometry (87%; p<0.01), and systolic and diastolic dysfunctions only detected by E/A ratio (2.0 vs 1.7, p<0.01), global longitudinal strain (-21.0% vs -16.5%, p<0.01), and early diastolic strain rate (3.2 vs 2.2, p<0.01). A correlation was found between impaired cardiac index and body mass index (BMI), high blood pressure, hyperglycemia, low HDL-cholesterol and hypertriglyceridemia. BMI and HDL-cholesterol were the most significant independent variables. No significant differences were found in structural and functional cardiac index when MHO and MUO subjects were compared (global longitudinal strain: -17.0% vs -16.4%, p0.79). Morbidly obese adolescents have an abnormal LV geometry, closely related to BMI, and systolic and diastolic LV dysfunctions. Adolescents labelled as MHO, despite exhibiting better BMI and insulin-resistance values, present the same pathological heart changes as MUO.


CO/chemosensitization/antiangiogenesis synergistic therapy with H2O2-responsive diselenide-containing polymer.
Carbon monoxide (CO) therapy and antiangiogenesis therapy (AAT) are regarded as promising approaches for cancer treatment. However, the poor tumor targeting ability and inevitable side effects prevent their clinical application. In this study, we developed H2O2-responsive diselenide-containing micelles that combined CO therapy with chemosensitization therapy and AAT in a single system. Under the interaction of intratumoral H2O2, CO and gemcitabine (GEM) were released in situ from the micelles to reduce side effects, and CO significantly sensitized the chemotherapeutic effect of GEM by elevating the level of reactive oxygen species (ROS) in human gastric cancer AGS cells. Furthermore, diselenide bonds in the micelles were oxidized to seleninic acid in organic form, which suppressed the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) to realize AAT. This study provides an integrated solution to combine CO therapy with chemosensitization therapy and AAT together with good biocompatibility.


Elimination of plasmid-linked polyglutamate production by Bacillus subtilis (natto) with acridine orange.
Treatment of Bacillus subtilis (natto) strains Asahikawa, F, and M with acridine orange resulted in the conversion of approximately 64.2% of the Asahikawa population, 22.4% of the F population, and 9.2% of the M population to polyglutamate-nonproducing colonies. Such curing is suggestive of the involvement of plasmid DNA. Samples of cleared lysates of both parental and their cured strains were subjected to agarose gel electrophoresis to determine the plasmid composition. Parental strains were found to possess a plasmid, but polyglutamate-nonproducing derivatives were missing the plasmid. The plasmid-linked polyglutamate production, which was originally isolated from B. subtilis (natto), could be transformed in B. subtilis.


Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent.
Mevinolin (MVN) has been used clinically for the treatment of hypercholesterolemia with very good tolerance by patients. Based on epidemiological evidences, MVN was suggested strongly for the treatment of neoplasia. Early experimental trials suggested the mixed apoptotic/necrotic cell death pathway was activated in response to MVN exposure. Herein, the cytotoxic profile of MVN was evaluated, compared to the robust and frequently used anti-cancer drug doxorubicin (DOX), against breast (MCF-7), cervical (HeLa) and liver (HepG(2)) transformed cell lines. MVN was showed comparable results in cytotoxic profile with DOX in all tested solid tumor cell lines. In addition, the MVN-induced cytotoxicity was inferred to be multi-factorial and not solely dependent on p53 expression. It was concluded that molecular and genetic assessment of MVN-induced cell death would be useful for developing cancer therapeutic treatments.


A thermospray liquid chromatography/mass spectrometry method for analysis of human urine for the major malondialdehyde-guanine adduct.
A method is described for detection and quantitation of the major malondialdehyde-guanine adduct (M1G) based on thermospray liquid chromatography/mass spectrometry. A stable isotope analog of M1G ([2H2]M1G) was used as an internal standard. Thermospray mass spectra of M1G and [2H2]M1G showed intense protonated molecular (MH+) ions that were suitable for use in quantitation of M1G. M1G was purified from human urine and reduced with NaBH4 to a dihydro derivative that was cleanly separated from the contaminants in the urine. The detection limit of reduced M1G by thermospray liquid chromatography/mass spectrometry in the selected ion monitoring mode was 250 fmol on column. Six human urine samples were analyzed, and the concentrations of M1G were below the limit of detection of the assay (500 fmol/mL).


Illuminating structural proteins in viral "dark matter" with metaproteomics.
Viruses are ecologically important, yet environmental virology is limited by dominance of unannotated genomic sequences representing taxonomic and functional "viral dark matter." Although recent analytical advances are rapidly improving taxonomic annotations, identifying functional dark matter remains problematic. Here, we apply paired metaproteomics and dsDNA-targeted metagenomics to identify 1,875 virion-associated proteins from the ocean. Over one-half of these proteins were newly functionally annotated and represent abundant and widespread viral metagenome-derived protein clusters (PCs). One primarily unannotated PC dominated the dataset, but structural modeling and genomic context identified this PC as a previously unidentified capsid protein from multiple uncultivated tailed virus families. Furthermore, four of the five most abundant PCs in the metaproteome represent capsid proteins containing the HK97-like protein fold previously found in many viruses that infect all three domains of life. The dominance of these proteins within our dataset, as well as their global distribution throughout the world's oceans and seas, supports prior hypotheses that this HK97-like protein fold is the most abundant biological structure on Earth. Together, these culture-independent analyses improve virion-associated protein annotations, facilitate the investigation of proteins within natural viral communities, and offer a high-throughput means of illuminating functional viral dark matter.


Inter- and intrafractional localisation errors in cone-beam CT guided stereotactic radiation therapy of tumours in the liver and lung.
Localisation errors in cone-beam CT (CBCT) guided stereotactic body radiation therapy (SBRT) were evaluated and compared to positioning using the external coordinates of a stereotactic body frame (SBF) alone. Possible correlations to patient- or treatment-specific factors such as body mass index (BMI), planning time, treatment delivery time, and distance between tumour and spinal cord were explored to determine whether they influenced on the benefit of image-guidance. A total of 34 patients received SBRT (3 fractions) for tumours in the liver (15 patients) or the lung (19 patients). Immobilisation and positioning was obtained with a SBF. Pre- and post-treatment CBCT scans were registered with the bony anatomy of the planning CT to find inter- and intrafractional patient positioning errors (PPE). For lung tumour patients, matching was also performed on the tumours to find the tumour positioning errors (TPE) and baseline shifts relative to bony anatomy. The mean inter- and intrafractional 3D vector PPE was 4.5 ± 2.7 mm (average ± SD) and 1.5 ± 0.6 mm, respectively, for the combined group of patients. For lung tumours, the interfractional misalignment was 5.6 ± 1.8 mm. The baseline shift was 3.9 ± 2.0 mm. Intrafractional TPE and baseline shifts were 2.1 ± 0.7 mm and 1.9 ± 0.6 mm, respectively. The magnitude of interfractional baseline shift was closely correlated with the distance between the tumour and the spinal cord. Intrafractional errors were independent of patient BMI, age or gender. Image-guidance reduced setup errors considerably. The study demonstrated the benefit of CBCT-guidance regardless of patient specific factors such as BMI, age or gender. Protection of the spinal cord was facilitated by the correlation between the tumour position relative to the spinal cord and the magnitude of baseline shift.


Zinc and Cadmium Mapping in the Apical Shoot and Hypocotyl Tissues of Radish by High-Resolution Secondary Ion Mass Spectrometry (NanoSIMS) after Short-Term Exposure to Metal Contamination.
Zinc (as an essential phytonutrient) and cadmium (as a toxic but readily bioavailable nonessential metal for plants) share similar routes for crossing plant biomembranes, although with a substantially different potential for translocation into above-ground tissues. The in situ distribution of these metals in plant cells and tissues (particularly intensively-dividing and fast-growing areas) is poorly understood. In this study, 17-day-old radish (Raphanus sativus L.) plants grown in nutrient solution were subjected to short-term (24 h) equimolar contamination (2.2 µM of each 70Zn and Cd) to investigate their accumulation and distribution in the shoot apex (leaf primordia) and edible fleshy hypocotyl tissues. After 24-h exposure, radish hypocotyl had similar concentration (in µg/g dry weight) of 70Zn (12.1 ± 1.1) and total Cd (12.9 ± 0.8), with relatively limited translocation of both metals to shoots (concentrations lower by 2.5-fold for 70Zn and 4.8-fold for Cd) as determined by inductively-coupled plasma mass spectrometry (ICP-MS). The in situ Zn/Cd distribution maps created by high-resolution secondary ion mass spectrometry (NanoSIMS, Cameca, Gennevilliers, France) imaging corresponded well with the ICP-MS data, confirming a similar pattern and uniform distribution of 70Zn and Cd across the examined areas. Both applied techniques can be powerful tools for quantification (ICP-MS) and localisation and visualisation (NanoSIMS) of some ultra-trace isotopes in the intensively-dividing cells and fast-growing tissues of non-metalophytes even after short-term metal exposure. The results emphasise the importance of the quality of (agro)ecosystem resources (growing media, metal-contaminated soils/waters) in the public health risk, given that, even under low contamination and short-term exposure, some of the most toxic metallic ions (e.g., Cd) can relatively rapidly enter the human food chain.


Crosstalk rejection in parallel optical coherence tomography using spatially incoherent illumination with partially coherent sources.
The continuing improvement of high-speed area-scan cameras has made possible the construction of parallel optical coherence tomography (OCT) systems that are competitive with the fastest demonstrated swept-source OCT systems. Unfortunately, when imaging through turbid media using a partially coherent source, parallel OCT suffers resolution loss from coherent multiple scattering, a phenomenon known as crosstalk. We demonstrate the use of a full-field OCT system employing multimode fiber in the illumination arm to reduce the spatial coherence of a partially coherent source. By reducing the spatial coherence area below the system's lateral resolution, we create a spatial coherence gate that rejects these multiply scattered photons. We quantify the image quality and resolution improvement of this method by comparing images of a USAF test chart acquired beneath turbid phantoms using both coherent and incoherent illumination and computing the resulting modulation transfer functions. We demonstrate the feasibility of this method for imaging biological specimens by imaging a Drosophila melanogaster sample.


Increasing awareness and prompting HIV testing: Contributions of Amsterdam HIV Testing Week 2016.
We evaluated Amsterdam HIV Testing Week (HTW) 2016 regarding its primary goals of raising awareness and prompting HIV testing. Participating services offered free, anonymous HIV testing, with a focus on reaching men who have sex with men (MSM) and people with a non-western migration background. Sociodemographic characteristics, HIV testing history, intention to test regularly, beliefs about personal risk and severity of HIV, and perceived social norms regarding HIV testing and people living with HIV were assessed among all who tested. A community quick scan assessed awareness of Amsterdam HTW 2016 and attitudes and intentions regarding HIV testing. Of 806 people tested, 59.6% (405/679) belonged to key populations. None tested HIV-positive and 37.6% intended to test regularly in the future. The community quick scan found moderate awareness of Amsterdam HTW 2016. Awareness was highest among recent testers and HIV-positive MSM and not associated with HIV testing attitudes and intentions. People tested during Amsterdam HTW 2016 were from key populations and/or were not (adequately) reached via traditional testing approaches. The contribution of the Amsterdam HTW approach to raising awareness and prompting HIV testing in key populations may benefit from focusing on HIV-negative individuals who have not been tested recently.


Karyology and tumorigenicity testing requirements: past, present and future.
At the present time, karyology and tumorigenicity are applied to primary, diploid, and continuous cell systems in an uneven and inappropriate manner, largely for historical reasons. It is a significant anomaly that such rigorous requirements are applied only to diploid cells when, of all three cell types, they represent the category with the least potential problems. During the 1992 presidential campaign in the U.S., a very direct and telling slogan was used to the advantage of Mr. Clinton: <<It's the economy, stupid>>. That message was meant to have the effect of focusing on the real issue that was of concern to the electorate. The other topics were of secondary significance and tended to act as distractions from the central issue. In a very similar sense, one could say: <<It's the product, ...., not the cells>>. In other words, we should be focussing our time and attention on the characteristics of the biological product manufactured in a given cell system that has been well characterized rather than continue to belabour the issue of cell substrates. To a large degree, this has already been initiated with the recommendations of various groups already mentioned. However, current diploid cell quality control regulations stand out as a peculiar throwback to an earlier era. HDCs should be treated on a par with primary and continuous cells. There are three basic questions related to the routine use karyology that need to be addressed: (i) is the original rationale for requiring cytogenetic analysis of a diploid cell substrate still valid; (ii) is there a new rationale that would warrant its continued use; and (iii) if there is a continuing need for karyology, is it unique to diploid cell cultures or does it need to be extended to all types of cell systems? The original rationale was that karyology provided evidence of the normal character of WI-38 cells and therefore supported its acceptability as a cell substrate for vaccine production. Karyology essentially has remained as a legacy of the intense debate that led to the acceptance of WI-38 cells. There is no new information over the past 30 years to suggest that there is a new rationale for instituting chromosomal analysis of cell substrates. If there were, however, it is difficult to imagine why it should not be applied to all types of cell substrates (primary, diploid, and continuous). Taking all the above into consideration, there would seem to be no rationale for continuing to single out diploid cell cultures as the only cell type for which karyology is required on a routine basis. As stated above, the initial characterization of a new diploid cell line should include karyology. Like karyology, tumorigenicity testing was incorporated into the assessment of diploid cells in an attempt to persuade regulatory authorities that the cells were normal and acceptable. Again, after 30 years of testing, there has never been an instance of normal diploid fibroblasts generating a tumour in any in vitro or in vivo assays. The futility of continuing to do these tests is obvious. A description of the tumorigenic potential of a cell substrate should be an element in the characterization of a new cell line; but it has little if any value as a routine test. If history teaches us anything at all about risk, it is that we need to focus serious attention on contaminants rather than be diverted to remote theoretical issues that may be interesting to discuss and argue about, but which pale in the face of the potential impact on public health of viral and viral-like contaminants of biological products. One has only to recall the transmission of SV-40 from primary monkey kidney cells that were used to produce polio vaccine, or more recently the transmission of Creutzfeld-Jacob disease to recipients of human growth hormone derived from human pituitaries and of HIV to recipients of blood and blood derivatives. (ABSTRACT TRUNCATED)


Multiple von Neumann computers: an evolutionary approach to functional emergence.
A novel system composed of multiple von Neumann computers and an appropriate problem environment is proposed and simulated. Each computer has a memory to store the machine instruction program, and when a program is executed, a series of machine codes in the memory is sequentially decoded, leading to register operations in the central processing unit (CPU). By means of these operations, the computer not only can handle its generally used registers but also can read and write the environmental database. Simulation is driven by genetic algorithms (GAs) performed on the population of program memories. Mutation and crossover create program diversity in the memory, and selection facilitates the reproduction of appropriate programs. Through these evolutionary operations, advantageous combinations of machine codes are created and fixed in the population one by one, and the higher function, which enables the computer to calculate an appropriate number from the environment, finally emerges in the program memory. In the latter half of the article, the performance of GAs on this system is studied. Under different sets of parameters, the evolutionary speed, which is determined by the time until the domination of the final program, is examined and the conditions for faster evolution are clarified. At an intermediate mutation rate and at an intermediate population size, crossover helps create novel advantageous sets of machine codes and evidently accelerates optimization by GAs.


Involvement of activated microglia in increased vulnerability of motoneurons after facial nerve avulsion in presymptomatic amyotrophic lateral sclerosis model rats.
Activated microglia are observed in various neurodegenerative diseases and are thought to be involved in the processes of neuronal cell death. Motoneuron damage in the facial nuclei after facial nerve avulsion is accelerated in presymptomatic transgenic rats expressing human mutant Cu(2+) /Zn(2+) superoxide dismutase 1 (SOD1), compared with that in wild-type rats. To reveal the functional role of microglia in motoneuronal death, we investigated the microglial response after facial nerve avulsion in presymptomatic mutant SOD1(H46R) (mSOD1(H46R) ) rats. At 3 days after avulsion, microglial clusters were observed in the facial nuclei of both wild-type and mSOD1(H46R) rats. The numbers of microglial clusters, proliferating microglia, and microglial attachments to motoneurons were significantly higher in mSOD1(H46R) rats, compared with those in wild-type rats. Immunopositive signals for the phagocytic marker ED1 were significantly stronger in mSOD1(H46R) rats, compared with that in wild-type rats, at 2 weeks after avulsion. Furthermore, primary microglia prepared from mSOD1(H46R) rats showed enhanced phagocytic activity, compared with that in wild-type rats. The expression of P2Y(12) mRNA was higher in the facial nuclei of mSOD1(H46R) rats, compared with that in wild-type rats. A laser microdissection system revealed that the expression of ATF3 mRNA was higher in the motoneurons of mSOD1(H46R) rats, compared with that in wild-type rats, at 2 days after avulsion. These results indicate that microglial activation in response to early neuronal damage increased in mSOD1(H46R) rats and suggest that the enhanced activation of microglia may lead to an increase in the vulnerability of motoneurons after avulsion in mSOD1(H46R) rats.


Vonoprazan-containing Helicobacter pylori triple therapies contribution to global antimicrobial resistance.
Amoxicillin and proton pump inhibitor dual Helicobacter pylori therapy has proved not to be reliably highly effective primarily because of traditional proton pump inhibitors' inability to maintain a high intragastric pH. Clarithromycin and proton pump inhibitor H. pylori dual therapy failed in part because clarithromycin resistance emerged during therapy causing treatment failures. The combination of amoxicillin, clarithromycin, and proton pump inhibitor was subsequently undermined by increasing clarithromycin resistance. Although vonoprazan appeared to restore the effectiveness of triple therapy, the improvement was almost entirely to improved effectiveness of amoxicillin dual therapy component and resulted in the majority (>85% currently in Japan) of those receiving vonoprazan-amoxicillin plus a second antibiotic (e.g. clarithromycin, metronidazole, fluoroquinolone, or rifabutin) receiving no benefit from the second antibiotic. The results in somewhere between 2800 and 5600 kg of unnecessary clarithromycin per one million H. pylori treatment courses per year in Japan. The only contribution of the second antibiotic is to increase global antimicrobial resistance. There are now sufficient data to prove that optimized vonoprazan-amoxicillin dual therapy can reliably achieve cure rates ≥95%. This manuscript discusses use of the principles of antimicrobial stewardship to develop potassium-competitive acid blocker-containing H. pylori therapies that will reliably achieve high H. pylori cure rates with minimal or no use of excess antibiotics. Such therapies are urgently needed so that use of vonoprazan triple therapies can be curtailed while also improving overall H. pylori cure rates.


Radiographic and clinical assessment of unidirectional porous hydroxyapatite to treat benign bone tumors.
Unidirectional porous hydroxyapatite (UDPHAp) was developed as an excellent scaffold with unidirectional pores oriented in the horizontal direction with interpore connections. The purpose of this study was to assess radiographic changes and clinical outcomes and complications following UDPHAp implantation to treat benign bone tumors. We retrospectively analyzed 44 patients treated with intralesional resection and UDPHAp implantation for benign bone tumors between 2010 and 2015. Clinical and radiographic findings were evaluated postoperatively at regular follow-up visits. The mean follow-up was 49 months. Radiographic changes were classified into five stages based on bone formation in the implanted UDPHAp according to Tamai's classification. All patients showed excellent bone formation inside and around implanted UDPHAp. Absorption of UDPHAp and bone marrow cavity remodeling was identified in 20 patients at a mean of 17 months postoperatively, and was significantly more common in young patients. Preoperative cortical thinning was completely regenerated in 26 of 31 patients on average 10 months after surgery. There were no cases of delayed wound healing, postoperative infection, or allergic reaction related to implanted UDPHAp. UDPHAp is a useful bone-filling substitute for treating benign bone tumor, and the use of this material has a low complication rate.


The end justifies the means, but only in the middle.
Achieving goals often requires the completion of sequential actions, such as finishing a series of assignments to pass a class. In the course of pursuing such goals, people can decide how closely to follow their personal standards for each action. We propose that actions at the beginning and end of a sequence appear more diagnostic of the pursuer's personal standards than do actions in the middle. Therefore, people are more likely to adhere to their standards at the beginning and end of goal pursuit-and slack in the middle. We demonstrate this pattern of judgment and behavior in adherence to ethical standards (e.g., cheating), religious traditions (e.g., skipping religious rituals), and performance standards (e.g., "cutting corners" on a task). We also show that the motivation to adhere to standards by using proper means is independent and follows a different pattern from the motivation to reach the end state of goal pursuit.


Stimulation of chloride transport by cAMP in rat proximal tubules.
We have previously demonstrated that formate and oxalate stimulate transcellular Cl- absorption (JCl) in the rat proximal tubule by a mechanism involving DIDS-sensitive anion exchange across the luminal membrane and diphenylamine-2-carboxylate (DPC)-sensitive Cl- channels in the basolateral membrane. Recent evidence indicates cAMP activation of Cl- channels in apical and basolateral membranes of proximal tubule cells. We therefore tested the effect of cAMP on Cl- and fluid transport in rat proximal tubule studied by luminal and capillary microperfusion in situ. The luminal perfusate contained 5 mM HCO3- and 145 mM Cl-, and the capillary perfusate contained 25 mM HCO3- and 110 mM Cl-, simulating conditions in the late proximal tubule. Addition of 0.5 mM dibutyryl cAMP markedly stimulated fluid absorption (Jv) and JCl. Similar effects resulted from addition of forskolin (10 microM) to stimulate cAMP production. The increments in Jv and JCl due to dibutyryl cAMP were abolished when the Cl- channel blocker DPC (200 microM) was added to the capillary perfusate but not when it was added to the lumen. The increments in Jv and JCl due to dibutyryl cAMP were unaffected by luminal DIDS (100 microM), which abolishes the increments in Jv and JCl induced by addition of oxalate. In contrast, the increments in Jv and JCl due to dibutyryl cAMP were abolished by luminal 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB; 10 microM), another Cl- channel blocker. Luminal NPPB had no effect on baseline Jv and JCl nor on the increments in Jv and JCl induced by addition of oxalate.(ABSTRACT TRUNCATED AT 250 WORDS)


Reversal of a virtual lesion in human pharyngeal motor cortex by high frequency contralesional brain stimulation.
Excitatory brain stimulation with repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for dysphagia after stroke. Moreover, 1-Hz rTMS can induce a "virtual lesion" in the human pharyngeal motor cortex that suppresses brain activity and temporarily disrupts swallowing. We thus examined if rTMS could reverse the disrupted brain and swallowing functions following a unilateral virtual lesion in the pharyngeal motor cortex, such that rTMS might be developed as a therapy. Healthy subjects (n = 23) were given varying conditions of 5-Hz rTMS over the pharyngeal motor cortex to determine the most effective excitatory parameters. Thereafter, a unilateral virtual lesion was made in the pharyngeal motor cortex using 1-Hz rTMS, followed by contralateral active or sham 5-Hz rTMS. Motor evoked potentials and serial swallowing reaction times were recorded before and for 60 minutes postlesion to assess reversibility of the disruption to the brain and swallowing. The greatest increase in pharyngeal motor cortex excitability was seen following 250 pulses of 5-Hz rTMS (F(1,11) = 10.3, P = .008), an effect that lasted over 2 hours. In contrast to sham rTMS, active contralateral 5-Hz rTMS completely abolished the cortical suppression induced by the virtual lesion, with effects occurring for up to 50 minutes in both unlesioned (F(1,11) = 6, P = .03) and lesioned (F(1,11) = 67, P < .001) hemispheres. Active rTMS also reversed the changes in swallowing behavior (F(1,8) = 9, P = .018), restoring function to prelesional levels. Contralesional-targeted neurostimulation modulates brain activity and swallowing motor behavior after experimental disruption and might be usefully applied in stroke-affected patients as a therapy for dysphagia.


Associations of Food Addiction Symptomatology and Disordered Eating Behaviors in a Pre-Surgical Bariatric Population.
The construct of food addiction (FA) has been highly debated in recent years particularly in the fields of disordered eating, medical weight management, and bariatric surgery. Some researchers have argued that FA symptoms are distinct, highly prevalent, and present a barrier for patients seeking medical treatment for obesity. The purpose of this study is to evaluate the cross-sectional associations between FA symptomatology, binge eating disorder (BED) and other appetitive traits, as well as dietary quality in a sample of adults with obesity seeking bariatric surgery. This post hoc analysis was conducted on a prospectively collected dataset from August 2020 to August 2022 at a single academic medical center. Descriptive statistics were used to characterize the sample. Additional analyses included: correlation coefficients, multivariable linear regression, and analysis of variance. A total of 587 patients were included in this analysis with low average scores for FA symptoms (mean: 1.48; standard deviation (SD): 2.15). Those with no BED symptoms had the lowest average FA symptoms scores (mean: 0.87; SD: 1.52) and those with both bingeing and LOCE had the highest average scores (mean: 3.35; SD: 2.81). This finding supports the hypothesis that, while related, FA and BED may represent different cognitions and behaviors.


"They don't care about us": older people's experiences of primary healthcare in Cape Town, South Africa.
As older people age, they have different health needs compared to younger people. South African elder care policy places a strong emphasis on ageing in community rather than institutional settings, but the primary healthcare system is not geared to address the health needs of older people living in community settings. This paper presents findings of nine focus groups conducted with community-dwelling older adults in three areas (high, medium and low-income) in Cape Town, South Africa over 2 months in 2017. These discussions addressed primary health services available to older persons, their ability to access these services and their expectations and experiences of care. Findings showed that while participants in the high-income area had few challenges accessing quality care or support services, services available in lower-income areas were much less responsive and participants displayed low trust in the healthcare system, feeling that their needs were overlooked. Participants who experienced poor doctor-patient communication often failed to comply with treatment, while those who experienced patient-centered communication, either through the private sector or NGO-public sector partnerships had better perceptions of care. Older persons' complex health needs cannot be adequately addressed by a process-driven approach to care. Supporting patient-centered communication and care may help health workers to understand older persons health needs and improve patient understanding, trust and co-operation. This paper suggests the importance of community support services in enhancing health access and developing systems that enable healthcare providers to better understand and respond to older persons' needs in resource-constrained settings.


Hospital laboratory reporting may be a barrier to detection of 'microsize' myocardial infarction in the US: an observational study.
International guidelines recommend that the decision threshold for troponin should be the 99th percentile of a normal population, or, if the laboratory assay is not sufficiently precise at this low level, the level at which the assay achieves a 10% or better coefficient of variation (CV). Our objectives were to examine US hospital laboratory troponin reports to determine whether either the 99th percentile or the 10% CV level were clearly indicated, and whether nonconcordance with these guidelines was a potential barrier to detecting clinically important microscopic or 'microsize' myocardial infarctions (MIs). To confirm past reports of the clinical importance of microsize MIs, we also contrasted in-hospital, 28-day and 1-year mortality among those with microsize and nonmicrosize MI. In the REasons for Geographic And Racial Differences in Stroke national prospective cohort study (n=30,239), 1029 participants were hospitalized for acute coronary syndrome (ACS) between 2003-2009. For each case, we recorded all thresholds of abnormal troponin on the laboratory report and whether the 99th percentile or 10% CV value were clearly identified. All cases were expert adjudicated for presence of MI. Peak troponin values were used to classify MIs as microsize MI (< five times the lowest listed upper limit of normal) and nonmicrosize MI. Participants were hospitalized at 649 acute care US hospitals, only 2% of whose lab reports clearly identified the 99th percentile or the 10% CV level; 52% of reports indicated an indeterminate range, a practice that is no longer recommended. There were 183 microsize MIs and 353 nonmicrosize MIs. In-hospital mortality tended to be lower in the microsize than in the nonmicrosize MI group (1.1 vs. 3.6%, p = 0.09), but 28-day and 1-year mortality were similar (2.5% vs. 2.7% [p = 0.93] and 5.2% vs. 4.3% [p = 0.64], respectively). Current practices in many US hospitals created barriers to the clinical recognition of microsize MI, which was common and clinically important in our study. Improved hospital troponin reporting is warranted.


Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects.
We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.


Lower extremity preventive measures for slips - joint moments and myoelectric analysis.
This study investigated the lower extremity preventive measures for slips on simulated slippery surfaces in construction worksites. A total of 15 harnessed Chinese males walked without slips on a 5-m walkway in 16 simulated conditions 10 times at their natural cadence. Joint moments were calculated from kinetics, kinematics and anthropometric data recorded from a force plate, a Novel Pedar system and a motion analysis system. Data were evaluated from footstrike to mid-stance at 10%-stance intervals. Electromyography signals from tibialis anterior, gastrocnemius, rectus femoris and biceps femoris in one stride were evaluated in four phases, including early/late stance and swing. Results showed that lower extremity preventive measures for slips included prolonged ankle plantar flexion moments from 25% to 92% stance, increased ankle plantar flexion moments from 30% stance to mid-stance, and diminished knee extension moments from 10% to 30% stance. Higher activity of rectus femoris and gastrocnemius were found in the late stance and the swing phase respectively.


Investigation of lipid peroxidation and antiapoptotic effects of zinc aganist liver damage in diabetic rats.
Several mechanisms for the pathogenesis of diabetic complications have been proposed, one of which is abnormal zinc (Zn) homeostasis. Zn is necessary for proper liver function since it has important antioxidant, anti-inflammatory, and antiapoptotic properties. We aimed to investigate whether or not Zn has morphologically protective effect on diabetes-induced liver damage in rats. In addition, we have investigated the role of Zn supplementation on apoptosis, lipid peroxidation levels, and the distribution of metallothionein (MT) in diabetic liver tissue. Wistar albino rats were divided into four groups: control, Zn, diabetic, and Zn-diabetic group. Experimental diabetes was induced by a single-dose streptozotocin intraperitoneally and Zn was administrated via gastric gavage tube for 6 weeks. MT expressions were showed with immunohistochemical staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used for apoptosis. Also, Zn, MT, and malondialdehyde (MDA) levels were determined in liver of rats. MDA levels of the Zn-supplemented diabetic group was less than the diabetic group though MT levels were increased. The number of apoptotic cells per unit area was found to be significantly decreased in this group. In the Zn-supplemented diabetic group, fibrotic tissue density and the collagen tissue density were observed less than the diabetic group. MT immunoreactivity was observed less in Zn-supplemented diabetic group. In conculusion, the present study indicated that Zn has a potential in preventing or even repairing effect against diabetic damage of the liver cells by increasing expression of MT and by reducing the apoptotic cell death and the oxidative stress.


Towards safer streets: A framework for unveiling pedestrians' perceived road safety using street view imagery.
Road safety has become a global concern but its impact in low- and middle-income countries is widespread mainly due to lack of appropriate crash database system and under-reporting. In this context, the primary objective of this paper is to provide a scalable framework for unveiling pedestrians' perceived road safety that can also be applied in regions where accessible crash data are limited or near-crashes are left unreported. In the first step of our methodology, a deep learning architecture-based semantic segmentation model (HRNet+OCR) is trained using labeled Google Street View (GSV) images from specific study areas in Dhaka, Bangladesh, which facilitates the identification of both man-made components (such as roads, sidewalks, buildings, and vehicles) and natural elements (including trees and sky). The developed model showed excellent performance in identifying different features in an image by achieving high precision (0.95), recall (0.97), F1-score (0.96), and intersection over union (IoU) (91.86). Secondly, a group of trained raters scored the perceived road safety on an ordinal scale from 0 to 10 (extremely unsafe to extremely safe to walk in terms of road crashes) by assessing the GSV images. Then, several regression models have been used on features extracted from GSV images, and socio-demographic factors (i.e., population density, and relative wealth index) to estimate the perceived road safety, and random forest regression model was found to perform the best. Further, Shapley Additive Explanations (SHAP), a model-agnostic technique has been used for examining feature importance by computing the contribution of each feature to the random forest regression model output. The results show that sidewalk, road, population density, wall, and relative wealth index have higher impact on determining the perceived road safety rating. Additionally, the results of t-tests between the average perceived road safety scores for crash-prone and non crash-prone areas revealed the existence of significant differences. This study also provides perceived road safety rating map on a neighborhood scale, which can be a useful visualization tool for policy-makers and practitioners to identify the road safety deficiencies at specific locations, and formulate appropriate and strategic countermeasures to improve pedestrians' road safety.


Regulation of proenkephalin A messenger ribonucleic acid levels in normal B lymphocytes: specific inhibition by glucocorticoid hormones and superinduction by cycloheximide.
Proenkephalin A (PEA) encodes a group of small peptides known to function as neurotransmitters, neuromodulators, and neurohormones in the nervous and neuroendocrine systems. This gene has been shown to be expressed in lymphoid cells, supporting the concept of bidirectional communication between the immune system and the central nervous system. In the present study, we investigated the effect of steroids and the inhibition of protein and RNA syntheses on the regulation of PEA expression in normal rat B cells. The transient expression of PEA messenger (m) RNA levels occurring normally in B cells was markedly inhibited by the presence of either 50 nM prednisolone or dexamethasone, both of which are glucocorticoids; other steroids, such as testosterone or the steroid-inactive metabolite androsterone, were ineffective. In the presence of cycloheximide, a protein synthesis inhibitor, PEA mRNA was superinduced by a factor of 15-fold. Sorting by flow cytometry of cycloheximide-treated cells followed by in situ hybridization analysis revealed that the expression of PEA mRNA was exclusively confined to a small fraction of B cells. These results indicate that the mechanisms regulating PEA gene expression in B cells differ from those previously described in cells of the neuroendocrine and the nervous systems.


Inhibition of anaplastic lymphoma kinase promotes apoptosis and suppresses proliferation in human hepatocellular carcinoma.
Our study was to examine the roles of crizotinib and ceritinib in hepatocellular carcinoma (HCC) cells and explore the possible mechanisms. MTT assay was employed to examine the proliferation of five HCC cell lines treated with various concentrations of crizotinib or ceritinib. HepG2 and HCCLM3 cells were incubated with 2 nmol/l ceritinib for 1 week, followed by crystal violet staining and cell counting. Protein amounts of t-ALK, p-ALK, t-AKT, p-AKT, t-ERK, p-ERK, Mcl-1, survivin, and XIAP in HepG2 cells under different culture conditions were evaluated by western blot. HepG2 and HCCLM3 cells were treated with vehicle or ceritinib and measured by flow cytometry apoptosis analysis with Annexin-V/propidium iodide staining. MTT assay showed that both crizotinib and ceritinib suppressed the proliferation of various human HCC cells. Crystal violet staining analysis also indicated that ceritinib effectively inhibited human HCC cell proliferation. Western blot analysis indicated that both crizotinib and ceritinib inhibited ALK, AKT, and ERK phosphorylations. In addition, ceritinib reduced antiapoptotic gene expressions in HepG2 cells. Flow cytometry analysis indicated that ceritinib induced HepG2 and HCCLM3 cells apoptosis. ALK inhibitor exhibited antitumor effects by inhibiting ALK activation, repressing AKT and ERK pathways, and suppressing antiapoptotic gene expressions, which subsequently promoted apoptosis and suppressed HCC cell proliferations.


Fathers show modifications of infant-directed action similar to that of mothers.
Mothers' actions are more enthusiastic, simple, and repetitive when demonstrating novel object properties to their infants than to adults, a behavioral modification called "infant-directed action" by Brand and colleagues (2002). The current study tested whether fathers also tailor their behavior when interacting with infants and whether this modification differs from the infant-directed action that mothers show. A sample of 42 parents (21 mothers and 21 fathers) demonstrated the properties of two novel toys to their infants (12-month-olds) and to other adults. Fathers and mothers modified their actions with respect to repetitiveness, rate, range of motion, proximity, interactiveness, and enthusiasm compared with interactions with other adults. Fathers differed from mothers with respect to proximity, carrying out actions closer to their infants than mothers did. These results provide evidence that fathers show modifications in their infant-directed action that is similar to that of mothers.


The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert.
FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B and Myc genes border a 1.2 Mb gene desert at 8q24.21. Co-amplification of both occurs in 20 cancer types. Mice deficient of a 430 Kb fragment within the 1.2 Mb gene desert have downregulated FAM84B and Myc expressions concurrent with reduced breast cancer growth. Intriguingly, Myc works in partnership with other oncogenes, including Ras. FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain. This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A1/2 and O-acyltransferase activities of HRASLS1-5. These enzymatic activities underlie their suppression of Ras. FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5. Deletion of this motif abolishes FAM84B oncogenic activities. These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions. Here, we will discuss recent research on FAM84B-derived oncogenic potential.


Identification and characterization of cDNA clones encoding plant calreticulin in barley.
Two cDNA clones (CRH1 and CRH2) homologous to animal calreticulin, a major calcium storage protein in the lumen of the endoplasmic reticulum, were isolated from an ovary cDNA library of barley through differential screening. The two clones differ in the 3' untranslated region and the 5' region that encodes a putative N-terminal signal sequence. CRH1 was mapped to the minus arm of chromosome 1. CRH2 was mapped to the minus arm of chromosome 2. The deduced amino acid sequences share 50 to 55% identity with animal calreticulins and exhibit the same three-zone characteristic. Recombinant protein stained blue with Stains-all and bound 45Ca2+ when transferred to nitrocellulose membranes. A native protein of approximately 55 kD was identified in ovary extract. Elevated gene expression was observed in ovaries 1 day after pollination and during early embryogenesis. CRH1 was expressed at a higher level than CRH2. These studies demonstrate the presence of calreticulin in plant cells and its developmental regulation in fertilization.


Electronic and optical properties of chlorinated silicon nanoparticles.
First-principles calculations are used to investigate the structure, electronic and optical properties of silicon nanocystals with chlorine-passivated surface. The nanocrystals considered were approximately spherical, with diameters between 1.5 and 3.0 nm. We show that the nanocrystals with chlorinated surface have a smaller bandgap, lower optical absorption threshold, and greater ionization energy and electron affinity than hydrogenated silicon nanocrystals of the same size.


Reduction of Brucella species and Francisella tularensis cross-reacting agglutinins by dithiothreitol.
Cross-reaction agglutinin titers to Brucella abortus antigen were found in 42 of 128 tularemia serum specimens, and cross-reaction titers to Francisella tularensis antigen were found in 8 of 34 brucellosis serum specimens. The cross-reaction titers were reduced to 10 or less by dithiothreitol, suggesting that the titers are due to immunoglobulin M antibody.


Novel species of Huntiella from naturally-occurring forest trees in Greece and South Africa.
Huntiella species are wood-infecting, filamentous ascomycetes that occur in fresh wounds on a wide variety of tree species. These fungi are mainly known as saprobes although some have been associated with disease symptoms. Six fungal isolates with typical culture characteristics of Huntiella spp. were collected from wounds on native forest trees in Greece and South Africa. The aim of this study was to identify these isolates, using morphological characters and multigene phylogenies of the rRNA internal transcribed spacer (ITS) region, portions of the β-tubulin (BT1) and translation elongation factor 1α (TEF-1α) genes. The mating strategies of these fungi were also determined through PCR amplification of mating type genes. The study revealed two new species; one from Platanus orientalis in Greece and one from Colophospermum mopane and Senegalia nigrescens in South Africa. These novel taxa have been provided with the names, H. hellenica sp. nov. and H. krugeri sp. nov., respectively. The former species was found to have a homothallic and the latter a heterothallic mating system.


Immune tolerance in allergy.
Research on the mechanisms of immune regulation in allergy and asthma has shown substantial progress in recent years and has led to a variety of allergen-specific therapeutic and preventive approaches. Studies on the area of allergen-specific immunotherapy (allergen-SIT) have provided substantial knowledge on the mechanisms of allergic disease with novel developments for treatment and prevention. Several studies have demonstrated that increased numbers and the activation of allergen-specific T regulatory cells correlate with successful allergen-SIT. Particularly, targeting of the molecular mechanisms of immune tolerance and reciprocal regulation of effector and regulatory T-cell subsets are foreseen for the development of new strategies for immune intervention. This review focuses on current knowledge of immune tolerance to allergens in healthy immune response to allergens and allergen-SIT.