Cross-language differences in the brain network subserving intelligible speech.
How is language processed in the brain by native speakers of different languages? Is there one brain system for all languages or are different languages subserved by different brain systems? The first view emphasizes commonality, whereas the second emphasizes specificity. We investigated the cortical dynamics involved in processing two very diverse languages: a tonal language (Chinese) and a nontonal language (English). We used functional MRI and dynamic causal modeling analysis to compute and compare brain network models exhaustively with all possible connections among nodes of language regions in temporal and frontal cortex and found that the information flow from the posterior to anterior portions of the temporal cortex was commonly shared by Chinese and English speakers during speech comprehension, whereas the inferior frontal gyrus received neural signals from the left posterior portion of the temporal cortex in English speakers and from the bilateral anterior portion of the temporal cortex in Chinese speakers. Our results revealed that, although speech processing is largely carried out in the common left hemisphere classical language areas (Broca's and Wernicke's areas) and anterior temporal cortex, speech comprehension across different language groups depends on how these brain regions interact with each other. Moreover, the right anterior temporal cortex, which is crucial for tone processing, is equally important as its left homolog, the left anterior temporal cortex, in modulating the cortical dynamics in tone language comprehension. The current study pinpoints the importance of the bilateral anterior temporal cortex in language comprehension that is downplayed or even ignored by popular contemporary models of speech comprehension.


A Green Bioactive By-Product Almond Skin Functional Extract for Developing Nutraceutical Formulations with Potential Antimetabolic Activity.
(1) Background: almond peels are rich in polyphenols such as catechin and epicatechin, which are important anti-free-radical agents, anti-inflammatory compounds, and capable of breaking down cholesterol plaques. This work aims to evaluate the biological and technological activity of a "green" dry aqueous extract from Sicilian almond peels, a waste product of the food industry, and to develop healthy nutraceuticals with natural ingredients. Eudraguard® Natural is a natural coating polymer chosen to develop atomized formulations that improve the technological properties of the extract. (2) Methods: the antioxidant and free radical scavenger activity of the extract was rated using different methods (DPPH assay, ABTS, ORAC, NO). The metalloproteinases of the extracts (MMP-2 and MMP-9), the enhanced inhibition of the final glycation products, and the effects of the compounds on cell viability were also tested. All pure materials and formulations were characterized using UV, HPLC, FTIR, DSC, and SEM methods. (3) Results: almond peel extract showed appreciable antioxidant and free radical activity with a stronger NO inhibition effect, strong activity on MMP-2, and good antiglycative effects. In light of this, a food supplement with added health value was formulated. Eudraguard® Natural acted as a swelling substrate by improving extract solubility and dissolution/release (4) Conclusions: almond peel extract has significant antioxidant activity and MMP/AGE inhibition effects, resulting in an optimal candidate to formulate safe microsystems with potential antimetabolic activity. Eudraguard® Natural is capable of obtaining spray-dried microsystems with an improvement in the extract's biological and technological characteristics. It also protects the dry extract from degradation and oxidation, prolonging the shelf life of the final product.


Upregulation of an inward rectifying K+ channel can rescue slow Ca2+ oscillations in K(ATP) channel deficient pancreatic islets.
Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the β-cell plasma membrane and terminates islet oscillations. Surprisingly, when K(ATP) channels are genetically knocked out, oscillations in islet activity persist, and relatively normal blood glucose levels are maintained. Compensation must therefore occur to overcome the loss of K(ATP) channels in K(ATP) knockout mice. In a companion study, we demonstrated a substantial increase in Kir2.1 protein occurs in β-cells lacking K(ATP) because of SUR1 deletion. In this report, we demonstrate that β-cells of SUR1 null islets have an upregulated inward rectifying K+ current that helps to compensate for the loss of K(ATP) channels. This current is likely due to the increased expression of Kir2.1 channels. We used mathematical modeling to determine whether an ionic current having the biophysical characteristics of Kir2.1 is capable of rescuing oscillations that are similar in period to those of wild-type islets. By experimentally testing a key model prediction we suggest that Kir2.1 current upregulation is a likely mechanism for rescuing the oscillations seen in islets from mice deficient in K(ATP) channels.


Initial assessment of protein and amino acid digestive dynamics in protein-rich feedstuffs for broiler chickens.
A study evaluating apparent digestibilities of protein and amino acids and their corresponding digestion rates in four small intestinal sites in broiler chickens was completed to further investigate dietary optimisation via synchronised nutrient digestion and absorption. A total of 288 male Ross 308 broiler chickens were offered semi-purified diets with eight protein-rich feedstuffs, including; blood meal (BM), plasma protein meal (PPM), cold pressed (CCM) and expeller-pressed (ECM) canola meal, high (SBM HCP) and low (SBM LCP) crude protein soybean meals, lupins and peas. Diets were iso-caloric, iso-nitrogenous and the test ingredient was the sole source of dietary nitrogen. Each diet was offered to 6 bioassay cages with 6 birds per cage from day 21 to 28 post hatch. On day 28, all birds were euthanized and digesta samples were collected from the proximal jejunum, distal jejunum, proximal ileum and distal ileum to determine apparent protein and amino acids digestibility coefficients, digestion rates and potential digestible protein and amino acids. Dietary protein source significantly influenced energy utilisation, nitrogen retention, apparent protein (N) digestibilities, digestion rates and potential digestible protein along the small intestine. Diets containing BM and SBM LCP exhibited the highest protein digestion rate and potential digestible protein, respectively. Digestibility coefficients and disappearance rates of the majority of amino acids in four sections of the small intestine were influenced by dietary protein source (P < 0.01) and blood meal had the fastest protein digestion rate. In general, jejunal amino acid and protein digestibilities were more variable in comparison to ileal digestibilities, and the differences in protein and amino acid disappearance rates were more pronounced between types of feedstuffs than sources of similar feedstuffs.


A Prospective Study on Functional Outcome of Internal Fixation of Tibial Pilon Fractures with Locking Plate using Minimally Invasive Plate Osteosynthesis Technique.
Managing pilon fractures is still a great challenge for surgeons in terms of reduction and fixation. The soft tissue anatomy and the bony configuration, results in angular and rotational instability and other bony and soft tissue complications. To evaluate the results of minimally invasive plate osteosynthesis using locking plates in management of fractures of tibial pilon in terms of radiological fracture union, restoration of ankle function and complications. A total of 18 patients with Ruedi Allgower class I, II & III fresh pilon fractures were taken into this study. All the patients underwent ankle spanning external fixator application on the day of presentation as a first stage. Wound debridement was done in patients with open fractures. Associated distal fibula fractures were fixed in the first stage. The second stage comprised of a definitive plate fixation using the minimally invasive plate osteosynthesis technique. This employed minimal periosteal and soft tissue dissection through a medial approach to the ankle. Postoperatively, all patients were reviewed at week six and 12 when partial weight bearing and full weight bearing mobilization was started respectively. The final review was done at 24 weeks when the final assessment of function was done as per the Mazur's scoring criteria. Analyses were done using frequency and proportions. Chi-square tests were used to assess the test of association. Three patients had excellent inference, nine patients had good inference, five patients had fair and one patient had poor inference as per the Mazur's scoring criteria. Two patients had scar dehiscence as a complication and one patient had a fixed equines deformity of the ankle who was under RuediAllgower class III. Minimally invasive plate osteosynthesis is an excellent method of treating pilon fractures with very good functional results and minimal complication rate.


Quantitative determination of aceclofenac and its three major metabolites in rat plasma by HPLC-MS/MS.
We developed a method for the simultaneous quantification of aceclofenac and its three major metabolites in rat plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard (IS), aceclofenac, diclofenac, 4'-hydroxyaceclofenac, 4'-hydroxydiclofenac, and the IS were chromatographed on a reverse-phase C18 analytical column. The isocratic mobile phase of acetonitrile/0.1% formic acid (aq; 9:1 [v/v]) was eluted at 0.3 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transitions were monitored in selective reaction-monitoring mode. The coefficient of variation in the assay precision was less than 8%, and the accuracy was 92-103%. This method was successfully used to measure the concentrations of aceclofenac and its three major metabolites in rat plasma following the oral administration of a single 20 mg/kg oral dose of aceclofenac.


Erythropoietin structure-function relationships: high degree of sequence homology among mammals.
To investigate structure-function relationships of erythropoietin (Epo), we have obtained cDNA sequences that encode the mature Epo protein of a variety of mammals. A first set of primers, corresponding to conserved nucleotide sequences between mouse and human DNAs, allowed us to amplify by polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing of these fragments permitted the design of a second generation of species-specific primers. RNA was prepared from anemic kidneys and reverse-transcribed. Using our battery of species-specific 5' primers, we were able to successfully PCR-amplify Epo cDNA from Rhesus monkey, rat, sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo proteins from these animals, in combination with known sequences for human, Cynomolgus monkey, and mouse, showed a high degree of homology, which explains the biologic and immunological cross-reactivity that has been observed in a number of species. Human Epo is 91% identical to monkey Epo, 85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos. There was full conservation of (1) the disulfide bridge linking the NH2 and COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic alpha-helices. In contrast, the short disulfide bridge (C29/C33 in humans) is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino acid replacements were conservative. The C-terminal part of the loop between the C and D helices showed the most variation, with several amino acid substitutions, deletions, and/or insertions. Calculations of maximum parsimony for intron 1/exon 2 sequences as well as coding sequences enabled the construction of cladograms that are in good agreement with known phylogenetic relationships.


Surgery to modify nutritional behaviour.
The main aim of obesity surgery is to change the dietary habits of morbidly obese patients. These are patients whose dietary habits nutritionists and psychologists have not been able to change during previous decades. The history of this surgery can teach us many important lessons. For example, procedures that have focused on effecting a malabsorptive state, but without addressing any behavioural mechanism for weight control, such as jejunoileal bypass, have failed. On the other hand, those that have centered on only addressing behavioural issues, the purely restrictive, are also difficult for patients to comply with and also have a high failure rate. To facilitate a change in the nutritional behaviour of morbidly obese patients which can lead to the loss of an adequate amount of weight, and which could be maintained in the long term is difficult. We need to stimulate changes that can be easily followed by the patient, and at the same time, provoke minimal medium and long term alterations in their nutritional state. To achieve and maintain this aim efficiently, it is necessary that the patients have confidence in and respect the physician, so that they can follow strictly their medical advice.


Possible homozygous factor VIIR disorder associated with fibrinolytic hyperactivity.
A family with inherited factor VII deficiency is described. The propositus is a 9-year-old girl with chronic haemorrhagic history of epistaxis and bleeding after tooth extractions. Her factor VII coagulant activity was less than 3% using rabbit thromboplastin. She had a factor VII antigen level of 50%. Both parents were heterozygous for factor VII deficiency. The father had procoagulant factor VII (VII-C) of 44% and factor VII antigen (VII-Ag) of 74%, and the mother had 54% of factor VII-C and 85% of VII-Ag. Her only brother had normal levels of factor VII-C (100%). Additionally, some abnormalities in the fibrinolytic system were detected both in the propositus and her brother with shortened euglobulin lysis times and increased functional levels of plasminogen activator. To our knowledge, the clinical association of inherited factor VII deficiency and familial fibrinolytic disturbances has not been described so far.


Balancing Accuracy and Speed in Gaze-Touch Grid Menu Selection in AR via Mapping Sub-Menus to a Hand-Held Device.
Eye gaze can be a potentially fast and ergonomic method for target selection in augmented reality (AR). However, the eye-tracking accuracy of current consumer-level AR systems is limited. While state-of-the-art AR target selection techniques based on eye gaze and touch (gaze-touch), which follow the "eye gaze pre-selects, touch refines and confirms" mechanism, can significantly enhance selection accuracy, their selection speeds are usually compromised. To balance accuracy and speed in gaze-touch grid menu selection in AR, we propose the Hand-Held Sub-Menu (HHSM) technique.tou HHSM divides a grid menu into several sub-menus and maps the sub-menu pointed to by eye gaze onto the touchscreen of a hand-held device. To select a target item, the user first selects the sub-menu containing it via eye gaze and then confirms the selection on the touchscreen via a single touch action. We derived the HHSM technique's design space and investigated it through a series of empirical studies. Through an empirical study involving 24 participants recruited from a local university, we found that HHSM can effectively balance accuracy and speed in gaze-touch grid menu selection in AR. The error rate was approximately 2%, and the completion time per selection was around 0.93 s when participants used two thumbs to interact with the touchscreen, and approximately 1.1 s when they used only one finger.


Paid health and family leave: the Canadian experience in the global context.
Two thirds of Canadian adults participate in the workforce. Their health and that of their families can be markedly affected by the availability of paid sick leave, paid leave to care for family members' health and paid parental leave. We gathered data from all Canadian provinces and territories on these essential leave policies and compared Canadian policies with data collected on 186 United Nations (UN) countries. While Canada pays sickness benefits for 15 weeks for serious illnesses, globally at least 90 countries provide benefits for at least 26 weeks or until recovery. Moreover, within Canada only Saskatchewan and Quebec guarantee job protection if sick leave lasts over 12 days. The federal government guarantees Canadian workers six weeks of paid leave to provide care or support to gravely ill family members. Only 39 countries guarantee such leave with pay. Most, but not all, provinces guarantee workers' job protection during compassionate care leave. Eligibility for job protection during parental leave varies across the country from having no restrictions to requiring at least one year of service. Compared with Canada, many countries offer a longer duration of paid sick leave for employees and replace a higher percentage of wages lost. Internationally, Canada performs well in having policies that guarantee paid leave to care for dependants with serious illnesses, but it lags behind in the provision of paid leave to address the health needs of children or family members' with non-life-threatening conditions. Finally, while paid parental leave is of adequate duration, the wage replacement rate lowers its accessibility to families with limited means.


Differential expression of the S-adenosyl-L-methionine synthase genes during pea development.
Two genes coding for S-adenosyl-l-methionine synthase (SAMS, EC 2.5. 1.6) were previously isolated from pea (Pisum sativum) ovaries. Both SAMS genes were highly homologous throughout their coding regions but showed a certain degree of sequence divergence within the 5' and the 3' untranslated regions. These regions have been used as gene-specific probes to analyze the differential expression of SAMS1 and SAMS2 genes in pea plants. The ribonuclease protection assay revealed different expression patterns for each individual gene. SAMS1 was strongly expressed in nearly all tissues, especially in roots. SAMS2 expression was weaker, reaching its highest level at the apex. Following pollination, SAMS1 was specifically up-regulated, whereas SAMS2 was expressed constitutively. The up-regulation of SAMS1 during ovary development was also observed in unpollinated ovaries treated with auxins. In unpollinated ovaries an increase in SAMS1 expression was observed as a consequence of ethylene production associated with the emasculation process. In senescing ovaries both SAMS1 and SAMS2 genes showed increased expression. Ethylene treatment of unpollinated ovaries led to an increase in the SAMS1 mRNA level. However, SAMS2 expression remained unchangeable after ethylene treatment, indicating that SAMS2 induction during ovary senescence was not ethylene dependent. SAMS mRNAs were localized by in situ hybridization at the endocarp of developing fruits and in the ovules of senescing ovaries. Our results indicate that the transcriptional regulation of SAMS genes is developmentally controlled in a specific way for each gene.


Nociceptin / orphanin FQ (NOP) receptors as novel potential target in the treatment of gastrointestinal diseases.
The nociceptin system, which consists of endogenous nociceptin/orphanin FQ and NOP receptors, is present in the central nervous system (CNS), as well as respiratory, cardiovascular, urogenital and gastrointestinal (GI) tissues. It is critically involved in nociception and pain signaling, as well as modulation of hormone and neurotransmitter release, stress responses and reversal of stress-induced analgesia. In the GI tract, the nociceptin system participates in the maintenance of homeostasis by affecting secretion and motility. Here we give an overview on the nociceptin system in the GI tract. The nociceptin system is an attractive target for novel drugs, which may be effective in the treatment of inflammatory or functional GI disorders, such as inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS).


Emergence of unusual nonfermenting Gram-negative nosocomial pathogens in a Saudi hospital.
This study aimed to determine the frequency of isolation and prevalence of drug resistance in nonfermenting Gram-negative bacilli (NFGNB) other than Pseudomonas aeruginosa and predisposing factors for the acquisition of nosocomial infections caused by these emerging pathogens in a Saudi tertiary care hospital. A total of 125 nonduplicating NFGNB nosocomial strains were isolated, of these, 68 (54.4%) were Acinetobacter baumannii, 26 (20.8%) Stenotrophomonas maltophilia, 14 (11.2%) Alcaligenes faecalis, 12 (9.6%) Chryseobacterium indologenes, and 5 (4%) Ralstonia pickettii. MICs of 11 antibiotics were determined using the reference broth microdilution method. With the exception of colistin that inhibited 100% of A. baumannii isolates, trimethoprim/sulfamethoxazole that inhibited 100% of S. maltophilia isolates, and carbapenems that inhibited 100% of A. faecalis isolates, none of the tested antimicrobial agents inhibited 100% of the other NFGNB spp. Our results emphasize that clinicians and microbiologists should consider A. faecalis, C. indologenes, and R. pickettii as emerging nosocomial pathogens. In addition, local resistance data are essential for helping physicians in deciding an appropriate antibiotic for empirical therapy of infections with these emerging and unusual NFGNB.


The case: voices.
Six caregivers comment on the aftermath of a patient's disabling stroke. Their remarks about the patient and his family situation reveal much about the dynamics of the hospital hierarchy--and, incidentally, the difficulty of uncovering the "facts."


Size, Stability, and Porosity of Mesoporous Nanoparticles Characterized with Light Scattering.
Silicon-based mesoporous nanoparticles have been extensively studied to meet the challenges in the drug delivery. Functionality of these nanoparticles depends on their properties which are often changing as a function of particle size and surrounding medium. Widely used characterization methods, dynamic light scattering (DLS), and transmission electron microscope (TEM) have both their weaknesses. We hypothesize that conventional light scattering (LS) methods can be used for a rigorous characterization of medium sensitive nanoparticles' properties, like size, stability, and porosity. Two fundamentally different silicon-based nanoparticles were made: porous silicon (PSi) from crystalline silicon and silica nanoparticles (SN) through sol-gel process. We studied the properties of these mesoporous nanoparticles with two different multiangle LS techniques, DLS and static light scattering (SLS), and compared the results to dry-state techniques, TEM, and nitrogen sorption. Comparison of particle radius from TEM and DLS revealed significant overestimation of the DLS result. Regarding to silica nanoparticles, the overestimation was attributed to agglomeration by analyzing radius of gyration and hydrodynamic radius. In case of PSi nanoparticles, strong correlation between LS result and specific surface area was found. Our results suggest that the multiangle LS methods could be used for the size, stability, and structure characterization of mesoporous nanoparticles.


"The Buoy": Utilization of a low-threshold ambulatory setting for traumatized children and adolescents in Austria.
This investigation intended to assess the use of an outpatient clinic providing low-threshold, short-term trauma therapy for children and adolescents across the first 6 years of its existence. A retrospective analysis of the records of all patients undergoing treatment in this institution between 2001 and 2007 (n = 2510) has been performed. We evaluated demographic data, reason for contacting the unit, the referring person or institution, the person or institution in charge of the care and custody of the child, the number of contacts with the clinic, presence of physical or psychiatric illness of a parent, and medications prescribed. Ages of patients ranged from 1 to 17. Gender distribution was even. Having experienced the death of a relative, experienced violence, or having witnessed traumatic death were the main reasons for presentation. The utilization rates of immigrants rose throughout the observation period. Children from foster care were seen less frequently than expected. Medication was hardly prescribed. Ample utilization of this institution clearly demonstrates the need for short-term acute outpatient trauma therapy for children and adolescents. Efforts to provide easily accessible institutions for youth who experience traumatic events should be stepped up.


Improving the performance of quantum dot sensitized solar cells through CdNiS quantum dots with reduced recombination and enhanced electron lifetime.
To make quantum dot-sensitized solar cells (QDSSCs) competitive, we investigated the effect of Ni(2+) ion incorporation into a CdS layer to create long-lived charge carriers and reduce the electron-hole recombination. The Ni(2+)-doped CdS (simplified as CdNiS) QD layer was introduced to a TiO2 surface via the simple successive ionic layer adsorption and reaction (SILAR) method in order to introduce intermediate-energy levels in the QDs. The effects of different Ni(2+) concentrations (5, 10, 15, and 20 mM) on the physical, chemical, and photovoltaic properties of the QDSSCs were investigated. The Ni(2+) dopant improves the light absorption of the device, accelerates the electron injection kinetics, and reduces the charge recombination, which results in improved charge transfer and collection. The 15% CdNiS cell exhibits the best photovoltaic performance with a power conversion efficiency (η) of 3.11% (JSC = 8.91 mA cm(-2), VOC = 0.643 V, FF = 0.543) under one full sun illumination (AM 1.5 G). These results are among the best achieved for CdS-based QDSSCs. Electrochemical impedance spectroscopy (EIS) and open circuit voltage decay (OCVD) measurements confirm that the Ni(2+) dopant can suppress charge recombination, prolong the electron lifetime, and improve the power conversion efficiency of the cells.


Increased vascular expression of iNOS at day but not at night in asthmatic subjects with increased nocturnal airway obstruction.
Nitric oxide production by endothelial cells may have important consequences for the development of airway inflammation as well as for airway obstruction. The present study investigated whether the expression of vascular inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in human bronchi differs between asthmatic and healthy subjects, and whether it shows a circadian rhythm, especially in subjects with increased nocturnal airway obstruction. Bronchial biopsy samples were taken at 16:00 and 04:00 h from 13 healthy and 25 asthmatic subjects, 18-45 yrs. Biopsy samples were snap-frozen and double-immunostained for iNOS and eNOS in combination with a common vascular antigen (CD31). The degree of immunopositivity was expressed as a percentage of CD31-positive vessels encountered in complete biopsy sections. Asthmatic subjects showed greater iNOS expression than healthy controls: 23+/-15 versus 7+/-17% (mean+/-SD) at 16:00 h (p<0.001) and 19+/-15 versus 8+/-11% at 04:00 h (p<0.05). Asthmatic subjects with a fall in forced expiratory volume in one second of >10% of the predicted value between 16:00 and 04:00 h showed greater iNOS expression at 16:00 than at 04:00 h: 32+/-16 versus 20+/-13% (p<0.05). eNOS expression did not differ between healthy controls and asthmatic patients, nor did it differ between 16:00 and 04:00 h. It is suggested that asthmatic subjects with increased nocturnal airway obstruction demonstrate increased activation of inducible nitric oxide synthase during the day. The resulting nitric oxide production might protect against airway obstruction during the day. However, at night, nitric oxide production is probably insufficient to counterbalance the bronchoconstricting forces.


Isolation of a recombinant between simian and bovine rotaviruses.
A recombinant between simian rotavirus, simian agent 11 (SA-11) and bovine rotavirus, neonatal calf diarrhoea virus (NCDV), was obtained by mixed infection of MA-104 cells with NCDV and u.v.-irradiated SA-11 virus, and isolation of a plaque formed in the presence of anti-NCDV serum. The genome of the recombinant contained dsRNA segments 4, 5 and 10 derived from SA-11 virus and segments 1, 2, 3, 6 and 11 derived from NCDV, and segments 7, 8 and 9 of undetermined origin. Polypeptides VP4, VP5, VP7a, VP7b, NCVP1 and MCVP3 were derived from SA-11 virus and polypeptides VP1, VP2, VP3, VP6, VP8, NCVP2a and NCVP2b from NCDV. Haemagglutination of the recombinant was inhibited and its infectivity neutralized by the antiserum against SA-11 virus but not by anti-NCDV serum.


Sleep in people with and without intellectual disabilities: a systematic review and meta-analysis.
Sleep problems are regularly reported in people with intellectual disabilities. Recent years have seen a substantial increase in studies comparing sleep in people with intellectual disabilities to control participants, with an increase in the use of validated, objective measures. Emerging patterns of differences in sleep time and sleep quality warrant pooled investigation. A systematic search was conducted across three databases (Ovid Embase, PsycInfo and Medline) and returned all papers comparing sleep in people with intellectual disabilities to a control group, published since the last meta-analysis on the topic. A quality framework was employed to rate the risk of bias across studies. Separate meta-analyses of sleep duration and sleep quality were conducted. Subgrouping compared findings for those studies with participants with genetic syndromes or neurodevelopmental conditions and those with heterogeneous intellectual disability. Thirteen new papers were identified and combined with those from the previous meta-analysis to provide 34 papers in total. Quality of studies was generally rated highly, though sampling provided risk of bias and adaptive functioning was rarely measured. People with intellectual disability associated with genetic syndromes or neurodevelopmental conditions sleep for shorter time periods (standardised mean difference = .26) and experience worse sleep quality (standardised mean difference = .68) than their peers. People with intellectual disability of heterogeneous origin show no difference in sleep time but have poorer sleep quality. There was some evidence that age moderated these effects. People with intellectual disability have poorer sleep than those without. Subtle patterns suggest that aetiology of intellectual disability moderates the topography of these difficulties, with further work needed to differentiate common and distinct mechanisms across groups.


A new tumor-promoting agent, dihydroteleocidin B, markedly enhances chemically induced malignant cell transformation.
Teleocidin, which was isolated from mycelia of Streptomyces, is a potent tumor promoter in mouse skin. The catalytically hydrogenated compound dihydroteleocidin B markedly enhanced malignant cell transformation induced by 3-methylcholanthrene or ultraviolet radiation. Dihydroteleocidin B was at least 100 times more effective in enhancing transformation than 12-O-tetradecanoyl phorbol-13-acetate, the strongest promoter known until now, whereas both promoters showed equal capacities to induce early membrane effects and DNA synthesis.


Nectin-4 regulates cellular senescence-associated enlargement of cell size.
Cellular senescence is defined as irreversible growth arrest induced by various stress, such as DNA damage and oxidative stress. Senescent cells exhibit various characteristic morphological changes including enlarged morphology. In our recent study, we identified Nectin-4 to be upregulated in cellular senescence by comparative transcriptomic analysis. However, there are few reports on the relationship between Nectin-4 and senescence. Therefore, we analyzed the function of Nectin-4 in senescence and its biological significance. When overexpressed with Nectin-4, the cells exhibited the enlarged cell morphology closely resembling senescent cells. In addition, the cell size enlargement during DNA damage-induced senescence was suppressed by knockdown of Nectin-4, while there were no significant changes in senescence induction. These results suggest that Nectin-4 is not involved in the regulation of senescence itself but contributes to the senescence-associated cell size increase. Furthermore, the Nectin-4-dependent cell size increase was found to be mediated by Src family kinase (SFK)/PI3 kinase (PI3K)/Rac1 pathway. To explore the functional consequences of cell size enlargement, we analyzed cell survival in Nectin-4-depleted senescent cells. Single-cell tracking experiments revealed that Nectin-4 knockdown induced apoptosis in senescent cells, and there is a strong positive correlation between cell size and survival rate. These results collectively indicate that Nectin-4 plays a causative role in the senescence-associated cell size enlargement via SFK/PI3K/Rac1, which can contribute to survival of senescent cells.


Mitogenome Phylogeny Including Data from Additional Subspecies Provides New Insights into the Historical Biogeography of the Eurasian lynx Lynx lynx.
Previous molecular studies of the wide-ranging Eurasian lynx Lynx lynx focused mainly on its northern Palearctic populations, with the consequence that the reconstruction of this species' evolutionary history did not include genetic variation present in its southern Palearctic distribution. We sampled a previously not considered Asian subspecies (L. l. dinniki), added published data from another Asian subspecies (L. l. isabellinus), and reassessed the Eurasian lynx mtDNA phylogeny along with previously published data from northern Palearctic populations. Our mitogenome-based analyses revealed the existence of three major clades (A: Central Asia, B: SE Europe/SW Asia, C: Europe and Northern Asia) and at least five lineages, with diversification in Lynx lynx commencing at least 28kyr earlier than hitherto estimated. The subspecies L. l. isabellinus harbors the most basal matriline, consistent with the origin of Lynx lynx in this subspecies' current range. L. l. dinniki harbors the second most basal matriline, which is related to, and may be the source of, the mtDNA diversity of the critically endangered Balkan lynx L. l. balcanicus. Our results suggest that the Anatolian peninsula was a glacial refugium for Eurasian lynx, with previously unconsidered implications for the colonization of Europe by this species.


Protection and recycling of alpha-tocopherol in human erythrocytes by intracellular ascorbic acid.
Ascorbic acid can recycle alpha-tocopherol from the tocopheroxyl free radical in lipid bilayers and in micelles, but such recycling has not been demonstrated to occur across cell membranes. In this work the ability of intracellular ascorbate to protect and to recycle alpha-tocopherol in intact human erythrocytes and erythrocyte ghosts was investigated. In erythrocytes that were 80% depleted of intracellular ascorbate by treatment with the nitroxide Tempol, both 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and ferricyanide oxidized alpha-tocopherol to a greater extent than in cells not depleted of ascorbate. In contrast, in erythrocytes in which the intracellular ascorbate concentration had been increased by loading with dehydroascorbate, loss of alpha-tocopherol was less with both oxidants than in control cells. Protection against AAPH-induced oxidation of alpha-tocopherol was not prevented by extracellular ascorbate oxidase, indicating that the protection was due to intracellular and not to extracellular ascorbate. Incubation of erythrocytes with lecithin liposomes also generated an oxidant stress, which caused lipid peroxidation in the liposomes and depleted erythrocyte alpha-tocopherol, leading to hemolysis. Ascorbate loading of the erythrocytes delayed liposome oxidation and decreased loss of alpha-tocopherol from both cells and from alpha-tocopherol-loaded liposomes. When erythrocyte ghosts were resealed to contain ascorbate and challenged with free radicals generated by AAPH outside the ghosts, intravesicular ascorbate was totally depleted over 1 h of incubation, whereas alpha-tocopherol decreased only after ascorbate was substantially oxidized. These results suggest that ascorbate within the erythrocyte protects alpha-tocopherol in the cell membrane by a direct recycling mechanism.


Structures of cationic and anionic polyelectrolytes in aqueous solutions: the sign effect.
In this study, we use molecular dynamics simulation to explore the structures of anionic and cationic polyelectrolytes in aqueous solutions. We first confirm the significantly stronger solvation effects of single anions compared to cations in water at the fixed ion radii, due to the reversal orientations of asymmetric dipolar H2O molecules around the ions. Based on this, we demonstrate that the solvation discrepancy of cations/anions and electrostatic correlations of ionic species can synergistically cause the nontrivial structural difference between single anionic and cationic polyelectrolytes. The cationic polyelectrolyte shows an extended structure whereas the anionic polyelectrolyte exhibits a collapsed structure, and their structural differences decline with increasing the counterion size. Furthermore, we corroborate that multiple cationic polyelectrolytes or multiple anionic polyelectrolytes can exhibit largely differential molecular architectures in aqueous solutions. In the solvation dominant regime, the polyelectrolyte solutions exhibit uniform structures; whereas, in the electrostatic correlation dominant regime, the polyelectrolyte solutions exhibit heterogeneous structures, in which the likely charged chains microscopically aggregate through counterion condensations. Increasing the intrinsic chain rigidity causes polyelectrolyte extension and hence moderately weakens the inter-chain clustering. Our work highlights the various, unique structures and molecular architectures of polyelectrolytes in solutions caused by the multi-body correlations between polyelectrolytes, counterions and asymmetric dipolar solvent molecules, which provides insights into the fundamental understanding of ion-containing polymers.


Marine toxins: chemistry, toxicity, occurrence and detection, with special reference to the Dutch situation.
Various species of algae can produce marine toxins under certain circumstances. These toxins can then accumulate in shellfish such as mussels, oysters and scallops. When these contaminated shellfish species are consumed severe intoxication can occur. The different types of syndromes that can occur after consumption of contaminated shellfish, the corresponding toxins and relevant legislation are discussed in this review. Amnesic Shellfish Poisoning (ASP), Paralytic Shellfish Poisoning (PSP), Diarrheic Shellfish Poisoning (DSP) and Azaspiracid Shellfish Poisoning (AZP) occur worldwide, Neurologic Shellfish Poisoning (NSP) is mainly limited to the USA and New Zealand while the toxins causing DSP and AZP occur most frequently in Europe. The latter two toxin groups are fat-soluble and can therefore also be classified as lipophilic marine toxins. A detailed overview of the official analytical methods used in the EU (mouse or rat bioassay) and the recently developed alternative methods for the lipophilic marine toxins is given. These alternative methods are based on functional assays, biochemical assays and chemical methods. From the literature it is clear that chemical methods offer the best potential to replace the animal tests that are still legislated worldwide. Finally, an overview is given of the situation of marine toxins in The Netherlands. The rat bioassay has been used for monitoring DSP and AZP toxins in The Netherlands since the 1970s. Nowadays, a combination of a chemical method and the rat bioassay is often used. In The Netherlands toxic events are mainly caused by DSP toxins, which have been found in Dutch shellfish for the first time in 1961, and have reoccurred at irregular intervals and in varying concentrations. From this review it is clear that considerable effort is being undertaken by various research groups to phase out the animal tests that are still used for the official routine monitoring programs.


Simulation and its role in training.
Despite its short history, surgical simulation has been successfully introduced into surgical residency programs in an effort to augment training. A wide range of simulator types and levels of complexity have proven an effective teaching method for surgical trainees. They have been used for training in areas such as general surgery, urology, gynecology, and ophthalmology among others. Coincident with the introduction of simulators is the need for objective evaluation of skills learned on them, which has led to the development and validation of multiple evaluation tools. This article evaluates the drivers for simulation, types of simulators, training, and evaluation of them especially as it pertains to laparoscopic colorectal surgery.


Virtual Assessment as a Way to Reduce Help-seeking Barriers in Older Adults With Subjective Cognitive Decline.
Subjective cognitive decline (SCD), a potential early marker for neurodegenerative disease such as Alzheimer's disease, is common among older adults. Although it is often regarded as a personal health concern, most individuals with SCD do not seek help from a health care professional. Help-seeking (HS) is a complex, individualized process with significant life-course implications, and older adults often face several barriers to HS across personal, socioeconomic, and cultural domains. The pandemic exacerbated these barriers by imposing additional limitations on in-person care. In response, virtual assessment became a popular method to conduct remote care. We provide a narrative review of the challenges and triumphs that came with the transition from in-person, pen-paper cognitive assessments to virtual cognitive assessments. In addition, we address the impact virtual assessment had in tackling barriers that previously limited individuals with SCD from formal HS. We argue that virtual cognitive assessment helps alleviate health access barriers to HS (e.g., cost, transportation, and physician availability) and allows individuals with different coping styles to undergo assessment within more convenient environments. We hope the findings presented in this review inform health care practice, public education, and future research targeted towards the use of virtual assessment to facilitate HS in older adults with SCD.


Common genetic variants in the TP53 pathway and their impact on cancer.
The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.


Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study.
Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years. Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.


Evaluation of the quality of clinical guidelines for cardiac rehabilitation: a critical review.
To evaluate the quality of clinical guidelines (CGs) for cardiac rehabilitation and to critically appraise exercise-related recommendations. critical review. main search engines, databases, clearinghouses, and guideline developers. We included evidence-based CGs specific to cardiac rehabilitation with recommendations for the period after diagnosis of myocardial infarction or acute coronary syndrome. Clinical guidelines needed to include an exercise component and at least 1 additional component in the cardiac rehabilitation program. Data extraction and appraisal: We evaluated the quality of GCs, using the Appraisal of Guidelines for Research and Evaluation Instrument, second version. Three reviewers independently extracted data, appraised the quality of included CGs, and resolved disagreements by consensus. Nine guidelines were included. The average scores were 79.84%, 59.88%, 55.56%, 85.18%, 48.92%, and 56.79% for the domains of scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, and editorial independence, respectively. The majority of guidelines recommended low- to moderate-intensity aerobic and resistance exercises, with moderate variability in the frequency and duration of sessions. Clinical guidelines consistently recommended aerobic and resistance exercises. Overall, our critical review showed that the quality of CGs was at least moderate, with the greatest deficiencies being related to applicability and rigor of development domains.


Role of breeding and natal movements in lifetime dispersal of a forest-dwelling rodent.
The lifetime movements of an individual determine the gene flow and invasion potential of the species. However, sex dependence of dispersal and selective pressures driving dispersal have gained much more attention than dispersal at different life and age stages. Natal dispersal is more common than dispersal between breeding attempts, but breeding dispersal may be promoted by resource availability and competition. Here, we utilize mark-recapture data on the nest-box population of Siberian flying squirrels to analyze lifetime dispersal patterns. Natal dispersal means the distance between the natal nest and the nest used the following year, whereas breeding movements refer to the nest site changes between breeding attempts. The movement distances observed here were comparable to distances reported earlier from radio-telemetry studies. Breeding movements did not contribute to lifetime dispersal distance and were not related to variation in food abundance or habitat patch size. Breeding movements of males were negatively, albeit not strongly, related to male population size. In females, breeding movement activity was low and was not related to previous breeding success or to competition between females for territories. Natal philopatry was linked to apparent death of a mother; that is, we did not find evidence for mothers bequeathing territories for offspring, like observed in some other rodent species. Our results give an example of a species in which breeding movements are not driven by environmental variability or nest site quality. Different evolutionary forces often operate in natal and breeding movements, and our study supports the view that juveniles are responsible for redistributing individuals within and between populations. This emphasizes the importance of knowledge on natal dispersal, if we want to understand consequences of movement ecology of the species at the population level.


What do they TEL(L)? A systematic analysis of master programs in technology-enhanced learning.
This article contributes to the debate on the growing number of interdisciplinary study programs in learning and technology, and aims to understand the diversity of programs as well as curricula structure in an international landscape. Scientific fields share their knowledge and recruit young researchers by offering discipline-specific study programs. Thus, study programs are a reflection of the fields they represent. As technology-enhanced learning is considered to be particularly interdisciplinary and heterogenous, it is important to better understand the landscape of study programs that represents the field. This article presents an analysis of master programs in technology-enhanced learning. A systematic review and analysis of master programs offered in English has been conducted and further used as input for hierarchical cluster analysis. The study identified general characteristics, curricula structure, and organization of topics of these programs. Hierarchical cluster analysis and qualitative content analysis helped us to identify the major types of curricular structures and typical topics covered by the courses. Results show that most study programs rely on interdisciplinary subjects in technology-enhanced learning with a considerable number of subjects from education, learning and psychology. Subjects related to technology, information and computer science appear in such programs less frequently.


The importance of IL-6 protein expression in primary human renal cell carcinoma: an immunohistochemical study.
Interleukin 6 (IL-6) is produced by some renal carcinoma cell lines in vitro. This might be biologically important because IL-6 is a cytokine of particular interest, owing to its involvement in the growth of renal cell carcinoma. In this study, the expression of IL-6 protein in tissue samples from primary renal cell carcinoma was analysed, and then its clinical importance was examined. The distribution of IL-6 in renal cell carcinoma was examined by means of an immunohistochemical method in 47 untreated primary renal cell carcinoma samples. The search for a significant difference between histological patterns, Furhman's grading system, TNM classification, and IL-6 protein expression was carried out. Immunohistochemistry demonstrated that IL-6 is expressed in 70% of primary tumours. There was no significant difference in the tumour size and grade between renal cell carcinomas with or without IL-6 expression. However, a relatively large number of high grade tumours expressed IL-6. The importance of IL-6 expression with regard to tumour size/local growth is questionable because IL-6 has been correlated with the development of metastatic disease. These data suggest that the production of IL-6 could exert a growth inhibitory effect on primary renal cell carcinoma.


Soybean lipoxygenase inactivation by pressure at subzero and elevated temperatures.
Soybean lipoxygenase (LOX) inactivation [0.4 mg/mL in Tris-HCl buffer (0.01 M, pH 9)] was studied quantitatively under constant pressure (up to 650 MPa) and temperature (-15 to 68 degrees C) conditions and kinetically characterized by rate constants, activation energies, and activation volumes. The irreversible LOX inactivation followed a first-order reaction at all pressure-temperature combinations tested. In the entire pressure-temperature area studied, LOX inactivation rate constants increased with increasing pressure at constant temperature. On the contrary, at constant pressure, the inactivation rate constants showed a minimum around 30 degrees C and could be increased by either a temperature increase or decrease. On the basis of the calculated rate constants at 102 pressure-temperature combinations, an iso-rate contour diagram was constructed as a function of pressure and temperature. The pressure-temperature dependence of the LOX inactivation rate constants was described successfully using a modified kinetic model of Hawley.


Epidemiological profile of Zika, Dengue and Chikungunya virus infections identified by medical and molecular evaluations in Rondonia, Brazil.
Several arboviruses have emerged and/or re-emerged in North, Central and South-American countries. Viruses from some regions of Africa and Asia, such as the Zika and Chikungunya virus have been introduced in new continents causing major public health problems. The aim of this study was to investigate the presence of RNA from Zika, Dengue and Chikungunya viruses in symptomatic patients from Rondonia, where the epidemiological profile is still little known, by one-step real-time RT-PCR. The main clinical signs and symtoms were fever (51.2%), headache (78%), chills (6.1%), pruritus (12.2%), exanthema (20.1%), arthralgia (35.3%), myalgia (26.8%) and retro-orbital pain (19.5%). Serum from 164 symptomatic patients were collected and tested for RNA of Zika, Dengue types 1 to 4 and Chikungunya viruses, in addition to antibodies against Dengue NS1 antigen. Direct microscopy for Malaria was also performed. Only ZIKV RNA was detected in 4.3% of the patients, and in the remaining 95.7% of the patients RNA for Zika, Dengue and Chikungunya viruses were not detected. This finding is intriguing as the region has been endemic for Dengue for a long time and more recently for Chikungunya virus as well. The results indicated that medical and molecular parameters obtained were suitable to describe the first report of symptomatic Zika infections in this region. Furthermore, the low rate of detection, compared to clinical signs and symptoms as the solely diagnosis criteria, suggests that molecular assays for detection of viruses or other pathogens that cause similar symptoms should be used and the corresponding diseases could be included in the compulsory notification list.


Disease, frequency-dependent selection, and genetic polymorphisms: experiments with stripe rust and wheat.
Pathogens have the potential to maintain genetic polymorphisms by creating frequency-dependent selection on their host. This can occur when a rare host genotype is less likely to be attacked by a pathogen (frequency-dependent disease attack) and has higher fitness at low frequency (negative frequency-dependent selection). In this study, we used wheat genotypes that were susceptible to different races of the pathogen Puccinia striiformis to test whether disease created frequency-selection on its host and whether such selection could maintain polymorphisms for resistance genes in the wheat populations. Four different two-way mixtures of wheat genotypes were planted at different frequencies in both the presence and absence of disease. Disease created frequency-dependent selection on its host in some populations. Unknown factors other than disease also created frequency-dependent selection in this system because, in some instances, rare genotype advantage was observed in the absence of disease. Although the pathogen created frequency-dependent selection on its host, this selection was not sufficient to maintain genetic polymorphism in the host populations. In all cases where frequency-dependent selection occurred only in the diseased plots, one of the two genotypes was predicted to dominate in the population and the same genotype was predicted to dominate in both the presence and absence of disease. Only in cases where frequency-dependent selection was not caused by disease was there evidence that genetic polymorphisms would be maintained in the population. The frequency-dependent selection described in this study is a consequence of epidemiological effects of disease and differs from the time-lagged frequency-dependent selection resulting from coevolution between hosts and parasites. The impact of this direct frequency-dependent selection on the maintenance of genetic polymorphisms in the host population is discussed.


Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging.
Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET.


Oral immunization of haemaggulutinin H5 expressed in plant endoplasmic reticulum with adjuvant saponin protects mice against highly pathogenic avian influenza A virus infection.
Pandemics in poultry caused by the highly pathogenic avian influenza (HPAI) A virus occur too frequently globally, and there is growing concern about the HPAI A virus due to the possibility of a pandemic among humans. Thus, it is important to develop a vaccine against HPAI suitable for both humans and animals. Various approaches are underway to develop such vaccines. In particular, an edible vaccine would be a convenient way to vaccinate poultry because of the behaviour of the animals. However, an edible vaccine is still not available. In this study, we developed a strategy of effective vaccination of mice by the oral administration of transgenic Arabidopsis plants (HA-TG) expressing haemagglutinin (HA) in the endoplasmic reticulum (ER). Expression of HA in the ER resulted in its high-level accumulation, N-glycosylation, protection from proteolytic degradation and long-term stability. Oral administration of HA-TG with saponin elicited high levels of HA-specific systemic IgG and mucosal IgA responses in mice, which resulted in protection against a lethal influenza virus infection with attenuated inflammatory symptoms. Based on these results, we propose that oral administration of freeze-dried leaf powders from transgenic plants expressing HA in the ER together with saponin is an attractive strategy for vaccination against influenza A virus.


Identifying the Transcriptional Regulatory Network Associated With Extrathyroidal Extension in Papillary Thyroid Carcinoma by Comprehensive Bioinformatics Analysis.
Extrathyroidal extension (ETE) affects papillary thyroid cancer (PTC) prognosis. The objective of this study was to identify biomarkers for ETE and explore the mechanisms controlling its development in PTC. We performed a comprehensive bioinformatics analysis using several datasets. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) on 58 paired PTC samples from The Cancer Genome Atlas (TCGA) were used to detect ETE-related mRNA and long noncoding (lnc) RNA modules and construct an lncRNA/mRNA network. An independent TCGA dataset containing 438 samples was utilized to validate and characterize the WGCNA results. Functional annotation was used to identify the biological functions and related pathways of ETE modules. Two independent RNA sequencing datasets were combined to crossvalidate relationships between lncRNAs and mRNAs by Pearson correlation analysis. Transcription factors (TFs) for affected genes were predicted using the binding motif data from Ensembl Biomart to construct a TF/lncRNA/mRNA network. Other two independent datasets were used to crossvalidate TF-mRNA associations. Finally, receiver operating characteristic, survival analyses, and Cox proportional hazard regression model were performed to explore the significance of hub genes in ETE diagnosis and PTC prognosis. Three mRNA modules and two lncRNA modules were significantly associated with ETE. Enrichment analysis showed extracellular matrix changes was closely related to the development of ETE. A TF/lncRNA/mRNA regulatory network was constructed containing 33 validated hub genes, 64 lncRNAs, and 64 TFs, all differentially expressed between ETE and non-ETE samples. Unc-5 family C-terminal like [area under the curve (AUC): 0.711], sushi repeat containing protein X-linked 2 (AUC: 0.706), lysyl oxidase (AUC: 0.704), collagen type I alpha 1 chain (AUC: 0.704), and collagen type X alpha 1 chain (AUC: 0.704) were the most highly significant hub genes for ETE diagnosis. The Cox proportional hazard regression model constructed with hub genes showed significant survival differences between low- and high-risk groups (p = 0.00025) and performed good prediction for PTC prognosis(AUC = 0.794; C-index = 0.895). The identification of 33 biomarkers and TF/lncRNA/mRNA regulatory network would provide new insights into the molecular mechanisms of ETE besides the prognosis model may have important clinical implications in the improvement of PTC risk stratification, therapeutic decision-making, and prognosis prediction.


Alopecia areata and relapsing polychondritis or mosaic autoimmunity? The first experience of co-trimoxazole treatment.
A 13 year old girl presented with auricular chondritis and recurrent episodes of unexplained chest pain, arthritis, bronchitis, conjunctivitis, prolonged steroid resistant alopecia areata, and a history of recurrent tonsillitis. Both the mosaic of autoimmunity and relapsing polychondritis were considered in the differential diagnosis. The patient was successfully treated with co-trimoxazole. The significance of co-trimoxazole, which is an antibiotic and an immunomodulatory drug, in the treatment of autoimmune disease is discussed.


Chronic variable stress impairs energy metabolism in prefrontal cortex and hippocampus of rats: prevention by chronic antioxidant treatment.
Since chronic stress has been used widely for studying clinical depression and that brain energy metabolism and oxidative stress might be involved in the pathophysiology of this illness, the objective of this study was investigate the activities of pyruvate kinase, complex II and IV (cytocrome c oxidase) in hippocampus and prefrontal cortex of rats submitted to chronic variable stress. We also evaluated if vitamins E and C administration could prevent such effects. During 40 days adult rats from the stressed group were subjected to one stressor per day, at a different time each day, in order to minimize predictability. The stressed group had gained less weight while its immobilization time in the forced swimming test was greater than that of the control group. Results showed that stressed group presented an inhibition in the activities of complex II and cytochrome c oxidase in prefrontal cortex, while in hippocampus just complex IV was inhibited. Pyruvate kinase activity was not altered in stressed group when compared to control. Vitamins E and C administration prevented the alterations on respiratory chain caused by stress. These data suggest that the impairment of energy metabolism and oxidative stress could be related with the pathogenic pathways in stress related disorders.


Enhanced skyrmion stability due to exchange frustration.
Skyrmions are localized, topologically non-trivial spin structures which have raised high hopes for future spintronic applications. A key issue is skyrmion stability with respect to annihilation into the ferromagnetic state. Energy barriers for this collapse have been calculated taking only nearest neighbor exchange interactions into account. Here, we demonstrate that exchange frustration can greatly enhance skyrmion stability. We focus on the prototypical film system Pd/Fe/Ir(111) and use an atomistic spin model parametrized from first-principles calculations. We show that energy barriers and critical fields of skyrmion collapse as well as skyrmion lifetimes are drastically enhanced due to frustrated exchange and that antiskyrmions are metastable. In contrast an effective nearest-neighbor exchange model can only account for equilibrium properties of skyrmions such as their magnetic field dependent profile or the zero temperature phase diagram. Our work shows that frustration of long range exchange interactions - a typical feature in itinerant electron magnets - is a route towards enhanced skyrmion stability even in systems with a ferromagnetic ground state.


Characteristics and Context of Veterans Experiencing Serious Suicidal Ideation or Suicide Attempt by Firearm which led to Hospitalization.
Suicide by former United States military service members is of great public health concern, and one area, veterans' suicide attempts involving firearms, is understudied. One group that has a unique perspective on this are veterans with a psychiatric admission following a firearm-related suicide crisis, such as making a suicide plan or a suicide rehearsal with a firearm within the preceding 72 hours. This study seeks to address this gap in the literature by describing the characteristics and context of non-fatal suicide events involving firearms among veterans. This convergent parallel mixed-methods design study collected both quantitative and qualitative data from male veterans (N = 15) who were hospitalized due to a suicide attempt or serious ideation using a firearm. Veterans admitted to a Veterans Affairs Medical Center (VAMC) were interviewed and asked to complete a survey. Qualitative data on characteristics and context were analyzed using a thematic analysis. The fifteen male U.S. military veterans described their personal characteristics, such as their beliefs, family beliefs and structure, emotions, and employment status. Most participants were unemployed (n = 10; 67%), divorced (n = 7; 47%) or married (n = 5; 33%). Seven themes related to context emerged from qualitative interviews to include: combat trauma, non-combat trauma and negative life event(s), current and past suicide attempt(s), firearms, substance use, known deaths by suicide, and protective factors for suicide. Results suggest that engaging support networks and communities is essential when developing programs to promote identification of early warning signs and implementation of interventions or programs for reducing veteran suicide.


Alcohol consumption and the risk of morbidity and mortality for different stroke types--a systematic review and meta-analysis.
Observational studies have suggested a complex relationship between alcohol consumption and stroke, dependent on sex, type of stroke and outcome (morbidity vs. mortality). We undertook a systematic review and a meta-analysis of studies assessing the association between levels of average alcohol consumption and relative risks of ischemic and hemorrhagic strokes separately by sex and outcome. This meta-analysis is the first to explicitly separate morbidity and mortality of alcohol-attributable stroke and thus has implications for public health and prevention. Using Medical Subject Headings (alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke), a literature search of MEDLINE, EMBASE, CINAHL, CABS, WHOlist, SIGLE, ETOH, and Web of Science databases between 1980 to June 2009 was performed followed by manual searches of bibliographies of key retrieved articles. From twenty-six observational studies (cohort or case-control) with ischemic or hemorrhagic strokes the relative risk or odds ratios or hazard ratios of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and life time abstention (manually estimated where data for current abstainers were given) was used as the reference group. Two reviewers independently extracted the information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, risk estimates and key criteria of study quality using a standardized protocol. The dose-response relationship for hemorrhagic stroke had monotonically increasing risk for increasing consumption, whereas ischemic stroke showed a curvilinear relationship, with a protective effect of alcohol for low to moderate consumption, and increased risk for higher exposure. For more than 3 drinks on average/day, in general women had higher risks than men, and the risks for mortality were higher compared to the risks for morbidity. These results indicate that heavy alcohol consumption increases the relative risk of any stroke while light or moderate alcohol consumption may be protective against ischemic stroke. Preventive measures that should be initiated are discussed.


Infection pattern and transmission potential of chikungunya virus in two New World laboratory-adapted Aedes aegypti strains.
Chikungunya virus (CHIKV) is an emerging mosquito-borne virus belonging to the Togaviridae, which is transmitted to humans by Aedes aegypti and Ae. albopictus. We describe the infection pattern of CHIKV in two New World Ae. aegypti strains, HWE and ORL. Both mosquito strains were susceptible to the virus but showed different infection patterns in midguts and salivary glands. Even though acquisition of a bloodmeal showed moderate levels of apoptosis in midgut tissue, there was no obvious additional CHIKV-induced apoptosis detectable during midgut infection. Analysis of expression of apoptosis-related genes suggested that CHIKV infection dampens rather than promotes apoptosis in the mosquito midgut. In both mosquito strains, the virus was present in saliva within two days post-oral infection. HWE and ORL mosquitoes exhibited no salivary gland infection barrier; however, only 60% (HWE) to 65% (ORL) of the females had released the virus in their saliva at one week post-oral acquisition, suggesting a salivary gland escape barrier. CHIKV induced an apoptotic response in salivary glands of HWE and ORL mosquitoes, demonstrating that the virus caused pathology in its natural vector.


Structure-Function Agreement Is Better Than Commonly Thought in Eyes With Early Glaucoma.
To assess the agreement between structural (optical coherence tomography [OCT]) and functional (visual field [VF]) glaucomatous damage with an automated method and deviation/probability maps, and to compare this method to a metric method. Wide-field spectral-domain OCT scans, including the disc and macula, and 24-2 and 10-2 VFs were obtained from 45 healthy control (H) eyes/individuals, and 53 eyes/patients with 24-2 mean deviation (MD) better than -6 dB diagnosed as "definite glaucoma" (DG) by experts. Abnormal structure-abnormal function (aS-aF) agreement was assessed with an automated topographic (T) method based upon VF pattern deviation and OCT probability maps. Results were compared to a metric (M) method optimized for accuracy, (abnormal 24-2 glaucoma hemifield test [GHT] or pattern standard deviation [PSD], or 10-2 PSD AND abnormal OCT [quadrant]). For the T-method, 47 (88.7%) of the 53 DG eyes showed aS-aF agreement, compared to 2 (4.5%) of the 45 H eyes. The aS-aF agreement for these two H eyes was easily identified as mistaken, and did not replicate on a subsequent test. Without the 10-2, the aS-aF agreement decreased from 47 to 34 (64.2%) of 53 DG eyes. For the M-method, 37 (69.8%) of the 53 DG eyes showed aS-aF agreement, while omitting the 10-2 VF resulted in agreement in only 33 (62.3%) eyes. There is good agreement between structural and functional damage, even in eyes with confirmed early glaucomatous damage, if both 24-2 and 10-2 VFs are obtained, and abnormal locations on the VFs are compared to abnormal regions seen on OCT macular and disc scans. This can be done in an objective, automated fashion. (ClinicalTrials.gov number, NCT02547740.).


Exploring candidate biological functions by Boolean Function Networks for Saccharomyces cerevisiae.
The great amount of gene expression data has brought a big challenge for the discovery of Gene Regulatory Network (GRN). For network reconstruction and the investigation of regulatory relations, it is desirable to ensure directness of links between genes on a map, infer their directionality and explore candidate biological functions from high-throughput transcriptomic data. To address these problems, we introduce a Boolean Function Network (BFN) model based on techniques of hidden Markov model (HMM), likelihood ratio test and Boolean logic functions. BFN consists of two consecutive tests to establish links between pairs of genes and check their directness. We evaluate the performance of BFN through the application to S. cerevisiae time course data. BFN produces regulatory relations which show consistency with succession of cell cycle phases. Furthermore, it also improves sensitivity and specificity when compared with alternative methods of genetic network reverse engineering. Moreover, we demonstrate that BFN can provide proper resolution for GO enrichment of gene sets. Finally, the Boolean functions discovered by BFN can provide useful insights for the identification of control mechanisms of regulatory processes, which is the special advantage of the proposed approach. In combination with low computational complexity, BFN can serve as an efficient screening tool to reconstruct genes relations on the whole genome level. In addition, the BFN approach is also feasible to a wide range of time course datasets.


A Chemical Strategy for the Degradation of the Main Protease of SARS-CoV-2 in Cells.
SARS-CoV-2 is the virus that causes the global pandemic of COVID-19. The main protease (Mpro) of SARS-CoV-2 is essential for viral infection and is one of the major therapeutic targets for COVID-19. Here, we report the design, synthesis, and biological characterization of a novel heterobifunctional small molecule that could effectively induce the degradation of SARS-CoV-2 Mpro and its drug-resistant mutants in HEK 293T cells, thus demonstrating a new alternative strategy for intervening with proteins important for this novel coronavirus.


Body piercing in England: a survey of piercing at sites other than earlobe.
To estimate the prevalence of body piercing, other than of earlobes, in the general adult population in England, and to describe the distribution of body piercing by age group, sex, social class, anatomical site, and who performed the piercings. To estimate the proportion of piercings that resulted in complications and the proportion of piercings that resulted in professional help being sought after the piercing. Cross sectional household survey. All regions of England 2005. 10,503 adults aged 16 and over identified with a two stage selection process: random selection of geographical areas and filling predefined quotas of individuals. Results weighted to reflect the national demographic profile of adults aged 16 and over. Estimates of the prevalence of body piercing overall and by age group, sex, and anatomical site. Estimates, in those aged 16-24, of the proportion of piercings associated with complications and the seeking of professional help. The prevalence of body piercing was 1049/10,503 (10%, 95% confidence interval 9.4% to 10.6%). Body piercing was more common in women than in men and in younger age groups. Nearly half the women aged 16-24 reported having had a piercing (305/659, 46.2%, 42.0% to 50.5%). Of the 754 piercings in those aged 16-24, complications were reported with 233 (31.0%, 26.8% to 35.5%); professional help was sought with 115 (15.2%, 11.8% to 19.5%); and hospital admission was required with seven (0.9%, 0.3% to 3.2%). Body piercing is common in adults in England, particularly in young women. Problems are common and the assistance of health services is often required. Though serious complications requiring admission to hospital seem uncommon, the popularity of the practice might place a substantial burden on health services.


Cross-linking of initiation factor IF3 to Escherichia coli 30S ribosomal subunit by trans-diamminedichloroplatinum(II): characterization of two cross-linking sites in 16S rRNA; a possible way of functioning for IF3.
The initiation factor IF3 is platinated with trans-diamminedichloroplatinum(II) and cross-linked to Escherichia coli 30S ribosomal subunit. Two cross-linking sites are unambiguously identified on the 16S rRNA: a major one, in the region 819-859 in the central domain, and a minor one, in the region 1506-1529 in the 3'-terminal domain. Specific features of these sequences together with their particular location within the 30S subunit lead us to postulate a role for IF3, that conciliates topographical and functional observations made so far.


Effect of sulforaphane on long-term storage of rabbit semen.
In this study, it was aimed to determine the effect of sulforaphane (SFN) on rabbit semen cryopreservation. Semen collected from animals was divided into 5 equal volumes as Control, SFN 5 µM, SFN 10 µM, SFN 25 µM and SFN 50 µM groups. Afterwards, semen analyzes were performed. According to our results, there was no statistical difference between the groups at 4°C. However after freezing thawing, the highest total motility, progressive motility and rapid spermatozoa rate was seen in the 10 µM SFN group, while the lowest was observed in the 50 µM SFN group (P<0.05). Static sperm ratio was highest in the 50 µM group, while the lowest was observed in the 10 µM SFN group. When flow cytometry results examined the rate of acrosomal damaged and dead sperm was the lowest in the 10 µM SFN group, a statistical difference was observed between the control group (P<0.05). The highest rate of sperm with high mitochondrial membrane potential was seen in the 5 µM SFN and 10 µM SFN groups. Apoptosis and ROS rates were found to be lower in the experimental groups compared to the control groups (P<0.05). As a result, SFN supplementation at a dose of 10 µM increased the quality of sperm in the freezing and thawing processes of rabbit semen. In conclusion, 10 µM SFN improved the quality of cryopreservation of rabbit semen.


MRI evidence of endolymphatic impermeability to the gadolinium molecule in the in vivo mouse inner ear at 9.4 tesla.
Previous in vivo experimental magnetic resonance imaging (MRI) investigations of the mammalian inner ear at 4.7 Tesla have indicated that intravenously injected gadolinium (Gd) penetrates the perilymphatic labyrinth, but not the endolymphatic membranous labyrinth. In the present study, high field MRI at 9.4T was used to visualize the in vivo mouse vestibulo-cochlea system, and to determine whether the endolymphatic system is permeable to a Gd complex. A 9.4 T Varian magnet equipped with a 12 cm inner diameter gradient system with maximum gradient strength of 600 mT/m, a millipede coil (Varian design) and a Gd contrast agent were used for image acquisition in the normal C57 BL-6 mouse. High-resolution 2D and 3D images of the mouse cochlea were acquired within 80 minutes following intravenous injection of Gd. Gd initially permeated the perilymphatic scala tympani and scala vestibuli, and permitted visualization of both cochlear turns from base to apex. The superior, inferior and lateral semicircular canals were subsequently visualized in 3 planes. The membranous endolymphatic labyrinth was impermeable to intravenously injected Gd, and thus showed no apparent uptake of Gd at 9.4T. The 9.4T field strength MRI permitted acquisition of high resolution images of anatomical and physiological features of the normal, wild type mouse perilymphatic inner ear in vivo, and provided further evidence that the endolymphatic system is impermeable to intravenously injected Gd.


IQGAP1 activates PLC-δ1 by direct binding and moving along microtubule with DLC-1 to cell surface.
Phospholipase C (PLC)-δ1, activated by p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1 (p122RhoGAP/DLC-1), contributes to the coronary spastic angina (CSA) pathogenesis. The present study aims to further investigate the p122RhoGAP/DLC-1 protein. We examined molecules assisting this protein and identified a scaffold protein-IQ motif-containing GTPase-activating protein 1 (IQGAP1). IQGAP1-C binds to the steroidogenic acute regulatory-related lipid transfer (START) domain of p122RhoGAP/DLC-1, and PLC-δ1 binds to IQGAP1-N, forming a complex. In fluorescence microscopy, small dots of PLC-δ1 created fine linear arrays like microtubules, and IQGAP1 and p122RhoGAP/DLC-1 were colocated in the cytoplasm with PLC-δ1. Ionomycin induced the raft recruitment of the PLC-δ1, IQGAP1, and p122RhoGAP/DLC-1 complex by translocation to the plasma membrane (PM), indicating the movement of this complex is along microtubules with the motor protein kinesin. Moreover, the IQGAP1 protein was elevated in skin fibroblasts obtained from patients with CSA, and it enhanced the PLC activity and peak intracellular calcium concentration in response to acetylcholine. IQGAP1, a novel stimulating protein, forms a complex with p122RhoGAP/DLC-1 and PLC-δ1 that moves along microtubules and enhances the PLC activity.


[Excessive osteoporosis screening in women under 65 years: a cross-sectional study].
Overuse of osteoporosis screening in women at low risk of fracture may lead to overdiagnosis, inappropriate treatment and medicalization. The objective of this work was to estimate the proportion of women aged 45 to 64 enrolled in a private health insurance plan in Buenos Aires undergoing hip dual-energy x-ray absorptiometry (DXA) in 2011 without meeting osteoporosis screening criteria. In this cross-sectional study, 4310 women of this age range that had undergone a hip DXA were identified. A randomly selected sub-group of 401 women was then assessed for the presence of risk factors for osteoporosis and complete data were retrieved for 178 women. Appropriate screening was defined by two criteria: 1) having a 10-year fracture risk higher than that of a 65-year old woman (estimated using the FRAX® tool); 2) having at least one risk factor for fracture. It was found that 86.5% of the women who underwent hip DXA did not exceed the minimum 10-year fracture risk threshold required for screening; 5.8% of them had osteoporosis and 61.0% osteopenia. According to the second criterion, 49.4% had no risk factors, 3.4% of these women had osteoporosis and 62.5% osteopenia. The results show that at least half the women screened did not meet osteoporosis screening criteria.


Use of physostigmine in tricyclic antidepressant poisoning.
The use of physotigmine in the treatment of tricyclic antidepressant overdose is discussed. The importance of continuous observation is emphasized and the method of preparation of physotigmine is outlined.


The Anatomy of the Facial Vein: Implications for Plastic, Reconstructive, and Aesthetic Procedures.
Anatomical knowledge of the facial vasculature is crucial for successful plastic, reconstructive, and minimally invasive procedures of the face. Whereas the majority of previous investigations focused on facial arteries, the precise course, variability, and relationship with adjacent structures of the facial vein have been widely neglected. Seventy-two fresh frozen human cephalic cadavers (32 male and 40 female cadavers; mean age, 75.2 ± 10.9 years; mean body mass index, 24.2 ± 6.6 kg/m; 99 percent Caucasian ethnicity) were investigated by means of layer-by-layer anatomical dissection. In addition, 10 cephalic specimens were investigated using contrast agent-enhanced computed tomographic imaging. The facial vein displayed a constant course in relation to the adjacent anatomical structures. The vein was identified posterior to the facial artery, anterior to the parotid duct, and deep to the zygomaticus major muscle. The angular vein formed the lateral boundary of the deep medial cheek fat and the premaxillary space, and the medial boundary of the deep lateral cheek fat and the sub-orbicularis oculi fat. The mean distance of the inferior and superior labial veins, of the deep facial vein, and of the angular vein from the inferior orbital margin was 51.6 ± 3.1, 42.6 ± 2.3, 27.4 ± 3.0, and 4.2 ± 0.7 mm, respectively. This work provides detailed information on the course of the facial vein in relation to neighboring structures. The presented clinically relevant anatomical observations and descriptions of landmarks will serve as helpful information for plastic, reconstructive, and aesthetic surgeons.


A Bayesian Vector Multidimensional Scaling Procedure Incorporating Dimension Reparameterization with Variable Selection.
We propose a two-way Bayesian vector spatial procedure incorporating dimension reparameterization with a variable selection option to determine the dimensionality and simultaneously identify the significant covariates that help interpret the derived dimensions in the joint space map. We discuss how we solve identifiability problems in a Bayesian context that are associated with the two-way vector spatial model, and demonstrate through a simulation study how our proposed model outperforms a popular benchmark model. In addition, an empirical application dealing with consumers' ratings of large sport utility vehicles is presented to illustrate the proposed methodology. We are able to obtain interpretable and managerially insightful results from our proposed model with variable selection in comparison with the benchmark model.


An Intrapancreatic accessory spleen presenting as a neuroendocrine tumor.
Although the second most common site of the accessory spleen is the tail of the pancreas, intrapancreatic accessory spleens (IPAS) are rarely recognized radiologically. When an accessory spleen is located in the pancreas, it may mimic a hypervascular pancreatic tumor. We report a case of intrapancreatic accessory spleen which radiologically (on TC) mimicked a neuroendocrine pancreatic tumor (PNET). It was not possible to be sure that the pancreatic nodule had no malignant potential; because of the close proximity to splenic vessel we performed en bloc resection of the spleen and distal pancreas. Postoperative course was uneventful. IPAS must be considered in the differential diagnosis of pancreatic tail tumors, particulary an asymptomatic small PNET; new and adequate diagnostic studies have demonstrated utility in defining these lesions. We review pertinent literature. KEY WORD: Intrapancreatic accessory spleen, Pancreatic neuroendocrine tumor.


Erectile dysfunction and its association with metabolic syndrome and endothelial function among patients with type 2 diabetes mellitus.
Evidence suggests that numerous comorbid conditions contribute to erectile dysfunction (ED) among patients with type 2 diabetes mellitus (T2DM). To review the relationship and mechanism between diabetes, metabolic syndrome, cardiovascular disease (CVD), and ED. A manual review of authoritative literature from peer-reviewed publications from January 2001 through July 2010 was performed. These publications were further mined to consider the impact of metabolic syndrome as a comorbid condition. Publications from key references were also consulted. The associations between obesity, dyslipidemia, metabolic syndrome, T2DM, CVD, and depression with sexual dysfunction suggest that sexual dysfunction, particularly ED, is a precursor to CVD. Because these conditions share important risk factors with CVD, identifying them and their relationships with the pathogenesis of ED is likely to be critical to the manner in which primary care physicians screen for and manage this condition. Primary care physicians ought to establish trusting relationships with their patients, providing opportunities for them to probe such sensitive issues as sexual activities, as a means of addressing the possibility of ED. When making the new diagnosis of sexual dysfunction in the absence of metabolic disease or CVD, physicians ought to consider the risk for T2DM and CVD. Associations between metabolic disease, heart disease, and sexual dysfunction further suggest that all patients who are obese and have dyslipidemia, T2DM, and/or depression should be further screened for ED.


Wild-type p53 is not sufficient for serum starvation-induced apoptosis in cancer cells but accelerates apoptosis in sensitive cells.
According to the conflicting growth signal model, cells that are driven to proliferate by certain oncogenes undergo apoptosis but not growth arrest upon withdrawal of growth factors. However, we found that the majority of human cancer cell lines continued to proliferate and did not undergo apoptosis following serum withdrawal. As an exeption, wild-type (wt) p53-expressing HCT116 human colon cancer cells underwent apoptosis within 24-36 h of serum deprivation. p53 degradation in human papilloma virus EG-expressing HCT116 cells led to enhanced survival that was not due to growth arrest. These results are consistent with a role for p53 in starvation-induced death in HCT116 cells. However, other cell lines did not undergo apoptosis despite their expression of wt p53. Thus, H460 cells (wt p53) were resistant to starvation-induced death but introduction of the adenovirus EIA oncoprotein induced p53 and also increased sensitivity to serum withdrawal. p53 was not stabilized by E1A and resistance to starvation-induced cell death was observed in E6-expressing H460 cells. These results suggest that although p53 contributes to starvation-induced apoptosis in sensitive (HCT116 and E1A-expressing H460) cancer cell lines, most cancer cells survived despite the presence of wt p53. We conclude that naturally selected human cancer cell lines suppress apoptosis due to conflicting growth signals.


Perceived depth scales with disparity gradient.
Perceived difference in depth between two adjacent stimuli decreases with increasing disparity gradient even if the disparity stays constant, ie when the stimuli approach each other along paths within fronto-parallel planes. This depth scaling effect is more pronounced with line stimuli than with two isolated points or two small symbols and is insignificant for easily discriminable symbols. The decrease in perceived depth is more pronounced for horizontal orientation than for oblique or vertical orientation. The ratio of perceived depth difference to displayed disparity difference also decreases when the distance between the stimuli increases at a constant gradient in depth. This is to say that we are more correct in our depth estimates for steep gradients in depth when the euclidean distance between the stimuli is short.


Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods.
Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte > MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.


Predictive modeling based on artificial neural networks for membrane fouling in a large pilot-scale anaerobic membrane bioreactor for treating real municipal wastewater.
Membrane fouling is the primary obstacle to applying anaerobic membrane bioreactors (AnMBRs) in municipal wastewater treatment. This issue holds critical significance as efficient wastewater treatment serves as a cornerstone for achieving environmental sustainability. This study uses machine learning to predict membrane fouling, taking advantage of rapid computational and algorithmic advances. Based on the 525-day operation data of a large pilot-scale AnMBR for treating real municipal wastewater, regression prediction was realized using multilayer perceptron (MLP) and long short-term memory (LSTM) artificial neural networks under substantial variations in operating conditions. The models involved employing the organic loading rate, suspended solids concentration, protein concentration in extracellular polymeric substance (EPSp), polysaccharide concentration in EPS (EPSc), reactor temperature, and flux as input features, and transmembrane pressure as the prediction target output. Hyperparameter optimization enhanced the regression prediction accuracies, and the rationality and utility of the MLP model for predicting large-scale AnMBR membrane fouling were confirmed at global and local levels of interpretability analysis. This work not only provides a methodological advance but also underscores the importance of merging environmental engineering with computational advancements to address pressing environmental challenges.


Dietary self-control influences top-down guidance of attention to food cues.
Motivational objects attract attention due to their rewarding properties, but less is known about the role that top-down cognitive processes play in the attention paid to motivationally relevant objects and how this is affected by relevant behavioral traits. Here we assess how thinking about food affects attentional guidance to food items and how this is modulated by traits relating to dietary self-control. Participants completed two tasks in which they were presented with an initial cue (food or non-food) to either hold in working memory (memory task) or to merely attend to (priming task). Holding food items in working memory strongly affected attention when the memorized cue re-appeared in the search display. Tendency towards disinhibited eating was associated with greater attention to food versus non-food pictures in both the priming and working memory tasks, consistent with greater attention to food cues per se. Successful dieters, defined as those high in dietary restraint and low in tendency to disinhibition, showed reduced attention to food when holding food-related information in working memory. These data suggest a strong top-down effect of thinking about food on attention to food items and indicate that the suppression of food items in working memory could be a marker of dieting success.


Ubiquitin C-Terminal Hydrolase L5 Plays an Essential Role in the Fly Innate Immune Defense against Bacterial Infection.
Drosophila ubiquitin carboxy-terminal hydrolase L5 (Uch-L5) functions as a critical component of the 26S proteasome to mediate degradation of polyubiquitinated proteins. It was recently shown to modulate tissue/organ development by targeting the Smoothened protein in the hedgehog pathway. However, whether it plays a role in controlling organismal immune response remains largely unknown. Reverse transcription plus quantitative polymerase chain reaction (RT-qPCR), dual-luciferase, and Western blot assays were used to explore the potential function of Uch-L5 in the innate immune regulation in cultured Drosophila S2 cells. Further genetic manipulations and bacterial infections were conducted to confirm the findings in vivo. Silencing of Uch-L5 antagonizes the immune deficiency (IMD) but not the Toll innate immune signaling both in vitro and in vivo. Moreover, Uch-L5 positively contributes to the Drosophila innate immune response via its N-terminal Uch domain, which is the catalytical triad executing its deubiquitinase activity. Our studies shed light on a novel function of the deubiquitinase Uch-L5 in governing the anti-microbial defense in Drosophila.