Effect of ankaferd blood stopper in experimental peritoneal adhesion model.
Ankaferd Blood Stopper (ABS) is an herbal extract attained from 5 different plants. It has the therapeutic potential to be used for the management of external hemorrhage and controlling gastrointestinal bleedings. To date, the safety of ABS for intraperitoneal usage is not clear. In this study, we investigated the effectiveness and safety of using intraperitoneal ABS in an experimental peritoneal adhesion model. Twenty-four male Wistar Albino rats were used in the study. The rats were randomly divided into 3 groups: saline, ABS, and control. On the 10th day, all rats were euthanized. The adhesions were evaluated by Nair's macroscopic adhesion classification, and pathologically evaluated with Zühlke's microscopic adhesion classification. macroscopic and microscopic comparison between the ABS and saline groups did not show any differences but both the ABS and saline groups were superior when compared to the control group. ABS was found equally effective with saline on the abdominal adhesions and to no effect on postoperative adhesion formation.


Schmallenberg virus challenge models in cattle: infectious serum or culture-grown virus?
Schmallenberg virus (SBV), discovered in Europe in 2011, causes mild transient disease in adult ruminants, but fetal infection can lead to severe malformation in cattle, sheep and goats.To elucidate the pathogenesis of this novel orthobunyavirus, considerable efforts are required. A reliable and standardized infection model is essential for in vivo studies. In the present study, two groups of four cattle were inoculated with either serum passaged in cattle only or cell culture-grown virus. The replication of culture-grown SBV in cattle was reduced compared to virus inoculated via infectious serum. In a second experiment, the infectious serum was titrated in calves; the tested batch contained 102.83 infectious doses per mL. Hence, serum-borne virus that was only passaged in the natural host is a suitable option for a standardized SBV infection model.


Review of national research ethics regulations and guidelines in Middle Eastern Arab countries.
Research ethics guidelines are essential for conducting medical research. Recently, numerous attempts have been made to establish national clinical research documents in the countries of the Middle East. This article analyzes these documents. Thirteen Arab countries in the Middle East were explored for available national codes, regulations, and guidelines concerning research ethics, and 10 documents from eight countries were found. We studied these documents, considering the ethical principles stated in the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) guidelines, and the International Conference of Harmonization-Guidelines for Good Clinical Practice (ICH-GCP). Our paper comprises a complete list of protections, such as confidentiality, informed consent, ethics committees, and others. This study found different levels and kinds of research ethics regulations and guidelines in the countries examined. Two groups can be distinguished: the countries in the first group have one or more research ethics regulations or guidelines, while the countries in the second group have not yet established any. Most of the documents showed various degrees of deficiencies in regard to ethical protection. The majority of the documents that were examined refer to one or more international documents on biomedical research ethics. Recently, a lot of efforts have been made in many countries in the Middle East. However, compared with international documents, most of the research ethics documents in use in this region demonstrate numerous deficiencies. As it relates to these documents, extensive differences could be observed in regard to development, structure, content, and reference to international guidelines.


Therapeutic drug monitoring in inflammatory bowel disease.
There are an expanding number of therapies available to treat pediatric inflammatory bowel disease (IBD). As pediatric gastroenterologists attempt to achieve complete intestinal mucosal healing for their patients, it has become more important to gain an understanding of how to maximize the efficacy of our medications while minimizing their toxicities. We aim to provide an overview of therapeutic drug monitoring in IBD with an emphasis on the biologic therapies (antitumor necrosis factor and anti-integrin monoclonal antibodies). Recent findings do support optimized drug dosing for infliximab based on early trough levels, but question the utility of checking these values in patients doing well in maintenance therapy. Patients with severe colonic inflammation may be at increased risk for needing optimization with dose escalation because of medication loss in the stool. Dose escalation can recapture response in some patients with a secondary loss of response, including those with low level antibody formation. The monitoring of nontrough drug levels to allow timelier dose adjustment as well as the role of drug monitoring with anti-integrin therapy are areas of active research. Therapeutic drug monitoring is an effective strategy in the management of pediatric IBD that can help patients achieve mucosal healing and aid the clinical decision-making of the pediatric gastroenterologist.


Potentiation of TRAP-6-induced platelet dense granule release by blockade of P2Y12 signaling with MRS2395.
The release of ADP from platelet dense granules and its binding to platelet P2Y12 receptors is key to amplifying the initial hemostatic response and propagating thrombus formation. P2Y12 has thus emerged as a therapeutic target to safely and effectively prevent secondary thrombotic events in patients with acute coronary syndrome or a history of myocardial infarction. Pharmacological inhibition of P2Y12 receptors represents a useful approach to better understand the signaling mediated by these receptors and to elucidate the role of these receptors in a multitude of platelet hemostatic and thrombotic responses. The present work examined and compared the effects of four different P2Y12 inhibitors (MRS2395, ticagrelor, PSB 0739, and AR-C 66096) on platelet function in a series of in vitro studies of platelet dense granule secretion and trafficking, calcium generation, and protein phosphorylation. Our results show that in platelets activated with the PAR-1 agonist TRAP-6 (thrombin receptor-activating peptide), inhibition of P2Y12 with the antagonist MRS2395, but not ticagrelor, PSB 0739 or AR-C 66096, potentiated human platelet dense granule trafficking to the plasma membrane and release into the extracellular space, cytosolic Ca2+ influx, and phosphorylation of GSK3β-Ser9 through a PKC-dependent pathway. These results suggest that inhibition of P2Y12 with MRS2395 may act in concert with PAR-1 signaling and result in the aberrant release of ADP by platelet dense granules, thus reducing or counteracting the anticipated anti-platelet efficacy of this inhibitor.


Progressive multifocal leukoencephalopathy and antipsoriatic drugs: assessing the risk of immunosuppressive treatments.
Progressive Multifocal Leukoencephalopathy (PML) is a rare and often fatal opportunistic demyelinating disorder secondary to central nervous system infection by the polyomavirus John Cunningham (JC), a common infecting agent in human populations, with 50-70% of healthy individuals having antibodies to the virus. Although human immunodeficiency virus (HIV) infection remains the most common predisposing factor for PML, which can occur also in association with hematologic malignant neoplasms or iatrogenic immunosuppression in the setting of organ transplantations, recently JC virus has been recognized as an important pathogen in patients with autoimmune and rheumatic diseases receiving immunosuppressive treatments. Following the availability of new biologic drugs, additional cases of PML have been reported in dermatologic patients as well. In particular, the occurrence of PML in psoriatic patients who had been taking efalizumab in the absence of any other concurrent immunosuppressive agents resulted in the decision of European Medicine Agency (EMEA) in February 2009 to recommend suspension of the marketing authorization for this drug in Europe. Some months later the manufacturer of the drug decided to voluntarily withdraw the product from the U.S. market. Since PML can occur as a potential side effect of different immunosuppressive drugs, including conventional treatments for psoriasis, and in consideration of the future development of new immunosuppressive biological agents, dermatologists need to become familiar with opportunistic infections including PML.


STAT6 signalling is important in CD8 T-cell activation and defence against Toxoplasma gondii infection in the brain.
Signal transducer and activator of transcription (STAT) 6 is a molecule involved in interleukin (IL)-4 and -13 signalling. We investigated the role of STAT6 signalling in Toxoplasma gondii-infected mice using STAT6-deficient (STAT6(-/-)) and wild-type (WT) mice. A significantly larger number of cysts were recovered from the brain in STAT6(-/-) than in WT mice on days 28 and 56 post-infection. CD8(+) T cells in cerebrospinal fluid and spleen stimulated with T. gondii antigen produced higher levels of interferon (IFN)-gamma in WT than in STAT6(-/-) mice. CD8(+) T-cell function, estimated by expression of CD25 and cytotoxic activity, was lower in STAT6(-/-) than in WT mice. Transfer of CD8(+) but not CD4(+) T cells, purified from infected WT mice, into STAT6(-/-) mice successfully prevented formation of cysts in the brain. However, transfer of naïve CD8(+) T cells from WT into STAT6(-/-) mice did not show either activation of CD8(+) T cells or a decrease in the number of cysts in the brain. Transfer of splenic adherent cells from WT into STAT6(-/-) mice induced activation of CD8(+) T cells and decreased the number of cysts in the brain. Expression of CD86 on splenic dendritic cells and IL-12 p40 production were weaker in STAT6(-/-) than in WT mice after T. gondii infection. These results indicate that STAT6 signalling is important in CD8(+) T-cell activation, possibly through regulation of antigen-presenting cells, which could suppress T. gondii infection in the brain.


Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop-signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age-matched healthy controls performed a stop-signal task that required responding with a button press to a right- or left-pointing black arrow (go-stimuli). In stop-trials, a red arrow (stop-stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go-trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition-related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error-related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS.


Measuring morphological features using light-scattering spectroscopy and Fourier-domain low-coherence interferometry.
We present measurements of morphological features in a thick turbid sample using light-scattering spectroscopy (LSS) and Fourier-domain low-coherence interferometry (fLCI) by processing with the dual-window (DW) method. A parallel frequency domain optical coherence tomography (OCT) system with a white-light source is used to image a two-layer phantom containing polystyrene beads of diameters 4.00 and 6.98 mum on the top and bottom layers, respectively. The DW method decomposes each OCT A-scan into a time-frequency distribution with simultaneously high spectral and spatial resolution. The spectral information from localized regions in the sample is used to determine scatterer structure. The results show that the two scatterer populations can be differentiated using LSS and fLCI.


The long-term effect of menopause on postmenopausal bone loss in Japanese women: results from a prospective study.
The aim of this study was to elucidate perimenopausal bone loss in relation to menstrual conditions and to investigate the long-term effect of menopause on bone loss in aged women. The rate of change in bone mineral density (BMD) was measured twice at an exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) at the lumbar spine in 176 pre- and postmenopausal healthy women 41-65 years of age. Serum follicle-stimulating hormone, intact and N-fragment osteocalcin (OC), three types of vitamin D3, parathyroid hormone (PTH), and calcitonin were also determined. Women who exercised regularly or had anatomical changes at the lumbar spine were excluded from this study. The subjects were divided into eight groups based on their menstrual status and years since menopause. Annual bone loss at the lumbar spine of premenopausal women with regular menstruation was -0.2+/-1.9% (95% confidence interval, -0.9 approximately -0.4%) and was not statistically different from zero, while that of women with irregular menstruation or at menopausal transition was -2.1+/-3.4% (-3.4 approximately -0.8%), and -3.3+/-2.3% (-5.2 approximately -0.3%), respectively, and was significantly different from zero. Serum OC levels of women at menopausal transition were significantly higher than those of women with regular menstruation, suggesting that bone loss had commenced in these women. The rate of annual change in BMD of women who were menopausal for 1-3, 4-6, 10-12, and more than 13 years was -3.1+/-4.0% (-4.7 approximately -1.5%), -1.2+/-2.6% (-2.2 approximately -0.2%), -1.0+/-3.0% (-2.3 approximately -0.3%), and -2.3+/-2.1% (-3.7 approximately -1.0%), respectively, and was significantly less than zero. But the annual bone loss of women who were menopausal for 7-9 years was -1.5+/-2.6% (-3.0 approximately -0.1%) and was not statistically significant from zero. These results indicate that postmenopausal women lose BMD in two phases. The early bone loss is rapid and commences during irregular menstruation, then is attenuated within 6 years after the onset of menopause. The second bone loss commences after the attenuation of the first bone loss. Among bone metabolic hormones, intact PTH alone showed an age-related increase and was suggested as being a causal factor of bone loss in women who were menopausal for 13 years or more.


Magnetic resonance metabolomics of intact tissue: a biotechnological tool in cancer diagnostics and treatment evaluation.
Personalized medicine is increasingly important in cancer treatment for its role in staging and its potential to improve stratification of patients. Different types of molecules, genes, proteins, and metabolites are being extensively explored as potential biomarkers. This review discusses the major findings and potential of tissue metabolites determined by high-resolution magic angle spinning magnetic resonance spectroscopy for cancer detection, characterization, and treatment monitoring.


Progress and prospects for accelerating materials science with automated and autonomous workflows.
Accelerating materials research by integrating automation with artificial intelligence is increasingly recognized as a grand scientific challenge to discover and develop materials for emerging and future technologies. While the solid state materials science community has demonstrated a broad range of high throughput methods and effectively leveraged computational techniques to accelerate individual research tasks, revolutionary acceleration of materials discovery has yet to be fully realized. This perspective review presents a framework and ontology to outline a materials experiment lifecycle and visualize materials discovery workflows, providing a context for mapping the realized levels of automation and the next generation of autonomous loops in terms of scientific and automation complexity. Expanding autonomous loops to encompass larger portions of complex workflows will require integration of a range of experimental techniques as well as automation of expert decisions, including subtle reasoning about data quality, responses to unexpected data, and model design. Recent demonstrations of workflows that integrate multiple techniques and include autonomous loops, combined with emerging advancements in artificial intelligence and high throughput experimentation, signal the imminence of a revolution in materials discovery.


Association of BMP4 polymorphisms with isolated tooth agenesis in a Chinese Han population: a case-control study.
Tooth agenesis is a common craniofacial anomaly in human beings. Mounting evidence has demonstrated that the bone morphogenetic protein 4 gene (BMP4) plays an important role in tooth development. This case-control study was designed to evaluate the association of the polymorphism rs17563 in BMP4 gene with susceptibility of isolated human tooth agenesis in a Chinese Han population. 335 tooth agenesis cases and 444 healthy controls were included in this study. Although no significant association was observed either in the overall or stratified analysis between the types and the severity of missing teeth. However, significant difference was observed between the anterior and posterior tooth agenesis (APTA) cases and the controls (p = 0.018 for allele distribution and OR = 0.39, 95% CI = 0.15-0.99). Furthermore, the heterozygote (TC) and dominant model (CC+TC) were associated with decreased risk of APTA compared with the control (phet = 0.018, ORhet = 0.39, 95% CIhet = 0.15-0.99 and pdom = 0.042, ORdom = 0.34, 95% CIdom = 0.13-0.87, respectively). These results indicated that rs17563 in BMP4 gene was potentially associated with APTA in Chinese Han population and further independent studies are required to verify these findings.


Colony-level effects of imidacloprid in subterranean termites (Isoptera: Rhinotermitidae).
We determined the impact of imidacloprid (Premise) on colonies of Reticulitermes spp. (Isoptera: Rhinotermitidae) through soil applications in the field. We selected 11 houses in the Raleigh, NC, area with active termite infestations. In-ground monitoring stations (mean = 75.9 stations) were installed around each house, and samples of termites visiting the monitors, in mud tubes, as well as samples from wood debris in the yard, were collected monthly for up to 14 mo to determine the numbers and locations of colonies present before treatment. We used microsatellite genetic markers to identify individual colonies present on each property. All houses were treated with Premise 75 WSP by using an exterior perimeter/interior spot treatment. After treatment, termite samples were collected monthly for 3 mo and then quarterly for 2 yr to track the fate of colonies. Of the 12 treated colonies (those attacking structures), 75% disappeared within 90 d and were not detected again. In contrast, only 25% of 48 untreated colonies (located 2 m or further from the treatment zone) and 40% of the six likely treated colonies (located within 0.5 m of the treatment zone but not known to be attacking the structure) were not detected again during the study. Our findings are consistent with strong colony-level effects of soil treatments with imidacloprid, resulting in the suppression or elimination of Reticulitermes spp. colonies in many cases.


Exponential adoption of battery electric cars.
The adoption of battery electric vehicles (BEVs) may significantly reduce greenhouse gas emissions caused by road transport. However, there is wide disagreement as to how soon battery electric vehicles will play a major role in overall transportation. Focusing on battery electric passenger cars, we analyze BEV adoption across 17 individual countries, Europe, and the World, and consistently find exponential growth trends. Modeling-based estimates of future adoption given past trends suggest system-wide adoption substantially faster than typical economic analyses have proposed so far. For instance, we estimate the majority of passenger cars in Europe to be electric by about 2031. Within regions, the predicted times of mass adoption are largely insensitive to model details. Despite significant differences in current electric fleet sizes across regions, their growth rates consistently indicate fast doubling times of approximately 15 months, hinting at radical economic and infrastructural consequences in the near future.


Evidence for 15-HETE synthesis by human umbilical vein endothelial cells.
Incubation of cultured human umbilical vein endothelial cells with [1-14C]-arachidonic acid, followed by RP-HPLC analysis, resulted in the appearance of two principal radioactive products besides 6-keto-PGF1 alpha. The first peak was HHT, a hydrolysis product of the prostaglandin endoperoxide. The second peak was esterified, converted to the trimethylsilyl ether derivative, and analyzed by GC/MS and was shown to be the lipoxygenase product 15-HETE. Stimulation of endothelial cells with thrombin enhanced 15-HETE synthesis from arachidonate. Subsequent experiments showed that 5-HETE and 12-HETE were also synthesized by endothelial cells, but no evidence of leukotriene synthesis was found. Incubation of the 15-HETE precursor 15-HPETE with endothelial cells resulted in the formation of four distinct ultraviolet light-absorbing peaks. Ultraviolet and GC/MS analysis showed these peaks to be 8,15-diHETEs that differed only in their hydroxyl configuration and cis-trans double-bond geometry. Formation of 8,15-diHETE molecules suggests the prior formation of the unstable epoxide molecule 14,15-LTA4 or an attack at C-10 of 15-HPETE by an enzyme with mechanistic features in common with a 12-lipoxygenase. The observation that endothelial cells can synthesize both 15-HETE and 8,15-diHETE molecules suggest that this cell type contains both a 15-lipoxygenase and a system that can synthesize 14,15-LTA4.


Prediction of Blood Lipid Phenotypes Using Obesity-Related Genetic Polymorphisms and Lifestyle Data in Subjects with Excessive Body Weight.
Individual lipid phenotypes including circulating total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) determinations are influenced by gene-environment interactions. The aim of this study was to predict blood lipid level (TC, LDL-c, HDL-c, and TG) variability using genetic and lifestyle data in subjects with excessive body weight-for-height. This cross-sectional study enrolled 304 unrelated overweight/obese adults of self-reported European ancestry. A total of 95 single nucleotide polymorphisms (SNPs) related to obesity and weight loss were analyzed by a targeted next-generation sequencing system. Relevant genotypes of each SNP were coded as 0 (nonrisk) and 1 (risk). Four genetic risk scores (GRS) for each lipid phenotype were calculated by adding the risk genotypes. Information concerning lifestyle (diet, physical activity, alcohol drinking, and smoking) was obtained using validated questionnaires. Total body fat (TFAT) and visceral fat (VFAT) were determined by dual-energy X-ray absorptiometry. Overall, 45 obesity-related genetic variants were associated with some of the studied blood lipids. In addition to conventional factors (age, sex, dietary intakes, and alcohol consumption), the calculated GRS significantly contributed to explain their corresponding plasma lipid trait. Thus, HDL-c, TG, TC, and LDL-c serum concentrations were predicted by approximately 28% (optimism-corrected adj. R 2 = 0.28), 25% (optimism-corrected adj. R 2 = 0.25), 24% (optimism-corrected adj. R 2 = 0.24), and 21% (optimism-corrected adj. R 2=0.21), respectively. Interestingly, GRS were the greatest contributors to TC (squared partial correlation (PC2) = 0.18) and LDL-c (PC2 = 0.18) features. Likewise, VFAT and GRS had a higher impact on HDL-c (PC2 = 0.09 and PC2 = 0.06, respectively) and TG levels (PC2 = 0.20 and PC2 = 0.07, respectively) than the rest of variables. Besides known lifestyle influences, some obesity-related genetic variants could help to predict blood lipid phenotypes.


CdSe/CdS/ZnS double shell nanorods with high photoluminescence efficiency and their exploitation as biolabeling probes.
We report the synthesis, the structural and optical characterization of CdSe/CdS/ZnS "double shell" nanorods and their exploitation in cell labeling experiments. To synthesize such nanorods, first "dot-in-a-rod" CdSe(dot)/CdS(rod) core/shell nanocrystals were prepared. Then a ZnS shell was grown epitaxially over these CdSe/CdS nanorods, which led to a fluorescence quantum yield of the final core-shell-shell nanorods that could be as high as 75%. The quantum efficiency was correlated with the aspect ratio of the nanorods and with the thickness of the ZnS shell around the starting CdSe/CdS rods, which varied from 1 to 4 monolayers (as supported by a combination of X-ray diffraction, elemental analysis with inductively coupled plasma atomic emission spectroscopy and high resolution transmission electron microscopy analysis). Pump-probe and time-resolved photoluminescence measurements confirmed the reduction of trapping at CdS surface due to the presence of the ZnS shell, which resulted in more efficient photoluminescence. These double shell nanorods have potential applications as fluorescent biological labels, as we found that they are brighter in cell imaging as compared to the starting CdSe/CdS nanorods and to the CdSe/ZnS quantum dots, therefore a lower amount of material is required to label the cells. Concerning their cytotoxicity, according to the MTT assay, the double shell nanorods were less toxic than the starting core/shell nanorods and than the CdSe/ZnS quantum dots, although the latter still exhibited a lower intracellular toxicity than both nanorod samples.


Ephemeral disturbances have long-lasting impacts on forest invasion dynamics.
Ephemeral disturbances are common in many systems. Often, these brief events are assumed to be a nuisance with little long-term ecological impact. We quantified the impact of the ephemeral forest disturbance caused by gypsy moth canopy defoliation on exotic plant invasion in eight hardwood forests in the Delaware Water Gap National Recreation Area, USA. Six years following the gypsy moth disturbance, we were able to predict 59% of the increase in Alliaria petiolata abundance and 42% of the increase in Microstegium vimineum abundance with models incorporating an interaction between disturbance severity and propagule pressure. In addition, we found that the disturbance timing had substantial impacts on the invasion dynamics of Alliaria petiolata. Our results suggest that ephemeral disturbances can have important and long-lasting impacts on plant communities, and highlight the need to account for variations in disturbance characteristics and the role of propagule pressure in determining the disturbance-invasion relationship.


Evolution of phosphorus-thioether ligands for asymmetric catalysis.
In the early 1990s chiral P-thiother ligands emerged as promising ligands in the field of asymmetric catalysis, with the development of many P-thioether ligand families. However, only a few of them have shown a broad reaction and substrate scope. So, compared with other heterodonor ligands such as the widely studied P-N ligands, their impact in asymmetric catalysis was not realised until recently. This has been mainly attributed to the difficulty of controlling the configuration at the sulfur atom when coordinated to the metal. More recently, it has been found that this problem could be solved by a rigorous choice of the ligand scaffold, a process usually aided by mechanistic studies. This allowed the recent discovery of new P-thioether ligand families with a broader versatility, both in reactions and in substrate/reagent scope. This feature article aims to highlight those new P-thioether ligand libraries and the relationship between the structure and catalytic performance.


PAC1 gene knockout reveals an essential role of chaperone-mediated 20S proteasome biogenesis and latent 20S proteasomes in cellular homeostasis.
The 26S proteasome, a central enzyme for ubiquitin-dependent proteolysis, is a highly complex structure comprising 33 distinct subunits. Recent studies have revealed multiple dedicated chaperones involved in proteasome assembly both in yeast and in mammals. However, none of these chaperones is essential for yeast viability. PAC1 is a mammalian proteasome assembly chaperone that plays a role in the initial assembly of the 20S proteasome, the catalytic core of the 26S proteasome, but does not cause a complete loss of the 20S proteasome when knocked down. Thus, both chaperone-dependent and -independent assembly pathways exist in cells, but the contribution of the chaperone-dependent pathway remains unclear. To elucidate its biological significance in mammals, we generated PAC1 conditional knockout mice. PAC1-null mice exhibited early embryonic lethality, demonstrating that PAC1 is essential for mammalian development, especially for explosive cell proliferation. In quiescent adult hepatocytes, PAC1 is responsible for producing the majority of the 20S proteasome. PAC1-deficient hepatocytes contained normal amounts of the 26S proteasome, but they completely lost the free latent 20S proteasome. They also accumulated ubiquitinated proteins and exhibited premature senescence. Our results demonstrate the importance of the PAC1-dependent assembly pathway and of the latent 20S proteasomes for maintaining cellular integrity.


Biomechanics of the hip joint and the effects of fracture of the acetabulum.
The biomechanical analysis of the normal and arthritic hip joint have been the subject of numerous publications in orthopaedics. Biomechanical investigations focusing on the effect of fractures of the acetabulum on the alteration of hip joint mechanics have been a recent development. This paper outlines currently available methodologies for simulating load across the hip, and as measuring articular contact and contact stresses. Results of investigations of posterior wall fractures and transverse fractures of the acetabulum are presented. Directions for future research in the area of mechanical investigations of acetabular fractures are discussed.


Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.
Plasmablastic lymphoma is an aggressive neoplasm that shares many cytomorphologic and immunophenotypic features with plasmablastic plasma cell myeloma. However, plasmablastic lymphoma is listed in the World Health Organization (WHO) classification as a variant of diffuse large B-cell lymphoma. To characterize the relationship between plasmablastic lymphoma and plasmablastic plasma cell myeloma, we performed immunohistochemistry using a large panel of B-cell and plasma cell markers on nine cases of plasmablastic lymphoma and seven cases of plasmablastic plasma cell myeloma with and without HIV/AIDS. The expression profiles of the tumor suppressor genes p53, p16, and p27, and the presence of Epstein-Barr virus (EBV) and human herpes virus type 8 (HHV-8) were also analyzed. All cases of plasmablastic lymphoma and plasmablastic plasma cell myeloma were positive for MUM1/IRF4, CD138, and CD38, and negative for CD20, corresponding to a plasma cell immunophenotype. PAX-5 and BCL-6 were weakly positive in 2/9 and 1/5 plasmablastic lymphomas, and negative in all plasmablastic plasma cell myelomas. Three markers that are often aberrantly expressed in cases of plasma cell myelomas, CD56, CD4 and CD10, were positive in 5/9, 2/5, and 6/9 plasmablastic lymphomas, and in 3/7, 1/5, and 2/7 plasmablastic plasma cell myelomas. A high Ki-67 proliferation index, overexpression of p53, and loss of expression of p16 and p27 were present in both tumors. No evidence of HHV-8 infection was detected in either neoplasm. The only significant difference between plasmablastic lymphoma and plasma cell myeloma was the presence of EBV-encoded RNA, which was positive in all plasmablastic lymphoma cases tested and negative in all plasma cell myelomas. In conclusion, most cases of AIDS-related plasmablastic lymphoma have an immunophenotype and tumor suppressor gene expression profile virtually identical to plasmablastic plasma cell myeloma, and unlike diffuse large B-cell lymphoma. These results do not support the suggestion in the WHO classification that plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma.


The neuromodulative role of earthing.
Neuromodulation is a process of inhibition, stimulation, modification and regulation or therapeutic alteration of activity, electrically and chemically in the peripheral, central or autonomic nervous systems. Direct electric current or electric field alternates the function of nervous system. Coupling the human organism with the Earth directly or via a wire conductor changes the electric potential not only on the surface of the body but also inside it, changing the potential of electric environment of the human organism. Earthing refers to a direct contact with the Earth with bare feet or contact with the Earth with the use of conductive wire attached to the human body during sleeping, or daily activities. During earthing this electric potential equals to electric potential of the Earth and the value of it depends on location, time, atmospheric conditions, moisture of the surface of the Earth. The earthing which changes the density of negative charge in electric environment of the human body influences physiological processes. Our medical hypothesis states that contact with the Earth (earthing) directly or via a conductive wire plays role as a neuromodulative factor, probably primary, which enables the nervous system to be better adapted to the demands of organism and ambient environment. It helps to restore natural, electrical status of the electrical environment of the organism and thus the nervous system. Earthing generates immediate changes in electroencephalography (EEG), surface electromyography (SEMG), and somato-sensory evoked potentials (SSEPs). We hypothesize that earthing through its complex action on bioelectrical environment of human organism and alternations in electrolyte concentrations regulates correct functioning of the nervous system. Earthing significantly influences on the electrical activity of the brain.


Weight lifting training and left ventricular function in adolescent subjects.
Training during adolescence may influence the myocardium's adaptation. Effects of exercise training on left ventricular function differ depending whether they result from pressure or volume overload. Accordingly, the present study was designed to examine, by echocardiography studies, the effects of endurance versus weight lifting training modes on left ventricular contractility in healthy adolescent boys. Sixty healthy adolescent boys were randomly and evenly divided into 3 groups: weightlifting training, run-training, and control. Exercising groups underwent 28-week training programs, 3-4 times a week, 35 min each session. The weight lifting program for consisted of training on 6 dynamic resistive machines at resistance corresponding to 6-repetition maximum. The running program was composed of aerobic exercise training at 65% of their VO(2max). At rest, only in the runners end diastolic volume and end systolic pressure-volume ratio differed significantly (P<0.05) from pre- to post-testing. During post-testing session at peak exercise, runners compared to weightlifters demonstrated improvement respectively in: wall stress (245+/-42 and 290+/-35 103 dyn.cm(2)), end systolic pressure-volume ratio (7.2+/-.7 and 6.4+/-.5 ratio) and ejection fraction (82+/-5% and 76+/-5%). Maximal oxygen uptake (48.2+/-3.2 and 43.8+/-3.5 mL.kg(-1).min(-1)), also improved significantly (P<0.05). Maximal load was significantly (P<0.05) higher in the runners and weight lifters than in the control group with significantly (P<0.05) higher values for the weight lifters than runners. This study has showed that in adolescent boys the mode of exercise training leads to significant differences in left ventricular function and contractility, related to differences in volume-after-load relationship and not to fundamental differences in the properties of the myocardium.


Behavioral and Neural Plasticity of Ocular Motor Control: Changes in Performance and fMRI Activity Following Antisaccade Training.
The antisaccade task provides a model paradigm that sets the inhibition of a reflexively driven behavior against the volitional control of a goal-directed behavior. The stability and adaptability of antisaccade performance was investigated in 23 neurologically healthy individuals. Behavior and brain function were measured using functional magnetic resonance imaging (fMRI) prior to and immediately following 2 weeks of daily antisaccade training. Participants performed antisaccade trials faster with no change in directional error rate following 2 weeks of training; however this increased speed came at the cost of the spatial accuracy of the saccade (gain) which became more hypometric following training. Training on the antisaccade task resulted in increases in fMRI activity in the fronto-basal ganglia-parietal-cerebellar ocular motor network. Following training, antisaccade latency was positively associated with fMRI activity in the frontal and supplementary eye fields, anterior cingulate and intraparietal sulcus; antisaccade gain was negatively associated with fMRI activity in supplementary eye fields, anterior cingulate, intraparietal sulcus, and cerebellar vermis. In sum, the results suggest that following training, larger antisaccade latency is associated with larger activity in fronto-parietal-cerebellar ocular motor regions, and smaller antisaccade gain is associated with larger activity in fronto-parietal ocular motor regions.


Flexibility in weight management.
The purpose of the study was to investigate the relationships between changes in flexible vs. rigid restraints of eating during weight management, as well as how changes in the cognitive restraint of eating were related to psychological well-being and flexibility. The data includes information on 49 overweight persons who participated in a weight loss and maintenance (WLM) intervention and a follow-up assessment after 8-9 months. An increase in flexible cognitive restraint during the weight loss intervention was related to better weight loss maintenance and well-being. The more flexible restraint increased during the WLM intervention, the more psychological distress decreased. Moreover, larger reduction of rigid restraint during the follow-up period (between the WLM intervention and the follow-up assessment) was related to a better maintenance of improved psychological well-being at the follow-up endpoint. These results suggest that increasing flexible control while reducing rigid control of eating after an active weight loss phase improves success in weight management and the psychological well-being of weight losers.


Can Heterocyclic γ-Peptides Provide Polyfunctional Platforms for Synthetic Glycocluster Construction?
Sugars play key roles in many molecular and cellular communication processes involving a family of proteins named lectins. The low affinity associated with sugar recognition is generally counterbalanced by the multivalent nature of the interaction. While many polyglycosylated architectures have been described, only a few studies focused on the impact of topology variations of the multivalent structures on the interaction with lectin proteins. One major interest of our group concerns the design of new highly predictable and stable molecular pseudo-peptide architectures for therapeutic applications. In such a context, we described a class of constrained heterocyclic γ-amino acids built around a thiazole ring, named ATCs. ATC oligomers are helical molecules resulting from the formation of a highly stable C9 hydrogen-bonding pattern. Following our program, we herein address the potential of ATC oligomers as tunable scaffolds for the development of original multivalent glycoclusters.


Analysis of multi-stage treatments for recurrent diseases.
Patients with a non-curable disease such as many types of cancer usually go through the process of initial treatment, a various number of disease recurrences and salvage treatments, and eventually death. The analysis of the effects of initial and salvage treatments on overall survival is not trivial. One may try to use disease recurrences and salvage treatments as time-dependent covariates in a Cox proportional hazards model. However, because disease recurrence is an intermediate outcome between initial treatment and final survival, the interpretation of such an estimation result is awkward. It does not estimate the causal effects of treatments on overall survival. Nevertheless, such causal effect estimates are critical for treatment decision making. Our approach to address this issue is that, at any treatment stage, for each patient, we compute a potential survival time if he or she would receive the optimal subsequent treatments, and use this potential survival time to do comparison between current-stage treatment groups. This potential survival time is assumed to follow an accelerated failure time model at each treatment stage and calculated by backward induction, starting from the last stage of treatment. By doing that, the effects on survival of different treatments at each stage can be consistently estimated and fairly compared. Under suitable conditions, these estimated effects have a causal interpretation. We evaluated the proposed model and estimation method by simulation studies and illustrated using the motivating, real data set that describes initial and salvage treatments for patients with soft tissue sarcoma.


Revealing novel telomere proteins using in vivo cross-linking, tandem affinity purification, and label-free quantitative LC-FTICR-MS.
Telomeres are DNA-protein structures that protect chromosome ends from the actions of the DNA repair machinery. When telomeric integrity is compromised, genomic instability ensues. Considerable effort has focused on identification of telomere-binding proteins and elucidation of their functions. To date, protein identification has relied on classical immunoprecipitation and mass spectrometric approaches, primarily under conditions that favor isolation of proteins with strong or long lived interactions that are present at sufficient quantities to visualize by SDS-PAGE. To facilitate identification of low abundance and transiently associated telomere-binding proteins, we developed a novel approach that combines in vivo protein-protein cross-linking, tandem affinity purification, and stringent sequential endoprotease digestion. Peptides were identified by label-free comparative nano-LC-FTICR-MS. Here, we expressed an epitope-tagged telomere-binding protein and utilized a modified chromatin immunoprecipitation approach to cross-link associated proteins. The resulting immunoprecipitant contained telomeric DNA, establishing that this approach captures bona fide telomere binding complexes. To identify proteins present in the immunocaptured complexes, samples were reduced, alkylated, and digested with sequential endoprotease treatment. The resulting peptides were purified using a microscale porous graphite stationary phase and analyzed using nano-LC-FTICR-MS. Proteins enriched in cells expressing HA-FLAG-TIN2 were identified by label-free quantitative analysis of the FTICR mass spectra from different samples and ion trap tandem mass spectrometry followed by database searching. We identified all of the proteins that constitute the telomeric shelterin complex, thus validating the robustness of this approach. We also identified 62 novel telomere-binding proteins. These results demonstrate that DNA-bound protein complexes, including those present at low molar ratios, can be identified by this approach. The success of this approach will allow us to create a more complete understanding of telomere maintenance and have broad applicability.


Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy.
Infections caused by influenza virus lead to an excess rate of hospitalization of children during winter months. Current recommendations for vaccination target only children >6 months who belong to specific risk groups. To identify possible benefits of universal influenza vaccination, this study aims to determine characteristics of children hospitalized at the Montreal Children's Hospital (MCH) because of an infection attributable to influenza virus as well as risk factors associated with hospitalization. We retrospectively reviewed records of all children with a laboratory-proven diagnosis of influenza seen at MCH between April 1, 1999, and April 1, 2002. Data were analyzed using the Student t test and logistic regression. We identified 182 patients hospitalized because of influenza and 114 patients who were not. Admission diagnoses were suspected sepsis (31%), lower respiratory tract infections (27%), and asthma or bronchiolitis (15%). Mean age of hospitalized patients was 26.1 month (median: 12 months), which was similar to that of patients not hospitalized, and 34% were <6 months. Seventy percent of those hospitalized did not have any underlying medical disorder and only 18% (33) were vaccine candidates according to current recommendations. Of the latter, less than half had been vaccinated. Factors associated with hospitalization were age <12 months (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.1-4.8), male gender (OR: 1.9; 95% CI: 1.0-3.7), dehydration (OR: 4.3; 95% CI: 1.2-16.0), and decreased oxygen saturation (OR: 32.1; 95% CI: 4.1-249). Considering that the majority of children hospitalized for influenza do not belong to the specific risk groups targeted by current recommendations, and that one third are <6 months of age, the target population for vaccination needs to be reexamined. Extending vaccination to all young children, to additional high-risk groups, and to pregnant women has potential to reduce the impact of influenza on children.


CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.
Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. The associations between CHRNA5-CHRNA3-CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p = .0025), more cigarettes smoked (p = .0057), and higher scores on the FTND (p =.0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p = .0026) and on FTND score (p = .0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target.


The (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) colorimetric assay for the quantitation of Actinobacillus pleuropneumoniae cytotoxin.
Using swine neutrophils as target cells, two MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) colorimetric assay systems, one with and one without phorbol 12-myristate 13-acetate (PMA) stimulation were established for the quantitation of Actinobacillus pleuropneumoniae cytotoxin. The MTT assays were optimized for the number of neutrophils, incubation time, and PMA concentration by a series of experiments. The optimal conditions were 25 x 10(4) cells/well incubated for four hours for the assay system without PMA stimulation, and 12.5 x 10(4) cells/well incubated for two hours for the assay system with PMA stimulation. One culture supernatant of a toxigenic Pasteurella multocida strain and five A. pleuropneumoniae cytotoxin preparations produced from three A. pleuropneumoniae strains were used to test assay reproducibility. Results showed both assays were reproducible with a coefficient of variation ranging from 7.8 to 18% for the assay system without PMA stimulation and from 10.7 to 18.2% for the assay system with PMA stimulation. The PMA-stimulated assay had 40 to 60-fold higher sensitivity than the nonstimulated MTT assay. The MTT assay also was applied to the measurement of neutralizing antibody titers against A. pleuropneumoniae cytotoxin.


Unlocking the passivation nature of the cathode-air interfacial reactions in lithium ion batteries.
It is classically well perceived that cathode-air interfacial reactions, often instantaneous and thermodynamic non-equilibrium, will lead to the formation of interfacial layers, which subsequently, often vitally, control the behaviour and performance of batteries. However, understanding of the nature of cathode-air interfacial reactions remain elusive. Here, using atomic-resolution, time-resolved in-situ environmental transmission electron microscopy and atomistic simulation, we reveal that the cathode-water interfacial reactions can lead to the surface passivation, where the resultant conformal LiOH layers present a critical thickness beyond which the otherwise sustained interfacial reactions are arrested. We rationalize that the passivation behavior is dictated by the Li+-water interaction driven Li-ion de-intercalation, rather than a direct cathode-gas chemical reaction. Further, we show that a thin disordered rocksalt layer formed on the cathode surface can effectively mitigate the surface degradation by suppressing chemical delithiation. The established passivation paradigm opens new venues for the development of novel high-energy and high-stability cathodes.


Personality profile of child synaesthetes.
Previous research into personality and synaesthesia has focused on adult populations and yielded mixed results. One particular challenge has been to distinguish traits associated with synaesthesia, from traits associated with the ways in which synaesthetes were recruited. In the current study we addressed recruitment issues by testing randomly sampled synaesthetes, and we looked particularly at synaesthesia in childhood. Our child synaesthetes were identified by a screening program across 22 primary schools in the South East of England (n = 3387; children aged 6 to 10 years old). This identified two types of synaesthete (grapheme-colour synaesthesia and sequence-personality synaesthesia), and we tested their personalities using both child-report and parent-report measures. We found strong support for synaesthesia being associated with high Openness to Experience, a personality trait linked to intelligence and creativity. Both synaesthesia subtypes showed this feature, supporting previous research in adults (1-3). We additionally found low Extraversion in grapheme-colour synaesthetes and high Conscientiousness in sequence-personality synaesthetes. We discuss our results with reference to earlier recruitment issues, and as to how perceptual differences such as synaesthesia might link to trait-differences in personality.


Making the most of a Morbidity and Mortality meeting.
Morbidity and Mortality meetings (M&Ms) are a fundamental element of surgical practice. However, there has been little investigation into best practices, to maximise education and improvement outcomes. Create a new, evidence-based M&M methodology, that facilitates standardised analysis of errors in a non-judgemental fashion, and highlights areas for improvement. A Quality Improvement (QI) methodology was used. This project encompassed a literature review and two sequential QI cycles. A literature review and initial survey highlighted best practice and identified areas for improvement. From this information, a new standardised format was created, which centred around a new modified Fishbone framework, incorporating the London Protocol methodology. The project then sequentially tested new formats, with feedback collected for every new format. The literature review and surveys guided improvement of the M&M. The need for standardisation was highlighted. The new PowerPoint template and modified Fishbone ensured presentations and analysis were consistent and systematic. Participants reported that M&Ms were more engaging, interactive and structured, ensuring improved discussion of errors. The modified Fishbone framework reinforced a blame-free, system-focused analysis. M&Ms are a critical aspect of patient safety. This project utilised simple QI tools to encourage collaborative reflection, learning and improvement.


Mechanistic study of partial oxidation of methane to syngas using in situ time-resolved FTIR and microprobe Raman spectroscopies.
In situ time-resolved Fourier transform infrared (FTIR) and microprobe Raman spectroscopies were used to characterize the reaction mechanisms of the partial oxidation of methane to syngas over SiO(2)- and gamma-Al(2)O(3)-supported rhodium and ruthenium catalysts. The interaction of both pure methane and a methane/oxygen mixture at a stoichiometric feed ratio with an oxygen-rich catalyst surface led to the formation of CO2 and H(2)O as the primary products. For the H(2)-pretreated samples, the reaction mechanisms with the catalysts differ. Only Rh/SiO(2) is capable of catalyzing the direct oxidation of methane to syngas, while syngas formation over Rh/gamma-Al(2)O(3), Ru/SiO(2), and Ru/gamma-Al(2)O(3) can be achieved mainly via a combustion-reforming scheme. The significant difference in the mechanisms for partial oxidation of methane to syngas over the catalysts can be correlated to the differences in the concentration of oxygen species (O(2-)) on the catalyst surface during the reaction, mainly due to the difference in the nature of the metals and supports.


Use of a mobile phone diary for observing weight management and related behaviours.
We studied self-observations related to weight management recorded with a Wellness Diary application on a mobile phone. The data were recorded by 27 participants in a 12-week study, which included a short weight management lecture followed by independent usage of the Wellness Diary. We studied the validity of self-observed weight, and behavioural changes and weight patterns related to weight management success. Self-observed weight data tended to underestimate pre- and poststudy measurements, but there were high correlations between the measures (r >or= 0.80). The amount of physical activity correlated significantly with weight loss (r = 0.44) as did different measures representing healthy changes in dietary behaviours (r >or= 0.45). Weight changes and the weekly rhythms of weight indicated a strong tendency to compensate for high-risk periods among successful weight-losers compared to unsuccessful ones. These preliminary results suggest that the mobile phone diary is a valid tool for observing weight management and related behaviours.


Cannabis cessation among youth: rates, patterns and academic outcomes in a large prospective cohort of Canadian high school students.
Following cannabis legalization in Canada, a better understanding of the prevalence of unprompted cannabis use reduction and subsequent effects on youth academic outcomes is needed to inform harm reduction and health promotion approaches. We analyzed a longitudinally linked sample (n = 91774) from the COMPASS prospective cohort study of Canadian high school students attending Grades 9-12 in Ontario and Alberta between 2013-2014 and 2016-2017. We investigated the prevalence of spontaneous cannabis use reduction and cessation between grade transitions (Grades 9-10, 10-11, 11-12) and the effect of cessation on academic achievement (current or recent math and English course marks) and rigour (usual homework completion and past-month truancy). Only 14.8% of cannabis users decreased their use between grades. Of these, two-thirds made only incremental downward changes, a pattern which held true for all three transitions. Cessation rates from daily and weekly use decreased every year. After cessation, students had better odds than continuing users (OR = 1.23, 95% CI: 1.03- 1.48) and worse odds than never-users (OR = 0.55, 95% CI: 0.31-0.97) for some subcategories of math performance. Students who quit cannabis universally improved class attendance (OR = 2.48, 95% CI: 1.93-3.19) and homework completion (OR = 2.32, 95% CI: 1.85-2.92) compared to continuing users. Increased academic rigour may underlie any improvements seen in academic performance after cannabis cessation. High school students who use cannabis likely need targeted support to facilitate reduction or cessation and subsequent academic recovery. This indicates that a school-based focus on cannabis harm reduction is justified.


Carbaryl-induced behavioural and reproductive abnormalities in the earthworm Metaphire posthuma: a sensitive model.
Carbaryl, an N-methyl carbamate insecticide, is used in India to control foliar insects, but, due to soil contamination, it also adversely affects non-target organisms such as earthworms. This paper deals with the toxic effects of carbaryl on the behavioural and reproductive profiles of the earthworm, Metaphire posthuma. Locomotion and geotaxis were significantly affected, even after a 20-minute exposure to 0.125ppm carbaryl. The hatching of cocoons was altered at 0.5ppm, whereas cocoon production was retarded even at 0.125ppm carbaryl. No cocoon production was observed at 2.0ppm carbaryl. Sperm head abnormalities were reported even at the lowest test concentration of 0.125ppm. Wavy head abnormalities were observed at 0.125ppm carbaryl, whereas at 0.25ppm and 0.5ppm, the sperm heads became amorphous and the head nucleus was turned into granules deposited within the wavy head. It is concluded that the earthworm could be used as an ecosystem model for the initial toxicity testing of environmental pollutants.


Independent and joint trajectories of depression and anxiety symptoms among Chinese male sailors throughout a prolonged non-24-h rotating shift schedule at sea: a parallel-process growth mixture modeling approach.
The predictive and protective effect of hardiness on mental health remains unclear among shift workers on non-24-h working schedules. The present study aimed to investigate the independent and joint trajectories of depression and anxiety symptoms and the role of hardiness during a prolonged period of non-24-h shift working schedule. Four hundred nine Chinese male sailors (working on 18-h watchstanding schedule) were recruited and completed all 5-wave tests through online questionnaires (at Day 1, 14, 28, 42, 55, respectively) during a 55-day sailing. The questionnaires included sociodemographic variables, hardiness, depression and anxiety symptoms. Independent and joint trajectories of depression and anxiety symptoms were estimated by latent growth mixture models. The effect of hardiness on trajectories was examined by logistic regression models. 2 and 3 latent trajectories were identified for depression and anxiety symptoms, respectively. Based on initial levels and development trends, 3 distinct joint trajectories of depression and anxiety were identifed and named as: "Low-Inverted U" group (73.6%), "Moderate-Deterioration" group (6.9%), and "High-Stable" group (9.5%). Sailors with higher levels of hardiness were more likely to follow the "Low-Inverted U" trajectory of depression and anxiety symptoms (all p < 0.001). There existed individual differences in the trajectories of depression and anxiety. Hardiness may have a protective effect that can prevent and alleviate depression and anxiety symptoms. Therefore, hardiness-based intervention programs are encouraged among the shift workers on non-24-h working and rest schedules.


Biofeedback Signals for Robotic Rehabilitation: Assessment of Wrist Muscle Activation Patterns in Healthy Humans.
Electrophysiological recordings from human muscles can serve as control signals for robotic rehabilitation devices. Given that many diseases affecting the human sensorimotor system are associated with abnormal patterns of muscle activation, such biofeedback can optimize human-robot interaction and ultimately enhance motor recovery. To understand how mechanical constraints and forces imposed by a robot affect muscle synergies, we mapped the muscle activity of seven major arm muscles in healthy individuals performing goal-directed discrete wrist movements constrained by a wrist robot. We tested six movement directions and four force conditions typically experienced during robotic rehabilitation. We analyzed electromyographic (EMG) signals using a space-by-time decomposition and we identified a set of spatial and temporal modules that compactly described the EMG activity and were robust across subjects. For each trial, coefficients expressing the strength of each combination of modules and representing the underlying muscle recruitment, allowed for a highly reliable decoding of all experimental conditions. The decomposition provides compact representations of the observable muscle activation constrained by a robotic device. Results indicate that a low-dimensional control scheme incorporating EMG biofeedback could be an effective add-on for robotic rehabilitative protocols seeking to improve impaired motor function in humans.


Urinary incontinence in women: quality of life and help-seeking.
Urinary incontinence on its own is not considered life-threatening, yet it has been shown to negatively affect a patient's wellbeing. While it is considered a common problem, with approximately 3 million women in the UK affected, the number of those women seeking help is much lower. This article will explore the relationship between urinary incontinence, quality of life (QoL), and barriers to help-seeking behaviour. Developing an understanding of this patient group will highlight implications for nursing practice. A number of factors appear to contribute to how women experience urinary incontinence, and how it impacts on QoL. While not all of these can be fully explored, the predominant factors appear to be: severity of urinary incontinence; type of urinary incontinence; age; and the actual QoL score itself. QoL 'scores' are significant when women decide whether or not to seek help for urinary incontinence. Seeking help often depends on beliefs and an understanding of how the condition can be treated. Health promotion, the training of health professionals, and further research are required to improve the understanding of women's experiences, and to develop appropriate services with which to manage this condition.


ICA-based Individualized Differential Structure Similarity Networks for Predicting Symptom Scores in Adolescents with Major Depressive Disorder.
Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified large scale structural brain alterations in MDD, yet most are group analyses with atlas-parcellated anatomical regions. Here we proposed a method to measure individual difference by independent component analysis (ICA)-based individual difference structural similarity network (IDSSN). This approach provided a data-adaptive, atlas-free solution that can be applied to new individual subjects. Specifically, we constructed individualized whole-brain structural covariance networks based on network perturbation approach using spatially constrained ICA. First, a set of benchmark independent components (ICs) were generated using gray matter volume (GMV) from all healthy controls. Then individual heterogeneity was obtained by calculating differences and other similarity metrics between ICs derived from "each one patient + all controls" and the benchmark ICs, resulting in 32 imaging features and structural similarity networks for each patient, which can be used for predicting multiple clinical symptoms. We estimated IDSSN for 189 adolescent MDD patients aged 10-20 years and compared them to 112 healthy adolescents. We tested their predictability of the Hamilton Anxiety Scale , the 17-item Hamilton Depression Scale and six clinical syndromes using connectome-based predictive modeling. The prediction results showed that ICA-based IDSSN features reveal more disease-specific information than those using other brain templates. We also found that depression-associated networks mainly involved the default-mode network and visual network. In conclusion, our study proposed an adaptive method that improves the ability to detect GMV deviations and specificity between one individual patient and healthy groups, providing a new perspectives and insights for evaluating individual-level clinical heterogeneity based on brain structures.


Posttranslational Modifications of Chloroplast Proteins: An Emerging Field.
Posttranslational modifications of proteins are key effectors of enzyme activity, protein interactions, targeting, and turnover rate, but despite their importance, they are still poorly understood in plants. Although numerous reports have revealed the regulatory role of protein phosphorylation in photosynthesis, various other protein modifications have been identified in chloroplasts only recently. It is known that posttranslational N(α)-acetylation occurs in both nuclear- and plastid-encoded chloroplast proteins, but the physiological significance of this acetylation is not yet understood. Lysine acetylation affects the localization and activity of key metabolic enzymes, and it may work antagonistically or cooperatively with lysine methylation, which also occurs in chloroplasts. In addition, tyrosine nitration may help regulate the repair cycle of photosystem II, while N-glycosylation determines enzyme activity of chloroplastic carbonic anhydrase. This review summarizes the progress in the research field of posttranslational modifications of chloroplast proteins and points out the importance of these modifications in the regulation of chloroplast metabolism.


Tobacco Smoking and Brain Endogenous Opioid Release: More Than Nicotine Alone.
The effects of smoking denicotinized (denic) and average nicotine (avnic) tobacco cigarettes were studied on brain mu opioid receptor binding by positron emission tomography with 11C carfentanil. The results indicated the importance of physiological and psychological effects induced by denic smoking. Regional mu opioid binding potential (nondisplaceable binding potential, BPND) was measured in 20 adult male overnight abstinent chronic tobacco smokers. The denic sessions were conducted about 8:00 am followed by avnic sessions about 2 hours later. Venous plasma nicotine levels and scores of craving to smoke were assessed before and after each smoking session. Fagerstrom scores of nicotine dependence were determined. Pearson's and Spearman's correlation tests were used to examine associations between BPND and other smoking parameters. Surprisingly, the very low plasma nicotine peak levels after denic smoking (mean ± SD: 3.3 ± 1.8 ng/mL) were significantly correlated with BPND after denic and avnic smoking. Equally surprising no association was found between nicotine levels after avnic smoking and BPND. Delta craving scores and Fagerstrom scores were correlated with both BPND after denic and avnic in several brain regions. Very small amounts of nicotine, psychological and behavioral effects of denic smoking appear to have important actions on the endogenous mu opioid system. Associations between very low venous plasma nicotine levels after denic smoking and regional brain mu opioid receptor availability are a surprising "placebo" effect. Delta craving and Fagerstrom scores were correlated with BPND in several brain regions including amygdala, hippocampus, insula, nucleus accumbens, putamen, and ventral striatum. This study is limited by modest Power (mean 1 - β = 0.6) for all correlation analyses.


Study of the Production of Poly(Hydroxybutyrate-co-Hydroxyhexanoate) and Poly(Hydroxybutyrate-co-Hydroxyvalerate-co-Hydroxyhexanoate) in Rhodospirillum rubrum.
Poly(hydroxybutyrate-co-hydroxyhexanoate) [P(HB-co-HHx)] and poly(hydroxybutyrate-co-hydroxyvalerate-co-hydroxyhexanoate) [P(HB-co-HV-co-HHx)] demonstrate interesting mechanical and thermal properties as well as excellent biocompatibility, making them suitable for multiple applications and notably biomedical purposes. The production of such polymers was described in Rhodospirillum rubrum, a purple nonsulfur bacteria in a nutrient-lacking environment where the HHx synthesis is triggered by the presence of hexanoate in the medium. However, the production of P(HB-co-HHx) under nutrient-balanced growth conditions in R. rubrum has not been described so far, and the assimilation of hexanoate is poorly documented. In this study, we used proteomic analysis and a mutant fitness assay to demonstrate that hexanoate assimilation involve β-oxidation and the ethylmalonyl-coenzyme A (CoA) (EMC) and methylbutanoyl-CoA (MBC) pathways, both being anaplerotic pathways already described in R. rubrum. Polyhydroxyalkanoate (PHA) production is likely to involve the de novo fatty acid synthesis pathway. Concerning the polymer composition, HB is the main component of the polymer, probably as acetyl-CoA and butyryl-CoA are intermediates of hexanoate assimilation pathways. When no essential nutrient is lacking in the medium, the synthesis of PHA seems to help maintain the redox balance of the cell. In this framework, we showed that the fixation of CO2 is required to sustain the growth. An increase in the proportion of HHx in the polymer was observed when redox stress was engendered in the cell under bicarbonate-limiting growth conditions. The addition of isoleucine or valerate in the medium also increased the HHx content of the polymer and allowed the production of a terpolymer of P(HB-co-HV-co-HHx). IMPORTANCE The use of purple bacteria, which can assimilate volatile fatty acids, for biotechnological applications has increased, since they reduce the production costs of added-value compounds such as PHA. P(HB-co-HHx) and P(HB-co-HV-co-HHx) have demonstrated interesting properties, notably for biomedical applications. In a nutrient-lacking environment, R. rubrum is known to synthesize such polymers when hexanoate is used as the carbon source. However, their production in R. rubrum in non-nutrient-lacking growth conditions has not been described so far, and the assimilation of hexanoate is poorly documented. As the carbon source and its assimilation directly impact the polymer composition, we studied under non-nutrient-lacking growth conditions the assimilation pathway of hexanoate and PHA production in R. rubrum. Proteomic analysis and mutant fitness assays allowed us to explain PHA production and composition. An increase in HHx content of the polymer and production of P(HB-co-HV-co-HHx) was possible using the knowledge gained on metabolism under hexanoate growth conditions.


Metabolic responses of resting man immersed in 25.5 degrees C and 33 degrees C water.
This study was undertaken to determine the hormonal responses to disabling hypothermia as a result of cold water immersion. Thermally unprotected male divers trained by the U.S. Navy were subjected to total body immersion in water at 25.5 degrees C and 33 degrees C. Plasma epinephrine, norepinephrine, growth hormone, and cortisol were measured. Other variables monitored included oxygen consumption, carbon dioxide production, minute ventilation, and rectal temperature. Immersion without cold stress caused suppression of plasma epinephrine without affecting plasma norepinephrine. Cold stress combined with immersion caused a significant increase in plasma norepinephrine in the absence of other indicators of a generalized stress reaction. The degree of chilling seen in this study will produce disabling hypothermia within 1-2 h and may be shown initially only by an increase in plasma norepinephrine.


[Osteonecrosis of the femur head caused by sickle cell anemia in Benin. Epidemiologic and radiologic aspects].
The author reports 19 aseptic necrosis of the femoral head, due to sickle cell anemia, collected in 14 black people native from Benin. Sickle cell anemia is the most frequent etiology of osteonecrosis there. They are generally observed between 10 and 30 years of age. A systematic and complete study of the radiological signs has been carried out. The peculiar severity of the disease in black Africa is related to the chronicity of the sickling disorder, the delay brought to the diagnostic, the lack in therapeutic media.


Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug.
Annexin A5 (AnxA5) is a potent anticoagulant protein that crystallizes over phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating coagulation reactions. This disruption may contribute to thrombosis and miscarriages in the antiphospholipid syndrome (APS). We investigated whether the antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic mechanism. Binding of AnxA5 to PLBs was measured with labeled AnxA5 and also imaged with atomic force microscopy. Immunoglobulin G levels, AnxA5, and plasma coagulation times were measured on cultured human umbilical vein endothelial cells and a syncytialized trophoblast cell line. AnxA5 anticoagulant activities of APS patient plasmas were also determined. HCQ reversed the effect of antiphospholipid antibodies on AnxA5 and restored AnxA5 binding to PLBs, an effect corroborated by atomic force microscopy. Similar reversals of antiphospholipid-induced abnormalities were measured on the surfaces of human umbilical vein endothelial cells and syncytialized trophoblast cell lines, wherein HCQ reduced the binding of antiphospholipid antibodies, increased cell-surface AnxA5 concentrations, and prolonged plasma coagulation to control levels. In addition, HCQ increased the AnxA5 anticoagulant activities of APS patient plasmas. In conclusion, HCQ reversed antiphospholipid-mediated disruptions of AnxA5 on PLBs and cultured cells, and in APS patient plasmas. These results support the concept of novel therapeutic approaches that address specific APS disease mechanisms.


Altered intestinal microbiota enhances adenoid hypertrophy by disrupting the immune balance.
Adenoid hypertrophy (AH) is a common upper respiratory disorder in children. Disturbances of gut microbiota have been implicated in AH. However, the interplay of alteration of gut microbiome and enlarged adenoids remains elusive. 119 AH children and 100 healthy controls were recruited, and microbiome profiling of fecal samples in participants was performed using 16S rRNA gene sequencing. Fecal microbiome transplantation (FMT) was conducted to verify the effects of gut microbiota on immune response in mice. In AH individuals, only a slight decrease of diversity in bacterial community was found, while significant changes of microbial composition were observed between these two groups. Compared with HCs, decreased abundances of Akkermansia, Oscillospiraceae and Eubacterium coprostanoligenes genera and increased abundances of Bacteroides, Faecalibacterium, Ruminococcus gnavus genera were revealed in AH patients. The abundance of Bacteroides remained stable with age in AH children. Notably, a microbial marker panel of 8 OTUs were identified, which discriminated AH from HC individuals with an area under the curve (AUC) of 0.9851 in the discovery set, and verified in the geographically different validation set, achieving an AUC of 0.9782. Furthermore, transfer of mice with fecal microbiota from AH patients dramatically reduced the proportion of Treg subsets within peripheral blood and nasal-associated lymphoid tissue (NALT) and promoted the expansion of Th2 cells in NALT. These findings highlight the effect of the altered gut microbiota in the AH pathogenesis.


Reproductive functional anatomy and oestrous cycle pattern of the female brush-tailed porcupine (Atherurus africanus, Gray 1842) from Gabon.
In the present study, we examined certain features of the functional anatomy of the female genital tract of the wild brush-tailed porcupine (Atherurus africanus) to obtain data on the reproductive biology of this African forest rodent. Two consecutive experiments were performed. The aim of the first was to establish macroscopic and microscopic features of the genital organs, and to explore correlations between predominant ovarian structures and vaginal contents in 20 wild, mature females. In the second experiment, we inspected the external genitalia and vaginal smears of a further 10 females in captivity on a daily basis for 90 days. The uterus of the brush-tailed porcupine is bicornuate and composed of two separated uterine horns, a uterine body and cervix. The genital tract does not present a vaginal vestibule. Thus, there is no portion common to genital and urinary tracts. Females in the follicular phase of the oestrous cycle showed increased cornification of the vaginal epithelium and a high density of eosinophilic cells in vaginal smears. The vulva and vaginal opening were open, reddish and tumefacted. In luteal phase or in pregnancy, epithelial cornification and eosinophilic features were notably reduced and the vagina presented a pale, non-tumefacted vulva and a vaginal closure membrane. Females in captivity showed spontaneous cycles, a polyoestrous reproduction pattern and, based on features of the external genitalia and vaginal smears, their oestrous cycle length was 27.1+/-6.4 days (n=12).


Experimental pathology of T-2 toxicosis and mycoplasma infection on performance and hepatic functions of broiler chickens.
This experiment was conducted using 192 day-old Ross 308 chicks, divided into 4 groups of 4 replicate consisting 48 birds. Group I was fed a control diet, Group II was fed control diet supplemented with 0.5 ppm T-2 toxin for 5 weeks, Group III was fed control diet supplemented with 8 × 10(8) cfu/mL of Mycoplasma gallisepticum, and group IV was fed control diet supplemented by T-2 toxin and Mycoplasma gallisepticum. Body weight and feed conversation ratio (FCR), relative organ weights, clinical signs, biochemical characteristics, and gross and histopathological lesions were recorded in the experimental groups at the end of the second and fifth weeks of age. Body weight and relative weights of bursa of Fabricius, thymus, and spleen decreased and FCR increased significantly (P ≤ 0.05), but the relative weights of liver and kidney showed no significant decrease (P ≤ 0.05) in the serum total proteins, albumin, and increase in aspartate aminotransferase and alanine transaminase were observed in T-2 toxin and T-2 accompanied with Mycoplasma fed birds when compared to the control group. Liver was enlarged, friable, and yellowish discoloration with distended gall bladder was noticed. Lymphoid organs such as bursa of Fabricius, thymus, and spleen were atrophied in group II and group IV throughout the study. Microscopically, liver showed vacuolar degeneration of hepatocytes, with increased Kupffer cell activity, bile duct epithelial hyperplasia, and infiltration of inflammatory cells. Kidney showed vacuolar degeneration of tubular epithelium along with pyknotic nuclei. Lymphoid organs showed lymphocytolysis and depletion with prominent reticuloepithelial cells. Proventriculus revealed desquamation of villous epithelial cells and lymphoid infiltration in submucosa. Heart showed mild hemorrhage with infiltration of inflammatory cells. Lung showed edema and inflammatory cells in the bronchioles. Trachea showed desquamation and erosions of mucosa. Proliferation of mucosal glands with increased mucous secretion was obvious. Air sacs showed thickening with presence of inflammatory cells and edema.


The promiscuous evolutionary history of the family Bromoviridae.
Recombination and segment reassortment are important contributors to the standing genetic variation of RNA viruses and are often involved in the genesis of new, emerging viruses. This study explored the role played by these two processes in the evolutionary radiation of the plant virus family Bromoviridae. The evolutionary history of this family has been explored previously using standard molecular phylogenetic methods, but incongruences have been found among the trees inferred from different gene sequences. This would not be surprising if RNA exchange was a common event, as it is well known that recombination and reassortment of genomes are poorly described by standard phylogenetic methods. In an attempt to reconcile these discrepancies, this study first explored the extent of segment reassortment and found that it was common at the origin of the bromoviruses and cucumoviruses and at least at the origin of alfalfa mosaic virus, American plum line pattern virus and citrus leaf rugose virus. Secondly, recombination analyses were performed on each of the three genomic RNAs and it was found that recombination was very common in members of the genera Bromovirus, Cucumovirus and Ilarvirus. Several cases of recombination involving species from different genera were also identified. Finally, a phylogenetic network was constructed reflecting these genetic exchanges. The network confirmed the taxonomic status of the different genera within the family, despite the phylogenetic noise introduced by genetic exchange.


Implementation of smoking cessation treatment in VHA substance use disorder residential treatment programs.
Although the prevalence of tobacco use among individuals with substance use disorders remains high, smoking cessation (SC) has not been a focus of addiction treatment programs. Veterans Health Administration (VHA) policy requires tobacco use screening and the availability of evidence-based SC treatment in specialty care settings, including substance use disorder programs. As part of a larger quality improvement effort, this qualitative study examined how SC treatment is delivered in VHA substance use disorder residential treatment programs (SRTPs) and the barriers and opportunities for growth that exist within these settings. Twenty-five staff were interviewed across a sample of 15 SRTPs. Participants were asked to describe their knowledge and attitudes about SC treatment as well as organizational barriers and facilitators related to implementation of SC treatment in their programs. Content analysis was used to extract responses within and across programs. Participants endorsed SC as a general goal and reported that SRTPs responded to patients who requested help. However, many programs did not emphasize SC as an important part of recovery from substance use disorders and did not document, reevaluate, or consistently address tobacco use. The results identified critical gaps in the provision of SC treatment in VHA SRTPs. These findings suggest actionable opportunities to improve SC treatment in SRTPs, including providing training opportunities, developing or enforcing policies that support SC, implementing systems to track and report tobacco-related diagnoses and treatment, and obtaining leadership support for building a culture that encourages SC.


Physical map and strand polarity of specific fragments of adenovirus-associated virus DNA produced by endonuclease R-EcoRI.
Cleavage of adenovirus-associated virus type 2 (AAV2) DNA linear duplex monomers with the restriction endonuclease R-EcoRI yielded three fragments, A, B, and C, having approximate mol wt of 1.6 X 10(6), 1.1 X 10(6), and 1.3 X 10(5), respectively. Radioactive labeling the 5' termini of AAV DNA before cleavage with R-EcoRI showed that A and B were terminal fragments and C was internal. Separation of the complementary strands of fragments A and B showed that A contained the 5' terminus of the minus strand and the 3' terminus of the plus strand, and conversely for fragment B. The physical map of the AAV R-EcoRI fragments can thus be unambiguously determined and is drawn with B at the left-hand and A at the right-hand end. On this map, transcription of stable AAV mRNA from the minus strand proceeds from left to right, beginning in fragment B and terminating in fragment A. The asymmetry in distribution of thymidine between the AAV DNA plus and minus strands is preferentially located in fragment A, which represents the right-hand half of the duplex molecule. These experiments enable preparative separation of all four single-strand termini of AAV DNA and provide a basis for orientation of fragment maps derived by cleavage with other restriction enzymes.


The control of trehalose biosynthesis in Saccharomyces cerevisiae: evidence for a catabolite inactivation and repression of trehalose-6-phosphate synthase and trehalose-6-phosphate phosphatase.
During diauxic growth of yeast in glucose-rich medium, the accumulation of trehalose started well after complete exhaustion of glucose from the medium. The accumulation of the disaccharide was concomitant with a resumption of cell growth on the ethanol accumulated in the medium, but not with a degradation of glycogen which occurred as soon as glucose had been consumed. In contrast, in a mutant deficient in phosphoenolpyruvate carboxykinase, the synthesis of trehalose coincided exactly with the degradation of glycogen. Upon inoculation of stationary phase wild-type cells into a glucose medium, the activities of trehalose-6-phosphate (Tre6P) synthase and Tre6P phosphatase dropped in parallel to reach only 15% of their initial values after 3 h, and only recovered their original values as cells re-entered stationary phase. In the presence of cycloheximide, the decrease in Tre6P synthase and Tre6P phosphatase activities was restricted to 50-60%, the remaining decrease being inhibited by the drug. Furthermore, the reappearance of the enzyme activities following transfer of cells to an acetate medium was blocked by cycloheximide. It was also shown that loss of activity of these two enzymes required a combination of metabolizable sugars together with a nitrogen source. Low activities of Tre6P synthase and Tre6P phosphatase were measured in mutants with increased adenylate cyclase activity (RAS2ala18val19 mutants). Moreover, derepression of these enzymes at the approach of stationary phase was prevented in a pde2 mutant when it was cultivated in the presence of exogenous cyclic nucleotide. The mechanism of this effect is not clear, but may involve a transcriptional regulation by cAMP of the genes encoding these proteins.


Proteasomal Degradation of Indoleamine 2,3-Dioxygenase in CD8 Dendritic Cells is Mediated by Suppressor of Cytokine Signaling 3 (SOCS3).
Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step of tryptophan catabolism in a specific pathway, resulting in a series of extracellular messengers collectively known as kynurenines. IDO has been recognized as an authentic regulator of immunity not only in mammalian pregnancy, but also in infection, autoimmunity, inflammation, allergy, transplantation, and neoplasia. Its suppressive effects are mostly mediated by dendritic cells (DCs) and involve tryptophan deprivation and/or production of kynurenines, which act on IDO-negative DCs as well as CD4(+) and CD8(+) T cells. We have found that mouse IDO contains two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY(115)CEL and LLY(253)EGV. We have also found that Suppressor of Cytokine Signaling 3 (SOCS3)-known to interact with phosphotyrosine-containing peptides and be selectively induced by interleukin 6 (IL-6)-binds mouse IDO, recruits the ECS (Elongin-Cullin-SOCS) E3 ligase, and targets the IDO/SOCS3 complex for proteasomal degradation. This event underlies the ability of IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context demands that IDO be degraded in tolerogenic DCs. These studies support the finding that IDO is regulated by proteasomal degradation in response to immunogenic and inflammatory stimuli.


Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol.
Neonates who receive repeated or prolonged general anesthesia before the age of 4 are at a significantly higher risk of developing cognitive dysfunction later in life. In this study, we investigated the effects of repeated neonatal propofol exposure on hippocampal synaptic plasticity, neuronal excitability, and cognitive function. Adeno-associated SIRT1 virus with CaMKIIɑ promotor and a viral vector carrying the photosensitive gene ChR2 with the CaMKIIɑ promotor, as well as their control vectors, were stereotaxically injected into the hippocampal CA1 region of postnatal day 5 (PND-5) rats. PND-7 rats were given intraperitoneal injection of 60 mg/kg propofol or fat emulsion for three consecutive days. Western blotting, Golgi staining, and double immunofluorescence staining were used to evaluate the SIRT1 expression, synaptic plasticity, and the excitability of neurons in the hippocampal CA1 region. The Morris water maze (MWM) test was conducted on PND-30 to assess the learning and memory abilities of rats. Repeated neonatal propofol exposure reduced SIRT1 expression, suppressed synaptic plasticity, decreased glutamatergic neuron excitability in the hippocampus, and damaged learning and memory abilities. Overexpression of SIRT1 attenuated propofol-induced cognitive dysfunction, excitation-inhibition imbalance, and synaptic plasticity damage. After optogenetic stimulation of glutamatergic neurons in the hippocampal CA1 region, the learning and memory abilities of rats exposed to propofol were improved on PND-30. Our findings demonstrate that SIRT1 plays an important role in cognitive dysfunction induced by repeated neonatal propofol exposure by suppressing synaptic plasticity and neuronal excitability.


Schedules of controlled substances: removal of naloxegol from control. Final rule.
With the issuance of this final rule, the Administrator of the Drug Enforcement Administration removes naloxegol ((5[alpha],6[alpha])-17-allyl-6-((20-hydroxy-3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol) and its salts from the schedules of the Controlled Substances Act (CSA). This scheduling action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Prior to the effective date of this rule, naloxegol was a schedule II controlled substance because it can be derived from opium alkaloids. This action removes the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle (manufacture, distribute, reverse distribute, dispense, conduct research, import, export, or conduct chemical analysis) or propose to handle naloxegol.


Population genetics of Lithuanians.
The primary objective of this article was to overview the present-day knowledge on genetic features of the Lithuanian population. Genetic differentiation within the Lithuanian population and the relationship between Lithuanians and other European populations was analysed by means of blood groups, serum protein polymorphisms and DNA markers including mtDNA. The results of the research have shown small differences between present-day Lithuanian ethnolinguistic groups, which probably go back to the prehistoric Baltic tribal structure. The Baltic peoples show a mixture of eastern and western genetic traits, e.g. a high frequency of the blood group B combined with a very high frequency of the Rh-negative blood group. Studies of the Baltic 'tribal gene' LWb indicate the presence of a considerable Baltic admixture in the neighbouring Finno-Ugric and Slavic populations.


Differential temporal expression profiles of heat shock protein genes in Drosophila melanogaster (Diptera: Drosophilidae) under ultraviolet A radiation stress.
Solar UV radiation is indispensable for certain behaviors of many organisms. Nevertheless, UV-A might be expected to stress insects that possess intensive positive taxis toward UV-A light. To avoid stress hazards, organisms generally exhibit the upregulation of heat shock proteins (Hsps) expression. To gain a better understanding of the roles of the different Hsps in response to UV-A stress in the diurnal phototactic fly Drosophila melanogaster Meigen, 1830 (Diptera: Drosophilidae), we tested the temporal expression patterns of 11 DmHsps following UV-A radiation. The results indicated that each DmHsp had a differential temporal expression profile under UV-A radiation stress. Potential transcription factor-binding motifs in the promoter regions of strongly inducible DmHsps were identified; results showed these transcription factor-binding motifs were highly homologous to binding sites that have been identified for transcription factors associated with UV radiation stimuli. So DmHsps might act in a coordinated and cooperative manner at the transcriptional level to counteract UV-A radiation-based stress.


The celebrated écorchés of Honoré Fragonard, part 1: The classical techniques of preparation of dry anatomical specimens in the 18th century.
The écorchés that Honoré Fragonard created between 1766 and 1771 have miraculously survived the ravages of time due to a technique of preparation which Fragonard never revealed. The present paper and a subsequent article aim to explain the classical methods used by anatomists of the 18th century (Part 1) and to throw light on the details of Fragonard's method (Part 2). Anatomists of the 18th century who wished to preserve their dissections used a method of mummification, which has now fallen into disuse: drying after immersion in alcohol. This article explains the stages of the classical method utilized by French anatomists of the Age of Enlightenment. The cadaver was selected with care before the vascular system was injected with a colored mixture of wax, animal fat, and plant resins. The body was then dehydrated by immersion in a bath of alcohol, after which it was removed and positioned by means of a wooden framework, which held the body in the desired pose while the alcohol evaporated. The vessels were painted, and finally the body was varnished.


Effects of fractionated x-irradiation on the Ly-6--Ril-1--Pol-5 region.
Our laboratory has focused on defining, localizing, and understanding the mode of action of genes involved in fractionated x-irradiation (FXI) leukemia in susceptible and restraint mouse strains. We have described the genetic and molecular evidence suggesting the existence of multiple independent loci involved in FXI-induced leukemogenesis. These studies indicated that one of these, Ril-1, a locus on the distal portion of chromosome 15, is the major locus influencing susceptibility to the disease. Our data unequivocally place Ril-1 in the gene complex Ly-6--Ril-1--Sis--H-30--Pol-5. Ril-1 appears to be closest to Ly-6 and Sis. We report that in FXI-induced leukemias there are hypomethylation changes in the Ly-6 region as compared to normal thymocytes. In contrast, Sis was found to be hypermethylated and not expressed. In addition, we have noted DNA rearrangements in the Ly-6--Pol-5 region in the majority of tumors examined using the Ly-6 and spleen focus-forming virus (SFFLV) molecular probes. Increased expression of Ly-6 and other surface markers encoded in this region has been noted in FXI-induced thymomas.


Multiresidue screening of milk withheld for sale at dairy farms in central New York State.
Many of the drugs commonly used in lactating dairy cows result in residues in the milk, prohibiting its sale for human consumption. Milk withheld for sale because of drug treatment or from cows with high somatic cell counts is commonly called "waste milk." One-third of dairy farms in the United States use waste milk to feed preweaned dairy calves. Limited information is currently available on the effect of this practice on the selection and dissemination of antibiotic-resistant bacteria. Pooled waste milk samples were collected from 34 dairy farms in central New York State with the objective of detecting the presence and quantity of drug residues in these samples. Samples were collected and refrigerated using ice packs and then stored at 4°C upon arrival at the Cornell laboratory (Ithaca, NY). Screening for β-lactam, tetracycline, and sulfonamide residues in the milk was performed using commercial enzyme-linked receptor-binding assay (SNAP) tests (Idexx Laboratories Inc., Westbrook, ME). Samples with a positive SNAP test were selected for screening using a multiresidue liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The SNAP tests revealed that 75, 14.3, and 7.1% of waste milk samples (n=34) contained β-lactam, tetracycline, and sulfamethazine residues, respectively. Of the samples sent for LC-MS/MS (n=28), half had detectable quantities of drug residues. The most prevalent drugs detected by LC-MS/MS were ceftiofur (39.2%; mean ± SE concentration=0.151 ± 0.042 μg/mL), penicillin G (14.2%; mean ± SE concentration=0.008 ± 0.001 µg/mL), and ampicillin (7.1%; mean ± SE concentration=0.472 ± 0.43 µg/mL). In addition, one sample had detectable concentrations of oxytetracycline and one sample had detectable concentrations of sulfadimethoxine. These results provide insight on drug residues present in waste milk from select farm in upstate New York, and additionally indicate the need for additional studies targeting on-farm treatments that could degrade drug residues present in waste milk and reduce the potential effects on the biosphere from the disposal and use of waste milk as a feed source.