Finding the targets of a drug by integration of gene expression data with a protein interaction network.
Polypharmacology, which focuses on designing drugs that bind efficiently to multiple targets, has emerged as a new strategic trend in today's drug discovery research. Many successful drugs achieve their effects via multi-target interactions. However, these targets are largely unknown for both marketed drugs and drugs in development. A better knowledge of a drug's mode of action could be of substantial value to future drug development, in particular for side effect prediction and drug repositioning. We propose a network-based computational method for drug target prediction, applicable on a genome-wide scale. Our approach relies on the analysis of gene expression following drug treatment in the context of a functional protein association network. By diffusing differential expression signals to neighboring or correlated nodes in the network, genes are prioritized as potential targets based on the transcriptional response of functionally related genes. Different diffusion strategies were evaluated on 235 publicly available gene expression datasets for treatment with bioactive molecules having a known target. AUC values of up to more than 90% demonstrate the effectiveness of our approach and indicate the predictive power of integrating experimental gene expression data with prior knowledge from protein association networks.


Intramuscular lipoma of the superior oblique muscle.
We describe a rare intramuscular infiltrating lipomatous tumor affecting the superior oblique muscle. A 37-year-old female presented with eyelid swelling, proptosis and motility disturbance. Imaging studies revealed enlargement of the superior oblique muscle with a fat-density infiltrating lesion within its belly. The clinical and radiologic findings suggested a cystic or necrotic lesion. Biopsy showed an infiltrative tumor consisting of adipocytes with included degenerated muscle fibers. Histologic features were consistent with a benign intramuscular lipoma, rather than the more aggressive well-differentiated liposarcoma. A review of the literature found three previously described periorbital cases, two in the eyelid, and one in the anterior orbit. Lipomas are common tumors that usually do not cause functional impairment but are very rare in the orbit. Intramuscular lipoma is a rare subtype that can result in significant morbidity. Enlargement of an extraocular or periorbital muscle with a low-density infiltrating lesion should raise suspicion for this unusual tumor.


Anti-actin antibodies of IgM and IgG class in chronic liver diseases detected by fluorometric immunoassay.
Using a sensitive fluoroimmunoassay, anti-actin antibodies (AA) of the IgM and IgG classes were measured in 240 patients with various chronic liver diseases and in 211 patients with non-hepatic autoimmune muscle, heart, malignant and inflammatory bowel diseases. Thirty-two out of 40 patients (80%) with autoimmune chronic active hepatitis (CAH) had AA only of the IgG class (geom. mean X = 1.78, SEM +/- 0.07) and only three patients (8%) had both IgG and IgM AA, the latter in lower titres. In patients with primary biliary cirrhosis (PBC) and AMA-positive cholestatic CAH, AA of both IgM and IgG classes were equally represented (60% IgG and 64% IgM AA in PBC, 73% IgG and 51% IgM AA in cholestatic CAH) but the titres were very low (geom. mean IgG AA in PBC 1.035, SEM +/- 0.03, in cholestatic CAH 1.18, SEM +/- 0.02). In contrast to autoimmune (lupoid) CAH, AA were rare in HBsAg positive CAH (9/43, 21%) and only present in low titres. However, in six out of 21 patients with anti-HBs and anti-HBc-positive chronic active hepatitis, high AA of IgG class were found, suggesting the autoimmune type of liver disease. In NANB virus-induced chronic liver disease after blood transfusion, AA were only occasionally found (IgG antibodies 1/19, IgM antibodies 3/19) and none were found in the eight patients with sporadic NANB hepatitis. They were also rare in 30 patients with alcoholic liver disease (3/30, 10%).(ABSTRACT TRUNCATED AT 250 WORDS)


Discrepancy between HCV structural and non structural genes in Georgian genotype two patients.
Correct identification of hepatitis C genotypes is an important diagnostic tool, which guarantees further selection of adequate treatment regimen and correct duration. Ideal approach for accurate genotyping is amplification of both structural and non structural parts of HCV genome. As different methods, which use either one or another region for HCV genotyping sometimes lead to indeterminate genotype and subtype results. Therefore, it is of importance to compare HCV genotyping results based on two different genomic regions. As part of this study, remnant 108 specimens, with previous history of successful genotype identification by 5'UTR/core Versant HCV genotyping kit, were retrospectively analyzed. "In house" HCV real time PCR based method that amplifies parts of NS5B region was used for this purpose. Based on our data, genotyping calls were concordant between genotype one and genotype three specimens group in both regions. However, discrepancy was evident among genotype 2 group. Of 25 specimens originally typed as genotype 2 in structural region, only 7 was confirmed in non structural region, remaining 18 specimens were typed as 1b. Therefore, the discordance rate between structural and non structural regions for genotyping call among genotype two was 72%. Our data showed highly discordant structural and non structural genome for genotype two identification in our specimens. We propose that this phenomenon might be due to the recombination event between genotype two and genotype one. Possible circulation of this strain in Georgia stresses the need for detailed sequencing and phylogenetic analyses of these specimens in both structural and non structural parts of HCV genome.


Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer.
Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.


Age-Dependent Degradation of Locomotion Encoding in Huntington's Disease R6/2 Model Mice.
Huntington's disease (HD) is an inherited fatal neurodegenerative disease, leading to neocortical and striatal atrophy. The commonly studied R6/2 HD transgenic mouse model displays progressive motor and cognitive deficits in parallel to major pathological changes in corticostriatal circuitry. To study how disease progression influences striatal encoding of movement. We chronically recorded neuronal activity in the dorsal striatum of R6/2 transgenic (Tg) mice and their age-matched nontransgenic littermate controls (WTs) during novel environment exposure, a paradigm which engages locomotion to explore the novel environment. Exploratory locomotion degraded with age in Tg mice as compared to WTs. We encountered fewer putative medium spiny neurons (MSNs)-striatal projection neurons, and more inhibitory interneurons-putative fast spiking interneurons (FSIs) in Tg mice as compared to WTs. MSNs from Tg mice fired less spikes in bursts without changing their firing rate, while FSIs from these mice had a lower firing rate and more of them were task-responsive as compared to WTs. Additionally, MSNs from Tg mice displayed a reduced ability to encode locomotion across age groups, likely associated with their low prevalence in Tg mice, whereas the encoding of locomotion by FSIs from Tg mice was substantially reduced solely in old Tg mice as compared to WTs. Our findings reveal an age-dependent decay in striatal information processing in transgenic mice. We propose that the ability of FSIs to compensate for the loss of MSNs by processes of recruitment and enhanced task-responsiveness diminishes with disease progression, possibly manifested in the displayed age-dependent degradation of exploratory locomotion.


Genetic microcephaly in a pair of monozygous twins.
A pair of monozygotic female twins with true primary microcephaly is described. The autosomal-recessive nature of the disease is supported by the following: the twins are concordant for the disease; the parents, themselves normal, are related; the reduced skull dimensions were noted at birth; neurologic problems are absent; the karyotype is normal; the gestation and delivery were normal, without any history of influences capable of inducing microcephaly. A detailed dermatoglyphic study is given.


In vivo selection during ofloxacin therapy of Escherichia coli with combined topoisomerase mutations that confer high resistance to ofloxacin but susceptibility to nalidixic acid.
To investigate quinolone resistance mechanisms in an Escherichia coli clinical isolate (Ar2) resistant to ofloxacin but susceptible to nalidixic acid selected after 10 days of ofloxacin therapy in a patient with prostatitis. Molecular typing (ERIC-PCR and RAPD), antibiotic susceptibility and gyrA, gyrB, parC and parE QRDR sequences were compared for E. coli Ar2 and a wild-type E. coli (Ar1) isolated 2 months earlier in the same patient. Ofloxacin-resistant mutants were selected in vitro in order to reproduce the mutations observed and the original phenotype. The two strains were similar with regard to antibiotic susceptibility except quinolones and for ERIC-PCR and RAPD patterns, suggesting a clonal relationship and acquisition of quinolone resistance by chromosomal mutation. Quinolone MICs were 3, 0.12, 0.05 and 0.02 mg/L of nalidixic acid, ofloxacin, levofloxacin and ciprofloxacin, respectively, for E. coli Ar1 and 6, 32, 8 and 1 mg/L, respectively, for E. coli Ar2. The strain Ar2 harboured two substitutions, Gly-81-->Asp in GyrA and Ser-80-->Arg in ParC. Introduction into E. coli Ar2 of the wild-type gyrA fully complemented fluoroquinolone resistance. Although the strain was not a hypermutator, ofloxacin first-step resistant mutants with gyrA mutations were easily obtained from E. coli Ar1 and 25% of them were at codon 81. In vitro stepwise combination of Gly-81-->Asp in GyrA and Ser-80-->Arg in ParC reproduced the original phenotype in E. coli KL16. A double topoisomerase mutant was selected in vivo by 10 days ofloxacin. The mutations were originally combined for a result of ofloxacin resistance but nalidixic acid susceptibility.


Online clustering algorithms.
We introduce a set of clustering algorithms whose performance function is such that the algorithms overcome one of the weaknesses of K-means, its sensitivity to initial conditions which leads it to converge to a local optimum rather than the global optimum. We derive online learning algorithms and illustrate their convergence to optimal solutions which K-means fails to find. We then extend the algorithm by underpinning it with a latent space which enables a topology preserving mapping to be found. We show visualisation results on some standard data sets.


Elastomeric hydrolyzable porous scaffolds: copolymers of aliphatic polyesters and a polyether-ester.
Porous scaffolds of 1,5-dioxepan-2-one (DXO), L-lactide (LLA), and epsilon-caprolactone (CL) were prepared by a solvent casting, salt particulate leaching technique in which the composites were detached from their mold using a novel methanol swelling procedure. By incorporating DXO segments into polymers containing LLA or CL, an increase in hydrophilicity is achieved, and incorporating soft amorphous domains in the crystalline sections enables tailoring of the mechanical properties. The porosities of the scaffolds ranged from 89.2% to 94.6%, and the pores were shown to be interconnected. The materials were synthesized by bulk copolymerization of 1,5-dioxepan-2-one (DXO), L-lactide (LLA), and epsilon-caprolactone (CL) using stannous 2-ethylhexanoate as catalyst. The copolymers formed varied in structure; poly(DXO-co-CL) is random in its arrangement, whereas poly(DXO-co-LLA) and poly(LLA-co-CL) are more blocky in their structures.


Demographic and behavioral contextual risk groups among men who have sex with men participating in a phase 3 HIV vaccine efficacy trial: implications for HIV prevention and behavioral/biomedical intervention trials.
Recent outbreaks of syphilis and gonorrhea coupled with reported increases in HIV-risk behavior among men who have sex with men (MSM) have raised concerns about a potential resurgence of HIV among MSM. These concerns have led some to suggest the need for a paradigm shift in how HIV-prevention programs are designed and implemented. In this analysis, baseline demographic, sexual partnership, and substance use information was used to identify contextual-risk groups among 5,095 HIV-seronegative MSM enrolled in a 36-month phase 3 HIV vaccine efficacy trial across 61 sites primarily in North America. Eight demographic and behavioral contextual risk groups were identified, with annualized HIV seroincidence ranging from 1.8% to 6.3% across groups. Men in primary HIV-serodiscordant relationships had the lowest HIV seroincidence (1.8%), while an older group of men with many sex partners had the highest (6.3%). Visit-schedule compliance and study retention were lowest among younger non-White men and highest among older popper users, with annualized HIV seroincidence of 2.9% and 3.5%, respectively. Differences in HIV incidence, study compliance, and retention observed among contextual-risk groups suggest that responsiveness to heterogeneity within risk group (eg, MSM) could benefit screening, enrollment, and retention of HIV-prevention programs and intervention trials, reducing the time and cost related to their design, implementation, and conclusion.


Age-Related Differences in Sleep Architecture and Electroencephalogram in Adolescents in the National Consortium on Alcohol and Neurodevelopment in Adolescence Sample.
To investigate age-related differences in polysomnographic and sleep electroencephalographic (EEG) measures, considering sex, pubertal stage, ethnicity, and scalp topography in a large group of adolescents in the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). Following an adaptation/clinical screening night, 141 healthy adolescents (12-21 y, 64 girls) had polysomnographic recordings, from which sleep staging and EEG measures were derived. The setting was the SRI International Human Sleep Laboratory and University of Pittsburgh Pediatric Sleep Laboratory. Older age was associated with a lower percentage of N3 sleep, accompanied by higher percentages of N2, N1, and rapid eye movement (REM) sleep. Older boys compared with younger boys had more frequent awakenings and wakefulness after sleep onset, effects that were absent in girls. Delta (0.3-4 Hz) EEG power in nonrapid eye movement NREM sleep was lower in older than younger adolescents at all electrode sites, with steeper slopes of decline over the occipital scalp. EEG power in higher frequency bands was also lower in older adolescents than younger adolescents, with equal effects across electrodes. Percent delta power in the first NREM period was similar across age. African Americans had lower EEG power across frequency bands (delta to sigma) compared with Caucasians. Finally, replacing age with pubertal status in the models showed similar relationships. Substantial differences in sleep architecture and EEG were evident across adolescence in this large group, with sex modifying some relationships. Establishment and follow-up of this cohort allows the investigation of sleep EEG-brain structural relationships and the effect of behaviors, such as alcohol and substance use, on sleep EEG maturation.


Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer.
Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous H2O2 triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1-2 cm away, promising for metastasis inhibition.


[Long-term followup of primary intestinal lymphangiectasia in the child. Six case reports].
Primary intestinal lymphangiectasia induce symptoms of protein-losing gastroenteropathy. Only very few studies evaluate the long term follow up of such patients. We reviewed six children diagnosed at 17 +/- 12 months and followed for 11 +/- 4.9 years. As soon as the diagnosis was made the patients were submitted to a strict low fat diet with added medium chain triglycerides and intermittent liposoluble vitamins perfusions. The diet allowed the disappearance of symptoms for all the patients but laboratory findings indicated continuing chyle leak for most of the children. Only one child who had normal biological parameters tolerates a normal diet since four years. Relaxation of the diet by two patients who had moderate hypoalbuminemia and lymphopenia led to severe clinical relapses 14 and 17 years after the diagnosis period with therapeutic difficulties. Three patients with long term strict low fat diet remain asymptomatic. In most asymptomatic patients, the underlying lymphatic defect remains with permanent biological abnormalities. Clinical relapses may be severe and difficult to treat; thus the need for dietary treatment appears to be permanent.


Use of synthetic oligonucleotide DNA probes for the identification of Bacteroides gingivalis.
Six different oligonucleotide probes complementary to the hypervariable regions of 16S rRNA of Bacteroides gingivalis were tested for specificity and sensitivity against 77 field strains of B. gingivalis and 105 strains of 12 other Bacteroides species. The data demonstrated that these probes were very specific (range, 0.85 to 1.00) and sensitive (1.00). Some limited cross-reactions with other Bacteroides species were observed. Four of these probes should be useful for rapid detection and identification of B. gingivalis.


Brachial plexopathies.
The main objective of this article is to offer a regional approach to brachial plexus assessment because, although the brachial plexus is the largest and most complex peripheral nervous system structure, most of its disorders involve only a portion of it. Consequently, regional assessment typically localizes and characterizes the lesion. The sensory axons traversing each region are known and provide localizing information. Because localization dictates the differential diagnosis and the resulting initial clinical management, examining physicians must first localize the lesion. Localization of a brachial plexus lesion requires an appreciation of brachial plexus anatomy, lesion classification, and the routes traversed by the various axons composing the brachial plexus, especially the sensory axons. This information is reviewed in this article and followed by discussions of several brachial plexus disorders, especially those with regional predilections.


Hereditary myotonia in cats associated with a new homozygous missense variant p.Ala331Pro in the muscle chloride channel ClC-1.
Three-related cats were evaluated for a history of short-strided gait and temporary recumbency after startle. Neurological examination, electromyography (EMG), muscle biopsies, and a chloride voltage-gated channel 1 (CLCN1) molecular study were performed. Clinically, all 3 cats presented myotonia with warm-up phenomenon and myotonic discharges during EMG examination. Muscle biopsies showed normal muscle architecture and variation in the diameter of myofiber size with the presence of numerous hypertrophic fibers. The molecular study revealed a missense variant (c.991G>C, p.Ala331Pro) in exon 9 of the CLCN1 gene, responsible for the first chloride channel extracellular loop. This mutation was screened in 104 control phenotypically normal unrelated cats, and all were wildtype. The alanine at this position is conserved in ClC-1 (chloride channel protein 1) in different species, and 2 mutations at this amino acid position are associated with human myotonia. This is the third CLCN1 mutation described in the literature associated with hereditary myotonia in cats and the first in domestic animals located in an extracellular muscle ClC-1 loop.


Is systems biology the key to preventing the next pandemic?
Sporadic outbreaks of epizootics including SARS coronavirus and H5N1 avian influenza remind us of the potential for communicable diseases to quickly spread into worldwide epidemics. To confront emerging viral threats, nations have implemented strategies to prepare for pandemics and to control virus spread. Despite improved surveillance and quarantine measures, we find ourselves in the midst of a H1N1 influenza pandemic. Effective therapeutics and vaccines are essential to protect against current and future pandemics. The best route to effective therapeutics and vaccines is through a detailed and global view of virus-host interactions that can be achieved using a systems biology approach. Here, we provide our perspective on the role of systems biology in deepening our understanding of virus-host interactions and in improving drug and vaccine development. We offer examples from influenza virus research, as well as from research on other pandemics of our time - HIV/AIDS and HCV - to demonstrate that systems biology offers one possible key to stopping the cycle of viral pandemics.


Fatigue in human metabolic myopathy.
The ability of muscle fibres to sustain force can be related to their economy of energy utilization and to their capacity to regenerate energy under the prevailing conditions (aerobic or anaerobic) of contraction. The pathophysiology of muscle fatigue is analysed in patients with thyroid dysfunction and with impaired glycogenolysis, and in a patient with abnormal mitochondrial function. Muscle from hypothyroid patients, like cooled muscle, is slow in relaxing and shows a reduced energy requirement (energy economy) and reduced fatiguability, whereas muscle of hyperthyroid patients may show the opposite features. In myophosphorylase deficiency the energy economy is normal in the fresh state and increases as contraction proceeds; however, fatigue is premature and associated with impaired excitation rather than an overall depletion of energy stores. With abnormal mitochondrial function the muscle tends to be effectively anaerobic and fatigue is associated with impaired excitation-contraction coupling. This appears to result from either muscle ischaemia or the dominant use of anaerobic metabolism for energy regeneration. Fatigue in these disorders of energy metabolism may ultimately be due to a reduced supply of ATP but direct evidence of this is lacking and, if it occurs, its physiological expression is probably variable.


Field grown transgenic Pm3e wheat lines show powdery mildew resistance and no fitness costs associated with high transgene expression.
Pm3 from wheat encodes a nucleotide-binding leucine-rich repeat type of receptor and confers resistance to powdery mildew caused by the fungal pathogen Blumeria graminis f.sp. tritici (Bgt). Each of the 17 functional Pm3 alleles identified so far confers resistance to a distinct spectrum of Bgt isolates. Variant Pm3e has been found in wheat donor line W150 and differs only by two amino acids from the non-functional variant Pm3CS. In order to evaluate the capability of Pm3e to provide powdery mildew field resistance, we generated transgenic Pm3e lines by biolistic transformation of the powdery mildew susceptible spring wheat cultivar Bobwhite. Field trials conducted during four field seasons in Switzerland showed significant and strong powdery mildew resistance of the Pm3e transgenic lines, whereas the corresponding biological sister lines, not containing the transgene, were severely powdery mildew infected. Thus Pm3e alone is responsible for the strong resistance phenotype. The field grown transgenic lines showed high transgene expression and Pm3e protein accumulation with no fitness costs on plant development and yield associated with Pm3e abundance. Line E#1 as well as sister line E#1 showed delayed flowering due to somaclonal variation. The study shows the capability of Pm3e in providing strong powdery mildew field resistance, making its use in wheat breeding programs very promising.


Hepatocellular carcinoma in primary biliary cirrhosis: an autopsy study.
A survey of Japanese autopsy cases of primary biliary cirrhosis disclosed that hepatocellular carcinoma is apparently becoming a better recognized complication of the advanced stage of primary biliary cirrhosis. Six autopsy cases (five women and one man) of primary biliary cirrhosis associated with hepatocellular carcinoma were obtained from several Japanese institutions and examined. All cases were in an established cirrhotic stage of primary biliary cirrhosis. Hepatocellular carcinoma was incidentally found at autopsy in four cases and, in these, the carcinomas were small in size and number. The other two cases showed advanced hepatocellular carcinoma and one case showed extrahepatic metastasis. Histologically, all cases showed well-differentiated hepatocellular carcinomas. Fatty changes or bile plugs were frequently seen within the tumors. Mallory body clusters and focal deposition of copper-binding protein were consistently found in cirrhotic liver tissues and also in the carcinoma tissues of almost all cases. The presence of atypical adenomatous hyperplasia in the peripheries of some carcinomas suggested that hepatocellular carcinoma in primary biliary cirrhosis may evolve through multiple steps.


Bacterium-like particles derived from probiotics: progress, challenges and prospects.
Bacterium-like particles (BLPs) are hollow peptidoglycan particles obtained from food-grade Lactococcus lactis inactivated by hot acid. With the advantage of easy preparation, high safety, great stability, high loading capacity, and high mucosal delivery efficiency, BLPs can load and display proteins on the surface with the help of protein anchor (PA), making BLPs a proper delivery system. Owning to these features, BLPs are widely used in the development of adjuvants, vaccine carriers, virus/antigens purification, and enzyme immobilization. This review has attempted to gather a full understanding of the technical composition, characteristics, applications. The mechanism by which BLPs induces superior adaptive immune responses is also discussed. Besides, this review tracked the latest developments in the field of BLPs, including Lactobacillus-derived BLPs and novel anchors. Finally, the main limitations and proposed breakthrough points to further enhance the immunogenicity of BLPs vaccines were discussed, providing directions for future research. We hope that further developments in the field of antigen delivery of subunit vaccines or others will benefit from BLPs.


Cognitive Load Impairs Time to Initiate and Complete Shooting Tasks in ROTC Members.
Multitasking typically requires an individual to simultaneously process cognitive information while performing a motor task. Cognitive motor interference (CMi) is encountered when cognitive challenges negatively impact motor task performance. Military personnel encounter cognitively taxing situations, especially during combat or other tactical performance scenarios, which may lead to injury or motor performance deficits (i.e., shooting inaccuracy, delayed stimulus-response time, and slowed movement speed). The purpose of the current study was to develop four cognitive motor shooting paradigms to determine the effects of cognitive load on shooting performance in healthy Reserve Officers' Training Corps (ROTC) cadets. Thirty-two healthy collegiate ROTC members (24 male and 8 female; 20.47 ± 1.24 years, 174.95 ± 10.58 cm, and 77.99 ± 13.90 kg) were recruited to complete four simulated shooting tasks with additional "motor" challenge (180° turn, gait, weighted, and unweighted landing) and with and without a "cognitive" decision-making challenge requiring response selection and inhibition to both auditory and visual stimuli, totaling eight multi-task cognitive motor shooting conditions. The current study was approved by the university's Institutional Review Board. Task initiation (seconds), task completion (seconds), and number of misses were calculated to determine marksmanship efficiency and accuracy. For each task, a multivariate repeated-measures analysis of variance (ANOVA) was conducted for the combined dependent variables. If the overall multivariate repeated-measures ANOVA was significant, follow-up univariate ANOVAs were conducted for each dependent variable. Alpha was set at α = 0.05 for all analyses. Task initiation increased for the cognitive condition for the 180° turn (4.29 ± 1.22 seconds baseline, 5.09 ± 1.39 seconds cognitive; P < .05), gait (2.76 ± .60 seconds baseline, 3.93 ± .62 seconds cognitive; P < .05), unweighted (1.27 ± .57 seconds baseline, 3.39 ± .63 seconds cognitive; P < .05), and weighted landing (1.46 ± .72 seconds baseline, 3.35 ± .60 seconds cognitive; P < .05). Task completion time increased for the cognitive condition for the 180° turn (3.48 ± 1.53 seconds baseline, 4.85 ± 1.24 seconds cognitive; P < .05), gait (7.84 ± 2.07 seconds baseline, 9.23 ± 1.76 seconds cognitive; P < .05), unweighted (5.98 ± 1.55 seconds baseline, 7.45 ± 1.51 seconds cognitive; P < .05), and weighted landing (6.09 ± 1.42 seconds baseline, 7.25 ± 1.79 seconds cognitive; P < .05). There were no statistically significant differences in the number of misses for any of the tasks between conditions (P > .05). The addition of a cognitive load increased both task initiation and task completion times during cognitive motor simulated shooting. Adding cognitive loads to tactical performance tasks can result in CMi and negatively impact tactical performance. Thus, consideration for additional cognitive challenges into training may be warranted to reduce the potential CMi effect on tactical performance.


Neuroaxonal Dystrophy and Cavitating Leukoencephalopathy of Chihuahua Dogs.
A novel form of neuroaxonal dystrophy is described in 3 Chihuahua pups, 2 of which were from the same litter. It was characterized not only by accumulation of numerous and widely distributed axonal swellings (spheroids) but also by a severe cavitating leukoencephalopathy. The dogs presented with progressive neurological signs, including gait abnormalities and postural reaction deficits. Magnetic resonance images and gross examination at necropsy revealed dilation of lateral ventricles and cerebral atrophy, accompanied by cavitation of the subcortical white matter. Histopathologically, severe axonal degeneration with formation of large spheroids was found in the cerebral and cerebellar white matter, thalamus, and brainstem nuclei. Small-caliber spheroids were observed in the cerebral and cerebellar gray matter. The telencephalic white matter had severe myelin loss and cavitation with relative sparing of the U-fibers. Different from previously reported cases of canine neuroaxonal dystrophy, in these Chihuahuas the spheroid distribution predominantly involved the white matter with secondary severe leukoencephalopathy.


The mechanism of anteroposterior cell determination in ascidian palleal buds: A gap of positional values triggers posterior formation.
Cell-cell interactions during the development of bud polarity in the polystyelid ascidianPolyandrocarpa misakiensis were studied by juxtaposing normally nondjacent bud pieces from marked stocks. These chimeras have been used to determine the prospective fate of each bud piece with respect to positional disparity. The results showed that the posterior end of a future zooid was always established around the proximal boundary region of the two bud pieces. The anteroposterior axis was skewed from this posterior end toward the bud piece arising from a lower (more anterior) level of the parental zooid, suggesting that the lower level tissue may provide a cue which establishes the site of the future anterior end. The role of positional disparity between bud pieces was further examined by sandwiching a host bud between two grafts of various parental positions. The results showed that an additional positional gap resulted in the formation of an additional posterior structure such as the digestive tract. For example, when the grafts were taken from two or more positions posterior to the host bud, biposterior zooids were induced in 20-30% of the cases. This induction ratio increased to 72.4% if two host buds were used instead of a single host. It is, therefore, concluded that the gap of positional values in ascidian buds triggers the formation of the posterior-most positional value. This cellular response to a positional gap contrasts with the intercalation theory that is predicted by the polar coordinate model for pattern formation.


Epidermal growth factor immunoreactive material in the rat brain. Localization and identification of multiple species.
Brains of adult male rats were dissected into five distinct regions: brainstem, cerebellum, hippocampus, diencephalon, and telencephalon. Epidermal growth factor-like immunoreactivity was isolated and characterized by radioimmunoassay and nondenaturing polyacrylamide gel electrophoresis. Radioimmunoassay indicated levels of standard rat epidermal growth factor equivalents ranging from 0.99 to 0.33 ng/g wet weight of brain tissue. Competition curves were not parallel to those generated with standard rat epidermal growth factor, indicating a lack of structural identity between the immunoreactive material in the brain and standard rat epidermal growth factor. Extracts of submandibular gland and blood did, however, produce parallel competition curves. Electrophoresis indicated the presence of multiple bands of immunoreactive material in each of the regions of the brain. The major bands of activity migrated to positions distinct from that of standard rat epidermal growth factor. This is the first demonstration of multiple forms of epidermal growth factor-like immunoreactive material in the central nervous system.


Impact of MR on mature adipocytes in high-fat/high-sucrose diet-induced obesity
Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice.


Incentive Use for Improving Maternal Health: Perspective From Behavioral Science.
Incentive use to improve maternal health behavior has been controversial, and guidelines to effectively design and implement such an intervention have been published. This commentary briefly describes a perspective from behavioral science for the existing guideline on the development of an incentive-based intervention to change maternal health behaviors. It is recommended to emphasize the saliency of incentives as an important variable to maintain the intervention effect while addressing barriers to feasibility and sustainability.


Melanoma histopathology reporting: are we complying with the National Minimum Dataset?
The Royal College of Pathologists introduced the National Minimum Dataset (NMDS) for the histopathological reporting of cutaneous melanoma in February 2002. To determine if histological reporting of invasive primary cutaneous melanoma in the West Midlands region of the UK was compliant with the NMDS. Reports were identified from March 2002 to March 2003 via the regional Cancer Intelligence Unit, and compared with the NMDS. If all items of the NMDS were adhered to, the report was considered compliant. If not compliant, the report was checked to see if it included selected clinical and staging parameters. 543 cases of invasive cutaneous melanoma were identified, but only 407 reports were analysed. 69/407 (17%) (95% CI 14% to 20%) reports were fully compliant with the NMDS. Of the non-complaint reports, 45/361 (12%) (95% CI 9% to 16%) reported all staging and clinically relevant parameters; 62/361 (17%) (95% CI 59% to 65%) reported all staging parameters. Breslow thickness was reported in all but one of the reports (99.7%), Clark's level was reported in 344/407 (85%), ulceration in 280/407 (69%), and microsatellites in 146/407 (36%). There was slow uptake of the NMDS in this region in the year following its introduction. Although major parameters required for staging were more consistently reported, ulceration and microsatellites were less frequently reported.


Anopheles species composition explains differences in Plasmodium transmission in La Guajira, northern Colombia.
Malaria in La Guajira, the most northern state of Colombia, shows two different epidemiological patterns. Malaria is endemic in the municipality of Dibulla whereas in Riohacha it is characterised by sporadic outbreaks. This study aimed to establish whether differences in transmission patterns could be attributed to different vector species. The most abundant adult female species were Anopheles aquasalis, exclusive to Riohacha, and Anopheles darlingi, restricted to Dibulla. Anopheles mosquitoes were identified using morphology and the molecular markers internal transcribed spacer 2 and cytochrome c oxidase I. All specimens (n = 1,393) were tested by ELISA to determine natural infection rates with Plasmodium falciparum and Plasmodium vivax. An. darlingi was positive for P. vivax 210, with an infection rate of 0.355% and an entomological inoculation rate of 15.87 infective bites/person/year. Anopheles albimanus larvae were the most common species in Riohacha, found in temporary swamps; in contrast, in Dibulla An. darlingi were detected mainly in permanent streams. Distinctive species composition and larval habitats in each municipality may explain the differences in Plasmodium transmission and suggest different local strategies should be used for vector control.


Relaxation processes and glass transition of confined polymer melts: A molecular dynamics simulation of 1,4-polybutadiene between graphite walls.
Molecular dynamics simulations of a chemically realistic model for 1,4-polybutadiene in a thin film geometry confined by two graphite walls are presented. Previous work on melts in the bulk has shown that the model faithfully reproduces static and dynamic properties of the real material over a wide temperature range. The present work studies how these properties change due to nano-confinement. The focus is on orientational correlations observable in nuclear magnetic resonance experiments and on the local intermediate incoherent neutron scattering function, Fs(qz, z, t), for distances z from the graphite walls in the range of a few nanometers. Temperatures from about 2Tg down to about 1.15Tg, where Tg is the glass transition temperature in the bulk, are studied. It is shown that weakly attractive forces between the wall atoms and the monomers suffice to effectively bind a polymer coil that is near the wall. For a wide regime of temperatures, the Arrhenius-like adsorption/desorption kinetics of the monomers is the slowest process, while very close to Tg the Vogel-Fulcher-Tammann-like α-relaxation takes over. The α-process is modified only for z≤1.2 nm due to the density changes near the walls, less than expected from studies of coarse-grained (bead-spring-type) models. The weakness of the surface effects on the glass transition in this case is attributed to the interplay of density changes near the wall with the torsional potential. A brief discussion of pertinent experiments is given.


[Imaging of acute stroke].
Acute stroke patients represent an important diagnostic and therapeutic challenge. Patients with brain damage in the ischemic, but not yet infarcted, phase have the greatest potential for recovery. Here we review the most commonly employed diagnostic tools that are currently used before stroke therapy. While computed tomography is pertinent to differentiate ischemic from hemorrhagic stroke, this technique cannot be used as an etiological screening too. The ischemic origin of symptoms can be confirmed with magnetic resonance imaging which also contributes to for therapeutic decision making, prognosis assessment and etiological screening.


Frequency and location of synkineses in patients with peripheral facial nerve paresis.
Synkinesis is an involuntary movement accompanying a voluntary one. These unintentional movements are caused by an undifferentiated regeneration of the facial nerve that occurs after being compressed or partially damaged. Synkinesis can affect eating, drinking, and speaking and can be socially distressing because of facial asymmetry and disruption of intended emotional expressions. This study aims to describe the frequency and location of synkinesis in patients with peripheral facial nerve paresis. Patients were observed on video and analyzed using a standardized Synkinesis Scoring Form. Five voluntary expressions, derived from the Sunnybrook Facial Grading Scale, were tested: brow lift, eye closure, smile, snarl, and lip pucker. The Kruskal-Wallis test, 95% confidence intervals, and analysis of variance were used to analyze data. Patients with a facial nerve paresis (n = 103) were observed, and all showed synkineses. Lifting-mouth-corner-synkinesis coupled to voluntary brow lift movements (89%) or eye closure (85%) occurred most frequently. The voluntary movement lip puckering evoked the most synkineses of the eye (narrowing, 82%). During all voluntary expressions lifting-brow-synkineses occurred the least (17%). A significant effect for sex and age (p < 0.05) was found but not for side and duration of the paresis (p > 0.05). Mouth-corner-synkinesis is most common in brow lift and eye movements, whereas eye synkinesis is coupled to mouth movements. These are important facts for rehabilitation of facial nerve pareses, to refine and intensify the inhibition and control of synkineses so that facial symmetry and expressions may improve.


Surgical Emphysema in a Pediatric Tertiary Referral Center.
Laryngeal trauma in pediatrics is extremely rare; however, because of the smaller pediatric larynx, it can have catastrophic consequences. Following laryngeal trauma, surgical emphysema is a relatively common presentation. In pediatrics, it can be a life-threatening condition. Here we describe 2 cases of laryngeal trauma resulting in extensive surgical emphysema. The first case described involves bilateral pneumothoraces, airway compromise, and respiratory arrest and was managed with bilateral chest drains, intubation, and tracheostomy. The second case resulted in widespread surgical emphysema in a stable patient and was managed conservatively. Both cases were monitored closely for a period of time to ensure there were no further sequelae. Patients with laryngeal trauma resulting in surgical emphysema have the potential to deteriorate rapidly. Furthermore, surgical emphysema degrades the quality of ultrasound images, which may delay the diagnosis. If there are any concerns about the safety of the airway, then it should be secured definitively with either endotracheal intubation or emergency tracheostomy depending on clinical judgment. It is acceptable to monitor patients closely in a high-dependency unit setting if they are stable and do not show any evidence of laryngeal edema. We present 2 cases of laryngeal trauma that were dealt with effectively so that both patients made a full recovery. It is important to act quickly to secure the airway if there are any concerns about its patency. Stable patients with no evidence of laryngeal edema can be managed conservatively. Close monitoring is essential to prevent any potential airway compromise.


Rhino-orbital-cerebral mucormycosis.
This review focuses on sinus, sino-orbital, and rhinocerebral infection caused by the Mucorales. As the traditional term of "rhinocerebral" mucormycosis omits the critical involvement of the eye, the more comprehensive term as rhino-orbital-cerebral mucormycosis (ROCM) is used. The most common underlying illnesses of ROCM are diabetes mellitus, hematological malignancies, hematopoietic stem cell transplantation, and solid organ transplantation. Sporangiospores are deposited in the nasal turbinates and paranasal sinuses in immunocompromised patients. Qualitative and quantitative abnormalities of neutrophils, monocytes and macrophages increase the risk for development of mucormycosis. Altered iron metabolism also is a critical factor in the pathogenesis of patients with diabetes mellitus who are at risk for ROCM. Angioinvasion with thrombosis and tissue necrosis is a key pathophysiological feature of human Mucorales infection. The ethmoid sinus is a critical site from which sinus mucormycosis may extend through the lamina papyracea into the orbit, extraocular muscles, and optic nerve. The brain may be seeded by invasion of the ethmoidal and orbital veins, which drain into the cavernous sinuses. Diplopia and ophthalmoplegia may be the earliest manifestations of cavernous sinus syndrome before changes are apparent on diagnostic imaging modalities. Negative diagnostic imaging does not exclude cavernous sinus mucormycosis. Mucormycosis of the maxillary sinus has a constellation of clinical features that are different from that of ethmoid sinus mucormycosis. A painful black necrotic ulceration may develop on the hard palate, indicating extension from the maxillary sinus into the oral cavity. Orbital apex syndrome is an ominous complication of mucormycosis of the orbit. Once within the orbital compartment, organisms may extend posteriorly to the optic foramen, where the ophthalmic artery, ophthalmic nerve and optic nerve are threatened by invasion, edema, inflammation and necrosis. Early diagnosis of sinus mucormycosis is critical for prevention of extension to orbital and cerebral tissues. Optimal therapy requires a multidisciplinary approach that relies on prompt institution of appropriate antifungal therapy with amphotericin B, reversal of underlying predisposing conditions, and, where possible, surgical debridement of devitalized tissue. Outcomes are highly dependent upon the degree of immunosuppression, site and extent of infection, timeliness of therapy, and type of treatment provided. New modalities for early diagnosis and therapeutic intervention are critically needed for improved outcome of patients with ROCM.


Adhesion and invasion of Clostridium perfringens type A into epithelial cells.
Clostridium perfringens is the causative agent for necrotic enteritis. It secretes the major virulence factors, and α- and NetB-toxins that are responsible for intestinal lesions. The TpeL toxin affects cell morphology by producing myonecrosis, but its role in the pathogenesis of necrotic enteritis is unclear. In this study, the presence of netB and tpeL genes in C. perfringens type A strains isolated from chickens with necrotic enteritis, their cytotoxic effects and role in adhesion and invasion of epithelial cells were evaluated. Six (27.3%) of the 22 C. perfringens type A strains were harboring the tpeL gene and produced morphological alterations in Vero cells after 6h of incubation. Strains tpeL (-) induced strong cell rounding after 6h of incubation and produced cell enlargement. None of the 22 strains harbored netB gene. All the six tpeL (+) gene strains were able to adhere to HEp-2 cells; however, only four of them (66.6%) were invasive. Thus, these results suggest that the presence of tpeL gene or TpeL toxin might be required for the adherence of bacteria to HEp-2 cells; however, it could not have any role in the invasion process.


stVAE deconvolves cell-type composition in large-scale cellular resolution spatial transcriptomics.
Recent rapid developments in spatial transcriptomic techniques at cellular resolution have gained increasing attention. However, the unique characteristics of large-scale cellular resolution spatial transcriptomic datasets, such as the limited number of transcripts captured per spot and the vast number of spots, pose significant challenges to current cell-type deconvolution methods. In this study, we introduce stVAE, a method based on the variational autoencoder framework to deconvolve the cell-type composition of cellular resolution spatial transcriptomic datasets. To assess the performance of stVAE, we apply it to five datasets across three different biological tissues. In the Stereo-seq and Slide-seqV2 datasets of the mouse brain, stVAE accurately reconstructs the laminar structure of the pyramidal cell layers in the cortex, which are mainly organized by the subtypes of telencephalon projecting excitatory neurons. In the Stereo-seq dataset of the E12.5 mouse embryo, stVAE resolves the complex spatial patterns of osteoblast subtypes, which are supported by their marker genes. In Stereo-seq and Pixel-seq datasets of the mouse olfactory bulb, stVAE accurately delineates the spatial distributions of known cell types. In summary, stVAE can accurately identify spatial patterns of cell types and their relative proportions across spots for cellular resolution spatial transcriptomic data. It is instrumental in understanding the heterogeneity of cell populations and their interactions within tissues. stVAE is available in GitHub (https://github.com/lichen2018/stVAE) and Figshare (https://figshare.com/articles/software/stVAE/23254538).


Primary ovarian leiomyoma in a postmenopausal woman: A case report.
Leiomyomas are benign neoplasms that can develop wherever smooth muscle is present. Primary leiomyomas of the ovary originate from smooth muscle cells of ovarian tissue and are rare, solitary tumors. Approximately 70 cases have been reported. They usually present in premenopausal women. The present case is a report of left ovarian leiomyoma in a postmenopausal woman.


Investigating the longitudinal effects of surface acting on managers' functioning through psychological needs.
This study is based on the premise that managers are expected to regulate their emotions in the form of surface acting. More specifically, drawing on self-determination theory, we explored the role of psychological needs for autonomy, competence, and relatedness in explaining the influence of surface acting on supervisors' job satisfaction and work engagement over time. Data were collected at 2 time points, over a 3-month period, from a sample of 435 French managers working in the health care industry. Results revealed that surface acting negatively predicted managers' job satisfaction and work engagement over time, through the satisfaction of their psychological needs. However, managers' need thwarting did not explain these positive outcomes. Overall, these findings provide insight into the longitudinal adverse effects of managers' surface acting on their functioning and corroborate the distinct role of psychological need satisfaction and thwarting. Theoretical contributions and perspectives, as well as implications for practice are discussed. (PsycINFO Database Record


Endoanal ultrasound.
This pictorial review demonstrates the normal anatomy and abnormalities that are readily demonstrated with endoanal ultrasound of the anal sphincters.


Anterior knee-pain syndrome.
Anterior knee-pain syndrome would best be defined as a painful condition that arises in or around the patellofemoral joint and is insidious in onset and bilateral, with no macroscopic gross pathology. Anterior knee pain as a descriptive term would define the need to search further for a specific cause of pain, because neither patellar cartilage damage nor malalignment would necessarily be correlated to pain. The examining physician should be aware that specifically in adolescents the higher chance would be that, eventually, no clear-cut pathology would be found; thus, great caution should be taken before diagnosing anterior knee-pain syndrome as existing unilaterally. It could be claimed, following the above, that as opposed to the term "anterior knee pain," the term "anterior knee-pain syndrome" is an exclusion diagnosis that can be applied after macroscopic pathology has been ruled out.


Pre-exposure prophylaxis among men who have sex with men in the Amsterdam Cohort Studies: Use, eligibility, and intention to use.
Currently, HIV pre-exposure prophylaxis (PrEP) is not covered by health insurance in the Netherlands. We examined time trends in use of PrEP, characteristics of PrEP users, PrEP eligibility and intention to use PrEP among HIV-negative men who have sex with men (MSM) participating in the Amsterdam Cohort Studies (ACS). Prospective cohort study. We used data from four 6-monthly questionnaire waves, collected between 2015-2017. PrEP use over time was examined in logistic regression models using generalized estimating equations. Using descriptive statistics, we compared PrEP users before first-time initiation to non-PrEP-users. We used national guidelines to assess PrEP eligibility. We included 687 MSM. Median age was 40 (IQR 33-47) years in 2015. Recent PrEP use was reported by 57/687 (8%) MSM. PrEP use increased over calendar time (P<0.001) to 7% in 2017. PrEP users did not differ from non-PrEP users in socio-demographic characteristics, but reported a significantly higher median number of casual sex partners, more often reported condomless anal sex and chemsex with casual partners, and more often had an sexually transmitted infection in the preceding 6 months (all P<0.05). PrEP eligibility increased over time, but the effect was not statistically significant (P = 0.075). PrEP eligibility criteria were met by 149/460 (32%) at wave 4, of whom 31/149 (21%) reported use of PrEP. The proportion with a high intention to use PrEP was greater among eligible than non-eligible MSM (51% vs. 24%, P<0.001). PrEP use increased over time but remained under 10%, even though 32% met the eligibility criteria, of whom 51% had a high intention to use PrEP. This suggests that a large proportion of Dutch MSM at risk could benefit from PrEP.


Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection.
Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.


MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells.
Amino acid (AA) deprivation in mammalian cells activates a collection of signaling cascades known as the AA response (AAR), which is characterized by transcriptional induction of stress-related genes, including FBJ murine osteosarcoma viral oncogene homolog (cFOS). The present study established that the signaling mechanism underlying the AA-dependent transcriptional regulation of the cFOS gene in HepG2 human hepatocellular carcinoma cells is independent of the classic GCN2-eIF2-ATF4 pathway. Instead, a RAS-RAF-MEK-ERK cascade mediates AAR signaling to the cFOS gene. Increased cFOS transcription is observed from 4-24 h after AAR-activation, exhibiting little or no overlap with the rapid and transient increase triggered by the well-known serum response. Furthermore, serum is not required for the AA-responsiveness of the cFOS gene and no phosphorylation of promoter-bound serum response factor (SRF) is observed. The ERK-phosphorylated transcription factor E-twenty six-like (p-ELK1) is increased in its association with the cFOS promoter after activation of the AAR. This research identified cFOS as a target of the AAR and further highlights the importance of AA-responsive MAPK signaling in HepG2 cells.


Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia-reperfusion injury.
Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model. The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW). The anti-Xa compound was injected intravenously before warm ischaemia and used during cold storage, and its effects were compared with those of intravenous injection of unfractionated heparin (UFH) before warm ischaemia and use during cold storage, or use of UW alone during cold storage. At 3 months after transplantation, anti-Xa treatment improved recovery of renal function and chronic serum creatinine levels compared with UW and UFH (mean(s.e.m.) 89(4), 250(4) and 217(8) µmol/l respectively). The anti-Xa treatment also reduced fibrosis, and decreased tissue expression of markers of the epithelial-mesenchymal transition compared with UW and UFH. Cleaved protease-activated receptor 2 was overexpressed in the UW group compared with the anti-Xa and UFH groups. Leucocyte infiltrates were decreased in the anti-Xa group compared with the UW and UFH groups. Macrophage invasion was also decreased by anticoagulation treatment. Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.


Reconciling Differences between Lipid Transfer in Free-Standing and Solid Supported Membranes: A Time-Resolved Small-Angle Neutron Scattering Study.
Maintaining compositional lipid gradients across membranes in animal cells is essential to biological function, but what is the energetic cost to maintain these differences? It has long been recognized that studying the passive movement of lipids in membranes can provide insight into this toll. Confusingly the reported values of inter- and, particularly, intra-lipid transport rates of lipids in membranes show significant differences. To overcome this difficulty, biases introduced by experimental approaches have to be identified. The present study addresses the difference in the reported intramembrane transport rates of dimyristoylphosphatidylcholine (DMPC) on flat solid supports (fast flipping) and in curved free-standing membranes (slow flipping). Two possible scenarios are potentially at play: one is the difference in curvature of the membranes studied and the other the presence (or not) of the support. Using DMPC vesicles and DMPC supported membranes on silica nanoparticles of different radii, we found that an increase in curvature (from a diameter of 30 nm to a diameter of 100 nm) does not change the rates significantly, differing only by factors of order ∼1. Additionally, we found that the exchange rates of DMPC in supported membranes are similar to the ones in vesicles. And as previously reported, we found that the activation energies for exchange on free-standing and supported membranes are similar (84 and 78 kJ/mol, respectively). However, DMPC's flip-flop rates increase significantly when in a supported membrane, surpassing the exchange rates and no longer limiting the exchange process. Although the presence of holes or cracks in supported membranes explains the occurrence of fast lipid flip-flop in many studies, in defect-free supported membranes we find that fast flip-flop is driven by the surface's induced disorder of the bilayer's acyl chain packing as evidenced from their broad melting temperature behavior.


Prevalence and distribution of caries in a Jerusalem adolescent population by age, sex, and family income.
Four hundred and fourteen high school students aged 12-17 were examined clinically using the DMFS index and bitewing radiographs. Analyses by age, sex, economic status, and types of teeth and tooth surfaces were performed and results were compared with other international studies. Only 7.5 percent of the study population had a zero DMFS score. Females had a significantly higher DMFS score than males (13.21 vs 9.59). Caries experience increased with age and a general trend of increasing DMFS was observed with increasing levels of income. Socioeconomic status (SES) was related directly to DMFS in Israel, in contrast to an inverse relationship observed in most other western countries. First molars were most susceptible to caries attack and accounted for 41.2 percent of the total DMFS. Almost 50 percent of all affected surfaces were occlusal and 29.4 percent were proximal. Caries prevalence in general and proximal caries in particular were found to be much higher in the study population than corresponding figures in other industrialized countries. A significant decrease in caries prevalence could be expected in Israel in the next decade if primary preventive measures are implemented immediately.


Combinatorial Effect of Abiraterone Acetate and NVP-BEZ235 on Prostate Tumor Progression in Rats.
Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.


Generation of Tumor Organoids from Genetically Engineered Mouse Models of Prostate Cancer.
Methods based on homologous recombination to modify genes have significantly furthered biological research. Genetically engineered mouse models (GEMMs) are a rigorous method for studying mammalian development and disease. Our laboratory has developed several GEMMs of prostate cancer (PCa) that lack expression of one or multiple tumor suppressor genes using the site-specific Cre-loxP recombinase system and a prostate-specific promoter. In this article, we describe our method for necropsy of these PCa GEMMs, primarily focusing on dissection of mouse prostate tumors. New methods developed over the last decade have facilitated the culture of epithelial-derived cells to model organ systems in vitro in three dimensions. We also detail a 3D cell culture method to generate tumor organoids from mouse PCa GEMMs. Pre-clinical cancer research has been dominated by 2D cell culture and cell line-derived or patient-derived xenograft models. These methods lack tumor microenvironment, a limitation of using these techniques in pre-clinical studies. GEMMs are more physiologically-relevant for understanding tumorigenesis and cancer progression. Tumor organoid culture is an in vitro model system that recapitulates tumor architecture and cell lineage characteristics. In addition, 3D cell culture methods allow for growth of normal cells for comparison to tumor cell cultures, rarely possible using 2D cell culture techniques. In combination, use of GEMMs and 3D cell culture in pre-clinical studies has the potential to improve our understanding of cancer biology.


Alkyne Hydrogenation Catalysis across a Family of Ga/In Layered Zintl Phases.
Transition-metal-free Zintl-Klemm phases have received little attention as heterogeneous catalysis. Here, we show that a large family of structurally and electronically similar layered Zintl-Klemm phases built from honeycomb layers of group 13 triel (Tr) or group 14 tetrel (Tt) networks separated by electropositive cations (A) and having a stoichiometry of ATr2 or ATrTt (A = Ca, Ba, Y, La, Eu; Tr = Ga, In; Tt = Si, Ge) exhibit varying degrees of activity for the hydrogenation of phenylacetylene to styrene and ethylbenzene at 51 bar H2 and 40-100 °C across a variety of solvents. The most active catalysts contain Ga with, formally, a half-filled pz orbital, and minimal bonding between neighboring Tr2 or TrTt layers. A 13-layer trigonal polytype of CaGaGe (13T-CaGaGe) was the most active, cyclable, and robust catalyst and under modest conditions (1 atm H2, 40 °C) had a surface specific activity (590 h-1) comparable to a commercial Lindlar's catalyst. Additionally, 13T-CaGaGe maintained 100% conversion of phenylacetylene to styrene at 51 bar H2, even after 5 months of air exposure. This work reveals the structural design elements that lead to particularly high catalytic activity in Zintl-Klemm phases, further establishing them as a promising materials platform for hydrogen-based heterogeneous catalysis.


Multicenter experience: prevention and management of left ventricular assist device infections.
Implantable left ventricular assist devices (LVADs) have demonstrated clinical success in both the bridge-to-transplantation and destination-therapy patient populations; however, infection remains one of the most common causes of mortality during mechanical circulatory support. Thus, serious LVAD infections may negate the benefits of LVAD implantation, resulting in decreased quality of life, increased morbidity and mortality, and increased costs associated with implantation. Prevention of device-related infection is crucial to the cost-effective use of mechanical circulatory support devices. Therefore, adherence to evidence-based infection control and prevention guidelines, meticulous surgical technique and optimal postoperative surgical site care form the foundation for LVAD associated infection prevention.


Uncertain responses by humans and rhesus monkeys (Macaca mulatta) in a psychophysical same-different task.
The authors asked whether animals, like humans, use an uncertain response adaptively to escape indeterminate stimulus relations. Humans and monkeys were placed in a same-different task, known to be challenging for animals. Its difficulty was increased further by reducing the size of the stimulus differences, thereby making many same and different trials difficult to tell apart. Monkeys do escape selectively from these threshold trials, even while coping with 7 absolute stimulus levels concurrently. Monkeys even adjust their response strategies on short time scales according to the local task conditions. Signal-detection and optimality analyses confirm the similarity of humans' and animals' performances. Whereas associative interpretations account poorly for these results, an intuitive uncertainty construct does so easily. The authors discuss the cognitive processes that allow uncertainty's adaptive use and recommend further comparative studies of metacognition.


Myocarditis in Paediatric Patients: Unveiling the Progression to Dilated Cardiomyopathy and Heart Failure.
Myocarditis is a challenging and potentially life-threatening disease associated with high morbidity in some paediatric patients, due to its ability to present as an acute and fulminant disease and to ultimately progress to dilated cardiomyopathy. It has been described as an inflammatory disease of the myocardium caused by diverse aetiologies. Viral infection is the most frequent cause of myocarditis in developed countries, but bacterial and protozoal infections or drug hypersensitivity may also be causative agents. The prompt diagnosis in paediatric patients is difficult, as the spectrum of clinical manifestation can range from no myocardial dysfunction to sudden cardiac death. Recent studies on myocarditis pathogenesis have revealed a triphasic nature of this disease, which influences the diagnostic and therapeutic strategies to adopt in each patient. Endomyocardial biopsy remains the gold standard for diagnosing myocarditis, and several non-invasive diagnostic tools can be used to support the diagnosis. Intravenous immunoglobulin has become part of routine practice in the treatment of myocarditis in paediatric patients at many centres, but its true effect on the cardiac function has been the target of many studies. The aim of this review is to approach the recently discovered facets of paediatric myocarditis regarding its progression to dilated cardiomyopathy.


Chemical Composition of Patrinia scabiosifolia Flower Absolute and Its Migratory and Proliferative Activities in Human Keratinocytes.
Patrinia scabiosifolia (PS) has bioactivities such as antitumor and anti-inflammation effects. However, its effects on human skin physiological activities, such as skin regeneration and wound healing, remain unclear. In this study, we investigated the effects of absolute extracted from PS flower (PSF) on migration and proliferation of human dermal keratinocyte (HaCat). The yield of PSF absolute obtained by solvent extraction method was 0.105 % and its five constituents were found in GC/MS analysis. The PSF absolute induced the proliferation and migration of HaCats. The absolute increased the phosphorylation of serine/threonine-specific protein kinase (Akt) and extracellular signal-regulated kinase1/2 (Erk1/2) in HaCats. In addition, the absolute stimulated the outgrowth of collagen sprouting of HaCats. These results demonstrated, for the first time, that PSF absolute may have positive effects on skin regeneration and/or wound healing by inducing migration and proliferation of dermal keratinocytes via the Akt/Erk1/2 pathway. Therefore, PSF absolute may be a useful natural material for skin regeneration and/or wound healing.


Perceived positive teacher-student relationship as a protective factor for Chinese left-behind children's emotional and behavioural adjustment.
Using cross-sectional data collected in rural communities of two provinces of China, this study examined the protective role of perceived positive teacher-student relationship for Chinese left-behind children. The participants included 1442 children with a mean age of 14.13 classified into two groups: a left-behind group (104 boys and 110 girls) and a comparison group (588 boys and 640 girls). Self-reported questionnaires concerning self-esteem, depression, problem behaviours and the teacher-student relationship were administered. Relative to the comparison group, after controlling for age, gender and family socioeconomic status, the left-behind group was disadvantaged in terms of self-esteem and depression but not in problem behaviours. As hypothesised, the results of regression analyses indicated that teacher-student relationship positively predicted self-esteem and negatively predicted depression and problem behaviours for both groups. Moreover, the association between teacher-student relationship and depression was stronger among the left-behind group, suggesting that left-behind children were more responsive to the positive effect of a desired teacher-student relationship. Taken together, the results of our study support the idea that perceived positive teacher-student relationship may serve as a protective factor for left-behind children. Practical implications and limitations of the present study are discussed.


Dracocephalum moldavica L. extract alleviates experimental colitis in rats by modulating gut microbiome and inflammatory pathways.
Several studies have revealed that an imbalance of the intestinal microbiota is involved in intestinal inflammation associated with ulcerative colitis (UC). Therefore, regulating the homeostasis of gut microbiota is critical for treating UC. Dracocephalum moldavica L. (DML) extract, a common traditional Chinese medicine, has been demonstrated to possess numerous pharmacological effects, such as antioxidative, anti‑inflammatory, and antibacterial properties. The aim of the present study was to evaluate the beneficial effects of DML extract and the probable mechanism of action in a dextran sulfate sodium‑induced chronic colitis model. It was found that DML extract ameliorated UC by improving disease activity index, weight loss, colon length, and histological scoring. DML extract administration also enhanced the count of Lactobacillus and reduced the count of Romboutsia. Furthermore, the results of network pharmacology analysis revealed that the active ingredients (including luteolin, rosmarinic acid, oleanolic acid, ursolic acid, apigenin, acacetin, kaempferol, and isorhamnetin) in the DML extract were closely associated with anti‑inflammatory activity via various signaling pathways, including the NF‑κB, IL‑17, TNF, and Toll‑like receptor (TLR) signaling pathways. Western blot analysis further indicated that DML extract downregulated the expression of members of the TLR4/NF‑κB signaling pathway, which was associated with colitis. Thus, it was hypothesized that DML extract exerted its anti‑colitis effects by modulating the gut microbiota and inflammatory pathways.


Explanatory Object Part Aggregation for Zero-Shot Learning.
Zero-shot learning (ZSL) aims to recognize objects from unseen classes only based on labeled images from seen classes. Most existing ZSL methods focus on optimizing feature spaces or generating visual features of unseen classes, both in conventional ZSL and generalized zero-shot learning (GZSL). However, since the learned feature spaces are suboptimal, there exists many virtual connections where visual features and semantic attributes are not corresponding to each other. To reduce virtual connections, in this paper, we propose to discover comprehensive and fine-grained object parts by building explanatory graphs based on convolutional feature maps, then aggregate object parts to train a part-net to obtain prediction results. Since the aggregated object parts contain comprehensive visual features for activating semantic attributes, the virtual connections can be reduced by a large extent. Since part-net aims to extract local fine-grained visual features, some attributes related to global structures are ignored. To take advantage of both local and global visual features, we design a feature distiller to distill local features into a master-net which aims to extract global features. The experimental results on AWA2, CUB, FLO, and SUN dataset demonstrate that our proposed method obviously outperforms the state-of-the-arts in both conventional ZSL and GZSL tasks.


Bimetallic metal organic frameworks with precisely positioned metal centers for efficient H2 storage.
We demonstrated that the ratio and position of two different metal ions, Pd and Cu, can be precisely controlled within MOFs through predesigned metal clusters. These MOF structures incorporating Pd-Cu paddle wheel units were synthesised simply by reacting Pd-Cu acetate metal clusters and tritopic organic linkers at room temperature. Pd-Cu open metal sites were found to be uniformly distributed throughout the MOFs with a ca. 1 : 1 ratio. The incorporation of Pd into the MOF structure also led to enhanced affinity towards H2 with Qst values up to 8.9 kJ mol-1.


Quadrupole-mediated dielectric response and the charge-asymmetric solvation of ions in water.
Treating water as a linearly responding dielectric continuum on molecular length scales allows very simple estimates of the solvation structure and thermodynamics for charged and polar solutes. While this approach can successfully account for basic length and energy scales of ion solvation, computer simulations indicate not only its quantitative inaccuracies but also its inability to capture some basic and important aspects of microscopic polarization response. Here, we consider one such shortcoming, a failure to distinguish the solvation thermodynamics of cations from that of otherwise-identical anions, and we pursue a simple, physically inspired modification of the dielectric continuum model to address it. The adaptation is motivated by analyzing the orientational response of an isolated water molecule whose dipole is rigidly constrained. Its free energy suggests a Hamiltonian for dipole fluctuations that accounts implicitly for the influence of higher-order multipole moments while respecting constraints of molecular geometry. We propose a field theory with the suggested form, whose nonlinear response breaks the charge symmetry of ion solvation. An approximate variational solution of this theory, with a single adjustable parameter, yields solvation free energies that agree closely with simulation results over a considerable range of solute size and charge.


In vitro studies of archaeal translational initiation.
Initiation is the step of translation that has incurred the greatest evolutionary divergence. In silico and experimental studies have shown that archaeal translation initiation resembles neither the bacterial nor the eukaryotic paradigm, but shares features with both. The structure of mRNA in archaea is similar to the bacterial one, although the protein factors that assist translational initiation are more numerous than in bacteria and are homologous to eukaryotic proteins. This chapter describes a number of techniques that can be used for in vitro studies of archaeal translation and translational initiation, using as a model system the thermophilic crenarcheon Sulfolobus solfataricus, growing optimally at about 80 degrees in an acidic environment.


Characterization of the murine heat-stable antigen: an hematolymphoid differentiation antigen defined by the J11d, M1/69 and B2A2 antibodies.
The heat-stable antigen (HSA) is a marker of hematopoietic differentiation in both the B and T cell lineages. The antigen is recognized by a series of monoclonal antibodies which includes J11d, M1/69 and B2A2, and in addition YBM5.10.4. We show here that all these antibodies recognize the same antigenic determinant which is expressed on a variably glycosylated membrane protein. Tunicamycin experiments show that the antigen is not carbohydrate in nature as it is expressed on two unglycosylated protein core molecules of molecular mass ca. 20 kDa and 17 kDa. Furthermore, the antigenic determinant appears to be lost following phosphatidylinositol-specific phospholipase C cleavage. Although the molecular mass of HSA appears to be heterogenous on cells of different lineages, these variations in size appear to be due primarily to differences in the extent of N-linked glycosylation, since both protein core molecules were found in all cell types investigated which express the antigen. These findings have important implications for the structure and function of this antigen and its role in hematopoietic development.


Quantum dynamics in simple fluids.
We use quantum-correction factors to calculate approximately the quantum velocity time-correlation function (TCF) of supercritical Lennard-Jones argon from the classical TCF. We find that for this quite classical system, several different quantum-correction schemes yield essentially identical results for the real and imaginary parts of the quantum TCF, and also agree well with the recent forward-backward semiclassical dynamics (FBSD) results of Wright and Makri [J. Chem. Phys. 119, 1634 (2003)]. We also consider a more quantum-mechanical fluid of lighter atoms (neon) at a lower temperature. In this case different quantum-correction schemes give different results. FBSD calculations show that the harmonic quantum correction factor works the best for this system


The influence of placebo administration on the first- night effect in patients with insomnia disorder.
We aimed to investigate the effects of placebo on the first-night effect (FNE) in insomniacs. In sum, 36 patients with insomnia disorder who met the DSM-5 criteria were enrolled in this study. Sixteen patients with insomnia disorder were given two days of placebo intervention (placebo-administration group, PL). Twenty patients with insomnia disorder (drug-free group, DF) were not given any interventions. All participants underwent two consecutive nights of polysomnographic (PSG) testing in the sleep laboratory. Sleep diaries were recorded during one week at home before the PSG nights and on two subsequent nights. The results demonstrated that compared with the DF group, sleep onset latency (SOL), time in bed (TIB) and wake after sleep onset (WASO) significantly increased and sleep efficiency (SE) significantly decreased in the first sleep lab night in the PL group (all p < 0.05). Moreover, compared with the second night, significant differences were observed in lower self-reported total sleep time (TST) and more subjective WASO during the first night in the PL group (all p < 0.05). However, no significant difference was found in the duration and percentage of N1, N2, N3 and REM between the two groups. In patients with insomnia disorder, placebo administration may increase the occurrence of worse sleep without causing a change in the duration and percentage of N1, N2, N3 and REM on the first sleep lab night. In some cases, a placebo may not serve as treatment but may result in a nocebo effect.


Assessment of the effects of multiple extreme floods on flow and transport processes under competing flood protection and environmental management strategies.
Extreme floods are regarded as one of the most catastrophic natural hazards and can result in significant morphological changes induced by pronounced sediment erosion and deposition processes over the landscape. However, the effects of extreme floods of different return intervals on the floodplain and river channel morphological evolution with the associated sediment transport processes are not well explored. Furthermore, different basin management action plans, such as engineering structure modifications, may also greatly affect the flood inundation, sediment transport, solute transport and morphological processes within extreme flood events. In this study, a coupled two-dimensional hydrodynamic, sediment transport and morphological model is applied to evaluate the impact of different river and basin management strategies on the flood inundation, sediment transport dynamics and morphological changes within extreme flood events of different magnitudes. The 10-year, 50-year, 100-year and 200-year floods are evaluated for the Lower Cache Creek system in California under existing condition and a potential future modification scenario. Modeling results showed that select locations of flood inundation within the study area tend to experience larger inundation depth and more sediment is likely to be trapped in the study area under potential modification scenario. The proposed two dimensional flow and sediment transport modeling approach implemented with a variety of inflow conditions can provide guidance to decision-makers when considering implementation of potential modification plans, especially as they relate to competing management strategies of large water bodies, such as the modeling area in this study.


[Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior].
Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed.


Prognostic evaluation by clinical exercise test scores in patients treated with primary percutaneous coronary intervention or fibrinolysis for acute myocardial infarction (a Danish Trial in Acute Myocardial Infarction-2 Sub-Study).
The prognostic accuracy of exercise testing after myocardial infarction is low, and different models have been proposed to enhance the predictive value for subsequent mortality. This study tested a simple score against 3 established scores. Patients with ST-elevation myocardial infarctions were randomized in the Danish Trial in Acute Myocardial Infarction-2 (DANAMI-2) to either primary percutaneous coronary intervention or fibrinolysis with predischarge exercise testing. Clinical and exercise test data were collected prospectively and were available for 1,115 patients. A simple score was derived, awarding 1 point for history or new signs of heart failure, 1 point for a left ventricular ejection fraction <40%, 1 point for age >65 years in men and age >70 years in women, and 1 point for exercise capacity <5 METs in men and exercise capacity <4 METs in women. This DANAMI score was compared with the Veterans Affairs Medical Center score, the Duke treadmill score, and the Gruppo Italiano per lo Studio Della Sopravvivenza nell'Infarto Miocardico-2 (GISSI-2) score in multivariate Cox models and receiver-operating characteristic plots. All scoring systems were predictive of adverse outcomes. The DANAMI score performed better, with greater chi-square values (142 vs 53 to 88 for the prediction of death). Areas under the receiver-operating characteristic curves were compared and were larger for the DANAMI score (C-statistic 0.79 vs 0.71 to 0.74 for the other tests regarding mortality). The DANAMI score stratified patients into a small high-risk group (8% of the population with 43% mortality in 6 years), an intermediate-risk group (13% with 16% mortality in 6 years), and a low-risk group (79% with 4% mortality in 6 years). In conclusion, a simple exercise test score composed of age, METs, heart failure, and a left ventricular ejection fraction <40% seems to outperform the Duke treadmill score, Veterans Affairs Medical Center score, and GISSI-2 score in risk stratifying patients after myocardial infarction and deserves further evaluation.


Effects of long- and short-term darbepoetin-α treatment on oxidative stress, inflammation and endothelial injury in ApoE knockout mice.
Atherosclerosis and atherosclerosis-related complications are the main cause of death in the world. Vascular injury in response to inflammation and enhanced oxidant stress promotes endothelial dysfunction and leads to atherosclerotic lesions. Low-dose treatment with darbepoetin-α may be a potential therapeutic tool for endothelial injury and atherosclerosis. In order to study the effect of darbepoetin-α on endothelial injury and atherosclerosis, we used ApoE-/- mice as the atherosclerotic mice model. We monitored atherosclerosis and plaque formation histochemically in ApoE knockout mice at early and late stages of atherosclerosis. Darbepoetin-α was injected intraperitoneally at a dose of 0.1 μg/kg to ApoE-/- mice. The results of 2 ApoE-/- mice groups injected with darbepoetin-α (early and late stages of atherosclerosis) were compared to the results of the corresponding saline injected ApoE-/- mice groups and the control (C57BL/6) mice. Lipid profile (total cholesterol, triglyceride), inflammation (CRP, IL-6, histamine), endothelial injury (ICAM-1, selectin) and oxidative stress markers (lipid peroxidation, protein oxidation) were significantly increased in 4 atherosclerotic groups compared to the control group. Short-term darbepoetin-α had no marked effects on indicators of inflammation and endothelial injury in the ApoE knockout mice groups compared to the ApoE knockout mice not treated with darbepoetin-α, however, darbepoetin-α significantly decreased 8-isoprostane and protein carbonyl content. Long term darbepoetin-α treatment reduced oxidative stress in ApoE-/- mice. This study contributes to understanding and elucidating the biochemical changes occurring during early and late stages of atherosclerosis development regarding lipid profile, inflammation, endothelial injury and oxidative stress markers.


Effect of syllable articulation on precision and power grip performance.
The present study was motivated by a theory, which proposes that speech includes articulatory gestures that are connected to particular hand actions. We hypothesized that certain articulatory gestures would be more associated with the precision grip than with the power grip, and vice versa. In the study, the participants pronounced a syllable and performed simultaneously a precision or power grip that was theorized to be either congruent or incongruent with the syllable. Relatively fast precision grip responses were associated with articulatory gestures in which the tip of the tongue contacted the alveolar ridge ([te]) or the aperture of the vocal tract remained small ([hi]), as well as gestures that required lip protrusion ([pu]). In contrast, relatively fast power grip responses were associated with gestures that were produced by moving the back of the tongue against the velum ([ke]) or in which the aperture of the vocal tract remained large ([hα]). In addition to demonstrating that certain articulatory gestures are systematically connected to different grip types, the study may shed some light on discussion concerning sound symbolism and evolution of speech.


Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids.
Muscle fatty acid binding protein (M-FABP) is one of a family of cytosolic lipid-binding proteins involved in fatty acid processing. In order to investigate the precise interactions between M-FABP and its ligands and to understand the structural basis of differential binding affinity, we have compared the structures of M-FABP in complex with three C18 fatty acids. We describe the crystal structures of M-FABP in complex with n-octadecanoate (stearate), trans-delta 9-octadecenoate (elaidate) and cis-delta 9-octadecenoate (oleate). These structures were refined using least-squares positional and anisotropic temperature factor refinement to final R-factors of 11.4%, 12.1% and 13.2% respectively for all the data between 8.0 A and 1.4 A resolution. Stearate, elaidate and oleate each adopt highly similar U-shaped conformations when they bind to M-FABP within a large interior binding cavity, which also contains 13 ordered water molecules. The atomic structure of the protein is virtually identical, regardless of the nature of the bound ligand. The fatty acid is thought to enter the interior cavity of the protein via a portal in its surface while interior solvent is released through a secondary opening. The ligand affinity can be correlated with the conformational energy and the solubility of the bound ligand.


Calorimetric study of octylcyanobiphenyl liquid crystal confined to a controlled-pore glass.
We present a calorimetric study of the phase behavior of octylcyanobiphenyl (8CB) liquid crystal confined to a controlled-pore glass (CPG). We used CPG matrices with characteristic void diameters ranging from 400 to 20 nm. In bulk we obtain weakly first-order isotropic to nematic (I-N) phase transition and nearly continuous character of the nematic to smectic-A (N-SmA) phase transition. In all CPG matrices the I-N transition remains weakly first order, while the N-SmA one becomes progressively suppressed with decreasing CPG pore radius. With decreased pore diameters both phase transition temperatures monotonously decrease following similar trends, but increasing the stability range of the N phase. The heat-capacity response at the weakly first order I-N and continuous N-SmA phase transitions gradually approaches the tricritical-like and three-dimensional XY behavior, respectively. The main observed features were explained using a bicomponent single pore type phenomenological model.