Thermodynamic efficiency of brittle frictional mountain building.
An active fold-and-thrust belt in unchanging tectonic and climatic conditions attains a dynamic steady-state in which the influx of accreted material at the toe is balanced by the erosive efflux off the top. The overall balance of energy in such a steady-state fold-and-thrust belt is described by the equation E = W(G) + Q, where E is the rate at which both mechanical and heat energy are added from external sources, W(G) is the rate of work performed against gravitational body forces, and Q is the rate at which waste heat flows out of the upper and lower boundaries. The total amount of power being supplied to the active Taiwan fold-and-thrust belt by the subducting Eurasian plate and in situ radioactivity is 4.2 gigawatts. Because only 0.5 gigawatts are expended in doing useful work against gravity and the remaining 3.7 gigawatts are ejected as heat, the efficiency of brittle frictional mountain building in Taiwan is 11 percent.


[CURRENT STATUS AND FUTURE PERSPECTIVES OF ROBOTIC SURGERY].
The Da Vinci Surgical System was developed to overcome some of the disadvantages of conventional endoscopic surgery. We have been performing robotic gastrectomy or esophagectomy in patients with resectable gastric or esophageal cancer who agreed to uninsured use of the robot since 2009, resulting in reduced postoperative local complications including pancreatic fistula following gastrectomy and recurrent laryngeal nerve palsy after esophagectomy. Moreover, the greater the extent of resection and lymph node dissection, the greater this effect, suggesting that the robot may be more beneficial for advanced cancer than for early cancer. In the meantime, there have been a considerable number of reports, mostly focusing on early cancer, that the use of the robot may reduce cost-effectiveness in comparison with the conventional laparoscopic or thoracoscopic approach. Thus, since the beginning of October 2014, we have been conducting a multiinstitutional, single-arm prospective study designed to determine the impact of robotic assistance, which has been approved as advanced medical technology (senshiniryo) by the Japanese Ministry of Health, Labor and Welfare, on the outcomes after minimally invasive radical gastrectomy to treat resectable gastric cancer, with a focus on postoperative complications, long-term outcomes, and cost.


Immunohistochemistry of pancreatic neoplasia.
Immunohistochemistry (IHC) is a valuable tool to visualize the distribution and localization of specific cellular components within morphologically preserved tissue sections or cell preparations. It combines the histologic morphology of tissues for detecting the actual antigen distribution, specificity of antibody-antigen interaction for optimal detection, and sensitivity of immunochemical methods for assessing the amount of antigen in tissues. It is routinely used clinically to diagnose type (benign or malignant), stage, and grade of cancer using specific tumor markers. The application of IHC ranges from disease diagnosis and prognosis to drug development and analysis of the pathobiological roles of various molecular players during disease development. Due to better availability of highly specific antibodies and optimal methodologies for performing immunohistochemical studies, IHC is being used at an expanding rate to understand pancreatic tumor biology as well as to study the fate of various molecular markers during the initiation, progression, and metastasis of pancreatic neoplasia. Herein, we describe the detailed protocol for IHC analyses of pancreatic intraepithelial neoplasia in tissues and fine needle aspirates from both human and mouse samples.


Creating a journal club competition improves paediatric nurses' participation and engagement.
To improve journal club participation, innovative approaches are required but few have been described. It was unknown if adding an element of competition, to an established journal club, would increase nurses' participation. To explore the impact on attendance and participation in a hospital-wide nursing journal club through the introduction of an element of competition. A descriptive exploratory study. An Australian specialist tertiary paediatric hospital with over 1600 nurses. In 2013, 12 hospital wards/departments were randomly assigned a month each to present journal club. Nurses were supported to evaluate an article according to a published framework. A predetermined rubric guided marking. Post competition, all hospital nurses received an anonymous online survey invitation. Demographic, Likert scale and qualitative data were collected. Questions elicited attitudes and perceived barriers or facilitators to participation in the journal club. Compared to 2012, there was a statistically significant increase in journal club attendance (2013 median=20.5 [IQR=18.2, 27.7] vs. 2012 median=9 [IQR=6.5, 12.5], Mann-Whitney U test, p<0.01). Full online survey responses were received from 289/1674 (response rate 17.3%) of sent invitations (Non-Attendees n=224, Attendees n=65 (including 18 presenters). Overall, Attendees reported journal club had a positive impact on their professional engagement. Presenters rated the journal club format highly as it developed skills and increased their confidence in journal club presentation. Emergent themes were time and location, engagement, topics and content. A competition format can increase nurses' journal club attendance and participation. Further work is required to establish applicability of this format to other settings.


Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004-18.
In China, mean body-mass index (BMI) and obesity in adults have increased steadily since the early 1980s. However, to our knowledge, there has been no reliable assessment of recent trends, nationally, regionally, or in certain population subgroups. To address this evidence gap, we present detailed analyses of relevant data from six consecutive nationally representative health surveys done between 2004 and 2018. We aimed to examine the long-term and recent trends in mean BMI and prevalence of obesity among Chinese adults, with specific emphasis on changes before and after 2010 (when various national non-communicable disease prevention programmes were initiated), assess how these trends might vary by sex, age, urban-rural locality, and socioeconomic status, and estimate the number of people who were obese in 2018 compared with 2004. We used data from the China Chronic Disease and Risk Factors Surveillance programme, which was established in 2004 with the aim to provide periodic nationwide data on the prevalence of major chronic diseases and the associated behavioural and metabolic risk factors in the general population. Between 2004 and 2018 six nationally representative surveys were done. 776 571 individuals were invited and 746 020 (96·1%) participated, including 33 051 in 2004, 51 050 in 2007, 98 174 in 2010, 189 115 in 2013, 189 754 in 2015, and 184 876 in 2018. After exclusions, 645 223 participants aged 18-69 years remained for the present analyses. The mean BMI and prevalence of obesity (BMI ≥30 kg/m2) were calculated and time trends compared by sex, age, urban-rural locality, geographical region, and socioeconomic status. Standardised mean BMI levels rose from 22·7 kg/m2 (95% CI 22·5-22·9) in 2004 to 24·4 kg/m2 (24·3-24·6) in 2018 and obesity prevalence from 3·1% (2·5-3·7) to 8·1% (7·6-8·7). Between 2010 and 2018, mean BMI rose by 0·09 kg/m2 annually (0·06-0·11), which was half of that reported during 2004-10 (0·17 kg/m2, 95% CI 0·12-0·22). Similarly, the annual increase in obesity prevalence was somewhat smaller after 2010 than before 2010 (6·0% annual relative increase, 95% CI 4·4-7·6 vs 8·7% annual relative increase, 4·9-12·8; p=0·13). Since 2010, the rise in mean BMI and obesity prevalence has slowed down substantially in urban men and women, and moderately in rural men, but continued steadily in rural women. By 2018, mean BMI was higher in rural than urban women (24·3 kg/m2vs 23·9 kg/m2; p=0·0045), but remained lower in rural than urban men (24·5 kg/m2vs 25·1 kg/m2; p=0·0007). Across all six surveys, mean BMI was persistently lower in women with higher levels of education compared with women with lower levels of education, but the inverse was true among men. Overall, an estimated 85 million adults (95% CI 70 million-100 million; 48 million men [95% CI 39 million-57 million] and 37 million women [31 million-43 million]) aged 18-69 years in China were obese in 2018, which was three times as many as in 2004. In China, the rise in mean BMI among the adult population appears to have slowed down over the past decade. However, we found divergent trends by sex, geographical area, and socioeconomic status, highlighting the need for a more targeted approach to prevent further increases in obesity in the Chinese general population. China National Key Research and Development Program, China National Key Project of Public Health Program, and Youth Scientific Research Foundation of the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention.


MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion.
The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway has been implicated in the regulation of cellular proliferation. MEK5 expression has been detected in prostate cancer cells, although the significance of the MEK5/ERK5 pathway in human prostate cancer has not been tested. We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters. We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue. Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival. Furthermore, among the patients with high Gleason score of 8-10, MEK5 overexpression has an additional prognostic value in survival. MEK5 transfection experiments confirm its ability to induce proliferation (P < 0.0001), motility (P = 0.0001) and invasion in prostate cancer cells (P = 0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the -670/MMP-9 promoter is upregulated by MEK5 and electromobility shift assay further suggests the involvement of activator protein-I (AP-1), but not the NF-kappa B, binding site in the MMP-9 promoter. Using an AP-1 luciferase construct, activation of MEK5 was confirmed to enhance AP-1 activities up to twofold. Taken together, our results establish MEK5 as a key signalling molecule associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly specific, it represents a potential target of therapy.


Gamma-aminobutyric acid-containing sympathetic preganglionic neurons in rat thoracic spinal cord send their axons to the superior cervical ganglion.
Gamma-aminobutyric acid (GABA)-containing fibers have been observed in the rat superior cervical ganglion (SCG) and, to a lesser extent, in the stellate ganglion (STG). The aim of present study is to clarify the source of these fibers. No cell body showed mRNAs for glutamic acid decarboxylases (GADs) or immunoreactivity for GAD of 67 kDa (GAD67) in the cervical sympathetic chain. Thus, GABA-containing fibers in the ganglia are suggested to be of extraganglionic origin. GAD67-immunoreactive fibers were found not in the dorsal roots or ganglia, but in the ventral roots, so GABA-containing fibers in the sympathetic ganglia were considered to originate from the spinal cord. Furthermore, almost all GAD67-immunoreactive fibers in the sympathetic ganglia showed immunoreactivity for vesicular acetylcholine transporter, suggesting that GABA was utilized by some cholinergic preganglionic neurons. This was confirmed by the following results. 1) After injection of Sindbis/palGFP virus into the intermediolateral nucleus, some anterogradely labeled fibers in the SCG were immunopositive for GAD67. 2) After injection of fluorogold into the SCG, some retrogradely labeled neurons in the thoracic spinal cord were positive for GAD67 mRNA. 3) When the ventral roots of the eighth cervical to the fourth thoracic segments were cut, almost all GAD67- and GABA-immunoreactive fibers disappeared from the ipsilateral SCG and STG, suggesting that the vast majority of GABA-containing fibers in those ganglia were of spinal origin. Thus, the present findings strongly indicate that some sympathetic preganglionic neurons are not only cholinergic but also GABAegic.


Assessment of dietary ratios of red clover and grass silages on milk production and milk quality in dairy cows.
Twenty-four multiparous Holstein-Friesian dairy cows were used in a replicated 4 x 4 Latin square changeover design experiment to test the effects of changing from ryegrass (Lolium perenne) silage to red clover (Trifolium pratense) silage in graded proportions on feed intakes, milk production, milk organoleptic qualities, and whole-body nitrogen partitioning. Four dietary treatments, comprising ad libitum access to 1 of 4 forage mixtures plus a standard allowance of 4 kg/d dairy concentrates, were offered. The 4 forage mixtures were, on a dry matter (DM) basis: 1) 100% grass silage, 2) 66% grass silage: 34% red clover silage, 3) 34% grass silage: 66% red clover silage, and 4) 100% red clover silage. In each of 4 experimental periods, there were 21 d for adaptation to diets and 7 d for measurements. There was an increase in both DM intakes and milk yields as the proportion of red clover in the diet increased. However, the increase in milk yield was not as great as the increase in DM intake, so that the efficiency of milk production, in terms of yield (kg) of milk per kg of DM intake, decreased. The concentrations of protein, milk fat, and the shorter chain saturated fatty acids decreased, whereas C18 polyunsaturated fatty acids (PUFA) and long-chain PUFA (C20+) increased as the proportion of red clover in the diet increased. There was little effect of dietary treatment on the organoleptic qualities of milk as assessed by taste panel analysis. There were no effects on the aroma of milk, on aftertaste, or overall liking of the milk. Milk was thicker and creamier in color when cows were fed grass silage compared with red clover silage. The flavor of milk was largely unaffected by dietary treatment. In conclusion, increasing the proportion of red clover in the diet of dairy cows increased feed intakes and milk yields, decreased the concentration of fat and protein in milk, increased PUFA for healthiness, and had little effect on milk organoleptic characteristics.


CT and MR imaging findings of benign cardiac tumors.
This imaging review describes the appearance of benign cardiac tumors on CT and MRI. Although rare, benign tumors outnumber their primary malignant counterparts three to one. Since mortality varies directly with invasion, identifying the neoplasm at an early stage helps focus treatment, especially in benign cases, which generally respond well to surgical resection. In adults and children, myxomas and rhabdomyomas, respectively, represent the most common benign tumors, which can be grouped into tissue-specific subtypes, such as rhabdomyomas, fibromas, lipomas, teratomas, etc. Besides their variable prevalence in particular age groups, these tumors also differ with regard to their gender predilection, location, and number. For example, myxomas appear predominantly in women and generally as a solitary mass in the left or right atrium, whereas rhabdomyomas present equally in boys and girls and chiefly as multiple masses in the ventricles. Despite their differences, however, both types share an association with heritable syndromes like the Carney complex for myxomas and tuberous sclerosis for rhabdomyomas. As with all cardiac tumors, echocardiographic findings usually suggest the initial diagnosis but cross-sectional imaging with CT and MRI can help resolve diagnostically challenging cases. For example, with its direct multiplanar capability, excellent contrast resolution, and large field of view, MRI permits a detailed examination of the entire mediastinum, helping to rule out an equivocal mass on echocardiography. Through dynamic techniques, MRI, in addition to morphologic characterization, can depict the pathophysiological effects of these tumors, for instance, with regard to myocardial contraction, valvular function, or blood flow.


Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up.
Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell proliferation, and their immunohistochemical expression may help to identify high-risk breast cancer patients. The authors evaluated p53 and Bcl-2 immunoreactivity in 178 node-negative breast cancers (NNBC) with long-term follow-up (median, 60 months). Bcl-2 was seen in 111 (62%) cases, and was significantly associated with small tumor size, nonductal morphology, low tumor grade, estrogen-receptor (ER) positivity, and p53 negativity. p53 overexpression (ie, > 15% reactive nuclei) was observed in 31 (17%) cases, and was associated with lower age, large tumor size, ductal morphology, high tumor grade, negative ER status, and lack of Bcl-2 immunoreactivity. In univariate analysis, the variables associated with short relapse-free survival (RFS) were large tumor size (P = .002), high histological grade (P = .01), high mitotic count (P = .03), and high Nottingham prognostic index (NPI) (P = .0002). In multivariate analysis (final model), only the NPI was of independent prognostic value concerning RFS.


SEEG initiative estimates of Brazilian greenhouse gas emissions from 1970 to 2015.
This work presents the SEEG platform, a 46-year long dataset of greenhouse gas emissions (GHG) in Brazil (1970-2015) providing more than 2 million data records for the Agriculture, Energy, Industry, Waste and Land Use Change Sectors at national and subnational levels. The SEEG dataset was developed by the Climate Observatory, a Brazilian civil society initiative, based on the IPCC guidelines and Brazilian National Inventories embedded with country specific emission factors and processes, raw data from multiple official and non-official sources, and organized together with social and economic indicators. Once completed, the SEEG dataset was converted into a spreadsheet format and shared via web-platform that, by means of simple queries, allows users to search data by emission sources and country and state activities. Because of its effectiveness in producing and making available data on a consistent and accessible basis, SEEG may significantly increase the capacity of civil society, scientists and stakeholders to understand and anticipate trends related to GHG emissions as well as its implications to public policies in Brazil.


Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy.
Friedreich's ataxia (FA), an autosomal recessive disorder caused by a deficiency in the expression of frataxin (FXN), is characterized by progressive ataxia and hypertrophic cardiomyopathy. Although cardiac dysfunction is the most common cause of mortality in FA, the cardiac disease remains subclinical for most of the clinical course because the neurologic disease limits muscle oxygen demands. Previous FXN knockout mouse models exhibit fatal cardiomyopathy similar to human FA, but in contrast to the human condition, untreated mice become moribund by 2 months of age, unlike humans where the cardiac disease often does not manifest until the third decade. The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving CRE recombinase cardiac-specific excision of FXN exon 4 to generate a mild, cardiac-specific FA model that is normal at rest, but exhibits the cardiac phenotype with stress. The hearts of αMyhc mice had decreased levels of FXN and activity of the mitochondrial complex II/complex IV respiratory chain. At rest, αMyhc mice exhibited normal cardiac function as assessed by echocardiographic assessment of ejection fraction and fractional shortening, but when the heart was stressed chemically with dobutamine, αMyhc mice compared with littermate control mice had a 62% reduction in the stress ejection fraction (p < 2 × 10-4) and 71% reduction in stress-related fractional shortening (p < 10-5). When assessing functional cardiac performance using running on an inclined treadmill, αMyhc mice stayed above the midline threefold less than littermate controls (p < 0.02). A one-time intravenous administration of 1011 genome copies of AAVrh.10hFXN, an adeno-associated virus (AAV) serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls (p > 0.07). These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.


Highly transparent organic light-emitting diodes with a metallic top electrode: the dual role of a Cs2CO3 layer.
Highly transparent organic light-emitting diodes (TrOLEDs) are demonstrated using damage-free top cathodes of Cs2CO3/ Ag capped with ZnS layers. The presence of ultrathin Cs2CO3 layers not only improves the electron injection properties but also makes Ag thin films more continuous and uniform, resulting in ideal top electrodes with low sheet resistance and high transmittance. The combination of the uniform Ag morphology enabled by Cs2CO3 and the optimized thickness of ZnS capping layers results in TrOLEDs that have a peak transmittance as large as 80% with a luminous transmittance of 76.4%. These TrOLEDs exhibit a low turn-on voltage of 2.6V due to injection improvement by the Cs2CO3 layers.


Protein profiling of isolated uterine AA amyloidosis causing fetal death in goats.
Pathologic amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic amyloid deposits is unclear. Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to amyloid formation. Here, we identified 8 amyloidosis cases with amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia and death. No other organ contained amyloid. SAA3 mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine peptides identified SAA3 as the predominant protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although amyloid A (AA) amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3 amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of amyloidosis and of AA amyloid deposited exclusively in the uterus.


Effect of aspirin on mortality in the primary prevention of cardiovascular disease.
The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention. Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs). Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups. Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.


MicroRNA-21: a ubiquitously expressed pro-survival factor in cancer and other diseases.
MiRNAs are a new class of small RNA molecules that regulate gene expression at the post-transcriptional and translational levels. MiRNAs have been implicated in the control of many vital biological processes including development, cell proliferation, differentiation, and apoptosis. A growing number of studies have shown that miRNAs also play an important role in carcinogenesis and other diseases. Among the miRNAs identified, miRNA-21 is dramatically up-regulated in cancer cells of various origins. It regulates a wide range of genes and pathways involved in cancer initiation, transformation, invasion, and metastasis. MiRNA-21 also acts as a pro-survival factor in cardiovascular diseases. Aberrant expression in these diseases makes miRNA-21 a potential marker for disease diagnosis and prognosis. This review highlights the complex roles that miRNA-21 plays in cancer and cardiovascular diseases and its potential clinical applications.


Dopant Diffusion and Activation in Silicon Nanowires Fabricated by ex Situ Doping: A Correlative Study via Atom-Probe Tomography and Scanning Tunneling Spectroscopy.
Dopants play a critical role in modulating the electric properties of semiconducting materials, ranging from bulk to nanoscale semiconductors, nanowires, and quantum dots. The application of traditional doping methods developed for bulk materials involves additional considerations for nanoscale semiconductors because of the influence of surfaces and stochastic fluctuations, which may become significant at the nanometer-scale level. Monolayer doping is an ex situ doping method that permits the post growth doping of nanowires. Herein, using atom-probe tomography (APT) with subnanometer spatial resolution and atomic-ppm detection limit, we study the distributions of boron and phosphorus in ex situ doped silicon nanowires with accurate control. A highly phosphorus doped outer region and a uniformly boron doped interior are observed, which are not predicted by criteria based on bulk silicon. These phenomena are explained by fast interfacial diffusion of phosphorus and enhanced bulk diffusion of boron, respectively. The APT results are compared with scanning tunneling spectroscopy data, which yields information concerning the electrically active dopants. Overall, comparing the information obtained by the two methods permits us to evaluate the diffusivities of each different dopant type at the nanowire oxide, interface, and core regions. The combined data sets permit us to evaluate the electrical activation and compensation of the dopants in different regions of the nanowires and understand the details that lead to the sharp p-i-n junctions formed across the nanowire for the ex situ doping process.


Pilates training improves 5-km run performance by changing metabolic cost and muscle activity in trained runners.
Strength training improves distance running economy and performance. This finding is based predominantly on maximal and explosive strength programmes applied to locomotor muscles, particularly on the lower limbs. It is not certain whether a minimization of metabolic cost (Cmet) and an improvement in running performance is feasible with strength training of the postural and trunk muscles. Using kinematic, neuromuscular and metabolic measurements of running at two different speeds before and after a 12-week Pilates training programme, we tested the hypothesis that core training might improve the running Cmet and performance of trained runners. Thirty-two individuals were randomly assigned to the control group (CG, n = 16) or the Pilates group (PG, n = 16). Confirming our hypothesis, a significant improvement (p<0.05) was observed for running performance in the PG (pre: 25.65±0.4 min; post: 23.23±0.4 min) compared to the CG (pre: 25.33±0.58 min; post: 24.61±0.52 min). Similarly, the PG (4.33±0.07 J.kg-1.m-1) had better responses than the CG (4.71±0.11 J.kg-1.m-1) during post-training for Cmet. These findings were accompanied by decreased electromyographic activity of the postural muscles at submaximal running intensities in the PG. Overall, these results provide a rationale for selecting strength training strategies that target adaptations on specific postural and locomotor muscles for trained distance runners.


Nuptial gifts and the use of body resources for reproduction in the green-veined white butterfly Pieris napi.
Reproduction in butterflies, as in many holometabolous insects, is usually constrained by the amount of nutrients the animals can collect as juveniles. In polyandric species the females can also supplement their larval-derived reserves with protein-rich donations, so-called nuptial gifts, delivered by the males at mating. Recent findings also indicate that females have access to nitrogen from the histolysis of flight muscles in the thorax. This field study examined how butterflies of the polyandric gift-giving species Pieris napi (Lepidoptera: Pieridae) use body resources in their reproduction and how the male donations affect the females use of stored reserves. The results support earlier studies, indicating that females use resources from the breakdown of thorax muscles to increase their reproductive potential and the results also indicate that males also use thorax material in their reproduction. The study also supports recent findings that the male donation increases the breakdown of body resources and thereby boosts the reproductive output of the female.


A multinational study on motor function in early-onset FSHD.
To investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age. We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats. Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05). Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.


Analysis of the Machining Process of Inconel 718 Parts Manufactured by Laser Metal Deposition.
Laser metal deposition (LMD) is an additive manufacturing process that allows the manufacturing of near-net-shape products. This could mean significant savings in terms of materials and costs in the manufacturing of high-performance components for the aeronautical industry. In this work, an analysis of how the LMD processing of alloy 718 affects the final machining has been carried out. For this purpose, a comparative study has been done by means of the monitoring of the end milling process of a part manufactured by LMD and a rough-milled part from forged material. Differences between process outputs such as chip morphology and cutting forces were studied. Material characteristics such as microstructure, hardness and mechanical properties were also analyzed.


The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition?
Awareness of the ancestral human diet might advance traditional nutrition science. The human genome has hardly changed since the emergence of behaviourally-modern humans in East Africa 100-50 x 10(3) years ago; genetically, man remains adapted for the foods consumed then. The best available estimates suggest that those ancestors obtained about 35% of their dietary energy from fats, 35% from carbohydrates and 30% from protein. Saturated fats contributed approximately 7.5% total energy and harmful trans-fatty acids contributed negligible amounts. Polyunsaturated fat intake was high, with n-6:n-3 approaching 2:1 (v. 10:1 today). Cholesterol consumption was substantial, perhaps 480 mg/d. Carbohydrate came from uncultivated fruits and vegetables, approximately 50% energy intake as compared with the present level of 16% energy intake for Americans. High fruit and vegetable intake and minimal grain and dairy consumption made ancestral diets base-yielding, unlike today's acid-producing pattern. Honey comprised 2-3% energy intake as compared with the 15% added sugars contribute currently. Fibre consumption was high, perhaps 100 g/d, but phytate content was minimal. Vitamin, mineral and (probably) phytochemical intake was typically 1.5 to eight times that of today except for that of Na, generally <1000 mg/d, i.e. much less than that of K. The field of nutrition science suffers from the absence of a unifying hypothesis on which to build a dietary strategy for prevention; there is no Kuhnian paradigm, which some researchers believe to be a prerequisite for progress in any scientific discipline. An understanding of human evolutionary experience and its relevance to contemporary nutritional requirements may address this critical deficiency.


Lysmata arvoredensis nov. sp. a new species of shrimp from the south coast of Brazil with a key to species of Lysmata (Caridea: Lysmatidae) recorded in the southwestern Atlantic.
Lysmata arvoredensis sp. nov. inhabits temperate waters in the south coast of Brazil and is named in tribute to the Marine Protected Area REBIO Arvoredo. This is the fourth species belonging to the genus Lysmata recorded for the region and the ninth for Brazil. L. arvoredensis sp. nov. can be distinguished from other species of Lysmata by the presence of a nearly completely fused accessory branch with a single free unguiform segment on the outer antennular flagellum; a rostrum with seven dorsal (2+5) and three ventral teeth; a stylocerite with a pointed tip bearing mesial setae; a second pereiopod with 22-24 carpal subsegments and 14-16 subsegments in the merus; a merus of the third pereiopod with five ventrolateral and 12 ventral spines on the propodus; and its color pattern, with red bands and patches in pleonites 2-3 that resemble a mask in dorsal view. Molecular characters demonstrate that L. arvoredensis sp. nov. is most closely related to other species of Lysmata belonging to the Neotropical and Cleaner clades. To support future ecological studies in the region, identification keys to the species of Lysmata recorded in the southwestern Atlantic Ocean are provided.


Perfect coupling of light to surface plasmons with ultra-narrow linewidths.
We examine the coupling of electromagnetic waves incident normal to a thin silver film that forms an oscillatory grating embedded between two otherwise uniform, semi-infinite half spaces. Two grating structures are considered, in one of which the midpoint of the Ag film remains fixed whereas the thickness varies sinusoidally, while in the other the mid point oscillates sinusoidally whereas the film thickness remains fixed. On reducing the light wavelength from the long wavelength limit, we encounter signatures in the transmission, T, and reflection, R, coefficients associated with: (i) the short-range surface plasmon mode, (ii) the long-range surface plasmon mode, and (iii) electromagnetic diffraction tangent to the grating. The first two features can be regarded as generalized (plasmon) Wood's anomalies whereas the third is the first-order conventional (electromagnetic) Wood's anomaly. The energy density at the film surface is enhanced for wavelengths corresponding to these three anomalies, particularly for the long-range plasmon mode in thin films. When exciting the silver film with a pair of waves incident from opposite directions, we find that by adjusting the grating oscillation amplitude and fixing the relative phase of the incoming waves to be even or odd, T+R can be made to vanish for one or the other of the plasmon modes; this corresponds to perfect coupling (impedance matching in the language of electrical engineering) between the incoming light and these modes.


Use of transcriptomics in understanding mechanisms of drug-induced toxicity.
Adverse drug reactions (ADRs) are an important clinical issue and a serious public health risk. Understanding the underlying mechanisms is critical for clinical diagnosis and management of different ADRs. Toxicogenomics can reveal impacts on biological pathways and processes that had not previously been considered to be involved in a drug response. Mechanistic hypotheses can be generated that can then be experimentally tested using the full arsenal of pharmacology, toxicology, molecular biology and genetics. Recent transcriptomic studies on drug-induced toxicity, which have provided valuable mechanistic insights into various ADRs, have been reviewed with a focus on nephrotoxicity and hepatotoxicity. Related issues have been discussed, including extrapolation of mechanistic findings from experimental model systems to humans using blood as a surrogate tissue for organ damage and comparative systems biology approaches.


Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates.
Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.


Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein.
We have recently reported that a novel molecule, murine IFN-gamma-inducing factor (IGIF) produced by mouse liver cells, possesses potent biologic activities, including the induction of IFN-gamma production by spleen cells and the enhancement of NK cell cytotoxicity. In this paper, we report on the isolation of human IGIF cDNA clones from normal human liver cDNA libraries using murine IGIF cDNA as a probe. The amino acid sequence deduced from the human cDNA clones indicated a 193-amino acid precursor peptide and revealed 65% homology with that of murine IGIF. The amino acid sequence of IGIF also included an IL-1 signature-like sequence. Subsequently, the cloned cDNA was expressed in Escherichia coli, and preliminary studies on the biologic activities of the recombinant protein were performed. The recombinant human IGIF induced IFN-gamma production by mitogen-stimulated PBMC and enhanced NK cell cytotoxicity, in a manner similar to murine IGIF. In addition, recombinant human IGIF also augmented granulocyte-macrophage-CSF production and decreased IL-10 production, but had no effect on IL-4 production by Con A-stimulated PBMC. Based on these pleiotropic effects of IGIF, we propose that this novel cytokine be designated as IL-18.


Comprehensive numerical analysis of a surface-plasmon-resonance sensor based on an H-shaped optical fiber.
We present and numerically characterize a surface-plasmon-resonance sensor based on an H-shaped optical fiber. In our design, the two U-shaped grooves of the H-fiber are first coated with a thin gold layer and then covered by a uniform titanium dioxide layer to facilitate spectral tuning of the device. A finite element method analysis of the sensor indicates that a refractive-index resolution of up to 5 · 10(3) nm/RIU can be obtained.


The Zipperator! A Novel Model to Simulate Penile Zipper Entrapment.
The Zipperator training model is designed for emergency medicine resident physicians and physicians. Zipper entrapment injuries are an uncommon cause of penile injury in the emergency department, representing an incidence of less than 0.5% of pediatric emergency department visits.1 However, they are one of the most common causes of genital injuries in young boys.1,2 Various methods proposed for releasing the entrapped tissue range from the use of mineral oil as lubrication to techniques to release the zipper mechanism or, in extreme cases, surgical procedures.3-6 A well-designed simulated task trainer would allow learners to practice these methods in a controlled environment conducive to learning 7,8. Given the low frequency of the chief complaint and with a wide variety of release techniques available, the purpose of this study was to build a simulation model that could improve learner confidence in troubleshooting this rarely performed procedure. Although past studies have designed similar task trainers, this novel model was built using a low-cost device ("Operation") to provide real-time alarm noises that reasonably simulate distress and procedural anxiety for both the patient and provider. Although pain and anxiety are separate outcomes from zipper entrapment release, including a component of these emotions may mimic the same emotional states that patients, their parental unit, and perhaps their provider may experience regarding this chief complaint given its rarity, anatomic vulnerability, and the overall sensitivity of the complaint's nature. After training on the Zipperator, learners will be able to:Demonstrate at least two techniques for zipper release and describe how methods would extrapolate to a real patient.Verbalize increased comfort with the diagnosis of zipper entrapment.Present a plan of care for this low-volume, high-anxiety presentation. As part of a voluntary Emergency Medicine curriculum at two different sites, we constructed an inexpensive model for penile zipper entrapment using a household gameboard, "Operation," and materials that are easily obtainable and assembled in any emergency department. "Operation" was selected for its ability to produce alarm noises in response to excessive movement, which would reasonably simulate distress and procedural anxiety that may be experienced by both the patient and provider. This task trainer was used to teach medical students and post graduate year (PGY) 1-4 resident learners. A brief hypothetical situation was presented to learners, highlighting patient and paternal unit anxiety. Following this, learners were given a survey and asked to complete pre-model training questions immediately prior to using the simulated model. Learners were then given the opportunity for hands-on skills-based practice. Postmodel training questions were made available in the same survey immediately following the exercise. This exercise was offered at two sites over a two-year period. Sixty learners participated in the exercise. Participation was voluntary, was not graded nor shared with the residency director, and all feedback was formative in nature. Selected faculty and research assistants provided asynchronous opportunities for learners to practice on the model. Before the exercise, the faculty or research assistant on site presented a brief hypothetical situation to simulate patient and paternal unit anxiety that could be expected in this chief complaint. Each learner was then allowed to select a variety of tools and methods to practice zipper entrapment release. Learners were asked to begin a survey prior to training on the model, and then complete the survey immediately after training on the model to evaluate its educational value. The survey created for this study consisted of a structured questionnaire that contained close-ended questions. Measures evaluated include experience with prior zipper entrapments, comfort with zipper entrapments before and after training on the simulated model, and user experience. Before the exercise, 68.3% of learners described their comfort with managing future zipper entrapments as very uncomfortable or totally uncomfortable. Although only 8.3% of learners had treated the zipper entrapment complaint prior to the exercise, 100% of those who had experienced treating the complaint felt that the simulated model was at least somewhat reflective of their experience with a real patient. 71.7% of the learners found the experience enjoyable, although 20% found the experience totally unenjoyable, of note, for unclear reasons and with unclear significance or etiology. After the exercise, 71.7% of learners indicated they felt comfortable to very comfortable regarding future cases of zipper entrapment. Through the use of a well-known household board game and supplies commonly found in the emergency department, we created a simulated model that could be easily replicated. This simple model provided practice of the hand motions necessary for zipper entrapment release, as well as familiarity with the mental and physical approaches to dislodging the entrapment. The resident physicians who had had a prior zipper entrapment patient reported the model was somewhat similar to actual patient encounters. Overall, this model was well-received by the learners, with most expressing it was enjoyable and feeling it increased their confidence for treating this chief complaint. Some learners had noted the experience was totally unenjoyable. This measure may not be an appropriate endpoint, however, and incongruencies may be addressed by implementing prizes or friendly competition for enjoyment. Another limitation of this study is the leap taken between movement and patient comfort. While possible that learners can manipulate the model to reduce movement of the needle without meaningful reduction in zipper movement, observation by the instructor was sufficient to ensure this finding was not observed in our learner population. We therefore submit this cheap, simple model as a potential method to teach approaches to teaching a low frequency, high anxiety chief complaint. Penile entrapment model, penile entrapment release, Emergency Medicine, Urology, Clinical/Procedural Skills Training.


Cyfra 21-1 as a biologic marker of non-small cell lung cancer. Evaluation of sensitivity, specificity, and prognostic role.
Cytokeratins are epithelial markers whose expression is not lost during malignant transformation. Cyfra 21-1 is a cytokeratin-19 fragment that is soluble in serum and may be a useful circulating tumor marker. The aims of this study were (1) to confirm sensitivity and specificity of Cyfra 21-1 in detecting non-small cell lung cancer (NSCLC) and especially the squamous cell subtype, (2) to assess the potential relationship between Cyfra 21-1 and disease stage of the disease in NSCLC, and (3) to evaluate prognostic effect of Cyfra 21-1 in NSCLC. An immunoradiometric assay of serum Cyfra 21-1 was performed in 161 patients with lung cancers and 71 others with benign lung diseases. The ability of Cyfra 21-1 to detect different histologic subtypes of lung cancer vs benign lung diseases was assessed through receiver operating characteristic (ROC) curves and comparisons with other tumor markers such as carcinoembryonic antigen, neuron-specific enolase, and squamous cell carcinoma antigen. Comparisons of Cyfra 21-1 levels according to histologic subtype and disease stage were done using Kruskal-Wallis test. Independent prognostic value of Cyfra 21-1 was studied with a multivariate analysis of survival (Cox's model). Using a threshold of 3.3 ng/mL for Cyfra 21-1, sensitivity and specificity were, respectively, 0.59 and 0.94 in NSCLC, 0.68 and 0.94 in the subgroup of the squamous cell carcinoma, and 0.19 and 0.94 in small cell lung cancer. Cyfra 21-1 levels were significantly higher in advanced NSCLC than in early-stage disease. All 29 patients with serum concentrations > 32 ng/mL had stage IIIB-IV and only one of 14 patients with stage I-II disease had Cyfra 21-1 level > 18 ng/mL. In the multivariate analysis of survival, Cyfra 21-1 was an independent prognostic factor along with performance status and disease stage in NSCLC. Cyfra 21-1 is a sensitive and specific tumor marker of NSCLC, especially of squamous cell subtype. It also reflects the extent of the disease and has an independent prognostic role along with performance status and disease stage in NSCLC. A high level of Cyfra 21-1 in apparently early-stage NSCLC should be an indication for more extensive workup before thoracotomy. The independent prognostic role of Cyfra 21-1 level may be useful in stratifying populations with advanced NSCLC or early-stage resected NSCLC as elevated Cyfra 21-1 levels might identify those patients at high risk for treatment failure.


[Pancreatitis--etiology and pathogenesis].
Pancreatic inflammatory disease can be classified as acute pancreatitis (AP) and chronic pancreatitis (CP) primarily by clinical criteria, with an obvious difference by restoration of normal function in the former or by permanent residual damage in the latter. Gallstones and alcohol are the most common causes of AP. Recent investigations have established that AP from all cause may disrupt normal stimulus-secretion coupling function within the acinar cell. This disruption within the acinar cell leads to an event termed 'co-localization' in which the digestive and lysosomal enzymes merge resulting in a premature activation of proteases. The mechanisms of inflammatory cells which adhere to endothelial cell are determined by a variety of mediators of cytokines released at the site of tissue damage. Cytokines hold the key for both local and systemic inflammatory response in AP. Besides, CP is a debilitating disease characterized by progressive and irreversible destruction of pancreatic tissue leading to exocrine and endocrine insufficiencies. Alcohol intake is the most common cause of CP. Mutations in the cationic trypsinogen gene were identified as causative gene for hereditary pancreatitis. The recognition of frequent cystic fibrosis transmembrane conductance regulator (CFTR) mutations and serine protease inhibitor, Kazal type 1 (SPINK1) mutations in idiopathic CP has hightened the awareness of importance of genetic mutations in CP. Pancreatic stellate cells represent the main cellular source of extracellular matrix in CP and play a key role in pancreatic fibrosis.


Regulation of IPSP theta rhythm by muscarinic receptors and endocannabinoids in hippocampus.
Theta rhythms are behaviorally relevant electrical oscillations in the mammalian brain, particularly the hippocampus. In many cases, theta oscillations are shaped by inhibitory postsynaptic potentials (IPSPs) that are driven by glutamatergic and/or cholinergic inputs. Here we show that hippocampal theta rhythm IPSPs induced in the CA1 region by muscarinic acetylcholine receptors independent of all glutamate receptors can be briefly interrupted by action potential-induced, retrograde endocannabinoid release. Theta IPSPs can be recorded in CA1 pyramidal cell somata surgically isolated from CA3, subiculum, and even from their own apical dendrites. These results suggest that perisomatic-targeting interneurons whose output is subject to inhibition by endocannabinoids are the likely source of theta IPSPs. Interneurons having these properties include the cholecystokinin-containing cells. Simultaneous recordings from pyramidal cell pairs reveal synchronous theta-frequency IPSPs in neighboring pyramidal cells, suggesting that these IPSPs may help entrain or modulate small groups of pyramidal cells.


Sexual activity and the risk of prostate cancer: Review article.
Sexual activity can affect prostate cancer pathogenesis in a variety of ways; including the proposed high androgen status, risk of sexually transmitted infections and the potential effect of retained carcinogens within the prostatic cells. PubMed review of all publications concerning sexual activity and the risk of prostate cancer was done by two researchers. Few publications could be detected and data were classified as a prostate cancer risk in association with either heterosexual or homosexual activities. Frequent ejaculation seems to be protective from the development of prostate cancer. Multiple sexual partners may be protective from prostate cancer, excluding the risk of sexually transmitted infections. Homosexual men are at a greater risk for the diagnosis of prostate cancer.


Targeted agents in treatment of neuroendocrine tumors of pancreas.
Neuroendocrine tumors (NET) of the pancreas are uncommon neoplasms that arise from the pancreatic islet cells. Surgical resections are being tested, as well as multiple chemotherapy agents. Current treatment options for nonresectable disease include somatostatin analogs and chemotherapy. New therapies focus on specific molecular targets such as sunitinib, angiogenesis inhibitor, that target vascular endothelial growth factor receptor (VEGFR) and other growth factor receptors and everolimus, an inhibitor of the mammalian target of rapamycin. Functionally based medical therapies for NET include somatostatin analogs to control symptoms. The 2014 annual meeting of American Society of Clinical Oncology (ASCO) brought us new insights into the management of pancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#e15160 and #e15161), that shed light on new therapeutic options that help target the unique pathways of this malignancies.


A new rhodopsin in R8 photoreceptors of Drosophila: evidence for coordinate expression with Rh3 in R7 cells.
The photoreceptor cells of the Drosophila compound eye are precisely organized in elementary units called ommatidia. The outer (R1-R6) and inner (R7, R8) photoreceptors represent two physiologically distinct systems with two different projection targets in the brain (for review see Hardie, 1985). All cells of the primary system, R1-R6, express the same rhodopsin and are functionally identical. In contrast, the R7 and R8 photoreceptors are different from each other. They occupy anatomically precise positions, with R7 on top of R8. In fact, there are several classes of R7/R8 pairs, which differ morphologically and functionally and are characterized by the expression of one of two R7-specific opsins, rh3 or rh4. Here, we describe the identification of a new opsin gene, rhodopsin 5, expressed in one subclass of R8 cells. Interestingly, this subclass represents R8 cells that are directly underneath the R7 photoreceptors expressing rh3, but are never under those expressing rh4. These results confirm the existence of two subpopulations of R7 and R8 cells, which coordinate the expression of their respective rh genes. Thus, developmental signaling pathways between R7 and R8 lead to the exclusive expression of a single rhodopsin gene per cell and to the coordinate expression of another one in the neighboring cell. Consistent with this, rh5 expression in R8 disappears when R7 cells are absent (in sevenless mutant). We propose a model for the concerted evolution of opsin genes and the elaboration of the architecture of the retina.


Soft X-ray spectro-tomography study of cyanobacterial biomineral nucleation.
Quantitative three-dimensional (3D) chemical mapping using angle-scan spectro-tomography in a scanning transmission (soft) X-ray microscope (STXM) has been used for the first time to characterize the early stages of CaCO(3) biomineral nucleation on the surface of planktonic freshwater cyanobacterial cells of the strain Synechococcus leopoliensis PCC 7942. The apparatus for STXM angle-scan tomography is described. Aspects of sample preparation, sample mounting and data acquisition and quantitative analysis and interpretation are discussed in detail. Angle-scan tomography and chemically selective 3D imaging at multiple photon energies has been combined with a complete 2D spectromicroscopic characterization of the biochemical and mineralogical composition. This has provided detailed insights into the mechanisms of mineral nucleation, leading to development of a detailed model of CaCO(3) nucleation by the cyanobacterial strain S. leopoliensis PCC 7942. It shows that Ca is absorbed by the extracellular polymeric substances (EPS) of the cyanobacteria and that CaCO(3) with aragonite-like short-range order is precipitated rather homogeneously within the EPS. The precipitation of the thermodynamically more stable calcite polymorph then starts at Ca-rich hot spots within the EPS and close to the cyanobacteria.


Physical Resilience in Daily Functioning Among Acutely Ill Hospitalized Older Adults: The Hospital-ADL Study.
Insight into older adults' physical resilience is needed to predict functional recovery after hospitalization. We assessed functional trajectories in response to acute illness and subsequent hospitalization and investigated baseline variables and dynamic variables associated with these trajectories. Prospective observational cohort study (Hospitalization-Associated Disability and impact on daily Life Study). This study included 207 older adults (aged 79.8 ± 6.9 years, 49% female, 57% frail) acutely hospitalized in 6 Dutch hospitals. Functional disability was assessed using the 15-item modified activities of daily living index retrospectively 2 weeks before admission, and prospectively from admission up to 3 months after discharge. Baseline variables including frailty, somatic, physical, and psychosocial factors were assessed at admission. Dynamic variables (step count, pain, fatigue, and fear of falling) were continuously or repeatedly assessed during hospitalization. We performed individual spline modeling using random effects. Baseline variables and within-person mean levels and variability in the dynamic variables were assessed as predictors of functional trajectories. Functional disability significantly increased before admission and decreased from admission to 3 months post discharge. Frail participants had a significantly higher increase in functional disability before admission compared with nonfrail participants. Lower step count, higher pain scores, and higher within-person variability in fear of falling were significantly associated with higher increase in functional disability before admission. Higher within-person variability in fear of falling was associated with more recovery. Older adults increase in functional disability before hospitalization and start to recover from admission onward. Frailty and dynamic variables are associated with a higher increase in functional disability after acute illness. Our findings give more insight into older adults' physical resilience, which may improve the prediction of functional recovery and may improve therapeutic decision-making and rehabilitation strategies to improve functional recovery after acute hospitalization.


State of the Evidence Traffic Lights 2019: Systematic Review of Interventions for Preventing and Treating Children with Cerebral Palsy.
Cerebral palsy is the most common physical disability of childhood, but the rate is falling, and severity is lessening. We conducted a systematic overview of best available evidence (2012-2019), appraising evidence using GRADE and the Evidence Alert Traffic Light System and then aggregated the new findings with our previous 2013 findings. This article summarizes the best available evidence interventions for preventing and managing cerebral palsy in 2019. Effective prevention strategies include antenatal corticosteroids, magnesium sulfate, caffeine, and neonatal hypothermia. Effective allied health interventions include acceptance and commitment therapy, action observations, bimanual training, casting, constraint-induced movement therapy, environmental enrichment, fitness training, goal-directed training, hippotherapy, home programs, literacy interventions, mobility training, oral sensorimotor, oral sensorimotor plus electrical stimulation, pressure care, stepping stones triple P, strength training, task-specific training, treadmill training, partial body weight support treadmill training, and weight-bearing. Effective medical and surgical interventions include anti-convulsants, bisphosphonates, botulinum toxin, botulinum toxin plus occupational therapy, botulinum toxin plus casting, diazepam, dentistry, hip surveillance, intrathecal baclofen, scoliosis correction, selective dorsal rhizotomy, and umbilical cord blood cell therapy. We have provided guidance about what works and what does not to inform decision-making, and highlighted areas for more research.


Why Robots Should Be Social: Enhancing Machine Learning through Social Human-Robot Interaction.
Social learning is a powerful method for cultural propagation of knowledge and skills relying on a complex interplay of learning strategies, social ecology and the human propensity for both learning and tutoring. Social learning has the potential to be an equally potent learning strategy for artificial systems and robots in specific. However, given the complexity and unstructured nature of social learning, implementing social machine learning proves to be a challenging problem. We study one particular aspect of social machine learning: that of offering social cues during the learning interaction. Specifically, we study whether people are sensitive to social cues offered by a learning robot, in a similar way to children's social bids for tutoring. We use a child-like social robot and a task in which the robot has to learn the meaning of words. For this a simple turn-based interaction is used, based on language games. Two conditions are tested: one in which the robot uses social means to invite a human teacher to provide information based on what the robot requires to fill gaps in its knowledge (i.e. expression of a learning preference); the other in which the robot does not provide social cues to communicate a learning preference. We observe that conveying a learning preference through the use of social cues results in better and faster learning by the robot. People also seem to form a "mental model" of the robot, tailoring the tutoring to the robot's performance as opposed to using simply random teaching. In addition, the social learning shows a clear gender effect with female participants being responsive to the robot's bids, while male teachers appear to be less receptive. This work shows how additional social cues in social machine learning can result in people offering better quality learning input to artificial systems, resulting in improved learning performance.


Somatic loss of p53 leads to stem/progenitor cell amplification in both mammary epithelial compartments, basal and luminal.
Mammary epithelium comprises a layer of luminal cells and a basal myoepithelial cell layer. Both mammary epithelial compartments, basal and luminal, contain stem and progenitor cells, but only basal cells are capable of gland regeneration upon transplantation. Aberrant expansion of stem/progenitor cell populations is considered to contribute to breast tumorigenesis. Germline deletions of p53 in humans and mice confer a predisposition to tumors, and stem cell frequency is abnormally high in the mammary epithelium of p53-deficient mice. However, it is unknown whether stem/progenitor cell amplification occurs in both, basal and luminal cell populations in p53-deficient mammary tissue. We used a conditional gene deletion approach to study the role of p53 in stem/progenitor cells residing in the mammary luminal and basal layers. Using two- and three-dimensional cell culture assays, we showed that p53 loss led to the expansion of clonogenic stem/progenitor cells in both mammary epithelial cell layers. Moreover, following p53 deletion, luminal and basal stem/progenitor cells acquired a capacity for unlimited propagation in mammosphere culture. Furthermore, limiting dilution and serial transplantation assays revealed amplification and enhanced self-renewal in the basal regenerating cell population of p53-deficient mammary epithelium. Our data suggest that the increase in stem/progenitor cell activity may be, at least, partially mediated by the Notch pathway. Taken together, these results strongly indicate that p53 restricts the propagation and self-renewal of stem/progenitor cells in both layers of the mammary epithelium providing further insight into the impact of p53 loss in breast cancerogenesis.


Astragaloside IV Inhibits Triglyceride Accumulation in Insulin-Resistant HepG2 Cells via AMPK-Induced SREBP-1c Phosphorylation.
Objective: Insulin resistance (IR) is a risk factor for non-alcoholic fatty liver disease (NAFLD), which is characterized by lipid accumulation in hepatocytes. AMP-activated protein kinase (AMPK)-induced sterol regulatory element binding protein-1c (SREBP-1c) phosphorylation is crucial for proper regulation of lipid metabolism in the liver. Astragaloside IV (AST-IV) was found to decrease lipid accumulation in hepatocytes by activating AMPK, which is required to regulate lipid metabolism in liver tissue by inducing SREBP-1c phosphorylation. Method: To evaluate the direct effect of AST on lipid accumulation in hepatocytes with IR and elucidate the underlying mechanisms, we induced IR in HepG2 cells, and used compound C and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) (an AMPK inhibitor and agonist, respectively) as control substances. We evaluated glucose, triglyceride (TG), and non-esterified fatty acid (NEFA) production, as well as SREBP-1c transcription, SREBP-1c protein expression, and downstream gene expression with or without the presence of AST. We also investigated whether phosphorylation of SREBP-1c at Ser372 was required for AST function. Results: We found that AST attenuated IR and lipid accumulation in HepG2 cells. As an AMPK activator, AST promoted gene expression and activation of AMPK by increasing phosphorylation of AMPKa. AST also inhibited translocation of SREBP-1c into the nucleus of insulin-resistant HepG2 cells by inducing phosphorylation of SREBP-1c at Ser372. Conclusion: This study demonstrated that AST attenuates IR and lipid accumulation in HepG2 cells by regulating AMPK-dependent phosphorylation of SREBP-1c at Ser372, suggesting AST as a promising drug for treating hepatic steatosis.


In vitro studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost.
With use of the Wong-Kilbourne derivative Chang conjunctival cell line, this study compared in vitro the ocular toxicity of three topical intraocular pressure (IOP)-lowering agents: travoprost 0.004% containing 0.015% benzalkonium chloride (BAK), travoprost Z 0.004%, a new formulation without BAK, and latanoprost 0.005% containing 0.02% BAK. Neutral red, Alamar blue, YOPRO-1, and annexin V/7-AAD assays were used to evaluate the effects of the IOP-lowering agents and BAK on cellular viability, membrane integrity, and apoptosis in the conjunctival cell line using microtitration fluorometric analysis and flow cytometry. All assessments were performed in a masked manner. Assessment of cell viability and membrane integrity revealed a significant effect by latanoprost with BAK or BAK alone but no effect by travoprost Z without BAK or buffer alone (P < 0.0001). Latanoprost with BAK, travoprost with BAK, and BAK alone were cytotoxic in Chang conjunctival cells, whereas no cytotoxicity was observed in cells exposed to travoprost Z without BAK or in cells treated with buffer (P < 0.0001). No increase in apoptosis or necrosis was observed in cells treated with control or travoprost Z without BAK compared with BAK, travoprost with BAK, and latanoprost with BAK (P < 0.0001). Latanoprost with BAK, travoprost with BAK, and BAK alone have significant cytotoxic effects on human conjunctiva-derived cells and are associated with apoptosis. These effects likely result from BAK used as a preservative. IOP-lowering agents with alternative preservatives instead of BAK will most likely have fewer ocular surface adverse effects than agents containing BAK.


Insights for Exercise Adherence From a Minimal Planning Intervention to Increase Physical Activity.
To test the impact of a minimal, online planning intervention on physical activity in Australian office workers. Employees were randomized to an implementation intention intervention (n = 124) or health information control group (n = 130). Measures of physical activity, past behavior, and motivation were taken at baseline and 6 weeks. Analysis revealed both groups increased weekly physical activity sessions (intervention M = 1.12, control M = 0.78) at follow-up, but no significant difference was found between groups. Because the sample consisted of experienced exercisers, secondary analyses investigated differential effects for those who had lapsed over the previous year (nonmaintainers) and those who had maintained their previous level of activity (maintainers). For nonmaintainers, both planning and information provision successfully changed behavior, but only planning significantly increased physical activity in maintainers over the study. Different minimal intervention approaches may be useful for preventing long-term relapse and assisting people to improve regular exercise routines. The practical and theoretical implications are discussed.


Increasing propensity to mind-wander with transcranial direct current stimulation.
Humans mind-wander quite intensely. Mind wandering is markedly different from other cognitive behaviors because it is spontaneous, self-generated, and inwardly directed (inner thoughts). However, can such an internal and intimate mental function also be modulated externally by means of brain stimulation? Addressing this question could also help identify the neural correlates of mind wandering in a causal manner, in contrast to the correlational methods used previously (primarily functional MRI). In our study, participants performed a monotonous task while we periodically sampled their thoughts to assess mind wandering. Concurrently, we applied transcranial direct current stimulation (tDCS). We found that stimulation of the frontal lobes [anode electrode at the left dorsolateral prefrontal cortex (DLPFC), cathode electrode at the right supraorbital area], but not of the occipital cortex or sham stimulation, increased the propensity to mind-wander. These results demonstrate for the first time, to our knowledge, that mind wandering can be enhanced externally using brain stimulation, and that the frontal lobes play a causal role in mind-wandering behavior. These results also suggest that the executive control network associated with the DLPFC might be an integral part of mind-wandering neural machinery.


Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly.
The high expression of somatostatin receptor subtype 2 (SSTR2 also known as sst2) usually present in growth hormone (GH)-secreting adenomas is the rationale for therapy with somatostatin analogs (SSAs) in acromegaly. Although SSTR2 expression is a good predictor for biochemical response to SSA treatment, we still face tumors resistant to SSAs despite high SSTR2 expression. Recently, beta-arrestins (β-arrestins) have been highlighted as key players in the regulation of SSTR2 function. To investigate whether β-arrestins might be useful predictors of responsiveness to long-term SSA treatment in acromegaly, we retrospectively evaluated 35 patients with acromegaly who underwent adenomectomy in two referral centers in The Netherlands. β-arrestin mRNA levels were evaluated in adenoma samples, together with SSTR2 (and SSTR5) mRNA and protein expression. Biochemical response to long-term SSA treatment (median 12 months) was assessed in 32 patients. β-arrestin 1 and 2 mRNA was significantly lower in adenoma tissues from patients who achieved insulin-like growth factor 1 normalization (P = 0.024 and P = 0.047) and complete biochemical control (P = 0.047 and P = 0.039). The SSTR2 mRNA was higher in SSA responder patients compared with the resistant ones (P = 0.026). This difference was more evident when analyzing the SSTR2/β-arrestin 1 and SSTR2/β-arrestin 2 ratio (P = 0.011 and P = 0.010). β-arrestin 1 and 2 expression showed a significant trend of higher median values from full responders, partial responders to resistant patients (P = 0.045 and P = 0.021, respectively). Interestingly, SSTR2 protein expression showed a strong inverse correlation with both β-arrestin 1 and 2 mRNA (ρ = -0.69, P = 0.0011 and ρ = -0.67, P = 0.0016). Low β-arrestin expression and high SSTR2/β-arrestin ratio correlate with the responsiveness to long-term treatment with SSAs in patients with acromegaly.


Reduction of ormaplatin by an extended series of thiols unravels a remarkable correlation.
Ormaplatin ([Pt(dach)Cl4]) represents one of the three primary structural prototypes of Pt(iv) anticancer-active prodrugs. The reduction of ormaplatin by an extended series of thiols has been studied kinetically in a broad pH range. A novel and remarkable correlation between log kRS- and the thiol dissociation constants pKRSH is disclosed: log kRS- = (0.50 ± 0.02)pKRSH + (0.68 ± 0.13), where kRS- denotes the second-order rate constant of each thiolate towards the reduction of ormaplatin.


An ordinary differential equation model for full thickness wounds and the effects of diabetes.
Wound healing is a complex process in which a sequence of interrelated phases contributes to a reduction in wound size. For diabetic patients, many of these processes are compromised, so that wound healing slows down. In this paper we present a simple ordinary differential equation model for wound healing in which attention focusses on the dominant processes that contribute to closure of a full thickness wound. Asymptotic analysis of the resulting model reveals that normal healing occurs in stages: the initial and rapid elastic recoil of the wound is followed by a longer proliferative phase during which growth in the dermis dominates healing. At longer times, fibroblasts exert contractile forces on the dermal tissue, the resulting tension stimulating further dermal tissue growth and enhancing wound closure. By fitting the model to experimental data we find that the major difference between normal and diabetic healing is a marked reduction in the rate of dermal tissue growth for diabetic patients. The model is used to estimate the breakdown of dermal healing into two processes: tissue growth and contraction, the proportions of which provide information about the quality of the healed wound. We show further that increasing dermal tissue growth in the diabetic wound produces closure times similar to those associated with normal healing and we discuss the clinical implications of this hypothesised treatment.


Modal warping: real-time simulation of large rotational deformation and manipulation.
This paper proposes a real-time simulation technique for large deformations. Green's nonlinear strain tensor accurately models large deformations; however, time stepping of the resulting nonlinear system can be computationally expensive. Modal analysis based on a linear strain tensor has been shown to be suitable for real-time simulation, but is accurate only for moderately small deformations. In the present work, we identify the rotational component of an infinitesimal deformation and extend traditional linear modal analysis to track that component. We then develop a procedure to integrate the small rotations occurring at the nodal points. An interesting feature of our formulation is that it can implement both position and orientation constraints in a straightforward manner. These constraints can be used to interactively manipulate the shape of a deformable solid by dragging/twisting a set of nodes. Experiments show that the proposed technique runs in real-time, even for a complex model, and that it can simulate large bending and/or twisting deformations with acceptable realism.


Helicobacter pylori infection in subjects negative for high titer serum antibody.
To investigate the clinicopathological features of the patients testing negative for high titer serum anti-Helicobacter pylori (H. pylori) antibody. The antibody titers were measured using antigens derived from Japanese individuals. 13C-urea breath test-positive individuals were defined as having H. pylori infection. We investigated the demographic characteristics, laboratory data, endoscopic findings including Kyoto classification of gastritis, and histology in negative-high titer patients without H. pylori eradication therapy. Kyoto classification consisted of scores for gastric atrophy, intestinal metaplasia, enlarged folds, nodularity, and redness. Of the 136 subjects enrolled, 23 (17%) had H. pylori infection. Kyoto classification had an excellent area under the receiver operating characteristics curve (0.886, 95% confidence interval: 0.803-0.968, P = 3.7 × 10-20) for predicting H. pylori infection with a cut-off value of 2. Further, Kyoto classification, H. pylori density, and neutrophil activity had high accuracies (89.7%, 96.3%, and 94.1%, respectively). Kyoto classification was independent of the demographic and laboratory parameters in multivariate analysis. Endoscopic Kyoto classification of gastritis is a useful predictor of H. pylori infection in negative-high titer antibody patients.


Membranous nephropathy in Schimke immuno-osseous dysplasia.
Schimke immuno-osseous dysplasia is a rare autosomal recessive multi-system disorder, with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome and immunodeficiency beginning in childhood. Here, we report a new case, in a 10-year-old boy with characteristic symptoms of Schimke immuno-osseous dysplasia. The patient presented with short stature and, later, developed nephrotic syndrome and peritonitis. In addition, he had perinuclear anti-neutrophilic cytoplasmic antibody (p-ANCA)-positive arthritis. Renal pathology of the patients with this disease usually show focal segmental glomerulonephritis, whereas our patient had membranous nephropathy, which has not previously been reported.


Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study.
Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [CI] 3·8-6·4) and 12·2 months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.


The molecular chaperone Hsp90 regulates accumulation of DNA polymerase eta at replication stalling sites in UV-irradiated cells.
DNA polymerase eta (Pol eta) is a member of the mammalian Y family polymerases and performs error-free translesion synthesis across UV-damaged DNA. For this function, Pol eta accumulates in nuclear foci at replication stalling sites via its interaction with monoubiquitinated PCNA. However, little is known about the posttranslational control mechanisms of Pol eta, which regulate its accumulation in replication foci. Here, we report that the molecular chaperone Hsp90 promotes UV irradiation-induced nuclear focus formation of Pol eta through control of its stability and binding to monoubiquitinated PCNA. Our data indicate that Hsp90 facilitates the folding of Pol eta into an active form in which PCNA- and ubiquitin-binding regions are functional. Furthermore, Hsp90 inhibition potentiates UV-induced cytotoxicity and mutagenesis in a Pol eta-dependent manner. Our studies identify Hsp90 as an essential regulator of Pol eta-mediated translesion synthesis.


Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.
In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results. To determine the association between the H. pylori infection and MS. 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups. H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate. Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation.


BRAF (V600E) mutation analysis on liquid-based cytology-processed aspiration biopsies predicts bilaterality and lymph node involvement in papillary thyroid microcarcinoma.
Activating mutations in the valine-to-glutamic acid substitution at position 600 of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF-1) gene are detected frequently in patients with papillary thyroid carcinoma (PTC). These mutations have been identified in approximately 29% to 69% of PTCs and in >80% of PTCs of the tall cell variant, whereas they have not been detected in benign lesions or in the majority of those (80%) with the follicular variant of PTC. The objective of the current study was to evaluate the role of liquid-based cytology (LBC) for the detection of BRAF mutations in the outcome of patients who have thyroid PTC measuring ≤ 1 cm and, hence, in guiding their clinical and surgical management. From October 2010 through June 2011, 230 consecutive cases were diagnosed as positive for malignancy on fine-needle aspiration cytology processed by LBC. Of these, 73 PTCs ≤ 1 cm underwent BRAF mutational analysis. The aspirated material was processed using an LBC technique. After DNA extraction of the residual material, BRAF mutation analysis was performed using a direct sequencing method. Fifty of 73 patients (68.5%) underwent surgery, and 34 of those patients (68%) had tumors that expressed a BRAF mutation (31 PTCs, including 11 tall cell variants and 3 follicular-variant PTCs). A significant association between BRAF mutation and bilaterality of cancer was observed (odds ratio, 0.077; P = .0007). BRAF mutation was associated significantly with lymph node involvement (odds ratio, 19; P = .0007) but not with extracapsular infiltration (odds ratio, 0.298; P = .179). The current results indicated that BRAF gene mutations can be identified successfully on LBC material and using other cytologic methods with high reproducibility, feasibility, and informative results. The presence of a BRAF mutation may preoperatively predict the behavior of microscopic PTC, suggesting a more aggressive surgical approach.


Development and Regulation of Novel Influenza Virus Vaccines: A United States Young Scientist Perspective.
Vaccination against influenza is the most effective approach for reducing influenza morbidity and mortality. However, influenza vaccines are unique among all licensed vaccines as they are updated and administered annually to antigenically match the vaccine strains and currently circulating influenza strains. Vaccine efficacy of each selected influenza virus vaccine varies depending on the antigenic match between circulating strains and vaccine strains, as well as the age and health status of the vaccine recipient. Low vaccine effectiveness of seasonal influenza vaccines in recent years provides an impetus to improve current seasonal influenza vaccines, and for development of next-generation influenza vaccines that can provide broader, long-lasting protection against both matching and antigenically diverse influenza strains. This review discusses a perspective on some of the issues and formidable challenges facing the development and regulation of the next-generation influenza vaccines.


Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms.
To assess the distribution of gains and losses of genetic material in malignant solid neoplasms, 11 tumor types for which at least 100 short-term cultured cases with clonal chromosome aberrations had been reported in the literature were selected. The study was based on cytogenetic information from 508 breast carcinomas, 447 malignant neuroglial tumors, 435 kidney carcinomas, 333 colon carcinomas, 304 ovarian carcinomas, 303 lung carcinomas, 209 testicular germ cell tumors, 206 head and neck carcinomas, 172 malignant melanomas, 142 Wilms' tumors, and 126 neuroblastomas. In each case, the net imbalances were calculated for each chromosome band. The profiles of gains and losses revealed that all tumor types display unique combinations of imbalances. However, there is also considerable overlap among the profiles of the different diagnostic entities, indicating that similar molecular mechanisms may be operative in the development of many types of neoplasia. Deletions were more common than gains in all tumor types, with chromosomes X, Y, 4, 10, 13-15, 18, and 22 and chromosome segments 1p22-pter, 3p13-pter, 6q14-qter, 8p, 9p, and 11p being particularly often deleted in the majority of tumors. To better delineate critical lost segments, deletion profiles based only on structural rearrangements were made for chromosomes 1, 3-12, and 17, which all had on average at least four registered deletions per band. The relative distribution of losses indicated that different bands/regions are affected in different tumor types and that, often, several distinct candidate tumor suppressor gene loci can be discerned within the same chromosome arm, e.g., 1p12-13, 1p22, 1p34, and 1p36 on the short arm of chromosome 1 and 7q22, 7q32, and 7q36 on the long arm of chromosome 7. The only chromosomes or chromosome segments more often gained than deleted were chromosomes 7 and 20 and the long arms of chromosomes 1 and 12, suggesting the presence there of dominantly acting growth-regulatory genes. The data presented in this study should be valuable as a guide for molecular genetic studies on allelic imbalances and for the interpretation of results from studies using comparative genomic hybridization.


Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors.
Antimicrobial peptides (AMPs) are produced by all living organisms exhibiting antimicrobial activities and representing the first line of innate defense against pathogens. In this context, AMPs are suggested as an alternative to classical antibiotics. However, several researchers reported their involvement in different processes defining them as Multifunctional AMPs (MF-AMPs). Interestingly, these agents act as the endogenous responses of the human organism against several dangerous stimuli. Still, they are identified in other organisms and evaluated for their anticancer therapy. Chromogranin A (CgA) is a glyco-phosphoprotein discovered for the first time in the adrenal medulla but also produced in several cells. CgA can generate different derived AMPs influencing numerous physiological processes. Dermaseptins (DRSs) are a family of α-helical-shaped polycationic peptides isolated from the skin secretions of several leaf frogs from the Phyllomedusidae family. Several DRSs were identified as AMPs and, until now, more than 65 DRSs have been classified. Recently, these exogenous molecules were characterized for their anticancer activity. In this review, we summarize the role of these two classes of MF-AMPs as an example of endogenous molecules for CgA-derived peptides, able to modulate inflammation but also as exogenous molecules for DRSs, exerting anticancer activities.


New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome.
Abstract Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit to prevent ischemic stroke and thromboembolic events in patients with atrial fibrillation (AF) or to prevent further ischemic complications in patients with acute coronary syndrome (ACS). Traditional anticoagulants (including unfractionated heparin, low-molecular-weight heparin, and warfarin) and antiplatelet agents (including aspirin, clopidogrel, and prasugrel) are typically used for these indications. Limitations to their use include variable pharmacokinetic and pharmacodynamic profiles, inability to inhibit fibrin-bound thrombin, risk of heparin-induced thrombocytopenia, delayed onset of action, numerous drug interactions, need for substantial laboratory monitoring and dosage titrations, hyporesponsiveness or resistance, hypersensitivity, adverse events, and bleeding. To overcome some of the limitations of traditional agents, new antithrombotic agents under development are highly selective for specific coagulation factors blocking the synthesis of thrombin. Clinicians must have an understanding of the new anticoagulants to aid in the selection of appropriate therapies for patients. We describe the most relevant phases II and III clinical trials that evaluated several recent emerging anticoagulant drugs for use in patients with AF or ACS. The advantages of many new agents include predictable pharmaco-dynamic response and pharmacokinetic parameters, allowing for fixed oral dosing with no need for laboratory monitoring. For patients with AF, dabigatran is already approved for the prevention of stroke and systemic embolism, rivaroxaban appears to be an effective alternative to warfarin in high-risk patients, and apixaban may also be an effective alternative to aspirin in patients unable to take warfarin. Otamixaban shows promise as an intravenous alternative for patients with ACS in the acute care setting. Likewise, rivaroxaban, dabigatran, and darexaban with or without dual antiplatelet therapy may be beneficial for secondary prevention of ischemic events in patients with ACS.


Thyrotropin secretion in rats after hypothalamic electrical stimulation or injection of synthetic TSH-releasing factor.
Plasma thyroid-stimulating hormone (TSH) levels, as measured by radioimmunoassay, begin to rise within 5 minutes after initiation of electrical stimulation of the medial-basal hypothalamus, become significantly elevated at 10 minutes, and reach a peak at 10 to 25 minutes. Intravenous administration of synthetic thyrotropin-releasing factor induces a marked rise in plasma thyroidstimulating hormone which is maximal within 5 minutes after administration. These data are interpreted to indicate that there are neuronal structures within the medial-basal hypothalamus which release preformed thyrotropin-releasing factor. The claim (based on bioassay data) that pyroglutamyl-histidyl-proline amide is a potent thyrotropin-releasing factor has also been confirmed by using a highly specific immunoassay system.


Scalable high-mobility MoS2 thin films fabricated by an atmospheric pressure chemical vapor deposition process at ambient temperature.
Nano-scale MoS2 thin films are successfully deposited on a variety of substrates by atmospheric pressure chemical vapor deposition (APCVD) at ambient temperature, followed by a two-step annealing process. These annealed MoS2 thin films are characterized with scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), micro-Raman, X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-VIS-NIR spectrometry, photoluminescence (PL) and Hall Effect measurement. Key optical and electronic properties of APCVD grown MoS2 thin films are determined. This APCVD process is scalable and can be easily incorporated with conventional lithography as the deposition is taking place at room temperature. We also find that the substrate material plays a significant role in the crystalline structure formation during the annealing process and single crystalline MoS2 thin films can be achieved by using both c-plane ZnO and c-plane sapphire substrates. These APCVD grown nano-scale MoS2 thin films show great promise for nanoelectronic and optoelectronic applications.


Proteomic analysis of iron acquisition, metabolic and regulatory responses of Yersinia pestis to iron starvation.
The Gram-negative bacterium Yersinia pestis is the causative agent of the bubonic plague. Efficient iron acquisition systems are critical to the ability of Y. pestis to infect, spread and grow in mammalian hosts, because iron is sequestered and is considered part of the innate host immune defence against invading pathogens. We used a proteomic approach to determine expression changes of iron uptake systems and intracellular consequences of iron deficiency in the Y. pestis strain KIM6+ at two physiologically relevant temperatures (26 degrees C and 37 degrees C). Differential protein display was performed for three Y. pestis subcellular fractions. Five characterized Y. pestis iron/siderophore acquisition systems (Ybt, Yfe, Yfu, Yiu and Hmu) and a putative iron/chelate outer membrane receptor (Y0850) were increased in abundance in iron-starved cells. The iron-sulfur (Fe-S) cluster assembly system Suf, adapted to oxidative stress and iron starvation in E. coli, was also more abundant, suggesting functional activity of Suf in Y. pestis under iron-limiting conditions. Metabolic and reactive oxygen-deactivating enzymes dependent on Fe-S clusters or other iron cofactors were decreased in abundance in iron-depleted cells. This data was consistent with lower activities of aconitase and catalase in iron-starved vs. iron-rich cells. In contrast, pyruvate oxidase B which metabolizes pyruvate via electron transfer to ubiquinone-8 for direct utilization in the respiratory chain was strongly increased in abundance and activity in iron-depleted cells. Many protein abundance differences were indicative of the important regulatory role of the ferric uptake regulator Fur. Iron deficiency seems to result in a coordinated shift from iron-utilizing to iron-independent biochemical pathways in the cytoplasm of Y. pestis. With growth temperature as an additional variable in proteomic comparisons of the Y. pestis fractions (26 degrees C and 37 degrees C), there was little evidence for temperature-specific adaptation processes to iron starvation.