Annotating and detecting phenotypic information for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) phenotypes cover a range of lung abnormalities. To allow text mining methods to identify pertinent and potentially complex information about these phenotypes from textual data, we have developed a novel annotated corpus, which we use to train a neural network-based named entity recognizer to detect fine-grained COPD phenotypic information. Since COPD phenotype descriptions often mention other concepts within them (proteins, treatments, etc.), our corpus annotations include both outermost phenotype descriptions and concepts nested within them. Our neural layered bidirectional long short-term memory conditional random field (BiLSTM-CRF) network firstly recognizes nested mentions, which are fed into subsequent BiLSTM-CRF layers, to help to recognize enclosing phenotype mentions. Our corpus of 30 full papers (available at: http://www.nactem.ac.uk/COPD) is annotated by experts with 27 030 phenotype-related concept mentions, most of which are automatically linked to UMLS Metathesaurus concepts. When trained using the corpus, our BiLSTM-CRF network outperforms other popular approaches in recognizing detailed phenotypic information. Information extracted by our method can facilitate efficient location and exploration of detailed information about phenotypes, for example, those specifically concerning reactions to treatments. The importance of our corpus for developing methods to extract fine-grained information about COPD phenotypes is demonstrated through its successful use to train a layered BiLSTM-CRF network to extract phenotypic information at various levels of granularity. The minimal human intervention needed for training should permit ready adaption to extracting phenotypic information about other diseases.


Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.
Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol. To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy. We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies. We included RCTs, irrespective of publication status, language, or blinding. Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses. We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence). This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.


Tuning Micellar Structures in Supercritical CO2 Using Surfactant and Amphiphile Mixtures.
For equivalent micellar volume fraction (ϕ), systems containing anisotropic micelles are generally more viscous than those comprising spherical micelles. Many surfactants used in water-in-CO2 (w/c) microemulsions are fluorinated analogues of sodium bis(2-ethylhexyl) sulfosuccinate (AOT): here it is proposed that mixtures of CO2-philic surfactants with hydrotropes and cosurfactants may generate elongated micelles in w/c systems at high-pressures (e.g., 100-400 bar). A range of novel w/c microemulsions, stabilized by new custom-synthesized CO2-phillic, partially fluorinated surfactants, were formulated with hydrotropes and cosurfactant. The effects of water content (w = [water]/[surfactant]), surfactant structure, and hydrotrope tail length were all investigated. Dispersed water domains were probed using high pressure small-angle neutron scattering (HP-SANS), which provided evidence for elongated reversed micelles in supercritical CO2. These new micelles have significantly lower fluorination levels than previously reported (6-29 wt % cf. 14-52 wt %), and furthermore, they support higher water dispersion levels than other related systems (w = 15 cf. w = 5). The intrinsic viscosities of these w/c microemulsions were estimated based on micelle aspect ratio; from this value a relative viscosity value can be estimated through combination with the micellar volume fraction (ϕ). Combining these new results with those for all other reported systems, it has been possible to "map" predicted viscosity increases in CO2 arising from elongated reversed micelles, as a function of surfactant fluorination and micellar aspect ratio.


Alkali hydrolysis of recombinant proteins allows for the rapid identification of class I MHC-restricted CTL epitopes.
The characterization of the epitopes recognized by CTL provides insights into the nature of protective immune responses and facilitates the development of methods to enhance immunity to human pathogens. However, no easily applicable approach for CTL epitope identification has been developed. We present a rapid and efficient method for locating CTL epitopes within a protein. The gene encoding the protein of interest is inserted into an inducible prokaryotic expression vector. Random peptides are then generated by alkali digestion of intact or lysed Escherichia coli expressing the protein and assayed for the presence of the epitope by coating target cells for a standard CTL targeting assay. A large panel of clones containing serial 3'-deletions of the gene is then generated by exonuclease III digestion, and the expressed truncated proteins are similarly analyzed for the presence of the antigenic peptide. The epitope is located by determining the deletion points of clones expressing sequential truncations and differing in Ag expression. This technique was used to identify the H-2Ld-restricted nonamer in E. coli beta-galactosidase, with residues 876-884 representing the naturally processed epitope. To test the applicability of this method to other proteins, two genes from human CMV, an often fatal pathogen in immunocompromised individuals, were screened for HLA class I-restricted epitopes. An HLA-B18-restricted epitope from the CMV major immediate-early protein was found to lie between residues 378 and 389, and an HLA-B35-restricted epitope from the CMV pp65 matrix protein was characterized as residues 123 to 131. The results demonstrate that this technique can be used to rapidly identify CTL epitopes within a chosen protein and should be useful for assaying viral isolates or neoplasms for loss of epitopes after mutation and selection by host immune responses.


DCAF4, a novel gene associated with leucocyte telomere length.
Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24). We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.


Aerobic Exercise for Reducing Migraine Burden: Mechanisms, Markers, and Models of Change Processes.
Engagement in regular exercise routinely is recommended as an intervention for managing and preventing migraine, and yet empirical support is far from definitive. We possess at best a weak understanding of how aerobic exercise and resulting change in aerobic capacity influence migraine, let alone the optimal parameters for exercise regimens as migraine therapy (eg, who will benefit, when to prescribe, optimal types, and doses/intensities of exercise, level of anticipated benefit). These fundamental knowledge gaps critically limit our capacity to deploy exercise as an intervention for migraine. Clear articulation of the markers and mechanisms through which aerobic exercise confers benefits for migraine would prove invaluable and could yield insights on migraine pathophysiology. Neurovascular and neuroinflammatory pathways, including an effect on obesity or adiposity, are obvious candidates for study given their role both in migraine as well as the changes known to accrue with regular exercise. In addition to these biological pathways, improvements in aerobic fitness and migraine alike also are mediated by changes in psychological and sociocognitive factors. Indeed a number of specific mechanisms and pathways likely are operational in the relationship between exercise and migraine improvement, and it remains to be established whether these pathways operate in parallel or synergistically. As heuristics that might conceptually benefit our research programs here forward, we: (1) provide an extensive listing of potential mechanisms and markers that could account for the effects of aerobic exercise on migraine and are worthy of empirical exploration and (2) present two exemplar conceptual models depicting pathways through which exercise may serve to reduce the burden of migraine. Should the promise of aerobic exercise as a feasible and effective migraine therapy be realized, this line of endeavor stands to benefit migraineurs (including the many who presently remain suboptimally treated) by providing a new therapeutic avenue as an alternative or augmentative compliment to established interventions for migraine.


Nocardia farcinica abortion in a goat.
A female goat fetus was received by the Colorado State University-Veterinary Diagnostic Laboratory following an isolated abortion of twins by a reportedly healthy doe. Postmortem examination did not reveal any gross abnormalities. Histologic evaluation revealed pyogranulomatous and necrotizing bronchopneumonia with intracellular and extracellular gram-positive and non-acid-fast filamentous bacilli. Aerobic culture of the stomach contents and pooled lung and liver tissue yielded light growth of Nocardia sp., which was identified by MALDI-TOF MS and 16s rDNA sequencing as Nocardia farcinica.


Sustained Exposure to High Carbohydrate Availability Does Not Influence Iron-Regulatory Responses in Elite Endurance Athletes.
This study implemented a 2-week high carbohydrate (CHO) diet intended to maximize CHO oxidation rates and examined the iron-regulatory response to a 26-km race walking effort. Twenty international-level, male race walkers were assigned to either a novel high CHO diet (MAX = 10 g/kg body mass CHO daily) inclusive of gut-training strategies, or a moderate CHO control diet (CON = 6 g/kg body mass CHO daily) for a 2-week training period. The athletes completed a 26-km race walking test protocol before and after the dietary intervention. Venous blood samples were collected pre-, post-, and 3 hr postexercise and measured for serum ferritin, interleukin-6, and hepcidin-25 concentrations. Similar decreases in serum ferritin (17-23%) occurred postintervention in MAX and CON. At the baseline, CON had a greater postexercise increase in interleukin-6 levels after 26 km of walking (20.1-fold, 95% CI [9.2, 35.7]) compared with MAX (10.2-fold, 95% CI [3.7, 18.7]). A similar finding was evident for hepcidin levels 3 hr postexercise (CON = 10.8-fold, 95% CI [4.8, 21.2]; MAX = 8.8-fold, 95% CI [3.9, 16.4]). Postintervention, there were no substantial differences in the interleukin-6 response (CON = 13.6-fold, 95% CI [9.2, 20.5]; MAX = 11.2-fold, 95% CI [6.5, 21.3]) or hepcidin levels (CON = 7.1-fold, 95% CI [2.1, 15.4]; MAX = 6.3-fold, 95% CI [1.8, 14.6]) between the dietary groups. Higher resting serum ferritin (p = .004) and hotter trial ambient temperatures (p = .014) were associated with greater hepcidin levels 3 hr postexercise. Very high CHO diets employed by endurance athletes to increase CHO oxidation have little impact on iron regulation in elite athletes. It appears that variations in serum ferritin concentration and ambient temperature, rather than dietary CHO, are associated with increased hepcidin concentrations 3 hr postexercise.


Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis.
In humans, HLA-DR alleles sharing amino acids at the third hypervariable region with DRB1*0401(shared epitope) are associated with a predisposition to rheumatoid arthritis, whereas DRB1*0402 is not associated with such a predisposition. Both DRB1*0402 and DRB1*0401 occur in linkage with DQ8 (DQB1*0302). We have previously shown that transgenic (Tg) mice expressing HLA-DRB1*0401 develop collagen-induced arthritis. To delineate the role of "shared epitope" and gene complementation between DR and DQ in arthritis, we generated DRB1*0402, DRB1*0401.DQ8, and DRB1*0402.DQ8 Tg mice lacking endogenous class II molecules, AE(o). DRB1*0402 mice are resistant to develop arthritis. In double-Tg mice, the DRB1*0401 gene contributes to the development of collagen-induced arthritis, whereas DRB1*0402 prevents the disease. Humoral response to type II collagen is not defective in resistant mice, although cellular response to type II collagen is lower in *0402 mice compared with *0401 mice. *0402 mice have lower numbers of T cells in thymus compared with *0401 mice, suggesting that the protective effect could be due to deletion of autoreactive T cells. Additionally, DRB1*0402 mice have a higher number of regulatory T cells and show increased activation-induced cell death, which might contribute toward protection. In DRB1*0401.DQ8 mice, activated CD4(+) T cells express class II genes and can present DR4- and DQ8-restricted peptides in vitro, suggesting a role of class II(+) CD4 T cells locally in the joints. The data suggest that polymorphism in DRB1 genes determines predisposition to develop arthritis by shaping the T cell repertoire in thymus and activating autoreactive or regulatory T cells.


Routine clinical use of circulating tumor cells for diagnosis of mutations and chromosomal rearrangements in non-small cell lung cancer-ready for prime-time?
In non-small cell lung cancer (NSCLC), diagnosis of predictive biomarkers for targeted therapies is currently done in small tumor biopsies. However, tumor biopsies can be invasive, in some cases associated with risk, and tissue adequacy, both in terms of quantity and quality is often insufficient. The development of efficient and non-invasive methods to identify genetic alterations is a key challenge which circulating tumor cells (CTCs) have the potential to be exploited for. CTCs are extremely rare and phenotypically diverse, two characteristics that impose technical challenges and impact the success of robust molecular analysis. Here we introduce the clinical needs in this disease that mainly consist of the diagnosis of epidermal growth factor receptor (EGFR) activating alterations and anaplastic lymphoma kinase (ALK) rearrangement. We present the proof-of-concept studies that explore the detection of these genetic alterations in CTCs from NSCLC patients. Finally, we discuss steps that are still required before CTCs are routinely used for diagnosis of EGFR-mutations and ALK-rearrangements in this disease.


Progression of Alzheimer's disease and effect of scFv-h3D6 immunotherapy in the 3xTg-AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy.
Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. In recent years, Aβ-immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv-h3D6 generated by our research group derives from this monoclonal antibody, which targets the N-terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils. In this study, 3xTg-AD mice were intraperitoneally and monthly treated with 100 μg of scFv-h3D6 (a dose of ~3.3 mg/kg) or PBS, from 5 to 12 months of age (-mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non-invasive manner and allowing to monitor its development across time. Compared with the genetic background, 3xTg-AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ1-42 at 12-mo, and an inflammation process at this age, in both the hippocampus (IL-6 and mIns) and cortex (IL-6). In addition, treatment with scFv-h3D6 partially recovered the values in brain volume, and Aβ, IL-6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.


Effects of evening light conditions on salivary melatonin of Japanese junior high school students.
BACKGROUND: In a previous study, when adult subjects were exposed to a level of 400 lux light for more than 30 min or a level of 300 lux light for more than 2 hours, salivary melatonin concentration during the night dropped lower than when the subjects were exposed to dim illumination. It was suggested that such light exposure in adolescents or children during the first half of subjective night in normal life might decrease the melatonin level and prevent the falling into sleep. However, there has been no actual study on the effects of light exposure in adolescents. METHODS: Effects of exposure to the bright light (2000 lux) from fluorescent light bulbs during a period of three hours from 19:30 to 22:30 in one evening were examined on evening salivary melatonin concentrations from 19:45 to 23:40. The control group was exposed to dim light (60 lux) during these three hours. Both the dim light control group [DLCG] and the bright light experimental group [BLEG] consisted of two female and three male adolescent participants aged 14-15 y. RESULTS: The salivary melatonin level increased rapidly from 3.00 pg/ml at 21:45 to 9.18 pg/ml at 23:40 in DLCG, whereas it remained at less than 1.3 pg/ml for the three hours in BLEG. Melatonin concentration by BLEG at 22:30 of the experimental day was lower than that at the same time on the day before the experimental day, whereas it was significantly higher in the experimental day than on the day before the experimental day in DLCG. CONCLUSIONS: Bright lights of 2000 lux and even moderate lights of 200-300 lux from fluorescent light bulbs can inhibit nocturnal melatonin concentration in adolescents. Ancient Japanese lighting from a traditional Japanese hearth, oil lamp or candle (20-30 lux) could be healthier for children and adolescents because rapid and clear increase in melatonin concentration in blood seems to occur at night under such dim light, thus facilitating a smooth falling into night sleep.


[Treatment of hepatitis C - an imminent revolution].
Treatment of hepatitis C is approaching a revolution. During the last years, many agents have been developed that directly interfere with the viral replication cycle. Therapy of hepatitis C will no longer need Interferon in the future. The new therapies will be shorter, more efficient and with fewer side effects. For patients, the burden of treatment will drop substantially. Even patients are traditionally classified who as "difficult to treat", such as cirrhotic patients, HIV/hepatitis C coinfected patients and patients after liver transplantation will have better chances of cure. For more patients to benefit from the new therapies, identification of infected individuals and diagnostic investigations have to be improved.


Age Effects in L2 Grammar Processing as Revealed by ERPs and How (Not) to Study Them.
In this study we investigate the effect of age of acquisition (AoA) on grammatical processing in second language learners as measured by event-related brain potentials (ERPs). We compare a traditional analysis involving the calculation of averages across a certain time window of the ERP waveform, analyzed with categorical groups (early vs. late), with a generalized additive modeling analysis, which allows us to take into account the full range of variability in both AoA and time. Sixty-six Slavic advanced learners of German listened to German sentences with correct and incorrect use of non-finite verbs and grammatical gender agreement. We show that the ERP signal depends on the AoA of the learner, as well as on the regularity of the structure under investigation. For gender agreement, a gradual change in processing strategies can be shown that varies by AoA, with younger learners showing a P600 and older learners showing a posterior negativity. For verb agreement, all learners show a P600 effect, irrespective of AoA. Based on their behavioral responses in an offline grammaticality judgment task, we argue that the late learners resort to computationally less efficient processing strategies when confronted with (lexically determined) syntactic constructions different from the L1. In addition, this study highlights the insights the explicit focus on the time course of the ERP signal in our analysis framework can offer compared to the traditional analysis.


Risky Sexual Behaviors and Associated Factors among Jiga High School and Preparatory School Students, Amhara Region, Ethiopia.
Background. Young people constitute a large number of population worldwide, and majority of this population group lives in developing countries. They are at high risk of engaging in risky sexual behaviors. These risk sexual behaviors predispose youths to several sexual and reproductive health problems like STIs, HIV, unwanted pregnancy, and abortion. So, this study was conducted to assess the magnitude of risky sexual behaviors and associated factors among Jiga high school and preparatory school students, northwest Ethiopia. Methodology. Institutional based cross-sectional study design was conducted among Jiga town high school and preparatory school students. A total of 311 students were included in the study. Systematic random sampling method was used to select study participants. Data was entered using EpiData version 3.1 and it was exported to SPSS version 22 for further analysis. Descriptive analysis and bivariate and multivariate analysis were also calculated to determine factors associated with risky sexual behavior. Result. Forty-eight (16%) of respondents reported that they had sexual intercourse. From those who start sex, 44 (14.7%) were involved in risky sexual behavior which could predispose them to sexual and reproductive health problems. More than half, 27 (56.3%), of respondents first sexual intercourse was before their eighteenth birthday. The mean age and SD of fist sexual initiation were 17.2 years old and 1.35 years, respectively. Factors associated with risky sexual behavior include respondents between the ages of 20 and 23 (AOR: 5, 95%, CI: 1.59-15.98), drinking alcohol (AOR: 2.48, 95% CI: 1.13-5.41), and having poor knowledge towards HIV/AIDS (AOR: 4.53, 95%, CI: 2.06-9.94). Conclusion. A large number of in-school youths are involved in risky sexual behaviors like early sexual initiation, having multiple sexual partners, inconsistence use of condom, and having sex with high risk partner (CSWs). Age of respondents, alcohol drinking, and poor knowledge towards HIV/AIDS were factors associated with risky sexual behavior. School and community based programs in reducing substance abuse among youths and increasing their knowledge towards HIV/AIDS are important.


System-wide changes to SUMO modifications in response to heat shock.
Covalent conjugation of the small ubiquitin-like modifier (SUMO) proteins to target proteins regulates many important eukaryotic cellular mechanisms. Although the molecular consequences of the conjugation of SUMO proteins are relatively well understood, little is known about the cellular signals that regulate the modification of their substrates. Here, we show that SUMO-2 and SUMO-3 are required for cells to survive heat shock. Through quantitative labeling techniques, stringent purification of SUMOylated proteins, advanced mass spectrometric technology, and novel techniques of data analysis, we quantified heat shock-induced changes in the SUMOylation state of 766 putative substrates. In response to heat shock, SUMO was polymerized into polySUMO chains and redistributed among a wide range of proteins involved in cell cycle regulation; apoptosis; the trafficking, folding, and degradation of proteins; transcription; translation; and DNA replication, recombination, and repair. This comprehensive proteomic analysis of the substrates of a ubiquitin-like modifier (Ubl) identifies a pervasive role for SUMO proteins in the biologic response to hyperthermic stress.


Regulation of the expression of the estrogen related receptors (ERRs).
Estrogen related receptors (ERRα, β and γ in mammals) are orphan members of the nuclear receptor superfamily acting as transcription factors. ERRs are expressed in several tissues and cells and they display various physiological and pathological functions, controlling, amongst others and depending on the receptor, bone homeostasis, energy metabolism, embryonic stem cell pluripotency, and cancer progression. In contrast to classical nuclear receptors, the activities of the ERRs are not controlled by a natural ligand. Regulation of their activities thus rely on other means such as post-translational modification or availability of transcriptional co-regulators. In addition, regulation of their mere expression under given physiological or pathological conditions is a particularly important level of control. Here we discuss the mechanisms involved in the regulation of ERRs expression and the reported means to impact on it using pharmacological approaches.


Reproductive and developmental toxicity studies of toluene. II. Effects of inhalation exposure on fertility in rats.
Male and female Sprague-Dawley rats were exposed to toluene vapor at 600 and 2000 ppm for 6 h/day, and effects on their fertility were investigated. Females were exposed from 14 days before mating until day 7 of gestation. Males were exposed for a total of 90 days, including the mating period; treatment was begun 60 days before pairing, and toxicity with respect to testicular and reproductive functions was examined. In females of the 2000 ppm-treated group, salivation and lacrimation that may have been caused by CNS depression were observed starting 20 days after exposure. Although no abnormalities were seen in mating behavior or fertility, fetal mortality and the number of dams with dead fetuses increased in the 2000 ppm group. In the males exposed to 2000 ppm toluene for 90 days, an increase in kidney weights and a decrease in thymus weights were observed. Basophilic changes and necrosis of kidney tubules were greater at the higher exposure level. Additionally, decreases in the weights of the epididymides and spermatic count were observed, indicating toxicity of toluene to the male reproductive system in vivo for the first time. In conclusion, embryo-fetal toxic effects were apparent in female rats exposed to toluene before and during the early stage of pregnancy. Subacute exposure to a high level (2000 ppm) of toluene vapor elicited mild toxic changes in the kidneys, thymus, and reproductive organs of males. Toxic effects on fertility and reproduction were thus demonstrated not only in females but also in males exposed to toluene vapor in the present study.


Nutritional parameters and carbohydrate and fat metabolism after prolonged salsolinol administration in rats fed normal or high-fat diets.
Previous studies have reported that exogenous salsolinol might contribute to myenteric cell death and altered gastrointestinal motility. Because the entire gut mucosal, entero-endocrine and motor functions are integrated by the enteric nervous system, the aim of the present study was to investigate if prolonged intraperitoneal salsolinol administration alters basic metabolism and nutritional parameters in adult Wistar rats fed normal or high-fat diets. Male Wistar rats were subjected to continuous intraperitoneal low dosing of salsolinol with ALZET osmotic mini-pumps for 2 or 4 weeks and fed either a normal or high-fat diet. Appropriate groups served as the controls. Nutritional status (food intake, body weight, and epididymal fat pads weight), residual solid food in the stomach and biochemical parameters (GIP, GLP-1, CRF, glucose, TG, LDL, HDL) were assessed. Prolonged salsolinol treatment significantly reduced total body mass and adipose tissue accumulation. The effects were more pronounced in the salsolinol-treated rats fed a high-fat diet. In salsolinol-treated rats, serum postprandial GIP levels were elevated, and serum postprandial GLP-1 levels were lower compared with the appropriate controls. Salsolinol might influence the regulatory mechanisms of body weight and epididymal fat pad accumulation through neurohormonal pathways.


Beach cusps as self-organized patterns.
Computer simulations of flow and sediment transport in the swash zone on a beach demonstrate that a model that couples local flow acceleration and alongshore surface gradient is sufficient to produce uniformly spaced beach cusps. The characteristics of the simulated cusps and the conditions under which they form are in reasonable agreement with observations of natural cusps. The self-organization mechanism in the model is incompatible with an accepted model in which standing alongshore waves drive the regular pattern of erosion and deposition that gives rise to beach cusps. Because the models make similar predictions, it is concluded that currently available observational data are insufficient for discrimination between them.


Mesonephric remnant hyperplasia involving prostate and periprostatic tissue: findings at radical prostatectomy.
Mesonephric remnant hyperplasia is a very rare benign mimicker of prostate adenocarcinoma. As most reported cases are from transurethral resection specimens, the anatomic location and histologic spectrum of this entity have not been fully elucidated. Its immunohistochemical profile using current prostatic diagnostic markers has also not been well studied. In this study, we retrospectively characterized 10 cases of mesonephric remnant hyperplasia involving the prostate and periprostatic tissue, including 8 cases seen in radical prostatectomy specimens, with emphasis on the histopathologic and immunohistochemical features. Patients ranged in age from 48 to 70 years (average, 60 y). Seven of them had concurrent prostatic adenocarcinoma and underwent radical prostatectomy; one patient underwent prostatectomy because of the misdiagnosis of mesonephric remnant hyperplasia on transurethral resection as carcinoma; 2 patients had transurethral resection for urinary obstruction. The distribution of prostatic mesonephric hyperplasia was concentrated in 2 areas: one was in the anterior fibromuscular stroma and adjacent anterolateral periprostatic tissue (n=6 of 8); the other was located toward the base posteriorly and posterolaterally either within or exterior to the prostate and around the seminal vesicle (n=4 of 8). Histologic patterns observed included the following: small-to-medium-sized acini or tubules with a lobular distribution (n=10 of 10); cysts either in clusters or scattered containing secretions (n=8 of 10); small or ill-formed glands with an infiltrative growth (n=7 of 10); glands with papillary infoldings or micropapillary tufts (n=4 of 10); and 2 cases exceptionally displayed nodules of ill-formed small glands intermixed with spindle cells, mimicking sclerosing adenosis or Gleason pattern 5 prostate cancer. Most cases (7 of 10) had florid hyperplasia and harbored 3 or more growth patterns. All cases were negative for prostate-specific antigen. Cytokeratin 34βE12 was diffusely positive in 4 of 9 cases, and showed focal immunoreactivity in the remaining 5 cases. Except for focal positivity seen in 4 of 7 cases, p63 was largely negative. Racemase was focally positive in 4 of 7 cases. Small glands with an infiltrative growth pattern, the most difficult to distinguish from cancer, were negative (n=3 of 6) or only focally positive (n=3 of 6) for 34βE12, negative for p63 (n=6 of 6), and focally positive for racemase (n=4 of 6). All cases examined in the study were diffusely positive for PAX8. In conclusion, mesonephric remnant hyperplasia not only involves the bladder neck and base of the prostate as previously described, but may also present as a florid growth in the anterior fibromuscular stroma from the apex to the base, closely mimicking prostate cancer. Although basal cell marker and racemase expression overlaps with prostate cancer, mesonephric hyperplasia's unique morphology along with distinctive immunohistochemical expression of PAX8 and lack of prostate-specific antigen can help in distinguishing this benign entity from prostatic adenocarcinoma.


TREM-1-accentuated lung injury via miR-155 is inhibited by LP17 nanomedicine.
Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. Synergy between TREM-1 and Toll-like receptor amplifies the inflammatory response; however, the mechanisms by which TREM-1 accentuates inflammation are not fully understood. In this study, we investigated the role of TREM-1 in a model of LPS-induced lung injury and neutrophilic inflammation. We show that TREM-1 is induced in lungs of mice with LPS-induced acute neutrophilic inflammation. TREM-1 knockout mice showed an improved survival after lethal doses of LPS with an attenuated inflammatory response in the lungs. Deletion of TREM-1 gene resulted in significantly reduced neutrophils and proinflammatory cytokines and chemokines, particularly IL-1β, TNF-α, and IL-6. Physiologically deletion of TREM-1 conferred an immunometabolic advantage with low oxygen consumption rate (OCR) sparing the respiratory capacity of macrophages challenged with LPS. Furthermore, we show that TREM-1 deletion results in significant attenuation of expression of miR-155 in macrophages and lungs of mice treated with LPS. Experiments with antagomir-155 confirmed that TREM-1-mediated changes were indeed dependent on miR-155 and are mediated by downregulation of suppressor of cytokine signaling-1 (SOCS-1) a key miR-155 target. These data for the first time show that TREM-1 accentuates inflammatory response by inducing the expression of miR-155 in macrophages and suggest a novel mechanism by which TREM-1 signaling contributes to lung injury. Inhibition of TREM-1 using a nanomicellar approach resulted in ablation of neutrophilic inflammation suggesting that TREM-1 inhibition is a potential therapeutic target for neutrophilic lung inflammation and acute respiratory distress syndrome (ARDS).


Fungal Symbionts of the Spruce Bark Beetle Synthesize the Beetle Aggregation Pheromone 2-Methyl-3-buten-2-ol.
Tree-killing bark beetles depend on aggregation pheromones to mass-attack their host trees and overwhelm their resistance. The beetles are always associated with phytopathogenic ophiostomatoid fungi that probably assist in breaking down tree resistance, but little is known about if or how much these fungal symbionts contribute to the beetles' aggregation behavior. In this study, we determined the ability of four major fungal symbionts of the spruce bark beetle Ips typographus to produce beetle aggregation pheromones. The fungi were incubated on Norway spruce Picea abies bark, malt agar, or malt agar amended with 0.5% (13)C glucose. Volatiles present in the headspace of each fungus were analyzed for 7 days after incubation using a SPME autosampler coupled to a GC/MS. Two Grosmannia species (G. penicillata and G. europhioides) produced large amounts of 2-methyl-3-buten-2-ol (MB), the major component in the beetles' aggregation pheromone blend, when growing on spruce bark or malt agar. Grosmannia europhioides also incorporated (13)C glucose into MB, demonstrating that the fungi can synthesize MB de novo using glucose as a carbon source. This is the first clear evidence that fungal symbionts of bark beetles can produce components in the aggregation pheromone blend of their beetle vectors. This provides new insight into the possible ecological roles of fungal symbionts in bark beetle systems and may deepen our understanding of species interactions and coevolution in these important biological systems.


Cyclodextrin-Based Macromolecular Systems as Cholesterol-Mopping Therapeutic Agents in Niemann-Pick Disease Type C.
Over the last decade, cyclodextrins (CDs) have gained considerable attention as a potential therapeutic intervention in the treatment of the rare genetic condition Niemann-Pick type C disease (NPC). However, the oligosaccharide in its monomeric form suffers from serious side effects, especially from a pharmacokinetic and biodistribution standpoint. CD-based macromolecular systems hold great promise to overcome such limitations and might provide an improved therapeutic approach in reducing cholesterol accumulation in NPC. In the present article, the latest developments and synthetic strategies in the preparation of CD-containing polymers as cholesterol-mopping therapeutic agents in NPC are summarized.


Curvature estimation from a volume-of-fluid indicator function for the simulation of surface tension and wetting with a free-surface lattice Boltzmann method.
The free surface lattice Boltzmann method (FSLBM) is a combination of the hydrodynamic lattice Boltzmann method with a volume-of-fluid (VOF) interface capturing technique for the simulation of incompressible free surface flows. Capillary effects are modeled by extracting the curvature of the interface from the VOF indicator function and imposing a pressure jump at the free boundary. However, obtaining accurate curvature estimates from a VOF description can introduce significant errors. This article reports numerical results for three different surface tension models in standard test cases and compares the according errors in the velocity field (spurious currents). Furthermore, the FSLBM is shown to be suited to simulate wetting effects at solid boundaries. To this end, a new method is developed to represent wetting boundary conditions in a least-squares curvature reconstruction technique. The main limitations of the current FSLBM are analyzed and are found to be caused by its simplified advection scheme. Possible improvements are suggested.


LncRNA: a link between RNA and cancer.
Unraveling the gene expression networks governing cancer initiation and development is essential while remains largely uncompleted. With the innovations in RNA-seq technologies and computational biology, long noncoding RNAs (lncRNAs) are being identified and characterized at a rapid pace. Recent findings reveal that lncRNAs are implicated in serial steps of cancer development. These lncRNAs interact with DNA, RNA, protein molecules and/or their combinations, acting as an essential regulator in chromatin organization, and transcriptional and post-transcriptional regulation. Their misexpression confers the cancer cell capacities for tumor initiation, growth, and metastasis. The review here will emphasize their aberrant expression and function in cancer, and the roles in cancer diagnosis and therapy will be also discussed.


Differential imaging of biological structures with doubly-resonant coherent anti-stokes Raman scattering (CARS).
Coherent Raman imaging techniques have seen a dramatic increase in activity over the past decade due to their promise to enable label-free optical imaging with high molecular specificity. The sensitivity of these techniques, however, is many orders of magnitude weaker than fluorescence, requiring milli-molar molecular concentrations. Here, we describe a technique that can enable the detection of weak or low concentrations of Raman-active molecules by amplifying their signal with that obtained from strong or abundant Raman scatterers. The interaction of short pulsed lasers in a biological sample generates a variety of coherent Raman scattering signals, each of which carry unique chemical information about the sample. Typically, only one of these signals, e.g. Coherent Anti-stokes Raman scattering (CARS), is used to generate an image while the others are discarded. However, when these other signals, including 3-color CARS and four-wave mixing (FWM), are collected and compared to the CARS signal, otherwise difficult to detect information can be extracted. For example, doubly-resonant CARS (DR-CARS) is the result of the constructive interference between two resonant signals. We demonstrate how tuning of the three lasers required to produce DR-CARS signals to the 2845 cm⁻¹ CH stretch vibration in lipids and the 2120 cm⁻¹ CD stretching vibration of a deuterated molecule (e.g. deuterated sugars, fatty acids, etc.) can be utilized to probe both Raman resonances simultaneously. Under these conditions, in addition to CARS signals from each resonance, a combined DR-CARS signal probing both is also generated. We demonstrate how detecting the difference between the DR-CARS signal and the amplifying signal from an abundant molecule's vibration can be used to enhance the sensitivity for the weaker signal. We further demonstrate that this approach even extends to applications where both signals are generated from different molecules, such that e.g. using the strong Raman signal of a solvent can enhance the weak Raman signal of a dilute solute.


The effects of glucagon on protein metabolism in normal man.
Plasma glucagon rises after major injury and could act to increase gluconeogenesis and ureagenesis in the post-traumatic state. This study documents the effect of prolonged glucagon infusion on ureagenesis and nitrogen excretion, as well as possible sources of the increased ureagenesis, in normal man. Four healthy men fasted for 6 days during intravenous infusion of glucose (750 gmday), establishing a steady state of minimal ureagenesis. Glucagon (1 mg/day) then was added to the infusion for 5 days. Glucose alone was given for the final 2 days. Forearm muscle flux of metabolites was determined by standard arterial-deep venous sampling and capacitance plethysmography. Glucagon concentration was suppressed during glucose infusion (11 +/- 13 pg/ml) and rose to levels seen in subjects with major trauma during glucagon infusion (669 +/- 138 pg/ml). Glucose infusion stabilized urine nitrogen excretion at 1.54 +/- 0.42 gm of N/sq m/day. Nitrogen excretion increased to 2.40 +/- 0.53 gm of N/sq m/day with glucagon infusion, with urea accounting for the increased excretion. Excretion of 3-methylhistidine was unchanged. Plasma amino acid concentration was strikingly reduced on the first day of glucagon infusion, where it stabilized. Forearm flux showed a slight net release of amino acid nitrogen during glucose infusion. Addition of glucagon to the glucose infusion resulted in a net uptake of nitrogen by forearm skeletal muscle. These evidences strong suggest that glucagon infusion in normal man increases ureagenesis, not only at the expense of the free amino acid pool, but by the hydrolysis of visceral protein as well, with muscle protein being maintained.


Optimal first-line treatment in ovarian cancer.
Treatment of ovarian cancer remains challenging despite the high complete response rate seen after maximal surgical debulking surgery and platinum-combination chemotherapy. as most patients will relapse and eventually succumb to ovarian cancer, new strategies are urgently required to improve survival. a platinum-taxane combination has been the cornerstone of treatment for >15 years. Better use of these drugs is being explored through scheduling studies, and dose-dense or intraperitoneal (IP) therapies. Further improvements in treatment will most likely come from the integration of optimal chemotherapy with one or more of the hundreds of molecular-targeted agents that could be active in ovarian cancer. The greatest experience has been with anti-angiogenic agents. Two large phase III trials in first-line ovarian cancer have demonstrated a positive effect of bevacizumab when administered concurrently with chemotherapy and then as a maintenance treatment. In this review, we discuss the existing treatments for ovarian cancer and highlight areas of recent progress.


A T cell-independent mechanism of macrophage activation by interferon-gamma.
A primary interest in immunity to intracellular pathogenic microorganisms and tumors is to understand the mechanisms by which macrophages are activated for various functions. Two parameters of macrophage activation are the expression of the class II histocompatibility proteins or Ia molecules (1), and cytotoxic activity. The ability of T cells to induce these responses has been extensively documented and occurs via their secretion of interferon-gamma (IFN-gamma) after interaction with antigen (2-6). However, in a recent study using mice with the severe combined immunodeficiency (scid) mutation (7) which have no detectable T or B cell functions (7-9), we were surprised to find the induction of Ia expression on macrophages and the partial inhibition of bacterial growth after infection with Listeria monocytogenes (10). We have now utilized neutralizing monoclonal antibodies specific for murine IFN-gamma to investigate the mechanism of macrophage activation in scid mice. We show here that IFN-gamma can be produced by scid mice in the absence of lymphocyte-mediated immunity, and this IFN-gamma is important for macrophage activation during infection with Listeria. These results indicate the presence of an important T lymphocyte-independent mechanism of macrophage activation and IFN-gamma production in response to infection.


Use of Kinesio taping in lower-extremity rehabilitation of post-stroke patients: A systematic review and meta-analysis.
and purpose: The benefits of Kinesio taping (KT) in post-stroke rehabilitation have not been determined. This study aimed to evaluate its effects on lower-extremity rehabilitation in patients after a stroke. A literature search was performed using EBSCOhost, Embase, Physiotherapy Evidence Database (PEDro), PubMed, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), SinoMed, and Wanfang Data through June 2018. Randomized controlled trials (RCTs) on the use of KT during lower-extremity, post-stroke rehabilitation were selected. Meta-analysis was conducted. A total of 14 RCTs of low to moderate quality were reviewed and included 783 participants. Results indicated that KT significantly improved patients' lower extremity spasticity, motor function, balance, ambulation, gait parameters, and daily activities, with few adverse effects. KT may have positive effects on lower-extremity, post-stroke rehabilitation. Due to the limited number and quality of the research, additional studies are needed to identify KT benefits.


Investment in preventing and preparing for biological emergencies and disasters: social and economic costs of disasters versus costs of surveillance and response preparedness.
Biological emergencies such as the appearance of an exotic transboundary or emerging disease can become disasters. The question that faces Veterinary Services in developing countries is how to balance resources dedicated to active insurance measures, such as border control, surveillance, working with the governments of developing countries, and investing in improving veterinary knowledge and tools, with passive measures, such as contingency funds and vaccine banks. There is strong evidence that the animal health situation in developed countries has improved and is relatively stable. In addition, through trade with other countries, developing countries are becoming part of the international animal health system, the status of which is improving, though with occasional setbacks. However, despite these improvements, the risk of a possible biological disaster still remains, and has increased in recent times because of the threat of bioterrorism. This paper suggests that a model that combines decision tree analysis with epidemiology is required to identify critical points in food chains that should be strengthened to reduce the risk of emergencies and prevent emergencies from becoming disasters.


Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines.
Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies. (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated. (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists. Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge.


Probing of molecular replication and accumulation in shallow heat gradients through numerical simulations.
How can living matter arise from dead matter? All known living systems are built around information stored in RNA and DNA. To protect this information against molecular degradation and diffusion, the second law of thermodynamics imposes the need for a non-equilibrium driving force. Following a series of successful experiments using thermal gradients, we have shown that heat gradients across sub-millimetre pores can drive accumulation, replication, and selection of ever longer molecules, implementing all the necessary parts for Darwinian evolution. For these lab experiments to proceed with ample speed, however, the temperature gradients have to be quite steep, reaching up to 30 K per 100 μm. Here we use computer simulations based on experimental data to show that 2000-fold shallower temperature gradients - down to 100 K over one metre - can still drive the accumulation of protobiomolecules. This finding opens the door for various environments to potentially host the origins of life: volcanic, water-vapour, or hydrothermal settings. Following the trajectories of single molecules in simulation, we also find that they are subjected to frequent temperature oscillations inside these pores, facilitating e.g. template-directed replication mechanisms. The tilting of the pore configuration is the central strategy to achieve replication in a shallow temperature gradient. Our results suggest that shallow thermal gradients across porous rocks could have facilitated the formation of evolutionary machines, significantly increasing the number of potential sites for the origin of life on young rocky planets.


Activation of activating protein 1 during hepatic acute phase response.
During an acute phase response following inflammatory stimuli, specific changes occur in the synthesis and secretion of many hepatic proteins. Because the expression of differentiated function requires the coordinated regulation of many genes, we investigated the activity of general and tissue-specific transcription factors using a rat liver model of the acute phase response induced by Freund's adjuvant. Nuclear extracts and RNAs were prepared throughout a 48-h posttreatment period. Mobility shift assays revealed increased binding activity by nuclear factor-kappa B, interleukin-6 (IL-6) responsive element binding protein, and activating protein 1 (AP-1). Two AP-1 complexes were induced during the acute phase response, and correlation between their presence and transcription activity was demonstrated by transfection studies. Elevated binding activity of AP-1 also correlated with elevated levels of c-jun, junD, junB, and c-fos mRNAs. Western blots showed elevated hepatic levels of c-Jun but not c-Fos proteins during the acute phase response. In addition, IL-6, tumor necrosis factor-alpha, and IL-1 beta, cytokine regulators of the acute phase response, stimulated expression of an AP-1 responsive reporter gene introduced by DNA-mediated transfection into adult rat hepatocytes in primary culture. These findings demonstrate the complexity of AP-1 hepatic transcription factor responses to humoral regulators with direct hepatocellular effects.


Virion-targeted viral inactivation: new therapy against viral infection.
Acquired immune deficiency syndrome (AIDS) is resistant to all current therapy. Gene therapy is an attractive alternative or additive to current, unsatisfactory AIDS therapy. To develop an antiviral molecule targeting viral integrase (HIV IN), we generated a single-chain antibody, termed scAb, which interacted with human immunodeficiency virus type 1 (HIV-1) IN and inhibited virus replication at the integration step when expressed intracellularly. To reduce infectivity from within the virus particles, we made expression plasmids (pC-scAbE-Vpr, pC-scAbE-CA, and pC-scAbE-WXXF), which expressed the anti-HIV IN scAb fused to the N-terminus of HIV-1-associated accessory protein R (Vpr), capsid protein (CA), and specific binding motif to Vpr (WXXF), respectively. All fusion proteins were tagged with a nine-amino acid peptide derived from influenza virus hemagglutinin (HA) at the C terminus. The fusion molecules, termed scAbE-Vpr, scAbE-CA, and scAbE-WXXF, interacted specifically with HIV IN immobilized on a nitrocellulose membrane. Immunoblot analysis showed that scAbE-Vpr, scAbE-CA, and scAbE-WXXF were incorporated into the virions produced by cotransfection of 293T cells with HIV-1 infectious clone DNA (pLAI) and pC-scAbE-Vpr, pC-scAbE-WXXF. A multinuclear activation galactosidase indicator (MAGI) assay revealed that the virions released from 293T cells cotransfected with pLAI and pC-scAbE-Vpr, pC-scAbE-WXXF had as little 1000-fold of the infectivity of the control wild-type virions, which were produced from the 293T cells transfected with pLAI alone. Furthermore, the virions produced from the 293T cells cotransfected with pLAI and an scAb expression vector (pC-scAb) showed only 1% of the infectivity of the control HIV-1 in a MAGI assay, although scAb was not incorporated into the virions. In either instance, the total quantity of the progeny virions released from the transfected 293T cells and the patterns of the virion proteins were hardly affected by the presence of scAb, scAbE-Vpr, or scAbE-WXXF, as determined by virion-associated reverse transcriptase assay and by immunoblot analysis, respectively. Because G418-selected HeLa clones carrying the expression plasmid for scAbE-WXXF were obtained much more frequently than those for scAbE-Vpr, scAbE-WXXF was inferred to be less toxic to cells than scAbE-Vpr. The result that scAbE-WXXF with viral incorporation achieved more than a 10-fold reduction in infectivity of the progeny virions than scAb without incorporation suggests that scAbE-WXXF is a potential antiviral molecule, inhibiting replication by neutralization of HIV IN activity both within cells and within virions. Moreover, it is nontoxic to human cells. We termed this gene therapy "virion-"targeted-viral inactivation" and these molecules "packageable antiviral therapeutics." This new gene therapy has the potential for wide application in many viral infectious diseases.


Reformulating infant and toddler social competence with peers.
Efforts to identify children at risk for social and academic difficulties at an early age have begun to apply conceptualizations of social competence with peers from childhood to infancy and toddlerhood. These attempts have had limited success, in part because social behaviors studied in later childhood such as negative or aggressive acts may not capture relevant dimensions of social competence with peers during the infant and toddler years. The present study conducted an exploratory factor analysis to begin developing a conceptualization of social competence with peers that is appropriate for use with infants and toddlers, and that captures individual differences capable of predicting later social functioning. Results indicate three dimensions of infant and toddler social competence with peers: peer sociability, active peer refusal, and passive peer avoidance. Negative and aggressive behaviors loaded on each of the three factors rather than emerging as a unique dimension of social competence. Each factor demonstrated both convergent and predictive validity, indicating that early identification of social skills remains a reasonable goal for practitioners and researchers alike. Finally, antecedents within children, families, and out-of-home child care environments helped to explain individual variability in each of these three factors of social competence with peers.


Clinical management and burden of bipolar disorder: a multinational longitudinal study (WAVE-bd study).
Studies in bipolar disorder (BD) to date are limited in their ability to provide a whole-disease perspective--their scope has generally been confined to a single disease phase and/or a specific treatment. Moreover, most clinical trials have focused on the manic phase of disease, and not on depression, which is associated with the greatest disease burden. There are few longitudinal studies covering both types of patients with BD (I and II) and the whole course of the disease, regardless of patients' symptomatology. Therefore, the Wide AmbispectiVE study of the clinical management and burden of Bipolar Disorder (WAVE-bd) (NCT01062607) aims to provide reliable information on the management of patients with BD in daily clinical practice. It also seeks to determine factors influencing clinical outcomes and resource use in relation to the management of BD. WAVE-bd is a multinational, multicentre, non-interventional, longitudinal study. Approximately 3000 patients diagnosed with BD type I or II with at least one mood event in the preceding 12 months were recruited at centres in Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela. Site selection methodology aimed to provide a balanced cross-section of patients cared for by different types of providers of medical aid (e.g. academic hospitals, private practices) in each country. Target recruitment percentages were derived either from scientific publications or from expert panels in each participating country. The minimum follow-up period will be 12 months, with a maximum of 27 months, taking into account the retrospective and the prospective parts of the study. Data on demographics, diagnosis, medical history, clinical management, clinical and functional outcomes (CGI-BP and FAST scales), adherence to treatment (DAI-10 scale and Medication Possession Ratio), quality of life (EQ-5D scale), healthcare resources, and caregiver burden (BAS scale) will be collected. Descriptive analysis with common statistics will be performed. This study will provide detailed descriptions of the management of BD in different countries, particularly in terms of clinical outcomes and resources used. Thus, it should provide psychiatrists with reliable and up-to-date information about those factors associated with different management patterns of BD. ClinicalTrials.gov: NCT01062607.


The Impact of COVID-19 on Epilepsy Care: A Survey of the American Epilepsy Society Membership.
The COVID-19 pandemic has impacted the delivery of care to people with epilepsy (PWE) in multiple ways including limitations on in-person contact and restrictions on neurophysiological procedures. To better study the effect of the pandemic on PWE, members of the American Epilepsy Society were surveyed between April 30 and June 14, 2020. There were 366 initial responses (9% response rate) and 337 respondents remained for analysis after screening out noncompleters and those not directly involved with clinical care; the majority were physicians from the United States. About a third (30%) of respondents stated that they had patients with COVID-19 and reported no significant change in seizure frequency. Conversely, one-third of respondents reported new onset seizures in patients with COVID-19 who had no prior history of seizures. The majority of respondents felt that there were at least some barriers for PWE in receiving appropriate clinical care, neurophysiologic procedures, and elective surgery. Medication shortages were noted by approximately 30% of respondents, with no clear pattern in types of medication involved. Telehealth was overwhelmingly found to have value. Among the limitation of the survey was that it was administered at a single point in time in a rapidly changing pandemic. The survey showed that almost all respondents were affected by the pandemic in a variety of ways.


Cell culture of human gingival fibroblasts, oral cancer cells and mesothelioma cells with serum-free media, STK1 and STK2.
The majority of cells are cultured with Dulbecco's modified Eagle's medium (DMEM) or RPMI supplemented with fetal bovine serum (FBS), which contains numerous factors, including cytokines, nutrients and unknown growth factors. These factors may affect cell growth, apoptosis and differentiation. The serum-free medium, STK2, has been previously reported as suitable for the cell culture of human mesenchymal stem cells. However, how STK1 or STK2 affect the cell proliferation of normal and cancer cells remains unknown. The present study examined the growth of the human gingival fibroblast (HGF-1) cell-line and the HSC-3, CA9-22 and MSTO cancer cell-lines, cultured with STK1 and STK2. STK1 increased the cell proliferation of HGF-1 compared to DMEM by assessment with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assay, whereas STK1 and STK2 markedly inhibited the cell proliferation of HSC-3 and MSTO. The cell proliferation rate of CA9-22 cultured with STK1 or STK2 for 96 h was ~2-fold higher than the rate for 24 h culture. The shape of the HSC-3 cells was also found to have changed to round when cultured with STK2. These results indicate that STK1 increased the cell proliferation of HGF-1 compared to DMEM, whereas the proliferation of HSC-3 and MSTO was inhibited by STK1 and STK2. Thus, STK1 and STK2 had different affects on the cell growth of HGF-1, CA9-22, HSC-3 and MSTO.


Optical properties of UV transmitting acrylics for use in a heavy water Cerenkov detector.
The absorption, refraction, and scattering properties of several UV transmitting acrylics have been investigated over the wavelength range 300-700 nm using a combination of near-normal incidence regular transmittance and reflectance and diffuse-only reflectance measurements, followed by a Fresnel and a Kubelka-Munk analysis. The samples were evaluated in the as-cast and thermoformed forms, and both before and after an accelerated aging procedure. The results show significant differences in the optical behavior of the various acrylics in the UV region and stress the importance of carefully characterizing acrylic from different sources for each intended use. In our case, acrylic is the proposed material for a heavy water containment vessel for the detection of solar neutrinos. The significance of our findings to the overall performance of this Cerenkov detector, known as the Sudbury neutrino observatory detector, is discussed.


Human adipose beiging in response to cold and mirabegron.
The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans to induce beige adipose tissue is unknown. We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system. Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects. Cold or β3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals. Clinicaltrials.gov NCT02596776, NCT02919176. NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).


Overview of molecular typing methods for outbreak detection and epidemiological surveillance.
Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage-type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages.


Aspergillus hyphae in infected tissue: evidence of physiologic adaptation and effect on culture recovery.
Microbiologic cultures of fungi are routinely incubated at ambient temperatures in room air, and the rate of recovery of Aspergillus species from clinical specimens is poor. Failure of current culture methods to mimic the physiologic temperature and low-oxygen environment found in hypha-laden infected tissue may underlie this poor recovery. Experiments were performed to compare the recovery of Aspergillus spp. incubated at 35 degrees C in 6% O(2)-10% CO(2) with that at 25 degrees C in room air. The samples tested included Aspergillus-infected tissue specimens from a dog model and human autopsies, experimental anaerobically stressed Aspergillus inocula, and 10,062 consecutive clinical specimens. Culture at 35 degrees C in 6% O(2)-10% CO(2) significantly enhanced the recovery of Aspergillus spp. from the infected autopsy tissue samples. Incubation at 35 degrees C alone resulted in approximately 10-fold-improved culture recovery from the experimentally stressed hyphae, and the 6% O(2)-10% CO(2) atmosphere independently favored growth under temperature-matched conditions. Finally, incubation at 35 degrees C (in room air) improved the overall recovery of Aspergillus spp. from clinical specimens by 31%. Culture at 35 degrees C in a microaerobic atmosphere significantly enhances the recovery of Aspergillus spp. from various sources. Aspergillus hyphae growing in infected tissue appear to be adapted to the physiologic temperature and hypoxic milieu.


Mechanistic attributes of S100A7 (psoriasin) in resistance of anoikis resulting tumor progression in squamous cell carcinoma of the oral cavity.
Squamous cell carcinoma of the oral cavity (SCCOC) is the dominant origin of cancer associated mortality. Previous findings by our study reported that acquisition of anoikis resistance has a significant role in tumor progression of oral cavity. Several genes were over-expressed in anoikis-resistant cells under detached conditions which we confirmed earlier by microarray. Normal oral squamous epithelia grow adherent to a basement membrane, and when detached from the extracellular matrix, undergoes programmed cell death. The acquisition of anoikis-resistance is crucial phenomena in oral tumor advancement. In the current study, we have identified S100A7 expression as contributing factor for anoikis resistance and tumorigenicity in human oral cancer cells. Further, we have explored that elevated S100A7 expression in anoikis-sensitive oral keratinocytes and cancer cells reshape them more resistant to anoikis and apoptosis inducers via activation of cellular intrinsic and extrinsic avenue. A subset of human cancer cell lines TU167, JMAR, JMARC39, JMARC42 and MDA-MB-468 were utilized for the generation of resistant stable cell lines. Further, immunohistochemistry, western blot and immunoprecipitation, assays of apoptosis, soft agar assay, orthotopic animal model and signaling elucidation were performed to establish our hypothesis. S100A7 gene is found to be responsible for anoikis resistance and tumorigenicity in human oral cancer cells. We have observed up-regulation of S100A7 in anoikis resistant cell lines, orthotropic model and patients samples with head and neck cancer. It is also noticed that secretion of S100A7 protein in conditioned medium by anoikis resistant head & neck cancer cell and in saliva of head and neck cancer patients. Up-regulation of S100A7 expression has triggered enhanced tumorigenicity and anchorage-independent growth of cancer cells through Akt phosphorylation leading to development of aniokis resistance in head and neck cancer cells. These data have led us to conclude that S100A7 is the major contributing factor in mediating anoikis-resistance of oral cancer cells and local tumor progression, and S100A7 might be useful as diagnostic marker for early detection of primary and recurrent squamous cell cancer.


Effects of cilazapril on cardiac structure and function in hypertension.
Peripheral vascular resistance, arterial blood pressure, and left ventricular hypertrophy (LVH) are closely related. In systemic hypertension, hemodynamic changes in systolic and diastolic function accompany LVH. Both of these cardiac functions are detected with echocardiography and were measured during this study in 23 essential hypertension patients treated with 2.5-5 mg of cilazapril daily for 6 months. Reduction in left ventricular mass was accompanied by an improvement in early diastolic filling pattern. This change in cardiac performance with cilazapril vasodilator monotherapy was characterized by a significant improvement in isovolumic relaxation time and normalized left ventricular early/atrial filling ratio.


Cardiac replacement with a total artificial heart as a bridge to transplantation.
The CardioWest Total Artificial Heart orthotopically replaces both native cardiac ventricles and all cardiac valves, thus eliminating problems commonly seen in the bridge to transplantation with left ventricular and biventricular assist devices, such as right heart failure, valvular regurgitation, cardiac arrhythmias, ventricular clots, intraventricular communications, and low blood flows. We conducted a nonrandomized, prospective study in five centers with the use of historical controls. The purpose was to assess the safety and efficacy of the CardioWest Total Artificial Heart in transplant-eligible patients at risk for imminent death from irreversible biventricular cardiac failure. The primary end points included the rates of survival to heart transplantation and of survival after transplantation. Eighty-one patients received the artificial-heart device. The rate of survival to transplantation was 79 percent (95 percent confidence interval, 68 to 87 percent). Of the 35 control patients who met the same entry criteria but did not receive the artificial heart, 46 percent survived to transplantation (P<0.001). Overall, the one-year survival rate among the patients who received the artificial heart was 70 percent, as compared with 31 percent among the controls (P<0.001). One-year and five-year survival rates after transplantation among patients who had received a total artificial heart as a bridge to transplantation were 86 and 64 percent. Implantation of the total artificial heart improved the rate of survival to cardiac transplantation and survival after transplantation. This device prevents death in critically ill patients who have irreversible biventricular failure and are candidates for cardiac transplantation.


The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism.
To establish a more precise use of the term alcoholism, a 23-member multidisciplinary committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine conducted a 2-year study of the definition of alcoholism in the light of current concepts. The goals of the committee were to create by consensus a revised definition that is (1) scientifically valid, (2) clinically useful, and (3) understandable by the general public. Therefore, the committee agreed to define alcoholism as a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic.


Cord Blood Transplantation Study (COBLT): cord blood bank standard operating procedures.
In 1995, the National Heart Lung and Blood Institute (NHLBI) solicited requests for a proposal (RFP) entitled "Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells." Three banks, six transplant centers, and one medical coordinating center (MCC) (Table 1) were funded with the overall goal of banking cord blood units (CBU) using a single manual of operations. Furthermore, the clinical protocols to evaluate the transplant outcome for adult and pediatric recipients of these well-characterized CBU would be analyzed in a uniform fashion. Because of the intense interest of the transplantation community in the policies and procedures for cord blood collection and processing, the principal investigators of the cord blood banks (CBB) and NHLBI elected to submit for publication the rationale and an abridged, but detailed, version of the standard operating procedures (SOP) developed between October 1996 and July 1998 prior to the initiation of the clinical protocols to be performed with these CBU. As the SOP will be refined over time, the complete SOP and subsequent amendments will be published and continually updated on the websites from the MCC-The EMMES Corporation (www.EMMES.com). All forms referred to in this document may be obtained from the EMMES website. It is hoped that the publication of this document will lay down a framework that will not only facilitate the development of other CBB but also help us more rapidly define what constitutes an "acceptable" CBU product.


Improving the sustainability of global meat and milk production.
Global demand for meat and dairy products has increased dramatically in recent decades and, through a combination of global population growth, increased lifespan and improved economic prosperity in the developing world will inevitably continue to increase. The predicted increases in livestock production will put a potentially unsustainable burden on global resources, including land for production of crops required for animal feed and fresh water. Furthermore, animal production itself is associated with greenhouse gas production, which may speed up global warming and thereby impact on our ability to produce food. There is, therefore, an urgent need to find methods to improve the sustainability of livestock production. This review will consider various options for improving the sustainability of livestock production with particular emphasis on finding ways to replace conventional crops as sources of animal feeds. Alternatives, such as currently underutilised crops (grown on a marginal land) and insects, reared on substrates not suitable for direct consumption by farm animals, represent possible solutions. Coupled with a moderation of excessive meat consumption in wealthier countries, such strategies may secure the long-term sustainability of meat and milk production and mitigate against the adverse health effects of excessive intake.


The personal writings of First World War nurses: a study of the interplay of authorial intention and scholarly interpretation.
The personal writings of First World War nurses and VADs (volunteers) provide the historian with a range of insights into the war and women's nursing roles within it. This paper offers a number of methodological perspectives on these writings. In particular, it emphasises two elements of engagement with texts that can act as important influences on subsequent historical writings: authorial intention and scholarly interpretation. In considering the interplay of these two elements, the paper emphasises the motivations both of those who produced primary sources and of those who later used them to 'serve' particular historical interpretations. The paper examines letters, diaries and semi-fictional writings, considering the influences of gender, class and professional background on the ways in which their authors wrote. It then briefly considers the uses to which historians have put these original writings. The paper offers insights into the ways in which complex personal writings can be interpreted and concludes that the writings of First World War nurses and volunteers offer a rich and varied set of perspectives on both the war itself and the nature of wartime nursing work.


Technological Competence Is a Pre-condition for Effective Implementation of Virtual Reality Head Mounted Displays in Human Neuroscience: A Technological Review and Meta-Analysis.
Immersive virtual reality (VR) emerges as a promising research and clinical tool. However, several studies suggest that VR induced adverse symptoms and effects (VRISE) may undermine the health and safety standards, and the reliability of the scientific results. In the current literature review, the technical reasons for the adverse symptomatology are investigated to provide suggestions and technological knowledge for the implementation of VR head-mounted display (HMD) systems in cognitive neuroscience. The technological systematic literature indicated features pertinent to display, sound, motion tracking, navigation, ergonomic interactions, user experience, and computer hardware that should be considered by the researchers. Subsequently, a meta-analysis of 44 neuroscientific or neuropsychological studies involving VR HMD systems was performed. The meta-analysis of the VR studies demonstrated that new generation HMDs induced significantly less VRISE and marginally fewer dropouts. Importantly, the commercial versions of the new generation HMDs with ergonomic interactions had zero incidents of adverse symptomatology and dropouts. HMDs equivalent to or greater than the commercial versions of contemporary HMDs accompanied with ergonomic interactions are suitable for implementation in cognitive neuroscience. In conclusion, researchers' technological competency, along with meticulous methods and reports pertinent to software, hardware, and VRISE, are paramount to ensure the health and safety standards and the reliability of neuroscientific results.


Social chromosome variants differentially affect queen determination and the survival of workers in the fire ant Solenopsis invicta.
Intraspecific variation in social organization is common, yet the underlying causes are rarely known. An exception is the fire ant Solenopsis invicta in which the existence of two distinct forms of social colony organization is under the control of the two variants of a pair of social chromosomes, SB and Sb. Colonies containing exclusively SB/SB workers accept only one single queen and she must be SB/SB. By contrast, when colonies contain more than 10% of SB/Sb workers, they accept several queens but only SB/Sb queens. The variants of the social chromosome are associated with several additional important phenotypic differences, including the size, fecundity and dispersal strategies of queens, aggressiveness of workers, and sperm count in males. However, little is known about whether social chromosome variants affect fitness in other life stages. Here, we perform experiments to determine whether differential selection occurs during development and in adult workers. We find evidence that the Sb variant of the social chromosome increases the likelihood of female brood to develop into queens and that adult SB/Sb workers, the workers that cull SB/SB queens, are overrepresented in comparison to SB/SB workers. This demonstrates that supergenes such as the social chromosome can have complex effects on phenotypes at various stages of development.


Human Adipose-Derived Hydrogel Characterization Based on In Vitro ASC Biocompatibility and Differentiation.
Hydrogels serve as three-dimensional scaffolds whose composition can be customized to allow attachment and proliferation of several different cell types. Extracellular matrix-derived hydrogels are considered close replicates of the tissue microenvironment. They can serve as scaffolds for in vitro tissue engineering and are a useful tool to study cell-scaffold interaction. The aim of the present study was to analyze the effect of adipose-derived stromal/stem cells (ASCs) and decellularized adipose tissue-derived (DAT) hydrogel interaction on ASC morphology, proliferation, differentiation, and DAT hydrogel microstructure. First, the ASCs were characterized using flow cytometry, adipogenic/osteogenic differentiation, colony-forming unit fibroblast assay and doubling time. The viability and proliferation assays showed that ASCs seeded in DAT hydrogel at different concentrations and cultured for 21 days remained viable and displayed proliferation. ASCs were seeded on DAT hydrogel and cultured in stromal, adipogenic, or osteogenic media for 14 or 28 days. The analysis of adipogenic differentiation demonstrated the upregulation of adipogenic marker genes and accumulation of oil droplets in the cells. Osteogenic differentiation demonstrated the upregulation of osteogenic marker genes and mineral deposition in the DAT hydrogel. The analysis of DAT hydrogel fiber metrics revealed that ASC seeding, and differentiation altered both the diameter and arrangement of fibers in the matrix. Matrix metalloproteinase-2 (MMP-2) activity was assessed to determine the possible mechanism for DAT hydrogel remodeling. MMP-2 activity was observed in all ASC seeded samples, with the osteogenic samples displaying the highest MMP-2 activity. These findings indicate that DAT hydrogel is a cytocompatible scaffold that supports the adipogenic and osteogenic differentiation of ASCs. Furthermore, the attachment of ASCs and differentiation along adipogenic and osteogenic lineages remodels the microstructure of DAT hydrogel.


Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer.
Patients with recurrent ovarian, peritoneal, or fallopian tube cancer have limited therapeutic options. There are no reports of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with recurrent platinum-sensitive disease. We report efficacy and toxicity with nab-paclitaxel in this group. Forty-seven patients enrolled (44 assessable patients). Main inclusion criteria were histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2 to 3 if stage I) and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) or elevated CA-125 (> 70 U/mL) in patients without measurable disease. Patients received nab-paclitaxel 260 mg/m(2) administered intravenously for 30 minutes on day 1 of a 21-day cycle for six cycles or until disease progression. Median age was 65.5 years; 76% of patients had stage IIIC or IV disease, 81% had Eastern Cooperative Oncology Group performance status of 0, and 94% had prior surgery. For assessable patients, the objective response rate (ORR) was 64% (15 complete responses [CR] and 13 partial responses [PR] among 44 assessable patients). In patients evaluated with RECIST only, the ORR was 45% (one CR and four PR of 11 patients). In patients with only elevated CA-125, ORR was 82% (seven CRs and two PRs of 11 patients). In patients meeting both RECIST and CA-125 criteria, the ORR was 64% (seven CRs and seven PRs of 22 patients). Median time to response was 1.3 months (range, 0.5 to 4.8 months). Estimated median progression-free survival was 8.5 months. The most frequent grade 3 to 4 treatment-related toxicities were neutropenia (24%) and neuropathy (9%). Nab-paclitaxel is active in this group of patients with recurrent ovarian, peritoneal, or fallopian tube cancer. The ORR was 64%. Toxicities were manageable. Further studies of nab-paclitaxel in combination with platinum are warranted.


Bulk advection and interfacial flows in the binary coalescence of surfactant-laden and surfactant-free drops.
This work focuses on the study of bulk flows accompanying the coalescence of two aqueous drops, one containing surfactant and the other surfactant-free, in silicone oils of various viscosities. It is observed that the surfactant-free drop intrudes into the surfactant-laden drop in the form of a penetrating jet whose speed increases and average radius decreases with increasing outer phase viscosity. Mixing patterns within the coalescing drops are due to the force imbalance caused by capillary pressure difference and surfactant-induced Marangoni stresses. The driving force for mixing associated with the difference in interfacial tension between the drops is considerably stronger than that related to the drop size. The long timescale mixing of the drops is driven by rapid interior convection, and the subsequent, slow, diffusive process. Three-dimensional numerical simulations show excellent qualitative and quantitative agreement with the experimental results. The implications of our results to formulation strategies of complex microstructures in practical applications are also discussed.


[Environment, health and sustainable development].
Environmental problems and their impact on health and welfare of the population, mainly the most deprived and excluded, from access to material and symbolic goods, provided only to a privileged minority, must be analyzed within the context of the global economic and financial crisis which swept the whole world since 2008. The collapse of the capitalist system and its negative impacts on production, income and employment provide evidence to the predatory nature of the underlying social and political relations which lead humanity to a catastrophic abyss whose consequences are felt on local, national and global levels. Appointing to the main aspects of environmental deterioration - greenhouse gases; pollution of rivers, lakes and oceans; the erosion and intoxication of soils; the lack of basic sanitation and fresh water supply in metropolitan areas, this essay refers to official health indicators published recently by the Ministry of Health of Brazil which documents destructive trends. Discussing the dysfunction and the paradoxes of capital accumulation the essay points out to the need for building a new development paradigm based on cooperation and solidarity; an equitable distribution of the social product and the reform of the political system leading from the present authoritarian patterns of social relations to a participative and a true democratic model.


Finding key nanoprecipitation variables for achieving uniform polymeric nanoparticles using neurofuzzy logic technology.
Nanoprecipitation is a simple and fast method to produce polymeric nanoparticles (Np); however, most applications require filtration or another separation technique to isolate the nanosuspension from aggregates or polydisperse particle production. In order to avoid variability introduced by these additional steps, we report here a systematic study of the process to yield monomodal and uniform Np production with the nanoprecipitation method. To further identify key variables and their interactions, we used artificial neural networks (ANN) to investigate the multiple variables which influence the process. In this work, a polymethacrylate derivative was used for Np (NpERS) and a database with several formulations and conditions was developed for the ANN model. The resulting ANN model had a high predictability (> 70%) for NpERS characteristics measured (mean size, PDI, zeta potential, and number of particle populations). Moreover, the model identified production variables leading to polymer supersaturation, such as mixing time and turbulence, as key in achieving monomodal and uniform NpERS in one production step. Polymer concentration and type of solvent, modifiers of polymer diffusion and supersaturation, were also shown to control NpERS characteristics. The ANN study allowed the identification of key variables and their interactions and resulted in a predictive model to study the NpERS production by nanoprecipitation. In turn, we have achieved an optimized method to yield uniform NpERS which could pave way for polymeric nanoparticle production methods with potential in biological and drug delivery applications.


Mixed-amphetamine salts increase abstinence from marijuana in patients with co-occurring attention-deficit/hyperactivity disorder and cocaine dependence.
The prevalence of ADHD is greater in substance use disorders than the general population, and ADHD and substance use disorders share neurobiological features such as dysregulation of reward circuitry. We tested the hypothesis that stimulants would decrease marijuana use in a randomized controlled trial of extended release mixed amphetamine salts (MAS-XR) for treatment of co-occurring ADHD and cocaine use disorders. Marijuana users were defined as participants reporting use in the 30 days before study initiation, collected with timeline follow-back. The original 14-week trial utilized a 3-arm randomized design, comparing placebo, MAS-XR 60 mg, and MAS-XR 80 mg. For this analysis, both MAS-XR groups were combined, leaving n = 20 in the placebo group and n = 37 in the MAS-XR group. The primary outcome was proportion of subjects reporting any marijuana use per study week. Comparisons between groups were made using a logistic mixed effects model incorporating multiple predictors and modeling time-by-treatment interactions. There were no significant baseline differences in marijuana use frequency and quantity. There was a significant decrease in the proportion of participants using marijuana over time in the MAS-XR group, but no difference in the proportion of marijuana-use days over time. Treatment of ADHD and comorbid cocaine use disorders with MAS-XR is associated with increased weekly abstinence from marijuana but not with a decrease in the proportion of marijuana using days per week. Stimulant treatment of ADHD and cocaine use disorders may diminish co-occurring cannabis use. (Am J Addict 2016;25:666-672).