Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.
Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.


Gender differences among young drivers in the association between high-risk driving and substance use/environmental influences.
The primary aim of this article is to assess young drivers' gender differences in the associations between substance use/environmental influences and high-risk driving behavior. We determine the association of 12th-grade self-reported substance use/ environmental influences with high-risk driving behavior as quantified by the number of offenses, serious offenses, crashes, and single-vehicle crashes on state driving records during subjects' (N = 3,607; 51% male) first 4 years of licensure. The associations between high-risk driving and substance use/environmental influences were generally stronger among women than among men. When matched by substance-use profiles, women had fewer risky-driving incidents than men. The results indicate that young women who exhibit high-risk driving behavior deviate more from the general population of young women with respect to alcohol use, alcohol misuse, and marijuana use than high-risk-driving young men differ from other young men. In addition, findings indicate that even if young men and women were to eventually have equal levels of substance use, women would likely retain their lower-risk driving profiles. These findings suggest the need for (1) future research to understand the differential associations, and (2) prevention programs that consider these gender differences.


The tobacco homolog of mammalian calreticulin is present in protein complexes in vivo.
The analysis of protein sorting signals responsible for the retention of reticuloplasmins (RPLs), a group of soluble proteins that reside in the lumen of the endoplasmic reticulum (ER), has revealed a structural similarity between mammalian and plant ER retention signals. We present evidence that the corresponding epitope is conserved in a vast family of soluble ER resident proteins. Microsequences of RPL60 and RPL90, two abundant members of this family, show high sequence similarity with mammalian calreticulin and endoplasmin. RPL60/calreticulin cofractionates and costains with the lumenal binding protein (BiP). Both proteins were detected in the nuclear envelope and the ER, and in mitotic cells in association with the spindle apparatus and the phragmoplast. Immunoprecipitation of proteins from in vivo-labeled cells demonstrated that RPL60/calreticulin is associated with other polypeptides in a stress- and ATP-dependent fashion. RPL60/calreticulin transcript levels increased rapidly in abundance during the proliferation of the secretory apparatus and the onset of hydrolase secretion in gibberellic acid-treated barley aleurone cells. This induction profile is identical to that of the well-characterized ER chaperones BiP and endoplasmin. However, expression patterns in response to different stress conditions as well as tissue-specific expression patterns indicate that these genes are differentially regulated and may not act in concert.


Spatial coherence mapping of structured sources: a flexible instrument for solar studies.
We conceptually describe and design, to first order, an instrument to locally map the spatial coherence of extended and structured sources, such as fiber bundles or the Sun, considered as a mosaic of individual solar cells, which is our main motivation. Our solar coherence instrument (SCI) is an instrument for an afocal solar space telescope; the light from its exit pupil dynamically selects one individual solar cell at a time and performs a series of Young-like experiments with different baselines in order to measure the spectral degree of coherence and therefore the effective correlation length that can be assigned for that solar cell. SCI needs flexibility in terms of selective imaging and Young experiments, which is provided by two digital micromirror devices (DMDs), a technology currently under space qualification. SCI is a compact instrument based on retroreflections, and it generates all data required to image the source, to select the cells, and to implement sequentially a series of Young apertures on a re-imaged pupil. It was designed using the (already launched) Hinode solar optical telescope as a baseline, and the first estimation of the SNR, using commercial DMDs and array sensors, while measuring the modulation of Young interference fringes validates our first-order design.


Manipulating optical polarization by stereo plasmonic structure.
We theoretically study a particular plasmonic structure with stereo nanoholes array in metallic film, which has remarkable abilities to manipulate the optical polarizations at optical frequencies. The main property is that any linear polarization states including a complete 90° optical rotation can be obtained in transmission by proper structural design in combination of enhanced transmission efficiency. Together with the polarization change, surface plasmon propagation bounded on the surface of transmission side also can be modulated. Furthermore, an analytical Coupled Mode Method (CMM) is developed by introducing a frequency dependent coupling coefficient to describe such optical rotation property in stereo plasmonic systems.


Overexpression of miR-122 promotes the hepatic differentiation and maturation of mouse ESCs through a miR-122/FoxA1/HNF4a-positive feedback loop.
microRNA-122 is the only identified liver-specific miRNA and plays a crucial role in liver development, maintenance of hepatic homeostasis as well as tumourigenesis. In our previous differentiation of ESCs into hepatocytes, microRNA-122 (miR-122) was expressed at a relatively low level. Here, we aim to elucidate the effect and underlying mechanisms of miR-122 during differentiation of ESCs into hepatocytes. Mouse ESCs were initially induced towards HPCs by activin A, FGF-4 and sodium butyrate and were subsequently transfected with a recombinant adenovirus expressing vector pAV.Ex1d-CMV>miR-122/IRES/eGFP 9 days after induction. Cells were analysed by real-time PCR, immunofluorescence, flow cytometry, microscopy and functional assays. Furthermore, microarray analysis was performed. We demonstrated that overexpression of miR-122 could effectively promote hepatic differentiation and maturation, as assessed by morphological and functional tests. The microarray analysis revealed that 323 genes were down-regulated, whereas 59 were up-regulated. Particularly, two liver-specific transcription factors, FoxA1 and HNF4a, were significantly up-regulated. Moreover, the expression of E-cadherin was dramatically increased and the proliferation of HPCs was suppressed, whereas knockdown of FoxA1 reduced E-cadherin expression and increased the proliferation of HPCs. In addition, the expression levels of FoxA1, HNF4a and E-cadherin in time-course transfection experiments with miR-122 were not significantly increased except in cells in which transfection with miR-122 occurred 9 days after induction. Overexpression of miR-122 at an appropriate stage could promote hepatic differentiation and maturation by regulating the balance between proliferation and differentiation, as well as the balance between EMT and MET, partially through a miR-122/FoxA1/HNF4a-positive feedback loop.


VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2.
Vascular endothelial growth factor (VEGF) is the most endothelial cell-specific angiogenic factor characterised to date, and it is produced by a variety of cell types. In macrophages, VEGF has been shown to be upregulated by the inflammatory mediator lipopolysaccharide (LPS) and by engagement of CD40 by CD40 ligand (CD40L). Because LPS and CD40L activate nuclear factor-kappaB (NF-kappaB) in monocytes, we investigated in this study whether VEGF production in macrophages, when stimulated with either LPS or CD40L, is NF-kappaB-dependent. We used adenoviral constructs over-expressing either IkappaBalpha (AdvIkappaBalpha), the endogenous inhibitor of NF-kappaB, or a kinase-defective mutant of IKK-2 (AdvIKK-2dn), an upstream activator of IkappaBalpha, to infect normal human monocyte-derived macrophages. We observed that LPS-induced production of VEGF in human macrophages was almost completely inhibited (>90%) following adenoviral transfer of IkappaBalpha. In addition, we observed significant inhibition of the CD40L-induced VEGF production in macrophages following infection with AdvIkappaBalpha. Expression of IKK-2dn in macrophages decreased VEGF production in response to LPS or CD40L by approximately 50%, suggesting that in addition to IKK-2, other kinases might be involved in NF-kappaB activation. These results show for the first time that VEGF production in human macrophages is NF-kappaB dependent. NF-kappaB regulates many of the genes involved in immune and inflammatory responses, and our study adds the angiogenic cytokine VEGF to the list of NF-kappaB-dependent cytokines.


Polyketides and a Dihydroquinolone Alkaloid from a Marine-Derived Strain of the Fungus Metarhizium marquandii.
Three new natural products (1-3), including two butenolide derivatives (1 and 2) and one dihydroquinolone derivative (3), together with nine known natural products were isolated from a marine-derived strain of the fungus Metarhizium marquandii. The structures of the new compounds were unambiguously deduced by spectroscopic means including HRESIMS and 1D/2D NMR spectroscopy, ECD, VCD, OR measurements, and calculations. The absolute configuration of marqualide (1) was determined by a combination of modified Mosher's method with TDDFT-ECD calculations at different levels, which revealed the importance of intramolecular hydrogen bonding in determining the ECD features. The (3R,4R) absolute configuration of aflaquinolone I (3), determined by OR, ECD, and VCD calculations, was found to be opposite of the (3S,4S) absolute configuration of the related aflaquinolones A-G, suggesting that the fungus M. marquandii produces aflaquinolone I with a different configuration (chiral switching). The absolute configuration of the known natural product terrestric acid hydrate (4) was likewise determined for the first time in this study. TDDFT-ECD calculations allowed determination of the absolute configuration of its chirality center remote from the stereogenic unsaturated γ-lactone chromophore. ECD calculations aided by solvent models revealed the importance of intramolecular hydrogen bond networks in stabilizing conformers and determining relationships between ECD transitions and absolute configurations.


Fate of Antioxidative Compounds within Bark during Storage: A Case of Norway Spruce Logs.
Softwood bark is an important by-product of forest industry. Currently, bark is under-utilized and mainly directed for energy production, although it can be extracted with hot water to obtain compounds for value-added use. In Norway spruce (Picea abies [L.] Karst.) bark, condensed tannins and stilbene glycosides are among the compounds that comprise majority of the antioxidative extractives. For developing feasible production chain for softwood bark extractives, knowledge on raw material quality is critical. This study examined the fate of spruce bark tannins and stilbenes during storage treatment with two seasonal replications (i.e., during winter and summer). In the experiment, mature logs were harvested and stored outside. During six-month-storage periods, samples were periodically collected for chemical analysis from both inner and outer bark layers. Additionally, bark extractives were analyzed for antioxidative activities by FRAP, ORAC, and H2O2 scavenging assays. According to the results, stilbenes rapidly degraded during storage, whereas tannins were more stable: only 5-7% of the original stilbene amount and ca. 30-50% of the original amount of condensed tannins were found after 24-week-storage. Summer conditions led to the faster modification of bark chemistry than winter conditions. Changes in antioxidative activity were less pronounced than those of analyzed chemical compounds, indicating that the derivatives of the compounds contribute to the antioxidative activity. The results of the assays showed that, on average, ca. 27% of the original antioxidative capacity remained 24 weeks after the onset of the storage treatment, while a large variation (2-95% of the original capacity remaining) was found between assays, seasons, and bark layers. Inner bark preserved its activities longer than outer bark, and intact bark attached to timber is expected to maintain its activities longer than a debarked one. Thus, to ensure prolonged quality, no debarking before storage is suggested: outer bark protects the inner bark, and debarking enhances the degradation.


Identification, classification and quantification of microplastics in road dust and stormwater.
Microplastics (MP) have become a major emerging class of pollutants representing significant eco-toxicological risks for ecosystems and marine environments. The aim of this study was to identify, classify and quantify MP present in both road dust and stormwater samples. A significantly higher level of MPs within road dust samples was detected from industrial area (1130 particles/kg of dust) than from residential area (520 particles/kg of dust), while stormwater samples from industrial and residential sites yielded 26 particles/L and 17 particles/L, respectively. Fiber-like shape accounted for 53% and 74% in road dust and stormwater samples, respectively. The main polymeric materials collected for both road dust and stormwater samples were, in order of occurrence (i) low-density polyethylene, (ii) high-density polyethylene, (iii) polypropylene, (iv) polyethylene terephthalate, (v) polystyrene, (vi) polyester and (vii) poly (amide). Most of the MP had an average maximum dimension smaller than 2 mm for both road dust and stormwater samples. The results from this study demonstrates that road dust is a significant contributor to MP pollution through direct polymeric materials wear off and transfer through stormwater, which eventually will end up in open water ways and broader ecological niches.


Mass spectrometry and photoelectron spectroscopy of o-, m-, and p-terphenyl cluster anions: the effect of molecular shape on molecular assembly and ion core character.
Mass spectrometry and photoelectron spectroscopy of o-, m-, and p-terphenyl cluster anions, (o-TP)n(-) (n = 2-100), (m-TP)n(-) (n = 2-100), and (p-TP)n(-) (n = 1-100), respectively, are conducted to investigate the effect of molecular shape on the molecular aggregation form and the resultant ion core character of the clusters. For (o-TP)n(-) and (m-TP)n(-), neither magic numbers nor discernible isomers are observed throughout the size range. Furthermore, their vertical detachment energies (VDEs) increase up to large n and depend linearly on n(-1/3), implying that they possess a three-dimensional (3D), highly reorganized structure encompassing a monomeric anion core. For (p-TP)n(-), in contrast, prominent magic numbers of n = 5, 7, 10, 12, and 14 are observed, and the VDEs show pronounced irregular shifts below n = 10, while they remain constant above n = 14 (isomer A). These results can be rationalized with two-dimensional (2D) orderings of p-TP molecules and different types of 2D shell closure at n = 7 and 14, the monomeric and multimeric anion core, respectively. Above n = 16, the new feature (isomer B) starts to appear at the higher binding side of isomer A, and it becomes dominant with n, while isomer A gradually disappears for larger sizes. In contrast to isomer A, the VDEs of isomer B continuously increase with the cluster size. This characteristic size evolution suggests that the transition to modified 2D aggregation forms from 2D ones occurs at around n = 20.


Entanglement in a solid-state spin ensemble.
Entanglement is the quintessential quantum phenomenon. It is a necessary ingredient in most emerging quantum technologies, including quantum repeaters, quantum information processing and the strongest forms of quantum cryptography. Spin ensembles, such as those used in liquid-state nuclear magnetic resonance, have been important for the development of quantum control methods. However, these demonstrations contain no entanglement and ultimately constitute classical simulations of quantum algorithms. Here we report the on-demand generation of entanglement between an ensemble of electron and nuclear spins in isotopically engineered, phosphorus-doped silicon. We combined high-field (3.4 T), low-temperature (2.9 K) electron spin resonance with hyperpolarization of the (31)P nuclear spin to obtain an initial state of sufficient purity to create a non-classical, inseparable state. The state was verified using density matrix tomography based on geometric phase gates, and had a fidelity of 98% relative to the ideal state at this field and temperature. The entanglement operation was performed simultaneously, with high fidelity, on 10(10) spin pairs; this fulfils one of the essential requirements for a silicon-based quantum information processor.


Inverse-electron-demand Diels-Alder reactions of α,β-unsaturated hydrazones with 3-methoxycarbonyl α-pyrones.
Inverse-electron-demand Diels-Alder reactions of 3-electron-withdrawing group substituted α-pyrones with α,β-unsaturated hydrazones as electron-rich counterparts are catalyzed by Eu(hfc)3 to afford bicyclic lactone cycloadducts. This is an example of umpolung cycloaddition based on functional transformation of carbonyls to hydrazones. A subsequent dehydrazonation reaction enables indirect synthesis of carbonyl group-containing bicyclic lactones, which cannot be easily obtained by the cycloaddition of α-pyrones and enals.


An important role of the SDF-1/CXCR4 axis in chronic skin inflammation.
Inflammatory angiogenesis and vascular remodeling play key roles in the chronic inflammatory skin disease psoriasis, but little is known about the molecular mediators of vascular activation. Based on the reported elevated mRNA levels of the angiogenic chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 in psoriasis, we investigated the relevance of the SDF-1/CXCR4 axis in two experimental models of chronic psoriasis-like skin inflammation. The cutaneous expression of both SDF-1 and CXCR4 was upregulated in the inflamed skin of K14-VEGF-A transgenic mice and in imiquimod-induced skin inflammation, with expression of CXCR4 by blood vessels and macrophages. Treatment with the CXCR4 antagonist AMD3100 potently inhibited skin inflammation in both models, associated with reduced inflammatory angiogenesis and inflammatory cell accumulation, including dermal CD4+ cells and intraepidermal CD8+ T cells. Similar anti-inflammatory effects were seen after treatment with a neutralizing anti-SDF-1 antibody. In vitro, inhibition of CXCR4 blocked SDF-1-induced chemotaxis of CD11b+ splenocytes, in agreement with the reduced number of macrophages after in vivo CXCR4 blockade. Our results reveal an important role of the SDF-1/CXCR4 axis in skin inflammation and inflammatory angiogenesis, and they indicate that inhibition of the SDF-1/CXCR4 axis might serve as a novel therapeutic strategy for chronic inflammatory skin diseases.


Preliminary DNA identification for the tsunami victims in Thailand.
The 2004 Southeast Asia Tsunami killed nearly 5,400 people in Southern Thailand, including foreign tourists and local residents. To recover DNA evidence as much as possible from the seriously decomposed bodies, we explored procedures of sample preparation from both bone and tooth samples as well as both mitochondrial and nuclear markers. Despite having failed to recover enough DNA for nuclear marker typing, we succeeded in obtaining fully informative results for mitochondrial markers (HV1 and HV2) from 258 tooth samples with a success rate of 51% (258/507). Using an organic DNA extraction method coupled with an ultrafiltration step, we obtained 16 STR (including 13 CODIS loci, one sex discrimination locus, and two Identifiler loci) profiles for 834 samples with a success rate of 79% (834/1,062). In addition, by comparing the allelic frequencies between the typed samples as a group and other index populations, we conclude that the Thai tsunami victims are a combined group of several populations. Our results provide valuable evidence and protocols for the future forensic practice.


Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma.
Thrombomodulin (TM) is a glycoprotein of molecular weight 75,000 kd that is normally present in restricted numbers of cells, including endothelial and mesothelial cells. In this study, the authors tested the possibility of using anti-TM to facilitate the diagnosis of mesothelioma. All of the 31 mesotheliomas and the two mesothelioma cell lines (MS-1 and MS-2) tested were stained positively with anti-TM. The specificity of anti-TM staining in mesothelioma cells was further confirmed by in situ hybridization of MS-1 cells with a TM-specific probe. The expression of TM in MS-1 cells was increased markedly when these cells were induced by 12-0-tetradecanyl phorbol 13-acetate (TPA) to differentiate. The expression of TM in mesothelioma cells, however, did not correlate with any particular phase of the cell cycle. In an attempt to differentiate pleural mesothelioma from pulmonary adenocarcinoma, the authors compared the expression of TM, carcinoembryonic antigen (CEA), and Leu M1 in these two types of tumors. Only four of 48 (8%) pulmonary adenocarcinomas were stained positively by antibodies to TM. Therefore, immunohistochemical staining with antibodies to TM yielded 100% sensitivity and 92% specificity for diagnosis of mesothelioma. All of the mesotheliomas stained negatively for CEA and Leu M1, except for one, which showed minimal focal positivity for Leu M1. In contrast, 79% and 60% of adenocarcinomas stained positively for CEA and Leu M1, respectively. These findings suggest that immunocytochemical staining with anti-TM should be added to the battery of tests to increase the diagnostic sensitivity and specificity for differentiating mesothelioma from pulmonary adenocarcinoma.


Young women's decisions to accept chlamydia screening: influences of stigma and doctor-patient interactions.
An understanding of the factors that encourage young women to accept, and discourage them from accepting, STI (sexually transmitted infection) testing is needed to underpin opportunistic screening programs for the STI Chlamydia trachomatis (opportunistic screening involves healthcare professionals offering chlamydia tests to people while they are attending health services for reasons that are usually unrelated to their sexual health). We conducted a qualitative study to identify and explore: how young women would feel about being offered opportunistic tests for chlamydia?; how young women would like to be offered screening, and who they wanted to be offered screening by?; and what factors would influence young women's partner notification preferences for chlamydia (who they would notify in the event of a positive diagnosis of chlamydia, how they would want to do this). Semi-structured interviews with 35 young women between eighteen and twenty nine years of age. The study was conducted in the Dublin and Galway regions of the Republic of Ireland. Young adults were recruited from General Practice (GP) practices, Third Level College health services, Family Planning clinics and specialist STI treatment services. Respondents were worried that their identities would become stigmatised if they accepted screening. Younger respondents and those from lower socio-economic backgrounds had the greatest stigma-related concerns. Most respondents indicated that they would accept screening if it was offered to them, however; accepting screening was seen as a correct, responsible action to engage in. Respondents wanted to be offered screening by younger female healthcare professionals. Respondents were willing to inform their current partners about positive chlamydia diagnoses, but were more ambivalent about informing their previous partners. If an effort is not put into reducing young women's stigma-related concerns the population coverage of Chlamydia screening might be reduced.


Occupational trichloroethylene hypersensitivity syndrome: human herpesvirus 6 reactivation and rash phenotypes.
Trichloroethylene (TCE) is an industrial solvent which can cause severe generalized dermatitis, i.e., occupational TCE hypersensitivity syndrome. Reactivation of latent human herpesvirus 6 (HHV6) can occur in such patients, which has made TCE known as a causative chemical of drug-induced hypersensitivity syndrome (DIHS). This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome. HHV6 DNA copy numbers, anti-HHV6 antibody titers, and cytokines were measured in blood prospectively sampled 5-7 times from 28 hospitalized patients with the disease. The patients (19 had exfoliative dermatitis (ED) and 9 had non-ED type rash) generally met the diagnostic criteria for DIHS. Viral reactivation defined as increases in either HHV6 DNA (≥100 genomic copies/10(6) peripheral blood mononuclear cells) or antibody titers was identified in 24 (89%) patients. HHV6 DNA, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-5, IL-6 and IL-10 concentrations were remarkably higher in the patients than in the healthy workers (p<0.01). Positive correlations between HHV6 DNA, TNF-α, IFN-γ, IL-6 and IL-10 were significant (p<0.05) except for that between HHV6 DNA and IFN-γ. An increase in HHV6 DNA was positively associated with an increase in TNF-α on admission (p<0.01). HHV6 DNA, the antibody titers, TNF-α and IL-10 concentrations were significantly higher in ED than in the non-ED type (p<0.05). Reactivated HHV6 and the increased cytokines could be biomarkers of TCE hypersensitivity syndrome. The higher-level reactivation and stronger humoral responses were associated with ED-type rash.


GSU Praat Tools: scripts for modifying and analyzing sounds using Praat acoustics software.
The Praat acoustics program (Boersma, 2001) is powerful freeware that is widely used bybehavioral scientists working with digital sound. This article describes GSU Praat Tools, a script package that helps simplify and automate such work. The routines use Praat's scripting language to create new menus and commands within the existing interface, and can operate either on individual files or in batch mode. The new functions facilitate selecting, displaying, editing, filtering, and otherwise modifying sounds, quantifying acoustic features, and saving results in text-based data files. The package includes an installation script and user's manual, and is available free from psyvoso.googlepages.com/softwaredownload.


Social support moderates posttraumatic stress and general distress after disaster.
Social support buffers the negative impact of stressful events. Less, however, is known about the characteristics of this association in the context of disaster and findings have been discrepant regarding direct and buffering effects. This study tested whether the protective effects of social support differed across levels of exposure severity (i.e., buffered distress) and assessed whether the buffering effect differed between event-specific and general distress. Participants were 4,600 adult Swedish tourists (44% of invited; 55% women) repatriated within 3 weeks after the 2004 Indian Ocean tsunami. A survey 14 months after the disaster included the Crisis Support Scale, the Impact of Event Scale-Revised (IES-R), and the General Health Questionnaire (GHQ-12). Social support buffered the negative impact of exposure on both outcomes. The support and distress association ranged from very small in participants with low exposure to moderate in those with high exposure (η(p)(2) = .004 to .053). The buffering effect was not found to differ between the IES-R and GHQ-12, F(2, 4589) = 0.87, p = .42. The findings suggest that social support moderates the stressor-distress relationship after disasters. This study might help explain discrepant findings and point to refinements of postdisaster interventions.


Vision-Based Corrosion Detection Assisted by a Micro-Aerial Vehicle in a Vessel Inspection Application.
Vessel maintenance requires periodic visual inspection of the hull in order to detect typical defective situations of steel structures such as, among others, coating breakdown and corrosion. These inspections are typically performed by well-trained surveyors at great cost because of the need for providing access means (e.g., scaffolding and/or cherry pickers) that allow the inspector to be at arm's reach from the structure under inspection. This paper describes a defect detection approach comprising a micro-aerial vehicle which is used to collect images from the surfaces under inspection, particularly focusing on remote areas where the surveyor has no visual access, and a coating breakdown/corrosion detector based on a three-layer feed-forward artificial neural network. As it is discussed in the paper, the success of the inspection process depends not only on the defect detection software but also on a number of assistance functions provided by the control architecture of the aerial platform, whose aim is to improve picture quality. Both aspects of the work are described along the different sections of the paper, as well as the classification performance attained.


Impact of an Integrated Hip Fracture Inpatient Program on Length of Stay and Costs.
Hip fractures are associated with significant morbidity and mortality. Co-management models pairing orthopaedic surgeons with hospitalists or geriatricians may be effective at improving processes of care and outcomes such as length of stay (LOS) and cost. We set out to determine the effect of an integrated hip fracture co-management model on LOS, cost, and process measures. We conducted a single-center pre-post study of 571 patients admitted to an academic medical center with hip fractures between January 2009 and December 2013. The group receiving an integrated medical-surgical co-management incorporating continuous improvement methodology was compared with a control population. Primary outcome was LOS. Secondary outcomes included cost per case, time to surgery, osteoporosis (OP) treatment, preoperative echocardiogram utilization, mortality, and readmission. LOS decreased from 18.2 (1.1) to 11.9 (1.5) days, a reduction of 6.3 days (P < 0.001). Mean cost decreased by $4953 (P < 0.001) per case. Mean time to surgery decreased from 45.8 (66.8) to 29.7 (17.9) hours (P < 0.001). Initiation of OP treatment increased from 55.8% to 96.4% (P < 0.001). Preoperative echocardiogram use decreased from 15.8% to 9.1% (P < 0.05). There was a nonsignificant difference in mortality rate (5.0% vs. 2.1%, P = 0.06). Readmission rate remained unchanged (4.6% vs. 6.0%, P = 0.56). An integrated medical-surgical co-management model incorporating continuous improvement methodology was associated with reduced LOS, costs, time to surgery, and increased initiation of appropriate OP treatment. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Elongation factor methyltransferase 3--a novel eukaryotic lysine methyltransferase.
Here we describe the discovery of Saccharomycescerevisiae protein YJR129Cp as a new eukaryotic seven-beta-strand lysine methyltransferase. An immunoblotting screen of 21 putative methyltransferases showed a loss in the methylation of elongation factor 2 (EF2) on knockout of YJR129C. Mass spectrometric analysis of EF2 tryptic peptides localised this loss of methylation to lysine 509, in peptide LVEGLKR. In vitro methylation, using recombinant methyltransferases and purified EF2, validated YJR129Cp as responsible for methylation of lysine 509 and Efm2p as responsible for methylation at lysine 613. Contextualised on previously described protein structures, both sites of methylation were found at the interaction interface between EF2 and the 40S ribosomal subunit. In line with the recently discovered Efm1 and Efm2 we propose that YJR129C be named elongation factor methyltransferase 3 (Efm3). The human homolog of Efm3 is likely to be the putative methyltransferase FAM86A, according to sequence homology and multiple lines of literature evidence.


Early urban development in the Near East.
It has been thought that the first cities in the Near East were spatially extensive and grew outward from a core nucleated village while maintaining a more or less constant density in terms of persons or households per unit of area. The general applicability outside of the Near East of this southern Mesopotamian.derived model has been questioned recently, and variations from it are increasingly recognized. We can now demonstrate that such variation was present at the beginnings of urbanism in the Near East as well.


SPIHT-based echocardiogram compression: clinical evaluation and recommendations of use.
This paper describes an echocardiogram coding method that takes into account the visualization modes in order to compress efficiently the echocardiogram, a methodology to evaluate compressed echocardiograms and the evaluation of the compression method using the proposed evaluation methodology. The compression method takes advantage of the particular characteristics of each visualization mode and uses different compression techniques for each mode to compress efficiently the echocardiogram. A complete evaluation has been designed in order to recommend a minimum transmission rate for each operation mode that guarantees sufficient clinical quality. The evaluation of the echocaradiograms compressed with the proposed method has been carried out. The recommended transmission rates have been established as the following: 200 kbps for the 2D and the color Doppler modes, and 40 kbps for the M and the pulsed/continuous Doppler modes. These rates, especially the latter, are very low compared to previous results. These recommendations are valid for all devices and images compressed with the proposed method. The evaluation process can be applied to any compression method.


The use of PROMs and shared decision-making in medical encounters with patients: An opportunity to deliver value-based health care to patients.
The recent emphasis on value-based health care (VBHC) is thought to provide new opportunities for shared decision-making (SDM) in the Netherlands, especially when using patient-reported outcome measures (PROMs) in routine medical encounters. It is still largely unclear about how PROMs could be linked to SDM and what we expect from clinicians in this respect. To describe approaches and lessons learned in the fields of SDM and VBHC implementation that converge in using PROMs in medical encounters. Based on input from three Dutch forerunner case examples and available evidence about SDM and VBHC, we describe barriers and facilitators regarding the use of PROMs and SDM in the medical encounter. Barriers and facilitators were structured according to a conversational model that included monitoring and managing, team talk, option talk, choice talk, and decision talk. Key lessons learned and recommendations were synthesized. The use of individual, N = 1 PROMs scores in the medical encounter has been largely achieved in the forerunner projects. Conversation on monitoring and managing is relatively well implemented, and option talk to some extent, unlike team talk, and decision talk. Aggregated PROMs information describing outcomes of treatment options seemed to be scarcely used. Experienced barriers largely corresponded to what is known from the literature, eg, perceived lack of time and lack of tools summarizing the options. Some concerns were identified about increasing health care consumption as a result of using PROMs and SDM in the medical encounter. Successful implementation of SDM within VBHC initiatives may not be self-evident, even though individual, N = 1 PROMs scores are being used in the medical encounter. Education and staff resources on meso and macro levels may facilitate the more time-consuming SDM aspects. It seems fruitful to especially target team talk and choice talk in redesigning clinical pathways.


Avoiding hypothermia, an intervention to prevent morbidity and mortality from pneumonia in young children.
Observations and experiments in animals and human beings grant plausibility to the hypothesis that hypothermia is a risk factor for pneumonia. Exposure of body to cold stress causes alterations in the systemic and local defenses against respiratory infections, favoring the infection by inhalation of pathogens normally present in the oropharynx. Neonates and young infants with hypothermia have an increased risk of death; however, there is no strong demonstration that hypothermia leads to pneumonia in these children. Studies that properly addressed the problem of confounding variables have shown an association between cold weather and pneumonia incidence. Probably the strongest evidence that supports the plausibility of the hypothesis is provided by the controlled comparison between patients with traumatic brain injury treated with hypothermia and those treated under normal body temperature. The association between exposure to cold and pneumonia is strong enough to warrant further research focused in young children in developing countries.


Risk factors for functional limitations in patients with long-standing ankylosing spondylitis.
To identify risk factors for functional limitations in patients with ankylosing spondylitis (AS) of at least 20 years' duration. Patients with AS for > or =20 years were enrolled in the cross-sectional component of the Prospective Study of Outcomes in AS. All patients had clinical evaluations and completed questionnaires on functional limitations and potential risk factors. Functional limitations were assessed using the Bath Ankylosing Spondylitis Functional Index (BASFI; score range 0-100, higher scores indicate more limitations) and the Health Assessment Questionnaire for the Spondylarthropathies (HAQS). Risk factors included demographic characteristics, duration of AS, smoking status, number of comorbid medical conditions, recalled level of recreational activity in teens and twenties, occupational physical activity throughout life (rated 1 = little, 2 = moderate, 3 = heavy, and weighted by the number of years in each job), and history of AS in a first-degree relative. The 326 patients (74% men) had a mean +/- SD age of 55.0 +/- 10.7 years, a mean duration of AS symptoms of 31.7 +/- 10.2 years, and a mean BASFI score of 40.7 +/- 25.6. BASFI scores increased with higher lifetime occupational physical activity (r = 0.31; P < 0.0001), the number of comorbid conditions (r = 0.25; P < 0.0001), and the duration of AS (r = 0.12; P = 0.04). BASFI scores were higher among current smokers compared with former/nonsmokers (55.5 versus 38.9; P = 0.0002), and among nonwhites compared with whites (49.9 versus 39.3; P = 0.02). In multivariable analyses, lifetime occupational physical activity, current smoking, education level, number of comorbid conditions, and family history were significantly associated with BASFI scores. The same risk factors were associated with the HAQS. Functional limitations in patients with AS for >/=20 years are greater among those with a history of more physically demanding jobs, more comorbid conditions, and among smokers, and are less severe among those with higher levels of education and a family history of AS.


Zr4+ doping in Li4Ti5O12 anode for lithium-ion batteries: open Li+ diffusion paths through structural imperfection.
One-dimensional nanomaterials have short Li(+) diffusion paths and promising structural stability, which results in a long cycle life during Li(+) insertion and extraction processes in lithium rechargeable batteries. In this study, we fabricated one-dimensional spinel Li4Ti5O12 (LTO) nanofibers using an electrospinning technique and studied the Zr(4+) doping effect on the lattice, electronic structure, and resultant electrochemical properties of Li-ion batteries (LIBs). Accommodating a small fraction of Zr(4+) ions in the Ti(4+) sites of the LTO structure gave rise to enhanced LIB performance, which was due to structural distortion through an increase in the average lattice constant and thereby enlarged Li(+) diffusion paths rather than changes to the electronic structure. Insulating ZrO2 nanoparticles present between the LTO grains due to the low Zr(4+) solubility had a negative effect on the Li(+) extraction capacity, however. These results could provide key design elements for LTO anodes based on atomic level insights that can pave the way to an optimal protocol to achieve particular functionalities.


Statistically derived geometrical landscapes capture principles of decision-making dynamics during cell fate transitions.
Fate decisions in developing tissues involve cells transitioning between discrete cell states, each defined by distinct gene expression profiles. The Waddington landscape, in which the development of a cell is viewed as a ball rolling through a valley filled terrain, is an appealing way to describe differentiation. To construct and validate accurate landscapes, quantitative methods based on experimental data are necessary. We combined principled statistical methods with a framework based on catastrophe theory and approximate Bayesian computation to formulate a quantitative dynamical landscape that accurately predicts cell fate outcomes of pluripotent stem cells exposed to different combinations of signaling factors. Analysis of the landscape revealed two distinct ways in which cells make a binary choice between one of two fates. We suggest that these represent archetypal designs for developmental decisions. The approach is broadly applicable for the quantitative analysis of differentiation and for determining the logic of developmental decisions.


Genetic regulation of the antibody response to H-2Db alloantigens in mice. III. Inhibition of the IgG Response to noncongenic cells by preimmunization with congenic cells.
When B10.A (5R) mice (H-12i5) are immunized with spleen cells from congenic B10 mice (H-12b), they respond to alloantigens of the H-2Db region by producing antibodies of only IgM type. In contrast, they produce both IgM and IgG antibodies when immunized with A.BY cells (H-2b) that carry other foreign cell surface antigens (non-H-2) in addition to H-2Db. Preimmunization of 5R mice with two injections of congenic cells leads to an H-2Db specific inhibition of the IgG response to a subsequent immunization with A.BY cells. It is concluded that congenic B10 cells fail to activate helper T cells which are necessary to induce the switch from IgM to IgG production. Instead T- or B-cell tolerance may be induced with prohibits the subsequent IgG response to A.BY cells, possibly by way of suppressor T cells which may act either on B cells directly or via helper T cells.


Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection.
Many viruses deliver their genomes into the host cell nucleus for replication. However, the size restrictions of the nuclear pore complex (NPC), which regulates the passage of proteins, nucleic acids, and solutes through the nuclear envelope, require virus capsid uncoating before viral DNA can access the nucleus. We report a microtubule motor kinesin-1-mediated and NPC-supported mechanism of adenovirus uncoating. The capsid binds to the NPC filament protein Nup214 and kinesin-1 light-chain Klc1/2. The nucleoporin Nup358, which is bound to Nup214/Nup88, interacts with the kinesin-1 heavy-chain Kif5c to indirectly link the capsid to the kinesin motor. Kinesin-1 disrupts capsids docked at Nup214, which compromises the NPC and dislocates nucleoporins and capsid fragments into the cytoplasm. NPC disruption increases nuclear envelope permeability as indicated by the nuclear influx of large cytoplasmic dextran polymers. Thus, kinesin-1 uncoats viral DNA and compromises NPC integrity, allowing viral genomes nuclear access to promote infection.


Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania.
The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61*02 allele. We show each copy of IGHV4-61*02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27-1.61, P=4.1 × 10-9). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.


Characterization of homologous and heterologous adaptive immune responses in porcine reproductive and respiratory syndrome virus infection.
The present study characterized the homologous and heterologous immune response in type-I porcine reproductive and respiratory syndrome virus (PRRSV) infection. Two experiments were conducted: in experiment 1, eight pigs were inoculated with PRRSV strain 3262 and 84 days post-inoculation (dpi) they were challenged with either strain 3262 or strain 3267 and followed for the next 14 days (98 dpi). In experiment 2, eight pigs were inoculated with strain 3267 and challenged at 84 dpi as above. Clinical course, viremia, humoral response (neutralizing and non-neutralizing antibodies, NA) and virus-specific IFN-γ responses (ELISPOT) were evaluated all throughout the study. Serum levels of IL-1, IL-6, IL-8, TNF-α and TGF-β were determined (ELISA) after the second challenge. In experiment 1 primo-inoculation with strain 3262 induced viremia of ≤ 28 days, low titres of homologous NA but strong IFN-γ responses. In contrast, strain 3267 induced longer viremias (up to 56 days), higher NA titres (≤ 6 log2) and lower IFN-γ responses. Inoculation with 3267 produced higher serum IL-8 levels. After the re-challenge at 84 dpi, pigs in experiment 1 developed mostly a one week viremia regardless of the strain used. In experiment 2, neither the homologous nor the heterologous challenge resulted in detectable viremia although PRRSV was present in tonsils of some animals. Homologous re-inoculation with 3267 produced elevated TGF-β levels in serum for 7-14 days but this did not occur with the heterologous re-inoculation. In conclusion, inoculation with different PRRSV strains result in different virological and immunological outcomes and in different degrees of homologous and heterologous protection.


Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function.
Loss-of-function mutations in the proton-coupled folate transporter (PCFT, SLC46A1) result in the autosomal recessive disorder, hereditary folate malabsorption (HFM). Identification and characterization of HFM mutations provide a wealth of information on the structure-function relationship of this transporter. In the current study, PCR-based random mutagenesis was employed to generate unbiased loss-of-function mutations of PCFT, simulating the spectrum of alterations that might occur in the human disorder. A total of 26 mutations were generated and 4 were identical to HFM mutations. Eleven were base deletion or insertion mutations that led to a frameshift and, along with similar HFM mutations, are predominantly localized to two narrow regions of the pcft gene at the 5'-end. Base substitution mutations identified in the current study and HFM patients were largely distributed across the pcft gene. Elimination of the ATG initiation codon by a one-base substitution (G > A) did not result in a complete lack of translation at the same codon consistent with rare non-ATG translation initiation. Among six missense mutants evaluated, three mutant PCFTs were not detected at the plasma membrane, one mutation resulted in decreased binding to folate substrate, and one had a reduced rate of conformational change associated with substrate translocation. The remaining PCFT mutant had defects in both processes. These results broaden understanding of the regions of the pcft gene prone to base insertion and deletion and inform further approaches to the analysis of the structure-function of PCFT.


Should screening of genital infections be part of antenatal care in areas of high HIV prevalence? A prospective cohort study from Kigali, Rwanda, 1992-1993. The Pregnancy and HIV (EGE) Group.
To study the prevalence and incidence of genital infections and their association with HIV-1 infection among pregnant women in Kigali, Rwanda. HIV+ and HIV- pregnant women were followed prospectively during the last three months of pregnancy. At enrolment, syphilis test (RPR) on blood sample, Chlamydiae trachomatis ELISA test on cervical smear, laboratory gonococcal culture, trichomonas and candida direct examination, CD4 lymphocyte count were performed. At each monthly follow-up clinic visit until delivery, genital infections were screened in the presence of clinical signs and symptoms. The HIV seroprevalence rate was 34.4% (N = 1233), 384 HIV+ women and 381 HIV- women of same parity and age were enrolled. Prevalence of genital infections at enrolment was generally higher in HIV+ women than in HIV- women: syphilis, 6.3% versus 3.7% (p = 0.13); Neisseria gonorrhoea, 7.0% versus 2.4% (p = 0.005); Trichomonas vaginalis, 20.2% versus 10.9% (p = 0.0007); Chlamydia trachomatis, 3.4% versus 5.5% (p = 0.21); Candida vaginalis, 22.3% versus 20.1% (p = 0.49). Until delivery, the relative risk of acquiring genital infections was also higher in HIV+ women than in HIV- women: 1.0 for syphilis (95% CI: 0.5-2.2), 3.7 for Neisseria gonorrhoea (1.0-13.3), 2.6 for Trichomonas vaginalis (1.5-4.6) and 1.6 for Candida vaginalis (1.1-2.4). In the context of high HIV-1 seroprevalence among pregnant women, prenatal care should include at least once screening for genital infections by clinical examination with speculum and a syphilis testing in Africa.


Second Harmonic Generation Imaging Analysis of Collagen Arrangement in Human Cornea.
To describe the horizontal arrangement of human corneal collagen bundles by using second harmonic generation (SHG) imaging. Human corneas were imaged with an inverted two photon excitation fluorescence microscope. The excitation laser (Ti:Sapphire) was tuned to 850 nm. Backscatter signals of SHG were collected through a 425/30-nm bandpass emission filter. Multiple, consecutive, and overlapping image stacks (z-stacks) were acquired to generate three dimensional data sets. ImageJ software was used to analyze the arrangement pattern (irregularity) of collagen bundles at each image plane. Collagen bundles in the corneal lamellae demonstrated a complex layout merging and splitting within a single lamellar plane. The patterns were significantly different in the superficial and limbal cornea when compared with deep and central regions. Collagen bundles were smaller in the superficial layer and larger in deep lamellae. By using SHG imaging, the horizontal arrangement of corneal collagen bundles was elucidated at different depths and focal regions of the human cornea.


Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor.
Complement C1q is part of the C1 macromolecular complex that mediates the classical complement activation pathway: a major arm of innate immune defense. C1q is composed of A, B, and C chains that require post-translational prolyl 4-hydroxylation of their N-terminal collagen-like domain to enable the formation of the functional triple helical multimers. The prolyl 4-hydroxylase(s) that hydroxylate C1q have not previously been identified. Recognized prolyl 4-hydroxylases include collagen prolyl-4-hydroxylases (CP4H) and the more recently described prolyl hydroxylase domain (PHD) enzymes that act as oxygen sensors regulating hypoxia-inducible factor (HIF). We show that several small-molecule prolyl hydroxylase inhibitors that activate HIF also potently suppress C1q secretion by human macrophages. However, reducing oxygenation to a level that activates HIF does not compromise C1q hydroxylation. In vitro studies showed that a C1q A chain peptide is not a substrate for PHD2 but is a substrate for CP4H1. Circulating levels of C1q did not differ between wild-type mice or mice with genetic deficits in PHD enzymes, but were reduced by prolyl hydroxylase inhibitors. Thus, C1q is hydroxylated by CP4H, but not the structurally related PHD hydroxylases. Hence, reduction of C1q levels may be an important off-target side effect of small molecule PHD inhibitors developed as treatments for renal anemia.


Evaluation of preservation methods for improving biogas production and enzymatic conversion yields of annual crops.
The use of energy crops and agricultural residues is expected to increase to fulfil the legislative demands of bio-based components in transport fuels. Ensiling methods, adapted from the feed sector, are suitable storage methods to preserve fresh crops throughout the year for, for example, biogas production. Various preservation methods, namely ensiling with and without acid addition for whole crop maize, fibre hemp and faba bean were investigated. For the drier fibre hemp, alkaline urea treatment was studied as well. These treatments were also explored as mild pretreatment methods to improve the disassembly and hydrolysis of these lignocellulosic substrates. The investigated storage treatments increased the availability of the substrates for biogas production from hemp and in most cases from whole maize but not from faba bean. Ensiling of hemp, without or with addition of formic acid, increased methane production by more than 50% compared to fresh hemp. Ensiling resulted in substantially increased methane yields also from maize, and the use of formic acid in ensiling of maize further enhanced methane yields by 16%, as compared with fresh maize. Ensiled faba bean, in contrast, yielded somewhat less methane than the fresh material. Acidic additives preserved and even increased the amount of the valuable water-soluble carbohydrates during storage, which affected most significantly the enzymatic hydrolysis yield of maize. However, preservation without additives decreased the enzymatic hydrolysis yield especially in maize, due to its high content of soluble sugars that were already converted to acids during storage. Urea-based preservation significantly increased the enzymatic hydrolysability of hemp. Hemp, preserved with urea, produced the highest carbohydrate increase of 46% in enzymatic hydrolysis as compared to the fresh material. Alkaline pretreatment conditions of hemp improved also the methane yields. The results of the present work show that ensiling and alkaline preservation of fresh crop materials are useful pretreatment methods for methane production. Improvements in enzymatic hydrolysis were also promising. While all three crops still require a more powerful pretreatment to release the maximum amount of carbohydrates, anaerobic preservation is clearly a suitable storage and pretreatment method prior to production of platform sugars from fresh crops.


Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.
Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.


Functional antibodies against Plasmodium falciparum sporozoites are associated with a longer time to qPCR-detected infection among schoolchildren in Burkina Faso.
Background: Individuals living in malaria-endemic regions develop immunity against severe malaria, but it is unclear whether immunity against pre-erythrocytic stages that blocks initiation of blood-stage infection after parasite inoculation develops following continuous natural exposure. Methods: We cleared schoolchildren living in an area (health district of Saponé, Burkina Faso) with highly endemic seasonal malaria of possible sub-patent infections and examined them weekly for incident infections by nested PCR. Plasma samples collected at enrolment were used to quantify antibodies to the pre-eryhrocytic-stage antigens circumsporozoite protein (CSP) and Liver stage antigen 1 (LSA-1). In vitro sporozoite gliding inhibition and hepatocyte invasion inhibition by naturally acquired antibodies were assessed using Plasmodium falciparum NF54 sporozoites. Associations between antibody responses, functional pre-erythrocytic immunity phenotypes and time to infection detected by 18S quantitative PCR were studied. Results: A total of 51 children were monitored. Anti-CSP antibody titres showed a positive association with sporozoite gliding motility inhibition (P<0.0001, Spearman's ρ=0.76). In vitro hepatocyte invasion was inhibited by naturally acquired antibodies (median inhibition, 19.4% [IQR 15.2-40.9%]), and there were positive correlations between invasion inhibition and gliding inhibition (P=0.005, Spearman's ρ=0.67) and between invasion inhibition and CSP-specific antibodies (P=0.002, Spearman's ρ=0.76). Survival analysis indicated longer time to infection in individuals displaying higher-than-median sporozoite gliding inhibition activity (P=0.01), although this association became non-significant after adjustment for blood-stage immunity (P = 0.06). Conclusions: In summary, functional antibodies against the pre-erythrocytic stages of malaria infection are acquired in children who are repeatedly exposed to Plasmodium parasites. This immune response does not prevent them from becoming infected during a malaria transmission season, but might delay the appearance of blood stage parasitaemia. Our approach could not fully separate the effects of pre-erythrocytic-specific and blood-stage-specific antibody-mediated immune responses in vivo; epidemiological studies powered and designed to address this important question should become a research priority.


Diversity and activity of marine bacterioplankton during a diatom bloom in the North Sea assessed by total RNA and pyrotag sequencing.
A recent investigation of bacterioplankton communities in the German Bight towards the end of a diatom-dominated spring phytoplankton bloom revealed pronounced successions of distinct bacterial clades. A combination of metagenomics and metaproteomics indicated that these clades had distinct substrate spectra and consumed different algal substrates. In this study we re-analyzed samples from the initial study by total community RNA (metatranscriptomics) and 16S rRNA gene amplicon sequencing. This complementary approach provided new insights into the community composition and expressed genes as well as the assessment of metabolic activity levels of distinct clades. Flavobacteria (genera Ulvibacter, Formosa, and Polaribacter), Alphaproteobacteria (SAR11 clade and Rhodobacteraceae) and Gammaproteobacteria (genus Reinekea and SAR92 clade) were the most abundant taxa. Mapping of the metatranscriptome data on assembled and taxonomically classified metagenome data of the same samples substantiated that Formosa and Polaribacter acted as major algal polymer degraders, whereas Rhodobacteraceae and Reinekea spp. exhibited less specialized substrate spectra. In addition, we found that members of the Rhodobacteraceae and SAR92 clade showed high metabolic activity levels, which suggests that these clades played a more important role during the bloom event as indicated by their in situ abundances.


Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer.
In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (δ) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably δ approximates the observed benefit (B) in RCTs that evaluated cancer treatment. RCTs evaluating systemic therapy in adult cancer patients published in 10 journals from January 1, 2005, through December 31, 2009, were identified. Data were extracted from each publication independently by two investigators. The related-samples Sign test was used to determine whether the median difference between δ and B was statistically significant in different study subsets and was two-sided. A total of 253 RCTs met the eligibility criteria and were included in the analysis. Regardless of whether benefit was defined as proportional change (median difference between δ and B = -13.0%, 95% confidence interval [CI] = -21.0% to -8.0%), absolute change (median difference between δ and B = -8.0%, 95% CI = -9.9% to -5.1%), or median increase in a time-to-event endpoint (median difference between δ and B = -1.4 months, 95% CI = -2.1 to -0.8 months), δ was consistently and statistically significantly larger than B (P < .001, for each, respectively). This relationship between δ and B was independent of year of publication, industry funding, management by cooperative trial groups, type of control arm, type of experimental arm, disease site, adjuvant treatment, or treatment for advanced disease, and likely contributed to the high proportion of negative RCTs (158 [62.5%] of 253 studies). Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of δ. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem.


Neuropathy of type 1 diabetes in the Arab world: A systematic review and meta-analysis.
Although type 1 diabetes (T1D) is a common disease in the Arab nations, there is no data available on the prevalence of peripheral neuropathy (PN) among T1D subjects in Arab countries. The aim of this study is to analyze the prevalence of PN in T1D subjects via published literature and to draw attention to the dearth of the published work in this serious complication of T1D. A meta-analysis was performed on studies representing different Arab countries with a total number of 2243 T1D subjects. The pooled prevalence of PN among T1D subjects in the Arab region was estimated as 18% with 95% confidence intervals (CI): 0.09-0.34. The PN prevalence was significantly higher in the >16-yr age group, with 59.1% (95% CI: 0.45-0.72) compared to 9.5% (95% CI: 0.05-0.19) in the <16-yr age group. Furthermore, the PN prevalence was significantly higher in the group with more than 10-yr T1D, 35% (95% CI: 0.15-0.62) than in the group with less than 10-yr T1D, 9.4% (95% CI: 0.04-0.21). In Arab countries, PN is common in adults and children with T1D, but prevalence varies widely. Older age Arab people (>16years) with T1D are affected more with PN than younger age Arab people (<16years). PN is more frequently present in Arab subjects with a longer duration of T1D diabetes than in those with shorter duration.


Clinical perspectives of emerging pathogens in bleeding disorders.
As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma.


Psychiatric symptoms and community violence among high-risk patients: A test of the relationship at the weekly level.
Given the availability of violence risk assessment tools, clinicians are now better able to identify high-risk patients. Once these patients have been identified, clinicians must monitor risk state and intervene when necessary to prevent harm. Clinical practice is dominated by the assumption that increases in psychiatric symptoms elevate risk of imminent violence. This intensive study of patients (N = 132) at high risk for community violence is the first to evaluate prospectively the temporal relation between symptoms and violence. Symptoms were assessed with the Brief Symptom Inventory and threat/control override (TCO) scales. Results indicate that a high-risk patient with increased anger in 1 week is significantly more likely to be involved in serious violence in the following week. This was not true of other symptom constellations (anxiety, depression, TCO) or general psychological distress. The authors found no evidence that increases in the latter symptoms during 1 week provide an independent foundation for expecting violence during the following week.


Shapley Homology: Topological Analysis of Sample Influence for Neural Networks.
Data samples collected for training machine learning models are typically assumed to be independent and identically distributed (i.i.d.). Recent research has demonstrated that this assumption can be problematic as it simplifies the manifold of structured data. This has motivated different research areas such as data poisoning, model improvement, and explanation of machine learning models. In this work, we study the influence of a sample on determining the intrinsic topological features of its underlying manifold. We propose the Shapley homology framework, which provides a quantitative metric for the influence of a sample of the homology of a simplicial complex. Our proposed framework consists of two main parts: homology analysis, where we compute the Betti number of the target topological space, and Shapley value calculation, where we decompose the topological features of a complex built from data points to individual points. By interpreting the influence as a probability measure, we further define an entropy that reflects the complexity of the data manifold. Furthermore, we provide a preliminary discussion of the connection of the Shapley homology to the Vapnik-Chervonenkis dimension. Empirical studies show that when the zero-dimensional Shapley homology is used on neighboring graphs, samples with higher influence scores have a greater impact on the accuracy of neural networks that determine graph connectivity and on several regular grammars whose higher entropy values imply greater difficulty in being learned.


Evaluation of Direct Surgical Remodeling of Frontal Bossing in Patients With Sagittal Synostosis.
The need for surgical correction of frontal bossing in patients with sagittal synostosis is currently debated. The authors retrospectively analyzed frontal bossing in patients with isolated, nonsyndromic sagittal synostosis who underwent calvarial remodeling with and without frontal craniotomy and compared with control subjects. The authors analyzed computed tomography (CT) scans of patients with sagittal synostosis <9 months of age (6.2 ± 1.6 months) who underwent modified-pi procedure either with frontal craniotomy (FC, n = 15) or without frontal craniotomy (NFC, n = 10). Only patients treated with both pre-operative and 1-year post-operative CT scans were included. Non-synostotic age-matched control scans were also analyzed. Cephalic index (CI), 3 previously validated measures of frontal bossing (bossing angle, horizontal bossing ratio, and vertical bossing ratio), and pre-nasion volume ratio were obtained. Additionally, three-dimensional photographs of 10 FC patients were evaluated for frontal bossing between 1 and 8 years post-operatively. Pre-operatively, no significant differences were found between the 2 groups (.064<P < 0.940). Both groups showed greater scaphocephaly and frontal bossing compared to controls (P < 0.001). One-year post-operatively, all measures improved but remained significantly different than normal values except: CI of NFC patients (P = 0.296); bossing angle (P = 0.068) and horizontal bossing ratio (P = 0.129) of FC patients. Compared to NFC patients, horizontal bossing ratio was significantly improved in FC patients (P = 0.017, mean difference of 0.047). No other statistically significant differences were found between the 2 techniques (0.127<P < 0.637).In our long-term study of FC patients up to 9 years of age (n = 10), the authors analyzed forehead inclination as our measure of frontal bossing in three-dimensional photographs. A linear regression analysis showed a significant reduction in forehead inclination with age, decreasing 1.3 ± 0.4 degrees per year (P = 0.021). Forehead inclination for controls did not change significantly with age (P = 0.558). At 1-year following modified-pi procedure, FC patients approached normalization of their forehead morphology to a greater extent than NFC patients. However, neither group completely normalized during this time period. Frontal bossing in FC patients continued to decrease with age, which reveals the post-operative dynamic nature of frontal bone morphology during childhood for these patients.


Drivers for precision livestock technology adoption: A study of factors associated with adoption of electronic identification technology by commercial sheep farmers in England and Wales.
The UK is the largest lamb meat producer in Europe. However, the low profitability of sheep farming sector suggests production efficiency could be improved. Although the use of technologies such as Electronic Identification (EID) tools could allow a better use of flock resources, anecdotal evidence suggests they are not widely used. The aim of this study was to assess uptake of EID technology, and explore drivers and barriers of adoption of related tools among English and Welsh farmers. Farm beliefs and management practices associated with adoption of this technology were investigated. A total of 2000 questionnaires were sent, with a response rate of 22%. Among the respondents, 87 had adopted EID tools for recording flock information, 97 intended to adopt it in the future, and 222 neither had adopted it, neither intended to adopt it. Exploratory factor analysis (EFA) and multivariable logistic regression modelling were used to identify farmer beliefs and management practices significantly associated with adoption of EID technology. EFA identified three factors expressing farmer's beliefs-external pressure and negative feelings, usefulness and practicality. Our results suggest farmer's beliefs play a significant role in technology uptake. Non-adopters were more likely than adopters to believe that 'government pressurise farmers to adopt technology'. In contrast, adopters were significantly more likely than non-adopters to see EID as practical and useful (p≤0.05). Farmers with higher information technologies literacy and intending to intensify production in the future were significantly more likely to adopt EID technology (p≤0.05). Importantly, flocks managed with EID tools had significantly lower farmer- reported flock lameness levels (p≤0.05). These findings bring insights on the dynamics of adoption of EID tools. Communicating evidence of the positive effects EID tools on flock performance and strengthening farmer's capability in use of technology are likely to enhance the uptake of this technology in sheep farms.


Influence of genes, sex, age and environment on the onset of autoimmune hepatitis.
The pathogenesis of autoimmune hepatitis (AIH) is complex. However, it is believed that a susceptible individual, owing to his genetic background, sex and age, can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However, several genes, inside and outside the HLA locus, have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified, but several have been proposed, mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers, emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.


Simplistic pathways or complex networks?
Signaling events are frequently described in textbooks as linear cascades. However, in reality, input cues are processed by dynamic and context-specific networks, which are assembled from numerous signaling molecules. Diseases, such as cancer, are typically associated with multiple genomic alterations that likely change the structure and dynamics of cellular signaling networks. To assess the impact of such genomic alterations on the structure of signaling networks and on the ability of cells to accurately translate environmental cues into phenotypic changes, we argue studies must be conducted on a network level. Advances in technologies and computational approaches for data integration have permitted network studies of signaling events in both cancer and normal cells. Here we will review recent advances and how they have impacted our view on signaling networks with a specific angle on signal processing in cancer.


Factors related to attrition in surgery residency based on application data.
To determine whether variables in the surgery resident selection process will predict attrition or performance during residency training. Retrospective study. A university residency program. A total of 111 categorical surgery residents matched during a 10-year period (1991-2000). Satisfactory outcome included successful completion of training and the American Board of Surgery examinations on the first attempt. Participants with a satisfactory outcome were stratified into good or marginal performance based on adverse actions during residency. Of 111 residents studied, 28 (25.2%) had an unsatisfactory outcome; attrition occurred in 25 (22.5%). Univariate analysis identified the following variables as predictors of unsatisfactory outcome: age at entry older than 29 years (P = .005), female sex (P = .02), courses repeated (P = .01), "C" grades on transcript (P = .01), no participation in team sports (P = .02), and lack of superlative comments in the dean's letter (P = .03). The following variables were retained in the multivariate model: age older than 29 years (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02-0.47; P = .003), summary comments in the dean's letter (OR, 4.57; 95% CI, 2.00-10.43; P < .001), participation in team sports (OR, 4.96; 95% CI, 1.36-18.05; P = .02), and merit scholarship in medical school (OR, 0.25; 95% CI, 0.08-0.78; P = .02). Attrition can be predicted from factors identified on residency applications, with nonacademic factors being more important. Among residents who completed the program, no predictors of performance were identified.


The OregonHeart Total Artificial Heart: Design and Performance on a Mock Circulatory Loop.
Widespread use of heart transplantation is limited by the scarcity of donor organs. Total artificial heart (TAH) development has been pursued to address this shortage, especially to treat patients who require biventricular support. We have developed a novel TAH that utilizes a continuously spinning rotor that shuttles between two positions to provide pulsatile, alternating blood flow to the systemic and pulmonary circulations without artificial valves. Flow rates and pressures generated by the TAH are controlled by adjusting rotor speed, cycle frequency, and the proportion of each cycle spent pumping to either circulation. To validate the design, a TAH prototype was placed in a mock circulatory loop that simulates vascular resistance, pressure, and compliance in normal and pathophysiologic conditions. At a systemic blood pressure of 120/80 mm Hg, nominal TAH output was 7.4 L/min with instantaneous flows reaching 17 L/min. Pulmonary artery, and left and right atrial pressures were all maintained within normal ranges. To simulate implant into a patient with severe pulmonary hypertension, the pulmonary vascular resistance of the mock loop was increased to 7.5 Wood units. By increasing pump speed to the pulmonary circulation, cardiac output could be maintained at 7.4 L/min as mean pulmonary artery pressure increased to 56 mm Hg while systemic blood pressures remained normal. This in vitro testing of a novel, shuttling TAH demonstrated that cardiac output could be maintained across a range of pathophysiologic conditions including pulmonary hypertension. These experiments serve as a proof-of-concept for the design, which has proceeded to in vivo testing.


Reliability of transcriptional cycles and the yeast cell-cycle oscillator.
A recently published transcriptional oscillator associated with the yeast cell cycle provides clues and raises questions about the mechanisms underlying autonomous cyclic processes in cells. Unlike other biological and synthetic oscillatory networks in the literature, this one does not seem to rely on a constitutive signal or positive auto-regulation, but rather to operate through stable transmission of a pulse on a slow positive feedback loop that determines its period. We construct a continuous-time Boolean model of this network, which permits the modeling of noise through small fluctuations in the timing of events, and show that it can sustain stable oscillations. Analysis of simpler network models shows how a few building blocks can be arranged to provide stability against fluctuations. Our findings suggest that the transcriptional oscillator in yeast belongs to a new class of biological oscillators.


Hope After Salvage Therapy Fails: Novel Agents for Relapsed/Refractory Hodgkin Lymphoma.
Hodgkin lymphoma is a highly curable malignancy, with an excellent prognosis. However, around 10% to 25% of patients will have primary refractory or relapsed disease, despite using risk-adapted strategies. The standard of care for patients with relapsed/refractory Hodgkin lymphoma has been cytoreduction using salvage chemotherapy, followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). Studies have shown that AHSCT produces a durable response rate of 50%, and that patients achieve a complete response with salvage chemotherapy. The outcomes for patients who do not respond to salvage chemotherapy or relapse after an AHSCT have been poor, with a median survival of 25 months. However, with the approval of novel agents over the last decade, the outcomes for patients with relapsed/refractory Hodgkin lymphoma have improved significantly. In this article, we present a case of a patient with relapsed Hodgkin lymphoma who responded to salvage chemotherapy incorporating brentuximab vedotin, a novel agent.


Temporal Frequency Abnormalities in Early-Stage Diabetic Retinopathy Assessed by Electroretinography.
To define the nature and extent of temporal frequency abnormalities in diabetics who have mild or no nonproliferative diabetic retinopathy (NPDR) by using the flicker electroretinogram (ERG). Light-adapted flicker ERGs were recorded from 20 diabetics who have no clinically apparent retinopathy, 20 diabetics who have mild NPDR, and 20 nondiabetic, age-equivalent controls. ERGs were elicited by full-field sinusoidal flicker across the temporal frequency range of 6 to 100 Hz and were recorded using conventional techniques. The amplitude and phase of the fundamental and harmonic response components were derived by Fourier analysis and compared among the groups. Analysis of variance indicated that compared with the controls, both patient groups had significant amplitude reductions of the fundamental ERG component for temporal frequencies greater than 56 Hz (all P ≤ 0.03). Modeling the amplitude measurements indicated that both patient groups had significant reductions in the high-frequency response cutoff. Response phase, however, did not differ significantly among the groups at any frequency. The amplitude and phase of the high-frequency harmonics (32-96 Hz) of the patients' responses to a low-frequency stimulus (16 Hz) were normal over the temporal frequency range that the fundamental response was abnormal. Taken together, the diabetics' fundamental amplitude attenuation for rapid flicker combined with their normal high-frequency harmonic responses generated by slow flicker suggest that the likely site of the abnormal temporal filtering occurs prior to the nonlinearity that generates the harmonic components of the ERG, implicating a photoreceptor origin.


Real time noninvasive assessment of external trunk geometry during surgical correction of adolescent idiopathic scoliosis.
The correction of trunk deformity is crucial in scoliosis surgery, especially for the patient's self-image. However, direct visualization of external scoliotic trunk deformity during surgical correction is difficult due to the covering draping sheets. An optoelectronic camera system with 10 passive markers is used to track the trunk geometry of 5 scoliotic patients during corrective surgery. The position of 10 anatomical landmarks and 5 trunk indices computed from the position of the passive markers are compared during and after instrumentation of the spine. Internal validation of the accuracy of tracking was evaluated at 0.41 +/- 0.05 mm RMS. Intra operative tracking during surgical maneuvers shows improvement of the shoulder balance during and after correction of the spine. Improvement of the overall patient balance is observed. At last, a minor increase of the spinal length can be noticed. Tracking of the external geometry of the trunk during surgical correction is useful to monitor changes occurring under the sterile draping sheets. Moreover, this technique can used be used to reach the optimal configuration on the operating frame before proceeding to surgery. The current tracking technique was able to detect significant changes in trunk geometry caused by posterior instrumentation of the spine despite significant correction of the spinal curvature. It could therefore become relevant for computer-assisted guidance of surgical maneuvers when performing posterior instrumentation of the scoliotic spine, provide important insights during positioning of patients.


Facile embedding of single vanadium atoms at the anatase TiO2(101) surface.
To understand the structure-reactivity relationships for mixed-metal oxide catalysts, well-defined systems are required. Mixtures of vanadia and titania (TiO2) are of particular interest for application in heterogeneous catalysis, with TiO2 often acting as the support. By utilizing high-resolution scanning tunneling microscopy, we studied the interaction of vanadium (V) with the anatase TiO2(101) surface in the sub-monolayer regime. At 80 K, metallic V nucleates into homogeneously distributed clusters onto the terraces with no preference for nucleation at the step edges. However, embedding of single V atoms into TiO2 occurs following annealing at room temperature. In conjunction with X-ray photoelectron spectroscopy data and density functional theory calculations, we propose that monomeric V atoms occupy positions of regular surface Ti sites, i.e., Ti atoms are substituted by V atoms.


Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.
Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia. Native leukemia blasts were stained to analyze for AKT phosphorylation levels on a flow cytometer. Efficacy of NVP-BGT226 in comparison to a second dual inhibitor, NVP-BEZ235, was determined with regard to cellular proliferation, autophagy, cell cycle regulation and induction of apoptosis in in vitro and ex vivo cellular assays as well as on the protein level. An isogenic AKT-autoactivated Ba/F3 model, different human leukemia cell lines as well as native leukemia patient blasts were studied. Isobologram analyses were set up to calculate for (super) additive or antagonistic effects of two agents. We show, that phosphorylation of AKT is frequently augmented in acute leukemia. NVP-BGT226 as well as NVP-BEZ235 profoundly and globally suppress AKT signaling pathways, which translates into potent antiproliferative effects. Furthermore, NVP-BGT226 has potent proapoptotic effects in vitro as well as in ex vivo native blasts. Surprisingly and in contrast, NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis. Combination with TK inhibitors, which are currently been tested in the treatment of acute leukemia subtypes, overcomes cell cycle arrest and results in (super)additive proapoptotic effects for NVP-BGT226--but also for NVP-BEZ235. Importantly, mononuclear donor cells show lower phospho-AKT expression levels and consequently, relative insensitivity towards dual PI3K-MTORC1/2 inhibition. Our data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235--which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.


Embryonic cell-free DNA versus trophectoderm biopsy for aneuploidy testing: concordance rate and clinical implications.
To study whether embryonic cell-free DNA (cfDNA) in spent blastocyst media is representative of the chromosomal constitution of a blastocyst. Pilot prospective blinded study. In vitro fertilization center and genetics laboratory. A total of 115 trophectoderm (TE) biopsies and spent blastocyst media (SBM) from 46 patients with ages ranging from 32 to 46 years, whose indications for preimplantation genetic testing of aneuploidy (PGT-A) were advanced maternal age, recurrent miscarriage, or recurrent implantation failure. Spent blastocyst media collection and TE biopsy. Concordance rates, sensitivity, and specificity between TE biopsies and SBM. Clinical outcomes in cases with euploid TE biopsies and euploid SBM compared with cases with euploid TE and aneuploid SBM. In general, the total concordance rate for ploidy and sex was 78.7%, and sensitivity and specificity were 94.5% and 71.7%, respectively. A significant increase for all parameters was observed for day 6/7 samples compared with day 5 samples, with day 6/7 samples showing total concordance for ploidy and sex of 84%, and sensitivity and specificity of 95.2% and 82.1%, respectively. Ongoing implantation rates in euploid TE/euploid SBM showed a threefold increase compared with euploid TE/aneuploid SBM (52.9% vs. 16.7%, respectively), without reaching significant differences. Interestingly, no miscarriages were observed when TE and SBM were euploidy concordant. These results offer a better understanding of the dynamics of cfDNA during embryo development and despite more basic research being needed, they are reassuring to consider in the future this noninvasive approach as an alternative to TE biopsy for PGT-A.


Engineering nanoparticle strategies for effective cancer immunotherapy.
Cancer immunotherapy has been emerging in recent years, due to the inherent nature of the immune system. Although recent successes of immunotherapeutics in clinical application have attracted development of a novel immunotherapeutics, the off-target side effect and low immunogenicity of them remain challenges for the effective cancer immunotherapy. Theranostic nanoparticle system may one of key technology to address these issues by offering targeted delivery of various types of immunotherapeutics, resulting in significant improvements in the tumor immunotherapy. However, appropriate design or engineering of nanoparticles will be needed to improve delivery efficiency of antigen, adjuvant and therapeutics, resulting in eliciting antitumor immunity. Here, we review the current state of the art of cancer immunotherapeutic strategies, mainly based on nanoparticles (NPs). This includes NP-based antigen/adjuvant delivery vehicles to draining lymph nodes, and tumor antigen-specific T-lymphocytes for cancer immunotherapy. Several NP-based examples are shown for immune checkpoint modulation and immunogenic cell death. These overall studies demonstrate the great potential of NPs in cancer immunotherapy. Finally, engineering NP strategies will provide great opportunities to improve therapeutic effects as well as optimization of treatment processes, allowing to meet the individual needs in the cancer immunotherapy.


Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival.
The integrin heterodimer alpha 6 beta 4 is expressed in many epithelia and in Schwann cells. In stratified epithelia, alpha 6 beta 4 couple with BPAG1-e and BPAG2 to form hemidesmosomes, attaching externally to laminin and internally to the keratin cytoskeleton. To explore the function of this atypical integrin, and its relation to conventional actin-associated integrins, we targeted the removal of the beta 4 gene in mice. Tissues that express alpha 6 beta 4 are grossly affected. Stratified tissues are devoid of hemidesmosomes, display only a very fragile attachment to the basal lamina, and exhibit signs of degeneration and tissue disorganization. Simple epithelia which express alpha 6 beta 4 are also defective in adherence, even though they do not form hemidesmosomes. In the absence of beta 4, alpha 6 is dramatically downregulated, and other integrins do not appear to compensate for the loss of this heterodimer. These data have important implications for understanding integrin function in cell-substratum adhesion, cell survival and differentiation, and for understanding the role of alpha 6 beta 4 in junctional epidermolysis bullosa, an often lethal human disorder with pathology similar to our mice.


Genetics of dopamine receptors and drug addiction: a comprehensive review.
Drug dependence is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviours persist despite serious negative consequences. Addictive substances, such as opioids, ethanol, psychostimulants and nicotine, induce pleasant states or relieve distress, effects that contribute to their recreational use. Dopamine is critically involved in drug addiction processes. However, the role of the various dopaminergic receptor subtypes has been difficult to delineate. Here, we will review the information collected implicating the receptors of the D1 family (DRD1 and DRD5) and of the D2 family (DRD2, DRD3 and DRD4) in drug addiction. We will summarize the distribution of these receptors in the brain, the preclinical experiments carried out with pharmacological and transgenic approaches and the genetic studies carried out linking genetic variants of these receptors to drug addiction phenotypes. A meta-analysis of the studies carried out evaluating DRD2 and alcohol dependence is also provided, which indicates a significant association. Overall, this review indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans.


[ENCODE apophenia or a panglossian analysis of the human genome].
In September 2012, a batch of more than 30 articles presenting the results of the ENCODE (Encyclopaedia of DNA Elements) project was released. Many of these articles appeared in Nature and Science, the two most prestigious interdisciplinary scientific journals. Since that time, hundreds of other articles dedicated to the further analyses of the Encode data have been published. The time of hundreds of scientists and hundreds of millions of dollars were not invested in vain since this project had led to an apparent paradigm shift: contrary to the classical view, 80% of the human genome is not junk DNA, but is functional. This hypothesis has been criticized by evolutionary biologists, sometimes eagerly, and detailed refutations have been published in specialized journals with impact factors far below those that published the main contribution of the Encode project to our understanding of genome architecture. In 2014, the Encode consortium released a new batch of articles that neither suggested that 80% of the genome is functional nor commented on the disappearance of their 2012 scientific breakthrough. Unfortunately, by that time many biologists had accepted the idea that 80% of the genome is functional, or at least, that this idea is a valid alternative to the long held evolutionary genetic view that it is not. In order to understand the dynamics of the genome, it is necessary to re-examine the basics of evolutionary genetics because, not only are they well established, they also will allow us to avoid the pitfall of a panglossian interpretation of Encode. Actually, the architecture of the genome and its dynamics are the product of trade-offs between various evolutionary forces, and many structural features are not related to functional properties. In other words, evolution does not produce the best of all worlds, not even the best of all possible worlds, but only one possible world.