Power Normalizations in Fine-Grained Image, Few-Shot Image and Graph Classification.
Power Normalizations (PN) are useful non-linear operators which tackle feature imbalances in classification problems. We study PNs in the deep learning setup via a novel PN layer pooling feature maps. Our layer combines the feature vectors and their respective spatial locations in the feature maps produced by the last convolutional layer of CNN into a positive definite matrix with second-order statistics to which PN operators are applied, forming so-called Second-order Pooling (SOP). As the main goal of this paper is to study Power Normalizations, we investigate the role and meaning of MaxExp and Gamma, two popular PN functions. To this end, we provide probabilistic interpretations of such element-wise operators and discover surrogates with well-behaved derivatives for end-to-end training. Furthermore, we look at the spectral applicability of MaxExp and Gamma by studying Spectral Power Normalizations (SPN). We show that SPN on the autocorrelation/covariance matrix and the Heat Diffusion Process (HDP) on a graph Laplacian matrix are closely related, thus sharing their properties. Such a finding leads us to the culmination of our work, a fast spectral MaxExp which is a variant of HDP for covariances/autocorrelation matrices. We evaluate our ideas on fine-grained recognition, scene recognition, and material classification, as well as in few-shot learning and graph classification.


Coronary artery fistula draining into the left ventricle.
We present a case of 48-year-old male who presented with coronary artery fistula draining into left ventricle. Transthoracic echocardiography showed abnormal blood flow draining into left ventricle, with enlarged coronary arteries and multiple vascular structures around ventricular myocardium. Coronary computed tomography revealed dilatation of entire left coronary artery which was wrapping around left ventricle, and draining into the posterior side of left ventricle. He did not undergo any invasive treatment, because he was not symptomatic.


Infection of HeLa cells with Chlamydia trachomatis inhibits protein synthesis and causes multiple changes to host cell pathways.
The obligate intracellular bacterium Chlamydia trachomatis replicates in a cytosolic vacuole in human epithelial cells. Infection of human cells with C. trachomatis causes substantial changes to many host cell-signalling pathways, but the molecular basis of such influence is not well understood. Studies of gene transcription of the infected cell have shown altered transcription of many host cell genes, indicating a transcriptional response of the host cell to the infection. We here describe that infection of HeLa cells with C. trachomatis as well as infection of murine cells with Chlamydia muridarum substantially inhibits protein synthesis of the infected host cell. This inhibition was accompanied by changes to the ribosomal profile of the infected cell indicative of a block of translation initiation, most likely as part of a stress response. The Chlamydia protease-like activity factor (CPAF) also reduced protein synthesis in uninfected cells, although CPAF-deficient C. trachomatis showed no defect in this respect. Analysis of polysomal mRNA as a proxy of actively transcribed mRNA identified a number of biological processes differentially affected by chlamydial infection. Mapping of differentially regulated genes onto a protein interaction network identified nodes of up- and down-regulated networks during chlamydial infection. Proteomic analysis of protein synthesis further suggested translational regulation of host cell functions by chlamydial infection. These results demonstrate reprogramming of the host cell during chlamydial infection through the alteration of protein synthesis.


Folate and choline metabolism gene variants in relation to ovarian cancer risk in the Polish population.
Data indicates that genetic factors alone do not account for ovarian tumorigenesis, suggesting that epigenetic status additionally affects this process. Therefore, we assessed the possible contribution of polymorphic variants of genes that may affect DNA methylation to the risk of ovarian cancer incidence in the Polish population. Using PCR-RFLP and HRM analyses, we studied the distribution of BHMT (rs3733890), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394) and TCN2 (rs1801198) genotypes and alleles in patients with ovarian cancer (n = 136) and controls (n = 160). Moreover, using DNA and methylation-specific PCR (MSP) we also determined the methylation of the Cadherin 13 (CDH13) promoter in cancerous tissue from these patients. We did not observe a significant association between all studied gene variants and the incidence of ovarian cancer. The lowest P (trend) = 0.1226 was observed for the MTHFR Ala222Val polymorphism. Moreover, the lowest P = 0.0772 was found in the comparison of MTHFR Ala/Ala versus Val/Val and Val/Ala genotypes in patients and control groups. The multifactor dimensionality reduction analysis also did not indicate a significant interactive genetic effect on ovarian cancer incidence for all analyzed SNPs. However, we observed frequent methylation of the CDH13 promoter in approximately 21% (29/136) patients with ovarian carcinomas. Our results might suggest that the selected polymorphic gene variants may not contribute to ovarian cancer incidence.


RNase H domain of Moloney murine leukemia virus reverse transcriptase retains activity but requires the polymerase domain for specificity.
The reverse transcriptase-associated RNase H activity of Moloney murine leukemia virus specifically cleaves within the polypurine tract region of the viral genome to generate the primer for plus-strand DNA synthesis and removes the tRNA primer after minus-strand initiation by preferentially cleaving the RNA one nucleotide before the RNA-DNA junction. Moreover, the enzyme is unable to cleave the extended tRNA substrate at the RNA-DNA junction even at high enzyme concentrations. The RNase H domain of the reverse transcriptase was expressed as a glutathione S-transferase fusion protein and purified from Escherichia coli extracts. Following removal of the glutathione S-transferase portion of the protein, the specificity of the isolated RNase H domain was determined in the plus-strand primer reaction and in the tRNA primer removal reaction. Although the isolated domain lacked specificity in both cases, it was still unable to cleave the tRNA substrate precisely at the RNA-DNA junction. Specificity in both cases could be restored by adding back a truncated form of Moloney murine leukemia virus reverse transcriptase lacking the RNase H domain. These results implicate the polymerase domain as a specificity determinant for the RNase H activity of reverse transcriptase. The isolated RNase H domain had higher activity in the presence of Mn2+ than in the presence of Mg2+, but neither the RNase H domain alone nor the RNase H domain coupled to the polymerase domain in wild-type protein exhibited the normal cleavage specificities in the presence of the nonphysiological divalent cation.


Dissociation of the stimulatory activities of staphylococcal enterotoxins for T cells and monocytes.
The staphylococcal enterotoxins (SEs) are homologous proteins related in their capacity for stimulating both T cells and monocytes. To assess the importance of conserved structure and sequence to functional activity, the role of the disulfide loop and adjacent sequence in these toxins was evaluated. Contrary to previous reports, we demonstrate here that the disulfide loop was required for the mitogenic activity of SEA and SEB. While T cell-stimulatory activity was compromised, reduced and alkylated SEs retained major histocompatibility complex class II-binding and monocyte-stimulatory activities, suggesting that their inability to induce T cell proliferation was due to failure to interact with T cell receptor (TCR) rather than with class II molecules. Reduction and alkylation did not affect the far-ultraviolet circular dichroic spectrum of SEA, suggesting that the loss of mitogenic activity was not associated with significant changes in secondary structure. The disulfide linkage imparts considerable stability to these toxins as peptide cleavages within the loop of SEB were not associated with detectable loss of function, although cleavage in the conserved sequence outside the loop of SEA resulted in loss of mitogenic activity. This report thus establishes a functional role for a conserved element in SEs, the disulfide loop, and further indicates that their class II- and TCR-binding activities can be dissociated.


Effect of brow lifting using botulinum a toxin on upper eyelid height in patients with ptosis undergoing the frontal sling technique.
In this study, brow lifting with botulinum A toxin was performed on patients whose ptosis was corrected using the frontal sling technique, and the effects of this application on ptosis were investigated. Seven patients (with 12 eyelids) on whom the frontal sling procedure was performed using a tensor fascia lata graft were enrolled in the study. The patients underwent brow lifting using botulinum A toxin. Digital photographs of the patients were obtained before and 21 days after botulinum A injection. In digital imaging analysis, although a statistically significant elevation was detected in the eyelids and brows of the patients following botulinum A injection, it did not to lead to a significant difference in the degree of lagophthalmos. In the current study, this procedure was found to reduce the degree of ptosis without increasing the degree of lagophthalmos in patients who had previously undergone ptosis correction using the frontal sling.


Less is more: Patient-level meta-analysis reveals paradoxical dose-response effects of a computer-based social anxiety intervention targeting attentional bias.
The past decade of research has seen considerable interest in computer-based approaches designed to directly target cognitive mechanisms of anxiety, such as attention bias modification (ABM). By pooling patient-level datasets from randomized controlled trials of ABM that utilized a dot-probe training procedure, we assessed the impact of training "dose" on relevant outcomes among a pooled sample of 693 socially anxious adults. A paradoxical effect of the number of training trials administered was observed for both posttraining social anxiety symptoms and behavioral attentional bias (AB) toward threat (the target mechanism of ABM). Studies administering a large (>1,280) number of training trials showed no benefit of ABM over control conditions, while those administering fewer training trials showed significant benefit for ABM in reducing social anxiety (P = .02). These moderating effects of dose were not better explained by other examined variables and previously identified moderators, including patient age, training setting (laboratory vs. home), or type of anxiety assessment (clinician vs. self-report). Findings inform the optimal dosing for future dot-probe style ABM applications in both research and clinical settings, and suggest several novel avenues for further research.


Solution structure of the C-terminal domain from poly(A)-binding protein in Trypanosoma cruzi: a vegetal PABC domain.
PABC is a phylogenetically conserved peptide-binding domain primarily found within the C terminus of poly(A)-binding proteins (PABPs). This domain recruits a series of translation factors including poly(A)-interacting proteins (Paip1 and Paip2) and release factor 3 (RF3/GSPT) to the initiation complex on mRNA. Here, we determine the solution structure of the Trypanosoma cruzi PABC domain (TcPABC), a representative of the vegetal class of PABP proteins. TcPABC is similar to human PABC (hPABC) and consists of five alpha-helices, in contrast to the four helices observed in PABC domains from yeast (yPABC) and hyper plastic disk proteins (hHYD). A mobile N-terminal helix is observed in TcPABC that does not pack against the core of the protein, as found in hPABC. Characteristic to all PABC domains, the last four helices of TcPABC fold into a right-handed super coil. TcPABC demonstrates high-affinity binding to PABP interacting motif-2 (PAM-2) and reveals a peptide-binding surface homologous to that of hPABC. Our results demonstrate the last four helices in TcPABC are sufficient for peptide recognition and we predict a similar binding mode in PABC domains. Furthermore, these results point to the presence of putative PAM-2 site-containing proteins in trypanosomes.


Systemic therapy for older women with breast cancer.
Breast cancer is a common problem in older women. As the number of medical illnesses increases with age and the life expectancy decreases, the benefits of systemic therapy for women with breast cancer become questionable. All women over age 65 years are at high enough risk of breast cancer to consider the risk/benefit ratio of preventive therapy with tamoxifen (Nolvadex) or participation in the Study of Tamoxifen and Raloxifene (STAR) trial. Adjuvant chemotherapy and hormonal therapies for early breast cancer significantly improve disease-free and overall survival; recommendations for their use are based on risk of tumor recurrence. Use of tamoxifen in the adjuvant setting in women with receptor-positive tumors is a relatively simple decision in light of its favorable toxicity profile. The delivery of adjuvant chemotherapy is a more complicated decision, and the patient's wishes, estimated life expectancy, presence of comorbid conditions, and estimated benefit from treatment should be considered. The primary goal of the treatment of metastatic breast cancer is palliation. We discuss trials specific to older women and make appropriate treatment recommendations. Unfortunately, there is a paucity of data from clinical trials in women over age 70 years. However, because the clinical trial is the primary scientific mechanism for testing the efficacy of a treatment, every effort should be made to enter older women into treatment protocols.


Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.
A method for obtaining strongly polarized nuclear spins in solution has been developed. The method uses low temperature, high magnetic field, and dynamic nuclear polarization (DNP) to strongly polarize nuclear spins in the solid state. The solid sample is subsequently dissolved rapidly in a suitable solvent to create a solution of molecules with hyperpolarized nuclear spins. The polarization is performed in a DNP polarizer, consisting of a super-conducting magnet (3.35 T) and a liquid-helium cooled sample space. The sample is irradiated with microwaves at approximately 94 GHz. Subsequent to polarization, the sample is dissolved by an injection system inside the DNP magnet. The dissolution process effectively preserves the nuclear polarization. The resulting hyperpolarized liquid sample can be transferred to a high-resolution NMR spectrometer, where an enhanced NMR signal can be acquired, or it may be used as an agent for in vivo imaging or spectroscopy. In this article we describe the use of the method on aqueous solutions of [13C]urea. Polarizations of 37% for 13C and 7.8% for 15N, respectively, were obtained after the dissolution. These polarizations correspond to an enhancement of 44,400 for 13C and 23,500 for 15N, respectively, compared with thermal equilibrium at 9.4 T and room temperature. The method can be used generally for signal enhancement and reduction of measurement time in liquid-state NMR and opens up for a variety of in vitro and in vivo applications of DNP-enhanced NMR.


Structural basis of the Axin-adenomatous polyposis coli interaction.
Axin and the adenomatous polyposis coli (APC) tumor suppressor protein are components of the Wnt/Wingless growth factor signaling pathway. In the absence of Wnt signal, Axin and APC regulate cytoplasmic levels of the proto-oncogene beta-catenin through the formation of a large complex containing these three proteins, glycogen synthase kinase 3beta (GSK3beta) and several other proteins. Both Axin and APC are known to be critical for beta-catenin regulation, and truncations in APC that eliminate the Axin-binding site result in human cancers. A protease-resistant domain of Axin that contains the APC-binding site is a member of the regulators of G-protein signaling (RGS) superfamily. The crystal structures of this domain alone and in complex with an Axin-binding sequence from APC reveal that the Axin-APC interaction occurs at a conserved groove on a face of the protein that is distinct from the G-protein interface of classical RGS proteins. The molecular interactions observed in the Axin-APC complex provide a rationale for the evolutionary conservation seen in both proteins.


Development of human cell-expressed tag-free rhMFG-E8 as a radiation mitigator and a therapeutic for acute kidney injury.
Human milk fat globule epidermal growth factor-factor VIII (MFG-E8) functions as a bridging molecule to promote the removal of dying cells by professional phagocytes. E. coli-expressed histidine-tagged recombinant human MFG-E8 (rhMFG-E8) is protective in various disease conditions. However, due to improper recombinant protein glycosylation, misfolding and possible antigenicity, E. coli-expressed histidine-tagged rhMFG-E8 is unsuitable for human therapy. Therefore, we hypothesize that human cell-expressed, tag-free rhMFG-E8 can be developed as a safe and effective novel biologic to treat inflammatory diseases such as radiation injury and acute kidney injury (AKI). We produced a new tag-free rhMFG-E8 protein by cloning the human MFG-E8 full-length coding sequence without any fusion tag into a mammalian vector and expressed it in HEK293-derived cells. The construct includes the leader sequence of cystatin S to maximize secretion of rhMFG-E8 into the culture medium. After purification and confirmation of the protein identity, we first evaluated its biological activity in vitro. We then determined its efficacy in vivo utilizing two experimental rodent models of organ injury: partial body irradiation (PBI) and ischemia/reperfusion-induced AKI. HEK293 cell supernatant containing tag-free rhMFG-E8 protein was concentrated, purified, and rhMFG-E8 was verified by SDS-PAGE analysis and mass spectrometry. The biological activity of human cell-expressed tag-free rhMFG-E8 was superior to that of E. coli-expressed His-tagged rhMFG-E8. Toxicity, stability, and pharmacokinetic studies indicate that tag-free rhMFG-E8 is safe, highly stable after lyophilization and long-term storage, and with an adequate half-life for therapeutic applications. In the PBI model, a dose-dependent improvement of the 30-day survival rate was observed after tag-free rhMFG-E8 treatment with a 30-day survival of 89%, which was significantly higher than the 25% survival in the vehicle group. The dose modification factor (DMF) of tag-free rhMFG-E8 was 1.073. Tag-free rhMFG-E8 also attenuated gastrointestinal damage after PBI. In the model of AKI, tag-free rhMFG-E8 treatment significantly attenuated kidney injury and inflammation, and improved the 10-day survival. Our new human cell-expressed tag-free rhMFG-E8 can be further developed as a safe and effective therapy to treat victims of severe acute radiation injury and patients with acute kidney injury.


[Theoretical basis of goldmann applanation tonometry].
For more than 50 years Goldmann applanation tonometry has been the internationally accepted method for measuring intraocular pressure. In Goldmann applanation tonometry, however, some basic physical properties are oversimplified and the method has some flaws and restrictions. This paper is intended to promote the understanding of the methodological basis of Goldmann applanation tonometry and describes the most important factors influencing the measurement of intraocular pressure (e. g., corneal thickness, corneal radius, axial length and corneal morphology). Furthermore, the basic principles of other commonly used tonometer devices will be discussed. New developments are anticipated that will measure the true intraocular pressure more accurately than Goldmann applanation tonometry.


Imaging of poly(NIPA-co-MAH)-HIgG conjugate with scanning tunneling microscopy.
Random copolymers of N-isopropylacrylamide (NIPA) and 2-methacryloylamidohistidine (MAH) with different MAH contents in the range of 0.125-0.725 mmol/g copolymer and with different molecular weights in the range of 62.0-77.5 kg/mol were synthesized by free radical copolymerization. Copolymers were interacted with human immunoglobulin-G (HIgG) in the aqueous medium with different concentrations. FT-IR and NMR data revealed both copolymer and copolymer-HIgG conjugates. The decrease in the lower critical solution temperature (LCST) of the copolymer observed was related with the increase in the HIgG content within the medium. The main goal of this study was imaging poly(NIPA-co-MAH)-HIgG conjugates using Scanning Tunneling Microscopy (STM), which is one of the widely used methods with the capability of atomic level imaging for biological molecules. STM images of the copolymer, HIgG and copolymer-HIgG conjugates were taken at room temperature at atmospheric pressure, using a 1-1.5 V sample bias and a tunneling current of 10-20 pA, which clearly demonstrated the formation of conjugates.


[Change in central hemodynamics and systolic phase structure as affected by reflexotherapy in patients with neurocirculatory dystonia].
Myocardial contractility was examined, using echo- and polycardiography, in patients with neurocirculatory dystonia. An increase was demonstrated in the duration of the phase of isometric tension, mechanical systole and cardiac index in the presence of raised peripheral resistance as well as increased energy spending and enhanced left-ventricular contraction. Auriculo-paravertebral method of reflexotherapy was applied, and the changed parameters returned to normal.


Alternative National Goals and Women's Employment: Career opportunities in the 1970's are contingent upon growth objectives.
I have stressed the importance of economic growth and employment policies for the furtherance of women's career objectives. Legal action to remove discrimination, as well as transformation of attitudes and expectations, will prove but hollow successes if adequate career opportunities do not become available. For this reason, the employment outlook for professional women in the 1970's has been examined on the basis of three alternative views of the future. All three involve elements of uncertainty and would require adjustments in the labor market. In the first alternative, although the BLS projected an overall balance in the labor market, supply and demand were expected to be ill-matched in several professional sectors, entailing burdensome retraining for those finding themselves in the areas of excess supply. The more pessimistic variant, based either on failure to reach growth and employment goals or on deliberate pursuit of reduced growth goals-combined with population stabilization and increased productivity-would require such fundamental adjustments in the labor market as work-sharing and early retirement or deemphasis of career objectives. The optimistic variant posits economic and social needs great enough to warrant high growth rates and views an expanded labor supply as a factor enabling the economy to attain such growth rates and to extend the utilization of professional personnel in new as well as in established areas (31). The major burden posed by the optimistic variant involves the need to achieve social consensus on the goals of society and to maintain the commitment to those goals with energy and intelligence.


Enhancing identification accuracy for powdery mildews using previously underexploited DNA loci.
The internal transcribed spacer (ITS) DNA marker is routinely used for fungal identification but gives a clear result for only three out of four powdery mildew samples. A search for new markers indicates that some genes offer enhanced identification in comparison with ITS. Others fail due to amplification and sequencing difficulties and lack of informative variability. Powdery mildews (Ascomycota, Erysiphales) are biotrophic, fungal plant pathogens that commonly occur worldwide on a wide range of host plants. They are unsightly and greatly reduce the vigor of their hosts and have major impacts on crop and other cultivated plants. Species within this order are straightforward to spot, but difficult to identify. A citizen science scheme was run in 2013-2016 in the UK to gather a wide array of samples on which identification methods could be developed. Current techniques for identification and phylogenetic reconstruction show scope for improvement. In this paper, we review genes used in other fungal groups for discrimination at species level. Working protocols for amplification and sequencing of seven genes (actin, β-tubulin, calmodulin,Chs, elongation factor 1-α [EF1-α], Mcm7, and Tsr1) are developed with varying success; Mcm7 proves to be the most useful at differentiation between closely related, phylogenetically young powdery mildew species for phylogenetic reconstruction when used separately and in tandem with ITS. We therefore propose this as the most appropriate candidate gene to be used commonly in powdery mildew diagnostics alongside the ITS; furthermore, this could be transferred to similarly troublesome fungal clades.


Targeting p63 Upregulation Abrogates Resistance to MAPK Inhibitors in Melanoma.
Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here, we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7-inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor-resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of Nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy. SIGNIFICANCE: Upregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.


Complexity of environment and parsimony of decision rules in insect societies.
This paper shows how colonies of social insects process information and solve problems in a complex environment, while keeping some parsimony at the level of the individuals' decision rules. Two studies on ant foraging reveal the diversity of adaptive colony-level patterns that can be generated through self-organization, based on the same individual-level recruitment rules. Regarding prey scavenging, the "ability to retrieve the prey" rule accounts for changes in foraging patterns, with increasing prey size, that show all stages intermediate between an individual and a mass exploitation of food resources. Regarding liquid food foraging, the "ability to ingest a desired volume" rule enables a colony to adjust the number of tending ants to the honeydew production of aphids. In both cases, decision rules are based on intelligent criteria that intrinsically integrate information on multiple variables that are relevant to the ants. Furthermore, the environment can contribute directly to the emergence of collective patterns, independently of any individual behavioral changes. Each environmental factor, including abiotic ones, that alters the dynamics of information transfer in group-living animals should be reconsidered not simply as a constraint but also as a part of the decision-making process and as a agent that shapes the collective pattern.


Demonstration of insulin-like growth factor (IGF-I and -II) receptors and binding protein in human breast cancer cell lines.
The insulin like growth factors (IGFs), potent mitogens for a variety of normal and transformed cells, have been reported to be secreted by several human breast cancer cell lines (BC). We have investigated the binding characteristics of IGF-I and -II in four human BC: MCF-7, T-47D, MDA 231 and Hs578T. Binding studies in microsomal membrane preparations detected high specific binding for both IGF in all four BC studied. Cross-linking with 125I-IGF-I, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reduced conditions, revealed the presence of an alpha subunit of apparent Mr = 130,000 in MCF-7, T-47D and MDA 213 cells. When 125I-IGF-II was cross-linked, a major band of apparent Mr = 260,000 was seen in all BC. This band was inhibited by IGF-II, but not by insulin. Cross-linking of 125I-IGF-I to conditioned media from BC demonstrated the presence of three binding proteins of apparent Mr = 45,000, 36,000 and 29,000 in all BC but T-47D, in which the 36,000 band was not seen. These data demonstrate that BC possess classical receptors for both IGF-I and -II and, furthermore, that BC produce specific binding proteins for these growth factors.


Interesting basis of vertebrobasilar arterial territory.
Vertebrobasilar arterial territory nourishes one-quarter of human brain. It constitutes some vital and strategic parts of the central nervous system. A number of keywords (vertebral, basilar, artery, and territory) were searched in MEDLINE (Ovid and PubMed) as well as Google, ProQuest, Scopus, Cochrane Library, and Science Direct online databases. Only articles containing all keywords were included. We also reviewed archives of libraries in Mashhad University of Medical Sciences (Iran) for all anatomy, embryology, neurology, and neuroscience books and journals about vertebrobasilar arterial territories. The vertebrobasilar arterial (VA) system has a high incidence of variations, anomalies, and persistent fetal vessels. Two important anatomic facts explain why VA origin lesions seldom cause chronic hemodynamically significant low flow to the vertebrobasilar system. First, the VAs are paired vessels that unite to form a single basilar artery. Second, the extracranial VA gives off numerous muscular and other branches as it ascends in the neck. Thus, in the VA system, there is much more potential for development of adequate collateral circulation. Even when there is bilateral occlusion of the VAs at their origins, patients do not often develop posterior circulation infarcts. VA origin disease is more benign than ICA origin disease from hemodynamic aspect. This important point could make influence in therapeutic interventional decisions in asymptomatic VA origin stenosis.


Teredinibacter waterburyi sp. nov., a marine, cellulolytic endosymbiotic bacterium isolated from the gills of the wood-boring mollusc Bankia setacea (Bivalvia: Teredinidae) and emended description of the genus Teredinibacter.
A cellulolytic, aerobic, gammaproteobacterium, designated strain Bs02T, was isolated from the gills of a marine wood-boring mollusc, Bankia setacea (Bivalvia: Teredinidae). The cells are Gram-stain-negative, slightly curved motile rods (2-5×0.4-0.6 µm) that bear a single polar flagellum and are capable of heterotrophic growth in a simple mineral medium supplemented with cellulose as a sole source of carbon and energy. Cellulose, carboxymethylcellulose, xylan, cellobiose and a variety of sugars also support growth. Strain Bs02T requires combined nitrogen for growth. Temperature, pH and salinity optima (range) for growth were 20 °C (range, 10-30 °C), 8.0 (pH 6.5-8.5) and 0.5 M NaCl (range, 0.0-0.8 M), respectively when grown on 0.5 % (w/v) galactose. Strain Bs02T does not require magnesium and calcium ion concentrations reflecting the proportions found in seawater. The genome size is approximately 4.03 Mbp and the DNA G+C content of the genome is 47.8 mol%. Phylogenetic analyses based on 16S rRNA gene sequences, and on conserved protein-coding sequences, show that strain Bs02T forms a well-supported clade with Teredinibacter turnerae. Average nucleotide identity and percentage of conserved proteins differentiate strain Bs02T from Teredinibacter turnerae at threshold values exceeding those proposed to distinguish bacterial species but not genera. These results indicate that strain Bs02T represents a novel species in the previously monotypic genus Teredinibacter for which the name Teredinibacter waterburyi sp. nov. is proposed. The strain has been deposited under accession numbers ATCC TSD-120T and KCTC 62963T.


Quantitation of cell-derived microparticles in plasma using flow rate based calibration.
Activation of vascular endothelium and blood cells can result in the formation of microparticles (MPs), which are membrane vesicles with a diameter < 1 microm which can play a pathogenetic role in a variety of infectious and other diseases. In this study, we validated a modified quantitative method called "flow rate based calibration", to measure circulating MPs in plasma of healthy subjects and malaria patients using FACSCalibur flow cytometry. MPs counts obtained from "flow rate based calibration" correlated closely with the standard method (R2 = 0.9, p = 0.001). The median (range) number of MPs in healthy subjects was 163/microl (81-375/microl). We demonstrated a flow rate based calibration for the quantitation of MPs in P. falciparum malaria-infected patients. The median (range) number of MPs was 2,051/microl (222-6,432/microl), n = 28 in patients with falciparum malaria. The number of MPs in plasma from patients with severe falciparum malaria was significantly higher than in uncomplicated falciparum malaria (2,567/microl (366-6,432/microl), n = 18 versus [1,947/microl (222-4,107/microl), n = 10, p < 0.01]. Cellular origin of MPs in malaria patients were mainly derived from red blood cells (35%), platelets (10%), and endothelial cells (5%). There was no significant correlation between the total number of MPs and parasitemia. Flow rate based calibration is a simple, reliable, reproducible method and more affordable to quantitate MPs.


Women's experiences of caring when in treatment for alcohol dependency.
Despite the fact of increased levels of alcohol dependency in women and gender differences in how the disease affects men and women, the research on alcohol dependency continues to have a dominating perspective on men. The meaning of the phenomenon of caring in formal care for women with alcohol dependency is not well known. Thus, formal caregivers may find it problematic to know what is caring for women with alcohol dependency. The aim of the study was to illuminate the meaning of caring in formal care for women with alcohol dependency, as narrated by the women. The study was performed using a phenomenological-hermeneutic method. Data were collected in ten in-depth interviews with alcohol-dependent women. The themes presented are availability, being a patient and being a learner. The findings reveal that the women with alcohol dependency receiving a mandate from formal care, experience the relation between them and their caregiver as a mutual transformation. Within the mutual transformation, the participants experienced being respected as a responsible human being which renders possibilities for the women with alcohol dependency to continue in formal care even when the struggle against the disease became hard. Continual meetings with the caregiver allowed the women to gain structure in their daily life as well as allowing the women and their caregivers to develop mutual transformation, which both relieved the women's suffering and increased their experience of being involved in the care process.


Characterization of foot-and-mouth disease viruses (FMDVs) from Ugandan cattle outbreaks during 2012-2013: evidence for circulation of multiple serotypes.
To investigate the foot-and-mouth disease virus (FMDV) serotypes circulating in Uganda's cattle population, both serological and virological analyses of samples from outbreaks that occurred during 2012-2013 were performed. Altogether, 79 sera and 60 oropharyngeal fluid (OP)/tissue/oral swab samples were collected from herds with reported FMD outbreaks in seven different Ugandan districts. Overall, 61/79 (77%) of the cattle sera were positive for antibodies against FMDV by PrioCHECK FMDV NS ELISA and solid phase blocking ELISA detected titres ≥ 80 for serotypes O, SAT 1, SAT 2 and SAT 3 in 41, 45, 30 and 45 of these 61 seropositive samples, respectively. Virus neutralisation tests detected the highest levels of neutralising antibodies (titres ≥ 45) against serotype O in the herds from Kween and Rakai districts, against SAT 1 in the herd from Nwoya district and against SAT 2 in the herds from Kiruhura, Isingiro and Ntungamo districts. The isolation of a SAT 2 FMDV from Isingiro was consistent with the detection of high levels of neutralising antibodies against SAT 2; sequencing (for the VP1 coding region) indicated that this virus belonged to lineage I within this serotype, like the currently used vaccine strain. From the Wakiso district 11 tissue/swab samples were collected; serotype A FMDV, genotype Africa (G-I), was isolated from the epithelial samples. This study shows that within a period of less than one year, FMD outbreaks in Uganda were caused by four different serotypes namely O, A, SAT 1 and SAT 2. Therefore, to enhance the control of FMD in Uganda, there is need for efficient and timely determination of outbreak virus strains/serotypes and vaccine matching. The value of incorporating serotype A antigen into the imported vaccines along with the current serotype O, SAT 1 and SAT 2 strains should be considered.


Influence of porcine somatotropin on the phosphorus requirement of finishing pigs: II. Carcass characteristics, tissue accretion rates, and chemical composition of the ham.
We investigated the effects of recombinant porcine somatotropin (pST) on the requirement for P to maximize lean tissue accretion and to minimize fat tissue accretion in two experiments using finishing pigs. Corn-soybean meal diets with varying levels of P were fed, and Ca was adjusted to maintain a Ca:P ratio of 1.1:1. In Exp. 1, 96 pigs were fed dietary P concentrations of .35, .45, and .65% from 75 to 109 kg BW. One-half of the pigs were injected daily with 4 mg of pST. Administration of pST increased (P < .05) percentages and accretion rates of lean tissue, bone, skin, water, and protein, but it reduced (P < .05) those of fat tissue and lipid. Increasing dietary P had little effect on chemical composition or accretion rates in untreated pigs, but it increased (P < .05) ash percentage and accretion in pigs treated with pST. Experiment 2 consisted of 66 pigs fed six dietary P concentrations (.35, .50, .65, .80, .95, and 1.10%) from 72 to 114 kg. One-half of the pigs were injected daily with 4 mg of pST. Percentages and accretion rates of lean tissue, bone, skin, water, and protein increased (P < .05) with pST, but those of fat tissue and lipid were reduced (P < .05). Increasing dietary P increased accretion rates of bone and skin (linear, P < .05), lean tissue, water, protein, and ash (quadratic, P <.05), and it reduced (quadratic, P < .05) that of lipid in pigs treated with pST. Dietary P level did not consistently affect percentages or accretion rates of tissues or chemical components in untreated pigs. In most instances, pigs treated with pST required higher dietary P levels and greater daily intakes of P to maximize lean tissue and protein deposition and to minimize fat tissue and lipid accretion than untreated pigs. These results indicate that finishing pigs treated with pST require higher dietary percentages of P to maximize carcass lean deposition as compared with untreated pigs.


Insights from clinical research completed during the west Africa Ebola virus disease epidemic.
The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research.


GFP tagging of sieve element occlusion (SEO) proteins results in green fluorescent forisomes.
Forisomes are Ca(2+)-driven, ATP-independent contractile protein bodies that reversibly occlude sieve elements in faboid legumes. They apparently consist of at least three proteins; potential candidates have been described previously as 'FOR' proteins. We isolated three genes from Medicago truncatula that correspond to the putative forisome proteins and expressed their green fluorescent protein (GFP) fusion products in Vicia faba and Glycine max using the composite plant methodology. In both species, expression of any of the constructs resulted in homogenously fluorescent forisomes that formed sieve tube plugs upon stimulation; no GFP fluorescence occurred elsewhere. Isolated fluorescent forisomes reacted to Ca(2+) and chelators by contraction and expansion, respectively, and did not lose fluorescence in the process. Wild-type forisomes showed no affinity for free GFP in vitro. The three proteins shared numerous conserved motifs between themselves and with hypothetical proteins derived from the genomes of M. truncatula, Vitis vinifera and Arabidopsis thaliana. However, they showed neither significant similarities to proteins of known function nor canonical metal-binding motifs. We conclude that 'FOR'-like proteins are components of forisomes that are encoded by a well-defined gene family with relatives in taxa that lack forisomes. Since the mnemonic FOR is already registered and in use for unrelated genes, we suggest the acronym SEO (sieve element occlusion) for this family. The absence of binding sites for divalent cations suggests that the Ca(2+) binding responsible for forisome contraction is achieved either by as yet unidentified additional proteins, or by SEO proteins through a novel, uncharacterized mechanism.


Process evaluation of school-based peer education for HIV prevention among Yemeni adolescents.
In 2005, a survey was conducted among all the 27 high schools of Aden, which revealed low levels of knowledge on major prevention measures, and a high level of stigma and discrimination towards people living with HIV (PLWH). The results served as a baseline for implementing a school-based peer education intervention for HIV prevention in the 27 schools of Aden. In 2008, and after 3 years of implementation, a quasi-experimental evaluation was conducted, which revealed that the peer education intervention has succeeded in improving HIV knowledge and skills; and in decreasing stigmatization of PLWH. This process evaluation aims to give a deeper understanding of the quasi-experimental evaluation which was conducted in the 27 high schools of Aden, and to highlight the factors that facilitated or inhibited school peer education in such a conservative Muslim setting. Qualitative methodologies were pursued, where 12 focus group discussions and 12 in-depth interviews were conducted with peer educators, targeted students, school principals, social workers, and parents of peer educators. Results revealed that school-peer education was well received. There was an apparent positive effect on the life skills of peer educators, but the intervention had a lesser effect on targeted students. Key enabling factors have been the high quality of training for peer educators, supportive school principals, and acceptance of the intervention by parents. These findings are important for improving the life skills and peer education intervention at the school level, and in better planning and implementation of life skills and peer programmes at a national scale.


An Open-label Comparison of a New Generic Sevoflurane Formulation With Original Sevoflurane in Patients Scheduled for Elective Surgery Under General Anesthesia.
To compare the stability, effectiveness, and safety profiles of a new generic sevoflurane with those of the original sevoflurane formulation in patients undergoing elective surgery. An accelerated 3-month storage test was performed to evaluate the compositional changes in generic sevoflurane stored in glass bottles. In addition, 182 patients were randomly allocated to receive generic (n = 89 [54 men and 35 women]; mean [SD] age, 49.9 [11.6] years) or original (n = 93 [61 men and 32 women]; mean [SD] age, 49.6 [11.1] years) sevoflurane at a gas flow of 3 L/min for approximately 3 hours. The mean minimum alveolar concentration (MAC) during sevoflurane anesthesia was evaluated, and gas samples for measuring compound A were collected from the inspiratory limb of the circuit at preset intervals. Blood samples for measuring serum inorganic fluoride were obtained at preset intervals (pharmacokinetic group: generic/original sevoflurane = 45/46). Renal biomarkers, such as N-acetyl-β-glucosaminidase, α- and π-glutathione-S-transferase, albumin, urine protein and osmolality, serum creatinine and osmolality, creatinine clearance, and blood urea nitrogen, were measured at preset intervals (renal biomarker group: generic/original sevoflurane = 44/47). Adverse reactions were monitored for 72 hours after discontinuation of sevoflurane use. Generic sevoflurane contained in glass bottles was stable for 3 months. The mean MAC was similar for generic and original sevoflurane (median [range], 0.93 [0.67-1.29] vs 0.94 [0.63-1.5] vol%). Adverse event rates were similar (90.3% vs 84.3%), as were the AUClast of inorganic fluoride (333.7 [112.7-1264.7] vs 311.9 [81.5-1266.5] hours·μmol/L) and compound A (51.8 [6.3-204.5] vs 55.3 [10.8-270.6] hours·ppm). Biomarkers associated with renal injury were not significantly different between the 2 formulations. No significant difference was found in the mean MAC between generic and original sevoflurane. ClinicalTrials.gov identifier: NCT01096212.


Effects of herbage intake on goat performance in the mediterranean type natural pastures.
This study aimed at identifying changes in natural pastures during the grazing season and investigating the effects of these changes on pasture feeding potential for high yielding dairy goats. During the study, 12 dairy goats were grazed on a 1.5 ha natural pasture for three months from April to June in 2003, 2004 and 2005. The goats were fed 0.5 kg/day of concentrate as a supplement during the grazing season. Botanical composition, herbage production and intake, crude protein (CP), neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents of the pasture were determined. Live weight, milk yield, milk dry matter (DM) and fat content of the goats were monitored. The data were analyzed using a linear model, which evaluated the effects of grazing seasons in each year. Based on the three-year average, 87% of pasture was herbaceous plants and the remaining was shrubs in DM basis with Cistus creticus, Quercus ithaburensis, Pistacia atlantica and Asparagus acutifolius being the major shrub species. The herbage yield in June was significantly lower than in other months in all years (P = 0.001). In all experimental years, the CP content of the pasture decreased but the structural carbohydrates increased as the grazing season proceeded. While live weight was not affected by grazing periods except for 2004 (P = 0.001), milk yield significantly decreased with advancing grazing period (P = 0.001). The results of the present study indicate that natural pasture has a supportive effect in April and May on the milk yield of lactating goats which are in mid-lactation, and suggested that supplementary feeding is required in consecutive grazing periods.


Regulation of jasmonate-mediated plant responses in arabidopsis.
Jasmonates (JAs) are signalling molecules that play a key role in the regulation of metabolic processes, reproduction, and defence against pathogens and insects. JAs regulate responses that are both local and systemic, and which are affected by outputs from signalling pathways regulated by ethylene, salicylic acid and auxin. This is a review of recent advances in our understanding of the regulation of JA perception in Arabidopsis thaliana, the different signalling functions of biologically active JAs, the post-translational control of JA responses leading to substantial transcriptional reprogramming, and the influence of other signalling pathways of systemic JA responses.


Phenotype, specificity, and function of T cell subsets and T cell interactions involved in skin allograft rejection.
In the present study we used an adoptive transfer model with athymic nude mice to characterize the T cells involved in initiating and mediating skin allograft rejection. It was found that skin allograft rejection in nude mice required the transfer of immunocompetent T cells and that such reconstitution did not itself stimulate the appearance of T cells derived from the nude host. Reconstitution with isolated populations of Lyt-2+/L3T4- T cells resulted in the rapid rejection of MHC class I-disparate skin allografts, whereas reconstitution with isolated populations of L3T4+/Lyt-2- T cells resulted in the rapid rejection of MHC class II-disparate and minor H-disparate skin allografts. By correlating these rejection responses with the functional capabilities of antigen-specific T cells contained within the reconstituting Lyt-2+ and L3T4+ T cell populations, it was noted that skin allografts were only rejected by mice that, as shown by in vitro assessment, contained both lymphokine-secreting Th cells and lymphokine-responsive Tk cells specific for the alloantigens of the graft. The ability of two such functionally distinct T cell subsets to interact in vivo to reject skin allografts was directly demonstrated in H-Y-specific rejection responses by taking advantage of the fact that H-Y-specific Th cells are L3T4+ while H-Y specific Tk cells are Lyt-2+. Finally, the importance of in vivo interactions between functionally distinct Th/T-inducer cells and T killer (Tk)/T-effector cells in skin allograft rejection was demonstrated by the observation that normal B6 mice retain Qala and Kbm6 skin allografts because of a selective deficiency in antigen-specific Th cells, even though they contain T-effector cells that, when activated, are able to reject such allografts. Thus, the ability to reject skin allografts is neither unique to a specialized subset of T cells with a given Lyt phenotype, nor unique to a specialized subset of helper-independent effector T cells with so-called dual function capability. Rather, skin allograft rejection can be mediated by in vivo collaborations between T-inducer cells and T-effector cells, and the two interacting T cell subsets can express different Lyt phenotypes as well as different antigen specificities.


Reproducibility of near-infrared spectroscopy measurements of oxidative function and postexercise recovery kinetics in the medial gastrocnemius muscle.
The purpose of this study was to assess the reproducibility of resting blood flow, resting oxygen consumption, and mitochondrial capacity in skeletal muscle using near-infrared spectroscopy (NIRS). We also determined the influence of 2 exercise modalities (ergometer and rubber exercise bands) on the NIRS measurements. Fifteen young, healthy participants (5 female, 10 male) were tested on 2 nonconsecutive occasions within an 8-day period. The NIRS device was placed on the medial gastrocnemius. Venous and arterial occlusions were performed to obtain blood flow and oxygen consumption. A series of repeated arterial occlusions was used to measure the recovery kinetics of muscle oxygen consumption after ∼7-10 s of voluntary plantar flexion exercise. Resting blood flow had mean coefficients of variation (CV) of 42% and 38% for bands and ergometer, respectively, and resting metabolism had mean CVs of 17% and 12% for bands and ergometer, respectively. The recovery time constant of oxygen consumption (day 1 bands and ergometer: 23.2 ± 3.7 s, 27.6 ± 6.5 s, respectively; day 2 bands and ergometer: 25.5 ± 5.4 s, 25.0 ± 4.9 s, respectively) had mean CVs of 10% and 11% for bands and ergometer, respectively. We conclude that measurements of oxygen consumption and mitochondrial capacity using NIRS can be obtained with good reproducibility.


Candidate genes for COPD in two large data sets.
Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV₁) % predicted and FEV₁/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV₁ % predicted and FEV₁/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.


Using discrete choice experiments to elicit the service preferences of people with mild intellectual disability: An exploratory study.
The National Disability Insurance Scheme (NDIS) in Australia and other similar international movements towards consumer direction have highlighted the importance of including consumers to ensure their service preferences are operationalised. Discrete Choice Experiments (DCEs) are an established method to quantify consumer preferences. The feasibility of using DCEs with people with intellectual disability is largely untested. Consenting participants eligible for disability support services (n = 18) participated in the mixed methods exploratory study. The DCE comprised a series of choices between two hypothetical service providers offering a combination of services relating to social and economic participation (e.g. support with finding and keeping a job), with four levels of service (no service, online support, group support, one to one support). Pictographs and simplified English were used to represent the hypothetical services and levels and a 'think aloud' protocol adopted. Most participants (N = 16, 89%) completed the DCE task. The findings from the think aloud task indicated that some participants were weighing up the options and making decisions based on their goals and personal preferences. However, other participants did not focus on all presented attributes and levels when making a decision; a common 'short-cut' heuristic also observed in DCE tasks with general population participants. Further research including investigating other DCE techniques, such as best-worst scaling, would be beneficial to identify how preference-elicitation tasks can be developed and applied with people with intellectual disabilities to ensure that future service innovations are designed and administered in ways which best meet their needs and preferences.


Sertoli cell only syndrome (SECOS): lessons from case studies.
Between June 85 and December 87, 69 testicular biopsies were submitted for histopathological examination during investigation of infertility; ten (14%) patients had a Sertoli cell only syndrome. The history, clinical features, and hormonal profiles were analyzed in an attempt to categorize these patients on aetiological basis. Two followed treatment of malignancy--one by radiation for testicular cancer and one by cyclophosphamide for a lymphoma. One had unilateral cryptorchidism. Mumps was etiological factor in one patient. FSH levels determined in 6 patients were elevated in all suggesting a possible dependence of (sick) Sertoli cells on spermatogenic cells for production of inhibin. Alternative explanations include changes in sertoli cell enzymes or FSH receptors. Testosterone levels are in the low normal range suggesting that Leydig cells may also be affected by the etiological factor producing the syndrome. Two patients who had earlier received a higher Johansen score were found to have a sertoli cell only syndrome on expert review of testicular biopsies. It is suggested that the condition is more common than hitherto reported and is often confused with maturation arrest. Testicular histopathology should be done by specialists in testicular pathology.


Cloning of m-fluorophenylalanine-resistant gene and mutational analysis of feedback-resistant prephenate dehydratase from Corynebacterium glutamicum.
Corynebacterium glutamicum was mutated by nitrosoguanidine and five m-fluorophenylalanine (mFP)-resistant mutants were isolated. The mutants were resistant to phenylalanine-mediated feedback inhibition of the prephenate dehydratase activity. Cloning and characterization of the mFP-resistant gene revealed that mutant prephenate dehydratase, encoded by the phe A gene, confers the mFP-resistant phenotype upon C. glutamicum. To determine the amino acid residues to which variation may result in the feedback resistance of prephenate dehydratase, the phe A gene was modified by site-directed mutagenesis and the activities of mutant enzymes were assayed in the presence of phenylalanine. The data indicated that Arg-202 and Gly-224 located at the C-terminal region of prephenate dehydratase were important residues regarding the feedback resistance. Variations of these residues rendered the enzyme insensitive to phenylalanine inhibition. The results also suggested that Gly-224 may reside at the entrance of phenylalanine-binding pocket.


Social frailty in older adults: a scoping review.
Social frailty is a rather unexplored concept. In this paper, the concept of social frailty among older people is explored utilizing a scoping review. In the first stage, 42 studies related to social frailty of older people were compiled from scientific databases and analyzed. In the second stage, the findings of this literature were structured using the social needs concept of Social Production Function theory. As a result, it was concluded that social frailty can be defined as a continuum of being at risk of losing, or having lost, resources that are important for fulfilling one or more basic social needs during the life span. Moreover, the results of this scoping review indicate that not only the (threat of) absence of social resources to fulfill basic social needs should be a component of the concept of social frailty, but also the (threat of) absence of social behaviors and social activities, as well as (threat of) the absence of self-management abilities. This conception of social frailty provides opportunities for future research, and guidelines for practice and policy.


Geochemical exploration for petroleum.
Geochemical methods used in exploring for oil and natural gas are based on the premise that hydrocarbons migrate upward from subsurface petroleum accumulations and produce anomalous patterns near the surface. Geochemical exploration techniques are both direct or indirect. Direct techniques require analysis of microquantities of hydrocarbons that occur in the free state in the soil interstices or that are adsorbed on the fine-grained portions of the soil. Indirect geochemical methods are based on the detection, in near-surface soils or in vegetation, of inorganic alteration products that result from upward migration of hydrocarbons.


Risk Factors for Pediatric Extubation Failure: The Importance of Respiratory Muscle Strength.
Respiratory muscle weakness frequently develops during mechanical ventilation, although in children there are limited data about its prevalence and whether it is associated with extubation outcomes. We sought to identify risk factors for pediatric extubation failure, with specific attention to respiratory muscle strength. Secondary analysis of prospectively collected data. Tertiary care PICU. Four hundred nine mechanically ventilated children. Respiratory measurements using esophageal manometry and respiratory inductance plethysmography were made preextubation during airway occlusion and on continuous positive airway pressure of 5 and pressure support of 10 above positive end-expiratory pressure 5 cm H2O, as well as 5 and 60 minutes postextubation. Thirty-four patients (8.3%) were reintubated within 48 hours of extubation. Reintubation risk factors included lower maximum airway pressure during airway occlusion (aPiMax) preextubation, longer length of ventilation, postextubation upper airway obstruction, high respiratory effort postextubation (pressure rate product, pressure time product, tension time index), and high postextubation phase angle. Nearly 35% of children had diminished respiratory muscle strength (aPiMax ≤ 30 cm H2O) at the time of extubation, and were nearly three times more likely to be reintubated than those with preserved strength (aPiMax > 30 cm H2O; 14% vs 5.5%; p = 0.006). Reintubation rates exceeded 20% when children with low aPiMax had moderately elevated effort after extubation (pressure rate product > 500), whereas children with preserved aPiMax had reintubation rates greater than 20% only when postextubation effort was very high (pressure rate product > 1,000). When children developed postextubation upper airway obstruction, reintubation rates were 47.4% for those with low aPiMax compared to 15.4% for those with preserved aPiMax (p = 0.02). Multivariable risk factors for reintubation included acute neurologic disease, lower aPiMax, postextubation upper airway obstruction, higher preextubation positive end-expiratory pressure, higher postextubation pressure rate product, and lower height. Neuromuscular weakness at the time of extubation was common in children and was independently associated with reintubation, particularly when postextubation effort was high.


Low-dose glucocorticoids maintain Na-H exchange in distal colon of adrenalectomized rats.
With in vivo perfusion we demonstrated that physiological doses of glucocorticoids restore Na and Cl absorption in adrenalectomized rat colon. The absorption is spironolactone and amiloride resistant and is inhibited by the Na-H inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA), suggesting that glucocorticoids modulate Na-H antiport. The present in vitro study examines pathways mediated by glucocorticoids in adrenalectomized rat distal colon and rectum. In vivo administration of 2.5 micrograms/100 g body wt dexamethasone did not alter serosal-to-mucosal flux or tissue electrical parameters but restored mucosal-to-serosal flux and net Na and Cl absorption within 2-3 h of administration to levels found in intact rat colon. Transport was not inhibited by 10(-5) M amiloride but was eliminated by 10(-5) M EIPA. After 26 h of dexamethasone, an amiloride-resistant short-circuit current was stimulated, accompanied by increased residual ion flux in rectum, but not distal colon, suggesting that a delayed or secondary effect of glucocorticoids is stimulation of electrogenic anion secretion. Thus adrenalectomy reduces net ion flux in distal colon by its effect on electroneutral mucosal-to-serosal NaCl flux. Small doses of glucocorticoids completely ameliorate this effect via stimulation of the Na-H antiport. Glucocorticoids maintain basal electroneutral NaCl absorption in distal rat colon.


Practice, supervision, consultancy and appraisal: a continuum of learning.
I examine four different kinds of learning conversation: reflective practice, clinical supervision, work consultancy and performance appraisal. I propose that there is a close and reciprocal relationship between these kinds of conversation, and that they represent different aspects of a unified field, or continuum. I argue that appraisal should be seen as part of this learning continuum rather than as form of monitoring.


Beneficial soil-borne bacteria and fungi: a promising way to improve plant nitrogen acquisition.
Nitrogen (N) is an essential element for plant productivity, thus, it is abundantly applied to the soil in the form of organic or chemical fertilizers that have negative impacts on the environment. Exploiting the potential of beneficial microbes and identifying crop genotypes that can capitalize on symbiotic associations may be possible ways to significantly reduce the use of N fertilizers. The best-known example of symbiotic association that can reduce the use of N fertilizers is the N2-fixing rhizobial bacteria and legumes. Bacterial taxa other than rhizobial species can develop associative symbiotic interactions with plants and also fix N. These include bacteria of the genera Azospirillum, Azotobacter, and Bacillus, some of which are commercialized as bio-inoculants. Arbuscular mycorrhizal fungi are other microorganisms that can develop symbiotic associations with most terrestrial plants, favoring access to nutrients in a larger soil volume through their extraradical mycelium. Using combinations of different beneficial microbial species is a promising strategy to boost plant N acquisition and foster a synergistic beneficial effect between symbiotic microorganisms. Complex biological mechanisms including molecular, metabolic, and physiological processes dictate the establishment and efficiency of such multipartite symbiotic associations. In this review, we present an overview of the current knowledge and future prospects regarding plant N nutrition improvement through the use of beneficial bacteria and fungi associated with plants, individually or in combination.


Growth changes in the thoracic aorta of the piglet following patch angioplasty.
Patch repair of the thoracic aorta using prosthetic graft material in neonates and infants has been advocated, but long-term results have not confirmed that the residual aorta grows. In this study five piglets had portions of aortic tissue excised, ranging from 38% to 72% of the aortic wall. Each pig underwent patch angioplasty repair of the thoracic aorta with prosthetic graft material. Piglets achieved full growth at approximately six months. Aortic catheterization and contrast angiography were done in each animal before it was killed. Growth and histologic study of the aorta was documented at postmortem examination. There were no blood pressure gradients at rest or with isoproterenol hydrochloride (Isuprel)-epinephrine challenge in four of the five piglets. In one animal that underwent a 72% resection of the aortic circumference, a 20-mm gradient was present at rest. It was concluded that the thoracic aorta in piglets will grow adequately to allow patch grafting of up to 70% of the aortic circumference.


Detecting rare asymmetrically methylated cytosines and decoding methylation patterns in the honeybee genome.
Context-dependent gene expression in eukaryotes is controlled by several mechanisms including cytosine methylation that primarily occurs in the CG dinucleotides (CpGs). However, less frequent non-CpG asymmetric methylation has been found in various cell types, such as mammalian neurons, and recent results suggest that these sites can repress transcription independently of CpG contexts. In addition, an emerging view is that CpG hemimethylation may arise not only from deregulation of cellular processes but also be a standard feature of the methylome. Here, we have applied a novel approach to examine whether asymmetric CpG methylation is present in a sparsely methylated genome of the honeybee, a social insect with a high level of epigenetically driven phenotypic plasticity. By combining strand-specific ultra-deep amplicon sequencing of illustrator genes with whole-genome methylomics and bioinformatics, we show that rare asymmetrically methylated CpGs can be unambiguously detected in the honeybee genome. Additionally, we confirm differential methylation between two phenotypically and reproductively distinct castes, queens and workers, and offer new insight into the heterogeneity of brain methylation patterns. In particular, we challenge the assumption that symmetrical methylation levels reflect symmetry in the underlying methylation patterns and conclude that hemimethylation may occur more frequently than indicated by methylation levels. Finally, we question the validity of a prior study in which most of cytosine methylation in this species was reported to be asymmetric.


Effects of low intensity laser in in vitro bacterial culture and in vivo infected wounds.
to compare the effects of low intensity laser therapy on in vitro bacterial growth and in vivo in infected wounds, and to analyze the effectiveness of the AsGa Laser technology in in vivo wound infections. in vitro: Staphylococcus aureus were incubated on blood agar plates, half of them being irradiated with 904 nm wavelength laser and dose of 3J/cm² daily for seven days. In vivo: 32 male Wistar rats were divided into control group (uninfected) and Experimental Group (Infected). Half of the animals had their wounds irradiated. in vitro: there was no statistically significant variation between the experimental groups as for the source plates and the derived ones (p>0.05). In vivo: there was a significant increase in the deposition of type I and III collagen in the wounds of the infected and irradiated animals when assessed on the fourth day of the experiment (p=0.034). low-intensity Laser Therapy applied with a wavelength of 904 nm and dose 3J/cm² did not alter the in vitro growth of S. aureus in experimental groups; in vivo, however, it showed significant increase in the deposition of type I and III collagen in the wound of infected and irradiated animals on the fourth day of the experiment.


Experiences from the use of twenty-four precordial chest leads in suspected acute myocardial infarction.
In 671 patients with suspected acute myocardial infarction (MI) and no previous MI, precordial mapping with a grid containing 24 chest leads was performed within a few hours (mean = 4.8 hours; range 0-42 hours) after arrival in hospital and four days later. In 76% of the patients the criteria for definite MI, based on serum enzymes and a 12 lead standard electrocardiogram, were fulfilled. Among patients classified as having no definite MI, 2% had abnormal Q-waves on mapping on the fourth day; among patients classified as having a subendocardial MI (no abnormal Q-waves in the 12 standard leads), 7% had abnormal Q-waves on mapping on the fourth day. In patients who subsequently developed anterior MI, changes in the sum of Q-waves and the sum of R-waves were observed for more than 12 hours after onset of pain. ST-elevations defined from a normal population were seen in the initial recording in 60% of patients with anterior MI. Among those in whom the first recording was performed less than or equal to 4 hours after onset of pain, ST elevation was initially seen in 72%. A positive correlation was observed between the initial ST elevation and severity of chest pain, incidence of congestive heart failure and two-year mortality rate. We thus conclude that some further information regarding presence of Q-waves can be obtained in about 5% of patients with suspected acute MI from an increased number of precordial leads.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of proton pump inhibitors and dual antiplatelet therapy cessation on outcomes following percutaneous coronary intervention: Results From the PARIS Registry.
Proton pump inhibitors (PPI) may decrease the availability of clopidogrel by competitive antagonism, leading to a potential increase in ischemic events. We evaluated patients from the all-comer PARIS registry treated with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel following coronary stenting for outcomes stratified by PPI use. Two-year major adverse cardiovascular events (MACE), composite of cardiac death, myocardial infarction, definite or probable stent thrombosis or target lesion revascularization (TLR), and net adverse cardiac events (NACE), composite of MACE or Bleeding Academic Research consortium (BARC) type 3 or 5 bleeding were assessed. We also explored associations between PPI use and patterns of 2-year DAPT cessation. The cohort comprised 4635 patients (23% PPI users) with mean age 64.4 ±11.4 years. Two year adjusted risk of MACE (HR: 1.27, 95% CI: 1.04-1.55), NACE (HR: 1.21, 95% CI: 1.01-1.44) and TLR (HR: 1.33, 95% CI: 1.04-1.71) were significantly higher in PPI users vs. non-users, without a difference in bleeding. Although the incidence of 2-year DAPT discontinuation and interruption was similar, DAPT disruption was significantly lower among PPI users vs. non-users (10.0% vs. 14.7%, P <0.0001). Compared to non-PPI users on continued DAPT, disruption was associated with higher MACE in both PPI users (HR: 2.34, 95% CI: 1.38-3.97) and non-users (HR: 1.41, 95% CI: 1.02-1.94) but greater BARC 3,5 bleeding only in non-PPI users (HR: 2.06, 95% CI: 1.21-3.51). In clopidogrel treated PCI patients, the 2-year adjusted risk of MACE and NACE was significantly higher in PPI users driven by higher TLR compared to non-PPI users, without a difference in bleeding. PPI use was associated with lower incidence of DAPT disruption without an increase in disruption related bleeding compared to non-PPI users on DAPT. © 2016 Wiley Periodicals, Inc.


Disentangling the perturbational effects of amino acid substitutions in the DNA-binding domain of p53.
The spectrum of somatic cancer-associated missense mutations in the human TP53 gene was studied in order to assess the potential structural and functional importance of various intra-molecular properties associated with these substitutions. Relating the observed frequency of particular amino acid substitutions in the p53 DNA-binding domain to their expected frequency, as calculated from DNA sequence-dependent mutation rates, yielded estimates of their relative clinical observation likelihood (RCOL). Several biophysical properties were found to display significant covariation with RCOL values. Thus RCOL values were observed to decrease with increasing solvent accessibility of the substituted residue and with increasing distance from the p53 DNA-binding and Zn2+ -binding sites. The number of adverse steric interactions introduced by an amino acid replacement was found to be positively correlated with its RCOL value, irrespective of the magnitude of the interactions. A gain in hydrogen bond number was found to be only half as likely to come to clinical attention as mutations involving either a reduction or no change in hydrogen bond number. When the difference in potential energy between the wild-type and mutant DNA-binding domains was considered, RCOL values exhibited a minimum around changes of zero. Finally, classification of mutated residues in terms of their protein/solvent environment yielded, for somatic p53 mutations, RCOL values that resembled those previously determined for inherited mutations of human factor IX causing haemophilia B, suggesting that similar mechanisms may be responsible for the mutation-related perturbation of biological function in different protein folds.


Identification of the source of nitrate contamination in ground water below an agricultural site, Jeungpyeong, Korea.
This study applied hydrogeological characterization and isotope investigation to identify source locations and to trace a plume of ground water contaminated by nitrate. Most of the study site is agricultural fields with the remainder being residential. A poultry farm is also within the study area, so that potential point and nonpoint sources were present. Estimates of seasonal ground water recharge from irrigation and precipitation, leakage of sewage, and the regional ground water flow were linked to the seasonal changes in isotopic values. Ground water recharge largely occurred in spring and summer following precipitation or irrigation, depending on the locations. Natural and fertilized soils were identified as nonpoint sources of nitrate contamination in this area, while septic and animal wastes were identified as small point sources. The seasonal changes in the relative impact of these sources on ground water contamination were related to such factors as source distribution, the aquifer confining condition, precipitation rate, infiltration capacity, recharge rate, and the land use pattern.


Effect of a valine-rich diet on a rat model of short bowel syndrome.
It has been recently reported that valine, which was one of the branched chain amino acids, enhanced liver regeneration after a hepatectomy in rats. The aim of this study is to investigate the effect of enteral valine supplementation on the intestinal adaptation of short bowel syndrome using a rat model. Seven-week-old male Lewis rats underwent a 90% small bowel resection. The rats were randomly divided into two groups; Group V (valine-rich diet which contains valine, five times as the normal amount of valine as that found in standard rat chow) and Group S (standard rat chow), according to the diet each group received. The rats were killed and evaluated at the operative day, and postoperative days (POD) 7, 14, 30, and 60, respectively. The parameters of estimation were body weight (BW), a blood amino acids analysis, a urine organic acids analysis and a morphological examination of the residual small intestines. The BW and the intestinal wet weight, jejunal crypt depth and proliferating cell nuclear antigen positive cells in Group V at POD 7 were significantly higher than in Group S, while those in the Group V at POD 30 and 60 were smaller than in Group S. The urine methylmalonic acid (MMA) level in Group V at POD 30 and 60 was much higher than in Group S. The valine-rich diet was thus found to enhance intestinal regeneration after a small bowel resection in the acute phase. However, the long-term valine-rich diet supplementation was found to disturb the intestinal adaptation, which might be caused by the high production of MMA due to the valine-rich diet. This is the first report in which valine was used as a promoter of intestinal adaptation.


Isolation and analysis of six timeless alleles that cause short- or long-period circadian rhythms in Drosophila.
In genetic screens for Drosophila mutations affecting circadian locomotion rhythms, we have isolated six new alleles of the timeless (tim) gene. Two of these mutations cause short-period rhythms of 21-22 hr in constant darkness, and four result in long-period cycles of 26-28 hr. All alleles are semidominant. Studies of the genetic interactions of some of the tim alleles with period-altering period (per) mutations indicate that these interactions are close to multiplicative; a given allele changes the period length of the genetic background by a fixed percentage, rather than by a fixed number of hours. The tim(L1) allele was studied in molecular detail. The long behavioral period of tim(L1) is reflected in a lengthened molecular oscillation of per and tim RNA and protein levels. The lengthened period is partly caused by delayed nuclear translocation of TIM(L1) protein, shown directly by immunocytochemistry and indirectly by an analysis of the phase response curve of tim(L1) flies.


Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.
In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. Randomized, double-blind, placebo-controlled trial with blinded joint assessors. 13 North American centers. 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.


Antagonistic effect of helpers on breeding male and female survival in a cooperatively breeding bird.
1. Cooperatively breeding species are typically long lived and hence, according to theory, are expected to maximize their lifetime reproductive success through maximizing survival. Under these circumstances, the presence of helpers could be used to lighten the effort of current reproduction for parents to achieve higher survival. 2. In addition, individuals of different sexes and ages may follow different strategies, but whether male and female breeders and individuals of different ages benefit differently from the presence of helpers has often been overlooked. Moreover, only one study that investigated the relationship between parental survival and the presence of helpers used capture-mark-recapture analyses (CMR). These methods are important since they allow us to account for the non-detection of individuals that are alive in the population but not detected, and thus, the effects on survival and recapture probability to be disentangled. 3. Here, we used multi-event CMR methods to investigate whether the number of helpers was associated with an increase in survival probability for male and female breeders of different ages in the sociable weaver Philetairus socius. In this species, both sexes reduce their feeding rate in the presence of helpers. We therefore predicted that the presence of helpers should increase the breeders' survival in both sexes, especially early in life when individuals potentially have more future breeding opportunities. In addition, sociable weaver females reduce their investment in eggs in the presence of helpers, so we predicted a stronger effect of helpers on female than male survival. 4. As expected we found that females had a higher survival probability when breeding with more helpers. Unexpectedly, however, male survival probability decreased with increasing number of helpers. This antagonistic effect diminished as the breeders grew older. 5. These results illustrate the complexity of fitness costs and benefits underlying cooperative behaviours and how these may vary with the individuals' sex and age. They also highlight the need for further studies on the sex-specific effects of helpers on survival.


Variables Affecting Intra-abdominal Pressure During Lifting in the Early Postpartum Period.
Intra-abdominal pressure (IAP) may contribute to pelvic floor health, although the direction and magnitude of such an effect, if any, are not yet known. Identifying individual characteristics, and in particular modifiable factors, associated with higher IAP during recovery from vaginal childbirth might serve to mitigate early pelvic floor dysfunction. The aim of this study was to identify characteristics associated with maximal IAP during lifting in postpartum primiparous women who delivered vaginally. At 6 to 10 weeks postpartum, we measured maximal IAP, assessed via an upper vaginal sensor, as participants (enrolled in an ongoing cohort study) lifted a weighted car seat (12.5 kg). We evaluated whether the following independent variables were associated with maximal IAP: age, ethnicity, body mass index, height, abdominal circumference, weight gain during pregnancy, lifting time, breath holding during lifting, lifting technique, measures of muscular fitness, and days since delivery. In the 206 participants, weight, waist circumference, body mass index, and days since delivery were positively associated with mean maximal IAP during lifting, whereas IAP decreased as height increased. As the duration of the lifting task increased, mean maximal IAP during lifting also increased, but there were no associations between lifting technique or breath holding during lifting and IAP. Neither pelvic floor muscle strength nor abdominal muscle endurance was associated with IAP during lifting. Other than measures of body habitus and lifting duration, we did not identify modifiable factors that could mitigate maximal pressures experienced by the pelvic floor during the early postpartum period.


The effect of education on health among US residents in relation to country of birth.
This research explores the impact of education on health in relation to an individual's country of birth using the US National Health and Nutrition Examination Surveys for 2001-2004. We analyze health equations that relate health to education and other variables. Health is measured in terms of self-reported overall health, an index of biological risk factors, and body mass index. The primary hypothesis tested is whether education has a greater impact on immigrants' productive and allocative efficiency, because of their need to learn about how to remain healthy and access appropriate health care in a new environment. The empirical results indicate that for US residents, who were foreign-born, education is associated with a greater beneficial effect on every health outcome compared to those born in the United States. More education is related to an even greater positive effect on health for immigrants from Mexico, the origin of most immigrants, than from other countries. These results provide additional support for the portions of the 2007 Immigration Reform Act rejected by the US Congress, which placed a higher priority on education and job skills than current law. Since increased education and improved health are associated, such policy reform would help reduce the demands on the US health-care system.


Eag1 channels as potential cancer biomarkers.
Cancer is a leading cause of death worldwide. New early tumor markers are needed to treat the disease at curable stages. In addition, new therapeutic targets are required to treat patients not responding to available treatments. Ion channels play major roles in health and disease, including cancer. Actually, several ion channels have been suggested as potential tumor markers and therapeutic targets for different types of malignancies. One of most studied ion channels in cancer is the voltage-gated potassium channel Eag1 (ether à go-go 1), which has a high potential to be used as a cancer biomarker. Eag1 is expressed in most human tumors, in contrast to its restricted distribution in healthy tissues. Several findings suggest Eag1 as a potential early marker for cervical, colon, and breast cancer. In addition, because Eag1 amplification/expression is associated with poor survival in leukemia, colon and ovarian cancer patients, it has also been proposed as a prognosis marker. Moreover, inhibition of either expression or activity of Eag1 leads to reduced proliferation of cancer cells, making Eag1 a potential anticancer target. Using Eag1 in cancer detection programs could help to reduce mortality from this disease.


Life Cycle Assessment and Release Studies for 15 Nanosilver-Enabled Consumer Products: Investigating Hotspots and Patterns of Contribution.
Increasing use of silver nanoparticles (AgNPs) in consumer products as antimicrobial agents has prompted extensive research toward the evaluation of their potential release to the environment and subsequent ecotoxicity to aquatic organisms. It has also been shown that AgNPs can pose significant burdens to the environment from life cycle emissions associated with their production, but these impacts must be considered in the context of actual products that contain nanosilver. Here, a cradle-to-gate life cycle assessment for the production of 15 different AgNP-enabled consumer products was performed, coupled with release studies of those same products, thus providing a consistent analytical platform for investigation of potential nanosilver impacts across a range of product types and concentrations. Environmental burdens were assessed over multiple impact categories defined by the United States Environmental Protection Agency's Tool for the Reduction and Assessment of Chemical and Other Environmental Impacts (TRACI 2.1) method. Depending on the product composition and silver loading, the contribution of AgNP synthesis to the overall impacts was seen to vary over a wide range from 1% to 99%. Release studies found that solid polymeric samples lost more silver during wash compared to fibrous materials. Estimates of direct ecotoxicity impacts of AgNP releases from those products with the highest leaching rates resulted in lower impact levels compared to cradle-to-gate ecotoxicity from production for those products. Considering both cradle-to-gate production impacts and nanoparticle release studies, in conjunction with estimates of life cycle environmental and health benefits of nanoparticle incorporation, can inform sustainable nanoenabled product design.


Seminoma with conspicuous signet ring cells: a rare, previously uncharacterized morphologic variant.
We report 2 seminomas with conspicuous numbers of signet ring cells. The tumors occurred in men, 24 and 69 years of age, who presented with testicular masses; 1 seminoma was a component of a mixed germ cell tumor and the other was pure. The signet ring cells occurred in a multifocal fashion in areas of otherwise typical seminoma and comprised approximately 70% and 10%, respectively, of the tumors. They had large, translucent to clear cytoplasmic vacuoles that compressed the nuclei to a peripheral crescent. In 1 case, the vacuoles contained numerous refractile, nonpolarizable globular deposits that were shown to be glycogen on the basis of periodic acid-Schiff stain positivity that was abolished by pretreatment with diastase; in the second case, they mostly appeared "empty" and lacked periodic acid-Schiff positivity. The signet ring cells were mucicarmine, cytokeratin (AE1/3) and alpha-fetoprotein negative, but positive for OCT3/4 and CD117, the latter 2 being expected for seminoma cells. A review of 30 randomly selected seminomas identified very rare, inconspicuous signet ring cells in 43%. The presence of prominent signet ring cells in seminoma may cause confusion as it has not been described previously in detail, and a variety of neoplasms, particularly metastasis, may be considered. The description of this phenomenon expands the known morphologic spectrum of the most common testicular neoplasm.


Translational pharmacokinetic-pharmacodynamic modeling for an orally available novel inhibitor of anaplastic lymphoma kinase and c-Ros oncogene 1.
An orally available macrocyclic small molecule, PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile], is a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-Ros oncogene 1 (ROS1). The objectives of the present study were to characterize the pharmacokinetic-pharmacodynamic relationships of PF06463922 between its systemic exposures, pharmacodynamic biomarker (target modulation), and pharmacologic response (antitumor efficacy) in athymic mice implanted with H3122 non-small cell lung carcinomas expressing echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutation (EML4-ALK(L1196M)) and with NIH3T3 cells expressing CD74-ROS1. In these nonclinical tumor models, PF06463922 was orally administered to animals with EML4-ALK(L1196M) and CD74-ROS1 at twice daily doses of 0.3-20 and 0.01-3 mg/kg per dose, respectively. Plasma concentration-time profiles of PF06463922 were adequately described by a one-compartment pharmacokinetic model. Using the model-simulated plasma concentrations, a pharmacodynamic indirect response model with a modulator sufficiently fit the time courses of target modulation (i.e., ALK phosphorylation) in tumors of EML4-ALK(L1196M)-driven models with EC50,in vivo of 36 nM free. A drug-disease model based on an indirect response model reasonably fit individual tumor growth curves in both EML4-ALK(L1196M)- and CD74-ROS1-driven models with the estimated tumor stasis concentrations of 51 and 6.2 nM free, respectively. Thus, the EC60,in vivo (52 nM free) for ALK inhibition roughly corresponded to the tumor stasis concentration in an EML4-ALK(L1196M)-driven model, suggesting that 60% ALK inhibition would be required for tumor stasis. Accordingly, we proposed that the EC60,in vivo for ALK inhibition corresponding to the tumor stasis could be considered a minimum target efficacious concentration of PF06463922 for cancer patients in a phase I trial.


High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats.
A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.


MALT1-ubiquitination triggers non-genomic NF-κB/IKK signaling upon platelet activation.
We have recently shown that IKK complex plays an important non-genomic role in platelet function, i.e., regulates SNARE machinery-dependent membrane fusion. In this connection, it is well known that MALT1, whose activity is modulated by proteasome, plays an important role in the regulation of IKK complex. Therefore, the present studies investigated the mechanism by which IKK signaling is regulated in the context of the platelet proteasome. It was found that platelets express a functional proteasome, and form CARMA/MALT1/Bcl10 (CBM) complex when activated. Using a pharmacological inhibitor, the proteasome was found to regulate platelet function (aggregation, integrin activation, secretion, phosphatidylserine exposure and changes in intracellular calcium). It was also found to regulate thrombogenesis and physiologic hemostasis. We also observed, upon platelet activation, that MALT1 is ubiquitinated, and this coincides with the activation of the IKK/NF-κB-signaling pathway. Finally, we observed that the proteasome inhibitor blocks CBM complex formation and the interaction of IKKγ and MALT1; abrogates SNARE formation, and the association of MALT1 with TAK1 and TAB2, which are upstream of the CBM complex. Thus, our data demonstrate that MALT1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing platelet signals to the NF-κB pathway.