Attention-grabbing news coverage: Violent images of the Black Lives Matter movement and how they attract user attention on Reddit.
Portrayals of violence are common in contemporary media reporting; they attract public attention and influence the reader's opinion. In the particular context of a social movement such as Black Lives Matter (BLM), the portrayal of violence in news coverage attracts public attention and can affect the movement's development, support, and public perception. Research on the relationship between digital news content featuring violence and user attention on social media has been scarce. This paper analyzes the relationship between violence in online reporting on BLM and its effect on user attention on the social media platform Reddit. The analysis focuses on the portrayal of violence in images used in BLM-related digital news coverage shared on Reddit. The dataset is comprised of 5,873 news articles with images. The classification of violent images is based on a VGG19 convolutional neural network (CNN) trained on a comprehensive dataset. The results suggest that what significantly affects user attention in digital news content is not the display of violence in images; rather, it is negative article titles, the news outlet's political leanings and level of factual reporting, and platform affordances that significantly affect user attention. Thus, this paper adds to the understanding of user attention distributions online and paves the way for future research in this field.


Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts.
Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokines, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction and chromosome segregation (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors and mitochondrial proteins. Focusing on the virus-host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus-human interaction data. Protein structure analysis further identifies positive selection in the interaction interfaces between viruses and their cellular receptors (CD4-HIV; CD46-measles, adenoviruses; CD55-picornaviruses). Finally, primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positive selection is a rich source for studying the genetics underlying human (antiviral) phenotypes. Procedures and data are available at https://github.com/robinvanderlee/positive-selection.


mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops.
Mammalian target of rapamycin (mTOR) serine threonine kinase is the enzyme that regulates cancer cell growth by altering nutrient supplies to cancer cells. The neuropeptide (proline-rich peptide 1 (PRP-1)), galarmin, produced by the brain neurosecretory cells is a mTOR kinase inhibitor with powerful 80% antiproliferative cytostatic effect in a high-grade chondosarcoma and other mesenchymal tumors. However, the negative feedback loop of phosphatidylinositol 3 kinase-Protein kinase B (PKB), PI3K-AKT and PI3K-rat sarcoma (RAS)-mitogen-activated protein kinase (MAPK) activation is well documented for mTOR inhibitors. This study explored the involvement of those loops in drug resistance after the treatment with mTOR complex 1 (mTORC1) inhibitor, PRP-1. Multidrug resistance assay (MDR) demonstrated that this cytokine did not inhibit permeability glycoprotein-mediated MDR in chondrosarcoma. Phospho-MAPK array in human chondrosarcoma cell line treated with galarmin (10 μg/ml,) showed a strong upregulation of phosphorylated glycogen synthase kinase 3β (GSK3β) via activation of PI3K-AKT and MAPK feedback loops. Such GSK3β inactivation leads to β-catenin accumulation that entails drug resistance. The ability of cells to metastasize is reflected in their capacity to adhere to extracellular matrix and endothelium. Laminin cell adhesion assay demonstrated that PRP-1 in the same concentrations that inhibit mTOR kinase inhibited JJ012 chondrosarcoma cell adhesion. The neuropeptide did not have any effect on the expression of total focal adhesion kinase and its phosphorylated form. Thus, it was not accompanied by total HAT downregulation and total HDAC upregulation. Combinatorial treatments of PRP-1 with MAPK and PI3K/AKT inhibitors most probably will lead to full cytotoxicity overcoming drug resistance.


Preparation of bio-oils by hydrothermal liquefaction (HTL) of penicillin fermentation residue (PR): Optimization of conditions and mechanistic studies.
Response surface methodology (RSM) was used to investigate factors influencing the yield of bio-oil from the hydrothermal liquefaction (HTL) process of penicillin fermentation residue (PR). The reaction mechanism of the HTL was also studied. The hydrolysis of organic compounds in PR was enhanced, and the bio-oil yield increased with an increase of temperature. When the temperature rose from 280 °C to 320 °C, the yield of bio-oil decreased due to condensation and pyrolysis. Both the residence time and total solid content had effects on the bio-oil yield. The predicted values from the RSM model was in good agreement with the experimental values. Optimized conditions showed that the predicted value of the highest bio-oil yield was 25.91 wt%. The optimized reaction conditions were as follows: reaction temperature was 300 °C, residence time was 174 min, and total solid content was 18 wt%. The bio-oil was analyzed by GC-MS, and showed that it consisted mainly of hydrocarbons, nitrogen-containing heterocyclic compounds, and oxygen-containing compounds. Finally, the formation mechanism of these components and their possible reaction paths are presented and discussed. The results will provide useful guidance for regulating the characteristics of antibiotic residues, and realizing their further utilization as a chemical feedstock.


Direct measurement of the amount of bound collagen which stimulates platelet aggregation.
The amount of collagen which binds to platelets has been correlated with aggregating activity in a platelet aggregometer. Aggregating activity requires only 0.22 microgram/ml (0.35 microgram/10(9) cells) of collagen bound, the reaction saturating with 4.9 microgram/ml (7.9 microgram/10(9) cells). On the basis of the fraction of collagen bound and its hydroxyproline/proline ratio, it is concluded that the activity resides in the type I collagen component.


Preparation and characterization of fentanyl-loaded PLGA microspheres: in vitro release profiles.
We developed several kinds of fentanyl-loaded poly(L-lactide-co-glycolide) (PLGA) microspheres (FMS) for sustained release of fentanyl. FMS were prepared by an emulsion solvent-evaporation method. In this study, the influences of several preparation parameters, such as initial drug loading, polymer concentration, and solvent volume on the release patterns of fentanyl were investigated. Furthermore, it has been well noted that the detection of fentanyl is extremely difficult because its clinical dose level is very low, about 1-3 ng/ml, in cancer-patient treatment. Therefore, we also developed a rapid and sensitive determination method for fentanyl in systemic circulation by employing gas chromatography (GC) system. Fentanyl was slowly released from FMS over 15 days with a quasi-zero order property. From the results, our FMS may be good formulations to deliver the analgesics and suitable for the treatment of severe pain over long periods.


Oxaliplatin-induced peripheral neuropathy can be minimized by pressurized regional intravascular delivery in an orthotopic murine pancreatic cancer model.
There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.


Community-based preventive medical department for individual risk factor assessment and intervention in an urban population.
In Malmö, a southern Swedish city of about 230,000 inhabitants, an institute of preventive medicine within the medical department of Malmö General Hospital has been in operation since 1975. It is directed against the major middle-aged internal medical health risks and complications such as cardiovascular diseases, diabetes mellitus, and alcohol complications, and contains both screening and intervention resources, mediated predominantly by an individually orientated approach both in the function of the department and in the preventive medical actions. The design, feasibility, and some of the quantitative results of the program are described.


Covalent modification of DNA by daunorubicin.
Daunorubicin, a clinically useful antitumor agent, induces mammary adenocarcinoma in Sprague-Dawley rats. As part of an investigation of the mechanism of tumor induction by daunorubicin, the formation of daunorubicin-DNA adducts has been investigated by 32P-postlabeling assay. Rat-liver DNA incubated with either 0.05 or 0.1 mM daunorubicin, rat-liver microsomes, and 5 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) for 1 h contained covalent DNA adducts in addition to the endogenous adduct profile present in control DNA. With 1.5 mM cumene hydroperoxide serving as a cofactor, higher levels of these two adducts and two additional adducts were formed, all of which most likely were daunorubicin-DNA adducts. This latter treatment also resulted in an intensification of three endogenous DNA modifications over levels occurring in control DNA. Covalent DNA alterations in vivo were studied in rats treated with 20 mg/kg daunorubicin for 2 days and 200 mg/kg on the 3rd day. Daunorubicin-DNA adducts as observed in vitro could not be detected in DNA of liver or mammary epithelial cells. The levels of endogenous modifications in drug-treated rats were increased by 200% in mammary DNA and by 50% in hepatic DNA as compared with controls. It was concluded from these experiments that daunorubicin may be metabolically activated to a reactive metabolite that binds covalently to DNA. These daunorubicin-DNA adducts may not play a role in tumor induction because they were not detectable in vivo. However, the increase in levels of endogenous DNA modifications induced by daunorubicin both in vitro and in vivo is consistent with a role of this class of DNA modification in the carcinogenic process.


Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes.
In latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), viral gene expression is extremely limited and copy numbers of viral genomes remain constant. Latency-associated nuclear antigen (LANA) is known to have a role in maintaining viral genome copy numbers in growing cells. Several studies have shown that LANA is localized in particular regions on mitotic chromosomes, such as centromeres/pericentromeres. We independently examined the distinct localization of LANA on mitotic chromosomes during mitosis, using super-resolution laser confocal microscopy and correlative fluorescence microscopy-electron microscopy (FM-EM) analyses. We found that the majority of LANA were not localized at particular regions such as telomeres/peritelomeres, centromeres/pericentromeres, and cohesion sites, but at the bodies of condensed chromosomes. Thus, LANA may undergo various interactions with the host factors on the condensed chromosomes in order to tether the viral genome to mitotic chromosomes and realize faithful viral genome segregation during cell division.


RecET direct cloning and Redαβ recombineering of biosynthetic gene clusters, large operons or single genes for heterologous expression.
Full-length RecE and RecT from Rac prophage mediate highly efficient linear-linear homologous recombination that can be used to clone large DNA regions directly from genomic DNA into expression vectors, bypassing library construction and screening. Homologous recombination mediated by Redαβ from lambda phage has been widely used for recombinant DNA engineering. Here we present a protocol for direct cloning and engineering of biosynthetic gene clusters, large operons or single genes from genomic DNA using one Escherichia coli host that harbors both RecET and Redαβ systems. The pipeline uses standardized cassettes for horizontal gene transfer options, as well as vectors with different replication origins configured to minimize recombineering background through the use of selectively replicating templates or CcdB counterselection. These optimized reagents and protocols facilitate fast acquisition of transgenes from genomic DNA preparations, which are ready for heterologous expression within 1 week.


Sleeveless guided implant placement compared to conventional approaches: An in vitro study at healed sites and fresh extraction sockets.
To investigate the accuracy of a novel sleeveless implant surgical guide by comparing it with a conventional closed-sleeve guide and a freehand approach. Custom resin maxillary casts with corticocancellous compartments were used (n = 30). Seven implant sites were present per maxillary cast, corresponding to healed (right and left first premolars, left second premolar and first molar) and extraction sites (right canine and central incisors). The casts were assigned into three groups: freehand (FH), conventional closed-sleeve guide (CG) and surgical guide (SG) groups. Each group comprised 10 casts and 70 implant sites (30 extraction sites and 40 healed sites). Digital planning was used to design 3D printed conventional and surgical guide templates. The primary study outcome was implant deviation. At extraction sites, the largest difference between groups occurred in angular deviation, where the SG group (3.80 ± 1.67 degrees) exhibited ~1.6 times smaller deviation relative to the FH group (6.02 ± 3.44 degrees; P = 0.004). The CG group (0.69 ± 0.40 mm) exhibited smaller coronal horizontal deviation compared to the SG group (1.08 ± 0.54 mm; P = 0.005). For healed sites, the largest difference occurred for angular deviation, where the SG group (2.31 ± 1.30 degrees) exhibited 1.9 times smaller deviation relative to the CG group (4.42 ± 1.51 degrees; P < 0.001), and 1.7 times smaller deviation relative to the FH group (3.84 ± 2.14 degrees). Significant differences were found for all parameters except depth and coronal horizontal deviation. For the guided groups, there were fewer significant differences between healed and immediate sites compared to the FH group. The novel sleeveless surgical guide showed similar accuracy to the conventional closed-sleeve guide.


Increased prevalence of hypothyroidism among human immunodeficiency virus-infected patients: a need for screening.
The aim of this cross-sectional multicenter study was to determine the prevalence of and risk factors for hypothyroidism in human immunodeficiency virus (HIV)-infected patients. Free T4, free T3, and thyroid-stimulating hormone levels were determined. Data on age, sex, weight variation, smoking status, duration of HIV infection, Centers for Disease Control and Prevention disease stage, CD4 cell count, HIV RNA load, lipodystrophy, HIV-hepatitis C virus coinfection, and antiretroviral treatment (type of drugs and total cumulative dose) were collected. The prevalence study included 350 HIV-infected patients. Sixteen percent of patients had hypothyroidism: 2.6% had overt hypothyroidism, 6.6% had subclinical hypothyroidism, and 6.8% had a low free T4 level. The prevalence of subclinical hypothyroidism was higher among HIV-infected men than among HIV-infected women. A case-control study was conducted that compared hypothyroid (n=56) and euthyroid (n=287) patients. In the multivariate analysis, receipt of stavudine and low CD4 cell count were associated with hypothyroidism. Therefore, screening may be indicated for patients, especially men, who have received stavudine or have decreased CD4 cell counts.


Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia.
Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.


What do foraging hummingbirds maximize?
Hainsworth and Wolf (1976) reported that under certain conditions hummingbirds made food choices which did not maximize their net rate of energy intake while foraging. They concluded that the birds were not foraging optimally. We show here that their birds probably maximized a different utility function, the net energy per unit volume consumed (NEVC), which appears to be an optimal choice on a time scale longer than that of a foraging bout. Our own experiments with Archilochus colubris support the conclusion that hummingbirds make foraging decisions that maximize NEVC. A simulation model shows that, in nature, NEVC maximization would require fewer foraging trips and visits to fewer flowers per day to balance daily energy budgets. For territorial birds this can lead to smaller territory sizes and reduced costs of territorial defense. Plants that evolutionarily increase corolla length to enhance pollinator specificity need only increase nectar concentration slightly to maintain the same net energy per unit volume consumed (NEVC) by a given hummingbird pollinator.


Source attribution of community-acquired cases of Legionnaires' disease-results from the German LeTriWa study; Berlin, 2016-2019.
Sources of infection of most cases of community-acquired Legionnaires' disease (CALD) are unknown. Identification of sources of infection of CALD. Berlin; December 2016-May 2019. Adult cases of CALD reported to district health authorities and consenting to the study; age and hospital matched controls. Percentage of cases of CALD with attributed source of infection. Analysis of secondary patient samples for monoclonal antibody (MAb) type (and sequence type); questionnaire-based interviews, analysis of standard household water samples for Legionella concentration followed by MAb (and sequence) typing of Legionella pneumophila serogroup 1 (Lp1) isolates; among cases taking of additional water samples to identify the infectious source as appropriate; recruitment of control persons for comparison of exposure history and Legionella in standard household water samples. For each case an appraisal matrix was filled in to attribute any of three source types (external (non-residence) source, residential non-drinking water (RnDW) source (not directly from drinking water outlet), residential drinking water (RDW) as source) using three evidence types (microbiological results, cluster evidence, analytical-comparative evidence (using added information from controls)). Inclusion of 111 study cases and 202 controls. Median age of cases was 67 years (range 25-93 years), 74 (67%) were male. Among 65 patients with urine typable for MAb type we found a MAb 3/1-positive strain in all of them. Compared to controls being a case was not associated with a higher Legionella concentration in standard household water samples, however, the presence of a MAb 3/1-positive strain was significantly associated (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7 to 11). Thus, a source was attributed by microbiological evidence if it contained a MAb 3/1-positive strain. A source was attributed by cluster evidence if at least two cases were exposed to the same source. Statistically significant general source types were attributed by calculating the population attributable risk (analytical-comparative evidence). We identified an external source in 16 (14%) cases, and RDW as source in 28 (25%). Wearing inadequately disinfected dentures was the only RnDW source significantly associated with cases (OR = 3.2, 95% CI 1.3 to 7.8) and led to an additional 8% of cases with source attribution, for a total of 48% of cases attributed. Using the appraisal matrix we attributed almost half of all cases of CALD to an infectious source, predominantly RDW. Risk for LD seems to be conferred primarily by the type of Legionella rather than the amount. Dentures as a new infectious source needs further, in particular, integrated microbiological, molecular and epidemiological confirmation.


Small vertebrates running on uneven terrain: a biomechanical study of two differently specialised lacertid lizards.
While running, small animals frequently encounter large terrain variations relative to their body size, therefore, terrain variations impose important functional demands on small animals. Nonetheless, we have previously observed in lizards that running specialists can maintain a surprisingly good running performance on very uneven terrains. The relatively large terrain variations are offset by their capacity for leg adjustability that ensures a 'smooth ride' of the centre of mass (CoM). The question as to how the effect of an uneven terrain on running performance and locomotor costs differs between species exhibiting diverse body build and locomotor specializations remains. We hypothesise that specialized runners with long hind limbs can cross uneven terrain more efficiently than specialized climbers with a dorso-ventrally flattened body and equally short fore and hind limbs. This study reports 3D kinematics using high-speed videos (325 Hz) to investigate leg adjustability and CoM movements in two lacertid lizards (Acanthodactylus boskianus, running specialist; Podarcis muralis, climbing specialist). We investigated these parameters while the animals were running on a level surface and over a custom-made uneven terrain. We analysed the CoM dynamics, we evaluated the fluctuations of the positive and negative mechanical energy, and we estimated the overall cost of transport. Firstly, the results reveal that the climbers ran at lower speeds on flat level terrain but had the same cost of transport as the runners. Secondly, contrary to the running specialists, the speed was lower and the energy expenditure higher in the climbing specialists while running on uneven terrain. While leg movements adjust to the substrates' variations and enhance the stability of the CoM in the running specialist, this is not the case in the climbing specialist. Although their legs are kept more extended, the amplitude of movement does not change, resulting in an increase of the movement of the CoM and a decrease in locomotor efficiency. These results are discussed in light of the respective (micro-)habitat of these species and suggest that energy economy can also be an important factor for small vertebrates.


Fit for Purpose? The Suitability of Oral Health Outcome Measures to Inform Policy.
Oral health research and program evaluation should consider alternative outcome measures for population oral health other than the DMFT index.


Optimising stable retroviral transduction of primary human synovial fibroblasts.
Fibroblast like synoviocytes are the main resident cells in normal joints and are known to play a major role in the pathogenesis of rheumatoid arthritis. Efficient gene targeting of fibroblast like synoviocytes (FLS) is a major goal of current ex vivo gene therapy approaches for the treatment of rheumatoid arthritis. However, there is a need to improve viral systems capable of delivering genes to human rheumatoid fibroblasts and attempts have been made to develop a protocol for high efficiency, reproducible gene transfer using a replication-defective retrovirus vector. The effects of different experimental conditions were examined as well as those related to cellular and viral features on the efficiency of transducing the retroviral-driven expression of enhanced green fluorescent protein (EGFP) to FLS harvested from patients with rheumatoid arthritis. The optimal method established involved a double round of infection by centrifugation with a resting period of 4h between rounds. This approach led to the transduction of 30-70% of FLS obtained from nine patients with rheumatoid arthritis. Consistent transduction efficiencies were achieved in repeat assays such that it could be inferred that the variations observed were attributable to the specific characteristics of each cell line. This simple protocol renders a consistent and reproducible efficiency of rheumatoid fibroblast transduction and makes stable gene targeting using non-replicating retrovirus derived vectors an affordable option for the treatment of rheumatoid arthritis.


The nutritional selectivity of a siderophore-catabolizing bacterium.
The ability of a siderophore-catabolizing bacterium to assimilate ferric ion was examined. While the bacterium utilizes the siderophore deferrioxamine B (DFB) as a carbon source, it was incapable of using the ferric ion analogue (ferrioxamine B) as an iron source. It did, however, assimilate the ferric ion of the chelator ferric nitrilotriacetic acid and of the siderophore ferrirhodotorulic acid (ferriRA). Neither ferriRA nor its deferrated analog (RA), however, were capable of functioning as carbon sources for the bacterium. The microbe thus employs a 'nutritional selectivity' with respect to these two siderophores. That is, it does not use the siderophore it employs as a carbon source (DFB) as an iron source nor does the siderophore utilized as an iron source, i.e. ferriRA, nor its deferrated analog (RA), serve as carbon sources for the organism.


The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis.
To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. NI is a histopathological hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms "pancreatic ductal adenocarcinoma", "pancreatic cancer", "survival", "tumor recurrence" and "perineural invasion". The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71-2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47-1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67-3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73-3.37: p < 0.00001) multivariate meta-analysis. Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.


Inhibition of mitochondrial function affects cellular Ca2+ handling in pancreatic B-cells.
The mitochondrial inhibitors NaN(3) and carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) were used to study the role of mitochondria in pancreatic B-cell Ca2+ homeostasis. In glucose-stimulated B-cells NaN(3) and FCCP both increased the K(ATP) current and thus hyperpolarized the cell membrane potential, as expected for agents depleting cellular ATP. NaN(3) and FCCP stopped the glucose-induced oscillations in the cytosolic free Ca2+ concentration ([Ca2+](c)) and elicited a biphasic response. After a first rapid and transient increase, [Ca2+](c) rose in a second slow phase to a sustained level. In cells pretreated with thapsigargin the first inhibitor-induced rise in [Ca2+](c) was absent, suggesting that it may be due to Ca2+ mobilization from intracellular stores. The glucose-induced oscillations were terminated again by NaN(3) and FCCP, respectively, but the slow increase in [Ca2+](c)of the second phase was still present. A minute increase in [Ca2+](c)elicited by NaN(3) or FCCP was even visible after the removal of extracellular Ca2+, suggesting that the inhibitors also mobilize Ca2+ from mitochondria. NaN(3) and FCCP induced Ca2+ influx into B-cells treated with low glucose concentrations whose voltage-dependent Ca2+ channels are closed. Experiments with thapsigargin-preincubated cells indicate that disturbance of mitochondrial function stimulates Ca2+ influx through voltage-independent Ca2+ pathways. During the NaN(3)-induced increase in [Ca2+](c), K+-elicited depolarizations of the cells did not further augment [Ca2+](c). Evidently, this is due to a direct inhibitory effect of azide on L-type Ca2+ channels. The data demonstrate that disturbing the mitochondrial function affects cellular Ca2+ homeostasis in B-cells at several sites. Thus, it is concluded that intact mitochondrial function is a prerequisite for regular Ca2+ handling in B-cells.


High Return to Play Rate and Reduced Career Longevity Following Surgical Management of Athletic Pubalgia in National Basketball Association Players.
To assess the effects of surgical treatment of athletic pubalgia (AP) on game use and performance metrics in National Basketball Association (NBA) players. A retrospective review of all NBA players who underwent surgical management for AP from 1996 to 2018 was performed. A matched control group was created for comparison. The index period was defined as the entire NBA season in which surgery occurred, including the corresponding offseason. Player demographics, use (games played, games started, and minutes per game) and performance (player efficiency rating) metrics were collected for all players. Statistical analysis was performed to compare data before and after return to play. Thirty players with a history of surgical management for AP were included in the final analysis. Following surgery for AP, NBA players were found to have a return to play (RTP) rate of 90.91% (30/33). The average RTP following surgery was 4.73 ± 2.62 months. Compared with control athletes, athletes in the AP group played significantly fewer seasons postinjury (4.17 ± 2.70 vs 5.49 ± 3.04 seasons, respectively; P = .02). During the first year following RTP, NBA players experienced significant reductions in game use and performance, both when compared with the year prior and matched control athletes (P < .05). At 3-year follow-up, players continued to demonstrate significant reductions in game use (minutes per game, P < .05) but not performance. Following surgical treatment of AP, NBA players demonstrated a high RTP rate, but shortened career. A short-term reduction in game use and performance metrics was found the year of return following surgery. However, 3-year follow-up performance metrics normalized when compared with healthy controls. Level III; retrospective case-control study.


Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development.
Preclinical models of human diseases are critical to our understanding of disease etiology, pathology, and progression and enable the development of effective treatments. An ideal model of human disease should capture anatomical features and pathophysiological mechanisms, mimic the progression pattern, and should be amenable to evaluating translational endpoints and treatment approaches. Preclinical animal models have been developed for a variety of human ophthalmological diseases to mirror disease mechanisms, location of the affected region in the eye and severity. These models offer clues to aid in our fundamental understanding of disease pathogenesis and enable progression of new therapies to clinical development by providing an opportunity to gain proof of concept (POC). Here, we review preclinical animal models associated with development of new therapies for diseases of the ocular surface, glaucoma, presbyopia, and retinal diseases, including diabetic retinopathy and age-related macular degeneration (AMD). We have focused on summarizing the models critical to new drug development and described the translational features of the models that contributed to our understanding of disease pathogenesis and establishment of preclinical POC.


Variable region usage in B cell deficient mice in a model of experimental herpes simplex virus retinitis.
By using PCR, we have found previously that differences in T cell receptor alpha/beta chain variable region (TCR alpha/beta) gene expression in lymph nodes (LN) existed between susceptible and resistant mice following anterior chamber (AC) inoculation with herpes simplex virus (HSV). We now report and compare the immunoglobulin gene variable region (Ig VH) and the TCR V beta mRNA expression in normal congenic mice (BALB/c and C.B-17) and also in B cell modulated C.B-17 mice (B-). RNA prepared from spleen and LN of these mice before and after HSV-AC inoculation was analysed by PCR using oligoprimers specific for 11 VH gene families and 19 V beta gene families. Densitometry analysis revealed that VH family mRNA expression levels in spleen and lymph nodes did not correlate with HSV susceptibility or resistance patterns in B-, BALB/c and C.B-17 mice. Analysis of TCR V beta chain genes showed that spleen of resistant C.B-17 and B-Ab transferred mice showed a preference for V beta 11 gene expression not seen in susceptible mice. In contrast, LN of BALB/c and B-, both susceptible mice, made TCR V beta transcripts that were indistinguishable from those generated by resistant C.B-17 mice, following HSV-AC inoculation. Finally, TCR V beta gene family repertoire appears to be severely diminished in uninfected B- mice (50% in LN and 45% in spleen) by anti-mu treatment.


Eliminating HPV-caused cancers in Europe: Achieving the possible.
The 690,000 cases of cancer caused worldwide each year by HPV (human papillomavirus) are among the easiest of all cancers to prevent. However, the actions so far taken in terms of both policy and practice by health systems in many European states have neither matched the scale of the problem nor seized the opportunities for disease prevention potentially offered by vaccination and screening. Treatments for HPV-caused cancers are also inequitably provided across the region and widespread misinformation about HPV undermines efforts to improve public health. The European Cancer Organisation's HPV Action Network has made the case for action for the elimination of all the cancers caused by HPV through gender-neutral vaccination, effective cervical cancer screening, better quality treatments, and public and professional education across Europe. The World Health Organisation's new global strategy for the elimination of cervical cancer (launched in November 2020), together with Europe's Beating Cancer Plan (February 2021), together provide a major opportunity to tackle decisively all the cancers caused by HPV. The Beating Cancer Plan, which was significantly influenced by evidence provided by the HPV Action Network, commits to supporting EU member states' efforts to extend routine vaccination of girls and boys and to creating a new EU-supported Cancer Screening Scheme to help Member States ensure that 90% of the EU population who qualify for cervical cancer screening are offered it by 2025. The goal of HPV cancer elimination is now both possible and achievable. The challenge is to ensure implementation and delivery by EU member states and more widely across the European region.


Phase I trial of gemcitabine and carboplatin in metastatic non-small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie Study.
The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m(2) on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5-7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m(2) (level 7). Twenty-nine patients were entered into this phase I study. At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m(2), the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m(2).


Validation of a questionnaire on problematic use of smartphones among a rural population of West Bengal.
While a smartphone can be a hugely productive tool, excessive use of this device can interfere with work, education, our physical and mental health, and productivity. Nowadays, we do not just use our smartphones, but we rely on them. The present study aims to develop and validate an instrument measuring the problematic use of smartphones among adults in a rural area of West Bengal, India. The questionnaire on problematic use of smartphone is a self-designed tool. The items were selected by literature review. The psychometric properties of the questionnaire were assessed by content validity, construct validity, and reliability. Exploratory factor analysis was performed to identify the factors. Forty-two items were generated by literature review. After final analysis, the main questionnaire contained 28 items with 5 domains, namely "impulsive use of phone," "dependence," "impaired control," "denial," "decreased productivity," and "emotional attachment." The Cronbach's alpha value for three domains was found to be >0.7 and >0.8 for the other three domains. Excessive mobile phone use is associated with various adverse consequences which is emerging as a public health problem in a large number of population in India. Problematic use of smartphone questionnaire is a valid and reliable tool to assess the pattern of mobile use among Indian population.


Angiotensin converting enzyme in kainic acid--injected striata.
The activity of angiotensin converting enzyme is decreased in kainic acid-injected neostriata of rats, providing another biochemical similarity between this animal model and Huntington's chorea.


IDENTITY FORMATION DIFFICULTIES IN IMMIGRANT ADOLESCENTS: THREE CASES FROM GERMANY.
Adolescence is a period of instability caused by biological changes and restructuring of the personality. An immigration background renders the process of identity formation even more difficult or fragile, with an additional burden coming from persecution and harassment. Three case studies of mentally disturbed adolescents with different immigration backgrounds illustrate the problems in diagnosis and psychotherapy. All three cases share a common feature--the particular influence of the native country on the psychic disorder of the adolescent, be it a suitable target of narcissistic self-aggrandizement, a reactivated metaphor of the past or a deposited conflict. I point out and discuss the danger of diagnostic colonization and activation of perpetrator-victim constellations--such as the Nazi past in the present. Offering a transcultural transitional space as a container yields a therapeutic approach to the different worlds of these borderland adolescents.


Patients aged 50-75 years take longer to achieve the patient acceptable symptom state than patients aged 20-34 years following primary hip arthroscopy for femoroacetabular impingement syndrome.
Though an increasing number of adults older than 50 years are undergoing hip arthroscopy for treatment of Femoroacetabular Impingement Syndrome (FAIS), it is unclear how their timeline for functional outcome improvement compares to that of younger patients. The purpose of this study was to assess the impact of age on time to achieving the Minimum Clinically Important Difference (MCID), Substantial Clinical Benefit (SCB), and Patient Acceptable Symptom State (PASS) following primary hip arthroscopy for FAIS. A retrospective comparative single-surgeon cohort study of primary hip arthroscopy patients with minimum 2-year follow-up was conducted. Age categories were 20-34 years, 35-49 years, and 50-75 years. All subjects completed the modified Harris Hip Score (mHHS) prior to surgery and at 6-month, 1-year, and 2-year follow-up. MCID and SCB cutoffs were defined as pre-to-postoperative increases in mHHS by ≥ 8.2 and ≥ 19.8, respectively. PASS cutoff was set at postoperative mHHS ≥ 74. Time to achievement of each milestone was compared using interval-censored survival analysis. The effect of age was adjusted for Body Mass Index (BMI), sex, and labral repair technique using an interval-censored proportional hazards model. Two hundred eighty-five patients were included in the analysis with 115 (40.4%) aged 20-34 years, 92 (32.3%) aged 35-49 years, and 78 (27.4%) aged 50-75 years. There were no significant differences between groups in time to achievement for the MCID (n.s.) or SCB (n.s.). However, patients in the oldest group had significantly longer time to PASS than those in the youngest group, both in the unadjusted analysis (p = 0.02) and after adjusting for BMI, sex, and labral repair technique (HR 0.68, 95% CI 0.48-0.96, p = 0.03). Achievement of the PASS, but not the MCID or SCB, is delayed among FAIS patients aged 50-75 years who undergo primary hip arthroscopy compared to those aged 20-34 years. Older FAIS patients should be counseled appropriately about their longer timeline to achieving hip function comparable to their younger counterparts. III.


Religiosity and the Naturalness Bias in Drug and Vaccine Choices.
Research reveals a bias for natural versus synthetic drugs. We sought to determine if this bias is associated with religiosity. Three cross-sectional studies (N = 1399 U.S. participants) were conducted to examine the impact of religiosity on the naturalness bias in the drug and vaccine domains. We assessed measures of religiosity, preferences for natural versus synthetic drugs and vaccines in hypothetical scenarios, and a health-related behavior (COVID-19 vaccination status). The results revealed that participants high versus low in religiosity had stronger preferences for natural versus synthetic drugs and vaccines. Furthermore, participants high versus low in religiosity were less likely to have taken the COVID-19 vaccine, and the natural drug bias was a mediator of this effect. Overall, participants higher in religiosity had a stronger preference for natural versus synthetic drugs and vaccines, and this preference had implications for health behavior.


CD147-specific chimeric antigen receptor T cells effectively inhibit T cell acute lymphoblastic leukemia.
T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mice were used to establish a T-ALL xenograft model and CD147-CAR T cells conferred robust protection against T-ALL progression and significantly improved survival in mice. Overall, we found that CD147 is a potential antigen target of CAR T cell therapy for T-ALL.


Vector competence of Aedes albopictus and Aedes aegypti (Diptera: Culicidae) for the DEN2-FJ10 and DEN2-FJ11 strains of the dengue 2 virus in Fujian, China.
Dengue is an acute, emerging, infectious disease transmitted by Aedes mosquitoes that has become a serious global public health problem. The DEN2-FJ10 and DEN2-FJ11 strains of the dengue 2 virus were originally isolated from the serum of a patient with dengue fever in Fujian Province, China, in 1999. Our data provide the first assessment of the vector competence of Aedes mosquitoes with respect to the DEN2-FJ10 and DEN2-FJ11 strains of the dengue virus. There were significant differences in the replication rates of these two viral strains in Aedes albopictus and Aedes aegypti (P<0.05); replication of the DEN2-FJ10 strain was greater in Ae. aegypti than in Ae. albopictus 5 days post infection whereas replication of the DEN2-FJ11 was greater in Ae. albopictus than in Ae. aegypti 7 days post infection. The replicative ability of the DEN2-FJ11 strain was greater than that of the DEN2-FJ10 strain in infected Ae. albopictus. In infected Ae. aegypti, rapid proliferation of the DEN2-FJ10 strain occurred earlier than in the DEN2-FJ11 strain. There were no significant differences in the midgut and salivary gland infection rates of Ae. albopictus and Ae. aegypti with respect to either viral strain. Although the DEN2-FJ10 and DEN2-FJ11 strains differ in their virulence to neonatal rats, there was no significant difference in the ability of either Ae. albopictus or Ae. aegypti to transmit the DEN2-FJ10 and DEN2-FJ10 strains of the dengue 2 virus (P>0.05). In summary, our results indicate that Ae. albopictus and Ae. aegypti mosquitoes are moderately competent vectors of the DEN2-FJ10 and DEN2-FJ11 strains of the dengue virus and provide the first evidence of the effect of these two viral strains on the vector competence of mosquitoes in China.


RJT-101, a novel camptothecin derivative, is highly effective in the treatment of melanoma through DNA damage by targeting topoisomerase 1.
Melanoma is one of the most aggressive malignancies. Drug resistance and toxicity limits the clinical efficacy of melanoma chemotherapeutic drugs such as dacarbazine. Therefore, the development of chemotherapeutic agents for melanoma treatment is urgently needed. RJT-101 significantly inhibits the proliferation of melanoma cells, however has low cytotoxicity to non-malignant cells. RJT-101 induces apoptosis, DNA damage, and G2/M phase arrest, as a consequent, attenuates tumor growth, lung metastasis in vivo as well as prolongs survival of tumor bearing mice. RJT-101 could block topoisomerase I (Top1) activity as well as induce its degradation through proteasome system. Interestingly, Top1 is over-expressed in melanoma cells, compared to non-malignant cells. Knock down of Top1 suppresses melanoma cells growth and induces apoptosis and DNA damage in melanoma cells. RJT-101 effectively inhibits melanoma cells (including vemurafenib-resistant melanoma cells) proliferation in vitro and in vivo through the induction of DNA damage and apoptosis by inhibiting of Top1, indicating RJT-101 warrants further clinical evaluation.


A lifeline for cancer patients in Africa.
In Rwanda, many people with cancer are diagnosed too late because of low awareness of the disease coupled with a lack of specialist facilities and staff. The opening of a specialist centre in the northern part of the country is extending and saving lives.


Real-time intravital imaging of pH variation associated with osteoclast activity.
Intravital imaging by two-photon excitation microscopy (TPEM) has been widely used to visualize cell functions. However, small molecular probes (SMPs), commonly used for cell imaging, cannot be simply applied to intravital imaging because of the challenge of delivering them into target tissues, as well as their undesirable physicochemical properties for TPEM imaging. Here, we designed and developed a functional SMP with an active-targeting moiety, higher photostability, and a fluorescence switch and then imaged target cell activity by injecting the SMP into living mice. The combination of the rationally designed SMP with a fluorescent protein as a reporter of cell localization enabled quantitation of osteoclast activity and time-lapse imaging of its in vivo function associated with changes in cell deformation and membrane fluctuations. Real-time imaging revealed heterogenic behaviors of osteoclasts in vivo and provided insights into the mechanism of bone resorption.


Effects of caffeine and tetracaine on outer hair cell shortening suggest intracellular calcium involvement.
Outer hair cell (OHC) shortening has previously been induced in vitro by the application of solutions containing high potassium (a depolarizing agent), acetylcholine (a suggested efferent transmitter) and cationized ferritin (a positively charged macromolecule), as well as by electrical current. The application of caffeine, which causes contractures in skeletal and smooth muscle by releasing calcium from intracellular stores to activate actin and myosin interaction, also causes shortening of OHCs. Tetracaine, which interferes with calcium movement in muscle and non-muscle cells, blocks potassium-induced and caffeine-induced shortening of OHCs, but does not block electrically-induced shortening. Sodium dantrolene which is an inhibitor of intracellular calcium release in skeletal muscle does not block potassium-induced OHC shortening. Immunocytochemical studies using antibodies to muscle-like contractile and regulatory proteins on unfixed, freeze-dried OHCs demonstrate the co-localization of calmodulin with actin throughout the OHC cytoplasm. These results support the ideas that in OHCs, intracellular calcium release is involved in the activation of shortening and that an actin-mediated cell shape change may be regulated by calmodulin in a manner similar to that which occurs in contraction of smooth muscle.


[Undescended testis: current treatment guidelines].
Cryptorchidism is the most common genital malformation in male newborns. In recent years, guidelines concerning diagnosis and therapy have undergone considerable evolution with the implementation of recent knowledge in pathophysiology, diagnosis, and therapy. The aim of this publication is to provide an overview of the current national and international guideline recommendations concerning diagnosis and treatment of cryptorchidism. Critical points are discussed in light of current scientific literature. The current guidelines of the European Association of Urology (EAU)/European Society for Pediatric Urology (ESPU), the American Association of Urology (AUA), the pediatric urologic task force of the Austrian Society of Urology (ÖGU), the international consultation on urological disease (ICUD) and the German Society of Urology (DGU)/German Association of Pediatric Surgery (DGKCh) have been analyzed concerning the most important aspects of treatment and diagnosis. There is broad consensus concerning most steps and decisions for the treatment of cryptorchidism. However, some aspects of diagnostic imaging, the use of hormonal therapy, and surgical access in nonpalpable testis warrant further discussion and are the fields of considerable changes.


Cerebrospinal Fluid Analysis for Viruses by Metagenomic Next-Generation Sequencing in Pediatric Encephalitis: Not Yet Ready for Prime Time?
Metagenomic next-generation sequencing offers an unbiased approach to identifying viral pathogens in cerebrospinal fluid of patients with meningoencephalitis of unknown etiology. In an 11-month case series, we investigated the use of cerebrospinal fluid metagenomic next-generation sequencing to diagnose viral infections among pediatric hospitalized patients presenting with encephalitis or meningoencephalitis of unknown etiology. Cerebrospinal fluid from patients with known enterovirus meningitis were included as positive controls. Cerebrospinal fluid from patients with primary intracranial hypertension were included to serve as controls without known infections. Cerebrospinal fluid metagenomic next-generation sequencing was performed for 37 patients. Among 27 patients with encephalitis or meningoencephalitis, 4 were later diagnosed with viral encephalitis, 6 had non-central nervous system infections with central nervous system manifestations, 6 had no positive diagnostic tests, and 11 were found to have a noninfectious diagnosis. Metagenomic next-generation sequencing identified West Nile virus (WNV) in the cerebrospinal fluid of 1 immunocompromised patient. Among the 4 patients with known enterovirus meningitis, metagenomic next-generation sequencing correctly identified enteroviruses and characterized the viral genotype. No viral sequences were detected in the cerebrospinal fluid of patients with primary intracranial hypertension. Metagenomic next-generation sequencing also identified sequences of nonpathogenic torque Teno virus in cerebrospinal fluid specimens from 13 patients. Our results showed viral detection by cerebrospinal fluid metagenomic next-generation sequencing only in 1 immunocompromised patient and did not offer a diagnostic advantage over conventional testing. Viral phylogenetic characterization by metagenomic next-generation sequencing could be used in epidemiologic investigations of some viral pathogens, such as enteroviruses. The finding of torque Teno viruses in cerebrospinal fluid by metagenomic next-generation sequencing is of unknown significance but may merit further exploration for a possible association with noninfectious central nervous system disorders.


Antibody responses induced by long-term vaccination with an octovalent conjugate Pseudomonas aeruginosa vaccine in children with cystic fibrosis.
We assessed the serological responses over 10 years to repeated immunization of cystic fibrosis (CF) patients with an O-polysaccharide (OPS)-toxin A conjugate vaccine against Pseudomonas aeruginosa. A retrospective analysis was performed with sera from 25 vaccinated and 25 unvaccinated children treated at the same CF centre and matched for clinical management, age and gender. Yearly immunization led to sustained elevations of serum immunoglobulin G (IgG) antibody levels to all vaccine components. Eighteen unvaccinated patients but only eight vaccinated ones developed chronic pseudomonal lung infections. Infection rapidly caused further marked elevations of polysaccharide- but not toxin A-specific serum IgG in both immunized and nonimmunized patients, indicating that protection did not depend on the quantity of IgG present. However, qualitative analyses revealed that the protective capacity of specific serum IgG antibodies was linked to high affinity and to specificity for OPS serotypes rather than for lipopolysaccharide core epitopes.


Life cycle of Coitocoecum plagiorchis (Trematoda: Digenea: Opecoelidae).
The life cycle of Coitocoecum plagiorchis Ozaki, 1926 (Coitocaecum is an incorrect subsequent spelling) was studied in the field and laboratory. The study was conducted at the Futatsu River and the Chikugo River, Kyushu, Japan. Adults of C. plagiorchis were obtained from fishes Coreoperca kawamebari, Rhinogobius spp. and Odontobutis obscura. Cotylomicrocercous cercariae with a two-point stylet (=Cercaria distyloides Faust, 1924) were detected in pleurocerid snails (Semisulcospira spp.). Metacercariae with a cyclocoel were obtained from shrimp (Neocaridina denticulata). The cercariae were experimentally exposed to the shrimp, and subsequently metacercariae with a cyclocoel were recovered from the shrimp within 24 days after exposure. These metacercariae were identified as C. plagiorchis. The sporocysts, cercariae, metacercariae and adults are briefly described.


In situ analysis of smoothelin-like 1 and calmodulin interactions in smooth muscle cells by proximity ligation.
The smoothelin-like 1 (SMTNL1) protein is the newest member of the smoothelin family of muscle proteins. Two calmodulin (CaM)-binding domains (CBD1 for Ca-CaM; CBD2 for apo-CaM) have been described for the SMTNL1 protein using in vitro assays. We now demonstrate in situ associations of SMTNL1 and CaM in A7r5 smooth muscle cells using the proximity ligation assay (PLA). We quantified CaM-SMTNL1 proximity events accurately after taking into account variations in protein expression levels. The refined method allows quantification of in situ proximity after transient transfection with an associated error of <10%. The proximity of SMTNL1 and CaM in A7r5 cells could be reduced by scrambling the amino acid sequence and mutation of large hydrophobic amino acids of CBD1. The truncation of CBD2 did not influence SMTNL1 proximity to CaM. Ultimately, we conclude that SMTNL1 forms complex interactions with CaM in smooth muscle cells, with a role for CBD1 and possibly the intrinsically disordered region.


Prevention of bacteremia in dogs undergoing dental scaling by prior administration of oral clindamycin or chlorhexidine oral rinse.
Dogs with periodontitis were used to determine the efficacy of an oral regimen of clindamycin versus chlorhexidine acetate oral rinse in reducing the total number of bacteria and the incidence of bacteremia before and after dental scaling. Aerobic and anaerobic bacteria, isolated from blood and gingival swab cultures, were identified to genus using an automated system.


The 2016-2017 Chikungunya Outbreak in Karachi.
Chikungunya is an incipient disease, caused by Chikungunya virus (CHKV) that belongs to genus alphavirus of the family Togaviridae. In this study, during an outbreak of CHKV in Dec 2016 in Karachi, Pakistan, samples were collected from patients presenting with fever, tiredness and pain in muscles and joints. Total 126 sera were tested for the presence of Chikungunya infection through ELISA and Real-time Reverse Transcriptase PCR assay. This study showed that approx 79.4% samples were positive for CHKV. To our knowledge, this is the first reported outbreak from last decades in which the presence of CHKV is confirmed in Karachi while affecting such large no. of individuals.. CHKV diagnosis should be considered by the scientists and clinicians as a differential diagnosis in febrile patients, and appropriate control strategies must be adopted for its surveillance.


Isolation of Single-Domain Antibodies to Transmembrane Proteins Using Magnetized Yeast Cell Targets.
The isolation of binding ligands from yeast-displayed combinatorial libraries has typically relied on the use of a soluble, recombinantly expressed form of the target protein when performing magnetic selections or fluorescence-activated cell sorting. When identifying binding ligands, appropriate target protein expression and subsequent purification represents a significant bottleneck. As an alternative, we describe the use of target proteins expressed on the surface of magnetized yeast cells in the selection of yeast-displayed nanobody libraries. In this approach, yeast cells displaying the target protein also co-express an iron oxide-binding protein; incubation with iron oxide nanopowder results in magnetization of target-displaying cells. Alternatively, target-displaying cells are magnetized by nonspecific adsorption of iron oxide nanopowder. Subsequently, any library cells that interact with the magnetized target cells can be isolated using a magnet. Here, we detail protocols for the isolation of binders to membrane protein targets from a yeast display nanobody library using magnetized yeast cell targets. We provide guidance on how to generate magnetic yeast cell targets as well as library selection conditions to bias the isolation of high affinity binders. We also discuss how to assess the affinity and specificity of the isolated nanobodies using flow cytometry.


Chromatography as Method for Analytical Confirmation of Paracetamol in Postmortem Material Together with Psychoactive Substances.
Paracetamol (Acetaminophen) in addition to aspirin is the most commonly used analgesic and antipyretic medication by millions of patients worldwide. It is an example that paracetamol as medicine that in the world is provided without a doctor's prescription, can lead to death. Today paracetamol became an integral part of a heroin mixture and is very popular at the street market. The main reason for this is that it can be obtained without a prescription, it is cheap, and by most people well tolerated without side effects. It is probably used for "cutting" the pure heroin, as it says in the jargon, and in that manner from small amount of pure drug is obtained greater amount, which is then sold on the street. The goal is to identify presence of paracetamol, by analytical method of gas chromatography mass spectrometer (GC-MS) in postmortem material together with psychoactive substances. For chemical-toxicological analysis is used biological material collected trough autopsy of 20 deceased people, suspected to have died due to psychoactive substance overdose. All received samples are stored at -20 ° C until analysis at our laboratory. From processed 47 samples that were analyzed in the period from 2014 to 2015, 19 are blood samples, urine 19, 3 samples of stomach contents, and 6 samples of bile content. Deceased were middle-aged, of which only 7 were female. The tested samples were processed according to two methods of extraction. Extraction by XAD-2 resin, and the extraction by the method of salting out with sodium tungstate. Extracts of the samples were then dissolved in chloroform and continued analysis at the analytical instrument. Identification of the paracetamol presence, in the test biological samples is demonstrated by the technique of gas chromatography with mass spectometry (hereinafter referred to as GC-MS). The technique of GC-MS is a selective, sensitive and reliable, and is therefore considered a "gold standard" for determining the drug, and the drug substance. Used GC-MS instrument was an Agilent 7890A with helium as the carrier gas. The analysis of blood samples, urine, bile and stomach contents, obtained after the autopsy of deceased persons, by using gas chromatography with mass spectrometry, in analytical manner confirmed the fact that paracetamol is a very common component of psychoactive substances poisoning. In our assay of samples we detected psychoactive substances (heroin, codeine, morphine, sertraline, diazepam), and almost all were found in the combination with paracetamol, indicating the poor quality of illicit drugs sold on the market. Paracetamol (Acetaminophen) is a very common component in mixtures of street drugs. Such mixtures almost anyone can afford, but the very quality of these drugs has become extremely low, because it does not sell the pure substance, but is mixed with various medications. According to research Pantazia et al. the heroin mixture proportion of the heroin is very small so a lot of that mixture has only 3% of heroin, a large number of cases can be only 1% of pure heroin. Most of the time it replaces caffeine and paracetamol. According to the Risser et al. reason why acetaminophen component is present in these mixtures is because it can be purchased without a prescription, it is cheap, well tolerated by most people and shows no side effects. When we talk about illegal drugs, we must emphasize the fact that there is no quality control, or the composition of the drug. The composition of the drug purchased on the black market is still unknown to potential user. While reaching the final drug users it pass through many hands, and at each step something is added to increase earnings. Most often present additives or impurities in narcotic drugs that are added are caffeine, ephedrine, acetaminophen, acetylsalicylic acid (aspirin) and additives such as powders, cement and chalk.


Long-term cost-consequence analysis of exenatide once weekly vs sitagliptin or pioglitazone for the treatment of type 2 diabetes patients in the United States.
Exenatide once-weekly (ExQW) is a GLP-1 receptor agonist shown to lower glucose and cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to estimate the clinical benefits and associated economic benefits of treatment with ExQW compared with sitagliptin or pioglitazone in the US. The IMS CORE Diabetes Model, a validated computer simulation model, was used to project lifetime clinical outcomes and complication costs. The costs of glucose-lowering drugs were excluded as not all prices were available. Baseline patient characteristics (mean values: age, 52.5 years; diabetes duration, 6 years; HbA1(c), 8.51%; body mass index, 32.12 kg/m(2)) and clinical data were derived from a phase 3 clinical trial that compared ExQW with sitagliptin or pioglitazone in T2DM patients. At 6 months, patients treated with ExQW had greater improvements in HbA1(c) and body weight than those treated with sitagliptin or pioglitazone. Complication costs were extracted from published sources. Health outcomes and costs were discounted at 3% per year. Sensitivity analyses were performed. Over 35 years, and compared with sitagliptin or pioglitazone, ExQW increased life expectancy by, respectively, 0.28 (13.76 ± 0.17 vs 13.48 ± 0.18) and 0.17 years (13.76 ± 0.17 vs 13.59 ± 0.17), and quality-adjusted life years by, respectively, 0.28 (9.56 ± 0.12 vs 9.28 ± 0.12) and 0.24 years (9.56 ± 0.12 vs 9.32 ± 0.12). ExQW was associated with lower lifetime complication costs: compared with sitagliptin or pioglitazone, ExQW saved, respectively US$2215 (US$55,647 ± 2039 vs US$57,862 ± 2159) and US$933 (US$55,647 ± 2039 vs US$56,580 ± 2007) direct cost per patient. Cost-savings resulted mainly from a lower projected cumulative incidence of cardiovascular diseases and neuropathic complications. Short-term changes in surrogate end-points were used to project lifetime effects on clinical outcomes. Pharmacy costs were excluded from the analyses. Over a patient's lifetime, ExQW was projected to improve health and decrease diabetes-related complication costs compared with sitagliptin or pioglitazone.


Stabilisation/solidification of synthetic petroleum drill cuttings.
This paper presents the results of an experimental investigation into the use of stabilisation/solidification (S/S) to treat synthetic drill cuttings as a pre-treatment to landfilling or for potential re-use as construction products. Two synthetic mixes were used based on average concentrations of specific contaminates present in typical drill cuttings from the North Sea and the Red Sea areas. The two synthetic drill cuttings contained similar chloride content of 2.03% and 2.13% by weight but different hydrocarbon content of 4.20% and 10.95% by weight, respectively; hence the mixes were denoted as low and high oil content mixes, respectively. A number of conventional S/S binders were tested including Portland cement (PC), lime and blast-furnace slag (BFS), in addition to novel binders such as microsilica and magnesium oxide cement. Physical, chemical and microstructural analyses were used to compare the relative performance of the different binder mixes. The unconfined compressive strength (UCS) values were observed to cover a wide range depending on the binder used. Despite the significant difference in the hydrocarbon content in the two synthetic cuttings, the measured UCS values of the mixes with the same binder type and content were similar. The leachability results showed the reduction of the synthetic drill cuttings to a stable non-reactive hazardous waste, compliant with the UK acceptance criteria for non-hazardous landfills: (a) by most of the binders for chloride concentrations, and (b) by the 20% BFS-PC and 30% PC binders for the low oil content mix. The 30% BFS-PC binder successfully reduced the leached oil concentration of the low oil content mix to inert levels. Finally, the microstructural analysis offered valuable information on the morphology and general behaviour of the mixes that were not depicted by the other tests.


Observations on the epidemiology and control of Strongylus vulgaris infections.
The epidemiology and control of helminth infections in the horse were studied in four small grazing experiments between 1981 and 1984 at the University of Utrecht. At autopsy in November or December negligible Strongylus vulgaris burdens were found in the cranial mesenteric artery of four groups of ponies, which had been treated with an anthelmintic in July and subsequently transferred to a clean pasture. Considerable arterial S. vulgaris burdens were seen in three groups of ponies which were treated with an anthelmintic in July without a move to clean pasture, and in another group of ponies in 1984, which was set stocked on a pasture used for horses in 1983 and which was treated with an anthelmintic (albendazole) 2 days before turnout in April and subsequently in May, June and July. A tracer pony, grazed with this group between the middle of September and the middle of November, harboured an even higher burden of arterial S. vulgaris larvae. The arterial S. vulgaris in the latter group could not be the result of contamination of the pasture with S. vulgaris eggs before July, as in the three other groups with considerable arterial S. vulgaris burdens. Pasture larval counts showed that S. vulgaris larvae do not only overwinter, but are able to survive in considerable numbers until autumn, longer than most other gastrointestinal nematodes. There were some indications that translation of infective larvae, which overwintered on pasture in some free living stage, occurred between May and July.


Towards models of the oxygen-evolving complex (OEC) of photosystem II: a Mn4Ca cluster of relevance to low oxidation states of the OEC.
Synthetic access has been achieved into high oxidation state Mn/Ca chemistry with the 4 : 1 Mn : Ca stoichiometry of the oxygen-evolving complex (OEC) of plants and cyanobacteria; the anion of (Et(3)NH)(2)[Mn(III)(4)Ca(O(2)CPh)(4)(shi)(4)] has a square pyramidal metal topology and an S = 0 ground state.


Baicalin protects against ethanol-induced chronic gastritis in rats by inhibiting Akt/NF-κB pathway.
Currently, chronic gastritis is a high incidence of digestive diseases, along with loss of appetite, abdominal pain and diarrhea. Baicalin belongs to the major bioactive flavonoids compounds from Scutellariae Radix, it exhibited anti-inflammatory and anti-bacteria activities. Nonetheless, the protective effects of baicalin on ethanol-induced gastritis have not been completely clarified. Our study was designed to evaluate the protective activity of baicalin on ethanol-induced chronic gastritis. Rat with chronic gastritis model was induced by the administration of 56% ethanol for four weeks. Baicalin (50 and 100 mg/kg) were orally administered for seven days to evaluate its curative effect, respectively. The production of TNF-α, interleukin (IL)-8, IL-1β, NO, ET-1, PGE2, LDH and COX-2 were determined by ELISA. The activities of Akt, p-Akt, IκBα, p-IκBα, NF-κBp65 and NF-κBp-p65 were tested by western blot. Immunofluorescence staining was employed to assess the location of NF-κBp65. The changes of the histopathological analysis and the levels of NO, ET-1, PGE2, LDH and COX-2 demonstrated that baicalin treatment ameliorated ethanol-induced gastritis. ELISA analysis showed that baicalin inhibited the levels of TNF-α, IL-8 and IL-1β. Besides, Akt, p-Akt, IκBα, p-IκBα, NF-κBp65 and NF-κBp-p65 expression were significantly suppressed by baicalin. Meanwhile, baicalin suppressed the translocation of NF-κBp65 to the cell nucleus through immunofluorescence staining, molecular docking analysis showed that baicalin had affinity with Akt and NF-κBp65. All results demonstrated that baicalin effectively alleviated chronic gastritis via suppressing the levels of inflammatory regulators and inhibiting Akt/NF-κB activation.


Thirteen years' experience of preimplantation diagnosis: report of the Fifth International Symposium on Preimplantation Genetics.
Preimplantation genetic diagnosis (PGD) has been further developed into a practical option for avoiding the birth of affected children, representing an important complement to traditional prenatal diagnosis. More than 1000 unaffected children have been born after PGD, suggesting the accuracy and safety of the procedure, which is currently also used with the establishment of potential donor progeny for stem cell treatment of siblings. Together with progress in the establishment of embryonic stem (ES) cells, this may contribute to the development and application of stem cell therapy. The accumulated experience of thousands of PGD cycles for poor prognosis IVF patients provides further evidence of the improvement of clinical outcome, particularly obvious from the reproductive history of PGD patients. A high prevalence of aneuploidies in oocytes and embryos may affect the accuracy of PGD for single gene disorders, making aneuploidy testing an important part of PGD for causative genes and preimplantation human leukocyte antigen (HLA) typing. A sequential sampling of both oocytes and the resulting embryos may improve accuracy of aneuploidy testing and may also allow the detection and avoidance of transfer of embryos with uniparental disomies. Current developments and application of nuclear transfer and sperm duplication techniques, and microarray technology, may also contribute to the improvement of PGD and help in the development of PGD for genetic expression disorders.


Dermoscopy of basosquamous carcinoma.
Basosquamous carcinoma (BSC) is a rare and potentially aggressive tumour, characterized by clinical and pathological features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). It is reported to have a nonspecific clinical presentation, which makes naked-eye diagnosis a challenge. To describe the dermoscopic patterns of BSC, which may facilitate early diagnosis and accurate management. This was a retrospective evaluation of clinical and dermoscopic images of histopathologically proven BSC, collected from skin cancer centres in Australia (Perth), Greece (Thessaloniki) and Italy (Naples, Reggio Emilia). Twenty-two tumours were included in the study. Our analysis revealed that the dermoscopic pattern of BSC comprises BCC-related criteria, as well as features that are known to characterize invasive SCC. The most frequently detected criteria were: unfocused (peripheral) arborizing vessels (73%), keratin masses (73%), white structureless areas (73%), superficial scale (68%), ulceration or blood crusts (68%), white structures (64%), blue-grey blotches (59%) and blood spots in keratin masses (55%). Notably, all but one of the tumours exhibited at least one BCC-related plus one SCC-related dermoscopic feature. BSC appears to have overlapping dermoscopic features of BCC and invasive SCC, and detection of at least one dermoscopic criterion of both BCC and SCC should raise suspicion for the tumour. Appreciation of the dermoscopic patterns of BSC might assist in the timely and accurate diagnosis and subsequent optimal management of this unusual and potentially metastatic skin tumour.


A blood pressure cut-off level identified for renal failure, but not for macrovascular complications in type 2 diabetes: a 10-year observation study.
Can a cut-off blood pressure level for major complications be identified? A 10 years observation study in 385 type 2 diabetic patients. 158 patients were affected with myocardial infarction, stroke, renal failure or death, which occurred in 68, 55, 19 and 109 patients, respectively. No patient with a blood pressure below 140 mmHg and/or a diastolic blood pressure below 75 mmHg developed uraemia during the observation period. No such cut-off level was seen for myocardial infarction, stroke or death. This study shows that there seems to be a cut-off level for blood pressure for development of renal failure, while no level was found for cardio- or cerebrovascular disorders.


Multispectral imaging with vertical silicon nanowires.
Multispectral imaging is a powerful tool that extends the capabilities of the human eye. However, multispectral imaging systems generally are expensive and bulky, and multiple exposures are needed. Here, we report the demonstration of a compact multispectral imaging system that uses vertical silicon nanowires to realize a filter array. Multiple filter functions covering visible to near-infrared (NIR) wavelengths are simultaneously defined in a single lithography step using a single material (silicon). Nanowires are then etched and embedded into polydimethylsiloxane (PDMS), thereby realizing a device with eight filter functions. By attaching it to a monochrome silicon image sensor, we successfully realize an all-silicon multispectral imaging system. We demonstrate visible and NIR imaging. We show that the latter is highly sensitive to vegetation and furthermore enables imaging through objects opaque to the eye.


Nonselective utilization of the endomannosidase pathway for processing glycoproteins by human hepatoma (HepG2) cells.
Endo-alpha-D-mannosidase, a Golgi-situated processing enzyme, provides a glucosidase-independent pathway for the formation of complex N-linked oligosaccharides of glycoproteins (Moore, S. E. H., and Spiro, R. G. (1990) J. Biol. Chem. 265, 13104-13112). The present report demonstrates that at least five distinct glycoproteins secreted by HepG2 cells (alpha 1-antitrypsin, transferrin, alpha 1-acid glycoprotein, alpha 1-antichymotrypsin, and alpha-fetoprotein) as well as cell surface components can effectively utilize this alternate processing route. During a castanospermine (CST)-imposed glucosidase blockade, these glycoproteins apparently were produced with their usual complement of complex carbohydrate units, and upon addition of the mannosidase I inhibitor, 1-deoxymannojirimycin (DMJ), to prevent further processing of deglucosylated N-linked oligosaccharides, Man6-8GlcNAc, but not Man9GlcNAc, were identified; the Man8GlcNAc component occurred as the characteristic isomer generated by endomannosidase cleavage. Although the endomannosidase-mediated deglucosylation pathway appeared to be nonselective, a differential inhibitory effect on the secretion of the various glycoproteins was noted in the presence of CST which was directly related to the number of their N-linked oligosaccharides, ranging from minimal in alpha-fetoprotein to substantial (approximately 65%) in alpha 1-acid glycoprotein. Addition of DMJ to CST-incubated cells did not further decrease secretion of the glycoproteins, although processing was now arrested at the polymannose stage, and a portion of the oligosaccharides were still in the glucosylated form. These latter findings indicate that complex carbohydrate units are not required for secretion of these glycoproteins and that any effect which glucose residues exert on their intracellular transit would be related to movement from the endoplasmic reticulum to the Golgi compartment.


Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles.
The nucleotide-binding oligomerization and leucine-rich repeat receptor (NLR) protein family consists of important immune sensors that form inflammasomes, a cytosolic multi-protein platform that induces caspase-1 activation and is involved in different inflammatory pathologies. The NLR family pyrin domain containing 6 (NLRP6) is a receptor that can signal by forming inflammasomes, but which can also play an important role without forming inflammasomes. NLRP6 regulates intestinal homeostasis and inflammation, but also is involved in cancer, the nervous system or liver diseases, with both protective and deleterious consequences. In the present article, we review the different roles of NLRP6 in these processes and offer new insights into NLRP6 activation.


Multiple-locus variable-number tandem-repeat analysis in Salmonella isolates as an effective molecular subtyping method.
Due to the limitations of serotyping, to differentiate closely related microbial isolates and to investigate disease outbreaks, molecular genotyping methods including multiple loci variable number of tandem repeats (VNTR) analysis (MLVA) has been developed. The usefulness of MLVA was recently demonstrated for Salmonella Infantis and Salmonella Enteritidis isolated from human sources in Iran. In the present study. The discriminatory ability of this method was investigated in 78 Iranian Salmonella enterica isolates. Salmonella strains isolated from human urine, stool, bone marrow, blood, ascites and synovial fluid sources in Iran during the years 2012 and 2015 were analyzed. Among these 78 Salmonella isolates, 70 isolates belonging to eight serotypes/serogroups, while eight were nontypeable. Six VNTR loci were amplified from all isolates. The isolates were distributed into 67 genotypes. Two out of the 6 markers (Sal20 and Sal16) were highly discriminatory for all strains (DI > 0.80) while composition of all VNTR loci produced 67 different types with 0.995 D value. The high discrimination power of MLVA in Salmonella molecular typing via combination of VNTR loci studied here, suggesting that this method is highly valuable for molecular epidemiology of Salmonella strains.


[Experience in the use of anti-colibacillus and Proteus lactoglobulin as a supplement to milk products in diet therapy at a specialized childrens' collective].
A new biologically active supplement (BAS) for infant food was tested at an Infant's Home. BAS-IG contains lactoglobulin, an immune preparation against colibacillus and Proteus. During the primary examination of the infants in the Infant's Home intestinal dysbacteriosis was revealed in 100% of the infants, clinical signs of dysbacteriosis were detected in 88.4% of the infants. Two successive courses of feeding the infants with products enriched with the new supplement resulted in a significant improvement of the microflora composition in them and in normalizing their clinical condition. At the same time positive changes in a number of immunological factors were recorded. The authors have recommended using BAS-IG for correction of dysbacteriosis in children at Infant's Homes.


Expression of human angiotensinogen-renin in rat: effects on transcription and heart function.
In double transgenic rats (dTGR) harboring the human angiotensinogen (hAOGEN) and human renin (hREN) genes, we studied cardiac transcript levels of hypertrophy-related, Ca(2+) regulatory, and beta-adrenoceptor-associated proteins. The contractile properties and the cellular signaling of isolated hearts exposed to (-)isoproterenol and/or angiotensin (Ang) I were evaluated. dTGR developed hypertension of 174.1+/- 7.6 versus 109.6 +/- 2.0 mm Hg (P<0.05) in Sprague-Dawley rats and heart hypertrophy. In hearts of dTGR, the transcript levels of ANP, beta-MHC, and alpha-MHC were altered (percentage versus Sprague-Dawley rats, 100%) by 304%, 178%, and 78%, respectively. Transcript levels of L-type Ca(2+) channel, Ca(2+) release channel, SERCA2a, phospholamban, G(i)- and G(s)-proteins were unchanged. Isolated hearts of dTGR indicated higher baseline contractility versus Sprague-Dawley rats. (-)Isoproterenol-modified contractility occurred in both groups; however, the extent (predrug value, 100%) was less in hearts of dTGR versus Sprague-Dawley rats (+dP/dt, 310 +/- 42% versus 534 +/- 63%; P<0.05). Interestingly, (-)isoproterenol shortened the relaxation time by equivalent to 25% in both groups. This finding was reflected by a protein kinase A-related phospholamban phosphorylation. Ang I depressed the heart contractility but did not interact with the protein kinase A pathway. In conclusion, we have found that expression of the hAOGEN-hREN complex in dTGR elicited specific effects on transcripts of ANP and myofibrillar proteins. Although the beta-adrenergically mediated relaxation was not impaired in the hypertrophied hearts, the extent of beta-adrenergic inotropic responsiveness was reduced.


[Electron microscopy study of mitochondria in the transversely striated muscles of birds after experimental hypergravitation].
An electronmicroscopical study has been carried out on the mitochondriae of transversely striated muscles in birds at experimentally induced hypergravitation. In the matrix of some mitochondriae sporadic small light focuses were observed located mainly at the periphery of the organelle. Thereby, however, no greater damage of the outer membranes was seen. The stress state of hypergravitation resulted in more important and more marked alterations on the inner membranes and the matrix of the mitochondriae of the femoral muscle.


Vibrational spectral and structural characterization of multicomponent ternary co-crystal formation within acetazolamide, nicotinamide and 2-pyridone.
Ternary co-crystal, as a novel co-crystal design strategy developed on the basis of binary co-crystal, could be used to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently. However, it is difficult to obtain specific ternary co-crystals since such ternary one involves complex assembly of three different molecules. There are few reports on the micro-molecular structure respect of specific ternary co-crystal systems. In present work, 1:1:1 ternary co-crystal between acetazolamide (ACZ), nicotinamide (NAM) and 2-pyridone (2HP) has been synthesized successfully by mechanical grinding approach, and their structures are investigated by terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy combined with theoretical calculation at the molecular level. The experimental THz spectral results showed that ACZ-NAM-2HP ternary co-crystal and the starting parent materials exhibited a few distinct spectral features in frequency-domain absorption spectra. Likewise, the Raman spectral result also shows some difference between the co-crystal and starting raw materials. Through density functional theory (DFT) calculations, the theoretical THz/Raman spectra and vibrational modes of two kind of possible ternary co-crystal theoretical forms (form I and II) between ACZ, NAM and 2HP were obtained. By comparing experimental and theoretical spectral results, the most suitable structure and vibrational modes of ACZ-NAM-2HP ternary co-crystal were determined. These results provide a wealth of information and unique method for studying molecular assembly and also inter-molecular interactions in specific ternary co-crystals at the molecular level in the emerging pharmaceutical co-crystal fields.


Phonological abstraction without phonemes in speech perception.
Recent evidence shows that listeners use abstract prelexical units in speech perception. Using the phenomenon of lexical retuning in speech processing, we ask whether those units are necessarily phonemic. Dutch listeners were exposed to a Dutch speaker producing ambiguous phones between the Dutch syllable-final allophones approximant [r] and dark [l]. These ambiguous phones replaced either final /r/ or final /l/ in words in a lexical-decision task. This differential exposure affected perception of ambiguous stimuli on the same allophone continuum in a subsequent phonetic-categorization test: Listeners exposed to ambiguous phones in /r/-final words were more likely to perceive test stimuli as /r/ than listeners with exposure in /l/-final words. This effect was not found for test stimuli on continua using other allophones of /r/ and /l/. These results confirm that listeners use phonological abstraction in speech perception. They also show that context-sensitive allophones can play a role in this process, and hence that context-insensitive phonemes are not necessary. We suggest there may be no one unit of perception.


Realization of user-friendly bioanalytical tools to quantify and monitor critical components in bio-industrial processes through conceptual design.
This minireview suggests a conceptual and user-oriented approach for the design of process monitoring systems in bioprocessing. Advancement of process analytical techniques for quantification of critical analytes can take advantage of basic conceptual process design to support reasoning, reconsidering and ranking solutions. Issues on analysis in complex bio-industrial media, sensitivity and selectivity are highlighted from users' perspectives. Meeting challenging analytical demands for understanding the critical interplay between the emerging bioprocesses, their biomolecular complexity and the needs for user-friendly analytical tools are discussed. By that, a thorough design approach is suggested based on a holistic design thinking in the quest for better analytical opportunities to solve established and emerging analytical needs.


Barrier cream based on CeO2 nanoparticles grafted polymer as an active compound against the penetration of organophosphates.
Due to their small size, nanoparticles possess unique properties. Cerium oxide nanoparticles have been already studied for their capacity to adsorb and neutralize toxic compounds including organophosphates. By covalently grafting these nanoparticles to a thickening polymer, their potential aggregation resulting in a loss of surface area and their potential toxicity are avoided. Indeed, copolymers easily form gels in water at neutral pH thanks to low interactions occurring between polymeric chains; thus, gels can be spread on membrane supports to afford protective barriers. However, as we demonstrated previously, a formulation step of these hydride nanoparticle-polymeric compounds is necessary to overcome the cracking of the coating during drying. This work reports the impact of many factors on the efficiency of a new active Topical Skin Protectant (aTSP) including: (1) the presence of CeO2 nanoparticles in the protective coating and their amount, (2) their grafting to a perfluorocarbon thickening polymer and (3) the formulation of the CeO2 nanoparticle-grafted polymer. The combination of all the benefit parameters led to a very effective new aTSP against paraoxon penetration. The major in vitro diffusion studies were performed in Franz-type diffusion cells on two artificial membranes (silicone and Strat-M) and final validation on ex vivo human skin. The comparison of 24 h-exposure between membrane results indicated a difference in the behavior between the two artificial supports and the biological model; Strat-M membranes seeming closer to human skin results. Therefore, positive results regarding occlusive conditions should be confirmed with human skin.


Effects of Sijunzi decoction and Yupingfeng powder on expression of janus kinase-signal transducer and activator of transcription signal pathway in the brain of spleen-deficiency model rats.
To observe the influence of Sijunzi decoction and Yupingfeng powder on the expression of the relevant DNAs of janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal pathway of the brain in spleen-deficiency model rats. Eighty male Wistar rats of sanitary degree were divided randomly into four groups: normal group, model group, treatment group 1, treatment group 2. Besides the rats in the normal group, all the rats in other 3 groups were prepared as spleen deficiency model. The treatment group 1 were treated with Sijunzi decoction and the treatment group 2 were treated with Yupingfeng powder. After treatment for 6 weeks, perfusion was given and the brain was taken for detection of the expression of the relevant DNAs of JAK-STAT signal pathway of the brain in SD rats bygene chip method. Spleen deficiency could lead to increase expression of JAK1, STAT1 and Interleukin 4 (IL-4) in the brain, but the decrease expression of Suppressor of cytokine signaling 1 (SOCS1), prolactin receptor (PRLR) and binding protein 3 (GATA 3). Sijunzi decoction could increase expression of STAT3, Prolactin (PRL) and GATA3, but decrease expression of JAK1, STAT, STAT4, Interleukin 10 receptor, alpha (IL10RA), Coagulation factor II (F2), PRLR, MAD homolog 3 (SMAD3) and IL-4. Yupingfeng powder could decrease expression of JAK1, STAT1, STAT4, SOCS4_ predicted, Epidermal growth factor receptor (EGFR), PRLR, High mobility group AT-hook 1 (HMGA10), IL-4. Sijunzi decoction and Yupingfeng powder can improve immune function of the rat through influencing the genetic expression of JAK-STAT signal pathway.


HPLC of trichothecenes - Separation of neosolaniol, NT-1 toxin, and NT-2 toxin.
A high pressure liquid chromatographic (HPLC) method is described for the isolation of trichothecenes formed on moldy rice. Extraction of the cultures was followed by purification and fractionation with a C18-Sep Pak cartridge. The polar fraction contained neosolaniol, 4,8-diacetoxy-12,13-epoxytrichothec-9-ene-3,15-diol (NT-1) and 4-acetoxy-12,13-epoxytrichothec-9ene-3,8,15-triol (NT-2), while in another fraction HT-2 toxin, T-2 toxin and acetyl-T-2 toxin were eluted. A high pressure liquid chromatograph equipped with a C18 μ Bondapak column and an R I-detector (differential refractometer) were used for the isolation procedure.


The wisdom in ISCHEMIA.
The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) study was published recently demonstrating that over a period of 3.3 years a routine invasive approach along with optimised medical therapy (OMT) was not superior to OMT alone in patients with stable coronary artery disease and at least moderate to severe ischemia. Considerable interest and discussion have emerged over the applicability of the trial to real-world settings and the limitations of the trial. Given the fact that no clinical trial will ever be designed that will be perfect, it is important to prise out the pearls that the findings reveal and not interpret the findings as either positive or negative towards one approach or the other.