Midwives' knowledge of pre-eclampsia management: A scoping review.
Pre-eclampsia is a multi-organ disease affecting pregnant women from the second trimester onwards resulting in multiple adverse outcomes. Sub-optimal treatment of pre-eclampsia is linked with unfavorable outcomes. It is critical for midwives as primary providers to be competent in the diagnosis and management of pre-eclampsia especially in low-and middle-income countries. To identify what midwives' around the world know about pre-eclampsia management. A scoping review using the JBI three-step search strategy was used to identify relevant research articles and grey literature on the subject. Database searches in PubMed, CINAHL, Cochrane Databases, Web of Science, and Scopus yielded twenty papers in addition to nine guidelines from Google Scholar. The findings were synthesised using a metasynthesis approach and presented as themes. Four themes were identified from the extracted data: Foundational knowledge of pre-eclampsia; Knowledge and management of a woman with pre-eclampsia according to guidelines; Knowledge of being prepared for emergency procedures and management of emergencies; Factors influencing knowledge. The first three themes addressed diagnosis and management whilst the last theme described how contextual factors led to either increased or decreased knowledge of pre-eclampsia. Worldwide, practicing midwives lack knowledge on several aspects of pre-eclampsia diagnosis and care. Policies on in-service training should be oriented to include innovative non-traditional methods that have the potential to increase midwives' knowledge.


Overnight dynamics in scale-free and oscillatory spectral parameters of NREM sleep EEG.
Unfolding the overnight dynamics in human sleep features plays a pivotal role in understanding sleep regulation. Studies revealed the complex reorganization of the frequency composition of sleep electroencephalogram (EEG) during the course of sleep, however the scale-free and the oscillatory measures remained undistinguished and improperly characterized before. By focusing on the first four non-rapid eye movement (NREM) periods of night sleep records of 251 healthy human subjects (4-69 years), here we reveal the flattening of spectral slopes and decrease in several measures of the spectral intercepts during consecutive sleep cycles. Slopes and intercepts are significant predictors of slow wave activity (SWA), the gold standard measure of sleep intensity. The overnight increase in spectral peak sizes (amplitudes relative to scale-free spectra) in the broad sigma range is paralleled by a U-shaped time course of peak frequencies in frontopolar regions. Although, the set of spectral indices analyzed herein reproduce known age- and sex-effects, the interindividual variability in spectral slope steepness is lower as compared to the variability in SWA. Findings indicate that distinct scale-free and oscillatory measures of sleep EEG could provide composite measures of sleep dynamics with low redundancy, potentially affording new insights into sleep regulatory processes in future studies.


Relationship of Vitamin D Deficiency and Fatty Liver in Children as Defined by Multiple Imaging and Histologic Endpoints.
The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population. Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically. N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores. VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.


Kidney disease in aging.
There is an increasing number of elderly patients with glomerulonephritis. A number of reports regarding renal function [1-9] and morphology [10-13] in aged people have been published. However, few studies have been reported on the effect of glomerulonephritis on the kidneys of aged patients. Recently, some articles concerning renal function and histological changes in aged nephritic patients were reported [14]. Several reports about the effects of aging in an experimental kidney disease model [15-23] and on cultured renal cells [22, 24, 25] have been published. This review will focus mainly on the mechanisms of the decrease in renal function and morphological changes with aging.


Caveolae-mediated internalization of extracellular HIV-1 tat fusion proteins visualized in real time.
The Tat protein from HIV-1, when fused with heterologous proteins or peptides, can traverse cell membranes. This ability has generated great interest due to potential therapeutic applications. However, the relevant cellular pathway and its dynamics have not been elucidated yet. Here we unravel the intracellular fate of exogenously added Tat fused with green fluorescent protein (GFP) in live HeLa and CHO cells, from the early interaction with the plasma membrane up to the long-term accumulation in the perinuclear region. We demonstrate that the internalization process of full-length Tat and of heterologous proteins fused to the transduction domain of Tat exploits a caveolar-mediated pathway and is inhibited at 4 degrees C. Remarkably, a slow linear movement toward the nucleus of individual GFP-tagged Tat-filled caveolae with an average velocity of 3 micro m/h was observed. No fluorescence was observed in the nucleus, possibly suggesting that Tat fusion protein unfolding is required for nuclear translocation. In addition, early sensitivity to cytochalasin-D treatment indicates the essential role of the actin cytoskeleton in the displacement of Tat vesicles toward the nucleus. Our results imply that HIV-1 Tat mediates the internalization of protein cargos in a slow and temperature-dependent manner by exploiting the caveolar pathway.


Hazard identification of the potential for dieldrin carcinogenicity to humans.
Although dieldrin׳s use in the U.S. was partially banned in the 1970s and its use was completely eliminated in 1987, dieldrin continues to be a common contaminant at hazardous waste sites. The USEPA׳s current cancer potency estimate for dieldrin was derived in 1987 and is based on the production of mouse liver tumors. Because of its environmental persistence and its relatively high USEPA cancer potency estimate, dieldrin functions as a cleanup "driver" in many hazardous site remediations. Since 1987, new risk assessment perspectives and new data on dieldrin׳s carcinogenic potential have arisen. This review presents a reassessment of dielrin׳s human cancer potential in light of these new data and new perspectives. Based on this reassessment, dieldrin may be carcinogenic through multiple modes of action. These modes of action may operate within the same tissue, or may be specific to individual tissues. Of the several possible carcinogenic modes of action for dieldrin, one or more may be more relevant to human cancer risk than others, but the relative importance of each is unknown. In addition, neither the details of the possible modes of action, nor the shape of the tumor dose-response curves associated with each are sufficiently well known to permit quantitative cancer dose-response modeling. Thus, the mouse liver tumor data used by the USEPA in its 1987 assessment remain the only quantitative data available for cancer dose-response modeling.


Manipulating the microbiome to enhance oral tolerance in food allergy.
Loss of oral tolerance (OT) to food antigens results in food allergies. One component of achieving OT is the symbiotic microorganisms living in the gut (microbiota). The composition of the microbiota can drive either pro-tolerogenic or pro-inflammatory responses against dietary antigens though interactions with the local immune cells within the gut. Products from bacterial fermentation, such as butyrate, are one of the main communication molecules involved in this interaction, however, this is released by a subset of bacterial species. Thus, strategies to specifically expand these bacteria with protolerogenic properties have been explored to complement oral immunotherapy in food allergy. These approaches either provide digestible biomolecules to induce beneficial bacteria species (prebiotics) or the direct administration of live bacteria species (probiotics). While this combined therapy has shown positive outcomes in clinical trials for cow's milk allergy, more research is needed to determine if this therapy can be extended to other food allergens.


Density triggers maternal hormones that increase adaptive offspring growth in a wild mammal.
In fluctuating environments, mothers may enhance the fitness of their offspring by adjusting offspring phenotypes to match the environment they will experience at independence. In free-ranging red squirrels, natural selection on offspring postnatal growth rates varies according to population density, with selection favoring faster-growing offspring under high-density conditions. We show that exposing mothers to high-density cues, accomplished via playbacks of territorial vocalizations, led to increased offspring growth rates in the absence of additional food resources. Experimental elevation of actual and perceived density induced higher maternal glucocorticoid levels, and females with naturally or experimentally increased glucocorticoids produced offspring that grew faster than controls. Therefore, social cues reflecting population density were sufficient to elicit increased offspring growth through an adaptive hormone-mediated maternal effect.


Determination of estrogen ring D glucuronides in pregnancy plasma by direct radioimmunoassay without hydrolysis.
A direct radioimmunoassay method using highly specific antisera without prior deconjugation has been developed for determination of estradiol 17-glucuronide and estriol 16-glucuronide in human plasma. Antisera were elicited in the rabbit by immunization with antigens in which the steroid haptens are linked to a carrier protein through the C-2 or C-4 position. After treatment with Rivanol the protein of albumin-free antiserum was covalently bound to a p-arylamine glass bead support through the cross-linkage with glutaraldehyde. A simple and reliable assay method employing the antibody-glass preparation was established and applied to measurement of estrogen ring D glucuronide concentration in peripheral plasma throughout normal pregnancy.


Purification and properties of peroxisomal carnitine palmitoyltransferase in chick embryo liver.
Peroxisomal carnitine palmitoyltransferase was purified by solubilization using Tween 20 and KCl from the large granule fraction of the liver of clofibrate-treated chick embryo, DEAE-Sephacel and blue Sepharose CL-6B column chromatography. The peroxisomal carnitine palmitoyltransferase was an Mr 64,000 polypeptide; the mitochondrial carnitine palmitoyltransferase had a subunit molecular weight of 69,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The carnitine acetyltransferase was an Mr 64,000 polypeptide. Antibody against purified peroxisomal carnitine palmitoyltransferase reacted only with peroxisomal carnitine palmitoyltransferase, but not with mitochondrial carnitine palmitoyltransferase or carnitine acetyltransferase. In addition, anti-peroxisomal carnitine palmitoyltransferase reacted only with the protein in peroxisomes purified from chick embryo liver by sucrose density gradient centrifugation. Thus, it was confirmed that purified peroxisomal carnitine palmitoyltransferase was a peroxisomal protein. Compared with mitochondrial carnitine palmitoyltransferase, peroxisomal carnitine palmitoyltransferase was extremely resistant to inactivation by trypsin. The pH optimum of peroxisomal carnitine palmitoyltransferase was 8.5, differing from that of mitochondrial carnitine palmitoyltransferase. The Km value of peroxisomal carnitine palmitoyltransferase for palmitoyl-CoA (32 microM) was similar to that of the mitochondrial one, whereas those values for L-carnitine (140 microM), palmitoyl-L-carnitine (43 microM) and CoA (9 microM) were lower than those of mitochondrial carnitine palmitoyltransferase. Peroxisomal carnitine palmitoyltransferase exhibited similar substrate specificities in both the forward and reverse reactions, with the highest activity toward lauroyl derivatives. Furthermore, this enzyme showed relatively high affinities for long-chain acyl derivatives (C10-C16) and similar Km values (30-50 microM) for acyl-CoAs, acylcarnitine and CoA, and a constant Km value (approximately 150 microM) for carnitine. These results indicate that peroxisomal carnitine palmitoyltransferase played a role in the modulation of the intracellular CoA/long-chain acyl-CoA ratio at the hatching stage of chicken when long-chain fatty acids are actively oxidized in peroxisomes.


Clinical nurse specialist leadership in computerized provider order entry design.
The purpose of this clinical project was to design and implement a computerized provider order entry system. Well-designed clinical computer systems can advance best practice and quality decision making, leading to improvements in patient and organizational outcomes. An Orders Design Group composed of clinical nurse specialists (CNSs), staff nurses, and information management personnel was formed. CNSs used competencies in the system sphere to lead the integration of the needs of patients, nurses, and organizations into new technologies. CNSs facilitated implementation of a collaboratively designed interdisciplinary computerized order entry process. Evaluation of the design and implementation process demonstrated greater success with the order entry system under the leadership of CNSs than past initiatives where CNSs were not in leadership roles. CNS competencies in designing and implementing innovative system-level solutions are key to clinical information systems design.


Polymorphonuclear leukocytes labeled with technetium-99m HMPAO. A potential bone marrow imaging agent.
A case of multifocal avascular necrosis of the bone complicating systemic lupus erythematosis is presented in which the extent of involvement was incidentally identified by Tc-99m HMPAO leukocyte imaging. Leukocytes labeled with Tc-99m HMPAO may be an excellent bone marrow imaging agent.


Long-term efficacy of complete trigonal electrofulguration for women with recurrent urinary tract infections.
Recurrent urinary tract infections (R-UTIs) have a negative impact on quality of life and contribute to antimicrobial resistance. Long-term antibiotic therapy is the main treatment alternative but, in some cases, this approach may not be accepted by the patient, is ineffective or poorly tolerated. In selected women, electrofulguration (EF) of trigonal lesions has been shown to reduce urinary tract infection (UTI) episodes. Between August 2006 and December 2017, 73 women with R-UTI had their data collected prospectively and analyzed. We evaluated the rate of UTIs during the initial 2 years of follow-up after fulguration based on symptoms and a positive urine culture. All patients failed with multiple antibiotic courses and were offered endoscopic electrofulguration of the entire trigonal and bladder neck mucosa with a rollerball probe. We present our long-term results using a strategy of complete fulguration of the trigone in women with R-UTIs. The median age was 64 years (range: 17-76 years) and the median follow-up time after EF was 4.2 years (range: 2.5-14 years). Overall, 70 patients (96%) remained free of UTI episodes during the first year of follow-up, at 2 years of follow-up, 57, 53% remained infection-free. Currently, UTIs are typically sparse, mild, and caused by multisensitive bacteria. Complete trigonal and bladder neck mucosal fulguration promoted a significant reduction of UTI episodes during the first 2 years of follow-up. Prospective controlled studies are needed to determine the role of EF in women with R-UTI.


[A new linear neural network multi-component analysis method and its application in the analysis of VC yinqiao tablets quantitative analysis].
We measured NIR spectrum of VC yinqiao tablets with spectral instrument, analyzed the contents of acetaminophen and vitamin C in the VC yinqiao tablets with principal component analysis (PCA) and Linear Neural Network, and discussed the choice of principal component number and ANN's parameters affecting the network. To compare arithmetic performance, the authors also processed the spectral data with partial least squares and PCA-BP neural network. Compared with other two data process methods, the experiment and the result of data process showed that the PCA-linear neural network possess the best forecasting precision.


Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival.
Sphingosine kinase 1 catalyses formation of the bioactive lipid, sphingosine 1-phosphate, which protects cancer cells from apoptosis. Therefore, sphingosine kinase 1 is a novel target for intervention with anti-cancer agents. We have assessed the effect of the anti-cancer agent, resveratrol and its dimers (ampelopsin A and balanocarpol) on sphingosine kinase 1 activity and on survival of MCF-7 breast cancer cells. Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on sphingosine kinase 1 activity and expression, [(3)H] thymidine incorporation, ERK-1/2 phosphorylation and PARP activity assessed in MCF-7 cells. Resveratrol, ampelopsin A and balanocarpol were novel inhibitors of sphingosine kinase 1 activity. Balanocarpol was a mixed inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 90 ± 10 µM and a K(iu) of ∼500 µM. Balanocarpol and ampelopsin A also induced down-regulation of sphingosine kinase 1 expression and reduced DNA synthesis, while balanocarpol stimulated PARP cleavage in MCF-7 breast cancer cells. Resveratrol was a competitive inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 160 ± 40 µM, reduced sphingosine kinase 1 expression and induced PARP cleavage in MCF-7 cells. Each molecule of balanocarpol may bind at least two sphingosine kinase 1 catalytic molecules to reduce the activity of each simultaneously. These findings suggest that resveratrol, ampelopsin A and balanocarpol could perturb sphingosine kinase 1-mediated signalling and this might explain their activity against MCF-7 breast cancer cells.


Extracellular matrix protein ITGBL1 promotes ovarian cancer cell migration and adhesion through Wnt/PCP signaling and FAK/SRC pathway.
Despite the advances in cancer treatment and the progresses in tumor biological, ovarian cancer remains a bad situation. In current study, we found a novel extracellular matrix protein, ITGBL1, which is highly expressed in ovarian cancer tissues by immunohistochemistry examination. The expression pattern of ITGBL1 in malignant tissues inspired us to investigate its role in ovarian cancer progression. Both loss- and gain-function assays revealed that ITGBL1 could promote ovarian cancer cell migration and adhesion. As it's a secreted protein, we further used recombinant ITGBL1 protein treated cancer cells and found that ITGBL1 promotes cell migration and adhesion in a concentration dependent manner. Furthermore, we found that ITGBL1 not only influences the activity of Wnt/PCP signaling but also affects FAK/src pathway in vitro. Taken together, our results suggest that highly expressed ITGBL1 could promotes cancer cell migration and adhesion in ovarian cancer and as a secreted protein, ITGBL1 might be a novel biomarker for ovarian cancer diagnosis.


The first identification of azaspiracids in shellfish from France and Spain.
Incidents of human intoxications throughout Europe, following the consumption of mussels have been attributed to Azaspiracid Poisoning (AZP). Although first discovered in Ireland, the search for the causative toxins, named azaspiracids, in other European countries has now led to the first discovery of these toxins in shellfish from France and Spain. Separation of the toxins, azaspiracid (AZA1) and analogues, AZA2 and AZA3, was achieved using isocratic reversed-phase liquid chromatography coupled, via an electrospray ionisation source, to an ion-trap mass spectrometer. Azaspiracids were identified in mussels (Mytilus galloprovincialis), 0.24 microg/g, from Galicia, Spain, and scallops (Pecten maximus), 0.32 microg/g, from Brittany, France. Toxin profiles were similar to those found in the equivalent shellfish in Ireland in which AZA1 was the predominant toxin.


Estimating incidence of venous thromboembolism in COVID-19: Methodological considerations.
Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID-19). Specifically, venous thromboembolism (VTE) has been reported as a frequent complication. By May 27, 2021, at least 93 original studies and 25 meta-analyses investigating VTE incidence in patients with COVID-19 had been published, showing large heterogeneity in reported VTE incidence ranging from 0% to 85%. This large variation complicates interpretation of individual study results as well as comparisons across studies, for example, to investigate changes in incidence over time, compare subgroups, and perform meta-analyses. This study sets out to provide an overview of sources of heterogeneity in VTE incidence studies in patients with COVID-19, illustrated using examples. The original studies of three meta-analyses were screened and a list of sources of heterogeneity that may explain observed heterogeneity across studies was composed. The sources of heterogeneity in VTE incidence were classified as clinical sources and methodologic sources. Clinical sources of heterogeneity include differences between studies regarding patient characteristics that affect baseline VTE risk and protocols used for VTE testing. Methodologic sources of heterogeneity include differences in VTE inclusion types, data quality, and the methods used for data analysis. To appreciate reported estimates of VTE incidence in patients with COVID-19 in relation to its etiology, prevention, and treatment, researchers should unambiguously report about possible clinical and methodological sources of heterogeneity in those estimates. This article provides suggestions for that.


Development of lysolipid-based thermosensitive liposomes for delivery of high molecular weight proteins.
The purpose of the present investigation was to determine the feasibility of using lysolipid-based thermal sensitive liposomes (145nm) for high molecular weight molecule delivery. Fluorescein isothiocyanate conjugate-albumin was used as a model drug (MW 66kDa). Thermal sensitive liposomes, which encapsulated the protein were prepared using a passive encapsulation methodology involving freeze-thawing cycles followed by extrusion. In vitro release studies at various temperatures indicated rapid release behaviour of the encapsulated protein at 42 and 44.5°C but a good stability at 37.5°C. The current findings suggest that lysolipid-based thermal sensitive liposomes can be used to deliver high molecular weight molecules.


Simultaneous determination of absorption of selenium from poultry meat and selenite in young men: application of a triple stable-isotope method.
A triple stable-isotope method was used to estimate simultaneously selenium absorption from poultry meat intrinsically labelled with 74Se and from an extrinsic tracer of 76SeO3(2-) in four young adult men. The subjects received an experimental diet based on chicken meat as the source of protein. Two diet periods, lasting from 5 to 10 d, depending on the frequency of stool output for each subject, were conducted to allow duplicate determinations within each subject of Se absorption from both sources. Absorption of Se was determined by the faecal isotope balance procedure through monitoring the stable isotopes 74Se, 76Se and 80Se by means of radiochemical neutron activation analysis. For the separate periods, mean (with SEM) absorption of 74Se from the intrinsically-labelled poultry meat was 70.9 (1.5)% and 72.0 (2.5)%. The absorption of Se from 76SeO3(2-) was 34.7 (5.5)% and 37.6 (3.2)% during the same periods. From these results it is concluded that, under the present experimental conditions, the intrinsic and extrinsic Se isotopes did not form a common pool before absorption. Possible reasons for this are discussed.


Endoscopic laser treatment of benign tracheal stenoses.
We present the technique and results of endoscopic neodymium-yttrium aluminum garnet laser treatment of benign tracheal stenoses. This therapy was used in 15 patients with tracheal stenoses. Benign tracheal granulomas were caused by prolonged tracheal intubation in eight patients, permanent maintenance of tracheostomy tube in five patients, and nonspecific inflammatory process of the trachea in two patients. The clinical picture was dominated by dyspnea and stridor. The achievement of normal tracheal patency required several laser therapy sessions, repeated at 5- to 7-day intervals. In 30% of patients additional laser vaporization was required as well. The immediate and short-term results were encouraging; in all cases the normal tracheal lumen was restored, resulting in alleviation of patients' symptoms.


Applications of neural networks to colour recognition.
Colour specification and matching are important tasks used in a number of different industries. However, current methods can employ very complicated, elaborate pieces of laboratory equipment which are not portable, such as spectrophotometers with combinations of calibrated light sources and a large number of narrow band filters. Simpler, portable devices are typically not sophisticated enough to give a high degree of quality control due to the less sophisticated light sources and the necessarily smaller number of filters employed. Lastly, techniques such as the 'match by eye' method can lead to deceptive metameric matches. This paper outlines the beginning of the development of a colour measurement system which is portable, easy to use, and more accurate than other portable devices by virtue of an artificial neural network used to analyze the data. With specialized training of the neural network, it could even be used in applications such as teeth and skin colour measurements.


Comparative transcriptome sequencing analysis to postulate the scheme of regulated leaf coloration in Perilla frutescens.
Perilla as herb, ornamental, oil and edible plant is widely used in East Asia. Until now, the mechanism of regulated leaf coloration is still unclear. In this study, four different kinds of leaf colors were used to measure pigment contents and do transcriptome sequence to postulate the mechanism of leaf coloration. The measurements of chlorophyll, carotenoid, flavonoid, and anthocyanin showed that higher contents of all the aforementioned four pigments were in full purple leaf 'M357', and they may be determined front and back leaf color formation with purple. Meanwhile, the content of anthocyanin was controlled back leaf coloration. The chromatic aberration analysis and correlative analysis between different pigments and L*a*b* values analysis also suggested front and back leaf color change was correlated with the above four pigments. The genes involved in leaf coloration were identified through transcriptome sequence. The expression levels of chlorophyll synthesis and degradation related genes, carotenoid synthesis related genes and anthocyanin synthesis genes showed up-/down-regulated expression in different color leaves and were consistent of accumulation of these pigments. It was suggested that they were the candidate genes regulated perilla leaf color formation, and genes including F3'H, F3H, F3',5'H, DFR, and ANS are probably important for regulating both front and back leaf purple formation. Transcription factors involved in anthocyanin accumulation, and regulating leaf coloration were also identified. Finally, the probable scheme of regulated both full green and full purple leaf coloration and back leaf coloration was postulated.


A caspase-resistant form of Bcl-X(L), but not wild type Bcl-X(L), promotes clonogenic survival after ionizing radiation.
Bcl-2 and Bcl-X(L) belong to a family of proteins overexpressed in a variety of human cancers which inhibit apoptosis in response to a number of stimuli including chemotherapeutic agents and ionizing radiation. To better understand the role of these polypeptides in modulating the response of cancer cells to ionizing radiation we used cell lines that were engineered to overexpress the two polypeptides. Although Bcl-2 and Bcl-X(L) overexpression resulted in inhibition of radiation-induced apoptosis, it did not result in enhanced clonogenic survival. Consistent with this was the observation that Bcl-2 and Bcl-X(L) protected cells from DNA fragmentation, loss of mitochondrial membrane potential, and caspase activation for up to 72 hours after irradiation. Beyond 72 hours, there was a rapid loss in the ability of Bcl-2 and Bcl-X(L) to inhibit these markers of apoptosis. When Bcl-X(L) was analyzed at 72 hours after irradiation and beyond, a rapid accumulation of a 16-kDa form of Bcl-X(L) was observed. To test the hypothesis that cleavage of the 29-kDa form of Bcl-X(L) by caspases to a 16-kDa polypeptide results in its inability to inhibit apoptosis beyond 72 hours, we constructed a cell line that overexpressed a caspase-resistant form of Bcl-X(L) (Bcl-X(L)-deltaloop). Cells overexpressing Bcl-X(L)-deltaloop were resistant to apoptosis beyond 72 hours after irradiation and did not contain the 16-kDa form at these time points. In addition, Bcl-X(L)-deltaloop overexpression resulted in enhanced clonogenic survival compared with control or Bcl-X(L) overexpressing cells. These results provide a molecular basis for the observation that expression of Bcl-2 or Bcl-X(L) is not a prognostic marker of tumor response to cancer therapy.


Mitogenic and anti-apoptotic actions of adipocyte-derived hormone leptin in prostate cancer cells.
To investigate the proliferative and anti-apoptotic effects of leptin on human prostate cancer cells, and the role of related signalling pathways in mediating these actions, as obesity is a possible risk factor for prostate cancer and leptin, an adipocyte-derived hormone, has mitogenic action in various cell types. Two human prostate cancer cell lines, DU145 and PC-3, were treated with leptin (5-100 ng/mL) for up to 48 h. Under serum-free conditions, cell proliferation was measured using a colorimetric tetrazolium assay and apoptosis by an enzyme-linked immunosorbent assay measuring cell death. Also, the phosphorylation of ERK1/2 and Akt was detected by Western blotting, and specific inhibitors of mitogen-activated protein kinase (MAPK) (PD98059; 40 microm) and phosphatidylinositol 3-kinase (PI3-K, LY294002; 40 microm) were used to evaluate the role of these signalling pathways. Leptin dose-dependently increased the cell number in both cell lines for up to 48 h of incubation, the mean (sem) percentage of the control being 189 (4.3)% for DU145 and 173 (7.5)% for PC-3 (100 ng/mL leptin, 48 h; P < 0.01). Leptin also significantly reduced the number of apoptotic cells after 24 h of treatment, dose-dependently caused ERK1/2 and Akt phosphorylation; pretreatment with inhibitors of MAPK and PI3-K inhibited these responses. These results show that chronic increases in leptin might enhance the growth of prostate cancer via the MAPK and PI3-K pathways. Further studies are needed to investigate whether the ability of leptin to stimulate mitogenic/anti-apoptotic signal transduction pathways could represent a target for anticancer drug discovery.


Emerging nanotherapeutics for antithrombotic treatment.
Thrombus causes insufficient blood flow and ischemia damages to brain and heart, leading to life-threatening cardio-cerebrovascular diseases. Development of efficient antithrombotic strategies has long been a high priority, owing to the high morbidity and mortality of thrombotic diseases. With the rapid development of biomedical nanotechnology in diagnosis and treatment of thrombotic disorder, remarkable progresses have been made in antithrombotic nanomedicines in recent years. Herein, we outline the recent advances in this field at the intersection of thrombus theranostics and biomedical nanotechnology. First, thrombus diagnosis techniques based on biomedical nanotechnology are presented. Then, emerging antithrombotic nanotherapeutics are overviewed, including thrombus-targeting strategies, thrombus stimuli-responsive nanosystems and phase transition-driven nanotherapeutics. Furthermore, multifunctional nanosystems for combination theranostics of thrombotic diseases are discussed. Finally, the design considerations, advantages and challenges of these biomedical nanotechnology-driven therapeutics in clinical translation are highlighted.


VOGT-KOYANAGI-HARADA DISEASE-LIKE UVEITIS IN A PATIENT WITH ADVANCED MELANOMA TREATED BY SEQUENTIAL ADMINISTRATION OF NIVOLUMAB AND DABRAFENIB/TRAMETINIB THERAPY.
To describe a case of bilateral Vogt-Koyanagi-Harada (VKH)-like uveitis during treatment with dabrafenib and trametinib and three months after discontinuation of nivolumab for malignant melanoma, and discuss the possible (synergistic) role(s) of mitogen-activated protein kinase (MAPK) inhibitors and immune checkpoint inhibitors in its pathophysiology. Retrospective case report with fluorescein angiography and optical coherence tomography. A 55-year old patient with metastatic melanoma presented with a complaint of gradually worsening blurry vision in the right eye during treatment with dabrafenib and trametinib, three months after discontinuation of nivolumab. Based on the clinical examination, optical coherence tomography and fluorescein angiography findings, and a thorough laboratory work-up, he was diagnosed with a bilateral VKH-like uveitis without extraocular manifestations. The uveitis responded well to oral corticosteroids. Vogt-Koyanagi-Harada-like uveitis is a rare adverse effect of MAPK inhibitors and immune checkpoint inhibitors. Similar pathogenetic mechanisms including a drug-induced autoimmunity targeted against benign and malignant melanocytes may underlie MAPK inhibitor-induced and immune checkpoint inhibitors-induced VKH-like uveitis. In our report, the patient developed a VKH-like uveitis during MAPK inhibition therapy, four months after discontinuation of nivolumab. It is difficult to delineate whether MAPK inhibition alone was responsible for this adverse effect, or whether, on the contrary, potentiation occurred as a result of immune modulation by previous treatment with an immune checkpoint inhibitor. Further cases are needed to further clarify this latter hypothesis.


Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor.
We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ratio of the initial lead led to the discovery of 5 and 23 (EC50=111 and 5 nM, respectively).


[Comparison, using RAST-inhibition, of the allergenic potency of Dermatophagoides pteronyssinus extracts obtained from: whole mite culture, fraction of enriched mite culture, fraction of feces enriched culture, purified mite bodies, commercial extracts].
The RAST-inhibition potency has been obtained from five extracts prepared by: whole mite culture, mites-enriched culture, faeces-enriched culture, purified mite bodies, commercial extract. The present study demonstrates that extracts of: a) purified bodies, and b) faeces-enriched culture are both potent preparations in RAST-inhibition.


Engineering tumor-derived small extra cellular vesicles to encapsulate miR-34a, effectively inhibits 4T1 cell proliferation, migration, and gene expression.
Tumor cells produce small extra cellular vesicles-(tsEV) massively, which act as cancer messengers that may also have anti-cancer effects. Based on this knowledge, we hypothesized that we can benefit from 4T1-derived sEVs to amplify the anti-cancer effects of miR-34a-replacement therapy in 4T1 cells. Supernatant of 4T1 cultured cells gathered after 24 h of exposure to serum-free media. tsEVs purified by commercial kit and characterized by transmission and scanning electron microscopy, dynamic light scattering, and bicinchoninic acid assay. Modified CaCl2 method applied for miR-34a loading in tsEV (tsEV-miR) and loading confirmation evaluated by the relative expression of miR-34a. MTT, annexin V/PI, cell cycle, scratch test, and real-time PCR were performed for proliferation, apoptosis, invasion, and relative expression of miR-34a target genes after treatment with tsEV/tsEV-miR, respectively. The results indicated that tsEV-miR provides a time-dose-dependent anti-proliferative effect versus tsEV/control group. tsEV-miR could induce apoptosis and arrest the cell cycle at G0/G1 phase, and moreover, it effectively halted the invasion capability of 4T1 cells. Treatment with tsEV-miR down-regulated miR-34a target genes, including B-cell lymphoma-2, vascular endothelial growth factor and its receptor, matrix metalloproteinase-2 and -9, and interleukin-6. Engineered tsEVs can affect different aspects of 4T1 cancer cells including proliferation, apoptosis, cell cycle, migration, and cancer-related gene expression profile. In this regard, tsEV could be considered a proper vehicle for miR-34a replacement therapy and could exacerbate its anti-cancer effects in triple-negative breast cancer. Indeed, TNBC can be targeted by multiple angles by its weapon.


The clinical development of mupirocin.
Mupirocin is a novel antibiotic totally unrelated in chemical structure and mode of action to any other clinically useful class of antibiotics. It has greatest antibacterial activity against aerobic gram-positive cocci, namely, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and other beta-hemolytic streptococci. Bactroban ointment is formulated as 2% mupirocin in polyethylene glycol ointment. No systemic absorption of mupirocin or its major metabolite, monic acid, has been detected in short courses of topical administration to healthy volunteers or to patients with epidermolysis bullosa after prolonged courses of therapy with Bactroban ointment. Randomized, multicenter, double-blind, vehicle-controlled clinical trials have shown that mupirocin is safe and effective for the treatment of impetigo.


Bone marrow transplantation correcting beta-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis.
Donor bone marrow engraftment, which resulted in complete normalization of white cell beta-galactosidase levels in a patient with presymptomatic juvenile onset GM1-gangliosidosis (McKusick 230600), did not improve long-term clinical outcome.


Donor-dependent aging of young and old red blood cell subpopulations: Metabolic and functional heterogeneity.
Characteristics of red blood cells (RBCs) are influenced by donor variability. This study assessed quality and metabolomic variables of RBC subpopulations of varied biologic age in red blood cell concentrates (RCCs) from male and female donors to evaluate their contribution to the storage lesion. Red blood cell concentrates from healthy male (n = 6) and female (n = 4) donors were Percoll separated into less dense ("young", Y-RCCs) and dense ("old", O-RCCs) subpopulations, which were assessed weekly for 28 days for changes in hemolysis, mean cell volume (MCV), hemoglobin concentration (MCHC), hemoglobin autofluorescence (HGB), morphology index (MI), oxygen affinity (p50), rigidity, intracellular reactive oxygen species (ROS), calcium ([Ca2+ ]), and mass spectrometry-based metabolomics. Young RCCs having disc-to-discoid morphology showed higher MCV and MI, but lower MCHC, HGB, and rigidity than O-RCCs, having discoid-to-spheroid shape. By Day 14, Y-RCCs retained lower hemolysis and rigidity and higher p50 compared to O-RCCs. Donor sex analyses indicated that females had higher MCV, HGB, ROS, and [Ca2+ ] and lower hemolysis than male RBCs, in addition to having a decreased rate of change in hemolysis by Day 28. Metabolic profiling indicated a significant sex-related signature across all groups with increased markers of high membrane lipid remodeling and antioxidant capacity in Y-RCCs, whereas O-RCCs had increased markers of oxidative stress and decreased coping capability. The structural, functional, and metabolic dissimilarities of Y-RCCs and O-RCCs from female and male donors demonstrate RCC heterogeneity, where RBCs from females contribute less to the storage lesion and age slower than males.


Fickian yet non-Gaussian diffusion of a quasi-2D colloidal system in an optical speckle field: experiment and simulations.
We investigate a quasi-2D suspension of Brownian particles in an optical speckle field produced by holographic manipulation of a laser wavefront. This system was developed to study, in a systematic and controllable way, a distinctive instance of diffusion, called Fickian yet Non Gaussian diffusion (FnGD), observed, during the last decade, for colloidal particles in a variety of complex and biological fluids. Our setup generates an optical speckle field that behaves like a disordered set of optical traps. First, we describe the experimental setup and the dynamics of the particles, focusing on mean square displacements, displacement distributions and kurtosis. Then, we present Brownian Dynamics simulations of point-like particles in a complex energy landscape, mimicking that generated by the optical speckle field. We show that our simulations can capture the salient features of the experimental results, including the emergence of FnGD, also covering times longer than the ones so far achieved in experiments. Some deviations are observed at long time only, with the Gaussian restoring being slower in simulations than in experiments. Overall, the introduced numerical model might be exploited to guide the design of upcoming experiments targeted, for example, to fully monitor the recovery of Gaussianity.


Compassion fatigue and burnout amongst clinicians: a medical exploratory study.
Compassion fatigue is a broad term comprising of two components - burnout and secondary traumatic stress. The current study is aimed at identifying 'burnout' and 'compassion fatigue' among clinicians involved in care of individuals suffering from medical illness. A total of 60 clinicians were included in the study. A semi-structured questionnaire was administered to gather information related to personal, professional, anthropometric, and metabolic profile of the study participants. Professional Quality of Life Scale (ProQoL Version V) was used to assess burnout, compassion satisfaction and secondary traumatic stress. Analysis was carried out using the SPSS version 19.0. The mean age of clinicians was 46.68±11.06 (range 26-67 years). Burnout score was significantly higher in those involved in diabetology practice. Similarly, compassion satisfaction score was greater among those with greater years of practice as well as among those in private practice. Clinicians who reported a poor working condition, as opposed to good, had more burnout and less compassion satisfaction. The current study suggests that it is important to find out ways of decreasing burnout and compassion fatigue among clinicians.


Inhibition of human NK cell cytotoxicity by induction of cyclic AMP depends on impaired target cell recognition.
Induction of cyclic AMP (cAMP) depresses natural killer (NK) cell activity. The present results demonstrate that this is dependent on a decreased capacity of the effector cells to conjugate to target cells. This was found either if dibutyryl-cAMP was used or if cAMP was induced by adenylate cyclase stimulation with prostaglandin E1 (PGE1) or by inhibition of phosphodiesterase activity with the inhibitor ZK 62711. The sites of action for cAMP-induced NK suppression and interferon (IFN)-induced NK enhancement are demonstrated to be distinct, since IFN acts by increasing the lytic efficiency and the recycling capacity without influencing target binding. Sequential treatment with cAMP/IFN and IFN/cAMP shows that IFN can neither restore target binding when added after cAMP nor protect against the cAMP-induced target binding inhibition when added before cAMP. The results are discussed in view of earlier data on cAMP in relation to cell membrane functions and cellular recognition, the mechanism underlying the cAMP-induced target binding inhibition, and the potential of the NK system as an indicator for immunosuppression. The present work also demonstrates the particular subpopulation in peripheral blood which mediates most NK activity, to respond strongly to PGE1 stimulation with regard to cAMP induction.


Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study.
We conducted a 3-year randomized placebo-controlled double-blind study to determine the effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the progress of renal function and histology in subjects with diabetes and microalbuminuria. Forty non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetic subjects, either normotensive or hypertensive, were randomly assigned to receive PE (n = 20) or placebo (n = 20). A percutaneous renal biopsy was performed initially in all patients and repeated in 29 patients after 3 years. The mean glomerular volume, glomerular basement membrane (GBM) thickness, interstitial fibrosis, sclerosed glomeruli, and volume fraction of capillary lumina were measured histomorphometrically. Before treatment, both groups had similar clinical characteristics, blood pressure, glycosylated hemoglobin (Hb), albumin excretion rate, glomerular filtration rate (GFR), serum creatinine, and renal structural damage. Blood pressure was well controlled in both groups. After 3 years' therapy, there was no significant change in renal function and albuminuria in the PE or placebo groups. The increase in GBM thickness in nine paired biopsies was significantly less in PE-treated subjects (P = .0275). Interstitial fibrosis tended to increase less in the PE group, although this did not reach statistical significance. This study indicates that long-term therapy with PE may decrease or delay the progression of structural glomerular damage in microalbuminuric diabetic subjects.


Design, synthesis, and bioactivity evaluation of antitumor sorafenib analogues.
Malignant tumors are a serious threat to human health and are generally treated with chemical therapy. This chemical therapy uses agents that act on signal transduction pathway mechanism of tumor with good selectivity and low toxicity. Sorafenib is a multikinase target inhibitor with good tumor inhibitory activity and a protein kinase inhibitor. In this research, a novel series of sorafenib analogues and derivatives were designed, synthesized, and evaluated as tumor inhibitors. These compounds used sorafenib as the lead compound and achieved modifications using bioisosteres and the alkyl principle. The in vitro the results showed that compounds 3c, 3d, 3h, 3n, 3r, and 3z had good inhibitory effects on human cervical cancer cells (Hela), while compounds 3t and 3v had good inhibitory effects on human lung cancer cells (H1975 and A549). Among these, compound 3d had an inhibitory activity (IC50) of 0.56 ± 0.04 μmol L-1 against Hela cells (human cervical cancer), the compound 3t had an IC50 of 2.34 ± 0.07 μmol L-1 against H1975 cells (human lung cancer), and compound 3v had an IC50 of 1.35 ± 0.03 μmol L-1 against A549 cells (human lung cancer). The in vivo results showed that these compounds had good antitumor effects and low acute toxicity.


Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries.
Approximately 15 million babies are born prematurely every year and many will face lifetime motor and/or cognitive deficits. Children born prematurely are at higher risk of developing perinatal brain lesions, especially white matter injuries (WMI). Evidence in humans and rodents demonstrates that systemic inflammation-induced neuroinflammation, including microglial and astrocyte reactivity, is the prominent processes of WMI associated with preterm birth. Thus, a new challenge in the field of perinatal brain injuries is to develop new neuroprotective strategies to target neuroinflammation to prevent WMI. Serotonin (5-HT) and its receptors play an important role in inflammation, and emerging evidence indicates that 5-HT may regulate brain inflammation by the modulation of microglial reactivity and astrocyte functions. The present study is based on a mouse model of WMI induced by intraperitoneal (i.p.) injections of IL-1β during the first 5 days of life. In this model, certain key lesions of preterm brain injuries can be summarized by (i) systemic inflammation, (ii) pro-inflammatory microglial and astrocyte activation, and (iii) inhibition of oligodendrocyte maturation, leading to hypomyelination. We demonstrate that Htr7 mRNA (coding for the HTR7/5-HT7 receptor) is significantly overexpressed in the anterior cortex of IL-1β-exposed animals, suggesting it as a potential therapeutic target. LP-211 is a specific high-affinity HTR7 agonist that crosses the blood-brain barrier (BBB). When co-injected with IL-1β, LP-211 treatment prevented glial reactivity, the down-regulation of myelin-associated proteins, and the apparition of anxiety-like phenotypes. Thus, HTR7 may represent an innovative therapeutic target to protect the developing brain from preterm brain injuries.


Word learning and phonetic processing in preschool-age children.
Consonants and vowels have been shown to play different relative roles in different processes, including retrieving known words from pseudowords during adulthood or simultaneously learning two phonetically similar pseudowords during infancy or toddlerhood. The current study explores the extent to which French-speaking 3- to 5-year-olds exhibit a so-called "consonant bias" in a task simulating word acquisition, that is, when learning new words for unfamiliar objects. In Experiment 1, the to-be-learned words differed both by a consonant and a vowel (e.g., /byf/-/duf/), and children needed to choose which of the two objects to associate with a third one whose name differed from both objects by either a consonant or a vowel (e.g., /dyf/). In such a conflict condition, children needed to favor (or neglect) either consonant information or vowel information. The results show that only 3-year-olds preferentially chose the consonant identity, thereby neglecting the vowel change. The older children (and adults) did not exhibit any response bias. In Experiment 2, children needed to pick up one of two objects whose names differed on either consonant information or vowel information. Whereas 3-year-olds performed better with pairs of pseudowords contrasting on consonants, the pattern of asymmetry was reversed in 4-year-olds, and 5-year-olds did not exhibit any significant response bias. Interestingly, girls showed overall better performance and exhibited earlier changes in performance than boys. The changes in consonant/vowel asymmetry in preschoolers are discussed in relation with developments in linguistic (lexical and morphosyntactic) and cognitive processing.


Optimal stimulation settings for CMAP scan registrations.
The CMAP (Compound Muscle Action Potential) scan is a non-invasive electrodiagnostic tool, which provides a quick and visual assessment of motor unit potentials as electrophysiological components that together constitute the CMAP. The CMAP scan records the electrical activity of the muscle (CMAP) in response to transcutaneous stimulation of the motor nerve with gradual changes in stimulus intensity. Large MUs, including those that result from collateral reinnervation, appear in the CMAP scan as so-called steps, i.e., clearly visible jumps in CMAP amplitude. The CMAP scan also provides information on nerve excitability. This study aims to evaluate the influence of the stimulation protocol used on the CMAP scan and its quantification. The stimulus frequency (1, 2 and 3 Hz), duration (0.05, 0.1 and 0.3 ms), or number (300, 500 and 1000 stimuli) in CMAP scans of 23 subjects was systematically varied while the other two parameters were kept constant. Pain was measured by means of a visual analogue scale (VAS). Non-parametric paired tests were used to assess significant differences in excitability and step variables and VAS scores between the different stimulus parameter settings. We found no effect of stimulus frequency on CMAP scan variables or VAS scores. Stimulus duration affected excitability variables significantly, with higher stimulus intensity values for shorter stimulus durations. Step variables showed a clear trend towards increasing values with decreasing stimulus number. A protocol delivering 500 stimuli at a frequency of 2 Hz with a 0.1 ms pulse duration optimized CMAP scan quantification with a minimum of subject discomfort, artefact and duration of the recording. CMAP scan variables were influenced by stimulus duration and number; hence, these need to be standardized in future studies.


The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland.
Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). MLD causes progressive loss of motor function and severe decline in cognitive function, leading to premature death. Early diagnosis of MLD provides the opportunity to begin treatment before the disease progresses and causes severe disability. MLD is not currently included in newborn screening (NBS) in the UK.This study consisted of an online survey, and follow-up semi-structured interviews open to MLD patients or caregivers, aged 18 years and over. The aims of the study were to understand the importance of early diagnosis and to establish the views of families and caregivers of patients with MLD on NBS.A total of 24 patients took part in the survey, representing 20 families (two families had two children with MLD, one family had three children with MLD). Following on from the survey, six parents participated in the interviews. Our data showed diagnostic delay from first symptoms was between 0 and 3 years, with a median of 1 year (n = 18); during this time deterioration was rapid, especially in earlier onset MLD. In patients with late infantile MLD (n = 10), 50% were wheelchair dependent, 30% were unable to speak, and 50% were tube fed when a diagnosis of MLD was confirmed. In patients with early juvenile MLD (n = 5), over half used a wheelchair some of the time, had uncontrollable crying, and difficulty speaking (all 60%) before or at the time of diagnosis. A high degree of support was expressed for NBS among caregivers, 95% described it as very or extremely important and 86% believed detection of MLD at birth would have changed their child's future. One parent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child's future: "It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister."The rapid rate of deterioration in MLD makes it an essential candidate for NBS, particularly now the first gene therapy (Libmeldy™) has been approved by the European Medicines Agency. Libmeldy™ has also been recommended as a treatment option in England and Wales by the National Institute for Health and Care Excellence (NICE) and is being made available to patients in Scotland via the Scottish Medicines Consortium's ultra-orphan pathway.


Understanding the COVID-19 tourist psyche: The Evolutionary Tourism Paradigm.
Studies across the social sciences are making increasing use of an evolutionary perspective. Yet, despite its potential, the application of evolutionary psychology in tourism research is scant. Evolutionary psychology is arguably one of the most useful approaches to understanding the effects of the Coronavirus pandemic on the tourist's psyche. This research highlights, explains, and empirically demonstrates the vast untapped potential of this perspective for post-COVID-19 tourism research. The authors develop an Evolutionary Tourism Paradigm, which is based on biological epistemology and theory to address questions in post-COVID-19 tourism research. This paradigm is brought to life through a developed ocean and islands model, and its utility for future research endeavors on the Coronavirus pandemic is empirically demonstrated in two studies.


M2 segment thrombectomy is not associated with increased complication risk compared to M1 segment: A meta-analysis of recent literature.
Recent clinical comparisons of M1 and M2 segment endovascular thrombectomy have reached incongruous results in rates of complication and functional outcomes. This study aims to clarify the controversy surrounding this rapidly advancing technique through literature review and meta-analysis. A Pubmed search was performed (January 2015-September 2019) using the following keywords: "M2 AND ("stroke" OR "occlusion") AND ("thrombectomy" OR "endovascular")". Safety and clinical outcomes were compared between segments via weighted Student's t-test, Chi-square and odds ratio while study heterogeneity was analyzed using Cochran Q and I2 tests. Pubmed identified 208 articles and eleven studies were included after full-text analysis, comprising 2,548 M1 and 758 M2 mechanical thrombectomy segment cases. Baseline National Institutes of Health Stroke Scale scores were comparatively lower in patients experiencing an M2 occlusion (16 ± 1.25 vs 13.6 ± 0.96, p < 0.01). Patients who underwent M2 mechanical thrombectomy were more likely to experience both good clinical outcomes (modified Rankin Scale 0-2) (48.6% vs 43.5% respectively, OR 1.24; CI 1.05-1.47, p = 0.01) and excellent clinical outcomes (modified Rankin Scale 0-1) (34.7% vs. 26.5%%, OR 1.6; CI 1.28-1.99, p < 0.01) at 90 days compared to M1 mechanical thrombectomy. Neither recanalization rates (75.3% vs 72.8%, OR 0.92, CI 0.75-1.13, p = 0.44) nor symptomatic intracranial hemorrhage rates (5.6% vs 4.9%, OR 0.92; CI 0.61-1.39, p= 0.7) were significantly different between M1 and M2 cohorts. Mortality was less frequent in the M2 cohort compared to M1 (16.3% vs 20.7%, OR 0.73; CI 0.57-0.94, p = 0.01). M1 and M2 cohorts did not differ in symptom onset-to-puncture (238.1 ± 46.7 vs 239.8 ± 43.9 min respectively, p=0.488) nor symptom onset-to recanalization times (318.7 ± 46.6 vs 317.7 ± 71.1 min respectively, p = 0.772), though mean operative duration was shorter in the M2 cohort (61.8 ± 25.5 vs 54.6 ± 24 min, p < 0.01). Patients who underwent M2 mechanical thrombectomy had a higher prevalence of good and excellent clinical outcomes compared to the M1 mechanical thrombectomy cohorts. Additionally, our data suggest lower mortality rates in the M2 cohort and symptomatic intracranial hemorrhage rates that are similar to the M1 cohort. Therefore, M2 segment thrombectomy likely does not pose a significantly elevated operative risk and may have a positive impact on patient outcomes.


Goodness-of-fit tests for locus order in three-point mapping.
For the case of three-point linkage analysis, a simple goodness-of-fit test is proposed to test the order of gene loci. To use it for testing one locus order against another, one may apply the principle that evidence for one order comes from lack of fit of the observations to the other order. With n = 30 offspring from a phase known triple backcross mating, at a recombination fraction of 20% between adjacent loci, the test achieves a power of 80% (5% significance level). Interference (real interference as well as interference assumed in the analysis) increases power.


Contamination of N-poor wastewater with emerging pollutants does not affect the performance of purple phototrophic bacteria and the subsequent resource recovery potential.
Propagation of emerging pollutants (EPs) in wastewater treatment plants has become a warning sign, especially for novel resource-recovery concepts. The fate of EPs on purple phototrophic bacteria (PPB)-based systems has not yet been determined. This work analyzes the performance of a photo-anaerobic membrane bioreactor treating a low-N wastewater contaminated with 25 EPs. The chemical oxygen demand (COD), N and P removal efficiencies were stable (76 ± 8, 62 ± 15 and 36 ± 8 %, respectively) for EPs loading rate ranging from 50 to 200 ng L-1 d-1. The PPB community adapted to changes in both the EPs concentration and the organic loading rate (OLR) and maintained dominance with >85 % of total 16S gene copies. Indeed, an increment of the OLR caused an increase of the biomass growth and activity concomitantly with a higher EPs removal efficiency (30 ± 13 vs 54 ± 11 % removal for OLR of 307 ± 4 and 590 ± 8 mgCOD L-1 d-1, respectively). Biodegradation is the main mechanism of EPs removal due to low EPs accumulation on the biomass, the membrane or the reactor walls. Low EPs adsorption avoided biomass contamination, resulting in no effect on its biological methane potential. These results support the use of PPB technologies for resource recovery with low EPs contamination of the products.


Age-dependent cerebrospinal fluid-tissue water exchange detected by magnetization transfer indirect spin labeling MRI.
A non-invasive magnetization transfer indirect spin labeling (MISL) MRI method is developed to quantify the water exchange between cerebrospinal fluid (CSF) and other tissues in the brain and to examine the age-dependence of water exchange. In the pulsed MISL, we implemented a short selective pulse followed by a post-labeling delay before an MRI acquisition with a long echo time; in the continuous MISL, a train of saturation pulses was applied. MISL signal (∆Z) was obtained by the subtraction of the label MRI at -3.5 ppm from the control MRI at 200 ppm. CSF was extracted from the mouse ventricles for the MISL optimization and validation. Comparison between wild type (WT) and aquaporin-4 knockout (AQP4-/- ) mice was performed to examine the contributions of CSF water exchange, whereas its age-dependence was investigated by comparing the adult and young WT mice. The pulsed MISL method observed that the MISL signal reached the maximum at 1.5 s. The continuous MISL method showed the highest MISL signal in the fourth ventricle (∆Z = 13.5% ± 1.4%), whereas the third ventricle and the lateral ventricles had similar MISL ∆Z values (∆Z = 12.0% ± 1.8%). Additionally, significantly lower ∆Z (9.3%-18.7% reduction) was found in all ventricles for the adult mice than those of the young mice (p < 0.02). For the AQP4-/- mice, the ∆Z values were 5.9%-8.3% smaller than those of the age-matched WT mice in the lateral and fourth ventricles, but were not significant. The MISL method has a great potential to study CSF water exchange with the surrounding tissues in brain.


Mediating effects of sleep on mental health in older adolescents: Findings from the Burn 2 Learn randomized controlled trial.
Our study explored the mediating effect of sleep-related variables on older adolescents' mental health in the context of a school-based physical activity intervention. We evaluated the Burn 2 Learn (B2L) intervention using a cluster randomized controlled trial, which included two cohorts. Participants for this sub-study were from the second cohort, which included 292 older adolescents (16.0 ± 0.5 years) from 10 secondary schools in New South Wales, Australia. Teachers at intervention schools delivered two high-intensity activity breaks (approximately 10 mins) per week to students during academic lessons. Participants completed measures of mental health (i.e., perceived stress and internalizing problems) and hypothesized mediators (i.e., sleep duration, sleep latency, awakenings, and daytime sleepiness) at baseline (February-April 2019) and post-intervention (August-September 2019). Single mediation analyses were conducted to explore the potential mediating effects of sleep variables on mental health outcomes using a product-of-coefficient test. We observed a small statistically significant effect for perceived stress (β = -0.11, SE = 0.034, p = 0.002), but not for internalizing problems (β = 0.02, SE = 0.051, p = 0.760). There were no significant intervention effects for sleep-related variables. Several sleep-related variables were associated with mental health outcomes but no mediated effects were found. The B2L intervention had a small beneficial effect on perceived stress, however our mediation analyses suggest this was not explained by changes in sleep-related variables. Markers of sleep were associated with mental health constructs, highlighting the importance of sleep for good psychological health. However, in the context of a physical activity intervention, effects on mental health may be driven by other behavioral, neurobiological, or psychosocial mechanisms.


Does secotioid inertia drive the evolution of false-truffles?
Secotioid inertia is a model implemented to explain the prevalence of highly derived false-truffles with no obvious connection to the Homobasidiomycetes. The model accommodates the apparent lack of epigeous sister taxa for some highly derived hypogeous lineages by assuming that gasteromycetation in some fungi leads to the extinction of their epigeous sister population. The derived state of some hypogeous lineages suggests that they arose early in the evolution of Homobasidiomycetes and that those groups were subject to conditions that favoured hypogeous lineages such that the hypogeous fruit body form became the predominant form for some lineages. The directional selection component of secotioid inertia, termed secotioid drive, led to the extinction of their epigeous sister taxon. Morphological and molecular data from Russulaceae are used to model the evolutionary stages of secotioid inertia. The resulting phylogenetic results are compared with data from the order Leucogastrales, and the genus Destuntzia. The implications of secotioid drive are discussed with reference to gasteromycete phylogenetics, evolution, and conservation. Specifically, secotioid inertia can be used to account for reversals in fruit body morphology and instability in mycorrhizal formation.


A bump in the node: The hydraulic implications of rhizomatous growth.
Rhizomatous growth characterizes numerous taxa among vascular plants. While abundant information exists on nutrient sharing and demography, the question of how these metameric organisms move water through their bodies remains largely unstudied. Moreover, we lack an understanding of the evolutionary implications of rhizomatous growth across vascular plants. Here, we examined these questions by investigating how rhizomatous growth and vascular construction affect whole-plant hydraulic function. In five terrestrial fern species with diverse vascular construction, we used microcomputed tomography and bright-field microscopy to examine vascular construction across nodes along the rhizome. These data were integrated with measurements of leaf stomatal conductance under rooted and uprooted conditions to relate vascular patterning and hydraulic architecture to leaf water status. Similar to phytomers of woody seed plants, nodal regions in rhizomatous ferns are areas of hydraulic resistance. While water is shared along the rhizomes of these investigated species, hydraulic conductivity drops at nodes and stomatal conductance declines when nodes were locally uprooted. Together, our data suggest that nodes are chokepoints in axial water movement along the rhizome. Nodal chokepoints decrease hydraulic integration between phytomers. At the same time, chokepoints may act as "safety valves", hydraulically localizing each phytomer-potentially decreasing embolism and pathogen spread. This suggests a potential trade-off in the principal construction of the fern rhizome. Moreover, we propose that shoot-borne roots (homorhizy) and the prostrate habit of rhizomatous ferns decrease the hydraulic and structural burdens that upright plants typically incur. The absence of these hydraulic and structural demands may be one reason ferns (and many rhizomatous plants) lack, or have minimally developed, secondary xylem.


Mitophagy-related long non-coding RNA signature predicts prognosis and drug response in Ovarian Cancer.
Ovarian cancer (OC) is the most malignant tumor with the worst prognosis in female reproductive system. Mitophagy and long non-coding RNAs (lncRNAs) play pivotal roles in tumorigenesis, development, and drug resistance. The effects of mitophagy-related lncRNAs on OC prognosis and therapeutic response remain unelucidated. We retrieved OC-related RNA sequence, copy number variation, somatic mutation, and clinicopathological information from The Cancer Genome Atlas database and mitophagy-related gene sets from the Reactome database. Pearson's correlation analysis was used to distinguish mitophagy-related lncRNAs. A prognostic lncRNA signature was constructed using UniCox, LASSO, and forward stepwise regression analysis. Individuals with a risk score above or below the median were classified as high- or low-risk groups, respectively. The risk model was analyzed using the Kaplan-Meier estimator, receiver operating characteristic curve, decision curve analysis, and Cox regression analysis and validated using an internal dataset. LINC00174 was validated in clinical samples and OC cell lines. We also reviewed reports on the role of LINC00174 in cancer. Subsequently, a nomogram model was constructed. Furthermore, the Genomics of Drug Sensitivity in Cancer database was used to explore the relationship between the risk model and anti-tumor drug sensitivity. Gene set variation analysis was performed to assess potential differences in biological functions between the two groups. Finally, a lncRNA prognostic signature-related competing endogenous RNA (ceRNA) network was constructed. The prognostic signature showed that patients in the high-risk group had a poorer prognosis. The nomogram exhibited satisfactory accuracy and predictive potential. LINC00174 mainly acts as an oncogene in cancer and is upregulated in OC; its knockdown inhibited the proliferation and migration, and promoted apoptosis of OC cells. High-risk patients were more insensitive to cisplatin and olaparib than low-risk patients. The ceRNA network may help explore the potential regulatory mechanisms of lncRNAs. The mitophagy-related lncRNA signature can help estimate the survival and drug sensitivity, the ceRNA network may provide novel therapeutic targets for patients with OC.


Near-ultraviolet laser diodes for brilliant ultraviolet fluorophore excitation.
Although multiple lasers are now standard equipment on most modern flow cytometers, ultraviolet (UV) lasers (325-365 nm) remain an uncommon excitation source for cytometry. Nd:YVO4 frequency-tripled diode pumped solid-state lasers emitting at 355 nm are now the primary means of providing UV excitation on multilaser flow cytometers. Although a number of UV excited fluorochromes are available for flow cytometry, the cost of solid-state UV lasers remains prohibitively high, limiting their use to all but the most sophisticated multilaser instruments. The recent introduction of the brilliant ultraviolet (BUV) series of fluorochromes for cell surface marker detection and their importance in increasing the number of simultaneous parameters for high-dimensional analysis has increased the urgency of including UV sources in cytometer designs; however, these lasers remain expensive. Near-UV laser diodes (NUVLDs), a direct diode laser source emitting in the 370-380 nm range, have been previously validated for flow cytometric analysis of most UV-excited probes, including quantum nanocrystals, the Hoechst dyes, and 4',6-diamidino-2-phenylindole. However, they remain a little-used laser source for cytometry, despite their significantly lower cost. In this study, the ability of NUVLDs to excite the BUV dyes was assessed, along with their compatibility with simultaneous brilliant violet (BV) labeling. A NUVLD emitting at 375 nm was found to excite most of the available BUV dyes at least as well as a UV 355 nm source. This slightly longer wavelength did produce some unwanted excitation of BV dyes, but at sufficiently low levels to require minimal additional compensation. NUVLDs are compact, relatively inexpensive lasers that have higher power levels than the newest generation of small 355 nm lasers. They can, therefore, make a useful, cost-effective substitute for traditional UV lasers in multicolor analysis involving the BUV and BV dyes.


Supratherapeutic response to ezetimibe administered with cyclosporine.
To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level < or = 97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (> or = 5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.


High rate of mobilization for blaCTX-Ms.
We constructed a phylogenetic analysis of class A beta-lactamases and found that the blaCTX-Ms have been mobilized to plasmids approximately 10 times more frequently than other class A beta-lactamases. We also found that the blaCTX-Ms are descended from a common ancestor that was incorporated in ancient times into the chromosome of the ancestor of Kluyvera species through horizontal transfer. Considerable sequence divergence has occurred among the descendents of that ancestral gene sequence since that gene was inserted. That divergence has mainly occurred in the presence of purifying selection, which indicates a slow rate of evolution for blaCTX-Ms in the pre-antimicrobial drug era.


Portopulmonary Hypertension.
PoPH is a well-recognized complication of portal hypertension with or without cirrhosis and is classified as a subset of PAH. Identification of PoPH is crucial as it has a major impact on prognosis and liver transplant candidacy. Echocardiogram is the initial screening tool of choice and the patient should proceed to RHC for confirmation. PAH-directed therapy is the treatment of choice, allowing the patient to achieve a hemodynamic threshold to undergo a liver transplant safely.


Real-time intraoperative transesophageal echocardiography--how useful? Experience of 5,016 cases.
To evaluate transesophageal echocardiography (TEE) as an intraoperative monitoring modality and to assess its safety, reliability, and overall utility in real-time use during cardiac surgery. Prospective, observational cohort study performed from January 1993 to June 1997. Operating room of a tertiary care hospital for cardiology and cardiovascular surgery. Five thousand and sixteen adult patients with acquired heart disease, who underwent 1,356 valve procedures and 3,660 coronary artery bypass graftings (CABGs). All patients were monitored with radial artery and pulmonary artery catheters, along with continuous TEE monitoring with a multiplane transducer. Prebypass imaging yielded unsuspected findings that either helped or modified the surgical plan in 158 of 1,356 valve procedures (11.65%) and in 993 of 3,660 CABGs (27.13%). There were 3,217 TEE-guided hemodynamic interventions in 944 patients (25.79%) in the CABG group and 629 in 142 patients (10.47%) in the valve group. TEE was the sole guiding factor in initiating therapy in 23.53% of events, whereas it was supportive to other monitoring modalities in 76.46% of events. Postbypass TEE identified the need for graft revision in 29 patients (0.8%), intra-aortic balloon pump (IABP) requirement in 29 patients (0.8%), and inadequate valve repair in 28 patients (2.08%). For the entire series, 38.78% of patients benefited from prebypass and 39.16% from postbypass use of TEE. There were no complications attributable to the use of TEE in the entire series. There was 87% concordance between online interpretation by a trained anesthesiologist and offline analysis by a cardiologist. Intraoperative TEE is useful in formulating the surgical plan, guiding various hemodynamic interventions, and assessing the immediate results of surgery. It is safe and the results are reliable in the hands of trained anesthesiologists.


Influence of wastewater matrix on the visible light degradation of phenol using AgCl/Bi24O31Cl10 photocatalyst.
A significant amount of research has been conducted on the development and application of photocatalytic materials for the visible light degradation of organic pollutants in wastewater. However, most pollutant degradation studies are conducted using simulated wastewater often prepared using DI water. This is far removed from the realities of environmentally relevant water systems. It is therefore important to investigate the activity of these semiconductor materials with real water samples. In this study, the photocatalytic activity of the photocatalyst was investigated in the secondary effluent of a wastewater treatment plant (WWTP) in Pretoria, South Africa, for the degradation of phenol under visible light irradiation. The experimental design was done using the Taguchi method L16 orthogonal tray with three factors (pH, initial phenol concentration, and photocatalyst dosage) and four levels. The results show that pH is the highest-ranked significant factor influencing the degradation rate, closely followed by the initial concentration of the pollutant. The photocatalyst dosage had the least significant impact on degradation. The effects of individual anion components such as Cl-, NO3-, NO2-, SO42- and cations such as Ca2+, Mg2+, Zn2+, and K+ were investigated. While Cl- did not negatively influence the degradation rate, the results show that NO3- and SO42- inhibit the degradation of phenol. More specifically, the presence of nitrites resulted in total impeding of the degradation process illustrating that nitrite concentrations ≥ 20 ppm should be removed from wastewater prior to photocatalytic degradation. The cations investigated promoted the degradation of phenol. Generally, there was enhanced degradation in the water matrix when compared to DI water, and the results revealed improved degradation efficiency due to the cumulative impact of various components of the wastewater.


A narrative review on trans-nasal pulmonary aerosol delivery.
The use of trans-nasal pulmonary aerosol delivery via high-flow nasal cannula (HFNC) has expanded in recent years. However, various factors influencing aerosol delivery in this setting have not been precisely defined, and no consensus has emerged regarding the optimal techniques for aerosol delivery with HFNC. Based on a comprehensive literature search, we reviewed studies that assessed trans-nasal pulmonary aerosol delivery with HFNC by in vitro experiments, and in vivo, by radiolabeled, pharmacokinetic and pharmacodynamic studies. In these investigations, the type of nebulizer employed and its placement, carrier gas, the relationship between gas flow and patient's inspiratory flow, aerosol delivery strategies (intermittent unit dose vs continuous administration by infusion pump), and open vs closed mouth breathing influenced aerosol delivery. The objective of this review was to provide rational recommendations for optimizing aerosol delivery with HFNC in various clinical settings.


Long-term cryostorage does not negatively affect the recovery of Caenorhabditis elegans.
Cryostorage of Caenorhabditis elegans nematodes is important to maintain the many lines used for research. The standard method uses 15% of glycerol in M9-Buffer and a cooling rate of 1 °C/min; then worms can be stored in a -80 °C freezer or in liquid nitrogen. The recovery of C. elegans from stocks stored in liquid nitrogen is reported to be in the range of 35-45% and slightly decreases after years of storage. The storage at -80 °C is also considered safe, but the recovery is not as high as in liquid nitrogen. These observations have not been experimentally reported and therefore require verification. In this study, the standard methods were used in a set of experiments to compare the recovery of larvae and adult worms stored at -80 °C or in liquid nitrogen, after short- (a week) or long-term storage (3.5 years). No differences were observed in recovery, either for the time of storage or for the temperature of storage. Recovery of larvae was 32% at -80 °C and 36% in liquid nitrogen after 3.5 yr and that was not significantly different from the 7-d recovery rates. Adult worm recovery was below 5% for all treatments. These results suggest that both methods of storage can be used to successfully store C. elegans larvae for at least 3.5 years.


Cytokines production of U5A2-13-positive T cells by stimulation with glycolipid alpha-galactosylceramide.
We have previously established and reported a novel monoclonal antibody (mAb), U5A2-13, which recognizes a phenotypically similar population of natural killer (NK)-like T cells. Using U5A2-13 mAb, we now describe the functional properties of U5A2-13(+) T cells in both NK1.1-positive or -negative mouse strains. Similar to NK1.1(+) T cells, hepatic U5A2-13(+) T cells of C57BL/6 (NK1.1(+) strain) mice, but not U5A2-13(-) T cells, could be induced to produce large amounts of IL-4 and IFN-gamma by stimulation with glycolipid alpha-galactosylceramide (alpha-GalCer) present on dendritic cells (DC) in a dose-dependent manner. The abundant production of these cytokines from U5A2-13(+) T cells of BALB/c (NK1.1(-) strain) mice is similar to that noted in C57BL/6 mice. Cytokine production by cultures stimulated with DC of beta2-microglobulin-deficient mice was significantly less than that of cultures stimulated with DC of intact mice. Overall, U5A2-13(+) T cells recognize alpha-GalCer presented by CD1d, indicating that U5A2-13(+) T cells can be used to analyze NK-like T cell function in various strains of mice.


Pre- and postoperative verbal memory and executive functioning in frontal versus temporal lobe epilepsy.
There is accumulating evidence for considerable overlap in preoperatively affected cognitive functions in patients with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE). The current study investigated whether it is possible to differentiate between patients with FLE and TLE prior to surgery, based on measures of verbal memory and executive functioning. Furthermore, the postoperative cognitive development was compared. Pre- and postoperative data from 109 patients with FLE and 194 patients with TLE were retrospectively analyzed. Preoperatively, there were no differences in verbal memory, and postoperatively, no distinctive cognitive change was found between patients with FLE and TLE. However, patients with FLE performed worse on a cognitive switching task. Notably, irrespective of localization, patients with a presumed epileptogenic area in the language-dominant hemisphere performed worse than patients with seizures that originated in the nonlanguage-dominant hemisphere on measures of verbal memory, both pre- and postoperatively. In sum, the results suggest that verbal memory scores may be less valuable for differentiation between TLE and FLE, while measures of executive functioning may help identify patients with FLE. Additionally, rather than the localization, epilepsy lateralization critically impacts the evaluation of verbal memory functioning in both TLE and FLE. The results are discussed in light of the current frameworks of functional disturbances in epileptic networks.


Selective phosphinate transition-state analogue inhibitors of the protease of human immunodeficiency virus.
The phosphinic acid isosteres of di-, tetra- and hexapeptides containing a hydrophobic amino acid side chains at the P1-P'1 positions are powerful inhibitors of Human Immunodeficiency Virus protease. Ki's ranged from 0.4 nM to 26 microM at pH 6.5 and were lower at pH 4.5. The compounds showed no activity against trypsin, weak activity against renin at pH 6.5, moderate activity against pepsin at pH 2.0 (Ki values in the microM range) and substantial activity against cathepsin D at pH 3.5 (Ki values from 9 to 300 nM).


Reducing current spread using current focusing in cochlear implant users.
Cochlear implant performance in difficult listening situations is limited by channel interactions. It is known that partial tripolar (PTP) stimulation reduces the spread of excitation (SOE). However, the greater the degree of current focusing, the greater the absolute current required to maintain a fixed loudness. As current increases, so does SOE. In experiment 1, the SOE for equally loud stimuli with different degrees of current focusing is measured via a forward-masking procedure. Results suggest that at a fixed loudness, some but not all patients have a reduced SOE with PTP stimulation. Therefore, it seems likely that a PTP speech processing strategy could improve spectral resolution for only those patients with a reduced SOE. In experiment 2, the ability to discriminate different levels of current focusing was measured. In experiment 3, patients subjectively scaled verbal descriptors of stimuli of various levels of current focusing. Both discrimination and scaling of verbal descriptors correlated well with SOE reduction, suggesting that either technique have the potential to be used clinically to quickly predict which patients would receive benefit from a current focusing strategy.


Compact organic liquid dielectric resonator antenna for air pressure sensing using soft material.
For the first time, a flexible and deformable liquid dielectric resonator antenna (LDRA) is proposed for air pressure sensing. The proposed LDRA can be made very compact as it has employed liquidized organic dielectric with high dielectric constant (~ 33) with low loss tangent (~ 0.05). Here, a soft elastomer container has been fabricated using soft-lithography method for holding the liquid, and an air cavity is tactfully embedded into the central part of a cylindrical DRA to form an annular structure that can be used for sensing air pressure. It will be shown that the inclusion of the air cavity is essential for making the antenna structure sensitive to pressure changes. Simulations and experiments have been conducted to verify the functionalities of the proposed organic LDRA as microwave radiator and as air pressure sensor. It has been proven to have higher antenna gain than the water LDRA in the frequency range of 1.8-2.8 GHz, while achieving a good air pressure sensitivity of 270 MHz/bar.


Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P < .0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine.


Is off-label thrombolysis safe and effective in a real-life primary stroke center? A retrospective analysis of data from a 5-year prospective database.
Intravenous thrombolysis (IVT) use for acute ischemic stroke (AIS) varies among countries, partly due to guidelines and product labeling changes. The study aim was to identify the characteristics of patients with AIS treated with off-label IVT and to determine its safety when performed in a primary stroke center (PSC). This observational, single-center study included all consecutive patients admitted to Perpignan PSC for AIS and treated with IVT and patients transferred for EVT, between January 1, 2015 and December 31, 2019. Data of patients treated with IVT according to ("in-label group") or outside ("off-label") the initial guidelines and manufacturer's product specification were compared. Safety was assessed using symptomatic intracerebral hemorrhage (SIH) as the main adverse event. Among the 892 patients in the database (834 screened by MRI, 93.5%), 746 were treated by IVT: 185 (24.8%) "in-label" and 561 (75.2%) "off-label". In the "off-label" group, 316 (42.4% of the cohort) had a single criterion for "off-label" use, 197 (26.4%) had two, and 48 (6.4%) had three or more criteria, without any difference in IVT safety pattern among them. SIH rates were comparable between the "off-label" and "in-label" groups (2.7% vs. 1.1%, P=0.21); early neurological deterioration and systematic adverse event due to IVT treatment were similar in the 2 groups. "Off-label" patients had higher in-hospital (8.7% vs. 3.8%, P=0.05) and 3-month mortality rates (12.1% vs 5.4%, P<0.01), but this is explained by confounding factors as they were older (76 vs 67 years, P<0.0001) and more dependent (median modified Rankin scale score 0.4 vs 0.1, P<0.0001) at admission. "Off-label" thrombolysis for AIS seems to be safe and effective in the routine setting of a primary stroke center.


The importance of being essential: EMBRYO-DEFECTIVE genes in Arabidopsis.
With the completion of the sequence of the first bacterial genomes, scientists have been able to address the question: How many genes are required for cell viability? In attempting to reply to this question, the concept of the minimal gene set was developed and validated by systematic gene disruption. In a similar manner, whole genome comparisons and systematic Knock-Out have been performed in eukaryotes and have led to the identification to date of the set of essential genes in yeast and C. elegans. In the plant kingdom, the sequence of the Arabidopsis genome together with large-scale functional genomics programs now allow us to address the question of essentiality in Arabidopsis. These concerted efforts have resulted in the identification to date of up to 219 genes essential for seed development (EMBRYO-DEFECTIVE, EMB, genes). With this basic knowledge, we can start a valid comparison of essentiality in Arabidopsis and in other eukaryotes based on functional categories and orthologous relationships. Furthermore, the function of the EMB genes in the particular context of eukaryote evolution driven by whole genome duplications and selective gene loss will be discussed.


New insights into activation and substrate recognition of polyhydroxyalkanoate synthase from Ralstonia eutropha.
The polyhydroxyalkanoate synthase of Ralstonia eutropha (PhaC(Re)) shows a lag time for the start of its polymerization reaction, which complicates kinetic analysis of PhaC(Re). In this study, we found that the lag can be virtually eliminated by addition of 50 mg/L TritonX-100 detergent into the reaction mixture, as well as addition of 2.5 g/L Hecameg detergent as previously reported by Gerngross and Martin (Proc Natl Sci USA 92: 6279-6283, 1995). TritonX-100 is an effective lag eliminator working at much lower concentration than Hecameg. Kinetic analysis of PhaC(Re) was conducted in the presence of TritonX-100, and PhaC(Re) obeyed Michaelis-Menten kinetics for (R)-3-hydroxybutyryl-CoA substrate. In inhibitory assays using various compounds such as adenosine derivatives and CoA derivatives, CoA free acid showed competitive inhibition but other compounds including 3'-dephospho CoA had no inhibitory effect. Furthermore, PhaC(Re) showed a considerably reduced reaction rate for 3'-dephospho (R)-3-hydroxybutyryl CoA substrate and did not follow typical Michaelis-Menten kinetics. These results suggest that the 3'-phosphate group of CoA plays a critical role in substrate recognition by PhaC(Re).


Heat shock protein B8 promotes proliferation and migration in lung adenocarcinoma A549 cells by maintaining mitochondrial function.
Heat shock protein B8 (HSPB8) impacts on tumor proliferation and migration of malignancy. However, the role of HSPB8 in lung adenocarcinoma (LUAC) remains unclear. The aim of this study, therefore, was to clarify whether HSPB8 could bring benefits to proliferation and migration of LUAC and its underlying mechanisms. The expression of HSPB8 was first evaluated by immunohistochemistry in 35 LUAC samples. Then, A549 lung adenocarcinoma cells were transfected with pcDNA-HSPB8 or si-HSPB8 to induce HSPB8 overexpression and silence. Cellular activity was evaluated with a Cell Counting Kit-8 (CCK-8) assay. Cell proliferation and migration were observed by EdU assay and scratch assay. Mitochondria-specific reactive oxygen species (mtROS) and membrane potential were measured using MitoSOX Red probe and JC-1 staining. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) level were measured using commercial kits, respectively. HSPB8 protein, mitochondrial fusion protein MFN2 and mitochondrial fission protein p-Drp1/Drp1 were measured using western blot. Compared with the normal tissues, the expression of HSPB8 protein was higher in LUAC tissues and upregulation of HSPB8 protein was related to tumor size and tumor location. Furthermore, HSPB8 overexpression aggravated cell proliferation and migration of A549 cells. Mechanistically, HSPB8 suppressed mitochondrial impairment, leading to promoting the progress of A549 lung adenocarcinoma cells. These data demonstrate that HSPB8 plays an important role in progression of LUAC and may be a new target to treat LUAC.


Reference Intervals of Fibrosis Index Based on Four Indicators in Healthy Elderly Chinese.
The establishment of reference intervals of total bilirubin, Alanine aminotransferase (ALT), aspartate aminotransferases (AST), and creatinine provided necessary reference in screening and diagnosis of various kidney and liver diseases. However, these reference intervals were not available to estimate liver fibrosis degree. The purpose of this study is to establish the reference intervals of fibrosis index based on the four indicators (FIB-4) in apparently healthy elderly Chinese. A total of 24,949 blood specimens were collected by the standard procedures, and ALT, AST, and PLT were determined. FIB-4 were calculated by the following formula: FIB-4 = (age [years] × AST [U/l])/((PLT [10(9) /l]) × (ALT [U/l])(1/2) ).The elderly's FIB-4 were analyzed between the same age of different sexes and different ages of the same sex. Statistical data were analyzed by SPSS18.0 software. Reference intervals of FIB-4 index, established for the healthy elderly, were 0.9923-4.5424 for males and 0.9007-4.1934 for females. We established reference intervals of FIB-4 index. This research provided reference value that can be used by relevant clinicians and inspection officers.