Characterization of the internal signal-anchor domain of Escherichia coli leader peptidase.
Leader peptidase, an integral transmembrane protein of Escherichia coli, is synthesized without a cleavable amino-terminal leader peptide. Of the five domains that participate in the membrane assembly of this protein, one is an internal "signal" region. We have used oligonucleotide-directed mutagenesis to examine the properties of the internal signal that are crucial for leader peptidase assembly. For this purpose, the net charge at the amino terminus of the internal signal was changed from +2 to +1 and -1 and, at the carboxyl terminus of the signal, from 0 to -1 or +1. These mutations had no effect on the membrane assembly of leader peptidase, suggesting that the charges have little role in the signal function. The apolar core of this signal was disrupted by substitution of basic amino acids for apolar residues. Substitution of an arginyl residue at position 70, or two arginyl residues at position 67 and 69, prevented membrane assembly. However, substitution of an arginyl residue at position 66 or either arginyl or lysyl residue at position 68 was without effect. Thus, while the apolar character of the internal signal is important, the precise position of a charged residue determines its effect on assembly.


Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats.
To investigate the effect of angiotensin II AT1 receptor blocker valsartan on hypoxia-inducible factor (HIF)-1α-mediated gene activation and its association with renal interstitial fibrosis (RIF) in diabetic nephropathy rats. Sprague-Dawley rats were randomly divided into 3 groups: control (C group), streptozocin-induced diabetic nephropathy (D group), and valsartan-treated D rats (T group). At end of the 4th, 8th and 12th week 6 rats from each group were sacrificed and blood, urine and kidneys were collected. Blood glucose, serum creatinine (Scr) and 24-h urinary protein were measured and kidneys were processed for Masson-stain as well as immunohistochemistry and real time-PCR analyses of the expressions of HIF-1α, and its target genes tissue inhibitor of metalloproteinase (TIMP)-1 and endothelin (ET)-1 in the kidney. (1) At the 4th, 8th and 12th week, the areas of RIF were significantly increased in D and T groups, which was accompanied by higher levels of 24-h urinary protein, Scr, HIF-1α, ET-1 and TIMP-1 compared with C group. (2) At the 8th and 12th week, the above changes were significantly attenuated in T group compared with D group. Valsartan may reduce HIF-1α-mediated gene activation and consequently improve kidney damage in diabetic nephropathy rats.


Highly efficient removal of silver nanoparticles by sponge-like hierarchically porous thiourea-formaldehyde resin from Water.
With the increasing production and rapid market penetration as well as the confirmation of the toxic effects, silver nanoparticles (AgNPs) are one kind of newly emerging environmental contaminants of high concern. It is urgent to develop the efficient method to remove them from the environment. In this study, the sponge-like hierarchically porous thiourea-formaldehyde (TF) resin rich with nitrogen and sulfur was for the first time proposed as the adsorbent to achieve this goal. With enormous interconnected layer structure and plentiful macropores, the porous TF resin provided abundant available interaction sites and fast mass transfer to adsorb citrate stabilized AgNPs (citrate-AgNPs). Fast adsorption rate and high adsorption capacity (2478 mg/g) were obtained based on the electrostatic and metal-ligand interactions. Heterogeneous aggregation and simultaneous adsorption contributed to this removal process. Furthermore, with the assistance of NaCl, the porous TF resin exhibited largely enhanced removal efficiency towards citrate-AgNPs up to 98.7 % in 5 min, possibly due to the co-operation of adsorption and coagulation. This study proposed a promising adsorbent to remove AgNPs and provided a referential strategy to design highly efficient adsorbents for removal of nanoparticles.


Long-term observation after transplantation of cultured human corneal endothelial cells for corneal endothelial dysfunction.
Corneal transplantation is the only way to treat serious corneal diseases caused by corneal endothelial dysfunction. However, the shortage of donor corneal tissues and human corneal endothelial cells (HCECs) remains a worldwide challenge. We cultivated HCECs by the use of a conditioned medium from orbital adipose-derived stem cells (OASC-CM) in vitro. Then the HCECs were used to treat animal corneal endothelial dysfunction models via cell transplantation. The purpose of this study was to conduct a long-term observation and evaluation after cell transplantation. Orbital adipose-derived stem cells (OASCs) were isolated to prepare the conditioned medium (CM). HCECs were cultivated and expanded by the usage of the CM (CM-HCECs). Then, related corneal endothelial cell (CEC) markers were analyzed by immunofluorescence. The cell proliferation ability was also tested. CM-HCECs were then transplanted into monkey corneal endothelial dysfunction models by injection. We carried out a 24-month postoperative preclinical observation and verified the long-term effect by histological examination and transcriptome sequencing. CM-HCECs strongly expressed CEC-related markers and maintained polygonal cell morphology even after 10 passages. At 24 months after cell transplantation, there was a CEC density of more than 2400 cells per square millimeter (range, 2408-2685) in the experimental group. A corneal thickness (CT) of less than 550 μm (range, 490-510) was attained. Gene sequencing showed that the gene expression pattern of CM-HCECs was similar to that of transplanted cells and HCECs. Transplantation of CM-HCECs into monkey corneal endothelial dysfunction models resulted in a transparent cornea after 24 months. This research provided a promising prospect of cell-based therapy for corneal endothelial diseases.


Occurrence of persistent and mobile chemicals and other contaminants of emerging concern in Spanish and Portuguese wastewater treatment plants, transnational river basins and coastal water.
This work investigated, during one year, the occurrence and fate of 52 contaminants of emerging concern (CECs) in transnational river basins and coastal areas of the North of Portugal and Galicia (NW Spain) and the wastewater treatment plants (WWTPs) discharging on these environments. The different CECs investigated included pharmaceuticals, personal care products, industrial chemicals, among others, of which ca. 90 % would fulfill the persistence, mobility and toxicity criteria proposed by the German Environmental Agency. The results showed the ubiquitous presence of these CECs and an incomplete removal of over 60 % of them with current conventional WWTPs. These findings highlight the requirement of a prominent and coordinated upgrade of WWTP treatments in order to meet the future European Union regulations on urban wastewater treatment and surface water quality. In fact, even some compounds exhibiting high removals, such as caffeine or xylene sulfonate, were frequently detected in river and estuarine waters at the high ng L-1 level. Thus, our preliminary risk assessment study concluded that 18 of the CECs presented a potential risk for the environment, being caffeine, sulpiride, perfluorooctanoic acid (PFOA), diclofenac, fipronil and perfluorobutanoic acid (PFBA) the most concerning ones. Yet, additional toxicity data as well as a more robust information on persistence and mobility of CECs are necessary for better estimating the magnitude of the problem and improve risk assessment. As an example, in the case of the antidiabetic metformin, recent research has revealed toxicity for model fish species at concentration levels below those found in 40 % of the river water samples analyzed in this work.


The effect of sub-lethal increases in temperature on the growth and population trajectories of three scleractinian corals on the southern Great Barrier Reef.
To date, coral death has been the most conspicuous outcome of warming tropical seas, but as temperatures stabilize at higher values, the consequences for the corals remaining will be mediated by their demographic responses to the sub-lethal effects of temperature. To gain insight into the nature of these responses, here I develop a model to test the effect of increased temperature on populations of three pocilloporid corals at One Tree Island, near the southern extreme of the Great Barrier Reef (GBR). Using Seriatopora hystrix, S. caliendrum and Pocillopora damicornis as study species, the effects of temperature on growth were determined empirically, and the dynamics of their populations determined under natural temperatures over a 6-month period between 1999 and 2000 [defined as the study year (SY)]. The two data sets were combined in a demographic test of the possibility that the thermal regime projected for the southern GBR in the next 55-83 years--warmer by 3 degrees C than the study year (the SY+3 regime), which is equivalent to 1.4 degrees C warmer than the recent warm year of 1998--would alter coral population trajectories through the effects on coral growth alone; the analyses first were completed by species, then by family after pooling among species. Laboratory experiments showed that growth rates (i.e., calcification) varied significantly among species and temperatures, and displayed curvilinear thermal responses with growth maxima at approximately 27.1 degrees C. Based on these temperature-growth responses, the SY+3 regime is projected to: (1) increase annualized growth rates of all taxa by 24-39%, and defer the timing of peak growth from the summer to the autumn and spring, (2) alter the intrinsic rate of population growth (lambda) for S. hystrix (lambda decreases 26%) and S. caliendrum (lambda increases 5%), but not for P. damicornis, and (3) have a minor effect on lambda (a 0.3% increase) for the Pocilloporidae, largely because lambda varies more among species than it does between temperatures. Ten-year population projections suggest that the effects of a sub-lethal increase in temperature (i.e., the SY+3 regime) are relatively small compared to the interspecific differences in population dynamics, but nevertheless will alter the population size and increase the relative abundance of large colonies at the expense of smaller colonies for all three species, as well as the Pocilloporidae. These effects may play an important role in determining the nuances of coral population structure as seawater warms, and their significance may intensity if the coral species pool is depleted of thermally sensitive species by bleaching.


Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells.
Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.


Ion homeostasis in differently adapted populations of Suaeda vera Forssk. ex J.F. Gmel. for phytoremediation of hypersaline soils.
Salt-accumulator species are of great interest for the phytoremediation of salt-affected soils to reclaim soil salinization, a major constraints causing germination retardation and growth restriction of plants as well as habitat degradation. Higher biomass production at ECe 23-36 dS m-1 indicated that this species grows better in high to moderate salinity that was linked to osmotic adjustment through higher ion accumulation (Na+, Cl‒, and Ca2+) and organic osmolytes (free amino acids and proline). Plants from highly and moderately saline habitats exhibited broader metaxylem vessels, which was associated with eased conduction of solutes leading to better growth. Leaf anatomical characteristics generally increased with increasing salinity except at the highest ECe 55 dS m-1. The increased leaf lamina thickness contributed to succulence because of increased storage parenchymatous spongy tissues (that can store high amounts of water), water contents and it is a reflection of maintaining ion homeostasis and colonizing hyper-saline soil. Reduced stomatal density and area under high salinity are critical to cope with environmental hazards. Under high salinity, compartmentalization of excessive Na+ and Cl- ions and accumulation of compatible osmolytes are directly related to high degree of salinity tolerance, and hence are useful for phyto-amelioration of salinity-impacted lands.


[Morphoimmunohistological differential diagnosis between Hodgkin's lymphoma with lymphoid prevalence and large B-cell lymphoma].
Morphological and immunophenotypical features of Hodgkin's lymphoma with lymphoid predominance are described: a variant with nodular lymphoid predominance (NLPHL) and variants of large-cell lymphoma including mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma rich with T-cells and/or histiocytes. In view of the fact that these lymphomas enter so-called "gray zone" criteria for immunohistochemical differential diagnosis are suggested.


Electrochemical synthesis of Fe2O3 on graphene matrix for indicator-free impedimetric aptasensing.
Herein, an electrochemical platform was employed for the detection of protein. Fe2O3 was electrochemically deposited on graphene modified glassy carbon electrode surface. Electrodeposition conditions, such as temperature, and time, were optimized for controlling morphologies and electrochemical activities of Fe2O3. Negatively charged lysozyme-binding aptamer (LBA) was immobilized on positively charged Fe2O3 (isoelectric point ≈ 7.0) via electrostatic interaction. Electrochemical impedance spectroscopy was adopted for indicator-free detection of lysozyme. The LBA on the outermost layer would catch lysozyme in solution by physical affinity, which induced the increase of impedimetric signals. In this strategy, a wide detection range (0.5 ng mL(-1)-5 μg mL(-1)) and low detection limit (0.16 ng mL(-1)) for model target lysozyme was obtained. The results showed that indicator-free impedimetric aptasensing strategy had good sensitivity and selectivity.


Avoid Excessive Oxygen Levels in Experiments with Organisms, Tissues and Cells.
O2 levels encountered in vivo in cells and tissues are almost always at least an order of magnitude less than atmospheric pO2 because of sensing, signalling and bioenergetic demand. Although deleterious reactions are minimized by protective mechanisms (residual toxic products scavenged and detoxified) ambient levels should be mimicked in experiments with whole organisms, their isolated organs, tissues or cells and also with cultures of cell lines. These are also important issues for microorganisms inhabiting low O2 niches within higher organisms and their cells. Here, we highlight the importance of optimization of micro-aerobic conditions for experimentation and the deleterious consequences of not doing so.


Synthetic Peptide Antibodies as TNF-α Inhibitors: Molecularly Imprinted Polymer Nanogels Neutralize the Inflammatory Activity of TNF-α in THP-1 Derived Macrophages.
Tumor Necrosis Factor-α (TNF-α) is a cytokine that is normally produced by immune cells when fighting an infection. But, when too much TNF-α is produced as in autoimmune diseases, this leads to unwanted and persistent inflammation. Anti-TNF-α monoclonal antibodies have revolutionized the therapy of these disorders by blocking TNF-α and preventing its binding to TNF-α receptors, thus suppressing the inflammation. Herein, we propose an alternative in the form of molecularly imprinted polymer nanogels (MIP-NGs). MIP-NGs are synthetic antibodies obtained by nanomoulding the 3-dimensional shape and chemical functionalities of a desired target in a synthetic polymer. Using an in-house developed in silico rational approach, epitope peptides of TNF-α were generated and 'synthetic peptide antibodies' were prepared. The resultant MIP-NGs bind the template peptide and recombinant TNF-α with high affinity and selectivity, and can block the binding of TNF-α to its receptor. Consequently they were applied to neutralize pro-inflammatory TNF-α in the supernatant of human THP-1 macrophages, leading to a downregulation of the secretion of pro-inflammatory cytokines. Our results suggest that MIP-NGs, which are thermally and biochemically more stable and easier to manufacture than antibodies, and cost-effective, are very promising as next generation TNF-α inhibitors for the treatment of inflammatory diseases.


Massive hemoptysis and complete unilateral lung collapse in pregnancy due to pulmonary tuberculosis with good maternal and fetal outcome: a case report.
We report an extremely rare case of massive hemoptysis and complete left-sided lung collapse in pregnancy due to pulmonary tuberculosis in a health care worker with good maternal and fetal outcome. A 33-year-old human immuno deficiency virus seronegative African health care worker in her fourth pregnancy with two previous second trimester miscarriages and an apparently healthy daughter from her third pregnancy presented coughing up copious amounts of blood at 18 weeks and two days of gestation. She had a cervical suture in situ for presumed cervical weakness. Computed tomography of her chest showed complete collapse of the left lung; subsequent bronchoscopy was apparently normal. Her serum β-human chorionic gonadotropin, tests for autoimmune disease and echocardiography were all normal. Her lung re-inflated spontaneously. Sputum for acid alcohol fast bacilli was positive; our patient was commenced on anti-tuberculosis medication and pyridoxine. At 41 weeks and three days of pregnancy our patient went into spontaneous labor and delivered a live born female baby weighing 2.6 kg with APGAR scores of nine and 10 at one and five minutes respectively. She and her baby are apparently doing well about 10 months after delivery. It is possible to have massive hemoptysis and complete unilateral lung collapse with spontaneous resolution in pregnancy due to pulmonary tuberculosis with good maternal and fetal outcome.


Constructed wetlands as neglected fixed source of microplastics and antibiotic resistance genes in natural water bodies?
The pollution status and the harm caused by microplastics and antibiotic resistance genes (ARGs) in aquatic ecosystems have been a growing concern. The presence of microplastics could accelerate the transfer and spread of ARGs. Before sewage reaches natural water bodies, microplastics and ARGs need to be eliminated through specific processes. Constructed wetlands are currently an effective and environmentally friendly wastewater treatment process. Research has shown significant effectiveness in removing microplastics and ARGs. Microplastics and ARGs can be removed through processes such as adsorption, capture, adhesion, and biodegradation. However, long-term continuous operation could lead to constructed wetlands becoming significant reservoirs of microplastics and ARGs. Inflow loads and seasonal variations in constructed wetlands may result in the reintroduction of persistent microplastics and ARGs into the receiving water body, establishing the constructed wetland as a continuous source of these pollutants in the receiving water body. The key to the widespread application of constructed wetlands lies in solving this challenging problem. Therefore, although constructed wetlands serve as a green strategy for removing microplastics and ARGs, there are still many gaps in our knowledge. Based on the current accumulation of microplastics and ARGs in constructed wetlands, this paper summarizes the removal of microplastics and ARGs in existing constructed wetlands and explores the interaction between them. Additionally, it proposes suggestions for optimizing the process and improving the reliability of monitoring microplastics and ARGs in sewage.


Analysis of the effects of bromocriptine on blood pressure and sympathetic nerve function.
Bromocriptine, a dopamine receptor agonist, lowered arterial blood pressure and caused significant impairment of the cardioacceleration observed during the stimulation of the right postganglionic cardiac sympathetic nerve fibers in pentobarbital-anethetized dogs. Prior administration of pimozide antagonized the hypotensive and the inhibitory action of bromocriptine on cardiac sympathetic function. These results suggest that while presynaptic dopamine receptors seem to be involved in mediating the inhibitory action of bromocriptine on cardiac sympathetic function, the role of presynaptic as well as dopamine receptors located at other sites in mediating the hypotensive action of bromocriptine needs to be further investigated.


Tranexamic Acid in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.
Tranexamic acid is proposed as a treatment for gastrointestinal bleeding. The Haemorrhage Alleviation with Tranexamic Acid-Intestinal System trial evaluated extended-use (24 hr) high-dose tranexamic acid, prompting a reappraisal for tranexamic acid in gastrointestinal bleeding. We conducted a systematic review and meta-analysis of randomized controlled trials comparing tranexamic acid with usual care or placebo in adults with gastrointestinal bleeding. We searched MEDLINE, EMBASE, and CENTRAL (inception to September 2019). Two reviewers independently screened citations, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool in duplicate. The main outcomes were mortality, bleeding, and adverse events. Studies were analyzed as high-dose IV tranexamic acid versus all other dosing strategies for tranexamic acid using fixed-effects models. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Five randomized controlled trials evaluated extended-use high-dose IV tranexamic acid, seven evaluating low-dose IV or enteral tranexamic acid. Extended-use high-dose IV tranexamic acid did not reduce mortality (relative risk, 0.98%; 95% CI, 0.88-1.09; I2 = 63%; high certainty) or bleeding (relative risk, 0.92; 95% CI, 0.82-1.04; p = 0.17 and absolute risk differences, -0.7%; 95% CI, -1.5 to 0.3; high certainty) but resulted in a small increase in deep venous thrombosis (relative risk, 2.01; 95% CI, 1.08-3.72; I2 = 0%), pulmonary embolism (relative risk, 1.78; 95% CI, 1.06-3.0; I2 = 0%), and seizure (relative risk, 1.73; 95% CI, 1.03-2.93) with high certainty. Low-dose IV/enteral tranexamic acid did not reduce mortality (relative risk, 0.62; 95% CI, 0.36-1.09; I2 = 0%) but did reduce risk of rebleeding (relative risk, 0.5; 95% CI, 0.33-0.75; I2 = 9%) and need for surgery (relative risk, 0.58; 95% CI, 0.38-0.88; I2 = 11%), with moderate certainty. Extended-use high-dose IV tranexamic acid does not improve mortality or bleeding outcomes and increases adverse events. Low-dose/enteral tranexamic acid may be effective in reducing hemorrhage; more evidence is required to demonstrate its safety.


Issues in aging. The role of the nurse in the care of older people with intellectual and developmental disabilities.
Many people with I/DD are growing older and in increasing numbers. Generally people with I/DD experience the same physical process of aging as do individuals without lifelong disabilities with the exception of those individuals who have Down syndrome who may show physical signs of aging as much as 20 years earlier. Individuals with I/DD may experience some unique concerns associated with aging with similar or even higher rates of age-related conditions than do older persons without lifelong disabilities [20]. Geriatric care principles will guide nurses caring for older people with I/DD, beginning with the assessment of functional status to determine interventions for developmental, aging, and health concerns and health promotion. Nursing interventions must be individualized both according to the person's preferences and health status. A primary goal is to prevent acute exacerbation of any underlying pathological process, prevent unnecessary deterioration of the older individual's physical condition, and maintain optimum physical and mental function. Nurses can provide individuals who are aging and their families or caregivers the needed anticipatory guidance about life transitions during the aging years, including palliative end-of-life care. This is an exciting and challenging time for nurses who care for aging people with I/DD. John F. Kennedy once said, "It is not enough for a great nation to have added new years to life. Our objective must be to add new life to those years." As a profession, nurses have historically added years to life. The challenge of nursing is now to add quality life to those years for all older persons with I/DD.


Amelioration of Cognitive and Olfactory System Deficits in APOE4 Transgenic Mice with DHA Treatment.
Olfactory dysfunction and atrophy of olfactory brain regions are observed early in mild cognitive impairment and Alzheimer disease. Despite substantial evidence showing neuroprotective effects in MCI/AD with treatment of docosahexaenoic acid (DHA), an omega-3 fatty acid, few studies have assessed DHA and its effects on the olfactory system deficits. We therefore performed structural (MRI), functional (olfactory behavior, novel object recognition), and molecular (markers of apoptosis and inflammation) assessments of APOE4 and wild-type mice ± DHA treatment at 3, 6, and 12 months of age. Our results demonstrate that APOE4 mice treated with the control diet show recognition memory deficits, abnormal olfactory habituation, and discrimination abilities and an increase in IBA-1 immunoreactivity in the olfactory bulb. These phenotypes were not present in APOE4 mice treated with a DHA diet. Alterations in some brain regions' weights and/or volumes were observed in the APOPE4 mice and may be due to caspase activation and/or neuroinflammatory events. These results suggest that the consumption of a diet rich in DHA may provide some benefit to E4 carriers but may not alleviate all symptoms.


Stochastic models of the meridional overturning circulation: time scales and patterns of variability.
The global meridional overturning circulation (MOC) varies over a wide range of space and time scales in response to fluctuating 'weather' perturbations that may be modelled as stochastic forcing. This study reviews model studies of the effects of climate noise on decadal to centennial MOC variability, on transitions between the MOC regimes and on the dynamics of Dansgaard-Oeschger events characteristic of glacial periods.


Mapping the road to resilience: novel math for the study of frailty.
Frailty stands at the nexus of geriatrics and gerontology, and requires both basic biology and clinical knowledge for its analysis. Understanding frailty difficulties much more than simply adding another outcome measure in epidemiological studies. The major challenge is the identification of multiple feed-forward and feed-back signaling pathways involved in the maintenance of biological homeostasis in complex organisms that may fail with aging. The cause of frailty and loss of resilience is probably a progressive loss of redundancy in these response patterns and connections. Advances toward the development of a theoretical model that can potentially embrace the complexity of frailty should be highly encouraged, especially models designed to explain the biology of aging which can promote a better integration and communication between scientists who study this problem from different perspectives.


Chronic intoxication by an herbicide, 2,4,5-trichlorophenoxyacetic acid, in the pond snail, Lymnaea stagnalis L.
Experiments of chronic intoxication with three concentrations (10, 20, and 40 ppm) of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were conducted in the freshwater mollusc Lymnaea stagnalis. Snail survival was concentration dependent. In all cases the growth can be described by the von Bertalanffy pattern (ht = h (1 - e-k(t-to)) and the variations of the k values showed that growth was significantly altered in all the groups treated. The overall fecundity (F) was always reduced; the decrease was due both to a lower number of eggs per egg mass (-7.8 to -12%) and to an earlier death of the intoxicated snails. Fecundity studied in terms of size, according to the law F = ahz, points out the loss of equilibrium between growth and fecundity: in all groups treated the values of the exponent z were increased. The importance of these perturbations can be quantified by the calculation of a "Snail Yield" which is reduced by 72.6% in the 40 ppm group. Egg fertility was also reduced. It can be concluded that 2,4,5-T disturbs the physiological equilibrium of Lymnaea stagnalis leading even to earlier death of the snails.


Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20.
Immunosafety analysis of pharmaceutical surfactants is an important step in understanding the complex mechanisms by which they induce side effects in susceptible patients. This paper provides experimental evidences that polyethoxylated surfactants, Cremophor-EL and Tween-80, also known as Polysorbate-80, activate the complement system in vitro, in normal human serum and plasma. They appeared to be more efficient reactogens than their structural homolog, Tween-20. Cremophor-EL and Tween-80 promoted the generation of biologically active complement products, C3a, C5a and C5b-9. Consistently, Paclitaxel and Taxotere (Docetaxel), pharmaceuticals formulated in Cremophor-EL and Tween-80, activated the complement system in similar extent. Moreover, comparison of serum reactivity against the drug-loaded and drug-free formulations exhibited a significant linear correlation. Taken together, these results are consistent with the hypothesis that therapeutic side effects, such as acute hypersensitivity and systemic immunostimulation, caused by intravenous nanomedicines containing polyethoxylated detergents such as Cremophor-EL and Tween-80, can be attributed to complement activation-derived inflammatory mediators.


RNA interference: A futuristic tool and its therapeutic applications.
RNA interference is a post transcriptional gene silencing mechanism that is triggered by double-stranded RNA (dsRNA). Various attributes of the 3' end structure, including overhang length and sequence composition, plays a primary role in determining the position of the Dicer cleavage in both dsRNA and unimolecular, short hairpin RNA (shRNA). The specificity and robustness of RNAi have triggered an immense interest in using RNAi as a tool in various settings. RNAi is a mechanism for controlling normal gene expression which has recently began to be employed as a potential therapeutic agent for a wide range of disorders, including cancer, infectious diseases and metabolic disorders. Clinical trials with RNAi have now begin, but major obstacles, such as off-target effects, toxicity and unsafe delivery methods, have to be overcome before RNAi can be considered as a conventional drug. It is also used as a tool to improve crops by providing resistance against parasites and modified versions of siRNA that are directed against disease causing genes are being developed, some of which are already tested in clinical trials. In this paper, we first reviewed the RNAi mechanism and then focussed on some of its applications in biomedical research such as treatment for HIV, viral hepatitis and several other diseases.


Intracellular O-linked glycosylation directly regulates cardiomyocyte L-type Ca2+ channel activity and excitation-contraction coupling.
Cardiomyocyte L-type Ca2+ channels (Cavs) are targets of signaling pathways that modulate channel activity in response to physiologic stimuli. Cav regulation is typically transient and beneficial but chronic stimulation can become pathologic; therefore, gaining a more complete understanding of Cav regulation is of critical importance. Intracellular O-linked glycosylation (O-GlcNAcylation), which is the result of two enzymes that dynamically add and remove single N-acetylglucosamines to and from intracellular serine/threonine residues (OGT and OGA respectively), has proven to be an increasingly important post-translational modification that contributes to the regulation of many physiologic processes. However, there is currently no known role for O-GlcNAcylation in the direct regulation of Cav activity nor is its contribution to cardiac electrical signaling and EC coupling well understood. Here we aimed to delineate the role of O-GlcNAcylation in regulating cardiomyocyte L-type Cav activity and its subsequent effect on EC coupling by utilizing a mouse strain possessing an inducible cardiomyocyte-specific OGT-null-transgene. Ablation of the OGT-gene in adult cardiomyocytes (OGTKO) reduced OGT expression and O-GlcNAcylation by > 90%. Voltage clamp recordings indicated an ~ 40% reduction in OGTKO Cav current (ICa), but with increased efficacy of adrenergic stimulation, and Cav steady-state gating and window current were significantly depolarized. Consistently, OGTKO cardiomyocyte intracellular Ca2+ release and contractility were diminished and demonstrated greater beat-to-beat variability. Additionally, we show that the Cav α1 and β2 subunits are O-GlcNAcylated while α2δ1 is not. Echocardiographic analyses indicated that the reductions in OGTKO cardiomyocyte Ca2+ handling and contractility were conserved at the whole-heart level as evidenced by significantly reduced left-ventricular contractility in the absence of hypertrophy. The data indicate, for the first time, that O-GlcNAc signaling is a critical and direct regulator of cardiomyocyte ICa achieved through altered Cav expression, gating, and response to adrenergic stimulation; these mechanisms have significant implications for understanding how EC coupling is regulated in health and disease.


Diagnosis of gastroesophageal varices and portal collateral venous abnormalities by endosonography in cirrhotic patients.
The role of endosonography (EUS) in the management of portal hypertension is not well defined. We aimed to study the use of a new generation video-echo endoscope in the diagnosis of gastroesophageal varices (GEV) and extraluminal venous abnormalities in cirrhotic patients. Cirrhotic patients were studied by echo endoscopy to assess esophageal varices endoscopically, and gastric varices and extraluminal venous abnormalities sonographically. The results were compared with esophagogastroduodenoscopy (EGD) examination. Dyspeptic patients served as controls. A total of 52 cirrhotic and 166 dyspeptic patients were studied. EUS identified esophageal varices (EV) endoscopically in 28 patients (53.8 %), which showed a good correlation with EGD findings (r = 0.855, P < 0.001). The red color sign and portal hypertensive gastropathy were diagnosed in six and seven patients, respectively, by both methods. EUS detected gastric varices sonographically in 16 patients (30.8 %), compared with detection in nine patients by EGD. Extraluminal venous abnormalities were detected in 48 cirrhotic patients (92 %) and in only nine dyspeptic patients (5.4 %) (P < 0.001). The size of extraluminal adventitial venous dilatation was significantly correlated with the severity of GEV and cirrhosis (P < 0.001). Perforating veins were identified in all patients with GEV. The new generation video-echo endoscope could be used as a single investigation in assessing both the intraluminal GEV and extraluminal venous abnormalities in cirrhotic patients. It may improve the management of patients with portal hypertension.


Evidence for TGF-beta1 and bleomycin intracellular signaling through autocrine regulation of Smad 3 binding to the proximal promoter of the Smad 7 gene.
Both Bleomycin and TGF-beta1 increase the transcription of the COL1A1 gene. Bleomycin acts through TGF-beta1. Bleomycin stimulates the COL1A1 promoter through the distal TGF-beta response element by intracellular and extracellular signaling. As demonstrated in this manuscript, Bleomycin's intracellular signaling can be explained by a decrease of Smad 3 transcription factor binding to the SBE located in the proximal promoter of the inhibitory Smad 7 gene. This would result in TGF-beta1-induced activated SMADS, which would result in more collagen. Bleomycin's extracellular signaling results from the secretion of more latent TGF-beta produced by lung fibroblasts and cleaved to active TGF-beta extracellularly. Since the TGF-beta genes are auto-induced in human embryonic IMR-90 lung fibroblasts, this study indicates an autocrine mechanism to maintain homeostasis in vivo for fibroblasts and other cell types, which produce TGF-beta1 to limit the fibrogenic response to TGF-beta1 and Bleomycin.


Continuous thoracic epidural analgesia for the control of pain in myocardial infarction.
Continuous thoracic epidural infusion of bupivacaine 0.25% for the relief of pain in acute myocardial infarction (AMI) was studied. The method was only employed for patients, who could not obtain adequate pain relief by parenteral opioid analgesics without unacceptable respiratory depression and/or emesis. The method was effective in controlling pain. The systolic blood pressure was reduced significantly, while the diastolic blood pressure and the heart rate did not change.


Mapping of groundwater salinization and modelling using meta-heuristic algorithms for the coastal aquifer of eastern Saudi Arabia.
The growing increase in groundwater (GW) salinization in the coastal aquifers has reached an alarming socio-economic menace in Saudi Arabia and various places globally due to several natural and anthropogenic activities. Hence, evaluating the GW salinization is paramount to safeguarding the water resources planning and management. This study presents three different scenarios viz.: real field investigation, experimental laboratory analysis (using ion chromatography (IC) and inductively coupled plasma mass spectrometry (ICP-MS), etc.), and artificial intelligence (AI) based metaheuristic optimization (MO) algorithms in Saudi Arabia. The main purpose of this study is to validate the obtained experimental-based analysis using hybrid MO techniques comprising of adaptive neuro-fuzzy inference system (ANFIS) hybridized with genetic algorithm (GA), particle swarm optimization (PSO), and biogeography-based optimization (BBO) for identification of GW salinization in the coastal region of eastern Saudi Arabia. Additionally, ArcGIS 10.3 software generates the prediction map based on ANFIS-GA, ANFIS-PSO, and ANFIS-BBO. Feature selection was assessed using the PSO algorithm, and four indices evaluated the estimated models, namely, root mean square error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE), and standard deviation (SD). The simulated results are based on three variable input combinations, which showed that the ANFIS-PSO (MAE = 0.00439) algorithm had the highest accuracy (99 %), followed by the ANFIS-GA (MAE = 0.00767) and ANFIS-BBO (MAE = 0.0132) algorithms. Besides, Ca2+, Na+, Mg2+, and Cl- were the most influential parameters. The accuracy also demonstrated the potential reliability of MO algorithms based on spatial distribution mapping. The employed approach proved to be merit and reliable tool for water resources decision-makers in the coastal aquifer of Saudi Arabia. This approach is believed to improve water scarcity as one of the essential targets for Goal 6 of Sustainable Development Vision 2030 and the Kingdom in general.


Plasminogen activator inhibitor-1 concentrations and bone mineral density in postmenopausal women with type 2 diabetes mellitus.
Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD). In experimental studies a potential role of plasminogen activator inhibitor-1 (PAI-1) in bone remodeling is suggested but studies in humans are lacking. This is a first study in humans investigating whether circulated levels of PAI-1 in postmenopausal women with T2DM are related to BMD and adiposity. Anthropometric variables, PAI-1 and insulin levels, serum lipids and bone turnover markers were measured in 127 postmenopausal women with T2DM. A total of 117 female patients were divided according to lumbar spine BMD measurements via dual-energy x-ray absorptiometry in three groups: 47 with osteopenia, 21 with osteoporosis and 49 with normal BMD. Diabetic patients with normal BMD had significantly higher BMI, greater waist circumference and lower bone turnover markers than diabetics with osteopenia and osteoporosis. PAI-1 was lower in diabetics with osteoporosis and osteopenia compared with diabetics with normal BMD. Multiple regression analysis revealed insulin, triglycerides levels, pyrilinks and beta blocker therapy to be the strongest predictors of PAI-1 levels. PAI-1 levels correlated with both L-BMD and hip BMD, but after adjustment for age and BMI association was no longer significant. Our findings suggest that elevated PAI-1 levels are associated with higher BMD in obese diabetic patients but the possible implications of this finding and underlying mechanisms still remain unclear. Obviously, metabolic parameters, may affect both BMD and PAI-levels, and association of PAI-1 and BMD could be indirect. However, as pyrilinks is also independently and significantly negatively correlated to PAI-1 its direct involvement in bone metabolism is also plausible. Further investigations are needed to elucidate the nature of interaction of this matrix modulator in relation to energy and bone metabolism in humans.


Infarct of the anterior limb of the right internal capsule causing left motor neglect: case report and cerebral blood flow study.
A sixty-nine year old hypertensive man had left motor neglect following an infarct of the anterior limb of the right internal capsule. He also had left auditory extinction on verbal dichotic listening and a sligh constructional apraxia. Regional cerebral blood flow (CBF) was measured at rest with Xenon 133 inhalation and was found to be slightly decreased in a diffuse fashion. Motor activation of the right hand resulted in an increase of CBF in the contralateral superior rolandic area, whereas no such increase was found during motor activation of the left hand. This lack of cortical CBF increase on contralateral motor activation is interpreted as a consequence of the failure of some corticosubcortical connexions involved in motor arousal. The specifically dynamic appearance of regional CBF abnormalities, i.e. during selective activation as opposed to rest measurements, is consistent with the functional character of neglect.


Cancer vaccines at an inflexion point: what next?
With the approval of the first therapeutic cancer vaccines for veterinarian and human use, the field reached a significant milestone after a considerable interval of tumultuous research and development marked by numerous ups and downs. As the mechanism of action and clinical benefit afforded by this class of agents are starkly different from that of conventional or small targeted therapies for cancer, there are still numerous hurdles that need to be overcome to fully unleash their potential. These challenges and efforts are illustrated in a book just published on this subject, a non-exhaustive yet representative synopsis of the latest advances in cancer vaccine technologies in various stages of development. Major lessons resulting from clinical testing of cancer vaccines and other immune interventions, are being integrated in novel, cutting edge platform technologies that blur the distinction between passive and active immunotherapies as well as carry the promise of fundamentally changing and improving the management of patients with cancer.


Loss of MPC1 reprograms retinal metabolism to impair visual function.
Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the "Warburg Effect"), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mitochondria is required for visual function, photoreceptor structure and viability, normal neuron-glial interaction, and homeostasis of retinal metabolism. The mitochondrial pyruvate carrier (MPC) links glycolysis and mitochondrial metabolism. Retina-specific deletion of MPC1 results in progressive retinal degeneration and decline of visual function in both rod and cone photoreceptors. Using targeted-metabolomics and 13C tracers, we found that MPC1 is required for cytosolic reducing power maintenance, glutamine/glutamate metabolism, and flexibility in fuel utilization.


miR-128-3p increases the radiosensitivity in nasopharyngeal carcinoma via regulating vascular endothelial growth factor C.
This study aims to investigate the role of miR-128-3p in the radiosensitivity of nasopharyngeal carcinoma (NPC) and its underlying mechanism. 6-10B cells were transfected with miR-128-3p mimic, pcDNA-VEGFC, and the corresponding negative control. C666-1 cells were transfected with miR-128-3p inhibitor, sh-VEGFC, and the corresponding negative control. RT-qPCR was used to determine the miR-128-3p and VEGFC mRNA expression level. Dual-luciferase assay was used to investigate the relationship between miR-128-3p and VEGFC. The protein levels of VEGFC, H2AX, γ-H2AX, p-P50, p-P65, p-IκB, and the apoptosis markers Bcl-2, caspase3, caspase9, and Bax were detected by Western blot. The proliferation activity was detected by CCK-8, and cell DNA damage was assessed by comet assay. The apoptosis rate was detected by flow cytometry. The growth of NPC in vivo was observed in mice through xenotransplantation. TUNEL staining was used to detect cell apoptosis in tumor tissues. miR-128-3p was targeted and was negatively regulated with VEGFC. Overexpression of miR-128-3p or knockdown VEGFC significantly inhibited the proliferation of 6-10B and C666-1 cells, induced DNA damage and apoptosis and promoted the radiosensitivity of cells. Knocking down miR-128-3p or up-regulated VEGFC promoted the proliferation of C666-1 and 6-10B cells, reduced cell DNA damage and apoptosis, and enhanced cell resistance to radiotherapy. Overexpression of miR-128-3p reversed the effect of VEGFC on 6-10B cells and inhibited P50/P65/IKB signal pathway. In vivo, experiments in mice confirmed that miR-128-3p significantly inhibited NPC proliferation and promoted DNA damage and apoptosis by targeting VEGFC. The miR-128-3p pathway is a novel therapy target to overcome radiation resistance in NPC.


Endocrinology of osmoregulation and thermoregulation of Australian desert tetrapods: A historical perspective.
Many Australian tetrapods inhabit desert environments characterised by low productivity, unpredictable rainfall, high temperatures and high incident solar radiation. Maintaining a homeostatic milieu intérieur by osmoregulation and thermoregulation are two physiological challenges faced by tetrapods in deserts, and the endocrine system plays an important role in regulating these processes. There is a considerable body of work examining the osmoregulatory role of antidiuretic hormones for Australian amphibians, reptiles and mammals, with particular contributions concerning their role and function for wild, free-living animals in arid environments. The osmoregulatory role of the natriuretic peptide system has received some attention, while the role of adrenal corticosteroids has been more thoroughly investigated for reptiles and marsupials. The endocrinology of thermoregulation has not received similar attention. Reptiles are best-studied, with research examining the influence of arginine vasotocin and melatonin on body temperature, the role of prostaglandins in heart rate hysteresis and the effect of melanocyte-stimulating hormone on skin reflectivity. Australian mammals have been under-utilised in studies examining the regulation, development and evolution of endothermy, and there is little information concerning the endocrinology of thermoregulation for desert species. There is a paucity of data concerning the endocrinology of osmoregulation and thermoregulation for Australian desert birds. Studies of Australian desert fauna have made substantial contributions to endocrinology, but there is considerable scope for further research. A co-ordinated approach to examine arid-habitat adaptations of the endocrine system in an environmental and evolutionary context would be of particular value.


Report from an ICT 2022 workshop on toxicology for Covid19 vaccines: Industry, regulatory and CRO perspectives.
The Covid pandemic took the world by surprise in late 2019 and the need for rapid development of vaccines became paramount. The challenge was how to accelerate standard vaccine development times as much as possible. With knowledge of the genetic code of SARsCOV2, vaccine manufacturers throughout the world have risen to the challenge and several new vaccines were rapidly developed for emergency use. In March 2020, global Regulatory Authorities met to consider how to start early clinical trials and accept rolling submissions. Before use in clinical trials or any mass vaccination campaigns, the safety of the candidate vaccine needs to be evaluated. Non-clinical toxicology studies are required as an important part of vaccine safety evaluation. The extent of the toxicology evaluation prior to the start of clinical trials depended on several factors, including: the type of the candidate vaccine as well as already available supportive information with the candidate vaccine or similar vaccine types. For vaccine candidates with pre-existing data, this would save valuable time whilst a full toxicology evaluation was completed in parallel. For vaccines with more limited data, toxicology data was required before clinical development could start. This workshop examined the nonclinical toxicology studies for new Covid vaccines from the perspectives of: Vaccine manufacturers with different vaccine technologies, managing global regulatory submissions/responses; CROs, managing the urgency of conducting and reporting studies and supporting new players in the vaccine world; and Regulatory Authorities, in supporting the review process, juggling the need for safety and quality with mounting pressure to approve vaccines.


Large diversity of the piggyBac-like elements in the genome of Tribolium castaneum.
The piggyBac transposable element (TE), originally discovered in the cabbage looper, Trichoplusia ni, has been widely used in insect transgenesis including the red flour beetle Tribolium castaneum. We surveyed piggyBac-like (PLE) sequences in the genome of T. castaneum by homology searches using as queries the diverse PLE sequences that have been described previously. The search yielded a total of 32 piggyBac-like elements (TcPLEs) which were classified into 14 distinct groups. Most of the TcPLEs contain defective functional motifs in that they are lacking inverted terminal repeats (ITRs) or have disrupted open reading frames. Only one single copy of TcPLE1 appears to be intact with imperfect 16bp ITRs flanking an open reading frame encoding a transposase of 571 amino acid residues. Many copies of TcPLEs were found to be inserted into or close to other transposon-like sequences. This large diversity of TcPLEs with generally low copy numbers suggests multiple invasions of the TcPLEs over a long evolutionary time without extensive multiplications or occurrence of rapid loss of TcPLEs copies.


Data on the effects of the anionic protein meal BioChlorⓇ on sows before and after farrowing.
Three hundred and two parity 3 and 4 sows were allocated to one of three treatment groups: A (n=106): Control group fed the standard lactation diet; B (n=94): Lactation diet supplemented with 10 kg BioChlor/T; C (n=102): Lactation diet supplemented with 20 kg BioChlor/T. The sows were randomly allocated to treatment on entry to the farrowing shed at 100 d of gestation. The numbers allocated to each treatment were not equal with fewer sows allocated to treatment B at the start of treatment feeding than originally intended. Six allocated sows were not pregnant at their due farrowing date and two control group sows died after treatment feeding commenced prior to farrowing. All sows were individually housed in sow stalls and were fed 3 kg of their treatment diet once a day from d 105 of gestation. At d 110 of gestation, sows were moved into farrowing crates and continued to be fed 3 kg of their treatment diet once a day until the day of farrowing followed by ad libitum feeding of the treatment diet during a 27-d lactation. Approximately 50 litters from each treatment were randomly weighed to determine treatment effects on piglet average daily gain from birth to weaning. Litters were standardized within treatment to 10 piglets per litter at d 3 of lactation by allocating piglets from sows within treatment that had more than 12 piglets. After weaning, all sows were transported to a commercial module and mated on the first display of estrus. Sows were offered a common boar shed diet (13.8 MJ DE/kg; 170 g protein/kg; 9 g lysine/kg) ad libitum from weaning to mating. Following mating, all animals were fed 2.5 kg of a gestation diet (13.0 MJ DE/kg; 125 g protein/kg; 6 g lysine/kg) until farrowing. All sows were stalled individually during the gestation period following treatment feeding. Measures included: date of birth, number of piglets stillborn, number of piglets born alive, total number of piglets born, number of mummified feti, litter weight and number of piglets weighed at birth, litter weight and number of piglets at d 3, 14, and 26, number of piglets stillborn (gestation 2), number of piglets born alive (gestation 2), and total number of piglets born (gestation 2). The number of piglets born alive, number of total piglets born, and all weight measures were analyzed with mixed models with treatment as a fixed effect and sow within farrowing house as a random effect. A negative binomial model was used to estimate the incidence of still birth with sow within farrowing house as a random effect. For the odds of being re-mated a logistic regression mixed model was used to evaluate differences among treatment groups. These data provide information on an individual animal basis that can be used to inform pig producers, nutritionists, veterinarians, and researchers for further investigation on the use of anionic feeds in gestation diets of pigs and is suitable for future meta-analyses.


Focal white matter abnormalities related to neurocognitive dysfunction: an objective diffusion tensor imaging study of children with Sturge-Weber syndrome.
White matter (WM) loss is associated with cognitive impairment in Sturge-Weber syndrome (SWS). In this study, we evaluated if cognitive and fine motor abnormalities are associated with impaired microstructural integrity in specific WM regions in SWS. Fifteen children with unilateral SWS (age: 3-12.4 y) and 11 controls (age: 6-12.8 y) underwent diffusion tensor imaging. Tract-based spatial statistics was used for objective comparisons of WM fractional anisotropy (FA) and mean diffusivity (MD) between the two groups. In the SWS group, WM FA and MD values were correlated with intelligence quotient (IQ) and fine motor scores, with age as a co-variate. Bilateral, multilobar WM areas showed decreased FA, whereas significant MD increases were confined to small ipsilateral posterior regions in SWS children. IQ in the SWS group (range: 47-128) was positively correlated with FA in the ipsilateral prefrontal WM and inversely associated with MD in the ipsilateral posterior parietal WM. A negative correlation between fine motor function and MD was found in ipsilateral frontal WM encompassing motor pathways. Microstructural WM abnormalities occur not only ipsilateral but also contralateral to the angioma in unilateral SWS. Nevertheless, cognitive and fine motor functions are related to diffusion abnormalities in specific ipsilateral, mostly frontal, WM regions.


"We don't need no education" - a qualitative study of barriers to continuous medical education among Danish general practitioners.
Continuous medical education is essential for the individual patient care, the society, and the wellbeing of the general practitioner. There has been research into the reasons for participation in continuous medical education, but little is known about the barriers to participation. To tailor continuous medical education targeting general practitioners who are currently deselecting education, systematic knowledge of the barriers is needed. Continuous medical education can in addition to professional growth stimulate job satisfaction, diminish burnout, and reinforce feelings of competence. Continuous medical education may have positive implications for patients and for healthcare expenditures. Despite renumeration and a comprehensive continuous education model some Danish general practitioners do not participate in continuous medical education. From a total of 3440 Danish general practitioners 243 did not apply for reimbursement for accredited continuous medical education in a two-year period. Ten general practitioners were selected for an interview regarding maximum variation in practice form, number of listed patients, seniority as a general practitioner, geography, gender, and age. All ten selected general practitioners accepted to be interviewed. The interviews were analysed using Systematic Text Condensation. Each of the ten interviewed general practitioners mentioned several barriers for participating in continuous education. The barriers fell into three main categories: barriers related to the individual general practitioner barriers related to the clinic barriers related to the accredited continuous medical education offered CONCLUSIONS: Approximately 7% of the Danish general practitioners did not participate in accredited remunerated continuous medical education. A knowledge of the barriers for participating in accredited continuous medical education can be used to better target continuous medical education to the general practitioners.


Changes in cranial and rectal temperature, blood pressure and arterial blood gas during and after unilateral and bilateral forebrain ischemia in Mongolian gerbils.
Transient forebrain ischemia was produced by occluding the common carotid arteries, either unilaterally or bilaterally, in Mongolian gerbils under halothane anesthesia. After 20-min ischemia, the cranial temperature measured in the temporal muscle decreased compared to the preischemic level, the decrease being larger after the bilateral than after the unilateral occlusion. After recirculation, cranial temperature recovered promptly to the preischemic level in the unilateral group, while it was elevated to above the preischemic level in the bilateral group. The rectal temperature also decreased with a similar time course. During 30-min ischemia, the blood pressure of both groups increased to above the preischemic level, the increase being larger in the bilateral group than in the unilateral group. After recirculation, blood pressure of the unilateral group recovered promptly to the preischemic level, while that of the bilateral group decreased to below the preischemic level. When forebrain ischemia was produced immediately after cessation of halothane inhalation, blood pH, PaO2 or PaCO2 did not change significantly from the control level. However, these values showed larger variation in the bilateral group than in the unilateral group. Unilateral occlusion in preselected gerbils provided a good model of transient brain ischemia, giving rise to uniform experimental results.


Cognitive protection of incretin-based therapies in patients with type 2 diabetes mellitus: A systematic review and meta-analysis based on clinical studies.
Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as an important complication of type 2 diabetes mellitus. The aims of the preset study was to investigate the cognitive protection of incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, in patients with type 2 diabetes mellitus. PubMed, EMBASE, Cochrane library, Web of Science and PsycINFO were searched from the inception through 17 January 2023 for randomized controlled trials and cohort studies on the association between incretin-based therapies and cognitive function. A total of 15 studies were finally included in our systematic review, and eight of which were incorporated into our meta-analysis. Pooled results showed that the Mini-Mental State Examination score in incretin-based therapy groups was increased by 1.20 compared with the control group (weighted mean difference 1.20, 95% confidence interval 0.39-2.01). The results of eight studies assessed by the Newcastle Ottawa Quality Assessment Scale and the Cochrane Collaboration's tool, and the quality of the eight studies were at a relatively high level. Egger's regression did not show significant publication bias. Current evidence shows that incretin-based therapies might be more effective, when compared with the other hypoglycemic drugs, for cognitive improvement in patients with type 2 diabetes mellitus.


Boosting protection for patients with non-acute cardiovascular disease: a focus on antithrombotic regimen (a consensus expert opinion from the Egyptian Society of Cardiology working group of thrombosis and prevention).
Till the moment of this document writing, no Egyptian consensus is there to guide selection of additional antithrombotic in stable patients with established CVD. Despite use of lifestyle measures and statins, those patients with established CVD still face a considerable burden of residual risk. With the evolvement of evidence-based medicine, there have been a lot of recommendations to use additional antithrombotic medications to maximize protection for those patients. Accordingly, the Egyptian Society of Cardiology working group of thrombosis and prevention took the responsibility of providing an expert consensus on the current recommendations for using antithrombotic medications to maximize protection in stable patients with established CVD. For stable patients with established CVD, in addition to proper lifestyle measures and appropriate dose statins, we recommend long-term aspirin therapy. In patients who are unable to take aspirin and in those with a history of gastrointestinal bleeding, clopidogrel is a reasonable alternative. For some stable atherosclerotic CVD patients who are at high risk of cardiovascular events and at low risk for bleeding, a regimen of rivaroxaban and aspirin might be taken into consideration.


Choice preference and willingness to pay for COVID-19 vaccination in Namibia.
Namibia has not been spared from the coronavirus (COVID-19) pandemic, and as intervention the Namibian government has rolled out vaccination programmes. This study was conducted before the roll out of these vaccines to assess the preference for COVID-19 vaccinations. Stated preference studies provide information about social demand, access, willingness-to-pay and financing for future COVID-19 vaccination. A stated choice experiment (SCE) survey was administered to a sample of 506 participants from Namibia's general population between October 2020 and December 2020. Participants were asked to make a series of hypothetical choices and estimate their preference for different attributes of a vaccine. A latent class model was used to analyse the SCE data. The study also assessed anti-vaccination behaviour, past vaccination behaviour, impacts of COVID-19 on mental and physical health and Willingness-To-Pay (WTP) measures. The WTP measures were captured as out-of-pocket and further calculated using the marginal rate of substitution method in SCE. Data from 269 participants was included in the analysis. Vaccine side effects (40.065), population coverage (4.688), payment fee to receive vaccine immediately (3.733) were the top three influential attributes for vaccine preferences. Accordingly, increases in mild and severe side effects of vaccine options had negative impacts on utility; with an average WTP of N$728.26 to reduce serious side effects. The average WTP to receive a high-quality vaccine with 90% efficient was found to be N$233.11 (US$15.14). Across classes, there was a strong preference for vaccines with high effectiveness over longer durations of time. The results provide useful information for the Namibian government to improve the current strategies for vaccine rollout interventions.


[Plantar forefoot lipoma: an uncommon case report].
The plantar tumors of soft tissues are rare and are characterized by their slow and asymptomatic evolution, which delays their diagnosis. The authors report an exceptional case of plantar foot lipoma. The diagnosis was suspected by magnetic resonance imagery, which represents the technique of choice for the investigation of soft tissue tumors of the foot. The surgical treatment made the histological diagnosis and restored a normal and painless plantar support. The lipoma, in spite of its exceptional localization at the plantar level, will have to be evoked like differential diagnosis of the benign tumors of the foot.


Quantification of hydrogen peroxide generation by Granuflex (DuoDERM) Hydrocolloid Granules and its constituents (gelatin, sodium carboxymethylcellulose, and pectin).
The hydrogen peroxide generating capacity of Granuflex Hydrocolloid Granules and its constituents (porcine gelatin, sodium carboxymethylcellulose and pectin) was examined using the scopoletin-horseradish peroxidase assay in the presence and absence of catalase. Oxygen purging reduced the formation of hydrogen peroxide by 77-96%. The total concentrations of hydrogen peroxide detected were 1.9 x 10(-6), 1.2 x 10(-6) and 2.3 x 10(-6) mol/l for Granuflex, pectin and gelatin (using 0.5% w/v), respectively, after 48 h incubation in a phosphate buffer, pH 7.4, at 37 degrees C. No hydrogen peroxide was formed by sodium carboxymethylcellulose. The results indicate that hydrogen peroxide generation by Granuflex may be ascribed to its gelatin and pectin components, but not to the sodium carboxymethylcellulose. The release of low levels of hydrogen peroxide into the wound environment could conceivably contribute both to the inflammatory phase and to fibroblast proliferation, and hence to the granulation phase of wound healing.


Real-time location system-based asset tracking in the healthcare field: lessons learned from a feasibility study.
Numerous hospitals and organizations have recently endeavored to study the effects of real-time location systems. However, their experiences of system adoption or pilot testing via implementation were not shared with others or evaluated in a real environment. Therefore, we aimed to share our experiences and insight regarding a real-time location system, obtained via the implementation and operation of a real-time asset tracking system based on Bluetooth Low Energy/WiFi in a tertiary care hospital, which can be used to improve hospital efficiency and nursing workflow. We developed tags that were attached to relevant assets paired with Bluetooth Low Energy sensor beacons, which served as the basis of the asset tracking system. Problems with the system were identified during implementation and operation, and the feasibility of introducing the system was evaluated via a satisfaction survey completed by end users after 3 months of use. The results showed that 117 nurses who had used the asset tracking system for 3 months were moderately satisfied (2.7 to 3.4 out of 5) with the system, rated it as helpful, and were willing to continue using it. In addition, we identified 4 factors (end users, target assets, tracking area, and type of sensor) that should be considered in the development of asset tracking systems, and 4 issues pertaining to usability (the active tag design, technical limitations, solution functions, and operational support). The successful introduction of asset tracking systems based on real-time location in hospitals requires the selection of clear targets (e.g., users and assets) via analysis of the user environment and implementation of appropriate technical improvements in the system as required (e.g., miniaturization of the tag size and improvement of the sensing accuracy).


Effectively facilitating the degradation of chloramphenicol by the synergism of Shewanella oneidensis MR-1 and the metal-organic framework.
Electroactive bacteria (EAB) and metal oxides are capable of synergistically removing chloramphenicol (CAP). However, the effects of redox-active metal-organic frameworks (MOFs) on CAP degradation with EAB are not yet known. This study investigated the synergism of iron-based MOFs (Fe-MIL-101) and Shewanella oneidensis MR-1 on CAP degradation. 0.5 g/L Fe-MIL-101 with more possible active sites led to a three-fold higher CAP removal rate in the synergistic system with MR-1 (initial bacterial concentration of 0.2 at OD600), and showed a superior catalytic effect than exogenously added Fe(III)/Fe(II) or magnetite. Mass spectrometry revealed that CAP was transformed into smaller molecular weight and less toxic metabolites in cultures. Transcriptomic analysis showed that Fe-MIL-101 enhanced the expression of genes related to nitro and chlorinated contaminants degradation. Additionally, genes encoding hydrogenases and c-type cytochromes associated with extracellular electron transfer were significantly upregulated, which may contribute to the simultaneous bioreduction of CAP both intracellularly and extracellularly. These results indicated that Fe-MIL-101 can be used as a catalyst to synergize with EAB to effectively facilitate CAP degradation, which might shed new light on the application in the in situ bioremediation of antibiotic-contaminated environments.


Evaluation of Percutaneous Mechanical Thrombectomy via the AngioJet System Combined with Catheter-Directed Thrombolysis for the Treatment of Symptomatic Lower Extremity Deep Venous Thrombosis.
Current methods of treating lower extremity deep venous thrombosis (LEDVT), such as catheter-directed thrombolysis (CDT) alone, or percutaneous mechanical thrombectomy (PMT) alone, are accompanied by unacceptably high risks of complications. This preliminary retrospective study evaluated the efficacy of CDT combined with PMT (via the AngioJet system), relative to CDT alone, in treating LEDVT. Forty-two patients (43 limbs) with symptomatic deep venous thrombosis received either CDT alone (n = 12) or PMT combined with CDT (PMT + CDT) from May 2012 to December 2016. The groups were compared for clinical outcomes and demographics, LEDVT risk factors, and dosages of urokinase. Thrombus removal, by venographic evidence, was classified as grades I (<50%), II (50 to 99%), or III (>99%). In the CDT (PMT + CDT) cohorts, grades I, II, and III thrombus removal was achieved by 8% (3%), 17% (10%), and 75% (87%) of patients, respectively. The urokinase dosage and hospitalization required by the CDT group (5.29 ± 0.45 million IU, 20.4 ± 4.6 days) were significantly greater than those required by the PMT + CDT group (4.08 ± 1.15 million IU, 16.0 ± 6.0 days; P = 0.001, 0.039). The clinical outcomes of the 2 groups were similar. Combined PMT and CDT was effective and safe for LEDVT clinical therapy, and hospital stay, urokinase dosage, and complications were less compared with patients who received CDT only.


A method for evaluation of brain tumor growth using implantable diffusion chambers.
Major drawbacks associated with in vitro assays for sensitivity of brain tumors to specific chemotherapeutic drugs include uncertainty of end-point validity, the need for large tissue samples, and cost. Furthermore, these assays do not address the question of conversion of the drug to active moeities by metabolic pathways in the host or alteration of drug activity by binding to plasma protein. We propose to develop a technique for growth and quantitation of tumor cells in small-pore diffusion chambers that contain the tumor cells and protect them from the immune system of the immunologically unrelated host. These chambers, fabricated from acrylic rings and membranes of 0.22 microns pore size, are sterilized, filled with a precisely quantitated inoculum of tumor cells, and implanted in the peritoneal cavity of rats. Replication of the cells is determined by enzymatic digestion of the supporting matrix of the cells within the chamber and counting the single cell suspension with a hemocytometer or automated cell counter. Precise comparison can thus be made between different drugs regarding their effect on cell growth in the host. This assay can be performed with the basic equipment and personnel available in most cell culture laboratories and requires a small number of tumor cells. Mass production of the diffusion chambers may make the assay less costly and faster than assays that do not involve exposure of tumor to drug in a living host. In addition, the assay should permit screening of new chemotherapeutic agents against human tumors under physiologic conditions.


Hierarchical dynamics as a macroscopic organizing principle of the human brain.
Multimodal evidence suggests that brain regions accumulate information over timescales that vary according to anatomical hierarchy. Thus, these experimentally defined "temporal receptive windows" are longest in cortical regions that are distant from sensory input. Interestingly, spontaneous activity in these regions also plays out over relatively slow timescales (i.e., exhibits slower temporal autocorrelation decay). These findings raise the possibility that hierarchical timescales represent an intrinsic organizing principle of brain function. Here, using resting-state functional MRI, we show that the timescale of ongoing dynamics follows hierarchical spatial gradients throughout human cerebral cortex. These intrinsic timescale gradients give rise to systematic frequency differences among large-scale cortical networks and predict individual-specific features of functional connectivity. Whole-brain coverage permitted us to further investigate the large-scale organization of subcortical dynamics. We show that cortical timescale gradients are topographically mirrored in striatum, thalamus, and cerebellum. Finally, timescales in the hippocampus followed a posterior-to-anterior gradient, corresponding to the longitudinal axis of increasing representational scale. Thus, hierarchical dynamics emerge as a global organizing principle of mammalian brains.


The role of Hebbian learning in human perception: a methodological and theoretical review of the human Visual Long-Term Potentiation paradigm.
Long-term potentiation (LTP) is one of the most widely studied forms of neural plasticity, and is thought to be the principle mechanism underlying long-term memory and learning in the brain. Sensory paradigms utilising electroencephalography (EEG) and sensory stimulation to induce LTP have allowed translation from rodent and primate invasive research to non-invasive human investigations. This review focusses on visual sensory LTP induced using repetitive visual stimulation, resulting in changes in the visually evoked response recorded at the scalp with EEG. Across 15 years of use and replication in humans several major paradigm variants for eliciting visual LTP have emerged. The application of different paradigms, and the broad implementation of visual LTP across different populations combines to provide a rich and sensitive account of Hebbian LTP, and potentially non-Hebbian plasticity mechanisms. This review will conclude with a discussion of how these findings have advanced existing theories of perceptual learning by positioning Hebbian learning both alongside and within other major theories such as Predictive Coding and The Free Energy Principle.


Pilot study: absorption and efficacy of multiple hormones delivered in a single cream applied to the mucous membranes of the labia and vagina.
There is a lack of evidence in the literature supporting vaginal application of a combination hormone-containing cream for local and systemic symptom relief. This pilot study examined the extent of absorption of a single cream containing estriol, estradiol, progesterone, DHEA, and testosterone. A combination cream was administered to 12 postmenopausal women in two differing doses over two independent time periods. Following 28 days (arm 1) and an additional 14 days (arm 2), measurement of hormones in saliva and blood and measurements of symptom relief, patient tolerability, and health-related quality of life (HRQoL) were obtained. The dosage and time of evaluation for study arm 1 was not ideal for providing documented increases in hormone levels. HRQoL measurements supported measured improvement in this arm. The second arm did document absorption of the various hormones when given vaginally. This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of HRQoL. This therapy was generally well-tolerated with only 2 patients experiencing minor irritation, not necessitating discontinuation. Additional studies in larger numbers of patients will provide better knowledge for clinicians wanting to provide similar therapy at the lowest effective dose.


Ovarian stimulation and borderline ovarian tumors: a case-control study.
To assess the risk of borderline ovarian cancer among infertile women treated with fertility drugs. Case-control study. Nationwide data obtained from public registers and postal questionnaires. All Danish women <60 years old with borderline ovarian cancer during the period 1989-1994 and randomly selected population controls. The analysis included 231 cases and 1,721 controls. None. Influence of parity, infertility, and fertility drugs on the risk of borderline ovarian cancer after multivariate confounder control. The odds ratio (OR) for borderline ovarian cancer among infertile untreated nulliparous women compared with fertile nulliparous women was 1.9. The OR for borderline ovarian cancer among treated nulliparous women compared with untreated infertile nulliparous women was 1.5, and the OR among treated parous women compared with untreated infertile parous women was 1.5. Among fertile women, the difference in the risk of borderline ovarian cancer between nulliparous women and parous women was not statistically significant. Nulliparous women who were infertile and who did not receive medical treatment had a twofold higher risk of borderline ovarian cancer than fertile nulliparous women. There was no statistically significant increase in the risk of borderline ovarian cancer among nulliparous women who were treated with fertility drugs compared with nulliparous untreated infertile women or among parous women who were treated with fertility drugs compared with parous untreated infertile women.


Urolithiasis in infants: evaluation of risk factors.
Urolithiasis in infants is not a very rare situation in Turkey, and the incidence has been increasing in recent years. The purpose of this paper was to investigate the clinical characteristics, metabolic and anatomic risk factors for urolithiasis and microlithiasis in infants. The cases of 178 infants (63 girls, 115 boys), who were referred to our department between 1999 and 2009 with urolithiasis, were evaluated. The mean age at diagnosis of stone disease was 11.5 months (range, 10 days-24 months). The mean follow-up duration was 33.6 months (1.2-110 months). The major clinical symptoms of our patients were restlessness in 24 children (13.5%) and vomiting in 23 (13%). Thirty-five infants (19.7%) had a urinary tract abnormality; vesico-ureteral reflux was the most common abnormality (12.9%). Hypercalciuria and hyperuricosuria were detected in 46 and 56%, respectively. Stone analysis was performed in 56 infants, and calcium oxalate was determined in 36 patients (64.3%). A family history of urolithiasis, presenting symptoms and underlying metabolic abnormalities were similar for patients with microlithiasis and those with larger stones. However, infants with microlithiasis had higher ratios for history of vitamin D administration and feeding with formula. Surgical treatment was performed in 42 infants and extracorporeal shock wave lithotripsy in 30 infants. Our results showed that urolithiasis in infants may present nonspecific symptoms and may even be asymptomatic and that a positive family history for urolithiasis, urologic abnormalities, metabolic disorders, urinary tract infections, vitamin D administration and feeding with formula may increase the occurrence of urolithiasis in infants.


Stabilization of the adenylate energy charge by the depletion of adenylates without glycolytic stimulation.
A relationship between the AMP deaminase reaction and the recovery of the energy charge was examined using permeabilized yeast cells. Citrate inhibited the glycolytic flux and the recovery of the energy charge. The addition of spermine enhanced the recovery of the energy charge without the reversal of the inhibition of glycolysis in the presence of excess citrate. The AMP deaminase reaction can participate in the stabilization of the energy charge only by the depletion of total adenylates, and not by the glycolytic stimulation under the conditions where citrate is highly increased during aerobic growth conditions.


Intracardiac papillary fibroelastoma: an occult cause of embolic neurologic deficit.
We report the case of a young woman with a transient ischemic attack secondary to a rare intracardiac tumor, a papillary fibroelastoma. The tumor was identified by two-dimensional echocardiography and was treated surgically. The intracardiac papillary fibroelastoma as an uncommon source of occult cerebral emboli is discussed.


Adult Human Dermal Progenitor Cell Transplantation Modulates the Functional Outcome of Split-Thickness Skin Xenografts.
Following full-thickness skin injuries, epithelialization of the wound is essential. The standard of care to achieve this wound "closure" in patients is autologous split-thickness skin grafting (STSG). However, patients living with STSGs report significant chronic impairments leading to functional deficiencies such as itch, altered sensation, fragility, hypertrophic scarring, and contractures. These features are attributable to the absence of functional dermis combined with the formation of disorganized fibrotic extracellular matrix. Recent work has demonstrated the existence of dermal progenitor cells (DPCs) residing within hair follicles that function to continuously regenerate mesenchymal tissue. The present work examines whether cultured DPCs could regenerate dermis within an STSG and improve overall graft function. Adult human DPCs were transplanted into a full-thickness skin wound in immune-compromised mice and closed with a human STSG. At 3 months, human DPCs (hDPCs) had successfully integrated into the xenograft and differentiated into various regionally specified phenotypes, improving both viscoelastic properties of the graft and mitigating pruritus.


A model for Vibrio cholerae colonization of the human intestine.
Vibrio cholerae is a strict human pathogen that causes the disease cholera. It is an old-world pathogen that has re-emerged as a new threat since the early 1990s. V. cholerae colonizes the upper, small intestine where it produces a toxin that leads to watery diarrhea, characterizing the disease (Kahn et al., 1988). The dynamics of colonization by the bacteria of the intestines are largely unknown. Although a large initial infectious dose is required for infection, data suggests that only a smaller sub-population colonizes a portion of the small bowel leading to disease. There are many barriers to colonization in the intestines including peristalsis, fluid wash-out, viscosity of the mucus layer, and pH. We are interested in identifying the mechanisms that allow this sub-population of bacteria to survive and colonize the intestines when faced with these barriers. To elaborate the dynamics of V. cholerae infection, we have developed a mathematical model based on a convection-diffusion-reaction-swimming equation capturing bacterial dynamics coupled with Stokes equations governing fluid velocity where we developed a novel non-local boundary condition. Our results indicate that both host and bacterial factors contribute to bacterial density in the gut. Host factors include intestinal diffusion and convection rates while bacterial factors include adherence, motility and growth rates. This model can ultimately be used to test therapeutic strategies against V. cholerae.


Porous silicon microparticle potentiates anti-tumor immunity by enhancing cross-presentation and inducing type I interferon response.
Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM)-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I) response in dendritic cells (DCs). PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy.


Molecular cloning, characterization and recombinant expression of crustacean hyperglycemic hormone in white shrimp Litopenaeus vannamei.
Crustacean hyperglycemic hormone (CHH) plays an important role in crustacean. In the present study, a full-length cDNA of CHH was cloned from the eyestalk of Litopenaeus vannamei by RACE approach for the first time. The full-length cDNA of LvCHH was 846 bp, containing a 5' untranslated region (UTR) of 65 bp, a 3' UTR of 436 bp with a canonical polyadenylation signal-sequence AATAA and a poly (A) tail, and an open reading frame (ORF) of 345 bp. The ORF encoded a polypeptide of 114 amino acids including a 24 amino acid signal peptide. The calculated molecular mass of the mature protein (74 amino acids) was 8.76 kDa with an estimated pI of 6.78. The sequence of LvCHH was submitted in NCBI GenBank under the accession number HM748790.2. Phylogenetic analysis revealed that LvCHH was clustered with CHH of other crustaceans. Tissue distribution analysis revealed that the expression of LvCHH mRNA was observed in all tissues but gill, and was highest in heart. Specific primers containing Xho I and BamH I restriction sites respectively, were designed based on the obtained ORF sequence of LvCHH gene and the cloning sites of expression vector pET-32a (+). The recombinant plasmid LvCHH-pET32a, was used to transform Escherichia coli BL21 (DE3). LvCHH was successfully expressed by means of SDS-PAGE and western blot analysis. We detected gill Na(+)/K(+)-ATPase activity after rLvCHH protein injection and found that All the experimental group Na(+)/K(+)-ATPase activity presented peak change among 0-6h, and the peaks of all treated groups occurred in 1 h. 20 and 30 μg/shrimp(-1) groups showed significant increase (P<0.05) in 1h post-injection. L. vannamei were exposed for 96h to hypo- and hyper-salinity challenge. Hypo-salinity caused a significant rise (P<0.05) in the mRNA expression of CHH and gill Na(+)/K(+)-ATPase activity at 12h and 24h respectively, then the CHH mRNA expression declining by 24h, and returned to control group level by 48 h, and the Na(+)/K(+)-ATPase activity tended to be stable after 72 h, and higher than that of control. The hyper-salinity challenge had the same trend at mRNA expression with the hypo-salinity group. The Na(+)/K(+)-ATPase activity had no significant change under the low salinity challenge. All these results indicate that LvCHH is an important hormone involved in the osmosis responses of swimming shrimps, and can provide further information of crustacean osmoregulation physiological mechanism.


High relative humidity in-package of fresh-cut fruits and vegetables: advantage or disadvantage considering microbiological problems and antimicrobial delivering systems?
This hypothesis article states that the high relative humidity (RH) of packaged fresh-cut fruits or vegetables that is associated with spoilage can be used as an advantageous way to deliver antimicrobial compounds using cyclodextrins (CDs) as carriers. CDs can function as antimicrobial delivery systems as they can release antioxidant and antimicrobial compounds (guest molecules) as the humidity levels increase in the headspace. Hydrophobic antimicrobial guests can be complexed with CDs due to the amphiphatic nature of the host. Then, at high RH values, due to the water-CDs interaction, host-guest interactions are weakened; consequently, the antimicrobial molecule is released and should protect the product against the microbial growth. Potential antimicrobial compounds capable of forming complexes with CDs are discussed, as well as possible applications to preserve fresh-cut produce and future research in this area.


Production and characterization of enzymatic cocktail produced by Aspergillus niger using green macroalgae as nitrogen source and its application in the pre-treatment for biogas production from Ulva rigida.
Marine macroalgae are gaining more and more importance as a renewable feedstock for durable bioenergy production, but polysaccharides of this macroalgae are structurally complex in its chemical composition. The use of enzymatic hydrolysis may provide new pathways in the conversion of complex polysaccharides to fermentable sugars. In this study, an enzymatic cocktail with high specificity was first isolated from Aspergillus niger using the green macroalgae Ulva rigida as nitrogen source. The cocktail is rich on β-glucosidase, pectinase and carboxy-methyl-cellulase (CMCase). The highest activity was obtained with β-glucosidase (109IUmL(-1)) and pectinase (76IUmL(-1)), while CMCase present the lowest activity 4.6IUmL(-1). The U. rigida pre-treatment with this enzymatic cocktail showed high rate of reduced sugar release, and could bring promising prospects for enzymatic pre-treatment of the biogas production from U. rigida biomass which reached 1175mLgCODint(-1).


5-HT(1A) receptor antagonist improves behavior performance of delirium rats through inhibiting PI3K/Akt/mTOR activation-induced NLRP3 activity.
Postoperative delirium is a common complication that often results in poor outcomes in surgical and elderly patients. Accumulating evidences suggest that the pathophysiology of delirium results from multiple neurotransmitter system dysfunctions. To further clarify the effects of the selective serotonin (5-HT) (1A) antagonist WAY-100635 on the behaviors in scopolamine induced-delirium rats and to explore the molecular mechanism, in this study, we investigated the change of monoamine levels in the cerebrospinal fluid (CSF) and different brain regions using high-performance liquid chromatography and assessed the behavioral retrieval of delirium rats treated with WAY-100635. It was found that 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations in the CSF of scopolamine-induced delirium rats were significantly increased, among which 5-HIAA was also increased in hippocampus and basolateral amygdala (BLA), and 5-HT(1A) receptor was significantly higher in the hippocampuses and BLA than other brain regions. Furthermore, intrahippocampus and intra-BLA stereotactic injection of WAY-100635 improved the delirium-like behavior of rats. Mechanistically, after WAY-100635 treatment, significant reduction of IL-1β release into CSF and NOD-like receptor family, pyrin domain containing 3 (NLRP3) expression, phosphorylated phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and S6K was observed. Altogether, these results suggest that delirium rats induced by scopolamine may be correlated with an increased cerebral concentration of 5-HT and dopamine neurotransmitters system; the selective 5-HT(1A) antagoniszts can reverse the delirium symptoms at some extent through tendering PI3K/Akt/mammalian target of rapamycin complex 1 (mTOR) activation-induced NLRP3 activity and then reducing IL-1β release.


Evolution and morphology of a contourite depositional system based on new evidence from 3D-seismic data offshore Madagascar (Paleogene, Morondava Basin).
Numerous bottom current-controlled depositional and erosional features, which together form Contourite Depositional Systems (CDS), have been recognized in deep-water settings over the past decade. Most of these systems are described based on two-dimensional (2D) seismic data, whereas only a few CDS have been characterised from high-resolution 3D data. Here we document a newly identified CDS that formed during the Paleocene within the Morondava Basin, offshore west Madagascar, through analysis of a depth-migrated 3D seismic survey, enhanced by the implementation of seismic attributes. Three seismic units (SU) mark the main evolutionary stages of the CDS: (a) the onset (SU1), (b) drift growth (SU2), and (c) burial (SU3) stages. The growth stage documents lateral upslope migration of a mounded drift and its associated moat. The increasing, long-term influence of bottom currents along the foot of the slope occurred simultaneously with plate tectonic, climatic and oceanographic changes. Evidence amassed from the CDS highly erosive bounding discontinuities, internal discontinuities, and moat architecture all indicate the intermittent behaviour of the currents over shorter time frames during its formation. Drift deposits form under the influence of weaker currents, while discontinuities appear to record the most vigorous currents, producing the large-scale morphology of the system.


Phylogenetic hierarchy of antigen-presenting ability in antigen-specific T cell activation.
The phylogenetic hierarchy of antigen-presenting ability was shown to exist in xenogeneic mouse, rat and human T cell-antigen-presenting cell (APC) interaction. The antigen-presenting ability of human APC is dominant over that of rat APC and the ability of rat APC is dominant over that of mouse APC. The HLA-DR molecule was shown to function for antigen presentation to PPD-specific autologous human and xenogeneic murine T cells.


Performance of neuroretinal rim thickness measurement by Cirrus high-definition optical coherence tomography in myopic eyes.
Neuroretinal rim (NRR) measurement can aid the diagnosis of glaucoma. A few studies reported that Cirrus optical coherence tomography (OCT) had NRR segmentation errors. The current study investigated segmentation success of NRR in myopic eyes using the Cirrus built-in software and to determine the number of acquisitions required to identify NRR thinning. Right eye of 87 healthy adult myopes had an optic disc scanned using Cirrus HD-OCT for five successive acquisitions. A masked examiner evaluated 36 radial line images of each scan to screen for segmentation errors using the built-in software at the Bruch's membrane opening (BMO) and/or internal limiting membrane (ILM). Participants with three accurate NRR acquisitions had their average NRR thickness determined. This result was compared with average of the two acquisitions and the first acquisition. Among 435 OCT scans of the optic disc (87 eyes × 5 acquisitions), 129 (29.7%) scans had segmentation errors that occurred mainly at the ILM. The inferior-temporal and superior meridians had slightly more segmentation errors than other meridians, independent of axial length, amount of myopia, or presence of peripapillary atrophy. Sixty-five eyes (74.7%) had at least three accurate NRR measurements. The three acquisitions had high reliability in NRR thickness in the four quadrants (intraclass correlation coefficient > 0.990, coefficient of variation < 3.9%). NRR difference between the first acquisition and the average of three acquisitions was small (mean difference 2 ± 13 μm, 95% limits of agreement within ± 30 μm) among the four quadrants. Segmentation errors in NRR measurements appeared regardless of axial length, amount of myopia, or presence of peripapillary atrophy. Cirrus segmentation lines should be manually inspected when measuring NRR thickness.


Correction to: Systolic modified Look-Locker inversion recovery myocardial T1 mapping improves the accuracy of T1 and extracellular volume fraction measurements of patients with high heart rate or atrial fibrillation.
The article "Systolic modified Look-Locker inversion recovery myocardial T1 mapping improves.


Synthesis of 2-Tetrazolyl-Substituted 3-Acylpyrroles via a Sequential Ugi-Azide/Ag-Catalyzed Oxidative Cycloisomerization Reaction.
A new efficient Ag-catalyed cascade cycloisomerization/aerobic oxidation reaction of a Ugi-azide adduct for the preparation of 3-acylpyrroles using molecular oxygen as the terminal oxidant has been developed. A series of 2-tetrazolyl-substituted 3-acylpyrroles were obtained in 62-89% yields from readily available enynals 1, primary amines 2, isocyanides 3, and trimethylsilyl azide 4 in the presence of a catalytic amount of AgNO3 and DMAP under an O2 atmosphere.