Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis.
Compare the radiographic progression of ankylosing spondylitis (AS) patients treated with infliximab (INF) versus historical controls (Herne cohort, HC) never treated with tumour necrosis factor (TNF)-blockers over 8 years. Patients were selected based on the availability of lateral cervical and lumbar radiographs at baseline (BL) and after 8 years. Radiographs were scored by two blinded readers using modified Stokes AS spinal score (mSASSS). Mixed linear models were applied to compare radiographic progression between cohorts after adjustment for baseline status. Patients in INF (n=22) and HC (n=34) did not differ in the mSASSS status: 13.2 ± 17.6 in INF versus 14.2 ± 13.8 in HC (p=0.254). Both showed progression at 8 years: mean mSASSS 20.2 ± 21.4 in INF and 25.9 ± 17.8 in HC. After adjustment for baseline damage the mean mSASSS (SEM) at 8 years was 21.0 (1.4) in INF and 25.5 (1.1) HC (p=0.047). The mean mSASSS difference was similar in the groups between baseline and 4 years but was more pronounced in HC between 4 and 8 years (p=0.03 between groups). The mean number of syndesmophytes, although similar at baseline, differed significantly at 8 years: 1.0 ± 0.6 new syndesmophytes/patient in INF versus 2.7 ± 0.8 in HC (p=0.007). Adjustment for age, symptom duration, HLA-B27, Bath AS disease activity index and Bath AS function index at baseline had no influence. Despite limitations of patient numbers and retrospective study design, these data show increase in new bone formation in both patients treated with anti-TNF and those who did not. However, since there was even less bone formation in the INF treated group after 8 years, these data argue against a major role for the TNF-brake hypothesis.


Phosphoproteome analysis reveals the involvement of protein dephosphorylation in ethylene-induced corolla senescence in petunia.
Senescence represents the last stage of flower development. Phosphorylation is the key posttranslational modification that regulates protein functions, and kinases may be more required than phosphatases during plant growth and development. However, little is known about global phosphorylation changes during flower senescence. In this work, we quantitatively investigated the petunia phosphoproteome following ethylene or air treatment. In total, 2170 phosphosites in 1184 protein groups were identified, among which 2059 sites in 1124 proteins were quantified. To our surprise, treatment with ethylene resulted in 697 downregulated and only 117 upregulated phosphosites using a 1.5-fold threshold (FDR < 0.05), which showed that ethylene negatively regulates global phosphorylation levels and that phosphorylation of many proteins was not necessary during flower senescence. Phosphoproteome analysis showed that ethylene regulates ethylene and ABA signalling transduction pathways via phosphorylation levels. One of the major targets of ethylene-induced dephosphorylation is the plant mRNA splicing machinery, and ethylene treatment increases the number of alternative splicing events of precursor RNAs in petunia corollas. Protein dephosphorylation could play an important role in ethylene-induced senescence, and ethylene treatment increased the number of AS precursor RNAs in petunia corollas.


Increased Single-Spectrum Top-Down Protein Sequence Coverage in Trapping Mass Spectrometers with Chimeric Ion Loading.
Fourier transform mass spectrometers routinely provide high mass resolution, mass measurement accuracy, and mass spectral dynamic range. In this work, we utilize 21 T Fourier transform ion cyclotron resonance (FT-ICR) to analyze product ions derived from the application of multiple dissociation techniques and/or multiple precursor ions within a single transient acquisition. This ion loading technique, which we call, "chimeric ion loading", saves valuable acquisition time, decreases sample consumption, and improves top-down protein sequence coverage. In the analysis of MCF7 cell lysate, we show collision-induced dissociation (CID) and electron-transfer dissociation (ETD) on each precursor on a liquid chromatography-mass spectrometry (LC-MS) timescale and improve mean sequence coverage dramatically (CID-only 15% vs chimeric 33%), even during discovery-based acquisition. This approach can also be utilized to multiplex the acquisition of product ion spectra of multiple charge states from a single protein precursor or multiple ETD/proton-transfer reactions (PTR) reaction periods. The analytical utility of chimeric ion loading is demonstrated for top-down proteomics, but it is also likely to be impactful for tandem mass spectrometry applications in other areas.


Effectiveness of salmon calcitonin administered as suppositories in tumor-induced hypercalcemia.
Although calcitonin is a natural, nontoxic, and rapid inhibitor of bone resorption, its use in the treatment of hypercalcemia is limited because of its transient efficacy and the need for repeated parenteral administration. In normal subjects, suppositories of calcitonin have been shown to be biologically active. Peak plasma concentrations of salmon calcitonin after rectal administration in six normal subjects were similar to those measured after parenteral administration. To evaluate the efficacy of calcitonin suppositories in disease states, 10 patients with moderate hypercalcemia due to malignancy were treated with salmon calcitonin, administered as suppositories containing 300 MRC units, three times a day for seven days. The mean plasma calcium level decreased significantly from 2.96 +/- 0.09 mmol/liter to 2.57 +/- 0.09 after one week (p less than 0.005) and rose again after discontinuation of treatment to 2.86 +/- 0.09 mmol/liter one week later. Urinary calcium and hydroxyproline values decreased during treatment and rose after discontinuation of treatment. The plasma calcium level decreased rapidly in six patients, becoming normal in five; three patients showed only a partial response, and one patient had no response at all. No side effects were observed, and clinical improvement was noted in nine of the 10 patients. Little or no response was observed in patients with extremely high urinary calcium or, to a lesser extent, high hydroxyproline excretion. There was a significant negative correlation between the maximal decrease in plasma calcium concentration and initial urinary calcium excretion (r -0.78, p less than 0.01). Thus, salmon calcitonin administered by the rectal route appears to be an easy, safe, and effective treatment of moderate hypercalcemia without apparent side effects.


Agonist induced constitutive receptor activation as a novel regulatory mechanism. Mu receptor regulation.
We propose the hypothesis that certain G protein coupled receptors can become constitutively activated during agonist stimulation so that the receptor remains active even after the agonist is removed. This new paradigm of receptor regulation may account for some long term effects of neurotransmitters and hormones. We have tested the hypothesis that constitutive mu receptor activation represents a crucial step driving narcotic tolerance and dependence. Our results indeed support the conversion of mu to a constitutively active state, mu*, observed in neuroblastoma SK-N-SH and SH-SY5Y tissue culture, in U293 cells transfected with the mu receptor gene, and in vivo. Constitutive mu activation may result from receptor phosphorylation to yield mu*, and further, in vivo studies indicate that formation of mu* could account for narcotic tolerance and dependence.


Correlation between benzodiazepine receptor occupation and anticonvulsant effects of diazepam.
The benzodiazepines are potent anticonvulsants for a wide variety of experimental and clinical seizure disorders. The demonstration of saturable, high-affinity and stereospecific binding sites for the benzodiazepines in the mammalian central nervous system suggests the presence of pharmacological receptors mediating the anticonvulsant properties of these compounds. The good correlation between the anticonvulsant potencies of a series of benzodiazepines and their ability to inhibit 3H-diazepam binding in vitro further supports this hypothesis, but evidence for a direct interaction between benzodiazepines and their receptors, and a subsequent inhibition of seizure activity (or elevation of seizure threshold) is lacking. Recent reports from our laboratory and others have demonstrated the feasibility of labelling benzodiazepine receptors in vivo following parental administration of tritiated benzodiazepine. This technique permits one to study the relationship between the anticonvulsant activity of the benzodiazepines in vivo and the number of 'drug-occupied' receptors in vitro. We now report that there is an excellent correlation between benzodiazepine receptor occupancy by diazepam and protection against pentylenetetrazol-induced seizures. Furthermore, these results demonstrate that only a small fraction of benzodiazepine receptors need be occupied to produce a complete anticonvulsant effect.


Efficacy of novel hypoxic cell sensitiser doranidazole in the treatment of locally advanced pancreatic cancer: long-term results of a placebo-controlled randomised study.
Novel hypoxic cell radiosensitiser doranidazole was tested for unresectable pancreatic cancer administered at intraoperative radiotherapy. Short-term survival was not different. However, difference has been observed concerning 3-year survival (doranidazole group vs. placebo; 23% vs. 0%, p=0.0192). This sensitiser might be effective in improving long-term survival for pancreatic cancer.


White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa.
To describe the effect of HIV on white matter integrity and neurocognitive function in children vertically infected with HIV, compared to a HIV-negative healthy control group. Cross-sectional. We compared 75 HIV-infected children aged 6-16 years, including children on antiretroviral therapy (ART) and those who were ART-naive, with 30 controls on diffusion tensor imaging and a neuropsychological battery sensitive to fronto-striatal pathology. In a secondary analysis, we compared 'slow progressor' ART-naive children, children on ART without a diagnosis of encephalopathy and children on ART with HIV encephalopathy. Compared to controls (n = 30), HIV-infected children (n = 75) displayed decreased fractional anisotropy and axial diffusion, and increased mean diffusivity and radial diffusion, indicating damaged neuronal microstructure. HIV-infected children performed poorly on the neuropsychological battery (P = <0.001). Within the HIV-infected group, children with HIV encephalopathy (n = 14) had poor white matter integrity when compared to ART-treated children without encephalopathy (n = 41), and there was significant myelin loss in ART-naive children (n = 20), compared with ART-treated children. ART-treated children had significant axonal damage in the corpus callosum (P = 0.009). Children infected with HIV, irrespective of treatment status, displayed significantly poorer white matter integrity and impaired cognition compared to HIV-negative controls. Our findings suggest that despite immune recovery in children on ART, they remain at risk for developing central nervous system disease, and that initiation of ART as early as possible may reduce the risk of developing white matter damage in ART-naive slow progressors.


Lipids and Long Chain Polyunsaturated Fatty Acids in Preterm Infants.
Fatty acids are critical bioactives for fetal and neonatal development. Premature delivery and current nutritional strategies pose several challenges in restoring fatty acid balance in the preterm infant. The impact on fatty acid balance and outcomes using lipid emulsions, enteral nutrition, and enteral supplements are reviewed, including a summary of the most recent large clinical trials of enteral fatty acid supplementation for the preterm infant. Research gaps remain in successfully implementing nutritional strategies to optimize fatty acid status in preterm infants.


Measuring the mismatch between field of study and occupation using a task-based approach.
This paper seeks to provide a continuous measure to represent the distance between skills acquired in tertiary education and those required in an individual's occupation. This distance measure, which is computed by combining data from the 2010 Brazilian census with information from the 2010 Brazilian classification of occupations, suggests that workers usually classified in most of the literature into a single group of mismatches are in fact quite heterogeneous in the way their occupations are associated with areas of study. Evidence also shows that, even among mismatched workers, hourly labor earnings tend to decrease as the distance measure increases. This indicates the labor earnings penalty is not the same for all mismatched workers, seemingly changing substantially depending on the level of similarity between occupation and field of study.


4-iodotamoxifen aziridine, a new affinity labeling agent for the rapid detection of estrogen receptor isoforms.
We describe the simple and fast preparation of a new radioiodinated probe for the detection of the estrogen receptor (ER) and its isoforms. Iodotamoxifen aziridine was labeled with iodine 125 ([125I]TAZ) in position 4 of the alpha aromatic ring. The yield was high (>75%), the label was stable and the specific activity was near optimal (1900-2170 Ci/mmol). The apparent relative binding affinity of the probe to a recombinant human ER (hER) was high (RBA = 35 vs estradiol = 100). Electrophoretic studies (SDS-PAGE) with this hER indicated the high potency of [125I]TAZ at very low concentration (<1 nM) to reveal ER bands after a short exposure time (1-4 days). Competition between this probe and various compounds as well as chemical treatments of the ER with SH-reactive chemicals, demonstrated the labeling specificity. Analysis of cytosols from a panel of cell lines and various rat reproductive organs displayed characteristic ER bands (67, 50 and 37 kDa) suppressed by unlabeled E2. Detection in nonreproductive organs of 43 kDa E2-nondisplaceable peptide raised the question upon the presence of altered and/or variant ERs in many tissues. Data concerning human breast cancer cytosols were in complete accordance with those established with [3H]TAZ: high ER polymorphism in most ER-positive samples and peculiar forms (mainly 43 kDa) in ER-negative samples. Hence, [125I]TAZ appears especially useful for the detection of altered ER or related peptides in breast cancers.


CPAP combined with oral appliance therapy reduces CPAP requirements and pharyngeal pressure swings in obstructive sleep apnea.
Oral appliance (OA) therapy is the leading alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). It is well tolerated compared with CPAP. However, ≥50% of patients using OA therapy have incomplete resolution of their OSA. Combination therapy with CPAP and oral appliance (CPAP + OA) is a potential alternative for incomplete responders to OA therapy. This study aimed to determine the extent to which combination therapy reduces therapeutic CPAP requirements using gold-standard physiological methodology in those who have an incomplete response to OA therapy alone. Sixteen incomplete responders [residual apnea/hypopnea index (AHI) > 10 events/h] to a novel OA with a built-in oral airway were recruited (3 women:13 men, aged 31-65 yr, body mass index: 22-38 kg/m2, residual AHI range: 13-63 events/h). Participants were fitted with a nasal mask, pneumotachograph, epiglottic pressure catheter, and standard polysomnography equipment. CPAP titrations were performed during non-rapid eye movement (NREM) supine sleep in each participant during three conditions (order randomized): CPAP only, CPAP + OA (oral airway open), and CPAP + OA (oral airway closed). OSA was resolved at pressures of 4 ± 2 and 5 ± 2 cmH2O during CPAP + OA (oral airway open) and CPAP + OA (oral airway closed) conditions versus 8 ± 2 cmH2O during CPAP only (P < 0.01). Negative epiglottic pressure swings in oral airway open and closed conditions were normalized to CPAP only levels [-2.5(-3.7, -2.6) vs. -2.3(-3.2, -2.4) vs. -2.1(-2.7, -2.3) cmH2O]. Combined CPAP and OA therapy reduces therapeutic CPAP requirements by 35%-45% and minimizes epiglottic pressure swings. This combination may be a therapeutic alternative for patients with incomplete responses to OA therapy alone and those who cannot tolerate high CPAP levels.NEW & NOTEWORTHY Combined CPAP and oral appliance therapy has been suggested as an alternative for incomplete responders to oral appliance therapy. We used a novel oral appliance incorporating an oral airway together with CPAP to show that pharyngeal pressure swings were normalized at reduced CPAP levels. Our findings demonstrate that using CPAP and oral appliance together may be a beneficial alternative for incomplete responders to oral appliance therapy and intolerant CPAP users due to high-pressure requirements.


Extensively drug-resistant Acinetobacter baumannii carrying blaOXA-23-like and armA in a hospital after an intervention in the intensive care unit which ended a long-standing endemicity.
The aim of the study was to evaluate for a long time the effectiveness of an intervention designed to reduce carbapenem-resistant Acinetobacter baumannii (CRAB) and its impact on colistin usage in the ICU of a tertiary hospital in Spain. The rate of carbapenem resistance declined drastically during the period of study (2015 to 2018), from 93.57 to 74.65%, especially in the ICU. A significant decrease in colistin usage, from 1.16 to 0.39 DOTs, was observed. Forty-nine CRAB isolates recovered nearly 1 year after starting the intervention were characterized. Most of them were recovered from patients admitted in wards other than ICU and were extensively drug-resistant, carried blaOXA-23-like and armA, and belonged to ST218. Implementation of control measures is crucial to CRAB control in ICUs but must be extended to all wards in order to eradicate CRAB from hospitals.


Impact of perioperative airway pathogens on living-donor lobar lung transplantation outcomes.
To elucidate the clinical impact of pathogenic organism (PO) positivity early after transplantation, we evaluated the impact of perioperative airway POs on outcomes after living-donor lobar lung transplantation (LDLLT), where the graft airway is supposed to be sterile from a healthy donor. A retrospective review of 67 adult LDLLT procedures involving 132 living donors was performed. Presence of POs in the recipients' airways was evaluated preoperatively and postoperatively in intensive-care units. POs were detected preoperatively in 13 (19.4%) recipients. No POs were isolated from the donor airways at transplantation. POs were detected in 39 (58.2%) recipients postoperatively; most were different from the POs isolated preoperatively. Postoperative PO isolation was not associated with short-term outcomes other than prolonged postoperative ventilation. The 5-year overall survival was significantly better in the PO-negative group than in the PO-positive group (89.1% vs. 63.7%, P = 0.014). In the multivariate analysis, advanced age (hazard ratio [HR]: 1.041 per 1-year increase, P = 0.033) and posttransplant PO positivity in the airway (HR: 3.684, P = 0.019) significantly affected the survival. The airways of the living-donor grafts were microbiologically sterile. PO positivity in the airway early after transplantation negatively impacted long-term outcomes.


Novel heterocycle-based two-photon absorbing dyes.
[structure: see text]. The synthesis and nonlinear optical characterization of two novel heteroaromatic-based chromophores is described. The new dyes present an A-pi-D-pi-A general framework, where A is a pi-deficient heteroaromatic ring (pyridine, quinoline, benzothiazole) and D a pi-excessive pyrrolyl moiety. Both systems exhibit large two-photon absorption (TPA) values in the femtoseconds regime (TPA cross section as high as 150 x 10(-50) cm(4) s photon(-1) molecule(-1) with 150 fs laser pulses). Their TPA-based optical limiting activity is also shown.


Spatio-temporal variation in environmental features predicts the distribution and abundance of Ixodes scapularis.
Many species have experienced dramatic changes in both geographic range and population sizes in recent history. Increases in the geographic range or population size of disease vectors have public health relevance as these increases often precipitate the emergence of infectious diseases in human populations. Accurately identifying environmental factors affecting the biogeographic patterns of vector species is a long-standing analytical challenge, stemming from a paucity of data capturing periods of rapid changes in vector demographics. We systematically investigated the occurrence and abundance of nymphal Ixodes scapularis ticks at 532 sampling locations throughout New York State (NY), USA, between 2008 and 2018, a time frame that encompasses the emergence of diseases vectored by these ticks. Analyses of these field-collected data demonstrated a range expansion into northern and western NY during the last decade. Nymphal abundances increased in newly colonised areas, while remaining stable in areas with long-standing populations over the last decade. These trends in the geographic range and abundance of nymphs correspond to both the geographic expansion of human Lyme disease cases and increases in incidence rates. Analytic models fitted to these data incorporating time, space, and environmental factors, accurately identified drivers of the observed changes in nymphal occurrence and abundance. These models accounted for the spatial and temporal variation in the occurrence and abundance of nymphs and can accurately predict nymphal population patterns in future years. Forecasting disease risk at fine spatial scales prior to the transmission season can influence both public health mitigation strategies and individual behaviours, potentially impacting tick-borne disease risk and subsequently human disease incidence.


Activation stabilization--further support for a new class of cardioactive substances.
Alinidine, a new compound with a bradycardic action, has a rate-decreasing and stabilizing action on the spontaneous contractions of single rat ventricular cardiac cells with a partially skinned and leaky sarcolemmal membrane but with a well-functioning sarcoplasmic reticulum. In the intact multicellular cat papillary muscle, alinidine delays the onset of mechanical activation at concentrations that hardly affect peak mechanical performance and the relaxation phase. From these results, we postulate that alinidine has a stabilizing action on activation, in particular on the release of calcium from the intracellular membranous system, with minimal effects on the total amount released and on the calcium reuptake or process of inactivation.


Ischiorectal fossa abscess after pelvic floor injection of botulinum toxin.
Botulinum toxin is used to treat pelvic floor tension myalgia; however, its safety profile is poorly understood. We report an ischiorectal fossa abscess after pelvic floor injections of botulinum toxin. Physicians need to be aware of this possible complication, consider alternate injection techniques and antiseptic preparation before injection.


Utility of a rapid diagnosis kit for Mycoplasma pneumoniae pneumonia in children, and the antimicrobial susceptibility of the isolates.
We evaluated a kit for the rapid diagnosis of Mycoplasma pneumoniae infection and investigated the antimicrobial susceptibility of the isolates. A total of 194 otherwise healthy children, aged 0.3-14.9 years, were diagnosed as having pneumonia by chest X-ray findings between December 2003 and November 2004, and were admitted to Showa Hospital. Isolation of M. pneumoniae was attempted from a throat swab obtained on admission, and the complement fixation titer was measured in paired serum samples obtained at admission and at the convalescent stage. We also used a rapid diagnosis kit (ImmunoCard Mycoplasma) for the detection of specific immunoglobulin M antibody in paired sera. Pneumonia due to M. pneumoniae was defined by isolation of this microorganism, or by seroconversion, or a >or=4-fold increase in the antibody titer. Using each isolate, we determined the minimum inhibitory concentrations for five antimicrobial agents by the broth dilution method. M. pneumoniae pneumonia was diagnosed in 45 children (23.2%). The ImmunoCard had a sensitivity of 31.8% using admission serum and 88.6% using paired sera, while the specificity was 78.1% and 70.5%, respectively. M. pneumoniae was isolated from 14 of the 45 patients (31.1%). The 50%/90% minimum inhibitory concentration (microg/ml) of erythromycin, clarithromycin, azithromycin, minocycline, and levofloxacin was 0.006/0.012, <or=0.003/<or=0.003, <or=0.003/<or=0.003, 0.78/1.56, and 0.39/0.78, respectively. For a rapid diagnosis of M. pneumoniae pneumonia, the ImmunoCard was not effective. Macrolides showed superior in vitro antimicrobial activity against M. pneumoniae isolates causing pediatric pneumonia.


Extracellular Vesicles and Cell-Cell Communication: New Insights and New Therapeutic Strategies Not Only in Oncology.
The discovery that tumors are not separated from systemic regulatory mechanisms of the body but are rather integrated into them, and even use these mechanisms for their own purposes, was one of the most important findings in tumor biology of the last few years [...].


Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India.
To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months. Community based, randomised, double blind, placebo controlled trial. Two rural districts of Tamil Nadu, southern India. 11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery. Primary outcome measure was mortality at age 6 months. Infants in the vitamin A group had a 22% reduction in total mortality (95% confidence interval 4% to 37%) compared with those in the placebo group. Vitamin A had an impact on mortality between two weeks and three months after treatment, with no additional impact after three months. Supplementing newborn infants with vitamin A can significantly reduce early infant mortality.


Skeletal uptake of pyrophosphate labeled with technetium-95m and technetium-96, as evaluated by autoradiography.
For animal experimentation, the 95m and 96 technetium isotopes offer many advantages over technetium-99m. Their long physical half-lives and the emission of extranuclear electrons of low penetrating power make it possible to obtain autoradiograms of a great precision. The uptake of technetium stannous pyrophosphate by the epiphyseal plate was studied using liquid-emulsion microautoradiography, 3 hr after i.v. injection into 10-week-old rabbits. Microautoradiograms showed a well-defined and rather specific pattern of localization with intense uptake beneath the epiphyseal disk on the extremities of the vascular buds and a lack of accumulation in the cartilage, whether calcified or uncalcified. In the metaphysis, the label was located where new bone was being laid down and also over the cytoplasm of osteoclasts. We deduce from these results that in normal bone the general distribution of this tracer reflects mainly the arrangement of the blood supply, but the specific sites of accumulation are the bone-forming surfaces and the active resorbing osteoclasts.


Silicon isotope evidence against an enstatite chondrite Earth.
The compositions of Earth materials are strikingly similar to those of enstatite chondrite meteorites in many isotope systems. Although this suggests that Earth largely accreted from enstatite chondrites, definitive proof of this model has been lacking. By comparing the silicon (Si) isotope signatures of several extraterrestrial materials with terrestrial samples, we show that they cannot be explained by core-formation scenarios involving a bulk Earth of enstatite chondrite composition. Si isotope similarities between the bulk silicate Earth and the Moon preclude the existence of a hidden reservoir in the lower mantle, a necessary condition of the enstatite chondrite model, and require an equilibrium process after the Moon-forming impact. A three-end-member chondritic mixing model for Earth reconciles the Si isotope similarities between enstatite chondrites and Earth.


Unraveling surface structures of gallium promoted transition metal catalysts in CO2 hydrogenation.
Gallium-containing alloys have recently been reported to hydrogenate CO2 to methanol at ambient pressures. However, a full understanding of the Ga-promoted catalysts is still missing due to the lack of information about the surface structures formed under reaction conditions. Here, we employed near ambient pressure scanning tunneling microscopy and x-ray photoelectron spectroscopy to monitor the evolution of well-defined Cu-Ga surfaces during CO2 hydrogenation. We show the formation of two-dimensional Ga(III) oxide islands embedded into the Cu surface in the reaction atmosphere. The islands are a few atomic layers in thickness and considerably differ from bulk Ga2O3 polymorphs. Such a complex structure, which could not be determined with conventional characterization methods on powder catalysts, should be used for elucidating the reaction mechanism on the Ga-promoted metal catalysts.


Influence of regulation on the productivity of waste utilities. What can we learn with the Portuguese experience?
This paper examines the merits and the perverse effects of quality of service regulation in the performance of urban waste services when implemented alone and compares the performance of different economic regulatory methods. By means of a productivity analysis, we investigate the influence of a five-year period of regulation on the performance of Portuguese urban waste utilities using an unbalanced panel data for the period 2001-2008. Different non-parametric methods were applied to estimate the productivity change, all leading to similar outcomes. We observed a tendency of productivity decline in the urban waste utilities and concluded that in spite of the unequivocal improvements in the quality of service induced by sunshine regulation, more should be done as far as economic regulation is concerned. We also found that the use of sunshine regulation together with low incentive economic regulatory methods is not positive, leading to overinvestment rather than to value for money.


Systems biology solutions for biochemical production challenges.
There is an urgent need to significantly accelerate the development of microbial cell factories to produce fuels and chemicals from renewable feedstocks in order to facilitate the transition to a biobased society. Methods commonly used within the field of systems biology including omics characterization, genome-scale metabolic modeling, and adaptive laboratory evolution can be readily deployed in metabolic engineering projects. However, high performance strains usually carry tens of genetic modifications and need to operate in challenging environmental conditions. This additional complexity compared to basic science research requires pushing systems biology strategies to their limits and often spurs innovative developments that benefit fields outside metabolic engineering. Here we survey recent advanced applications of systems biology methods in engineering microbial production strains for biofuels and -chemicals.


An Intelligent System to Enhance the Performance of Brain Tumor Diagnosis from MR Images.
In the human body, cancer is caused by aberrant cell proliferation. Brain tumors are created when cells in the human brain proliferate out of control. Brain tumors consist of two types: benign and malignant. The aberrant parts of benign tumors, which contain dormant tumor cells, can be cured with the appropriate medication. On the other hand, malignant tumors are tumors that contain abnormal cells and an unorganized area of these abnormal cells that cannot be treated with medication. Therefore, surgery is required to remove these brain tumors. Brain cancers are manually identified and diagnosed by a skilled radiologist using traditional procedures. It's a lengthy and error-prone procedure. As a result, it is unsuitable for emerging countries with large populations. So computer-assisted automatic identification and diagnosis of brain tumors are recommended. This work proposes and implements a CAD system for the diagnosis of brain cancers using magnetic resonance imaging (MRI). Preprocessing, segmentation, feature extraction, and classification are the stages of automatic brain MRI processing that necessitate software based on a sophisticated algorithm. Image normalization with contourlet transform (INCT) is used in the preprocessing step to remove undesirable or noisy data. The performance metrics such as PSNR, MSE, and RMSE are computed. Then, the modified hierarchical k-means with firefly clustering (MHKFC) technique is used in the segmentation step to precisely recover the afflicted (tumor) area from the preprocessed image. The enhanced monarch butterfly optimization (EMBO) is used to select and then extract the most important gray-level co-occurrence matrix feature from the segmented image. The classification task was finally completed using the adaptive neuro-fuzzy inference system (ANFIS). The overall classification accuracy is 95.4% ( BRATS 2015), 96.6% ( BRATS 2021), and 93.7% (clinical data) is obtained.


Shotgun metagenomic sequencing data of sunflower rhizosphere microbial community in South Africa.
This dataset presents shotgun metagenomic sequencing of sunflower rhizosphere microbiome in Bloemhof, South Africa. Data were collected to decipher the structure and function in the sunflower microbial community. Illumina HiSeq platform using next generation sequencing of the DNA was carried out. The metagenome comprised 8,991,566 sequences totaling 1,607,022,279 bp size and 66% GC content. The metagenome was deposited into the NCBI database and can be accessed with the SRA accession number SRR10418054. An online metagenome server (MG RAST) using the subsystem database revealed bacteria had the highest taxonomical representation with 98.47%, eukaryote at 1.23%, and archaea at 0.20%. The most abundant genera were the Conexibacter (17%), Nocardioides (8%), Streptomyces (7%), Geodermatophilus (6%), Methylobacterium (5%), and Burkholderia (4%). MG-RAST assisted analysis also revealed functional annotation based on subsystem, carbohydrates sequence had 13.74%, clustering based subsystem 12.93%, amino acids and derivatives 10.30% coupled with other useful functional traits needed for plant growth and health.


Axilla nerve block in the emergency department.
The axilla nerve block is versatile and covers injuries from the elbow to the hand, such as wrist fracture reductions, and may be an option to improve patient care, reduce both length of stay and resource allocation.


Expression of mRNAs coding for VAP1/crotastatin-like metalloproteases in the venom glands of three South American pit vipers assessed by quantitative real-time PCR.
Snake venom metalloproteases encompass a large family of toxins, with approximately 200 members already catalogued, which exhibit a diversity of structures and biological functions. From this relatively large number, only a dozen examples of apoptosis-inducing metalloproteases, like VAP1 and 2 from the venom of Crotalus atrox, are known. Since most VAP1-like toxins ever characterized were purified from the venom of Viperidae species inhabiting diverse places on earth, we investigate the expression of VAP-like metalloproteases in the venom gland of three representative pit vipers of the Brazilian territory. By molecular cloning and quantitative real-time polymerase chain reaction, using as calibrator gene the Crotalus durissus terrificus homolog of VAP1, named crotastatin, it is reported here that VAP1/crotastatin-like homologues in the venom gland of Bothrops atrox, C. d. cascavella and Lachesis m. rhombeata are expressed at different levels. Hence, batroxstatins, the crotastatin-like precursors from B. atrox, are expressed 87 times more than crotastatin-1, from C. d. cascavella, and 7.5-fold that lachestatins, from L. m. rhombeata. Moreover, in silico structural analysis of amino acid sequences indicates that batroxstatin-2, crotastatins and lachestatin-1 and -2 which share the archetypal motifs and metal- binding sites of VAP1, are subgrouped in a branch that comprises some apoptosis-inducing toxins.


Digital image-based titrations.
The exploitation of digital images obtained from a CCD camera (WebCam) as a novel instrumental detection technique for titration is proposed for the first time. Named of digital image-based (DIB) titration, it also requires, as a traditional titration (for example, spectrophotometric, potentiometric, conductimetric), a discontinuity in titration curves where there is an end point, which is associated to the chemical equivalence condition. The monitored signal in the DIB titration is a RGB-based value that is calculated, for each digital image, by using a proposed procedure based on the red, green, and blue colour system. The DIB titration was applied to determine HCl and H3PO4 in aqueous solutions and total alkalinity in mineral and tap waters. Its results were compared to the spectrophotometric (SPEC) titration and, by applying the paired t-test, no statistic difference between the results of both methods was verified at the 95% confidence level. Identical standard deviations were obtained by both titrations in the determinations of HCl and H3PO4, with a slightly better precision for DIB titration in the determinations of total alkalinity. The DIB titration shows to be an efficient and promising tool for quantitative chemical analysis and, as it employs an inexpensive device (WebCam) as analytical detector, it offers an economically viable alternative to titrations that need instrumental detection.


The Fight Just Born-Neonatal Cancer: Rare Occurrence with a Favorable Outcome but Challenging Management.
The occurrence of cancer in newborns within the first 28 days of life is uncommon, with different clinical presentation from other age groups. Prenatal diagnosis is reported in about half of patients, while a genetic predisposition condition is supposed. The management of a newborn with cancer can be challenging and needs to be tailored according to the histology and the primary tumor site; surgery represents the main strategy, while chemotherapy should be considered with caution because of the higher toxicity and mortality due to different pharmacokinetics in neonates compared to older children. We describe the first Italian series over a 15-year period of patients affected by both benign and malignant neoplastic diseases diagnosed within the first 28 days of life; 74 newborns were diagnosed with neonatal tumors, representing 1.5% of the cancer population in the same period, and a prevalence of germ cell tumors (55%) and neuroblastoma (16%) was observed. Surgery was performed on 80% of patients, while chemotherapy was necessary for about 20% of patients. The 5-year overall survival (OS) exceeded 90%; treatment-related deaths are a major concern, representing 80% of overall deaths. A genetic/syndromic condition was detected in 16% of the population; additionally, a cancer predisposition syndrome (CPS) was identified in about 10% of patients. According to our experience, all newborns affected by cancer should warrant genetic counselling and a screening test for CPS.


Combination of RNA sequencing and metabolite data to elucidate improved toxic compound tolerance and butanol fermentation of Clostridium acetobutylicum from wheat straw hydrolysate by supplying sodium sulfide.
Sodium sulfide (SS) was added to the non-detoxified wheat straw hydrolysate for ABE fermentation by Clostridium acetobutylicum CICC8012. Biochemical measurements demonstrated that supplementation with SS promoted earlier and enhanced conversion of acid to ABE and led to a 27.48% improvement in sugar consumption, a 20.48% improvement in the sugar-based ABE yield, a 47.63% improvement in the butanol titer, and a 53.50% improvement in the ABE concentration. The response of C. acetobutylicum CICC8012 at the mRNA level was examined by a transcriptional analysis performed with RNA sequencing. The expression of genes involved in the membrane transport of carbohydrates, glycolysis, and ABE formation increased following SS-supplemented fermentation, whereas the expression of genes encoding enzymes involved in acid formation decreased, which indicates that supplemental SS affected the central fermentative pathway, down-regulated the metabolic flux toward the acid formation branches, and up-regulated the metabolic flux toward the ABE formation branches.


Heat transfer control using a thermal analogue of coherent perfect absorption.
Recent investigations on non-Hermitian physics have unlocked new possibilities to manipulate wave scattering on lossy materials. Coherent perfect absorption is such an effect that enables all-light control by incorporating a suitable amount of loss. On the other hand, controlling heat transfer with heat may empower a distinct paradigm other than using thermal metamaterials. However, since heat neither propagates nor carries any momentum, almost all concepts in wave scattering are ill-defined for steady-state heat diffusion, making it formidable to understand or utilize any coherent effect. Here, we establish a scattering theory for heat diffusion by introducing an imitated momentum for thermal fields. The thermal analogue of coherent perfect absorption is thus predicted and demonstrated as the perfect absorption of exergy fluxes and undisturbed temperature fields. Unlike its photonic counterpart, thermal coherent perfect absorption can be realized for regular thermal materials, and be generalized for various objects.


High performance liquid chromatographic determination of ambroxol in the presence of different preservatives in pharmaceutical formulations.
A high-performance chromatographic method is described for simultaneous determination of ambroxol in the presence of different preservatives in syrups. The method separates ambroxol from methyl- ethyl-, propyl- and butyl paraben and from other multi-component mixtures. The retention behaviour of ambroxol and parabens as a function of both pH and mobile phase composition was investigated. The eluents were monitored with a UV detector at 247 nm. Linear relationships between the amount of pharmaceutical compounds and peak heights were confirmed at the concentrations of 0.74-14.08 microg ml(-1). The high recovery (no extraction of the samples is required) and the low %RSD confirm the suitability of the proposed method for the determination of ambroxol in different pharmaceutical preparations.


Rigid, Bistable Molecular Shuttles Combining T-shaped Benzimidazolium and Y-shaped Imidazolium Recognition Sites.
Two different recognition sites, one a T-shaped 2,4,7-triphenylbenzimidazolium and the other a Y-shaped 2,4,5-triphenylimidazolium are combined to construct a rigid bistable [2]rotaxane molecular shuttle on which the position of a 24-membered crown ether macrocycle can be controlled by acid-base chemistry. Molecular shuttling in both the neutral and dicationic versions were studied.


Diagnostic value of bronchoscopy, CT and transbronchial biopsies in diffuse pulmonary lymphangiomatosis: case report and review of the literature.
The authors present the case of a 48-year-old man with diffuse pulmonary lymphangiomatosis. This rare lymphatic disorder is characterized by proliferation of anastomosing lymphatic vessels varying in size. Clinical presentation and imaging findings are highly suggestive. Bronchoscopic examination of this patient showed, for the first time to our knowledge, vesicles disseminated throughout the bronchial tree. Histopathological examinations are necessary to differentiate lymphangiomatosis from lymphangiectasis. The diagnosis can be made by transbronchial biopsy without performing open lung biopsy which was, until now, considered necessary for diagnosis.


A sensitive chromatographic strip test for the rapid detection of enrofloxacin in chicken muscle.
A sensitive colloidal gold immunochromatography assay using a specific monoclonal antibody was developed for the rapid detection of enrofloxacin (ENR) residues in chicken muscles. Anti-ENR antibodies with high sensitivity and specificity are generated by immunising BALB/c mice with well-characterised ENR-bovine serum albumin conjugate. An orthogonal L₉(3)³ test was designed, and various parameters that influenced the assay performance were investigated and optimised. Under the optimised conditions, the cut-off limits of semi-quantitative test strips for ENR were found to be 3 ng/mL in phosphate-buffered saline and 8 µg/kg in chicken muscle. The ENR test strips showed a 6% cross-reactivity with ciprofloxacin, 3% with norfloxacin, less than 1% with ofloxacin and sarafloxacin and 0.1% with the other eight fluoroquinolones including enoxacin, difloxacin, danofloxacin, pefloxacin, lomefloxacin, sparfloxacin, oxolinic acid and flumequine. Consistent results are produced from the parallel analysis of ENR-contaminated chicken muscle extracts using test strips and ELISA.


Cost-effectiveness of newborn screening for severe combined immunodeficiency.
Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at young age. Early detection shortly after birth, followed by treatment before infections occur, largely increases the chances of survival. As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is relevant for decision making. Lifetime costs and effects of newborn screening for SCID were compared to a situation without screening in the Netherlands in a decision analysis model. Model parameters were based on literature and expert opinions. Sensitivity analyses were performed. Due to earlier detection, the number of deaths due to SCID per 100,000 children was assessed to decrease from 0.57 to 0.23 and a number of 11.7 quality adjusted life-years (QALYs) gained was expected. Total yearly healthcare costs, including costs of screening, diagnostics, and treatment, were €390,800 higher in a situation with screening compared to a situation without screening, resulting in a cost-utility ratio of €33,400 per QALY gained.Conclusion: Newborn screening for SCID might be cost-effective. However, there is still a lot of uncertainty around the cost-effectiveness estimate. Pilot screening projects are warranted to obtain more accurate estimates for the European situation. What is Known: • Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at a young age. • As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is needed. What is New: • Newborn screening for SCID is expected to reduce mortality from 0.57 to 0.23 per 100,000 children at additional healthcare costs of €390,800. The cost-utility ratio is €33,400 per QALY gained. • Due to large uncertainty around cost-effectiveness estimates, pilot screening projects are warranted for Europe.


Improved Yet Varied Clinical Outcomes Observed With Comparison of Arthroscopic Superior Capsular Reconstruction Versus Arthroscopy-Assisted Lower Trapezius Transfer for Patients With Irreparable Rotator Cuff Tears.
To evaluate the outcomes of arthroscopic superior capsular reconstruction (SCR) and arthroscopy-assisted lower trapezius tendon transfer (LTT) for posterosuperior irreparable rotator cuff tears (IRCTs). Over an almost 6-year period (October 2015 to March 2021), all patients who underwent IRCT surgery with a minimum 12-month follow-up period were identified. For patients with a substantial active external rotation (ER) deficit or lag sign, LTT was preferentially selected. Patient-reported outcome scores included the visual analog scale (VAS) pain score, strength score, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, Single Assessment Numeric Evaluation (SANE) score, and Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score. We included 32 SCR patients and 72 LTT patients. Preoperatively, LTT patients had more advanced teres minor fatty infiltration (0.3 vs 1.1, P = .009), a higher global fatty infiltration index (1.5 vs 1.9, P = .035), and a higher presence of the ER lag sign (15.6% vs 48.6%, P < .001). At a mean follow-up of 2.9 ± 1.3 years (range, 1.0-6.3 years), no differences in patient-reported outcome scores were observed. Postoperatively, SCR patients had a lower VAS score (0.3 vs 1.1, P = .017), higher forward elevation (FE) (156° vs 143°, P = .004), and higher FE strength (4.8 vs 4.5, P = .005) and showed greater improvements in the VAS score (6.8 vs 5.1, P = .009), FE (56° vs 31°, P = .004), and FE strength (1.0 vs 0.4, P < .001). LTT patients showed greater improvement in ER (17° vs 29°, P = .026). There was no statistically significant between-cohort difference in complication rate (9.4% vs 12.5%, P = .645) or reoperation rate (3.1% vs 10%, P = .231). With adequate selection criteria, both SCR and LTT provided improved clinical outcomes for posterosuperior IRCTs. Additionally, SCR led to better pain relief and restoration of FE whereas LTT provided more reliable improvement in ER. Level III, treatment study with retrospective cohort comparison.


Polymorphisms within the RANK and RANKL Encoding Genes in Patients with Rheumatoid Arthritis: Association with Disease Progression and Effectiveness of the Biological Treatment.
Inconsistency of the results regarding the genetic variability within genes coding for receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) in rheumatoid arthritis (RA) prompted us to study the RANK and RANKL polymorphisms as potential biomarkers associated with disease predisposition and response to anti-TNF treatment in a group of Polish patients with RA. This study enrolled 318 RA patients and 163 controls. RANK (rs8086340, C > G; rs1805034, C > T) and RANKL (rs7325635, G > A; rs7988338 G > A) alleles were determined by real-time PCR with melting curve analysis and related with clinical parameters. In addition, RANKL serum levels were measured by ELISA. The RANK rs8086340-G allele was overrepresented among patients as compared to controls (OD = 1.777, p = 0.038). C-reactive protein (CRP) levels were significantly (p < 0.05) associated with RANK rs8086340 polymorphism and were higher in the CC-homozygotes at the baseline while lower in the GG-carriers at the 12th week of the treatment. At the latter time point RANKL rs7325635-GG-positive patients also showed significantly lower CRP concentrations. Higher alkaline phosphatase levels before induction of anti-TNF therapy were observed in RANK rs8086340 and RANK rs1805034 CC homozygotes (p = 0.057 and p = 0.035, respectively). The GG homozygosity of both RANKL single nucleotide polymorphisms was significantly associated with the number of swollen joints (rs7988338 and rs7325635, before and at the 12th week of therapy, respectively, p < 0.05 in both cases). These results imply that polymorphisms within the RANK and RANKL genes affect RA susceptibility and anti-TNF treatment outcome.


Functional expression and production of human H-ferritin in Pichia pastoris.
Human heavy chain ferritin (H-ferritin) was cloned from human heart cDNA library and expressed in Pichia pastoris. The H-ferritin transformant was cultivated by fed-batch and the cell mass reached about 52 g cell dry wt l(-1) after 150 h. In atomic absorption spectrometry analysis, intracellular content of iron in H-ferritin transformant was measured to 3038 +/- 72 microg g(-1) which was 9.6-fold more than that of control strain.


Impact of Recovery from Acute Kidney Injury After Aortic Arch Repair.
The impact of recovery from acute kidney injury (AKI) after open thoracic aortic surgery on follow-up outcomes is unclear. This retrospective study included 214 patients who underwent aortic arch surgery requiring hypothermic circulatory arrest between 2007 and 2019. Patients who required preoperative renal replacement therapy and patients who died within 7 postoperative days were excluded. The incidence of recovery from AKI was examined. Renal outcomes were compared among patients with no AKI (Group N), recovery from AKI (Group R), and persistent AKI (Group P). Preoperative kidney function was similar among the 3 groups. Among the 115 patients who developed postoperative AKI, 80.9% recovered from AKI at discharge. The 5-year cumulative mortality rate was 18.0%, 24.5%, and 68.4% in Group N, R, and P, respectively (P < .001, Group R vs Group P). The 5-year cumulative incidence of renal replacement therapy dependency was 0.0%, 5.4%, and 22.7%, respectively (P = .04, Group N vs Group R; P = .01, Group R vs Group P). The medians (interquartile range) of estimated glomerular filtration rate (mL/min/1.73 m2) 2 years after surgery were 65.2 (50.4-80.2), 54.3 (41.4-65.9), and 56.9 (40.2-67.5), respectively (P = .03, Group N vs Group R). The majority of patients recovered from AKI after thoracic aortic repair by discharge. However, the prolonged impact of AKI recovery on kidney function was observed during the follow-up period. Diligent follow-up after discharge is warranted for early identification of patients at high risk of kidney disease progression.


University of Wisconsin solution and human saphenous vein graft preservation: preliminary anatomic report.
Endothelial damage of human saphenous vein (HSV) during the preparation for bypass grafting could affect graft patency. Improving the preservation of HSV could provide a longer and better patency of coronary artery bypass grafts. An electron microscopic comparative analysis of the effects of three different preservatives on HSV morphology was carried on in order to determine the best method to prevent or minimize possible endothelial damage. Distal segments of HSVs were harvested from 15 patients with a "no-touch" technique. Each segment was divided into seven specimens after a low pressure distension with saline solution. The first of them was fixed immediately after harvesting with 2.5% glutaraldehyde solution, for basal evaluation. Three were fixed after 30 min and three after 5 h preservation at 4 degrees C in a) autologous, oxygenated, and heparinized blood (AOHB), b) heparinized saline solution with papaverine (HSSP) and c) University of Wisconsin solution (UWS). The specimens preserved in AOHB showed marked endothelial cell detachment and endothelial cell loss after both preservation times (30 min and 5 h). The specimens preserved in HSSP for 30 min showed no alteration in endothelium in 12 cases, while a partial endothelial detachment with intracellular edema was present in the last 3 cases; all 5 h specimens showed only a few remnants of endothelial cells. The specimens preserved in UWS for 30 min showed a morphology comparable to specimens preserved in the saline solution for the same time; in the 5 h specimens a well preserved endothelium was found in 11 cases and partial endothelial detachment and subendothelial edema in the other 4.(ABSTRACT TRUNCATED AT 250 WORDS)


Residual quantification and oxidative stress induced by malachite green after subacute and sublethal exposure in red tilapia.
Malachite green (MG) is an effective antiparasitic and antifungal chemical for treatment of fish. However, MG is reported to be a potential carcinogen. Yet, it is widely used in aquaculture despite its prohibition for use in food-producing animals by the EU and USFDA. The present study quantified MG residues and evaluated the oxidative stress in red tilapia when exposed to subacute and sublethal concentrations of MG. Red tilapia exposed to subacute (0.105 mg/L for 20 days) and sublethal (0.053 mg/L for 60 days) concentrations were evaluated for total plasma protein, total immunoglobulin, nitroblue tetrazolium activity, malondialdehyde, reduced glutathione (GSH), and catalase (CAT) activity levels. The residues of MG and leuco-MG (LMG) were also quantified in the fish muscles using liquid chromatography-tandem mass spectrometry. Fish exposed to subacute concentration showed higher CAT on day 10 in the liver and days 5 and 15 in the spleen, whereas in fish exposed to the sublethal concentration, higher levels of GSH were observed on day 1 in the kidney and day 50 in the spleen. Fish muscle was able to accumulate the sum of MG and LMG of 108.04 µg/kg for subacute (day 20) and 82.68 µg/kg for sublethal (day 60). This study showed that red tilapia was able to adapt to the stress caused by exposure to MG at sublethal concentration.


Safety assessment of oil extracted from lacquer (Toxicodendron vernicifluum (Stokes) F.A. Barkley) seed: acute and subchronic toxicity studies in rats.
Toxicodendron vernicifluum (Stokes) F.A. Barkley (RVS) is an economic tree species and widely distributed in East Asia. Wood parts and raw lacquers of RVS have been used in coatings, herbal medicines or food supplements, and the leaves, flowers, roots, and fruits of RVS are also widely used in medicine traditionally. Lacquer seed oil (LSO) has potential health benefits and has not previously been evaluated for safety. The aim of the present study was to investigate the toxicological potential of LSO by acute and subchronic toxicity tests. The characterization of fatty acids of the LSO was carried out by gas chromatography. In the acute toxicity study, LSO was administered at single doses of 5000 or 10000 mg/kg by oral gavage. The subchronic toxicity study was conducted by daily oral administration of LSO at doses of 1250, 2500 and 5000 mg/kg/day for 30 consecutive days. The animals were evaluated for clinical observations, body weight, organ weight, feed consumption, biochemical and hematological parameters, and liver, lung, and kidney histology. There were no mortality and toxic changes were observed in acute toxicity study. The results of subchronic toxicity showed no toxicologically significant changes in clinical observations, body weight, organ weight, biochemical or hematological parameters. Histopathologic results indicated slight hepatic steatosis and inflammatory infiltration in the rats of 5000 mg/kg/day LSO treated group. However, the histopathologic observation was not confirmed by hepatic biochemical analysis. These results suggested that the LD50 of LSO is over 10000 mg/kg and LSO is non-toxic for SD rats in acute toxicity study. The no observed adverse effect level (NOAEL) of LSO in rats is considered to be 5000 mg/kg/day, and liver is the potential target organ of LSO for 30-day subchronic toxicity study.


Impact of intravenous ferric carboxymaltose on heart failure with preserved and reduced ejection fraction.
Heart failure (HF) is a proinflammatory disease often associated with the onset of iron deficiency (ID). ID alters mitochondrial function, reducing the generation of cellular energy in skeletal muscle and cardiomyocytes. This study aimed to analyse the response of patients with HF to intravenous iron administration according to the type of HF: preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF). We conducted a retrospective, single-centre study of 565 consecutive outpatients diagnosed with HF, recruited over 5 years, who were given intravenous ferric carboxymaltose (FCM) for the treatment of ID [defined as ferritin < 100 μg/L or ferritin 100-300 μg/L with transferrin saturation (TSAT) < 20%]. Clinical, laboratory, and echocardiographic parameters were analysed before and after administration. After FCM administration, overall ferritin, TSAT, and haemoglobin levels increased up to 5-fold, 1.6-fold, and 1.1-fold, respectively, relative to baseline values in HF patients with reduced and preserved ejection fraction (P < 0.0001), with a greater increase in ferritin and TSAT in HFpEF patients. The left ventricular ejection fraction of the overall series improved by 8 percentage points in both types of HF (from 40% to 48%, P < 0.0001). The percentage of patients with normalization of right ventricular function increased by 6.9 points (from 74.1% to 81%) in HFpEF patients and by 6.4 points (from 53% to 59.4%) in the HFrEF subgroup (P < 0.0001). New York Heart Association functional status slightly improved, from a median of 2.4 (interquartile range, IQR: 2-2.7) to 1.9 (IQR: 1.5-2.5; P < 0.0001) after FCM in both types of HF. No changes were noted in plasma levels of liver enzymes, creatinine, or natriuretic peptide (P > 0.05). Intravenous iron administration appeared to improve ejection fraction and cardiac functional status in outpatients with ID and HF with both preserved and reduced ejection fraction.


Changes in actin cytoskeleton during volume regulation in C6 glial cells.
Changes in actin cytoskeleton in the C6 rat glial cell line were studied during decrease or increase (abrupt or gradual) of extracellular osmolality. Actin cytoskeleton was visualized by confocal microscopy after FITC-phalloidin labeling. G-actin, Triton-soluble F-actin and Triton-insoluble F-actin subfractions were determined by gel electrophoresis and scanning, and by DNase I inhibition assays. In control conditions C6 glial cells exhibited well-defined stress fibers and a relatively smooth cortical network. Extracellular anisosmotic changes induced a rapid actin cytoskeletal reorganization, which further progressed and was not reversed upon cell volume recovery. Hypotonic shock caused membrane ruffling and a shift towards polymerized actin, whereas hypertonicity (abrupt or gradual) led to a distinct morphological appearance of abundant short actin microfilaments with, however, no detectable alteration in actin subfractions. When anisosmotic cell volume regulation was prevented, cytoskeleton reorganization depended on the osmotic change and the experimental protocol, but was not related to the absence of volume readjustment. Therefore, although involvement of cytoskeletal alterations in transduction of volume regulatory responses cannot be excluded, it is likely that the observed changes in actin cytoskeleton in C6 glial cells are linked with, but do not initiate, cell volume regulatory processes.


Functional of tongue sole (Cynoglossus semilaevis) gamma-interferon-inducible lysosomal thiol reductase with implications in innate immune reponse depend on CXXC active site.
The enzyme gamma-interferon-inducible lysosomal thiol reductase (GILT) plays an important role in promoting the processing and presentation of major histocompatibility complex (MHC) class II-restricted antigens. It is also involved in MHC I-restricted antigens catalyzing disulfide bond reduction in fishes' adaptive immunity. The open reading frame of tongue sole (Cynoglossus semilaevis) GILT (tsGILT) gene is 771 bp long, encoding 257 amino acids, with a calculated molecular weight of 28.465 kDa and isoelectric point (pI) of 5.35. After induction with lipopolysaccharide, the expression of tsGILT mRNA was upregulated in spleen and kidney and recombinant tsGILT protein transferred to late endosomes and lysosomes in HeLa cells. The refolded tsGILT was capable of catalyzing the reduction of the interchain disulfide bonds against an IgG substrate depend on the active site CXXC motif at residues 75-78. The process of immune response to bacteria challenge needs GILT to catalyze the reduction of disulfide bond and unfolding native protein antigens, promoting their hydrolysis by proteases. Whether a single mutation or a double mutation of active site CXXC at residues75-78, the 3D structure of tsGILT protein has undergone major changes and lost its activity of catalyzing the reduction of the interchain disulfide bonds.


Correction: Identifying Maternal Constraints on Fetal Growth and Subsequent Perinatal Outcomes Using a Multiple Embryo Implantation Model.
[This corrects the article DOI: 10.1371/journal.pone.0166222.].


[Inpatient psychotherapy].
In German-speaking countries inpatient psychotherapy plays a major role in the mental healthcare system. Due to its characteristic features, i. e. multiprofessionalism, multimodality and method integration, the inpatient approach represents a unique and independent type of psychotherapy. In order to be helpful, the manifold verbal and non-verbal methods need to be embedded into an overall treatment plan. Additionally, the therapeutic milieu of the hospital represents an important effective factor and its organization requires a more active construction. The indications for inpatient psychotherapy are not only based on the mental disorder but also on illness, setting and healthcare system-related criteria. In integrative concepts, the multiprofessional team is a key component with many functions. The effectiveness of psychotherapeutic hospital treatment has been proven by meta-analysis studies; however, 20-30% of patients do not benefit from inpatient psychotherapy and almost 13% drop-out prematurely.


Evaluation of the ornithogenic influence on the trophic state of East Mediterranean wetland ecosystem using trend analysis.
The Great Rift Valley portion of the East African-Eurasian Migratory Flyway is extremely important globally because of the numbers (>500 million) and diversity of seasonal traveling birds. The construction of the Agmon wetland (1.1km(2)) in the Hula Valley, Israel in 1994 and a change in crop type and rotation has attracted increasing number of Eurasian cranes (Grus grus) to winter in the wetland (>40,000 in 2014). The birds are fed in an area of 100ha and roost during the night in the wetland for protection from predators. Feeding practices have yielded an eco-tourism bonanza with over 400,000 visitors annually. However, this practice may have negative impacts on the trophic state of the wetland. We performed trend analyses using monthly means of selected constituents collected from mid-1994 to 2014. The temporal distribution of TN and TP concentrations in the inlets did not change with time. The concentrations of TN and TP in the outlet increased significantly during the earlier monitoring period. Kendall-Theil regression showed that TP concentrations in the outlet increased significantly from a monthly mean of 180μgL(-1) in 2010 to a monthly mean of 260μgL(-1) in 2014. Similarly, the results of chlorophyll a concentrations in the outlet showed a sharp upturn in the latter part of the series from a mean of 66mgL(-1) in 2010 to a mean of 122mgL(-1) in 2014. The concurrent increase of TP and chlorophyll a, the two most important parameters affecting a waterbody trophic index coincided with the observed increase in the number of roosting cranes in the wetland. Hence, we assume that the continued increases in TP concentrations could transform the wetland from a mild eutrophic to a permanent hypereutrophic state. Reducing the number of roosting cranes may prevent this from happening.


Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes.
In this study we aimed to identify the physiological roles of G protein-coupled receptor 84 (GPR84) in adipose tissue, together with medium-chain fatty acids (MCFAs), the specific ligands for GPR84. In mice, high-fat diet up-regulated GPR84 expression in fat pads. In 3T3-L1 adipocytes, co-culture with a macrophage cell line, RAW264, or TNFα remarkably enhanced GPR84 expression. In the presence of TNFα, MCFAs down-regulated adiponectin mRNA expression in 3T3-L1 adipocytes. Taken together, our results suggest that GPR84 emerges in adipocytes in response to TNFα from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity.


Microbiological and chemical dehydrogenation of withaferin A.
Arthrobacter simplex dehydrogenated withaferin A to 4-dehydrowithaferin A but it was not able to dehydrogenate this substrate in position 27. 27-Dehydrowithaferin A was prepared chemically using pyridinium chlorochromate. Whereas 4-dehydrowithaferin A surpassed in its effect on leukemic (388 cells the original compound and all its derivates synthesized so far, 27-dehydrowithaferin A was biologically inactive.


Potential Effects of Dynamic Stretching on Injury Incidence of Athletes: A Narrative Review of Risk Factors.
The use of dynamic stretching as a replacement for static stretching in the warm-up is widespread based on the reports of static stretching-induced performance impairments. While acute and chronic static stretching has been reported to reduce musculotendinous injuries, especially with explosive and change of direction actions, the influence of dynamic stretching on injury incidence lacks a similar volume of literature for acute and chronic responses. It was the objective of this narrative review to examine the acute and training effects of dynamic stretching on injury incidence and possible moderating variables such as dynamic stretching effects on range of motion, strength, balance, proprioception, muscle morphology, and psycho-physiological responses. One study demonstrated no significant difference regarding injury incidence when comparing a dynamic stretching-only group versus a combined dynamic stretching plus static stretching group. The only other study examined functional dynamic stretching training with injured dancers and reported improved ankle joint stability. However, several studies have shown that dynamic activity with some dynamic stretching exercises within a warm-up consistently demonstrates positive effects on injury incidence. Regarding moderating variables, while there is evidence that an acute bout of dynamic stretching can enhance range of motion, the acute and training effects of dynamic stretching on strength, balance, proprioception, and musculotendinous stiffness/compliance are less clear. The acute effects of dynamic stretching on thixotropic effects and psycho-physiological responses could be beneficial for injury reduction. However, the overall conflicting studies and a lack of substantial literature compared with SS effects points to a need for more extensive studies in this area.


Alteration of muscarinic acetylcholine binding sites in the postischemic brain areas of the rat using in vitro autoradiography.
We studied the postischemic alteration of muscarinic acetylcholine binding sites in the rat brain using in vitro [3H]quinuclidinyl benzilate (QNB) autoradiography. Transient ischemia was induced by the occlusion of the middle cerebral artery (MCA) for 90 min and such occlusion followed by various recirculation periods of up to 4 weeks. After 90 min of ischemia followed by 3 days of recirculation, [3H]QNB binding sites were found to be significantly decreased in the cerebral cortex (P < 0.01) and lateral segment of the caudate putamen (P < 0.05), both supplied by the occluded MCA; thereafter, the binding sites decreased progressively in those ischemic foci. Moreover, 3 days after the ischemia, significant decreases of [3H]QNB binding sites were observed in the ipsilateral thalamus and the amygdala, and also in the substantia nigra 1 week after the ischemia, areas which had not been directly affected by the original ischemic insult. This postischemic phenomenon observed in the thalamus and the substantia nigra developed concurrently with 45Ca accumulation, which was detected there in our previous study. These results indicate that alteration of muscarinic acetylcholine binding sites may be involved not only in the ischemic foci, but also in the exo-focal remote areas, in which delayed neuronal degeneration due to neuronal network disturbances after the ischemia was observed. We suggest that multifocal postischemic alterations of muscarinic acetylcholine binding sites may exacerbate the clinical symptoms of patients during the chronic stage of stroke.


Comparative Performance of Body Composition Parameters in Prediction of Death in Hospitalized Patients on Maintenance Hemodialysis: A Cohort Study.
We compared the prognostic value of nutritional or volumetric parameters measured by body composition in hospitalized patients on maintenance hemodialysis. We conducted a cohort study to assess the association of different parameters of body composition with all-cause mortality in inpatients admitted to our nephrology department from January 2014 to December 2016. Of the 704 study patients, 160 (22.7%) died during a median follow-up of 33 months. In multivariate adjusted Cox models, higher ratio of extracellular water to body cell mass (ECW/BCM) (adjusted HR per 1-SD, 1.49; 95% CI, 1.19 to 1.85), lower lean tissue index (LTI) (adjusted HR per 1-SD, 0.70; 95% CI, 0.57 to 0.86) and lower body cell mass index (BCMI) (adjusted HR per 1-SD, 0.70; 95% CI, 0.58 to 0.85) were associated with a significantly greater risk of death. When these parameters were added to the fully adjusted model, BCMI performed best in improving the predictability for all-cause mortality (integrated discrimination improvement = 0.02, P = 0.04; net reclassification index = 0.11, P = 0.04). Among body composition indexes, ECW/BCM was the most relevant fluid volume indices to mortality and BCMI and LTI were the most relevant nutritional status indices to mortality in maintenance hemodialysis patients.


Comparative subcellular immunolocation of polypeptides associated with xylan and callose synthases in French bean (Phaseolus vulgaris) during secondary wall formation.
The Golgi apparatus of plant cells is thought to be the main site of synthesis of cell wall matrix polysaccharides and the terminal glycosylation of glycoproteins. Much of this evidence still depends on earlier biochemical studies employing subcellular fractionation. However acquiring pure Golgi membranes is still difficult and the question of spatial organisation of glycosyl transferases can be addressed by immunolocation of the enzymes. An antibody to a xylan synthase-associated polypeptide from French bean, the enzyme which synthesises the core polysaccharide for secondary wall xylan, has been raised and shown to inhibit its activity. Xylan is deposited in secondary thickenings and the xylan synthase was only detected in appreciable amounts in developing xylem cells. The location within the Golgi stack was observed throughout the dictyosomes. Some enzyme subunits were also detected in post-Golgi vesicles. A second antibody to a non-catalytic M(r) 65000 subunit of beta 1,3- glucan (callose) synthase was used for a comparative study. Although the bulk of this enzyme has been detected in previous studies at plasmamembrane-wall interfaces in sieve plates and stressed tissue, a Golgi-location can be observed in root tip meristematic cells during cell plate formation. The enzyme was present throughout the stacks. Callose was also immunolocated in a similar manner to xylan in secondary walls and thickenings and in pits in developing xylem. In these cells, the callose synthase was detected at the surface of the growing thickenings and the plasmamembrane within the pits.


Avian and mammalian "prefrontal cortices": limited degrees of freedom in the evolution of the neural mechanisms of goal-state maintenance.
Is it possible to produce the same cognitive function with different brain organizations? This question is approached for working memory, a cognitive entity that is equally organized in birds and mammals. The critical forebrain structure for working memory is the nidopallium caudolaterale (NCL) in birds and the prefrontal cortex (PFC) in mammals. Although both structures share a large number of neural architectural features, they are probably not homologous but represent a remarkable case of convergent evolution. In reviewing the neuronal mechanisms for working memory in birds and mammals it becomes apparent that the similarities of NCL and PFC extend from the neuronal activation patterns during memory tasks down to the biophysical mechanisms of synaptic currents. Both in mammals and birds, dopamine acts via D1-receptors to tune preactivated neurons into sustained high-frequency patterns with which goal states can be held over time until an appropriate response can be generated. The degrees of freedom to create different neural architectures to solve the problem of 'stimulus maintenance' seem to be very small.


RNA-seq analysis reveals candidate genes associated with proliferation, invasion, and migration in BCL11A knockdown B-NHL cell lines.
B-cell lymphoma/leukemia 11A (BCL11A) is highly expressed in B-cell non-Hodgkin lymphoma (B-NHL), blocks cell differentiation, and inhibits cell apoptosis. However, little is known about BCL11A in the proliferation, invasion, and migration of B-NHL cells. Here, we found increased expression of BCL11A in B-NHL patients and cell lines. Knockdown of BCL11A suppressed the proliferation, invasion, and migration of B-NHL cells in vitro and reduced tumor growth in vivo. RNA sequencing (RNA-seq) and KEGG pathway analysis demonstrated that BCL11A-targeted genes were significantly enriched in the PI3K/AKT signaling pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction (including COL4A1, COL4A2, FN1, SPP1), and SPP1 was the most significantly downregulated gene. qRT‒PCR, western blotting, and immunohistochemistry revealed that silencing BCL11A reduced the expression level of SPP1 in Raji cells. Our study suggested that high level of BCL11A may promote B-NHL proliferation, invasion, and migration, and the BCL11A-SPP1 regulatory axis may play an important role in Burkitt's lymphoma.


Prophylactic anticoagulation in children receiving home parenteral nutrition.
Children with intestinal failure (IF) are at risk of loss of vascular access because of catheter-related venous thrombosis. Whether primary prophylactic anticoagulation is effective and safe in preventing catheter-related thrombosis is largely unknown. Our aim was to assess the incidences of catheter-related venous thrombosis and bleeding complications in children with IF receiving home parenteral nutrition (HPN) treated with primary prophylactic anticoagulation. All children, aged 0-18 years, treated with HPN at the Emma Children's Hospital/Amsterdam UMC were followed from January 2007 to July 2019. All patients were offered primary prophylactic anticoagulation from the start of HPN. The primary outcomes were catheter-related venous thrombosis and bleeding on prophylactic anticoagulation. In total, 55 (76%) of 74 patients received primary prophylactic anticoagulation. The median age at the start of prophylaxis was 8.4 (interquartile range [IQR], 5.0-55.7) months. Patients were followed for a median of 31.2 (IQR, 10.7-53.5) months, with a total of 65,463 catheter days. The incidence of catheter-related thrombosis on prophylactic anticoagulation was 0.2 per 1000 catheter days. In total, the incidence of clinically relevant bleeding was 0.1 per 1000 catheter days. The median time to first event was 1268 (IQR, 149-2014) days for thrombosis and 389 (IQR, 227-2912) days for clinically relevant bleeding. Cumulative event-free survival after 5 years was 78% for thrombosis. Our study shows a low rate of catheter-related venous thrombosis and a slightly elevated rate of clinically relevant bleeding in children receiving HPN and primary prophylactic anticoagulation.


Passive water transport in biological pores.
Three kinds of membrane proteins have been shown to have water channels properties: the aquaporins, the cotransporters, and the uniports. A molecular-kinetic description of water transport in pores is compared to analytical models based on macroscopic parameters such as pore diameter and length. The use and limitations of irreversible thermodynamics is discussed. Experimental data on water and solute permeability in aquaporins are reviewed. No unifying transport model based on macroscopic parameters can be set up; for example, there is no correlation between solute diameter and permeability. Instead, the influence of hydrogen bonds between solute and pore, and the pH dependence of permeability, point toward a model based upon chemical interactions. The atomic model for AQP1 based on electron crystallographic data defines the dimensions and chemical nature of the aqueous pore. These structural data combined with quantum mechanical modeling and computer simulation might result in a realistic description of water transport. Data on water and solute permeability in cotransporters and uniports are reviewed. The function of these proteins as substrate transporters involves a series of conformational changes. The role of conformational equilibria on the water permeability will be discussed.


Subcutaneous Fat Necrosis of the Newborn: A Case Report of a Term Infant Presenting with Malaise and Fever at Age of 9 Weeks.
Background. Subcutaneous fat necrosis (SFN) is a rare, temporary, self-limited pathology affecting adipose tissue of full-term or postmature neonates. It is a rare entity especially in Nigeria and usually occurs in the first weeks following a complicated delivery. Because it is not very common, diagnosis is easily missed. It may resolve spontaneously without sequelae but patients need to be followed up because of development of late complications especially hypercalcemia. We report a case of SFN of the newborn noted within one week of birth and highlight the need for proper prompt diagnosis and the need for follow-up to assess possible complications.


Monitoring oil displacement processes with k-t accelerated spin echo SPI.
Magnetic resonance imaging (MRI) is a robust tool to monitor oil displacement processes in porous media. Conventional MRI measurement times can be lengthy, which hinders monitoring time-dependent displacements. Knowledge of the oil and water microscopic distribution is important because their pore scale behavior reflects the oil trapping mechanisms. The oil and water pore scale distribution is reflected in the magnetic resonance T2 signal lifetime distribution. In this work, a pure phase-encoding MRI technique, spin echo SPI (SE-SPI), was employed to monitor oil displacement during water flooding and polymer flooding. A k-t acceleration method, with low-rank matrix completion, was employed to improve the temporal resolution of the SE-SPI MRI measurements. Comparison to conventional SE-SPI T2 mapping measurements revealed that the k-t accelerated measurement was more sensitive and provided higher-quality results. It was demonstrated that the k-t acceleration decreased the average measurement time from 66.7 to 20.3 min in this work. A perfluorinated oil, containing no (1) H, and H2 O brine were employed to distinguish oil and water phases in model flooding experiments. High-quality 1D water saturation profiles were acquired from the k-t accelerated SE-SPI measurements. Spatially and temporally resolved T2 distributions were extracted from the profile data. The shift in the (1) H T2 distribution of water in the pore space to longer lifetimes during water flooding and polymer flooding is consistent with increased water content in the pore space. Copyright © 2015 John Wiley & Sons, Ltd.


A parentally administered cognitive development assessment for children from 10 to 24 months.
The Cognitive Development Questionnaire (CDQ) allows accurate assessment of cognitive development of children from 10 to 24 months by parents and caregivers in the home. It takes between 1 and 2h to complete over about a week. Three phases of work are described, in which the instrument is progressively refined to improve its validity and reliability. This resulting version of the CDQ shows excellent correlation with age, and with the Mental Scale of the Bayley Scales of Infant Development (Bayley, 1993). The CDQ thus offers researchers and clinicians a useful alternative to professionally administered cognitive assessment in infancy.


Domains of the human neutrophil N-formyl peptide receptor involved in G protein coupling. Mapping with receptor-derived peptides.
Chemotactic signaling by the human neutrophil N-formyl peptide receptor requires its association with heterotrimeric G protein. Synthetic peptides and a fusion protein derived from the intracellular regions of the receptor were used to identify sites which interact with G protein. A peptide derived from the second intracellular loop (C12R), and peptides (F15R and S22L) and a fusion protein derived from the receptor's carboxyl terminus inhibited binding of anti-Gi alpha antibody (R16,17) to Gi alpha in a competitive enzyme-linked immunoassay, and antagonized pertussis-toxin catalyzed ADP-ribosylation of Gi alpha. C12R also inhibited G protein-dependent, high affinity ligand binding to the receptor and physical coupling of receptor to G protein. In contrast, a peptide consisting of the entire third loop of the N-formyl peptide receptor was totally inactive in these assays. Collectively, these data suggest that the second intracellular loop and the carboxyl-terminal tail are important for effective N-formyl peptide receptor/G protein coupling, but that the third intracellular loop is less important in coupling, unlike previous findings with other G protein-coupled receptor systems. The chemoattractant receptor family may rely on different structural determinants to interact with GTP-binding proteins.


NKG2D-mediated cytotoxicity improves after primary surgery for high-grade serous ovarian cancer.
Tumors compromise the patients' immune system to promote their own survival. We have previously reported that HGSC exosomes play a central role, downregulating NKG2D cytotoxicity. Primary surgery's effect on tumor exosomes and NKG2D cytotoxicity in HGSC patients has not been studied before. The overall objective of this study was to explore the effect of surgery on the exosome-induced impairment of NKG2D cytotoxicity in HGSC. Paired pre- and post-operative blood samples were subjected to cell and exosome analyses regarding the NKG2D receptor and ligands, and NKG2D-mediated cytotoxicity. Lymphocytes were phenotyped by immunoflow cytometry. Exosomes, isolated by ultracentrifugation, and characterized by nanoparticle tracking analysis, transmission and immune electron microscopy and western blot were used in functional cytotoxic experiments. HGSC explant culture-derived exosomes, previously studied by us, were used for comparison. HGSC exosomes from patients' sera downregulated NKG2D-mediated cytotoxicity in NK cells of healthy donors. In a subgroup of subjects, NKG2D expression on CTLs and NK cells was upregulated after surgery, correlating to a decrease in the concentration of exosomes in postoperative sera. An overall significantly improved NKG2D-mediated cytotoxic response of the HGSC patients' own NK cells in postoperative compared to preoperative samples was noted. Surgical removal of the primary tumor has a beneficial effect, relieving the exosome-mediated suppression of NKG2D cytotoxicity in HGSC patients, thus boostering their ability to combat cancer.


Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation.
Changes in synaptic efficacy are believed to mediate the processes of learning and memory formation. Accumulating evidence implicates cell adhesion molecules in activity-dependent synaptic modifications associated with long-term potentiation (LTP); however, there is no precedence for the selective role of this molecule class in long-term depression (LTD). The mechanisms that modulate these processes still remain unclear. We report a novel role for glycosylphosphatidyl inositol (GPI)-anchored contactin in hippocampal CA1 synaptic plasticity. Contactin selectively supports paired-pulse facilitation (PPF) and NMDA (N-methyl-D-aspartate) receptor-dependent LTD but is not required for synaptic morphology, basal transmission, or LTP. Molecular analyses indicate that contactin is essential for the membrane and synaptic targeting of the contactin-associated protein (Caspr/paranodin) and for the proper distribution of a presumptive ligand, receptor protein tyrosine phosphatase beta (RPTPbeta)/phosphacan. These results indicate that contactin plays a selective role in synaptic plasticity and identify PPF and LTD, but not LTP, as contactin-dependent processes. Engagement of the contactin-Caspr complex with RPTPbeta may thus regulate cell-cell interactions contributing to specific synaptic plasticity forms.


A computationally efficient method for solving the redundant problem in biomechanics.
Determining the optimal set of musculotendon forces with which to produce a forward dynamic simulation of movement typically involves a huge investment of time and computational resources. A new, computationally efficient method is proposed that simultaneously achieves the desired trajectory and the dynamically optimized set of muscle stresses, and hence forces, according to the maximal endurance criterion function of Crowninshield and Brand (1981). Muscle-induced accelerations of the system resulting from unit stress contractions of individual muscles are superposed via the new pseudoinverse method to yield the desired motion trajectory. The method is tested on a control problem involving a five degree-of-freedom (DOF), 30 muscle, upper extremity model, which incorporates a dual rigid-body forearm to represent pronation and supination more adequately. The pseudoinverse method delivered the desired motion to within 0.25 degrees for each DOF during a three-second simulation. It is anticipated that the methodology can be easily and accurately applied to other highly redundant optimal control problems in biomechanics.


A survey on the resources and practices in pediatric critical care of resource-rich and resource-limited countries.
Contemporary critical care research necessitates involvement of multiple centers, preferably from many countries. Adult and pediatric research networks have produced outstanding data; however, their involvement is restricted to a small percentage of the industrialized nations. Implementation of their findings in low- and middle-income countries (LMICs) is fraught with challenges. We conducted an online international survey to assess and compare disease burden and resources to participate in multicenter research studies through a listserv of the World Federation of Pediatric Intensive and Critical Care Societies. Respondents were grouped into high-income countries and LMICs on the basis of World Bank classification. Survey was completed by 73 centers in 34 countries (34 from high-income countries and 39 from LMICs). Compared with high-income countries, the pediatric intensive care units in LMICs were characterized by a lower number of critical care specialists, more difficult access to hemodialysis, and a lower number of elective postoperative patients, but a similar overall disease burden. Training and resources for research were comparable in the two cohorts. Although differences exist in access to both trained providers and equipment, the survey results were more striking in their similarity. It is essential that centers from LMICs be included in multinational studies, to generate results applicable to all children worldwide.


Regulation of the sumoylation system in gene expression.
Protein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the small ubiquitin-like modifier (SUMO) conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other post-translational modifications, including phosphorylation, ubiquitination, and acetylation.


A fully validated simple new method for environmental monitoring by surface sampling for cytotoxics.
A wipe sampling procedure followed by a simple ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous quantification of six cytotoxic drugs: 5-fluorouracil (5FU), doxorubicin (DOXO), epirubicin (EPI), ifosfamide (IF), cyclophosphamide (CP) and gemcitabine (GEM), as surrogate markers for occupational exposure. After a solid-phase extraction of wiping filter on 10 × 10 cm surface, the separation was performed within 6.5 min, using a gradient mobile phase and the analytes were detected by mass spectrometry in the multiple reaction ion monitoring mode. The method was validated according to the recommendations of the US Food and Drug Administration. The method was linear (r2 > 0.9912) between 2.5 and 200 ng per wiping sample (25 to 2000 pg/cm2) for 5FU, doxorubicin and epirubicin and between 0.2 and 40 ng per wiping sample (2 to 400 pg/cm2) for cyclophosphamide, ifosfamide and gemcitabine. The lower limits of quantification were 2.5 ng (25 pg/ cm2) for 5FU, doxorubicin and epirubicin, and 0.2 ng (2 pg/cm2) for CP, IF and GEM. Within-day and between-day imprecisions were <14.0, 10.6, 11.1, 8.7, 11.2 and 10.9% for 5-fluorouracil, doxorubicin, epirubicin, ifosfamide cyclophosphamide and gemcitabine, respectively. The inaccuracies did not exceed 2.7, 10.9, 1.1, 4.5, 1.6 and 2.9% for the studied molecules, respectively. This new sensitive validated method for surface contamination studies of cytotoxics was successfully applied on different localizations in hospital. This approach is particularly suitable to assess occupational exposure risk to cytotoxic drugs.


Extranodal NK/T-cell lymphoma, nasal type: a case report of 7-year natural course and review of literature.
We present our experience a vary case of Extranodal natural killer (NK)/T-cell lymphomas, nasal type (ENKL) who survived for 7 years, and review the recent advances on the differential diagnosis.


Characterization of VOC emissions from construction machinery and river ships in the Pearl River Delta of China.
Speciated characterization of Volatile Organic Compounds (VOCs), including oxygenated VOCs (OVOCs), from construction machinery and river ships in China is currently lacking. In this regard, we conducted field measurement on speciated VOC (including OVOC) emissions from six construction machinery and five river ships in the Pearl River Delta (PRD) region to identify VOC emission characteristics. We noticed that OVOC emissions from construction machinery and ships accounted for more than 50% of the total VOC emissions, followed by alkenes, aromatics and alkanes. Formaldehyde and acetaldehyde were the most emission species, accounting for 61.8%-83.2% of OVOCs. For construction machinery, the fuel-based emission factors of roller, grader and pile driver were 3.12, 3.12 and 7.36 g/kg, respectively. With the rigorous restraint by the national emission standards, VOC emissions of construction machinery had decreased considerably, especially during stage Ⅲ. Ozone formation potential was also significantly reduced due to the significant decrease in emissions of OVOCs and alkenes with higher reactivity. For river ships, the fuel-based emission factors of cargo ships and speedboat were 1.46 and 0.44 g/kg, respectively. VOC emissions from construction machinery and river ships in Guangdong Province in 2017 were 8851.0 and 4361.0 ton, respectively. This study filled the knowledge gaps of reactive gas emissions from different kinds of non-road mobile sources over the PRD, and more importantly, highlighted the necessity in adding OVOC measurement to give a complete and accurate depiction of reactive gas emissions from non-road mobile sources.


Spatial distribution and impact of cattle-raising on ticks in the Pantanal region of Brazil by using the CO(2) tick trap.
This study evaluates the impact of cattle-raising on ticks associated with wildlife in the Pantanal region of Brazil, by trapping free-living ticks using a CO(2) tick trap. The traps were equally distributed in two areas: a 600-ha protected area (PA) and the Nhumirim Ranch (NR). Both areas are contiguous and located at the sub-region of Nhecolândia (18 degrees 59'S; 56 degrees 39'W), Pantanal, Brazil. In each area, four habitat types were selected: cerrado (tropical savanna), forest patches, lakes and soda lakes. The last two are temporary lagoons of fresh and salted water, respectively. A total of 980 nymphs, 613 adults and 13 larvae of ticks Amblyomma were collected in 256 h of collection. In a pen of calves infested by Ornithodoros rostratus 114 specimens were collected, including larvae, nymphs and adults. Adults of A. cajennense and A. parvum were more abundant in the savanna at NR, but not differed among habitat types at PA. There was a tendency of having more nymphs in NR than in PA. The higher number of ticks found in the NR in comparison to the PA is not due to the presence of cattle itself but probably due to introduced dogs and horses, habitat alteration.


[A surgical approach for the cochlear implant (author's transl)].
Although the round window is most commonly employed for insertion of a cochlear electrode, manipulation through this route can be difficult. The author gives data for orientation to a new approach for placing a cochlear implant. In this manner, the nerve fibers of the N. cochlearis in the entire cochlear region can be reached and stimulated.