Nortriterpenoids and lignans from Schisandra sphenanthera.
Nortriterpenoids, sphenadilactone C (1) and sphenasin A (2), together with four known lignans (3-6), were isolated from the leaves and stems of Schisandra sphenanthera. Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and compound 2 was further confirmed by single-crystal X-ray diffraction. Compound 1 features a partial enol moiety and an acetamide group in its structure. In addition, compounds 1, 3-6 showed weak anti-HIV-1 activity with EC(50) values in the range of 15.5-29.5 microg/mL.


Reliability and validity of the Chinese version of the mental vulnerability questionnaire for the undergraduate students.
The aim of this study was to assess the validity and reliability of the Chinese version of mental vulnerability questionnaire (MVQ) for undergraduate students. A cross-sectional design was conducted in a sample of 1217 undergraduate students. The Cronbach's α of the overall scale was 0.901, the split-half reliability coefficient was 0.742, and the test-retest reliability coefficient was 0.935. Three-factors model was got by using exploratory factor analysis, the communalities of the items were 0.646 to 0.848, explaining 75.736% variance. With confirmatory factor analysis the fit indices were chi-square/degree of freedom (CMIN/DF) = 2.796, comparative fit index (CFI) = 0947, GFI = 0.920, adjustedgoodness of fit index (AGFI) = 0.902, incremental fit index (IFI) = 0.947, root mean squareerror of approximation (RMSEA) = 0.055, Tucker Lewis index (TLI) = 0.940, root mean residual (RMR) = 0.051. The Mental Vulnerability Questionnaire has a good reliability and validity, it can be considered as a tool to evaluate the mental vulnerability for undergraduate students.


Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation.
Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2-M cell-cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1-S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1-S and G2-M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wild-type p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell-cycle distribution profiling indicates constantly lower G1 and higher G2-M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared with the parental counterpart. The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, as p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA-damaging agents for MET-positive/p53-negative tumors.


Stress response mechanisms in protein misfolding diseases: Profiling a cellular model of Huntington's disease.
Stress response pathways like the integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt) and the heat shock response (HSR) have emerged as part of the pathophysiology of neurodegenerative diseases, including Huntington's disease (HD) - a currently incurable disease caused by the production of mutant huntingtin (mut-Htt). Previous data from HD patients suggest that ISR is activated while UPRmt and HSR are impaired in HD. The study of these stress response pathways as potential therapeutic targets in HD requires cellular models that mimic the activation status found in HD patients of such pathways. PC12 cells with inducible expression of the N-terminal fragment of mut-Htt are among the most used cell lines to model HD, however the activation of stress responses remains unclear in this model. The goal of this study is to characterize the activation of ISR, UPRmt and HSR in this HD cell model and evaluate if it mimics the activation status found in HD patients. We show that PC12 HD cell model presents reduced levels of Hsp90 and mitochondrial chaperones, suggesting an impaired activation or function of HSR and UPRmt. This HD model also presents increased levels of phosphorylated eIF2α, the master regulator of the ISR, but overall similar levels of ATF4 and decreased levels of CHOP - transcription factors downstream to eIF2α - in comparison to control, suggesting an initial activation of ISR. These results show that this model mimics the ISR activation and the impaired UPRmt and HSR found in HD patients. This work suggests that the PC12 N-terminal HD model is suitable for studying the role of stress response pathways in the pathophysiology of HD and for exploratory studies investigating the therapeutic potential of drugs targeting stress responses.


Microwave absorption properties of Ni/(C, silicides) nanocapsules.
The microwave absorption properties of Ni/(C, silicides) nanocapsules prepared by an arc discharge method have been studied. The composition and the microstructure of the Ni/(C, silicides) nanocapsules were determined by means of X-ray diffraction, X-ray photoelectric spectroscopy, and transmission electron microscope observations. Silicides, in the forms of SiOx and SiC, mainly exist in the shells of the nanocapsules and result in a large amount of defects at the 'core/shell' interfaces as well as in the shells. The complex permittivity and microwave absorption properties of the Ni/(C, silicides) nanocapsules are improved by the doped silicides. Compared with those of Ni/C nanocapsules, the positions of maximum absorption peaks of the Ni/(C, silicides) nanocapsules exhibit large red shifts. An electric dipole model is proposed to explain this red shift phenomenon.


The accuracy of radiological estimates of gestational age using early fetal crown-rump length measurements by ultrasound as a basis for comparison.
Radiological estimates of gestational age in late pregnancy were compared with the gestational ages based on first trimester ultrasound crown-rump length measurements in a series of 125 patients. It was found that the 95 per cent confidence limits of a radiological estimate were +/- 3 1/2 weeks, that both distal femoral and upper tibial epiphyses were frequently present much earlier than 36 and 38 weeks respectively, and that in almost half of the growth-retarded babies in the series there was a bone-age discrepancy of three or more weeks. It is recommended that more liberal use is made of early ultrasound measurements for the assessment of gestational age.


Difference in sensitivity of cardiovascular and respiratory control neurons in the subretrofacial nucleus to glutamate receptor subtype agonists in SHR, WKY and cats.
Using spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and cats, either glutamate or a glutamate receptor subtype agonist was injected into the subretrofacial nucleus (SRF) in the rostral ventrolateral medulla at the site where the pressor response had been evoked by electrical stimulation. The sensitivity of SRF neurons to the electrical stimulation or glutamate receptor agonist was estimated by the threshold current or dose required to evoke the pressor response. The threshold of SRF neurons to electrical stimulation was similar in the three animal groups, while that to the glutamate receptor agonist was different. The significance of the difference in threshold between WKY and SHR was calculated as was that between WKY and cats. The threshold for kainate stimulation was ten times lower for SHR (0.016 pmol, P less than 0.001) and five times higher for cats (0.78 pmol, P less than 0.05); that for quisqualate stimulation was fifty times lower for SHR (0.016 pmol, P less than 0.001) but similar for cats; that for NMDA stimulation was twelve times lower for SHR (0.13 pmol, P less than 0.001) but seven times higher for cats (11 pmol, P less than 0.01); that for glutamate stimulation was ten times lower for SHR (4.2 pmol, P less than 0.001) but similar for cats. The heart rate and respiratory responses associated with the pressor response were tachycardiac and hypopneic in SHR and WKY, but bradycardiac and hyperpneic in cats. These responses were less dominant than the pressor response. We suggest that the pathogenesis of hypertension in SHR may be partly due to abnormal properties of glutamate receptor subtypes acting on vasomotor control neurons in the SRF.


Mindfulness-based therapy for psychogenic nonepileptic seizures.
Mindfulness-based therapies (MBTs) are effective in many neuropsychiatric disorders, and represent a potential therapeutic strategy for psychogenic nonepileptic seizures (PNES). The objective of this study was to investigate the clinical effect of a manualized 12-session MBT for PNES in an uncontrolled trial. We hypothesized reductions in PNES frequency, intensity, and duration, and improvements in quality of life and psychiatric symptom severity at treatment completion. Between August 2014 and February 2018, 49 patients with documented PNES (with video electroencephalography [EEG]) were recruited at Brigham and Women's Hospital to participate in the MBT for PNES treatment study. Baseline demographic and clinical information and self-rating scales were obtained during the diagnostic evaluation (T0). Baseline PNES frequency, intensity, and duration were collected at the first follow-up postdiagnosis (T1). Frequency was obtained at each subsequent MBT session and analyzed over time with median regression analysis. Outcomes for other measures were collected at the last MBT session (T3), and compared to baseline measures using linear mixed models. Twenty-six patients completed the 12-session MBT program and were included in the analysis. Median PNES frequency decreased by 0.12 events/week on average with each successive MBT session (p = 0.002). At session 12, 70% of participants endorsed a reduction in PNES frequency of at least 50%. Freedom from PNES was reported by 50% of participants by treatment conclusion. Seventy percent reported a 50% reduction in frequency from baseline and 50% reported remission at session 12. By treatment end, PNES intensity decreased (p = 0.012) and quality of life improved (p = 0.002). Event duration and psychiatric symptom severity were lower after treatment, but reductions were not statistically significant. Completion of a manualized 12-session MBT for PNES provides improvement in PNES frequency, intensity, and quality of life. The high dropout rate is consistent with adherence studies in PNES. Possible reasons for dropout are discussed. Randomized controlled trials and longer-term outcomes are needed to demonstrate the efficacy of MBT in PNES.


Empirical foundations for the diagnosis of somatization: implications for DSM-5.
The aim of this study was to develop empirically validated criteria for the diagnoses of clinically relevant somatization. This study was performed in a population-representative cohort consisting of 461 males (47.8%) and 503 females (52.2%), with an average age of 55.8 years (s.d.=11.1). Somatization, anxiety and depression were derived from the Composite International Diagnostic Interview. Mplus was used to perform confirmative factor analyses on the current DSM-IV symptom groups; on alternative symptom clusters previously suggested; and to perform latent class analysis in order to define an empirically derived cut-off for somatization. The existence of symptom groups as described in DSM-IV was not supported by our data, whereas a differentiation between cardiopulmonary, musculoskeletal, gastrointestinal and general somatic symptoms did fit our data. Latent class analysis revealed two classes characterized by few (n=859) and many (n=105) symptoms. The class of subjects could be approached by a simple cut-off of four functional symptoms (sensitivity 79%, specificity 98%, positive predictive value 82%, negative predictive value 97%) regardless of the number of organ systems involved. This study in a large population-representative cohort suggests that a simple symptom count can be used as a dimensional diagnosis of somatization. In those instances in which a categorical diagnosis is preferred, a simple cut-off of four out of 43 functional symptoms best fitted our data. We did not find any added value for incorporating the number of symptom clusters into the diagnostic criteria.


Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181.
In the phase III KEYNOTE-181 study (NCT02564263) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations. HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales. The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, -1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups. In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.


Proteus rettgeri infections: a review.
Proteus rettgeri is an aerobic gram-negative bacillus that displays marked resistance against most of the antibiotics presently available. This organism causes infections usually confined to the urinary tract of certain types of compromised patients. Occasionally, it is recovered from soft tissue abscesses, and rarely from the blood and respiratory tract. Proteus rettgeri is notorious for causing nosocomial outbreaks of urinary tract infections in urological and physical medicine wards. Our experience with a patient who had bacteremia with a multi-drug resistant strain of Proteus rettgeri prompted a review of the literature concerning infections with this organism. The salient features of these reports are discussed and summarized. Data on the antibiotic sensitivity of 15 other strains of Proteus rettgeri are included.


The application of nano-medicine to overcome the challenges related to immune checkpoint blockades in cancer immunotherapy: Recent advances and opportunities.
Although immunosurveillance mechanisms are doing their best to counteract with the development of malignant cells, immune checkpoints may serve as the "Achilles' heel" that are exploited by malignant cells. Notably, a deep understanding of this fragile site of the immune system later led to the development of immune checkpoint blockades (ICBs). At the beginning of the discovery, it seemed that these agents could push the boundaries of cancer treatment, however, their life-threatening adverse events have muted the enthusiasm into their application in cancer. It was here that nanotechnology came to the aid of ICBs, as it became evident that the combination of nano-products with ICBs guarantees the delivery of the agents into the tumor nidus, where paralyzed immune cells are waiting for healing. In the present review, we tried to illustrate a new portrait from the befitting impacts of ICBs either as single or in a combined-modal strategy with nanoparticles.


Cancer Cell Membrane-Coated Gambogic Acid Nanoparticles for Effective Anticancer Vaccination by Activating Dendritic Cells.
Recent studies have shown that traditional Chinese medicine (TCM), such as gambogic acid (GA), is involved in the regulation of tumor immune microenvironment and can be combined with other anti-tumor treatment strategies. Here, we used GA as an adjuvant to construct a nano-vaccine to improve the anti-tumor immune response of colorectal cancer (CRC). We used a previously reported two-step emulsification method to obtain poly (lactic-co-glycolic acid) /GA nanoparticles (PLGA/GA NPs), and then CT26 colon cancer cell membrane (CCM) was used to obtain CCM-PLGA/GA NPs. This novel nano-vaccine, CCM-PLGA/GA NPs, was co-synthesized with GA as an adjuvant and neoantigen provided by CT26 CCM. We further confirmed the stability, tumor targeting, and cytotoxicity of CCM-PLGA/GA NPs. The regulatory effect on the tumor immune microenvironment, the anti-tumor efficacy, and the combined anti-tumor efficacy with anti-PD-1 monoclonal Antibodies (mAbs) of this novel nano-vaccine was also detected in vivo. We successfully constructed the CCM-PLGA/GA NPs. In vitro and in vivo tests showed low biological toxicity, as well as the high tumor-targeting ability of the CCM-PLGA/GA NPs. Besides, we revealed a remarkable effect of CCM-PLGA/GA NPs to activate the maturation of dendritic cells (DCs) and the formation of a positive anti-tumor immune microenvironment. This novel nano-vaccine constructed with GA as the adjuvant and CCM providing the tumor antigen can not only directly kill tumors by enhancing the ability of GA to target tumors, but also indirectly kill tumors by regulating tumor immune microenvironment, providing a new strategy for immunotherapy of CRC.


CK-7 negative primary lung adenocarcinoma.
Cytokeratin (CK) 7 is normally expressed in the vast majority of lung adenocarcinoma (ADC). However, on rare occasions, as reported in this paper, CK7 negativity can challenge the diagnosis of pulmonary ADC. Hence, the need to use a combination of 'immunomarkers' such as thyroid transcription factor 1, Napsin A, p40, p63 and CK20.


Eosinophilic gastroenteritis and graft-versus-host disease induced by transmission of Norovirus with fecal microbiota transplant.
Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic-resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft-versus-host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus-free FMT from another donor.


Biochemistry without oxygen.
Published procedures for experimentation under anoxic conditions generally involve specialized apparatus that hinders the easy manipulation of experimental samples. We describe here some procedures that rapidly remove oxygen from experimental solutions, maintain anoxia with simple equipment for long periods of time, and do not interfere with normal sample addition and removal, spectrometric measurements, chromatographic manipulations, and the like. Anoxia can be achieved and maintained by the use of an enzyme system (glucose oxidase, glucose, catalase), or an inorganic oxygen-reducing system (ferrous pyrophosphate), or dithionite. Physical isolation of experimental samples from atmospheric oxygen can be maintained by continuous flushing with treated argon gas and/or by an overlay of heavy mineral oil.


Rapid enzymatic degradation of [125I] (Tyr 10) FGF (1-10) by serum in vitro and involvement in the determination of circulating FGF by RIA.
In the conditions used in the RIA procedure for circulating FGF quantitation, the tracer [125I] (Tyr 10) FGF (1-10) was extensively degraded into two non immunoreactive peptides corresponding to a sequential removal of two amino acid residues at the NH2-terminus i.e. Pro and Ala. A FGF like immunoreactive fraction exists in serum the molecular weight of which was estimated to be 240 Kda. This fraction was also able to perform the same extensive degradation of (Tyr 10) FGF (1-10) than whole serum. The results presented raise the question of the validity of RIA for the determination of circulating FGF. They also present evidence that a high molecular weight serum fraction which reacts as immunoreactive FGF is an enzymatic activity responsible for biodegradation of the growth factor rather than a distinct biological entity which is related to the FGF structure.


Differential signaling of sphingosine derivatives in U937 human monocytes depends on the degree of N-methylation.
Previously, we studied N,N-dimethyl-D-erythro-sphingosine (DMS)-induced cell death and signaling in U937 human monocytes; we found that DMS-induced sphingosine kinase- and PKC-independent apoptosis. In the present study, we studied apoptotic responses by three N-methyl derivatives of sphingosine: N-monomethyl-D-erythro-sphingosine (MMS), N,N,N-trimethyl-D-erythro-sphingosine (TMS), and D-erythro-sphingosine (SPH). The potency order in the apoptotic response was DMS>or=MMS>TMS>SPH. We compared cellular responses to the derivatives in terms of activities of MAPK signaling molecules, mitochondrial membrane potential (DeltaPsi(m)), and reactive oxygen species (ROS) generation. Our results suggest that the degree of N-methylation affects the apoptosis-inducing capacity and other related responses including MAPK modulation, DeltaPsi(m), and ROS generation. Dimethylation and monomethylation on the C2 amine of sphingosine enhance the apoptotic response; however, trimethylation induces differential modulation of signaling molecules and less cytotoxicity. Our investigation will be useful for understanding the actions of sphingolipids in apoptosis and for developing chemotherapeutics based on DMS structure.


Quantitative comparison of food niches in some freshwater zooplankton : A multi-tracer-cell approach.
The abilities of some zooplankton (rotifers, cladocerans, copepods) to ingest different sizes and kinds of food cells were quantified by determining the relative efficiencies with which they ingested nine tracer-cell types, ranging from a coccoid bacterium (0.45 μm3) to the alga Cryptomonas erosa (800-920 μm3). These efficiencies were obtained by dividing the clearance rate of each zooplankton group (species population, developmental stage or size class of a species population) on each 32P-labeled cell type by that of a simultaneously-offered, 33P-labeled, standard cell type - Chlamydomonas reinhardtii. Similarities of efficiency patterns on these cell types (food niches) between all possible pairs of the 17 zooplankton groups from 4 ecosystems were determined by calculating correlation coefficients. Although the utilization of the tested cell types may vary greatly within a species, three feeding guilds could be distinguished - based primarily on the efficiencies with which the smallest cell types were ingested. Guild I (Poyarthra vulgaris, Keratella crassa, Diaptomus minutus nauplii) ate the smallest cells (<4 μm diameter) (bacterium, Synechococcus, Nannochloris) and Ankistrodesmus very ineffifently but the three Cryptomonas species very efficiently. Guild II (Bosmina longirostris, D. minutus copepodites and Adults) had higher efficiencies on Synechococcus, Nannochloris, Ankistrodesmus, Stichococcus, and Stephanodiscus than guild I but similarly low ones on the bacterium and high ones on the Cryptomonas species. Guild III (Conochilus inicornis, Keratella cochlearis, Ceriodaphnia quadrangula, Diaphanosoma leuchtembergianum) differed from guilds I and II in having uniformly high efficiencies on all the small cells as well ad the larger ones. Principal component analysis of the matrix of correlation coefficients provided objective confirmation of the three guilds and provided a visual representation of the food niches of the 17 zooplankton groups in 3-dimensional space.


Fli1 acts downstream of Etv2 to govern cell survival and vascular homeostasis via positive autoregulation.
Cardiovascular health depends on proper development and integrity of blood vessels. Ets variant 2 (Etv2), a member of the E26 transforming-specific family of transcription factors, is essential to initiate a transcriptional program leading to vascular morphogenesis in early mouse embryos. However, endothelial expression of the Etv2 gene ceases at midgestation; therefore, vascular development past this stage must continue independent of Etv2. To identify molecular mechanisms underlying transcriptional regulation of vascular morphogenesis and homeostasis in the absence of Etv2. Using loss- and gain-of-function strategies and a series of molecular techniques, we identify Friend leukemia integration 1 (Fli1), another E26 transforming-specific family transcription factor, as a downstream target of Etv2. We demonstrate that Etv2 binds to conserved Ets-binding sites within the promoter region of the Fli1 gene and governs Fli1 expression. Importantly, in the absence of Etv2 at midgestation, binding of Etv2 at Ets-binding sites in the Fli1 promoter is replaced by Fli1 protein itself, sustaining expression of Fli1 as well as selective Etv2-regulated endothelial genes to promote endothelial cell survival and vascular integrity. Consistent with this, we report that Fli1 binds to the conserved Ets-binding sites within promoter and enhancer regions of other Etv2-regulated endothelial genes, including Tie2, to control their expression at and beyond midgestation. We have identified a novel positive feed-forward regulatory loop in which Etv2 activates expression of genes involved in vasculogenesis, including Fli1. Once the program is activated in early embryos, Fli1 then takes over to sustain the process in the absence of Etv2.


[Incidence of residual thrombi following successful thrombolytic therapy in acute myocardial infarct and their significance for the rate of early re-occlusion. A report of a multicenter dose-finding study for thrombolytic therapy with urokinase preactivated natural prourokinase (TCL 598)].
Thrombolysis with urokinase preactivated prourokinase was performed in 74 patients. At control angiography, 90 min into thrombolysis, in 39 (52.7%) patients the infarct-related coronary artery was found patent. However, 26 out of the 39 patients (66.7%) with a patent infarct artery demonstrated angiographic signs of residual coronary thrombi. With an estimated average of 75 +/- 25% in both, patients with and without residual thrombus, the severity of the residual stenosis after thrombolysis was found to be independent from the presence of angiographic signs of residual coronary artery thrombosis. In patients with residual coronary thrombi, however, a trend towards poorer coronary perfusion was observed (50% vs 77% of the patients with prompt antegrade [TIMI grade III] perfusion [p less than 0.2]. Control angiography performed 24 to 36h after thrombolysis revealed reocclusion of the infarct artery in 26.3% of the patients with residual coronary thrombi, while none of the infarct vessels without angiographic signs of residual thrombosis had reoccluded (p less than 0.05). At follow-up angiography 17 to 23 days after thrombolysis this difference in the incidence of reocclusions had further increased to 43.8% of patients with vs 12.5% of patients without residual coronary thrombus (p less than 0.01). Thus, after thrombolysis, residual thrombotic material remaining in the infarct related vessel seems to be a major risk factor, indicating early reocclusion of the infarct artery.


A systematic review of multifocal and multicentric glioblastoma.
Multiple glioblastoma multiforme (GBM) is classified as multifocal and multicentric GBM according to whether there is communication between the lesions. Multiple GBM is more genetically heterogeneous, aggressive and resistant to chemoradiotherapy than unifocal GBM, and has a worse prognosis. There is no international consensus on the treatment of multiple GBM. This review discusses some paradigms of multiple GBM and focuses on the heterogeneity spread pathway, imaging diagnosis, pathology, molecular characterization and prognosis of multifocal and multicentric GBM. Several promising therapeutic methods of multiple GBM are also recommended.


Generalized anxiety disorder: neurobiological and pharmacotherapeutic perspectives.
The concept of generalized anxiety has evolved over many years, from initial descriptions of "anxiety neurosis" to recognition of generalized anxiety disorder (GAD) as a clinical entity included in the 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980. Since 1980, the definition of GAD has undergone further change, with modifications in the salience of autonomic and panic like symptoms, duration, and allowance of comorbidity. The importance of these historical considerations lies in the fact that most of our current knowledge about GAD rests on outdated definitions, including most of the literature pertaining to treatment. Indeed, we cannot be sure that the DSM-III definition of GAD bears resemblance to the current concept, and these differences may have profound implications for findings from research. The following two-part report comprises i) a review of the basic neurobiology of GAD, with reference to serotonergic, noradrenergic, neuroendocrine, autonomic imaging, and other systems; and ii) an overview of the current status of pharmacotherapy for GAD.


Codon bias in actin multigene families and effects on the reconstruction of phylogenetic relationships.
Codon usage patterns and phylogenetic relationships in the actin multigene family have been analyzed for three dipteran species--Drosophila melanogaster, Bactrocera dorsalis, and Ceratitis capitata. In certain phylogenetic tree reconstructions, using synonymous distances, some gene relationships are altered due to a homogenization phenomenon. We present evidence to show that this homogenization phenomenon is due to codon usage bias. A survey of the pattern of synonymous codon preferences for 11 actin genes from these three species reveals that five out of the six Drosophila actin genes show high degrees of codon bias as indicated by scaled chi 2 values. In contrast to this, four out of the five actin genes from the other species have low codon bias values. A Monte Carlo contingency test indicates that for those Drosophila actin genes which exhibit codon bias, the patterns of codon usage are different compared to actin genes from the other species. In addition, the genes exhibiting codon bias also appear to have reduced rates of synonymous substitution. The homogenization phenomenon seen in terms of synonymous substitutions is not observed for nonsynonymous changes. Because of this homogenization phenomenon, "trees" constructed based on synonymous substitutions will be affected. These effects can be overt in the case of multigene families, but similar distortions may underlie reconstructions based on single-copy genes which exhibit codon usage bias.


Calves are socially motivated.
Most dairy calves are housed individually in the first weeks and sometimes months of their lives. Lack of social interaction can negatively impact feed intake, social skills, coping abilities, and cognitive performance, but the motivation of calves to seek companionship has seldom been investigated. In this study, 10 Holstein bull calves (Bos taurus; averaging 5.4 ± 2.6 d old upon entering the study) were housed individually in a central home pen with access to one pen on either side, each connected by a push gate. One side pen housed another calf of similar age and the same sex, and the second was otherwise identical in size and resources (feed and water) but without a social companion. Each time the test calf pushed open the gate to access a side pen, he would be left in it until the next feeding (approximately 0800 and 1600 h), at which time he was returned to the central home pen. After each successful pushing event, additional weight was added to the gate (initially a small amount, then incrementally higher). All calves but one pushed for the first time on d 1 of enrollment (within 9.4 ± 14.8 min of experimental start); the remaining calf pushed on d 3 of the test. Each calf was tested for 15 d and we recorded the maximum weight pushed for both side pens. Calves pushed a higher maximum weight (and pushed more frequently) for access to the pen with a social partner compared with the empty pen. We conclude that calves are socially motivated, even at a young age, and that calves can benefit from access to social contact.


The expression of NR2B subunit of NMDA receptor in the suprachiasmatic nucleus of Wistar rats and its role in glutamate-induced CREB and ERK1/2 phosphorylation.
Most behavioral and physiological processes in living organisms exhibit periodic circadian rhythmicity. In mammals, these rhythms are coordinated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In order to precisely synchronize free-running circadian oscillations to the 24h solar cycle, signals from the external environment, primarily the light/dark cycle, must reach the circadian clock within the SCN. A light pulse elevates intracellular Ca(2+) levels, and activates signaling cascades, leading to transcriptional activation of the clock genes mPer1 and mPer2 via phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2) and cyclic AMP-responsive element binding protein (CREB). Glutamate is the primary excitatory transmitter in retinal terminals in the SCN, and NMDA receptors (NMDAR) are the principal glutamate receptors that mediate the effect of light on resetting the circadian clock. Here we show the circadian rhythm in mRNA expression and protein level of the NMDAR 2B subunit (NR2B) in the SCN, with a peak at night. Also, we demonstrate ifenprodil inhibition of glutamate-induced phosphorylation of CREB (pCREB) and ERK1/2 (pERK1/2), and support thus the evidence for NR2B role in activation of signaling cascade involved in photic resetting of the circadian clock.


[Monocional immunoglobulins associated with bacterial endocarditis. Two case reports (author's transl)].
An IgGK monoclonal gammopathy occured in two patients with streptococcus viridans bacterial endocarditis. The gammopathy has been unchanged, respectively for 32 and 21 months following its detection. The alternate physiopathologic hypothesis are argued.


The influence of GABA on discharges of cortical epileptogenic focus.
GABA, when applied locally, acted similarly on both primary and mirror cortical focus: the negative component of the spike discharge was suppressed or inverted in polarity, whereas the late slow negative wave was strongly potentiated. Recordings from deep cortical layers suggested a different origin of these 2 surface-negative components of focal discharges.


[Relationship between the increase of hepatic D-bifunctional protein activity and bile acid biosynthesis in rats].
To determine the physiological role of D-bifunctional protein (DBP) in bile acid biosynthesis through investigating the effect of increasing activity of DBP on bile acid biosynthesis. Twenty male Wistar rats were divided into two groups: diethylhexyl phthalate (DEHP) group (n = 10) and control group (n = 10). Serum triglyceride, total cholesterol, hepatic DBP activity, and fecal bile acids were assayed. The mRNA levels of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha), DBP, and cholesterol 7alpha-hydroxylase (CYP7A1) were detected by RT-PCR. Compared with control group, serum triglyceride level was decreased significantly and PPARalphamRNA level was increased significantly in DEHP group (P < 0.01). Together with a sharp induction of DBP mRNA expression and DBP activity in DEHP group (P < 0.01), the levels of CYP7A1 mRNA and fecal bile acids were significantly increased by 1.9 times and 1.6 times respectively compared to control group (P < 0.01). There was a significantly positive correlation between DBP mRNA level or DBP activity and CYP7A1 mRNA level (r = 0.89, P < 0.01; r = 0.95, P < 0.01). The up-regulation of DBP mRNA and activity in liver can result in the increase in CYP7A1 mRNA expression and bile acid biosynthesis, suggesting that DBP may be involved in bile acid biosynthesis together with CYP7A1.


A study on the antibacterial activity of one-dimensional ZnO nanowire arrays: effects of the orientation and plane surface.
In this study, ZnO nanowire arrays with different orientations were prepared. Confocal laser scanning microscopy (CLSM) and field-emission scanning electron microscope (FE-SEM) technique were employed for understanding the disparities in antibacterial activity between different orientations of ZnO nanoarrays. The effects of the different planes of ZnO nanowire were also discussed for the first time.


Nuclear inclusions in the nerve cells of the sphenopalatine ganglion of the dog.
Large numbers of nuclear inclusions have been found in the nerve cells of the sphenopalatine ganglia of six healthy adult dogs. Their morphological characteristics are similar to those previously described elsewhere. The presence of simple and granular bodies in normal cells seems to support the hypothesis that these nuclear structures might be considered as normal nuclear organelles related to cellular metabolic activity.


COVID-19 and finance: Agendas for future research.
This paper highlights the enormous economic and social impact of COVID-19 with respect to articles that have either prognosticated such a large-scale event, and its economic consequences, or have assessed the impacts of other epidemics and pandemics. A consideration of possible impacts of COVID-19 on financial markets and institutions, either directly or indirectly, is briefly outlined by drawing on a variety of literatures. A consideration of the characteristics of COVID-19, along with what research suggests have been the impacts of other past events that in some ways roughly parallel COVID-19, points toward avenues of future investigation.


Appropriate use of psychotropic drugs in physical illness.
Psychotropic drugs have a useful place as an adjunct to the treatment of patients with certain categories of physical illness, but must never substitute for an integrated and coherent approach to the patient.


A large-scale genome-wide cross-trait analysis for the effect of COVID-19 on female-specific cancers.
Little is known regarding the long-term adverse effects of COVID-19 on female-specific cancers, nor the shared genetic influences underlying these conditions. We performed a comprehensive genome-wide cross-trait analysis to investigate the shared genetic architecture between COVID-19 (infection, hospitalization, and critical illness) with three female-specific cancers (breast cancer (BC), epithelial ovarian cancer (EOC), and endometrial cancer (EC)). We identified significant genome-wide genetic correlations with EC for both hospitalization (rg = 0.19, p = 0.01) and critical illness (rg = 0.29, p = 3.00 × 10-4). Mendelian randomization demonstrated no valid association of COVID-19 with any cancer of interest, except for suggestive associations of genetically predicted hospitalization (ORIVW = 1.09, p = 0.04) and critical illness (ORIVW = 1.06, p = 0.04) with EC risk, none withstanding multiple correction. Cross-trait meta-analysis identified 20 SNPs shared between COVID-19 with BC, 15 with EOC, and 5 with EC; and transcriptome-wide association studies revealed multiple shared genes. Findings support intrinsic links underlying these complex traits, highlighting shared mechanisms rather than causal associations.


Surface decoration of development-inspired synthetic N-cadherin motif via Ac-BP promotes osseointegration of metal implants.
Research works on the synergistic effect of surface modified bioactive molecules and bone metal implants have been highlighted. N-cadherin is regarded as a key factor in directing cell-cell interactions during the mesenchymal condensation preceding the osteogenesis in the musculoskeletal system. In this study, the N-cadherin mimetic peptide (Cad) was biofunctionalized on the titanium metal surface via the acryloyl bisphosphonate (Ac-BP). To learn the synergistic effect of N-cadherin mimetic peptide, when tethered with titanium substrates, on promoting osteogenic differentiation of the seeded human mesenchymal stem cells (hMSCs) and the osseointegration at the bone-implant interfaces. Results show that the conjugation of N-cadherin mimetic peptide with Ac-BP promoted the osteogenic gene markers expression in the hMSCs. The biofunctionalized biomaterial surfaces promote the expression of the Wnt/β-catenin downstream axis in the attached hMSCs, and then enhance the in-situ bone formation and osseointegration at the bone-implant interfaces. We conclude that this N-cadherin mimetic peptide tethered on Ti surface promote osteogenic differentiation of hMSCs and osseointegration of biomaterial implants in vitro and in vivo. These findings demonstrate the importance of the development-inspired surface bioactivation of metal implants and shed light on the possible cellular mechanisms of the enhanced osseointegration.


Cross-modal performance in patients with cerebral lesions.
52 patients with circumscribed cerebral lesions, and 35 control patients (lesions in the posterior fossa or in the spinal cord), were assessed for their ability to match spatial configurations: matching was either cross-modal (visual-tactual or tactual-visual). or within-modal (visual-visual or tactual-tactual). They were also tested for cross-modal transfer (visual-tactual or tactual-visual). All materials were "easy" or "hard". Associated defects (e.g. dysphasia, apraxia) were also assessed. It was found that neither site of lesion, nor laterality of lesion, nor presence of any associated defect was significantly and selectively associated with impairment of cross-modal performance.


Polysaccharides from seeds of Strychnos species.
The chemical composition of polysaccharide fractions from Strychnos nux-vomica and S. innocua seeds and comparison with those from S. potatorum seeds are reported. The structural features of the galactomannans from the three Strychnos species are also discussed.


Fabrication, characterizations and performance of a high-efficiency micro-electrolysis filler for isobutyl xanthate (IBX) degradation.
Micro-electrolysis is a cost-effective method widely applied in wastewater treatment. In this paper, a high-efficiency micro-electrolysis filler was prepared by a facile calcination method for the degradation of isobutyl xanthate (IBX). The optimization of filler fabrication process was investigated from aspects of compressive strength, abrasion loss and degradation rate. Combined with multi-characterization techniques, it can be found that the zero-valent iron (ZVI) was partially changed to Fe(2+) in the phase of fayalite (Fe2SiO4) during the treatment. The influence of operation parameters of filler dosage, initial pH and initial concentration were thoroughly studied. The result shows that the IBX degradation rate by optimized filler can reach 93.30%, superior to that of Fe/C filler (the element Fe kept at ZVI during heat treatment) with 61.8% removal. The degradation pathway of IBX was studied by GC-MS in details and the bis(2-methylpropyl)carbonate was postulated as the main by-product. The stability of filler was evaluated by batch cycle tests and column tests. This work provides a novel perspective about micro-electrolysis filler preparation. The extraordinary performance brings it potential for industrial application.


Magneto-mechanical stimulation modulates osteocyte fate via the ECM-integrin-CSK axis and wnt pathway.
Osteocytes are the mechano-sensors of bones. Large gradient high-static magnetic fields (LG-HMFs) produce stable, high-precision, and non-attenuation mechanical forces. We discovered that magnetic forces opposite to gravity inhibited MLO-Y4 osteocyte proliferation and viability by inducing structural damage and apoptosis. In contrast, magnetic force loading in the same direction as that of gravity promoted the proliferation and inhibited apoptosis of MLO-Y4 osteocytes. Differentially expressed gene (DEG) analysis after magnetic force stimulation indicated that the ECM-integrin-CSK axis responded most significantly to mechanical signals. Wisp2 was the most significant DEG between the 12 T upward and downward groups, showing the highest correlation with the Wnt pathway according to the STRING protein interaction database. Explaining the cellular and molecular mechanisms by which mechanical stimuli influence bone remodeling is currently the focus of osteocyte-related research. Our findings provide insights into the effects of LG-HMFs on bone cells, which have further implications in clinical practice.


IRBIT activates NBCe1-B by releasing the auto-inhibition module from the transmembrane domain.
The electrogenic Na+ /HCO3- cotransporter NBCe1-B is widely expressed in many tissues, including pancreas, submandibular gland, brain, heart, etc. NBCe1-B has very low activity under basal condition due to auto-inhibition, but can be fully activated by protein interaction with the IP3R-binding protein released with inositol 1,4,5-trisphosphate (IRBIT). The structural components of the auto-inhibition domain and the IRBIT-binding domain of NBCe1-B are finely characterized based on systematic mutations in the present study and data from previous studies. Reducing negative charges on the cytosol side of the transmembrane domain greatly decreases the magnitude of the auto-inhibition of NBCe1-B. We propose that the auto-inhibition domain functions as a brake module that inactivates NBCe1-B by binding to, via electrostatic attraction, the transmembrane domain; IRBIT activates NBCe1-B by releasing the brake from the transmembrane domain via competitive binding to the auto-inhibition domain. The electrogenic Na+ /HCO3- cotransporter NBCe1-B is widely expressed in many tissues in the body. NBCe1-B exhibits only basal activity due to the action of the auto-inhibition domain (AID) in its unique amino-terminus. However, NBCe1-B can be activated by interaction with the IP3R-binding protein released with inositol 1,4,5-trisphosphate (IRBIT). Here, we investigate the molecular mechanism underlying the auto-inhibition of NBCe1-B and its activation by IRBIT. The IRBIT-binding domain (IBD) of NBCe1-B spans residues 1-52, essentially consisting of two arms, one negatively charged (residues 1-24) and the other positively charged (residues 40-52). The AID mainly spans residues 40-85, overlapping with the IBD in the positively charged arm. The magnitude of auto-inhibition of NBCe1-B is greatly decreased by manipulating the positively charged residues in the AID or by replacing a set of negatively charged residues with neutral ones in the transmembrane domain. The interaction between IRBIT and NBCe1-B is abolished by mutating a set of negatively charged Asp/Glu residues (to Asn/Gln) plus a set of Ser/Thr residues (to Ala) in the PEST domain of IRBIT. However, this interaction is not affected by replacing the same set of Ser/Thr residues in the PEST domain with Asp. We propose that: (1) the AID, acting as a brake, binds to the transmembrane domain via electrostatic interaction to slow down NBCe1-B; (2) IRBIT activates NBCe1-B by releasing the brake from the transmembrane domain.


Reviewing 39Ar and 37Ar underground production in shallow depths with implications for groundwater dating.
Argon-37 (37Ar) and Argon-39 (39Ar) are used for groundwater dating on timescales from weeks to centuries. For both isotopes, the quantification of underground sources is essential to accurately infer water residence times from sampled dissolved activities. Subsurface production resulting from interactions with neutrons from the natural radioactivity in rocks and with primary cosmogenic neutrons has been known for a long time. More recently, the capture of slow negative muons and reactions with muon-induced neutrons were documented for 39Ar subsurface production in the context of underground particle detectors (e.g. for Dark Matter research). However, the contribution from these particles was never considered for groundwater dating applications. Here, we reevaluate the importance of all potential depth-related production channels at depth ranges relevant for 39Ar groundwater dating [0 - 200 meters below the surface (m.b.s)]. The production of radioargon by muon-induced processes is considered in this depth range for the first time. The uncertainty on the total depth-dependent production rate is estimated with Monte Carlo simulations assuming a uniform distribution of the parameter uncertainties. This work aims to provide a comprehensive framework for interpreting 39Ar activities in terms of groundwater residence times and for exposure age dating of rocks. The production of 37Ar is also addressed since this isotope is relevant as a proxy for 39Ar production, for the timing of river-groundwater exchanges, and in the context of on-site inspections (OSI) within the verification framework of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). In this perspective, we provide an interactive web-based application for the calculation of 37Ar and 39Ar production rates in rocks.


Injection Molding and its application to drug delivery.
Injection Molding (IM) consists in the injection, under high pressure conditions, of heat-induced softened materials into a mold cavity where they are shaped. The advantages the technique may offer in the development of drug products concern both production costs (no need for water or other solvents, continuous manufacturing, scalability, patentability) and technological/biopharmaceutical characteristics of the molded items (versatility of the design and composition, possibility of obtaining solid molecular dispersions/solutions of the active ingredient). In this article, process steps and formulation aspects relevant to IM are discussed, with emphasis on the issues and advantages connected with the transfer of this technique from the plastics industry to the production of conventional and controlled-release dosage forms. Moreover, its pharmaceutical applications thus far proposed in the primary literature, intended as either alternative manufacturing strategies for existing products or innovative systems with improved design and performance characteristics, are critically reviewed.


Retraction Note to: Direct renin inhibition: clinical pharmacology.
Retraction to: J Mol Med 86(6): 647-54DOI 10.1007/s00109-008-0329-z. The Editors of the Journal of Molecular Medicine in agreement with the author and the publisher hereby retract this article. The article is retracted due to copyright issues that cannot be resolved.


The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Role of antiseizure prophylaxis following head injury.
The majority of studies do not support the use of the prophylactic anticonvulsants studied thus far for the prevention of late PTS. Routine seizure prophylaxis later than 1 week following head injury is, therefore, not recommended. If late PTS occur, patients should be managed in accordance with standard approaches to patients with new onset seizures. Phenytoin and carbamazepine have been shown to reduce the incidence of early PTS. Valproate may also have a comparable effect to phenytoin on reducing early PTS but may also be associated with a higher mortality. It is, therefore, an option to use phenytoin or carbamazepine to prevent the occurrence of seizures in high-risk patients during the first week following head injury.


Donor-derived CD19 chimeric antigen receptor T cells.
As immunotherapy matures into possible front-line therapy, new approaches are necessary to expand the capacity to treat more patients. Although most technologies for chimeric antigen receptor (CAR) therapies require autologous T cells, 'off the shelf' sources are highly desired. Sources of T cells for modification with CARs include cord blood and either related or unrelated allogeneic donors. Strategies to manipulate these sources focus on reducing the risk of alloreactivity, while maintaining the potential for high function and long persistence associated with successful CAR T-cell therapies. Recent research implies that manipulating nonautologous T-cell sources can result in well tolerated and effective products, but work remains to determine if these approaches will reach the efficacy of autologous products.


Macular OCT Characteristics at 36 Weeks' Postmenstrual Age in Infants Examined for Retinopathy of Prematurity.
To report our ability to capture,-grade reliably, and analyze bedside macular OCT images from preterm infants and relate OCT findings to biological factors and retinopathy of prematurity (ROP) status at a single time window in the Study of Eye Imaging in Preterm Infants (BabySTEPS). Prospective, observational study. Preterm infants eligible for ROP screening with parental consent for research and a 36 ± 1 weeks' postmenstrual age (PMA) visit. We imaged both eyes of preterm infants with an investigational noncontact, handheld swept-source (SS) OCT at the time of clinical ROP examinations. Macular OCT features and layer thicknesses for untreated eyes of infants at 36 ± 1 weeks' PMA were compared with demographic data and clinical ROP examination performed by experts. Statistical analyses accounted for the use of both eyes of infants. Macular OCT features and layer thicknesses, gender, race or ethnicity, gestational age, birth weight, ROP stage, and plus disease. We captured macular OCT from 169 eyes (1 eye excluded because of prior ROP treatment) at 36 ± 1 weeks' PMA. The quality of OCT volumes was excellent in 33 eyes (19%), acceptable in 112 eyes (67%), poor in 24 eyes (14%), and unusable in 0 eyes (0%). Macular edema was present in 60% of eyes and was bilateral in 82% of infants with edema. At the fovea, retinal and inner nuclear layer thickness increased with edema severity: 183 ± 36 μm and 51 ± 27 μm in mild (16% of eyes), 308 ± 57 μm and 163 ± 53 μm in moderate (25%), and 460 ± 76 μm and 280 ± 83 μm in severe edema (12%), respectively. With an increase in ROP stage from 0 to 2, the mean ± standard deviation retinal thickness at the fovea increased from 227± 124 μm to 297 ± 99 μm (P < 0.001). The choroid was thinner, 155 ± 72 μm, with preplus or plus disease versus without, 236 ± 79 μm (P = 0.04), whereas retinal thickness did not vary. We demonstrated the reliability of methods and the prevalence of OCT findings in preterm infants enrolled in BabySTEPS at a single time point of 36 ± 1 weeks' PMA. Variations in layer thicknesses in infants at this time point may reflect abnormalities resulting from delay in foveal development that may be impacted by macular edema, ROP, or both.


Childhood exposure to polybrominated diphenyl ethers and neurodevelopment at six years of age.
Mixtures of polybrominated diphenyl ethers (PBDEs) are present in indoor environments. Studies of the developmental effects of exposure to these chemicals in large prospective mother-child cohorts are required, with data on prenatal exposure and long-term follow-up of the children. We aimed to investigate the relationship between prenatal and childhood exposure to PBDEs and neurodevelopment at the age of six years. We determined the levels of PBDEs and other neurotoxicants in cord blood and dust collected from the homes of children for 246 families included in the PELAGIE mother-child cohort in France. We assessed two cognitive domains of the six-year-old children using the Wechsler Intelligence Scale for Children-IV. Verbal comprehension scores were lower in children from homes with higher concentrations of BDE99 (βDetects<median_vs_NonDetects=-1.6; 95% CI: -6.1, 2.9; βDetects≥median_vs_NonDetects=-5.4; -9.9, -1.0; p trend=0.02) and of BDE209 (β2nd_vs_1st_tertile=-1.8; 95% CI: -6.1, 2.5; β3rd_vs_1st_tertile=-3.2; -7.5, 1.2; p trend=0.15) in dust, particularly for boys (p trend=0.02 and 0.04, respectively). Working memory scores seemed to be lower in children with higher BDE99 concentrations in dust (p trend=0.10). No association was observed with cord blood levels of BDE209. Our findings are in agreement with those of four previous studies suggesting adverse cognitive outcomes among children associated with early-life exposure to penta-BDE mixtures, and provide new evidence for the potential neurotoxicity of BDE209. Several countries are in the process of banning the use of PBDE mixtures as flame-retardants. However, these compounds are likely to remain present in the environment for a long time to come.


Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2.
Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members, the exact mechanism for the peripheral localization of APC remains unclear. Here we show that the heavy chain of kinesin-1 directly interacts with the APC C-terminus, contributing to the peripheral localisation of APC in fibroblasts. In rat hippocampal neurons the kinesin-1 binding domain of APC is required for its axon tip enrichment. Moreover, we demonstrate that APC requires interactions with both kinesin-2 and kinesin-1 for this localisation. Underlining the importance of the kinesin-1 association, neurons expressing APC lacking kinesin-1-binding domain have shorter axons. The identification of this novel kinesin-1-APC interaction highlights the complexity and significance of APC localisation in neurons.


The influence of subcutaneously administered lead(II) acetate on the concentrations of copper, iron, and zinc in the blood, kidney, liver, and spleen of rats.
The concentrations of copper, iron, lead, and zinc in the blood, kidney, liver and spleen were determined before and after subcutaneous administration of lead(II) acetate (100 mg Pb kg-1 body weight) to male albino Wistar rats. The control rats had the following concentrations (microgram g-1 dry weight) of Cu, Fe, Pb and Zn: blood, 4.5, 3200, 2.1, 182; kidney, 36, 585, 120, 92; liver, 11.1, 720, 14.3, 124; spleen, 4.5, 420, 7.0, 76. After administration of lead, rats were sacrificed after 12, 24, 48, 72 and 96 h. The Pb concentration in the blood remained constant for the first 24 h at the level of the control group (2.1 micrograms g-1) and had decreased to half that level at 96 h. The lead concentrations peaked in the organs at 110-142% of those in the control group and had decreased at 96 h to levels considerably below those in the control group. The concentrations of Cu, Fe and Zn increased in the three organs to values 117-161% found for the control group. At 96 h the concentrations of Cu, Fe and Zn in the spleen had returned to levels of the control group; the concentrations in the liver were 112-153%, and in the blood 89-93% of those of the control group. In the kidney the iron (110%) and the zinc (126%) concentrations at 96 h were higher than the control values, whereas the copper concentration was the same as the control value. The concentrations in the blood were least affected. The most drastic changes were observed in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)


Docosahexaenoic acid promotes M2 microglia phenotype via activating PPARγ-mediated ERK/AKT pathway against cerebral ischemia-reperfusion injury.
In ischemia-reperfusion stroke, microglia play a dual role in brain injury as well as brain repair, and promoting their switch from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype is considered to be a potential therapeutic strategy. Docosahexaenoic acid (DHA) is an essential long-chain omega-3 polyunsaturated fatty acid that exhibits potent anti-inflammatory properties in the acute phase of ischemic stroke, but its effect on microglia polarization is unknown. Thus, the objective of this study was to investigate the neuroprotective effects of DHA on rat brain following ischemia-reperfusion injury, and to investigate the mechanism by which DHA regulates microglia polarization. We administered DHA 5 mg/kg intraperitoneally daily for 3 d following a transient middle cerebral artery occlusion reperfusion model in rats. The protective effects of DHA on cerebral ischemia-reperfusion injury were detected by TTC staining, HE staining, Nissler staining, and TUNEL staining. Quantitative real-time PCR, immunofluorescence, western blot, and enzyme-linked immunosorbent assay were used to detect the expression of M1 and M2 microglia-associated markers and PPARγ-mediated ERK/AKT signaling pathway proteins. We found that DHA significantly improved brain injury by decreasing the expression of the M1 phenotypic marker (iNOS, CD16) and increasing the expression of the M2 phenotypic marker (Arg-1, CD206). DHA also increased the expression of peroxisome proliferator-activated receptor gamma (PPARγ) mRNA and protein, increased the expression of the pathway protein AKT, and decreased the expression of ERK1/2. In addition, DHA promoted the expression of anti-inflammatory factor IL-10 and decreased the expression of pro-inflammatory factors TNF-α and IL-1β. However, the PPARγ antagonist GW9662 greatly blocked these beneficial effects. These results suggest that DHA may activate PPARγ to inhibit ERK and activate AKT signaling pathways to regulate microglia polarization, thereby reducing neuroinflammation and promoting neurological recovery to alleviate cerebral ischemia-reperfusion injury.


Molecular phylogeny of selected dorid nudibranchs based on complete mitochondrial genome.
Dorid nudibranchs are a large group of mollusks with approximately 2,000 recorded species. Although agreement exists on the monophyletic nature of the dorid nudibranch group, the interfamily relationships of the suborder are subject to debate. Despite efforts to elucidate this issue using short molecular markers, the conclusiveness of the findings has been hindered by branching polytomy. Mitogenomes are known to be effective markers for use in phylogenetic investigations. In this study, eight mitogenomes of dorid nudibranchs were decoded and analyzed. Gene content and structure showed little change among species, reflecting the conserved mitogenomes of dorid nudibranchs. For most genes, the direction was typical for nudibranchs; nevertheless, tRNACys had an inverse direction in Cadlinidae species. Phylogenetic trees based on nucleotide and amino acid datasets revealed a relatively consistent pattern of interfamily relationships with little difference for positions of Phyllidiidae and Cadlinidae. Species of Cadlinidae were clustered together and did not form a clade with Chromododidae. Additionally, Goniodorididae was sister to Aegiridae, whereas Discodoridae was sister to Dorididae. This finding was supported by tree topology test based on mitogenome data. The results of the present study indicate that complete mitogenomes are promising markers for investigating interfamily relationships among dorid nudibranchs.


A Cu(I)-catalyzed C-H alpha-amination of esters. Direct synthesis of hydantoins.
This paper describes a novel intermolecular alpha-amination process of esters using CuCl as catalyst and di-tert-butyldiaziridinone as nitrogen source. A variety of hydantoins can be formed effectively under mild reaction conditions.


A microfluidic approach for early prediction of thrombosis in patients with cancer.
Li and colleagues have made a notable advancement in predicting cancer-associated thrombosis with a microfluidic device that monitors circulating platelet activity.1 This tool could improve the management of thrombotic events in patients with cancer, guiding timely treatment and potentially reducing mortality.


[Severe bacterial infection: increased mortality in elderly women with low body weight taking drugs prolonging the QTc interval].
Women have a higher risk of acquired long QT syndrome which could be of vital importance in severe bacterial infections when macrolides or fluoroquinolones are administered. This study evaluated whether age, drugs prolonging the QTc interval and body weight were additional influencing factors on mortality in the critically ill with respect to gender. In an exploratory investigation 204 intensive care unit (ICU) patients (78 f, 126 m, 61.1±16.1 years) with severe bacterial infections were studied (mortality probability model II(0) 49.1±28%). Antibiotic therapy was carried out following standard guidelines. In 65.2% of patients potentially QTc prolonging drugs were administered for ≥48 h. Body weight was ascertained on ICU admission. By comparable severity of illness and comparable effect of antibiotic therapy, age, QTc prolonging drugs and less body weight showed significant effects on survival in women (p<0.001, 0.008 and 0.009, respectively). For women mortality increased with age ≥60 years (p=0.01). The division between survival versus non-survival was intensified by addition of QTc prolonging medication and body weight. As such a best risk assessment in women was achieved if age, QTc prolonging therapy and less body weight were combined (p<0.001). In a direct comparison to men, women with at least two of these factors had a significantly poorer outcome (OR 2.37; 95% CI 1.13-4.98; p=0.022). Age, QTc prolonging drugs and lower body weight can additionally increase mortality in critically ill women. If negative outcome is attributed to a higher dosage, an adjustment for body weight must be carried out. Until now it should be considered whether it would be better to replace QTc prolonging antibiotics in routinely performed drug alternation in elderly lean women.


Control and perception of balance at elevated and sloped surfaces.
Understanding roof-work-related risk of falls and developing low-cost, practical engineering controls for reducing this risk remain in high demand in the construction industry. This study investigated the effects of the roof work environment characteristics of surface slope, height, and visual reference on standing balance in construction workers. The 24 participants were tested in a laboratory setting at 4 slopes (0 degrees, 18 degrees, 26 degrees, and 34 degrees), 2 heights (0, 3 m), and 2 visual conditions (with and without visual references). Postural sway characteristics were calculated using center of pressure recordings from a force platform. Workers' perceptions of postural sway and instability were also evaluated. The results indicated that slope and height synergistically increased workers' standing postural instability. Workers recognized the individual destabilizing effects of slope and height but did not recognize the synergistic effect of the two. Visual references significantly reduced the destabilizing effects of height and slope. Actual and potential applications of this research include the use of temporary level work surfaces and proximal vertical reference structures as postural instability control measures during roofing work.


Molecular consequences of specific intron mutations on yeast mRNA splicing in vivo and in vitro.
We have altered the TACTAAC sequence in the yeast CYH2m gene intron to TACTACC. This mutation changes the nucleotide at the normal position of the branch in intron RNA lariats produced during pre-mRNA splicing, and it prevents splicing in vivo. In a yeast pre-mRNA splicing system, CYH2m pre-mRNA carrying the TACTACC mutation is not specifically cut or rearranged in any way. Substitution of an A for the first G of the CYH2m intron, converting the highly conserved GTATGT 5' splice site sequence to ATATGT, also blocks intron excision in vivo and in vitro: pre-mRNA carrying this mutation was still cut normally at the mutant 5' splice site in vitro, to give authentic exon 1 and an intron-exon 2 lariat RNA with an A-A 2'-5' phosphodiester linkage at the branch point. This lariat RNA is a dead-end product. The subsequent cleavage at the 3' splice site is therefore sensitive to the sequence of the 5' end of the intron attached at the branch point.


Evoked potential abnormalities in myotonic dystrophy.
Past investigators have reported evidence of central nervous system involvement in myotonic dystrophy (MYD), including EEG abnormalities, ventricular enlargement, thalamic inclusion bodies, and impaired tests of cognitive function. Brain stem auditory evoked potentials have not been reported in myotonic dystrophy. We report the results of brain stem auditory (BAEP) and median nerve somatosensory (MSSEP) evoked potentials in 15 patients with MYD (9 males, 6 females, mean age = 35.8 +/- 11.4 years). BAEPs were abnormal in 53.3% (P less than 0.05). Four patients had abnormal wave I-III interwave latencies, 3 had abnormal wave III-V latencies, and 1 patient had both wave I-III and wave III-V latencies prolonged. MSSEPs were abnormal in 13.3% (P N.S.). Both patients showed a delay of the P15-N19 thalamic complex. Both patients had a normal clinical sensory examination and normal peripheral nerve conduction. No correlation was found between abnormal evoked potentials and patient age. A sex difference, however, was noted with 8/9 males having one or more abnormal evoked potentials compared with 0/6 females. Though our finding of abnormal MSSEPs was not statistically significant, both patients showed delay at the thalamic level, where pathology has been described. Abnormal ocular pursuit and sluggish pupillary reaction have implicated brain stem involvement in MYD. The abnormal BAEPs at the level of the pons and midbrain in this study provide neurophysiological evidence of brain stem pathology in MYD.


Square wave voltammetric study of interaction between 9-acridinyl amino acid derivatives and DNA.
Electrochemical oxidation of newly synthesized acridine derivatives (ADs): PG, PA, EG and EA was studied using square wave voltammetry at a glassy carbon electrode. Oxidation occurs as an irreversible process for all ADs. The ADs interaction with DNA was investigated using multi-layer DNA electrochemical biosensor. The shift of dA peak in positive direction indicated that the type of interaction is most likely an intercalation. PG showed the widest range of concentration capable to interact with DNA (1 × 10-7 M - 2.5 × 10-4 M). Analysing logIcomplexIDNA-IcomplexvslogcAD plots, the binding constants were determined. For the lowest PG concentrations, obtained K value close to 106 M-1 refers to strong binding. The values of K for PA may be classified as medium strength, while EG and EA showed low K values. Our results unequivocally showed that the characteristics of association complexes may vary depending on the concentration of the interacting substance. The negative ΔG value for all ADs, (- 21 to - 34 kJ mol-1), confirms the process spontaneity. The best result, indicating the most stable formed complex with DNA adsorbed at the electrode surface, showed PG when present in low concentration, order of 10-7 M. The intercalation of ADs into DNA was supported by molecular docking analysis.


Optical coherence tomography angiography for identifying choroidal neovascular membranes: a masked study in clinical practice.
Optical coherence tomography angiography (OCT-A) allows non-invasive imaging of chorio-retinal vasculature, and is a potential alternative to fluorescein angiography (FA). Sensitivity and specificity of OCT-A for detecting choroidal neovascularisation (CNV) in treatment-naïve neovascular age-related macular degeneration (nAMD) patients is examined, using the Heidelberg Spectralis in a 'real world' setting. Overall, 43 eyes from 26 patients were included in the study. Spectral domain OCT (SD-OCT), OCT-A and FA images were obtained at baseline. Each of the three retinal image modalities was systematically assessed by three masked clinicians. Decisions about the presence/absence of CNV were recorded using an automated segmentation for OCT-A, a manual method, and using both OCT-A and SD-OCT in conjunction. Additional information about the presence of sub-retinal hyper-reflective material (SHRM) and the 'double layer sign' (DLS) were recorded. The average sensitivity and specificity of the OCT-A for the detection of CNV in treatment naïve AMD was 89% and 87% for the combined SD-OCT and OCT-A, 76% and 91% for the automated segmentation and 84% and 85% for the manual segmentation, respectively. Inter-clinician agreement was 0.59-65 kappa. In patients without CNV, SHRM was present in only 6% while DLS was present in 28%. Sensitivity and specificity was >78% for both SHRM and DLS. OCT-A provides a reliable tool for detecting CNV in treatment naïve nAMD patients, with high sensitivity and specificity. Combined use of SD-OCT images and SHRM as an additional bio-marker, OCT-A could become an alternative to FA in routine clinical practice.


The encircling Silastic 3 mm band without cautery in retinal detachment surgery.
Retinal detachment with tears can be cured by scleral buckling by synthetic material pressure retino-choroidopathy without cautery (diathermy, cryo- or photocoagulation) to tear edges on conditions: (1) To use the encircling Silastic 3-mm band (equatorial or oblique according to tear site) giving a permanent buckle. The segmental buckle may recede reopening the tear and its retino-choroidopathy effect may not be sufficient to seal the tear. (2) Not to evacuate the subretinal fluid leaving the ocular tension at end of operation a bit high [about 25 mm Hg in the first operation and 5 mm Hg (Schøtz) in the recent reoperation above the preoperative level]. The synthetic material pressure retino-choroidopathy seals the tear and lowers the ocular tension in subsequent days with beter buckling. (3) As these conditions may not be attained, it is wiser to use minimal diathermy or cryo-therapy to seal the tear.


Shifts in microbial community structure of granular and liquid biomass in response to changes to infeed and digester design in anaerobic digesters receiving food-processing wastes.
There have been few studies, to date, examining the effect of seed sludge on the microbial community established in a new anaerobic digestion (AD) system and whether or not the population present in the seed sludge establishes it self as the predominant population. Further, no reported studies have yet examined the differences in microbial populations that result from the formation of granular biomass in upflow anaerobic sludge blanket (UASB) systems. This study focused on examining the changes in microbial diversity between the initial seed sludge and the community that becomes established in a new digester. Using 16S rRNA clone libraries the diversity of microbes in both the granular and liquid biomass fractions from 3 AD sludge samples was examined and compared. Results showed that each sample had unique microbial community, with the distribution of sequences at the phylum level highly variable. This suggests that the feedstock had an effect of enriching microbial populations that are uniquely suited to a particular feedstock. Differences between the granular and liquid biomass fractions of each sample were less pronounced than differences attributable to the change in feedstock, however the results suggest that there are different functional groups in each fraction.


HIWDNet: A hybrid image-wavelet domain network for fast magnetic resonance image reconstruction.
The application of Magnetic Resonance Imaging (MRI) is limited due to the long acquisition time of k-space signals. Recently, many deep learning-based MR image reconstruction methods have been proposed to reduce acquisition time and improve MRI image quality by reconstructing images from under-sampled k-space data. However, these methods suffer from two shortcomings. Firstly, the reconstruction network are mainly designed in the image domain or frequency domain, while ignoring the characteristics of time-frequency features in the wavelet domain. In addition, the existing cross-domain methods design the same reconstruction network in different transform domains, so that the network cannot learn targeted information for different domains. To solve the above problems, we propose a Hybrid Image-Wavelet Domain Reconstruction Network (HIWDNet) for fast MRI reconstruction. Specifically, we employ Cross-scale Dense Feature Fusion Module (CDFFM) in the image domain to reconstruct the basic structure of MR images, while introducing Region Adaptive Artifact Removal Module (RAARM) to remove aliasing artifacts in large areas. Then, a Wavelet Sub-band Reconstruction Module (WSRM) is proposed to refine wavelet sub-bands to improve the accuracy of HIWDNet. The proposed method is evaluated in different sampling modes on the fastMRI dataset, the CC359 dataset and the IXI dataset. Extensive experimental results show that HIWDNet achieves better results on both SSIM and PSNR evaluation metrics compared with other methods.


TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum.
Neurotrophins are essential to the normal development and maintenance of the nervous system. Neurotrophin signaling is mediated by Trk family tyrosine kinases such as TrkA, TrkB and TrkC, as well as by the pan-neurotrophin receptor p75NTR. Here we have deleted the trkB gene in cerebellar precursors by Wnt1-driven Cre--mediated recombination to study the function of the TrkB in the cerebellum. Despite the absence of TrkB, the mature cerebellum of mutant mice appears similar to that of wild type, with all types of cell present in normal numbers and positions. Granule and Purkinje cell dendrites appear normal and the former have typical numbers of excitatory synapses. By contrast, inhibitory interneurons are strongly affected: although present in normal numbers, they express reduced amounts of GABAergic markers and develop reduced numbers of GABAergic boutons and synaptic specializations. Thus, TrkB is essential to the development of GABAergic neurons and regulates synapse formation in addition to its role in the development of axon terminals.


Synergistic Development of Biochips and Cell Preservation Methodologies: A Tale of Converging Technologies.
Over the past several decades, cryopreservation has been widely used to preserve cells during long term storage, but advances in stem cell therapies, regenerative medicine, and miniaturized cell-based diagnostics and sensors are providing new targets of opportunity for advancing preservation methodologies. The advent of microfluidics-based devices is an interesting case in which the technology has been used to improve preservation processing, but as the devices have evolved to also include cells, tissues, and simulated organs as part of the architecture, the biochip itself is a desirable target for preservation. In this review, we will focus on the synergistic co-development of preservation methods and biochip technologies, while identifying where the challenges and opportunities lie in developing methods to place on-chip biologics on the shelf, ready for use. Emerging studies are demonstrating that the cost of some biochips have been reduced to the extent that they will have high utility in point-of-care settings, especially in low resource environments where diagnostic capabilities are limited. Ice-free low temperature vitrification and anhydrous vitrification technologies will likely emerge as the preferred strategy for long-term preservation of bio-chips. The development of preservation methodologies for partially or fully assembled biochips would enable the widespread distribution of these technologies and enhance their application.


Overview of authorized drug products for subcutaneous administration: Pharmaceutical, therapeutic, and physicochemical properties.
There is a growing body of research about subcutaneously administered biologics, emphasizing the need for optimized bioavailability predictions. It is important to inform both translational and in silico models with properties of the drug products and compounds. However, the pharmaceutical, therapeutic and physicochemical properties of market authorized drug products for subcutaneous administration are currently not collated in the public domain. We provide an overview of subcutaneous administered drug products for humans and animals market authorized in EU, Canada, and the US. Data on the drug products were collected from the respective authorities, i.e. European Medicines Agency, Health Canada, and U.S. Food and Drug Administration. Physicochemical properties of active substances were gathered from DrugBank. Human drug products were often indicated for treatment of diabetes and anemia. EU veterinary drug products were often immunologicals. Canadian and US veterinary drug products often acted as antiinfectives for systemic use, on the genito-urinary system or as sex hormones. The final dataset with >1700 subcutaneous drug products is provided. In EU drug products, the majority of active substances were biologics. In the US, drug products most often contained small molecules. Solutions, emulsions and suspensions were the most common dosage forms. A minority of subcutaneous drug products were also registered for intramuscular or intravenous administration. The analysis presented here could aid further research, exploring formulation properties, prescription or sales of market authorized SC drug products and development of inclusive in silico models.


Treatment of age-related macular degeneration after cataract surgery: a study from the Swedish National Cataract and Macula Registers.
To characterize pre- and perioperative factors associated with treatment for wet age-related macular degeneration (wet AMD) after cataract surgery. This register-based cohort study with data from the Swedish National Cataract Register (NCR) and the Swedish Macula Register (SMR) from 2010 to 2017 compared eyes with and without preoperative AMD that had undergone cataract surgery and was subsequently treated for wet AMD to eyes not treated within the study period. All first-eye surgeries registered in the NCR from 2010 to 2017 and matching eyes found in the SMR that had undergone treatment for wet AMD ≥ 1 year after the cataract procedure were included. Data for cataract surgery date, age and gender, use of a blue-blocking IOL, preoperative visual acuity, ocular comorbidities, posterior capsule rupture and date of AMD treatment initiation were extracted. The only independent factor associated with postoperative treatment of wet AMD in both groups was female gender (67.3% vs. 58.8%, p < 0.001 and 66.4% vs. 60.6%, p = 0.001, respectively). Older age was an independent factor in eyes without preoperative AMD (78.4 ± 6.5 vs. 73.4 ± 9.6 years, p < 0.001). A blue-blocking IOL appeared to decrease the likelihood of subsequent wet AMD treatment slightly but not statistically significant in eyes with preoperative AMD (52.7% vs. 56.8%, p = 0.110). Some factors (female gender, high age) are associated with undergoing subsequent treatment for wet AMD to a higher extent. If the use of a blue-blocking IOL offers any protection from undergoing AMD treatment after cataract surgery, such an effect must be very small.


Aortic Coarctation Diagnosed During Pregnancy in a Woman With Repaired Tetralogy of Fallot.
Aortic coarctation is thought to be a rare condition in patients with tetralogy of Fallot. We report the case of a 26 year old woman presenting with systemic hypertension at 17 weeks of pregnancy after repair of tetralogy of Fallot in childhood. Echocardiography and magnetic resonance imaging revealed right aortic arch with severe isthmic coarctation. Her blood pressure was controlled medically during the rest of her pregnancy, and delivery was uneventful. Successful transcatheter placement of a covered stent at the level of the coarctation was performed after delivery. To our knowledge, this is the first reported case of aortic coarctation diagnosed in an adult patient late after repair of tetralogy of Fallot.


Role of oral care to prevent VAP in mechanically ventilated Intensive Care Unit patients.
Ventilator associated pneumonia (VAP) is the most common nosocomial infection in Intensive Care Unit. One major factor causing VAP is the aspiration of oral colonization because of poor oral care practices. We feel the role of simple measure like oral care is neglected, despite the ample evidence of it being instrumental in preventing VAP.


Voltammetric determination of organic UV filters by carbon paste electrodes modified with pyridinium-based ionic liquids.
The rapid and sensitive voltammetric determination of organic UV filters benzophenone-3 (BP-3) and avobenzone (AVO) was performed by an ionic liquid carbon paste electrode (IL-CPE). Namely, the synthesized pyridinium-based ILs, 1-butyl-3-methylpyridinium chloride ([N-C4-3C1Py]Cl) and 1-ethoxyethyl-3-methylpyridinium chloride ([N-C2OC2-3C1Py]Cl) were compared as bulk CPE modifiers for BP-3 determination. [N-C4-3C1Py]Cl-CPE showed more favorable interactions with the target analyte, and it was tested for AVO determination, too. Cyclic voltammetric (CV) studies suggested that the irreversible electrode reaction is adsorption controlled in the case of both UV filters. Also, the square-wave adsorptive stripping voltammetric (SW-AdSV) method was optimized for quantifying selected UV filters. In the model solutions, the linear calibration curve was obtained by the SW-AdSV method in the concentration range from 0.05 to 0.89 μg mL-1 at pH 3.0 for BP-3 (Eacc = -0.7 V, tacc = 100 s), and from 0.05 to 1.77 μg mL-1 at pH 11.98 for AVO (Eacc = 0.2 V, tacc = 100 s). The evaluated limit of detection (LOD) was 0.015 μg mL-1 in both cases, while the relative standard deviation (RSD) was lower than 1.5%. The affordable IL-based voltammetric sensor fulfills the main requirements for application in real samples due to an adequate selectivity towards selected analytes in the presence of interferents usually found in swimming pool water. Therefore, the BP-3 and AVO were quantified in a swimming pool water matrix with good repeatability and recovery. The obtained results demonstrate an excellent potential of the IL-CPEs, especially of the [N-C4-3C1Py]Cl-CPE, for determining selected UV filters in various real samples.


GABAergic transmission in hepatic encephalopathy.
Hepatic encephalopathy (HE)(1) is a neuropsychiatric disorder caused by chronic or acute liver failure. Nearly thirty years ago a hypothesis was formulated explaining the neuropathology of HE by increased GABAergic tone. Recent progress in the GABAA-receptor (GABAAR) molecular pharmacology and biochemistry as well as the physiology of GABAergic transmission provided better understanding of GABA's role in health and disease. A detailed analysis of neuronal populations and their GABAergic afferents affected in HE is still missing. The slow progress in understanding the pathology of GABAergic transmission in HE is due to the high complexity of brain circuitries controlled by multiple types of GABAergic interneurons and the large variety of GABAAR, which are differently affected by pathological conditions and not yet fully identified. The mechanisms of action of the GABAAR agonist taurine, allosteric positive modulators (inhibitory neurosteroids, anaesthetics, benzodiazepines and histamine) and inhibitors of the GABAAR (excitatory neurosteroids, Ro15-4513) are discussed with respect to HE pathophysiology. Perspectives for GABAergic drugs in the symptomatic treatment of HE are suggested.


Glutathione S-transferase P1 mRNA expression in plasma cell disorders and its correlation with polymorphic variants and clinical outcome.
Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in detoxification of carcinogens. GSTP1 gene overexpression has been observed in a variety of human cancers but there are no studies in plasma cell disorders. The aim of this study was to examine GSTP1 mRNA expression level in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). In addition, we have determined GSTP1 polymorphic variants in order to estimate MM risk and their relationship with the expression level. Results were also correlated with laboratory parameters and clinical outcome. Bone marrow mononuclear cells from 125 patients with plasma cell disorders were studied. Peripheral blood samples of 110 age and sex matched healthy controls were also evaluated. Real-Time Quantitative RT-PCR and PCR-RFLP assays were used. Upregulation of GSTP1 was observed in 37.7% MM and in 22.6% MGUS patients. A significant increase of GSTP1 expression in MM with respect to MGUS was detected (p=0.0427). Most MM patients that achieved complete remission had low transcription levels (77.8%) compared to those who did not reach this condition (44.4%) (p=0.0347). GSTP1 heterozygous carriers showed reduced expression compared to those with homozygous wild type genotype (p=0.0135). Our findings suggest, for the first time, a role for GSTP1 expression in development and/or progression of plasma cell disorders, and a probable influence of functional capacity of the enzyme on clinical outcome. These results and those of the literature support GSTP1 as an interesting tumor marker and a potential therapeutic target.


A genome-wide co-expression network analysis revealed ZmNRAMP6-mediated regulatory pathway involved in maize tolerance to lead stress.
A metal transporter ZmNRAMP6 was identified by using a trait-associated co-expression network analysis at a genome-wide level. ZmNRAMP6 confers maize sensitivity to Pb by accumulating it to maize shoots. ZmNRAMP6 knockout detains Pb in roots, activates antioxidant enzymes, and improves Pb tolerance. Lead (Pb) is one of the most toxic heavy metal pollutants, which can penetrate plant cells via root absorption and thus cause irreversible damages to the human body through the food chain. To identify the key gene responsible for Pb tolerance in maize, we performed a trait-associated co-expression network analysis at a genome-wide level, using two maize lines with contrasting Pb tolerances. Finally, ZmNRAMP6 that encodes a metal transporter was identified as the key gene among the Pb tolerance-associated co-expression module. Heterologous expression of ZmNRAMP6 in yeast verified its role in Pb transport. Combined Arabidopsis overexpression and maize mutant analysis suggested that ZmNRAMP6 conferred plant sensitivity to Pb stress by mediating Pb distribution across the roots and shoots. Knockout of ZmNRAMP6 caused Pb retention in the roots and activation of the antioxidant enzyme system, resulting in an increased Pb tolerance in maize. ZmNRAMP6 was likely to transport Pb from the roots to shoots and environment. An integration of yeast one-hybrid and dual-luciferase reporter assay uncovered that ZmNRAMP6 was negatively regulated by a known Pb tolerance-related transcript factor ZmbZIP54. Collectively, knockout of ZmNRAMP6 will aid in the bioremediation of contaminated soil and food safety guarantee of forage and grain corn.


Study on the phenolic composition and antioxidant properties of white-, yellow-, and black-corn (Zea mays L.) foodstuffs.
Black corn possesses potent antioxidants, but these are mostly lost during processing. In this study we evaluated the antioxidant content of two different black ('Millo Corvo') corn-based products (i.e. tortillas and cookies) subject to moderate processing. A parallel study on white and yellow corns was carried out for comparison. Raw 'Millo Corvo' flour exhibited higher contents of phenolic acids, flavonoids, and particularly anthocyanins than white and yellow flours did. Phenolic acids decreased in cookies but did not in tortillas; flavonoids did not exhibit a clear tendency, and anthocyanins were always preserved. Antioxidant activity (AA) obtained for 'Millo Corvo' samples was twice as high as the value measured in white and yellow corns in terms of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. The difference in AA was even more remarkable in terms of photochemiluminiscence antiradical activity. The conditions used during the cookie-making process enabled the natural antioxidant characteristics of 'Millo Corvo' to be preserved. However, the conditions applied to prepare tortillas resulted in major losses. The initial phenolics, in particular anthocyanins, and AA of 'Millo Corvo' flour can be maintained during processing as long as the conditions applied are 183 °C for 20 min in the absence of a high water content. Millo corvo products possess improved antioxidant characteristics compared with those from white and yellow corns. Millo corvo is a promising black corn type to prepare health-promoting corn-based foodstuffs. © 2023 Society of Chemical Industry.


Anti-inflammatory effect of green photobiomodulation in human adipose-derived mesenchymal stem cells.
Photo biomodulation (PBM) as a non-invasive and safe treatment has been demonstrated the anti-inflammatory potential in a variety of cell types, including stem cells. However, further investigations using different laser parameters combined with more accurate methods such as quantitative measurement of inflammatory gene expression at the mRNA level are still necessary. The aim of this study was to evaluate the effect of 532 nm green laser on cell proliferation as well as expression of inflammatory genes in human adipose-derived mesenchymal stem cells (hADMSCs) using RNA sequencing (RNA-seq) technique and confirmatory RT-PCR. hADMSCs were cultured in DMEM low glocuse medium with 10% fetal bovine serum until the fourth passage. Cultured cells were divided in two groups: control group (no laser irradiation) and laser group, irradiated with 532 nm laser at 44 m J/cm2 with an output power of 50 mW and a density of 6 mW/cm2, every other day, 7 s each time. The cell viability was assessed using MTT assay 24 h after each irradiation on days 3, 5, and 7 after cell seeding, followed by performing RNA-seq and RT-PCR. The MTT assay showed that PBM increased cell proliferation on day 5 after irradiation compared to day 3 and decreased on day 7 compared to day 5. In addition, gene expression analysis in hADMSCs using RNA-seq revealed down-regulation of inflammatory genes including CSF2, CXCL2, 3, 5, 6, 8, and CCL2, 7. These results indicate that 532 nm PBM with the parameters used in this study has a time-dependent effect on hADMSCs proliferation as well as anti-inflammatory potential.


Retracted: Modeling and Optimization of Water Distribution in Mineral Processing considering Water Cost and Recycled Water.
[This retracts the article DOI: 10.1155/2022/2314788.].


[Ontogenic development of the incudostapedial joint].
To study the development of the incudostapedial joint in human embryos and foetuses. 46 temporal bones with specimens between 9 mm and newborns were studied. The preparations were sliced serially and dyed using the Martins trichrome technique. The incudostapedial joint takes on the characteristics of a spheroidal joint at 16 weeks of development. The cartilage covering the articular surfaces is formed by different strata that develop in succession: the superficial stratum at 19 weeks, the transitional between 20 and 23 weeks, and the radial from 24 weeks on. The subchondral bone develops after 29 weeks by the mechanisms of apposition and extension of the periosteal and endosteal bones, but it is not until week 34 that it completely covers the articular surfaces, following constitution of the bone fascicles transmitting the lines of force. The articular capsule is formed from the inter-zone, the surface zone develops the capsular ligament, and the internal surface develops the synovial membrane. At the time of birth, the incudostapedial joint is completely developed.


Cancer Incidence and Mortality Rates in Multiple Sclerosis: A Matched Cohort Study.
To determine whether cancer risk differs in people with and without multiple sclerosis (MS), we compared incidence rates and cancer-specific mortality rates in MS and matched cohorts using population-based data sources. We conducted a retrospective matched cohort study using population-based administrative data from Manitoba and Ontario, Canada. We applied a validated case definition to identify MS cases, then selected 5 controls without MS matched on birth year, sex, and region. We linked these cohorts to cancer registries, and estimated incidence of breast, colorectal, and 13 other cancers. For breast and colorectal cancers, we constructed Cox models adjusting for age at the index date, area-level socioeconomic status, region, birth cohort year, and comorbidity. We pooled findings across provinces using meta-analysis. We included 53,983 MS cases and 269,915 controls. Multivariable analyses showed no difference in breast cancer risk (pooled hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.78-1.09]) or colorectal cancer risk (pooled HR 0.83 [95% CI 0.64-1.07]) between the cohorts. Mortality rates for breast and colorectal did not differ between cohorts. Bladder cancer incidence and mortality rates were higher among the MS cohort. Although the incidence of prostate, uterine, and CNS cancers differed between the MS and matched cohorts, mortality rates did not. The incidence of breast and colorectal cancers does not differ between persons with and without MS; however, the incidence of bladder cancer is increased. Reported differences in the incidence of some cancers in the MS population may reflect ascertainment differences rather than true differences.