Deeper insights into the drug defense of glioma cells against hydrophobic molecules.
By means of fluorescence microscopy the intracellular distribution of fluorescent drugs with different hydrophobicity (quinizarin, emodin and hypericin) was studied. Selective photoactivation of these drugs in precisely defined position (nuclear envelope) allowed moderately hydrophobic emodin enter the nucleus. Highly hydrophobic hypericin was predominantly kept in the membranes with no fluorescence observed in the nucleus. The redistribution of quinizarin, emodin and hypericin between lipids, proteins and DNA was studied in solutions and cells. Based on these results was proposed theoretical model of hydrophobic drugs' nuclear internalization after photo-activation. Molecular docking models showed that hypericin has the strongest affinity to P-glycoprotein involved in the cell detoxification. Presence of 10 μM quinizarin, emodin or hypericin increased P-glycoprotein function in U87 MG cells. Moreover, emodin pretreatment allowed quinizarin nuclear internalization without photo-activation, which was not the case for hypericin. The synergy of such pretreatment and photo-activation should lessen the drug doses with simultaneous increase of drug efficacy triggering cell apoptosis/necrosis.


Phylogeny of immunoglobulin structure and function XV. Idiotypic analysis of shark antibodies.
Nurse shark antibodies to the streptococcal A-variant carbohydrate were specifically purified from the sera of four individual animals and used as immunogens in guinea pigs. The resultant guinea pig antisera contained antibodies with apparent idiotypic specificities for the homologous shark proteins. The shark idiotypic sites were located on the Fab fragments and appeared to require the participation of H and L chains for full expression. Tests for cross reactivity employing the four guinea pig anti-idiotypic sera and antibodies from 13 immunized sharks were positive in only two cases (heterologous inhibition). These findings indicate that the idiotypic library (and by inference the antibody combining site repertoire) of nurse sharks to the streptococcal A-variant antigen is probably quite extensive.


Explaining the Genetic Causality for Complex Phenotype via Deep Association Kernel Learning.
The genetic effect explains the causality from genetic mutations to the development of complex diseases. Existing genome-wide association study (GWAS) approaches are always built under a linear assumption, restricting their generalization in dissecting complicated causality such as the recessive genetic effect. Therefore, a sophisticated and general GWAS model that can work with different types of genetic effects is highly desired. Here, we introduce a deep association kernel learning (DAK) model to enable automatic causal genotype encoding for GWAS at pathway level. DAK can detect both common and rare variants with complicated genetic effects where existing approaches fail. When applied to four real-world GWAS datasets including cancers and schizophrenia, our DAK discovered potential casual pathways, including the association between dilated cardiomyopathy pathway and schizophrenia.


Special Issue: "James D. McChesney, Vision, Passion and Leadership in the Development of Plant-Derived Natural Products".
It is a distinct pleasure for me to offer something in recognition of and tribute to Dr [...].


Efficacy of low-intensity laser therapy in reducing treatment time and orthodontic pain: a clinical investigation.
The long duration of orthodontic treatment is a major concern for patients. A noninvasive method of accelerating tooth movement in a physiologic manner is needed. The aim of this study was to evaluate of the efficacy of low-intensity laser therapy in reducing orthodontic treatment duration and pain. Twenty patients requiring extraction of first premolars were selected for this study. We used a randomly assigned incomplete block split-mouth design. Individual canine retraction by a nickel-titanium closed-coil spring was studied. The experimental side received infrared radiation from a semiconductor (aluminium gallium arsenide) diode laser with a wavelength of 810 nm. The laser regimen was applied on days 0, 3, 7, and 14 in the first month, and thereafter on every 15th day until complete canine retraction was achieved on the experimental side. Tooth movement was measured on progress models. Each patient's pain response was ranked according to a visual analog scale. An average increase of 30% in the rate of tooth movement was observed with the low-intensity laser therapy. Pain scores on the experimental sides were significantly lower compared with the control sides. Low-intensity laser therapy is a good option to reduce treatment duration and pain.


Monitoring clinical progression with mitochondrial disease biomarkers.
Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies.


Pentoxifylline suppresses interleukin-2-mediated activation of immature human natural killer cells by inhibiting endogenous tumor necrosis factor-alpha secretion.
We recently reported that immature human peripheral blood-derived natural killer (NK) cells, the free NK subset, can be activated by interleukin-2 (IL-2) to become killer cells and to undergo proliferation. Activation by IL-2 is dependent on endogenous secretion of tumor necrosis factor-alpha (TNF-alpha) by the free cells. Because pentoxifylline (PTX) inhibits TNF-alpha synthesis and secretion in monocytes, we hypothesized that PTX may also inhibit TNF-alpha secretion by NK cells and thus would inhibit IL-2-mediated activation of free cells. The free NK cells were separated from purified NK cells by flow cytometry and cell sorting of non-target binding cells. IL-2-mediated secretion of TNF-alpha by the free cells was inhibited by PTX. In the presence of PTX, IL-2-mediated activation of free cells into cytotoxic function, proliferation, and recruitment of binder and killer cells was markedly inhibited. Also, PTX inhibited IL-2-triggered upregulation of the expression of CD69, CD25, ICAM-1, and p75TNF-R on the cell surface. These findings demonstrate that PTX has a marked suppression on IL-2-mediated activation of immature free NK cells and that the suppression is due, in large part, to PTX-mediated inhibition of endogenous TNF-alpha secretion. The implication of these findings in the clinical use of PTX for therapy is discussed.


Use of endotoxin as a positive (toxic) control in the mouse embryo assay.
The mouse embryo assay (MEA) is used to test media used for in vitro fertilization (IVF). Negative controls usually consist of previously tested media known to support growth of embryos to the blastocyst stage by 72 h. Often, no concurrent positive (toxic) controls are reported. Thus, any unusually hardy cohort of embryos may go undetected. Endotoxin was tested for its suitability as a positive control in the MEA. Female mice were stimulated with gonadotropins mated with males, and embryos flushed from their oviducts 36 h after HCG injection. Two-cell embryos were pooled and randomly distributed to culture dishes containing media without protein supplement. Endotoxin inhibited blastocyst growth beginning at 50 micrograms/ml, with complete suppression of development at 5000 micrograms/ml. With 500 micrograms/ml endotoxin, an average of 34.8% of the embryos developed to the blastocyst stage for eight separate assays. The interassay coefficient of variation (CV) was 76%, while the intraassay CV was 9.4%. At 48 h the zona pellucida was absent from all of the embryos exposed to the endotoxin. A large difference was found between two lots of endotoxin with the same claimed potency. These studies demonstrate the importance for inclusion of a well-defined positive control when performing the mouse embryo assay.


The role of CD4-dependent signaling in interleukin-16 induced c-Fos expression and facilitation of neurite outgrowth in cerebellar granule neurons.
Neuronal interleukin 16 (NIL-16) is the larger neural-specific splice variant of the interleukin-16 (IL16) gene and shows restricted expression to post-mitotic neurons of the mammalian hippocampus and cerebellum. Although the N-terminus of NIL-16 is unique to the neuronal variant, the C-terminus is identical to pro-IL-16, the IL-16 precursor expressed primarily in T-cells. IL-16 was originally described as a proinflammatory cytokine and has diverse immunoregulatory effects which involve signaling through CD4. NIL-16-expressing neurons can secrete IL-16 and may express CD4; moreover, treatment of cultured cerebellar granule neurons (CGCs) with IL-16 increases the expression of c-Fos, an immediate-early gene which transcriptionally regulates genes directing survival, proliferation, and growth. Taken together, we hypothesize that IL-16 functions as a neuroregulatory cytokine which signals through neuronal CD4 receptors. In this study, we investigated the role of CD4 in IL-16-induced c-Fos expression in CGCs, as well as the effects of IL-16 on neuronal survival and growth. We detected components involved in IL-16-signaling in lymphocytes, including CD4 and the associated tyrosine kinase p56(lck), in CGCs using qRT-PCR and immunoblotting. We also show that IL-16 induces c-Fos expression in wild-type CGCs, but not CD4-deficient CGCs or following inhibition of p56(lck). Finally, treatment of CGCs with IL-16 enhanced neurite outgrowth, an effect also observed in CD4-deficient CGCs. Taken together, our results indicate that IL-16-signaling affects neuronal gene expression and growth through CD4-dependent and independent pathways.


Synthesis and activity on rat aorta rings and rat pancreatic beta-cells of ring-opened analogues of benzopyran-type potassium channel activators.
Ring-opened analogues of dihydrobenzopyran potassium channel openers (PCOs) were prepared and evaluated as putative PCOs on rat aorta rings (myorelaxant effect) and rat pancreatic beta-cells (inhibition of insulin secretion). These derivatives are characterized by the presence of a sulfonylurea, a urea or an amide function. Some compounds bearing an arylurea moiety provoked vasorelaxant effects and a marked inhibition of insulin release. Derivatives bearing a sulfonylurea or an amide function were, however, poorly active on both tissues. Structure-activity relationships and apparent tissue selectivity are discussed.


Monoclonal antibodies against the main immunogenic region of the acetylcholine receptor. Mapping on the intact molecule.
About two-thirds of the antibodies to the nicotinic acetylcholine receptor (AChR) in myasthenic patients, and in rats immunized with intact AChR, bind to the main immunogenic region (MIR) on the alpha-subunit. We tested all available anti-MIR monoclonal antibodies (mAbs) by competition experiments for binding on the intact AChR from Torpedo electric organ and human muscle. Practically complete competition between all possible paired combinations of anti-MIR mAbs was found. As a consequence, the MIR must be a very concrete and small region. Furthermore, the location of the MIR relative to some other less immunogenic regions was also determined.


Formation of DNA adducts and water-soluble metabolites of benzo[a]pyrene in human monocytes is genetically controlled.
Formation of DNA adducts and of water-soluble metabolites was studied in monocytes of 86 first-degree relatives of 15 families. Tests were performed with blood monocytes using (G-3H)-benzo[a]pyrene as a model pro-carcinogen. Variance analysis revealed significantly higher inter-familial than intra-familial variations. From these data we conclude that the formation of DNA adducts is genetically controlled. Therefore the enhanced formation of benzo[a]pyrene DNA adducts in lung cancer patients found in earlier studies may reflect a genetic predisposition for lung cancer in some patients.


Differentiation of benign from malignant cervical lymph nodes in patients with head and neck cancer using PET/CT imaging.
To differentiate malignant from benign cervical lymph nodes in patients with head/neck cancer. In this retrospective study, 39 patients with primary head/neck cancer who underwent Positron Emission Tomography (PET)/Computerized Tomography (CT) and image-guided lymph node biopsy were included. Overall, 23 (59%) patients had biopsy-proven malignant cervical lymphadenopathy. Malignant lymph nodes had higher maximum standardized uptake (SUV-max) value (P<.001) and short-axis diameter (P=.015) compared to benign nodes. An SUV-max of ≥2.5 was 100% sensitive, and an SUV-max ≥5.5 was 100% specific for malignant lymphadenopathy. The PET/CT SUV-max value can help with differentiation of malignant cervical lymph nodes in patients with head/neck cancer.


An Experimental Therapeutics Approach to the Development of a Novel Computerized Treatment Targeting Error-Related Brain Activity in Young Children.
In the current study, we utilize an experimental medicine approach to examine the extent to which a single-session, computerized intervention impacts a transdiagnostic neural marker of risk (i.e., the error-related negativity [ERN]) in 70 children between the ages of 6 and 9 years. The ERN is a deflection in the event-related potential occurring after an individual makes a mistake on a lab-based task and has been shown to be transdiagnostically associated with a variety of anxiety disorders (e.g., social anxiety, generalized anxiety), obsessive-compulsive disorder, and depressive disorders in over 60 studies to date. Building on these findings, work has been done to link an increased ERN to negative reactions to, and avoidance of, making mistakes (i.e., error sensitivity). In the current study, we capitalize on this previous work by examining the extent to which a single-session, computerized intervention may engage the target of "error sensitivity" (measured by the ERN, as well as self-report of error sensitivity). We examine the convergence of multiple measures of the construct of "error sensitivity" (i.e., child self-report, parent report on child, and child electroencephalogram [EEG]). We also examine relationships between these three measures of "error sensitivity" and child anxiety symptoms. Overall, results suggested that treatment condition predicted changes in self-reported error sensitivity but not changes in ERN. Based on the lack of previous work in this area, we view this study as a novel, preliminary, first step toward using an experimental medicine approach to examine our ability to engage the target of the ERN (i.e., error sensitivity) early in development.


Subpallial origin of part of the calbindin-positive neurons of the claustral complex and piriform cortex.
The aim of the present study was to investigate whether part of the calbindin-positive neurons of the claustral complex and piriform cortex originate in the subpallium. To that end, we prepared organotypic cultures of embryonic telencephalic slices, and applied the cell tracker CMTMR to the ventricular/subventricular zone of the lateral or medial ganglionic eminence. Following 48 h of incubation, we observed a number of CMTMR-labeled cells (showing red fluorescence) of subpallial origin in the claustral complex and piriform cortex. To know whether some of these cells of subpallial origin were calbindin-positive, we performed immunofluorescence for calbindin using an Alexa 488-conjugated secondary antiserum (green fluorescence). Our results showed that some of the CMTMR-labeled cells of subpallial origin in the claustral complex and piriform cortex are calbindin-positive (and possibly GABAergic). The subpallial origin of part of these cells was confirmed by observation of double labeled neurons in the claustral complex that expressed both Lhx6 mRNA (a marker of cells derived from the medial ganglionic eminence) and calbindin. Future studies will be required to analyze the existence of a subpopulation of non-GABAergic calbindin cells in the claustral complex and piriform cortex, and to know their origin.


Progressive polysystemic immune-mediated disease in a dog.
A dog with polyarthritis, angular joint deformities, and a high serum antinucleolar antibody titer was treated over a period of 20 months. During the clinical course, leukopenia, thrombocytopenia, Coombs' positive hemolytic anemia, and a pemphigus-type skin disorder developed, all of which responded to immunosuppressive therapy. It is not known whether the polysystemic disease in this dog represents a pleomorphic manifestation of canine systemic lupus erythematosus or multiple autoimmune disorders occurring in the same animal.


Local atopy is more relevant than serum sIgE in reflecting allergy in childhood adenotonsillar hypertrophy.
There was a lack of convincing evidence supporting the influence of allergy on the adenotonsillar hypertrophy (ATH). We investigated the presence of specific IgE (sIgE) in the serum and adenotonsillar tissues in children with ATH. A Pharmacia ImmunoCAP system was used to test sIgE against 31 allergens in the serum in 83 children with ATH before adenotonsillectomy. sIgE against 15 representative allergens were detected in adenotonsillar tissues from 20 of those children. A total of 51 (61.45%) children had positive serum sIgE. 20 children with ATH had positive sIgE to more than two allergens at both tonsils and adenoids, although half of them were serum sIgE negative. The percentage of subjects with positive sIgE expression in adenoids and tonsils was 50.0% and 42.9%, respectively, among the subjects with positive serum sIgE expression. Of subjects with negative serum sIgE expression, local sIgE was detected in 36.0% of adenoids and 43.8% of tonsils, respectively. The rate of sIgE presence in local tissue (adenoids or tonsils) was significantly higher than that seen in the serum. This study provided evidence that there was an important role for allergic inflammation in the ATH. The inconsistency in sIgE expression between adenotonsillar and serum suggests a role of local atopy in childhood ATH.


Deoxygenation of sulfoxides to sulfides with thionyl chloride and triphenylphosphine: competition with the pummerer reaction.
Although a number of methods have been developed to reduce sulfoxides to sulfides, many of these processes are limited by side reactions, low yields, poorly available reagents, or harsh reaction conditions. We recently studied the reaction of various sulfoxides with SOCl2 and Ph3P. We were able to obtain the corresponding sulfides in excellent yields (>90%) when aliphatic and aromatic sulfoxides were treated with SOCl2 as a catalyst and Ph3P in THF at room temperature.


Evolving transpeptidase and hydrolytic variants of γ-glutamyl transpeptidase from Bacillus licheniformis by targeted mutations of conserved residue Arg109 and their biotechnological relevance.
γ-Glutamyl transpeptidase (GGT) catalyzes the transfer of the γ-glutamyl moiety from donor compounds such as l-glutamine (Gln) and glutathione (GSH) to an acceptor. During the biosynthesis of various γ-glutamyl-containing compounds using GGT enzyme, auto-transpeptidation reaction leads to the formation of unwanted byproducts. Therefore, in order to alter the auto-transpeptidase activity of the GGT enzyme, the binding affinity of Gln should be modified. Structural studies of the Bacillus licheniformis GGT (BlGT) complexed with the glutamic acid has shown that glutamic acid has strong ionic interactions through its α-carboxlic group with the guanidine moiety of Arg109. This interaction appears to be an important contributor for the binding affinity of Gln. In view of this, six mutants of Bacillus licheniformis ER15 GGT (BlGGT) viz. Arg109Lys, Arg109Ser, Arg109Met, Arg109Leu, Arg109Glu and Arg109Phe were prepared. As seen from the structure of BlGT, the mutation of Arg109 to Lys109 may reduce the affinity for Gln to some extent, whereas the other mutations are expected to lower the affinity much more. Biophysical characterization and functional studies revealed that Arg109Lys mutant has increased transpeptidation activity and catalytic efficiency than the other mutants. The Arg109Lys mutant showed high conversion rates for l-theanine synthesis as well. Moreover, the Arg109Met mutant showed increased hydrolytic activity as it completely altered the binding of Gln at the active site. Also, the salt stability of the enzyme was significantly improved on replacing Arg109 by Met109 which is required for hydrolytic applications of GGTs in food industries.


C-reactive protein: a valuable acute investigation. A case of pneumococcal meningitis presenting as ankle pain.
A case is presented in which the decision to admit and treat an adult with musculoskeletal pain and pyrexia was based on her markedly raised c-reactive protein (CRP). At the time of admission she was apyrexial and the CRP was the only haematological investigation that was out of the normal range. She subsequently became precipitously septic with pneumococcal bacteraemia and meningitis. The CRP is an important investigation for emergency departments.


Changes in gentamicin pharmacokinetics after reduction of renal parenchyma.
The relationship between the elimination constant of gentamicin and the percentage of functioning nephrons in rats cannot be characterized by a simple linear relation. The results support the assumption that gentamicin elimination per residual nephron increased.


An evolutionary analysis of nitric oxide reductase gene norV in enterohemorrhagic Escherichia coli O157.
A novel virulence gene, norV, that encodes nitric oxide (NO) reductase, was examined to investigate the emergence of enterohemorrhagic Escherichia coli (EHEC) O157 subgroup C clusters 2 and 3 from subgroup C cluster 1. Deletion of norV occurred at a point between cluster 1 and cluster 2 just after or at the same time that an stx2 bacteriophage, which retains Shiga toxin 2 gene, was inserted into wrbA, which encodes a novel multimeric flavodoxin-like protein, in EHEC O157. Sensitivity of NO to anaerobic growth was correlated with the deletion of norV in all EHEC O157 individuals tested. The C467A mutation of fimH, which encodes minor component of type 1 fimbriae, occurred within cluster 1, not as a transition from cluster 1 to cluster 2, indicating that there is a cluster 1 minority branch that leads to cluster 2. These data refine the evolutionary history of an emerging EHEC O157.


Diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) immunoexpression in follicular-patterned lesions of the thyroid gland.
Neutrophil gelatinase-associated lipocalin (NGAL) is a protein which participates in iron trafficking and which is involved in cancerogenesis and cancer progression. Since its over-expression has been documented in thyroid malignancies in comparison to thyroid normal gland, in the present study, we aimed to determine whether the evaluation of NGAL immunoexpression may be of help in the differential diagnosis of follicular-patterned thyroid lesions. Our additional aim was to test the possible interference of endogenous biotin on the immunohistochemical findings. Thus, all the immunohistochemical procedures, carried out with labeled streptavidin biotin method, were doubly performed, with or without the preliminary inhibition of endogenous biotin. No NGAL staining was found in the normal thyroid gland nor in the nodular colloid goiters or in Hashimoto's thyroiditis. NGAL expression appeared to be significantly more frequent in the malignant tumors in comparison to benign ones (P < 0.000001). Even more, NGAL expression appeared to be specific (specificity 93%) for carcinoma and represented a sensitive method (sensitivity 84%), with high negative (88%) and positive (94%) predictive values, as well as high diagnostic accuracy (88%), in the identification of follicular-patterned thyroid malignant tumors. The specificity, positive predictive value and diagnostic accuracy lowered when biotin was not preliminary inhibited, due to the presence of false positives among benign Hürthle cell tumors. In conclusion, the immunohistochemical detection of NGAL may be helpful in the differential diagnosis between malignant and benign follicular-patterned lesions of the thyroid. The use of biotin free system or the preliminary biotin inhibition is warranted for the detection of NGAL in thyroid samples, especially when dealing with Hürthle cell tumors.


The use of amplified flanking region-PCR in the isolation of laccase promoter sequences from the edible fungus Pleurotus sajor-caju.
To determine the regulation of laccase isozyme gene transcription in Pleurotus sajor-caju in response to different aromatic inducers and physiological parameters. The promoter regions for each of four different laccase isozymes were cloned from P. sajor-caju, using amplified flanking region-PCR (AFR-PCR). Sequences stretching 724, 214, 840 and 1740 bp upstream from the predicted start codons for lac1, lac2, lac3 and lac4, respectively, were cloned in each case and analysed for the presence of putative transcriptional response elements. A number of putative response elements including metal response elements, xenobiotic response elements and antioxidant response elements appear to be present. In addition putative consensus sequences such as those for the binding of AP1, AP2, creA and NIT2 transcription factors, which are involved in nitrogen and carbon regulation in different fungi, are also present in the promoter regions of some of the isozymes. These elements may be involved in the transcriptional regulation of laccase gene expression in P. sajor-caju. The presence of a number of putative transcriptional response elements in the promoter regions of different isozyme genes indicates a potential role for these sites in regulating laccase gene transcription in P. sajor-caju. In addition this work demonstrates the potential usefulness of AFR-PCR as a technique to clone fungal DNA sequences located upstream from known sequences.


Human estrogen receptor regulation in a yeast model system and studies on receptor agonists and antagonists.
An expression system that utilized yeast copper metallothionein promoter and ubiquitin fusion technology to express the human estrogen receptor gene in yeast is described. We have studied the biochemical and transcriptional regulatory properties of the human estrogen receptor. The biochemical properties of the yeast expressed receptors are identical to the receptors isolated from human tissue. Estradiol mediated activation of transcription by the receptor was studied by a reporter beta-galactosidase gene where expression was under the control of estrogen response elements. Using this expression system and a hyperpermeable yeast strain we have studied the effects of various antiestrogens on the regulation of estrogen receptor function. We demonstrate that tamoxifen and ICI 164,384 are capable of binding to the receptor but neither antiestrogen was able to block the estradiol mediated increase in transcription. In fact, both antiestrogens exerted weak agonist activity in this system.


Peripheral input pathways projecting to the motor cortex in the cat.
The possibility that the motor cortex receives peripheral input directly from the thalamus was examined using the evoked potential method and the following results were obtained. Potentials in the motor cortex evoked by stimulation of superficial radial (SR) or group II deep radial (DR) nerve were neither abolished nor delayed by ablation of the sensory cortex. Potentials in the motor cortex evoked by stimulation of group II DR nerve were most severely reduced by interruption of the spinocervcial tract. Potentials evoked by stimulation of SR nerve were more severely reduced in the sensory cortex than in the motor cortex by section of the dorsal funiculus or cooling of the cuneate nucleus. The size of evoked potentials in the motor cortex increased rapidly when stimulus intensity to DR nerve exceeded the threshold to group II fibers. The results suggest that some inputs from the SR and group II DR nerves reach the motor cortex without a relay through the sensory cortex.


GP-3, a newly characterized glycoprotein on the inner surface of the zymogen granule membrane, undergoes regulated secretion.
We have recently reported the cloning of the rat zymogen granule membrane glycoprotein GP-3 and the related pancreatic secretory lipase (Wishart, M. J., Andrews, P. C., Nichols, R., Blevins, G. T., Logsdon, C.D., and Williams, J. A. (1993) J. Biol. Chem. 268, 10303-10311). Specific antipeptide antibodies were generated against both GP-3 and secretory lipase and used for the biochemical and physiological characterization of GP-3. Western blotting confirmed that GP-3 was found exclusively in zymogen granule membranes and was absent from zymogen granule content which contains the majority of secretory lipase. Extraction of zymogen granule membranes with Triton X-114 showed GP-3 to be significantly more hydrophobic than lipase. The GP-3 amino acid sequence contains one potential N-linked glycosylation site at Asn-336. The loss of concanavalin A labeling after both chemical deglycosylation with trifluoromethanesulfonic acid and enzymatic deglycosylation with N-glycanase showed GP-3 to possess a small N-linked oligosaccharide side chain. Digestion of intact and permeabilized zymogen granules with the nonspecific protease Pronase localized GP-3 to the inner surface of zymogen granule membranes. Since GP-3 is resident on the inner surface of the zymogen granule membrane, it should appear on the outer cellular surface after exocytosis. Although membrane attachment of GP-3 was resistant to treatment with phosphatidylinositol-specific phospholipase C, we observed that GP-3 is released into the pancreatic juice and that secretion of GP-3 was greatly enhanced by cholecystokinin.


Neuroradiologic evaluation of patients with central auditory lesions.
CT and MR imaging have revolutionized diagnostic medical imaging. MR scanning in particular is the method of choice to evaluate the CP angle lesion or other posterior fossa lesion. With CT pneumocisternography, neurovascular structures of the internal auditory canal and lesions can be visualized. Experience indicates that MR scanning will replace CT.


Assessment of gas generation and energy recovery from municipal solid waste in Kanpur city, India.
The study reported herein presents the methane generation potential from municipal solid waste (MSW) generated in Kanpur city using four established methods, namely: the IPCC Default Method (DM), EPER Germany, The IPCC First Order Decay (FOD) method, and the Modified Triangular Method (MTM). Results revealed that the average maximum and minimum emissions with respect to total MSW generated and considered over the study period were obtained in the IPCC Default Method (19.17Gg/year) and the MTM (1.00Gg/year), respectively. Furthermore, the sensitivity analysis carried out revealed that the MTM method is the least uncertain method in predicting the methane emissions. Energy generation using the Yedla method and the Stoichiometric method was also carried out, highlighting the potential for energy recovery using methane emissions. The total energy generation potential using the Yedla method over the entire study period was determined to be 924 TJ, with an increased potential of 30% between the periods of 2022 to 2031. According to the study, there exists significant potential for effectively managing the greenhouse gas emissions from open dumpsite by harnessing the methane produced and using it for energy generation.


Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells.
Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3-expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.


Collective volume plasmons in manganites with nanoscale phase separation: simulation of the measured infrared spectra of La(0.7)Ca(0.3)MnO3.
Optical characteristics of manganites with nanoscale electronic phase separation are simulated using an exact renormalization group transformation in Kirchhoff's equations. The local electric field is found to be highly inhomogeneous, exceeding the incident-wave field by orders of magnitude when the permittivities of the phases have opposite signs and plasmons are excited. The spatial scale of the field fluctuations suggests the collective character of the plasmon modes. The results of the simulation explain the optical anomalies of La(0.7)Ca(0.3)MnO(3) single crystals and films in the infrared frequency range in a natural way.


A novel sequential structure for lightweight multi-scale feature learning under limited available images.
Although multi-scale feature learning can improve the performances of deep models, its parallel structure quadratically increases the model parameters and causes deep models to become larger and larger when enlarging the receptive fields (RFs). This leads to deep models easily suffering from over-fitting issue in many practical applications where the available training samples are always insufficient or limited. In addition, under this limited situation, although lightweight models (with fewer model parameters) can effectively reduce over-fitting, they may suffer from under-fitting because of insufficient training data for effective feature learning. In this work, a lightweight model called Sequential Multi-scale Feature Learning Network (SMF-Net) is proposed to alleviate these two issues simultaneously using a novel sequential structure of multi-scale feature learning. Compared to both deep and lightweight models, the proposed sequential structure in SMF-Net can easily extract features with larger RFs for multi-scale feature learning only with a few and linearly increased model parameters. The experimental results on both classification and segmentation tasks demonstrate that our SMF-Net only has 1.25M model parameters (5.3% of Res2Net50) with 0.7G FLOPS (14.6% of Res2Net50) for classification and 1.54M parameters (8.9% of UNet) with 3.35G FLOPs (10.9% of UNet) for segmentation but achieves higher accuracy than SOTA deep models and lightweight models, even when the training data is very limited available.


Ultrastructure and histochemical analysis of extracellular matrix surface network in kiwifruit endosperm-derived callus culture.
The study used Actinidia deliciosa endosperm-derived callus to investigate aspects of the morphology, histology and chemistry of extracellular matrix (ECM) structures in morphogenically stable tissue from long-term culture. SEM showed ECM as a membranous layer or reticulated fibrillar and granular structure linking the peripheral cells of callus domains. TEM confirmed that ECM is a distinct heterogeneous layer, up to 4 mum thick and consisting of amorphous dark-staining material, osmiophilic granules and reticulated fibres present outside the outer callus cell wall. ECM covered the surface of cells forming morphogenic domains and was reduced during organ growth. This structure may be linked to acquisition of morphogenic competence and thus may serve as a structural marker of it in endosperm-derived callus. ECM was also observed on senescent cells in contact with the morphogenic area. Treatment of living calluses with chloroform and washing with ether-methanol led to partial destruction of the extracellular layer. Digestion with pectinase removed the membranous layer almost completely and exposed thick fibrillar strands and granular remnants. Digestion with protease did not visibly affect the surface layer. Indirect immunofluorescence showed low-methylesterified pectic epitopes labelled by JIM5 monoclonal antibody. Immunolabelling, histochemistry, and solvent and enzyme treatments suggested pectins and lipids as components of the surface layer. These compounds may indicate protective, water retention and/or cell communication functions for this external layer.


Eukaryotic lipid-biosynthetic enzymes: the same but not the same.
The discovery that different eukaryotic enzymes catalyse the same lipid-biosynthetic reaction has paralleled the recognition that segregated pools of lipids have unique biological functions. This review considers enzymes involved in the synthesis of diverse classes of lipids--glycerolipid precursors, phospholipids, sterols and eicosanoids--and summarizes recent data that show that these duplicate enzymes are frequently encoded by different genes and have unique subcellular locations. Does this duality merely represent redundancy or do the different isoforms provide pools of lipids for specific biological purposes?


Relationship building through the development of international nursing curricula: a literature review.
This expository paper explores the literature related to the development of international nursing (or midwifery) curricula as a vehicle for studying relationship-building. International nursing curriculum development can be interpreted as a sanctioned extension of transnational, cross-cultural, political and economic professional outreach activities. Extensive literature searches were conducted in the CINAHL, ERIC, PsychINFO and ABI/INFORM Global databases of the key terms: relationship-building; international; curriculum development; and nursing. The review revealed developing international nursing curricula through cooperative partnerships between institutions of higher learning and/or international development agencies provides a vehicle to build international collegial relationships among nursing faculty and professionals worldwide. A summary is provided in a table. Relationship-building through the development of international nursing curricula merits focused investigation.


An exploration of participant experience of a communication training program for people with traumatic brain injury and their communication partners.
To investigate the experiences of participants who attended communication training programs for people with traumatic brain injury (TBI) and their everyday communication partners (CP) as part of a non-randomised controlled trial. The participants were people with TBI and their CP, who were family members or carers of the people with TBI. Twenty-six participants (13 participants with TBI and 13 CP) completed the JOINT program, which involved participants with TBI and CP attending the program together. Fourteen participants with TBI completed the TBI SOLO training program, which did not involve the participation of a CP. Semi-structured videotaped interviews were completed by all participants at the end of the training. Using a six-step generic analysis procedure, data were categorised into topics and then subtopics to identify conceptually discrete units. Participants described improvements in communication skills, the impact of improved communication skills, valuable components of the programs and components that needed changes. The accounts of participants provided additional evidence for the effectiveness of the training programs, assisted with identifying helpful components of the training and demonstrated the usefulness of a qualitative research methodology as part of evaluating the outcomes of the clinical trial.


Effects of new insulin analogues HMR1964 (insulin glulisine) and HMR1423 on insulin receptors.
New insulin analogues have been created by amino-acid exchange to provide an improved pharmacokinetic profile. However, safety issues have been raised regarding their use, as amino-acid exchange of insulin may induce altered metabolic and mitogenic effects. For example, the insulin analogue Asp(B10) causes breast cancer in rodents. The aim of this study was to compare two new insulin analogues HMR1964 (Lys[B3],Glu[B29]) (insulin glulisine) and HMR1423 (Gly[A21],His[B31],His[B32]) with regular insulin and the mitogenic analogue Asp(B10). We analysed insulin receptor binding characteristics and dissociation kinetics, as well as insulin-induced receptor auto- and dephosphorylation kinetics, in rat-1 fibroblasts overexpressing the human insulin receptor isoform B. Mitogenic activity was tested in the non-malignant cell line MCF10. Regular insulin, HMR1964 and HMR1423 showed no significant differences in receptor association, dissociation and receptor binding affinity, while Asp(B10) displayed markedly increased insulin receptor affinity. All of the analogues induced rapid insulin receptor autophosphorylation, reaching a maximum 10 min after stimulation (10(-9) mmol/l insulin). In contrast, Asp(B10) induced a prolonged phosphorylation and dephosphorylation state of the 95 kDa insulin receptor beta-subunit. With respect to [3H]thymidine incorporation, the new analogues had similar (HMR1423) or even lower (HMR1964) effects than regular insulin in the mammary epithelial cell line MCF10, while Asp(B10) showed increased [3H]thymidine incorporation. HMR1964 and HMR1423 displayed the same association, dissociation and insulin receptor affinity kinetics as regular insulin, and might therefore be useful for the treatment of diabetes.


Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors.
Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10-50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.


Microbial community and metabolic pathway succession driven by changed nutrient inputs in tailings: effects of different nutrients on tailing remediation.
To solve the competition problem of acidophilic bacteria and sulfate-reducing bacteria in the practical application of mine tailing bioremediation, research into the mechanisms of using different nutrients to adjust the microbial community was conducted. Competition experiments involving acidophilic bacteria and sulfate-reducing bacteria were performed by supplementing the media with yeast extract, tryptone, lactate, and glucose. The physiochemical properties were determined, and the microbial community structure and biomass were investigated using MiSeq sequencing and qRT-PCR, respectively. Four nutrients had different remediation mechanisms and yielded different remediation effects. Yeast extract and tryptone (more than 1.6 g/L) promoted sulfate-reducing bacteria and inhibited acidophilic bacteria. Lactate inhibited both sulfate-reducing and acidophilic bacteria. Glucose promoted acidophilic bacteria more than sulfate-reducing bacteria. Yeast extract was the best choice for adjusting the microbial community and bioremediation, followed by tryptone. Lactate kept the physiochemical properties stable or made slight improvements; however, glucose was not suitable for mine tailing remediation. Different nutrients had significant effects on the abundance of the second enzyme of the sulfate-reducing pathway (p < 0.05), which is the rate-limiting step of sulfate-reducing pathways. Nutrients changed the remediation effects effectively by adjusting the microbial community and the abundance of the sulfate-reducing rate-limiting enzyme.


High-affinity sequence-selective DNA binding by iridium(III) polypyridyl organometallopeptides.
We demonstrate the application of solid-phase peptide synthesis methods for the straightforward assembly of polynuclear Ir(III) organometallopeptides, and show that their oligoarginine derivatives exhibit high DNA binding affinity, sequence selectivity, and high cytotoxicity towards a set of cancer cell lines.


Calcium phosphate-quercetin nanocomposite (CPQN): A multi-functional nanoparticle having pH indicating, highly fluorescent and anti-oxidant properties.
Calcium phosphate quercetin nanocomposite (CPQN) i.e., quercetin entrapped in calcium phosphate nanoparticle was synthesized by a precipitation method at 80°C, taking ammonium hydrogen phosphate, calcium nitrate and quercetin as precursors and sodium citrate as stabilizer. The nanocomposite suspension had different color at different pH values, a property that could render the nanoparticle a pH indicator. Besides color, the particles also had different size, shape, stability and quercetin content with change of pH. In addition, the CPQN was highly fluorescent having two sharp emission peaks at 460 and 497nm, when excited at 370nm; by this property it behaved as an effective fluorophore to label biological cell. Moreover, the nanocomposite had potential anti-oxidant property, for which mortality of mouse neuroblastoma cell N2A, by H2O2-induced oxidative stress, was found to be lowered by the pre-treatment of the cells with CPQN.


The presence of thromboxane A2 receptors in cultured astrocytes from rabbit brain.
We have previously shown that human astrocytoma cells (1321N1) express thromboxane A2 (TXA2) receptors, of which stimulation activates phosphoinositide hydrolysis (Nakahata et al., Eur. J. Pharmacol. 162 (1989) 407). In order to examine whether TXA2 receptors exist in native astrocytes or not, rabbit cultured astrocytes were used. Glial fibrillary acidic protein (GFAP)-positive astrocytes were obtained three weeks after culture of brain. [3H]ONO NT-126, a TXA2 antagonist, bound to the membranes derived from cultured rabbit astrocytes with the dissociation constant (Kd) of 0.23 nM and the maximum binding site (Bmax) of 69.5 fmol/mg protein. STA2, a stable TXA2 receptor agonist, activates phosphoinositide hydrolysis in a concentration-dependent manner, and S-145, a TXA2 antagonist, inhibited STA2-induced phosphoinositide hydrolysis. The results indicate that TXA2 receptors exist in cultured rabbit astrocytes and the activation of TXA2 receptors results in phosphoinositide hydrolysis.


5-Fluorouracil induced dysregulation of the microbiome-gut-brain axis manifesting as depressive like behaviors in rats.
Disturbances of the gut microbiome have been widely suggested to be associated with 5-fluorouracil (5-Fu) induced digestive pathologies. Furthermore, it has been elucidated that the gut microbiome may play a key role in the pathogenesis of depressive disorders via the microbiota-gut-brain axis. Despite the speculation, there exists no direct evidence proving the causality between disturbances in the gut microbiome induced by 5-Fu and depressive mood dysregulation. Herein, behavioral testing was used to evaluate depressive-like behaviors in 5-Fu treated rats. Subsequently, the gut microbiota and prefrontal cortex (PFC) metabolic were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (1H NMR). To clarify the association between the gut microbiota and their role on depressive-like behaviors caused by 5-Fu, a fecal microbiota transplantation (FMT) experiment was carried out. The results suggested that 5-Fu could significantly alter the diversity and abundance of the gut microbiome, and induce PFC metabolic disorders, as well as depressive behaviors in rats. Transplantation of fecal microbiota from healthy control into 5-Fu treated rats significantly alleviated the PFC metabolic disorder and depressive-like behaviors. In conclusion, this study demonstrated that the gut microbiome was actively involved in the occurrence of 5-Fu induced depressive-like behaviors, and manipulation of specific gut microbiome parameters may serve as a promising novel target for side effects of 5-Fu treatment.


Determination of water distribution in sludge by a multiple headspace extraction analytical technique.
This paper reported a new method for the determination of the water distribution in sludge. It was based on a multiple headspace extraction (MHE) procedure to step-wise remove the water vapor from a closed vial containing a sludge sample, followed by a gas chromatographic measurement (GC). By plotting the GC signal of water vapor vs. the headspace extraction number, three different trend lines from the profile can be observed. From which two transition points can be determined and thus the stages for the free water, capillary water, and adsorption water release can be divided. Based on the sum of GC peak areas ate each stage, the content of these water types in the sludge can be calculated through a method calibration. The results showed that the MHE-GC method has a better measurement repeatability (RSD < 18.6%) and sensitivity (limit of quantitation = 0.028%) than the thermal drying method (used as a reference method). There was also a good agreement between the MHE-GC and the reference method on the free water and capillary water analysis. Moreover, the results on the adsorption water and bound water testing by the present method is more justifiable than the reference method.


Light-Driven Redox Activation of CO2- and H2-Activating Complexes in a Self-Assembled Triad.
We report a self-assembled triad for artificial photosynthesis composed of a chromophore, carbon-dioxide reduction catalyst, and hydrogen-oxidation complex, which is designed to operate without conventional sacrificial redox equivalents. Excitation of the zinc-porphyrin chromophore of the triad results in ultrafast charge transfer between a tungsten-alkylidyne donor and a rhenium diimine tricarbonyl acceptor, producing a charge-separated state that persists on the time scale of tens of nanoseconds and is thermodynamically capable of the primary dihydrogen and carbon dioxide binding steps for initiating the reverse water-gas shift reaction. The charge-transfer behavior of this system was probed using transient absorption spectroscopy in the visible, near-infrared, and mid-infrared spectral regions. The behavior of the triad was compared with that of the zinc-porphyrin-rhenium-diimide dyad; the triad was found to have a significantly longer charge-separated lifetime than other previously reported porphyrin-rhenium diimine compounds.


[The effect of sodium polyanethol sulfonate (SPS) on the growth of bacteria in blood cultures].
The effect of SPS on growth of bacteria in blood cultures were studied. For that reason, 752 blood cultures (in media with and without SPS) were detected and found that SPS may help to growth only micrococcus species.


Stimulatory effects of the ionic products from Ca-Mg-Si bioceramics on both osteogenesis and angiogenesis in vitro.
Ideal biomaterials for bone tissue engineering should have the capability to guide the osteogenic differentiation of mesenchymal stem cells and, at the same time, to stimulate angiogenesis of endothelia cells. In this study it was found that three Ca-Mg-Si-containing bioceramics (bredigite Ca7MgSi4O16, akermanite Ca2MgSi2O7 and diopside CaMgSi2O6) had osteogenic and angiogenic potential. The effects of three silicate ceramics on the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) and the angiogenesis of human aortic endothelial cells (HAECs) were explored in comparison with β-tricalcium phosphate (β-TCP) bioceramics. The proliferation, alkaline phosphatase (ALPase) activity and bone-related gene expression (COL1, ALPase, OP, BSP and OC) of hBMSCs were significantly enhanced upon stimulation with ionic extracts of these silicate bioceramics. In addition, the results showed that extracts from the three silicate bioceramics also stimulated HAEC proliferation and in vitro angiogenesis with improved NO synthesis and angiogenic gene expression (KDR, FGFR1, ACVRL1 and NOS3). Among the three silicate ceramics bredigite showed the highest osteogenic and angiogenic potential and with the highest extract Si (possibly Si(OH)3O(-)) concentration, while diopside had the lowest osteogenic and angiogenic potential with the lowest extract Si concentration. Furthermore, it was found that the concentration of Si ions in extracts of the three silicate bioceramics was obviously higher than that of β-TCP ceramics, indicating an important role of Si ions in stimulating cell proliferation, osteogenic differentiation and angiogenesis. The results suggest that the silicate-based akermanite and bredigite ceramics might be good scaffold biomaterials for bone tissue engineering applications due to their distinctive dual functions of osteogenesis/angiogenesis stimulation.


Association between low dietary zinc and hyperuricaemia in middle-aged and older males in China: a cross-sectional study.
To examine the associations between dietary zinc intake and hyperuricaemia. Cross-sectional study. This study was conducted in a health examination centre of China. A total of 5168 middle-aged and older participants (aged 40 years or above) (2697 men and 2471 women) were included. Dietary zinc intake was assessed using a validated semiquantitative food frequency questionnaire. Hyperuricaemia was defined as uric acid ≥416 µmol/L for males and ≥360 µmol/L for females. For males, the prevalence of hyperuricaemia was 22.9%. After adjusting for age, body mass index (BMI) and energy intake, the ORs were 0.68 (95% CI 0.45 to 0.92) in the second quintile, 0.63 (95% CI 0.45 to 0.89) in the third quintile, 0.68 (95% CI 0.46 to 1.00) in the fourth quintile and 0.55 (95% CI 0.35 to 0.87) in the fifth quintile comparing the lowest quintile of Zn intake, respectively (p for trend=0.03). In the multivariable adjusted model, the relative odds of hyperuricaemia were significantly decreased by 0.71 times in the second quintile of zinc intake (OR 0.71, 95% CI 0.52 to 0.98), 0.64 times in the third quintile (OR 0.65, 95% CI 0.44 to 0.94) and 0.55 times in the fifth quintile (OR 0.56, 95% CI 0.32 to 0.97) compared with those in the lowest quintile, and p for trend was 0.064. For females, the prevalence of hyperuricaemia was 10.0%, and unadjusted, minimally adjusted as well as multivariable adjusted ORs all suggested no significant association between dietary zinc intake and hyperuricaemia. The findings of this cross-sectional study indicated that dietary zinc intake was inversely associated with hyperuricaemia in middle-aged and older males, but not in females. The association was significant after considering the influence of age, BMI and energy intake, and after that, minimum adjustment remained independent of further confounding factors such as vitamin C intake, alcohol drinking status and nutrient supplementation.


An equilibrium model of the metastable binding sites of alpha 2-macroglobulin and complement proteins C3 and C4.
Two cyclic structures, the 15-membered thiolactone A and the 5-membered lactam P, have been proposed for the metastable binding sites of the serum proteins C3, C4, and alpha 2-macroglobulin. Neither structure alone adequately explains two unusual reactions of these sites, namely, covalent attachment to nucleophiles with liberation of a thiol group and spontaneous hydrolysis (autolysis) of an internal peptide bond. The metastable binding sites of these proteins were modeled with the 15-membered thiolactone 1 (Khan, S. A., and Erickson, B. W. (1981) J. Am. Chem. Soc. 103, 7374-7376) and the isomeric 5-membered lactam 2, which contains an internal pyroglutamyl (Glp) residue. Under physiologic conditions (phosphate-buffered saline, pH 7.3, 37 degrees C), thiolactone 1 and lactam 2 exist in dynamic equilibrium. Since the molar ratio of 2/1 is 11:1 at equilibrium, lactam 2 is 15 kcal/mol more stable than thiolactone 1. The activation energy for isomerization of 1 into 2 is 18 kcal/mol, which is about 5 kcal/mol lower than that for hydrolysis of the acyclic thiolester N,S-diacetyl-L-cysteine methylamide. Part of the chemistry of the metastable binding sites can be explained by an analogous equilibrium between protein structures A and B. Lactam B may be a key intermediate in the biosynthesis of thiolactone A. Under denaturating conditions, thiolactone A could either bind covalently to a receptive surface or isomerize into lactam B, which could undergo spontaneous hydrolysis of the Glu-Glp peptide bond.


Effects of almix herbicide on profile of digestive enzymes of three freshwater teleostean fishes in rice field condition.
The present investigation was carried out to compare the alterations of digestive enzymes like amylase, lipase, and protease activities in three teleostean fishes viz., Anabas testudineus, Heteropneustes fossilis and Oreochromis niloticus after application of almix herbicide for 30 days at rice field concentration i.e., 8 g/acre. Highest amylase activity was observed in intestine of A. testudineus (300.76%) and lowest in intestine of H. fossilis (103.89%), while maximum lipase activity was found in stomach of O. niloticus (203.27%) and lowest in stomach of H. fossilis (109.65%). Protease activity was also highest in liver of O. niloticus (270.47%) but lowest in stomach of H. fossilis (114.04%). Changes in the enzymes' activity were different in respect to fishes and their tissues. According to this analysis, A. testudineus and O. niloticus were more sensitive. So, it can be inferred that long-term exposure of almix even at environment-friendly concentration may cause alterations in the digestive functions.


Donor-derived anti-CD19 CAR T cells compared with donor lymphocyte infusion for recurrent B-ALL after allogeneic hematopoietic stem cell transplantation.
The efficacy and safety of donor-derived anti-CD19 CAR T cells vs DLI for the management of relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allo-hematopoietic stem cell transplantation (HSCT) remain unclear. Thirteen B-ALL patients with relapsed after allo-HSCT and thus were treated with donor-derived anti-CD19 CAR T-cell (study group). Fifteen B-ALL patients relapsed after allo-HSCT and thus were treated with DLI (DLI group). The rates of MRD-negative complete remission (61.5%) in the study group were significantly higher than those in the DLI group (13.3%) (p = 0.02). The complete remission duration in study group and DLI group were median 8.0 months (range, 3-25 months) and 4.4 months (range, 1-25 months; p = 0.026), respectively. The overall survival of patients in the study group was superior to that of the DLI group: 9.5 months (range,3-25 months) versus 5.5 months (range, 1-25 months; p = 0.030). One patient with grade 1 acute graft-versus-host disease (aGVHD) was identified in the study group. While five (33.3%) patients in the DLI group developed grades III-IV aGVHD. Three patients (23.07%) developed grade 3 or 4 cytokine release syndrome in the study group. This study suggested that donor-derived anti-CD19 CAR T-cell therapy is promising, safe, and potentially effective for relapsed B-ALL after allo-HSCT and may be superior to DLI.


1-D and 2-D coordination networks based on tetrathiacalix[]arene derivative generated with mercury and cobalt salts.
The combination of four iso-nicotinate appended tetrathiacalix[4]arene (TCA-1) in 1,2-alternate imposed conformation behaving as neutral tectons with Co(II)Cl2 and Hg(II)Cl2 metallic salts, leads to the formation of neutral, new coordination networks. Indeed, the tetrasubstituted TCA-1 derivative leads to a 1D coordination polymer with Co(II)Cl2 and a 2D grid-like network with, Hg(II)Cl2. The effect of the nature of the metal used on the dimensionality was demonstrated by X-ray diffraction studies on a single crystal.


Effects of the Otago exercise program on falls, balance, and physical performance in older nursing home residents with high fall risk: a randomized controlled trial.
The aim of this study was to evaluate the effects of Otago exercises on falls, balance, and physical performance in old-aged adults with high fall risk living in a nursing home. This randomized controlled trial included 72 individuals over 65 years of age residing in a single nursing home in Izmir, Turkey. The participants were randomized into the Otago exercise group and walking (control) group. The Otago group performed 45 min of Otago exercises 3 days/week for 12 weeks plus a walking program on 3 other days of the week. The control group did only the walking program (minimum of 30 min 3 days/week). Number of falls, Berg Balance Scale (BBS), 30-s Chair Stand Test (30 s-CST), and 6-min Walk Test (6MWT) were assessed before the intervention and at the end of the 3-month intervention. The primary outcome was number of falls. The groups were well matched in terms of age (74.6 ± 5.9 vs. 75.8 ± 4.5) and sex (p > 0.05). The Otago group showed a significantly greater reduction in number of falls at the end of the intervention (p < 0.05). Of the secondary outcomes, the Otago group had greater median increases in BBS score (p < 0.05) and 30 s-CST score (p < 0.05) post-intervention compared to the walking group. There was no significant difference between the groups in terms of post-intervention change in 6MWT distance (p > 0.05). The Otago exercise program improved balance and physical performance and reduced falls in our sample and may be effective in falls prevention interventions for old-aged nursing home residents.


Natural diversity in phenolic components and antioxidant properties of oregano (Origanum vulgare L.) accessions, grown under the same conditions.
Oregano (Origanum vulgare L.) is a rich source of biologically active components such as phenolic compounds. Here, seven pot grown O. vulgare accessions belonging to three subspecies (subsp. virens, subsp. vulgare and subsp. gracile) were investigated for their content in sixteen bioactive phenolic compounds as well as their antioxidant capacities (DPPH• and FRAP tests), total phenolic content (TPC) and total flavonoid content (TFC) in order to identify the most suitable ones on an industrial level. HPLC analyses showed that rosmarinic acid (659.6-1646.9 mg/100 g DW) was by far the most abundant constituent, followed by luteolin (46.5-345.4 mg/100 g DW), chicoric acid (36.3-212.5 mg/100 g DW), coumarin (65.7-193.9 mg/100 g DW) and quercetin (10.6-106.1 mg/100 g DW), with variability in concentration depending on the accession and subspecies. The highest level of rosmarinic acid and TPC was obtained from Ardabil accession (subsp. virens). There was a significant and positive correlation between rosmarinic acid and antioxidant activity (r = 0.46). TFC significantly correlated to TPC (r = 0.57) as well as to chicoric acid (r = 0.73). Cluster (CA) and principal component (PCA) analyses classified the investigated accessions in three different groups. Such natural variabilities in phenolics provide the possibility of using elite plants for nutraceutical and pharmaceutical industries and domestication of highly antioxidative accessions of oregano.


NOD2 deletion promotes cardiac hypertrophy and fibrosis induced by pressure overload.
Nucleotide-binding oligomerization domain-2 (NOD2, also designated CARD15), a member of the NOD-leucine-rich repeat (LRR) protein family (also called the CATERPILLAR family), is upregulated in atheroma lesions and has an important role in regulating the intracellular recognition of bacterial components by immune cells. However, the effect of NOD2 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of NOD2 deficiency on cardiac hypertrophy induced by aortic banding (AB) in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. NOD2 expression was upregulated in cardiomyocytes after aortic banding surgery in wild-type (WT) mice. NOD2 deficiency promoted cardiac hypertrophy and fibrosis 4 weeks after AB. Further, the enhanced activation of TLR4 and the MAPKs, NF-κB and TGF-β/Smad pathways were found in NOD2-knockout (KO) mice compared with WT mice. Our results suggest that NOD2 attenuates cardiac hypertrophy and fibrosis via regulation of multiple pathways.


Steady-state analysis of alpha-melanotropin in the pars intermedia of Anolis carolinensis: effect of background adaptation.
The steady-state levels of alpha-melanotropin-stimulating hormone (alpha-MSH)-related peptides were examined in the pars intermedia of the reptile Anolis carolinensis as a function of background adaptation. After a 7-day period, the content of immunoreactive alpha-MSH-related material in the pars intermedia of light-adapted animals was approximately fourfold higher than that of animals maintained on a dark background for the same period. The immunoreactive alpha-MSH-related material present in the pars intermedia of light-adapted and dark-adapted animals was separately analyzed by gel filtration chromatography, reverse-phase HPLC, and cation-exchange chromatography. For light-adapted animals the major form of alpha-MSH had an apparent molecular weight of 1.5 kDa and a net charge of +4 at pH 3.5. Following reverse-phase HPLC this material eluted as a single peak of immunoreactivity with a retention time distinct from that of both mammalian ACTH(1-13)amide and N-acetyl-ACTH(1-13)amide. For dark-adapted animals a peak of alpha-MSH-sized material with an apparent molecular weight of 1.5 kDa was also detected. Following reverse-phase HPLC analysis this material eluted as an apparent single peak of immunoreactivity with a retention time distinct from that of the mammalian standards. Subsequent analysis of this major HPLC peak by cation-exchange chromatography revealed the presence of at least two forms of immunoreactive alpha-MSH. These forms differed in relative proportions. The major peak of immunoreactivity had a net charge of +4, whereas the minor peak had a net charge of +3. The +3 immunoreactive form was not detected to any appreciable degree in light-adapted animals.


Autochthonous cutaneous larva migrans infection in Guipúzcoa.
Cutaneous larva migrans (LM) infection forms a serpiginous eruption caused by the migration of nematode helminths through the epidermis. The parasites are acquired when the skin comes into contact with soil contaminated by the feces of infected animals. Until now, infections have been believed to be imported from tropical and subtropical regions. Our aim was to study cases of cutaneous LM diagnosed in residents of the Spanish province of Guipúzcoa who had not recently traveled to such regions. Cross-sectional observational study of LM cases diagnosed in Hospital Universitario Donostia from 2011 to 2015 in patients who had not visited a region where this nematode infection is endemic. Clinical diagnoses were based on characteristic lesions. We studied the following variables: age, sex, site of lesions, date of onset of symptoms, possible source of contagion, pathologic findings, treatment, and clinical course. We found 4 cases, all in men (mean age, 60 years). Lesions were on the lower extremities in 3 patients and on the trunk in 1 patient. All had been in contact with soil that could have been contaminated by feces and was the most likely source of the parasite. The lesions disappeared after treatment with oral albendazole. The appearance of cases of autochthonous LM in Europe requires investigation of the culprit species, a review of the epidemiology of this infection, which was once considered imported, and the planning of public health measures to prevent it from becoming endemic.


Subphenotypes in acute kidney injury: a narrative review.
Acute kidney injury (AKI) is a frequently encountered syndrome especially among the critically ill. Current diagnosis of AKI is based on acute deterioration of kidney function, indicated by an increase in creatinine and/or reduced urine output. However, this syndromic definition encompasses a wide variety of distinct clinical features, varying pathophysiology, etiology and risk factors, and finally very different short- and long-term outcomes. Lumping all AKI together may conceal unique pathophysiologic processes specific to certain AKI populations, and discovering these AKI subphenotypes might help to develop targeted therapies tackling unique pathophysiological processes. In this review, we discuss the concept of AKI subphenotypes, current knowledge regarding both clinical and biomarker-driven subphenotypes, interplay with AKI subphenotypes and other ICU syndromes, and potential future and clinical implications.


Is Sound Exposure Level a Convenient Metric to Characterize Fatiguing Sounds? A Study in Beluga Whales.
Both the level and duration of fatiguing sounds influence temporary threshold shifts (TTSs) in odontocetes. These two parameters were combined into a sound exposure level (SEL). In the beluga whale Delphinapterus leucas, TTSs were investigated at various sound pressure level (SPL)-to-duration ratios at a specific SEL. At low SPL-to-duration ratios, the dependence was positive: shorter high-level sounds produced greater TTSs than long low-level sounds of the same SEL. At high SPL-to-duration ratios, the dependence was negative: long low-level sounds produced greater TTSs than short high-level sounds of the same SEL. Thus, the validity of SEL as a metric for fatiguing sound efficiency is limited.


Recent advancement in Bi5O7I-based nanocomposites for high performance photocatalysts.
Bi5O7I belongs to the family of bismuth oxyhalides (BiOX, X = Cl, Br, I), having a unique layered structure with an internal electrostatic field that promotes the separation and transfer of photo-generated charge carriers. Interestingly, Bi5O7I exhibits higher thermal stability compared to its other BiOX member compounds and absorption spectrum extended to the visible region. Bi5O7I has demonstrated applications in diverse fields such as photocatalytic degradation of various organic pollutants, marine antifouling, etc. Unfortunately, owing to its wide band gap of ∼2.9 eV, its absorption lies mainly in the ultraviolet region, and a tiny portion of absorption lies in the visible region. Due to limited absorption, the photocatalytic performance of pure Bi5O7I is still facing challenges. In order to reduce the band gap and increase the light absorption capability of Bi5O7I, doping and formation of heterostructure strategies have been employed, which showed promising results in the photocatalytic performance. In addition, the plasmonic heterostructures of Bi5O7I were also developed to further boost the efficiency of Bi5O7I as a photocatalyst. Here, in this review article, we present such recent efforts made for the advanced development of Bi5O7I regarding its synthesis, properties and applications. The strategies for photocatalytic performance enhancement have been discussed in detail. Moreover, in the conclusion section, we have presented the current challenges and discussed possible prospective developments in this field.


Closed Management of a Distal Radius Refracture Through a Bent Volar Plate: Can an Open Procedure be Avoided?: A Case Report.
A 55-year-old man sustained a distal radius fracture, which was fixed with a volar plate 20 years ago. He then fell from 2 m and sustained a refracture with a bent but intact volar plate. A manipulation under anaesthetic/anaesthesia was attempted. Satisfactory reduction was confirmed and maintained, with bony union confirmed at 6 months. Regular follow-up showed continuing functional improvement. This rare case avoided surgical intervention and its associated risks and costs. Attempted closed reduction can be considered a treatment option before open revision fixation, with demonstrated ability for fracture healing in an acceptable position.


High performance of electrocatalytic oxidation and determination of hydrazine based on Pt nanoparticles/TiO2 nanosheets.
In this work, highly dispersed Pt nanoparticles (PtNPs) were deposited on the surface of the TiO2 nanosheets (TiO2NSs) by the photodeposition method in the presence of methanol as holes scavengers. The results indicated that PtNPs were distributed on TiO2NSs successfully with the diameter of ca. 5-9 nm. The electrochemical experiments such as electrochemical impedance spectroscopy and cyclic voltammetry were used to study the electrochemical properties of the PtNPs/TiO2NSs modified glassy carbon electrode (GCE). The as-prepared PtNPs/TiO2NSs/GCE presents excellent electrocatalytic activity for hydrazine. The sensor can be used to determine hydrazine at low potential with a wide linear range, high sensitivity, and fast response time. Moreover, the sensor exhibits good selectivity and reproducibility. In addition, the recoveries were 100.1-105.3% for hydrazine in the tap water, indicating the PtNPs/TiO2NSs/GCE should be a promising sensor for the determination of hydrazine in real samples.


Topographical localization of substance P in the human post-mortem brainstem. An immunohistochemical study in the newborn and adult tissue.
The localization of substance P-immunoreactive nervous structures in the newborn and adult human brainstem is studied by the indirect immunofluorescence technique of Coons and collaborators. Substance P-containing perikarya, nerve fibres and terminals are widely and unevenly distributed in several areas of the human brainstem, with a location similar to that described in other mammals; however, some remarkable differences are detectable, which speak in favour of the existence of species differences. For example, in the human brain there is a dense plexus of substance P-immunoreactive fibres in the cuneate fasciculus. The use of the newborn tissue is very helpful in the detection of the immunoreactive neuronal cell bodies. The comparative study of the newborn and the adult tissue reveals that the distribution of the substance P-like immunoreactivity changes in man during ontogeny and results in a more complete map of the substance P-containing neuron system.


Leaf flushing phenology and herbivory in a tropical dry deciduous forest, southern India.
Patterns of leaf-flushing phenology of trees in relation to insect herbivore damage were studied at two sites in a seasonal tropical dry forest in Mudumalai, southern India, from April 1988 to August 1990. At both sites the trees began to flush leaves during the dry season, reaching a peak leaf-flushing phase before the onset of rains. Herbivorous insects emerged with the rains and attained a peak biomass during the wet months. Trees that flushed leaves later in the season suffered significantly higher damage by insects compared to those that flushed early or in synchrony during the peak flushing phase. Species whose leaves were endowed with physical defenses such as waxes suffered less damage than those not possessing such defenses. There was a positive association between the abundance of a species and leaf damage levels. These observations indicate that herbivory may have played a major role in moulding leaf flushing phenology in trees of the seasonal tropics.


Immunohistochemical detection and quantification of T cells in the small intestine of Isospora suis-infected piglets--influence of fixation technique and intestinal segment.
Quantification of immunohistochemical results constitutes an important tool in the analysis of cells and tissue that is not readily replaced by other techniques. For reliable quantification, it is essential to consider factors such as tissue fixation and tissue sampling. We report a study on the model of the intestine of Isospora suis-infected piglets, in which we addressed (1) whether the quantity of detectable T cells in the intestinal mucosa is the same in formalin-, HOPE®-, and cryo-conserved material or whether the amounts of T cells at least correlate with one another; and (2) whether single jejunal segments differ in regard to the quantity of mucosal T cells and variability of lymphocyte infiltration. Quantification of T cells in histological sections of different parts of the jejunum of 15-22 day old piglets infected with I. suis was performed using an anti-CD3-antibody and stereological point counting. Area fractions of T-cell profiles per intestinal mucosa profile were higher in cryo-conserved samples than in HOPE®- and formalin-conserved material but no correlation between different fixations could be found. The proximal part of the jejunum contained fewer T cells compared with mid- and end-jejunum. Coefficients of variation did not differ between the intestinal segments. For quantification of T cells in the gut mucosa of piglets infected with I. suis, the cryo-conserved mid jejunum seems most suitable in cases when unbiased sampling of the complete intestine is not feasible. It is generally not possible to compare quantitative results of immunostaining in samples conserved by different methods.


White-light performance of a polarization-independent liquid-crystal phase modulator.
The broadband performance of a polarization-insensitive liquid-crystal phase modulator is analyzed, and its effect on an adaptive optics system is quantified.


Ultra-trace level speciated isotope dilution measurement of Cr(VI) using ion chromatography tandem mass spectrometry in environmental waters.
The reliable analysis of highly toxic hexavalent chromium, Cr(VI), at ultra-trace levels remains challenging, given its easy conversion to non-toxic trivalent chromium. This work demonstrates a novel analytical method to quantify Cr(VI) at low ngL(-1) concentration levels in environmental water samples by using speciated isotope dilution (SID) analysis and double-spiking with Cr(III) and Cr(VI) enriched for different isotopes. Ion chromatography tandem mass spectrometry (IC-MS/MS) was used for the analysis of Cr(VI) as HCrO4(-) → CrO3(-). Whereas the classical linear multipoint calibration (MPC) curve approach obtained a method detection limit (MDL) of 7ngL(-1) Cr(VI), the modified SID-MS method adapted from U. S. EPA 6800 allowed for the quantification of Cr(VI) with an MDL of 2ngL(-1) and provided results corrected for Cr(VI) loss occurred after sample collection. The adapted SID-MS approach proved to yield more accurate and precise results than the MPC method, allowed for compensation of Cr(VI) reduction during sample transportation and storage while eliminating the need for frequent external calibration. The developed method is a complementary tool to routinely used inductively-coupled plasma (ICP) MS and circumvents typically experienced interferences.


Craniospinal irradiation for trilateral retinoblastoma following ocular irradiation.
A case study is presented. Craniospinal radiotherapy and a three-fold pineal boost for trilateral retinoblastoma were delivered to a patient previously irradiated for ocular retinoblastoma. The availability of CT-based three-dimensional treatment planning provided the capability of identifying the previously irradiated volume as a three-dimensional anatomic structure and of designing a highly customized set of treatment beams that minimized reirradiation of that volume.


Protective action of Cecropia pachystachya extract and enriched flavonoid fraction against memory deficits, inflammation and oxidative damage in lipopolysaccharide challenged mice.
Cecropia pachystachya (CP) Trécul is a medicinal plant native to South and Central America with several pharmacological properties, such as anti-inflammatory and neuroprotective. In this study, we investigated the effect of CP extract (200 mg/kg) and its enriched flavonoid fraction (EFF-CP) (50 and 100 mg/kg) in a model of lipopolysaccharide (LPS)-induced neuroinflammation. CP and EFF-CP were administered intragastrically for 14 days and LPS (250 μg/kg) was administered intraperitoneally from the 8th to the 14th days. LC/DAD/MS analysis showed the presence of isoorientin, orientin, and isovitexin as major compounds. The results demonstrated that CP extract and EFF-CP gave protection against LPS-induced short-term and long-term memory deficits. The treatment with CP and/or EFF-CP protected against LPS-induced increases in reactive species, nitrites, total thiol and lipoperoxidation in the cerebral cortex, hippocampus and striatum. Moreover, CP and EFF-CP restored superoxide dismutase and catalase activities that had been reduced by LPS in the cerebral cortex, hippocampus and striatum. TNF-α levels were increased in the cortex, striatum and hippocampus in the LPS group, while CP treatment prevented this change in the cerebral cortex. EFF-CP decreased the levels of this cytokine in all structures analyzed at both doses. CP extract and its EFF-CP are important therapeutic targets for the management of neuroinflammation observed in neurodegenerative diseases.


Successful drug treatment of schistosomal myelopathy. A case report.
In a patient who presented with quadriplegia a large mass was demonstrated radiologically in the cervical part of the spinal canal. The patient came from an area where there is a high prevalence of schistosomiasis, and antischistosomal antibodies were present in the serum. Treatment with the antischistosomal drug niridazole led to a total clinical recovery and almost complete disappearance of the myelographic filling defect.


Impact of Levetiracetam Treatment on 5-Aminolevulinic Acid Fluorescence Expression in IDH1 Wild-Type Glioblastoma.
The amino acid 5-aminolevulinic acid (5-ALA) is the most established neurosurgical fluorescent dye and facilitates the achievement of gross total resection. In vitro studies raised concerns that antiepileptic drugs (AED) reduce the quality of fluorescence. Between 2013 and 2018, 175 IDH1 wild-type glioblastoma (GB) patients underwent 5-ALA guided surgery. Patients' data were retrospectively reviewed regarding demographics, comorbidities, medications, tumor morphology, neuropathological characteristics, and their association with intraoperative 5-ALA fluorescence. The fluorescence of 5-ALA was graded in a three point scaling system (grade 0 = no; grade 1 = weak; grade 2 = strong). Univariable analysis shows that the intake of dexamethasone or levetiracetam, and larger preoperative tumor area significantly reduce the intraoperative fluorescence activity (fluorescence grade: 0 + 1). Multivariable binary logistic regression analysis demonstrates the preoperative intake of levetiracetam (adjusted odds ratio: 12.05, 95% confidence interval: 3.91-37.16, p = 0.001) as the only independent and significant risk factor for reduced fluorescence quality. Preoperative levetiracetam intake significantly reduced intraoperative fluorescence. The indication for levetiracetam in suspected GB should be carefully reviewed and prophylactic treatment avoided for this tumor entity. Future comparative trials of neurosurgical fluorescent dyes need a special focus on the influence of levetiracetam on fluorescence intensity. Further trials must validate our findings.


Erratum: Guidelines for the management of ulcerative colitis. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology. Erratum.
[This corrects the article DOI: 10.5114/pg.2023.125882.].


Abundance of microplastics in cultured oysters (Crassostrea gigas) from Danang Bay of Vietnam.
This study focuses on determination of quantity, shape, size and polymer types of microplastics in Pacific oysters (Crassostrea gigas) cultured in Danang Bay, Vietnam. Visual verification and chemical identification of microplastics was carried out by μFT-IR spectra using Nicolet iN10 MX Infrared Imaging Microscope. The average abundance of microplastic in oysters was 1.88 ± 1.58 particles/g (wet weight) and 18.54 ± 10.08 particles/individual. The prevalent shape of microplastics included three main forms as fragment, fiber and bead corresponding to 73.71; 25.84 and 0.45%, respectively. Additionally, the size of microplastics was a range of 22.4-1318.8 μm, and the most common size was less than 100 μm, accounted for 77.30%. Fifteen polymer types were detected while Nylon was the most abundant polymer type with 50.56%. In this study, microplastics accumulation with their abundance and polymeric structures could be considered as reliable evidence for further studies on assessment of their potential risk to human health.


Contemporary prevalence and correlates of incident heart failure with preserved ejection fraction.
We assessed the prevalence of preserved left ventricular ejection fraction in patients with incident heart failure and differences in the demographic and clinical characteristics that may differentiate patients presenting with heart failure with preserved versus reduced left ventricular ejection fraction. We identified all patients with newly diagnosed heart failure between 2005 and 2008 from 4 sites in the Cardiovascular Research Network on the basis of hospital discharge and ambulatory visit diagnoses, and assigned a category of preserved, borderline, or reduced left ventricular ejection fraction using data from electronic databases and chart review. We identified 11,994 patients with incident heart failure; of these, 6210 (51.8%) had preserved left ventricular ejection fraction, 1870 (15.6%) had borderline systolic dysfunction, and 3914 (32.6%) had reduced left ventricular ejection fraction. For those with heart failure with preserved left ventricular ejection fraction, the mean age was 74.7 years and 57.1% were women; for those with borderline systolic dysfunction, the mean age was 71.6 years and 38.4% were women; and for those with reduced left ventricular ejection fraction, the mean age was 69.1 years and 32.6% were women. Compared with white patients, black patients were less likely to have heart failure with preserved systolic function. Those with a history of coronary artery bypass surgery, mitral or aortic valvular disease, atrial fibrillation or flutter, or a diagnosis of hypertension were more likely to have heart failure with preserved systolic function, as were those with a diverse range of noncardiac comorbid conditions, including chronic lung disease, chronic liver disease, a history of a hospitalized bleed, a history of a mechanical fall, a diagnosis of depression, and a diagnosis of dementia. Patients with a history of acute myocardial infarction and a history of ventricular fibrillation or ventricular tachycardia were less likely to have heart failure with preserved left ventricular ejection fraction. Patients with higher systolic blood pressures at baseline and lower low-density lipoprotein levels were more likely to have heart failure with preserved left ventricular ejection fraction, as were those with lower hemoglobin levels and the lowest glomerular filtration rates. Heart failure with preserved left ventricular ejection fraction is the most common form of the heart failure syndrome among patients newly presenting with this condition, and women and older adults are especially affected. Evidence-based treatment strategies apply to less than one third of patients with newly diagnosed heart failure.


Associations between climate variables and water quality in low- and middle-income countries: A scoping review.
Understanding how climate change will affect water quality and therefore, health, is critical for building resilient water services in low- and middle-income countries (LMICs) where the effect of climate change will be felt most acutely. Evidence of the effect of climate variables such as temperate and rainfall on water quality can generate insights into the likely impact of future climate change. While the seasonal effects on water quality are known, and there is strong qualitative evidence that climate change will impact water quality, there are no reviews that synthesise quantitative evidence from LMICs on links between climate variables and water quality. We mapped the available evidence on a range of climate exposures and water quality outcomes and identified 98 peer-reviewed studies. This included observational studies on the impact of temperature and rainfall events (which may cause short-term changes in contaminant concentrations), and modelling studies on the long-term impacts of sea level rise. Evidence on links between antecedent rainfall and microbiological contamination of water supplies is strong and relatively evenly distributed geographically, but largely focused on faecal indicator bacteria and on untreated shallow groundwater sources of drinking water. The literature on climate effects on geogenic contaminants was sparse. There is substantial research on the links between water temperature and cyanobacteria blooms in surface waters, although most studies were from two countries and did not examine potential effects on water treatment. Similarly, studies modelling the impact of sea level rise on groundwater salinity, mostly from south-Asia and the Middle East, did not discuss challenges for drinking water supplies. We identified key future research priorities based on this review. These include: more studies on specific pathogens (including opportunistic pathogens) in water supplies and their relationships with climate variables; more studies that assess likely relationships between climate variables and water treatment processes; studies into the relationships between climate variables and geogenic contaminants, including risks from heavy metals released as glacier retreat; and, research into the impacts of wildfires on water quality in LMICs given the current dearth of studies but recognised importance.


Decision-level fusion of Sentinel-1 SAR and Landsat 8 OLI texture features for crop discrimination and classification: case of Masvingo, Zimbabwe.
Radar imagery have few polarization bands which can limit the ability to do traditional digital classification. Harmonization of Sentinel-1 and Landsat 8 data despite having complementary texture information can be a challenge. The objectives of this paper are to explore texture features derived from Landsat 8 OLI and dual-polarized Sentinel-1 SAR speckle filtered and unfiltered backscatter, to aggregate classification results using Decision-Level Fusion (DLF), and to evaluate the performance of decision-level fused maps. Gray Level Co-occurrence Matrix (GLCM) is employed to derive sets of seven texture features for Landsat 8 bands and VV + VH backscatter using 5 × 5, 7 × 7, 9 × 9, and 11 × 11 window sizes. Each texture feature is stacked with a respective source image and classified using Support Vector Machine (SVM). Classified maps from the best three performers from both speckle filtered and unfiltered are aggregated with classified maps from Landsat 8 using plurality voting algorithm and compared using Z-test. Results indicate an overall classification accuracy of 96.02% from DLF images of Landsat and non-speckle filtered maps, whereas Landsat and speckle filtered achieved 94.69%. The best texture information are derived from the blue band followed by the red band, whereas speckle unfiltered textures performed better than speckle filtered textures. We conclude that integration of Landsat 8 and Sentinel-1, either speckle filtered or unfiltered, improves crop classification and speckles do not have statistically significant effects (p = 0.1208).


A signaling complex of adenylate cyclase CyaC of Sinorhizobium meliloti with cAMP and the transcriptional regulators Clr and CycR.
Adenylate cyclases (ACs) generate the second messenger cyclic AMP (cAMP), which is found in all domains of life and is involved in the regulation of various cell physiological and metabolic processes. In the plant symbiotic bacterium Sinorhizobium meliloti, synthesis of cAMP by the membrane-bound AC CyaC responds to the redox state of the respiratory chain and the respiratory quinones. However, nothing is known about the signaling cascade that is initiated by cAMP produced by CyaC. Here, the CRP-like transcriptional regulator Clr and the TetR-like regulator CycR (TR01819 protein) were identified to interact with CyaC using the bacterial two-hybrid system (BACTH), co-sedimentation assays, and surface plasmon resonance spectroscopy. Interaction of CycR with Clr, and of CyaC with Clr requires the presence of cAMP and of ATP, respectively, whereas that of CyaC with CycR was independent of the nucleotides. The data implicate a ternary CyaC×CycR×cAMP-Clr complex, functioning as a specific signaling cascade which is formed after activation of CyaC and synthesis of cAMP. cAMP-Clr is thought to work in complex with CycR to regulate a subset of genes of the cAMP-Clr regulon in S. meliloti.


Allozymic heterozygosity and morphological variation in house sparrows.
Several reports have shown that greater heterozygosity (both between individuals and between populations) is associated with lower morphological variance and asymmetry. Most previous work concerned poikilothermic organisms (for example, fish, butterflies, lizards, shellfish, salamanders and plants). Reports concerning two homoiotherms gave conflicting results. The report by Handford on a songbird, Zonotrichia capensis, failed to support the relationship, although these results have been questioned in the literature. Handford suggested that the lack of relationship in Zonotrichia could indicate a fundamental difference between homoiotherms and poikilotherms, reflected in their apparent differences in heterozygosity. However, we report here on electrophoretic and morphometric studies on another songbird species (Passer domesticus), in which the relationship appears to be upheld. We find consistently, among four locality samples, that the class of individuals of greatest allozyme heterozygosity nearly always exhibits the lowest multivariate morphological variance, and the class of greatest homozygosity nearly always exhibits the highest.


Microstructural control of new intercalation layered titanoniobates with large and reversible d-spacing for easy Na+ ion uptake.
Key issues for Na-ion batteries are the development of promising electrode materials with favorable sites for Na+ ion intercalation/deintercalation and an understanding of the reaction mechanisms due to its high activation energy and poor electrochemical reversibility. We first report a layered H0.43Ti0.93Nb1.07O5 as a new anode material. This anode material is engineered to have dominant (200) and (020) planes with both a sufficiently large d-spacing of ~8.3 Å and two-dimensional ionic channels for easy Na+ ion uptake, which leads to a small volume expansion of ~0.6 Å along the c direction upon Na insertion (discharging) and the lowest energy barrier of 0.19 eV in the [020] plane among titanium oxide-based materials ever reported. The material intercalates and deintercalates reversibly 1.7 Na ions (~200 mAh g-1) without a capacity fading in a potential window of 0.01 to 3.0 V versus Na/Na+. Na insertion/deinsertion takes place through a solid-solution reaction without a phase separation, which prevents coherent strain or stress in the microstructure during cycling and ensures promising sodium storage properties. These findings demonstrate a great potential of H0.43Ti0.93Nb1.07O5 as the anode, and our strategy can be applied to other layered metal oxides for promising sodium storage properties.