Crosstalk between the brain and bone.
Bone alters its metabolic and anabolic activities in response to the variety of systemic and local factors such as hormones and growth factors. The responsiveness of bone is accomplished by the action of osteoblasts, osteoclasts and osteocytes through the process of bone remodeling. The importance of the nervous system on body homeostasis systems has been described (1) and has been suggested that organogenesis and tissue repair are under neuronal control.The first documentation of an anatomic relationship between nerves and bone was made via woodcut, by Charles Estienne in Paris in 1545, which demonstrated nerves entering and leaving the bones of a skeleton (2). Later, several authors showed that cortical bone is densely innervated (3) and differentiated myelinated and non-myelinated fibers are associated with the arterial vessels and venous sinusoids in bone (4). This began a steady flow of studies of various nerve types in bone by a number of different groups (2). The field has recently been reinvigorated by the observation of an important role of neural control of many aspects of bone metabolism (2).


Communities of Putative Ericoid Mycorrhizal Fungi Isolated from Alpine Dwarf Shrubs in Japan: Effects of Host Identity and Microhabitat.
Dwarf shrubs of the family Ericaceae are common in arctic and alpine regions. Many of these plants are associated with ericoid mycorrhizal (ERM) fungi, which allow them to take nutrients and water from the soil under harsh environmental conditions and, thus, affect host plant survival. Despite the importance of ERM fungi to alpine plant communities, limited information is available on the effects of microhabitat and host identity on ERM fungal communities. We investigated the communities of putative ERM fungi isolated from five dwarf shrub species (Arcterica nana, Diapensia lapponica, Empetrum nigrum, Loiseleuria procumbens, and Vaccinium vitis-idaea) that co-occur in an alpine region of Japan, with reference to distinct microhabitats provided by large stone pine (Pinus pumila) shrubs (i.e. bare ground, the edge of stone pine shrubs, and the inside of stone pine shrubs). We obtained 703 fungal isolates from 222 individual plants. These isolates were classified into 55 operational taxonomic units (OTUs) based on the sequencing of internal transcribed spacer regions in ribosomal DNA. These putative ERM fungal communities were dominated by Helotiales fungi for all host species. Cistella and Trimmatostroma species, which have rarely been detected in ERM roots in previous studies, were abundant. ERM fungal communities were significantly different among microhabitats (R2=0.28), while the host effect explained less variance in the fungal communities after excluding the microhabitat effect (R2=0.17). Our results suggest that the host effect on ERM fungal communities is minor and the distributions of hosts and fungal communities may be assessed based on microhabitat conditions.


Diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer: current practice.
Nuclear medicine techniques continue to be important non-invasive imaging tools assisting the diagnosis, monitoring and--in some cases--treatment of prostate cancer. Bone scintigraphy was the premier modality to have an extensive role in the staging of prostate cancer and has remained an integral tool for over three decades in the assessment of newly diagnosed disease or in follow-up staging. Therapeutic treatment and palliation of disseminated disease, particularly in the skeleton, has also been successful with several radioisotopes including strontium-89 chloride. Despite advances in nuclear medicine techniques and molecular imaging technology such as positron emission tomography and radioimmunoscintigraphy, bone scintigraphy still remains the gold standard in the assessment of osseous metastatic disease in prostate cancer. Thus, it is important to continually review the modalities that have remained important over time and not just to focus on newer technologies. This article summarizes the current diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer with particular reference to radionuclide bone scintigraphy and positron emission tomography.


Using matched survey and administrative data to estimate eligibility for the Medicare Part D low-income subsidy program.
This article uses matched survey and administrative data to estimate, as of 2006, the size of the population eligible for the Low-Income Subsidy (LIS), which was designed to provide "extra help" with premiums, deductibles, and copayments for Medicare Part D beneficiaries with low income and limited assets. We employ individual-level data from the Survey of Income and Program Participation and the Health and Retirement Study to cover the potentially LIS-eligible noninstitutionalized and institutionalized populations of all ages. The survey data are matched to Social Security administrative data to improve on potentially error-ridden survey measures of income and program participation. Our baseline estimate, based on the matched data, is that about 12 million individuals were potentially eligible for the LIS as of 2006. A sensitivity analysis indicates that the use of administrative data has a relatively small effect on the estimates, but does suggest that measurement error is important to account for.


MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features.
The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10-12), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.


Fish oil attenuates adrenergic overactivity without altering glucose metabolism during an oral glucose load in haemodialysis patients.
Haemodialysis patients display an increased cardiac mortality, which may be partly related to increased sympathoadrenal activity and insulin resistance. Fish oil decreases adrenal activation induced by mental stress and has an insulin sensitizing effect in healthy subjects. Whole-body glucose metabolism after oral glucose was studied in eight haemodialysis patients before and after a 3-week oral fish oil supplementation (i.e. EPA + DHA at 1.8 g/d). Plasma glucose fluxes were traced by using [6,6- (2)H2]glucose infusion. Substrate oxidation was determined by using indirect calorimetry. Each patient was studied in the basal state and over the 6 h following absorption of a 1 g/kg glucose load. Energy expenditure in response to glucose re-increased over the last 2 h of the experiment (P < 0.05), which coincided with an increase in plasma catecholamines, especially epinephrine (P < 0.05), strongly suggesting a sympathoadrenal overactivity. Fish oil supplementation blunted both re-increase in thermogenic response and concomitant increase in plasma epinephrine, but not in plasma norepinephrine, over the last 2 h of the experiment. Fish oil did not alter either whole-body glucose metabolism or substrate oxidation. These data show that in haemodialysis patients, fish oil attenuates adrenal overactivity induced by oral glucose but does not modulate whole-body glucose metabolism and insulin sensitivity.


Identification of key uric acid synthesis pathway in a unique mutant silkworm Bombyx mori model of Parkinson's disease.
Plasma uric acid (UA) levels decrease following clinical progression and stage development of Parkinson's disease (PD). However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori) op. Initially, we investigated the causality of the phenotypic "op" by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH) and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD.


Effect of external stress on density and size of glandular trichomes in full-grown Artemisia annua, the source of anti-malarial artemisinin.
Glandular trichomes (GT) of Artemisia annua produce valuable compounds for pharmaceutical and industrial uses, most notably the anti-malarial artemisinin. Our aim was to find out whether the density, number and size of GT can be manipulated to advantage by environmental stress. A range of external stress treatments, including stress response regulators, was therefore given to fully grown plants under field and greenhouse conditions. In a field experiment (Ex1), seed-grown plants were subjected to chemical or physical stress and plants analysed after 5 weeks. In a greenhouse experiment (Ex2), three groups of clonally derived plants were stressed at weekly intervals for 5 weeks. Stress treatments included sandblasting, leaf cutting and spraying with jasmonic acid, salicylic acid, chitosan oligosaccharide (COS), H(2)O(2) (HP) and NaCl (SC)at different concentrations. Leaves from an upper and a lower position on the plants were analysed by fluorescence microscopy to determine the density and size of GT. Densities of GT on upper leaves of full-grown A. annua plants generally showed no response to external stress and only plants from one clone of Ex2 supported the hypothesis that increased density of GT was inducible in upper leaves by stress (significant for SC, HP and COS). The density of GT on lower leaves was not affected by stress in any experiment. Glandular trichomes were significantly smaller on the lower leaves in response to stress in Ex2, and a similar non-significant trend was observed in Ex1. The results indicate a dynamic system in which stress treatments of large A. annua plants had a minor promoting effect on the initiation of GT in developing leaves, and a maturing effect of GT later in the lifetime of the individual GT. The hypothesis that applying stress can induce larger GT or more numerous GT was rejected.


Risk factors associated with sleep disturbance following traumatic brain injury: clinical findings and questionnaire based study.
Sleep disturbance is very common following traumatic brain injury (TBI), which may initiate or exacerbate a variety of co-morbidities and negatively impact rehabilitative treatments. To date, there are paradoxical reports regarding the associations between inherent characteristics of TBI and sleep disturbance in TBI population. The current study was designed to explore the relationship between the presence of sleep disturbance and characteristics of TBI and identify the factors which are closely related to the presence of sleep disturbance in TBI population. 98 TBI patients (72 males, mean age ± SD, 47 ± 13 years, range 18-70) were recruited. Severity of TBI was evaluated based on Glasgow Coma Scale (GCS). All participants performed cranial computed tomography and were examined on self-reported sleep quality, anxiety, and depression. TBI was mild in 69 (70%), moderate in 15 (15%) and severe in 14 (15%) patients. 37 of 98 patients (38%) reported sleep disturbance following TBI. Insomnia was diagnosed in 28 patients (29%) and post-traumatic hypersomnia in 9 patients (9%). In TBI with insomnia group, 5 patients (18%) complained of difficulty falling asleep only, 8 patients (29%) had difficulty maintaining sleep without difficulty in initial sleep and 15 patients (53%) presented both difficulty falling asleep and difficulty maintaining sleep. Risk factors associated with insomnia were headache and/or dizziness and more symptoms of anxiety and depression rather than GCS. In contrast, GCS was independently associated with the presence of hypersomnia following TBI. Furthermore, there was no evidence of an association between locations of brain injury and the presence of sleep disturbance after TBI. Our data support and contribute to a growing body of evidence which indicates that TBI patients with insomnia are prone to suffer from concomitant headache and/or dizziness, report more symptoms of anxiety and depression and severe TBI patients are likely to experience hypersomnia.


Ab initio calculations to model anomalous fluorine behavior.
Implanted fluorine is observed to behave unusually in silicon, manifesting apparent uphill diffusion and reducing diffusion and enhancing activation of boron. In order to investigate fluorine behavior, we calculate the energy of fluorine defect structures in the framework of density functional theory. In addition to identifying the ground-state configuration and diffusion migration barrier of a single fluorine atom in silicon, a set of energetically favorable fluorine defect structures were found (F(n)V(m)). The decoration of vacancies and dangling silicon bonds by fluorine suggests that fluorine accumulates in vacancy-rich regions, which explains the fluorine redistribution behavior reported experimentally.


Synthesis of nitrogen-functionalized beta-cycloaltrins.
We report the synthesis of functionalized beta-cycloaltrins having azido groups at C-3, C-6, and both C-3 and C-6 by nucleophilic epoxy ring-opening of per-2,3-anhidro-beta-cyclomannin derivatives. The value of these compounds as templates for further functionalization is exemplified by the conversion of heptakis(3,6-diazido-3,6-dideoxy)-beta-cycloaltrin into the per-3,6-diamino, per-3,6-diacetamido, per-3,6-dichloroacetamido, and per[3,6-bis(N'-ethylureido)] derivatives in good yields.


Plantar fascia rupture in a professional soccer player.
We report the case of a 29-year-old male professional soccer player who presented with symptoms of plantar fasciitis. His symptoms occurred with no remarkable triggers and gradually worsened despite conservative treatments including taping, use of insoles, and physical therapy. Local corticosteroid injection was given twice as a further intervention, but his plantar fascia partially ruptured 49 days after the second injection. He was treated conservatively with platelet-rich plasma, and magnetic resonance imaging showed regenerative change of the ruptured fascia. Five months after the rupture, he returned to his original level of training. If professional athletes find it difficult to refrain from athletic activity, as in the present case, the risk of rupture due to corticosteroid injection should not be overlooked.


Hygroscopic properties of two model humic-like substances and their mixtures with inorganics of atmospheric importance.
Water-soluble macromolecular polyacids can play a potentially important role in the hygroscopic properties of atmospheric aerosols. These acids have molecular structures similar to natural fulvic acids (FA) (or humic acids) and are referred to as humic-like substances (HULIS). In this study, the hygroscopicity of HULIS and the mixture of HULIS and sodium chloride (NaCl) and that of HULIS and ammonium sulfate (AS) aerosols at a mass ratio of 1:1 are studied using two natural FA: the Nordic Aquatic Fulvic Acid (NAFA) and the Suwannee River Fulvic Acid (SRFA) as model compounds in an electrodynamic balance. NAFA and SRFA both absorbed and desorbed water reversibly without crystallization and retained water at a relative humidity (RH) < 10%. NAFA and SRFA have a mass growth ratio of 1.25 and 1.45 from RH = 10% to RH = 90%, respectively. However, these results are different from those of another natural FA (the Nordic River Fulvic Acid Reference) in the literature. The differences are possibly due to the differences in the chemical composition of the natural FA, which depends on their sources and the isolation methods. These results suggest that a standardization of the isolation methods of HULIS is needed for better understanding of their atmospheric properties and environmental impacts. In general, the deliquescence and crystallization RH of FA-inorganic mixtures are comparable with those of their respective pure inorganic species. Since FA are less hygroscopic than NaCl and AS, all mixtures absorb less water compared to their respective pure inorganic species of equal particle mass. The FA-AS mixtures have a larger water uptake than the sum of those of the FA and AS individually following a simple additivity rule as noninteracting species at RH = 90%. This enhancement effect increases as the RH decreases. There is no such enhancement effect for the FA-NaCl mixtures until RH is below 90%. These results reveal that the effect of the interactions between FA and inorganic species on the water uptake of the mixtures, in general, is a function of RH.


Activation of the E3 ubiquitin ligase Parkin.
The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.


Studies on the in vivo metabolism of the SARM YK11: Identification and characterization of metabolites potentially useful for doping controls.
A steroidal compound was recently detected in a seized black market product and was identified as (17α,20E)-17,20-[(1-methoxyethylidene) bis (oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11). This compound is described to possess selective androgen receptor modulator- and myostatin inhibitor-like properties. As YK11 is an experimental drug candidate and a non-approved substance for humans, scientific data on its metabolism is scarce. Due to its steroidal backbone and the arguably labile orthoester-derived moiety positioned at the D-ring, substantial metabolic conversion in vivo was anticipated. To unambiguously detect urinary metabolites of YK11, an elimination study with six-fold deuterated YK11 was conducted. Post-administration specimens were analyzed using hydrogen isotope ratio mass spectrometry coupled to single quadrupole mass spectrometry to identify metabolites alongside basic mass spectrometric data. Further characterization of those metabolites relevant to sports drug testing was accomplished using gas chromatography-high resolution-high accuracy mass spectrometry. Fourteen deuterated urinary metabolites were detected comprising unconjugated, glucuronidated, and sulfoconjugated metabolites. As expected, no intact YK11 was observed in the elimination study urine samples. While the unconjugated metabolites disappeared within 24 hours post-administration, both glucuronidated and sulfated metabolites were traceable for more than 48 hours. The chemical structures of the two most promising glucuronidated metabolites (5β-19-nor-pregnane-3α,17β,20-triol and 5β-19-nor-pregnane-3α,17β-diol-20-one) were verified by in-house synthesis of both metabolites and confirmed by nuclear magnetic resonance analysis. In order to elucidate their potential in sports drug testing, both were successfully implemented into the currently applied analytical method for the detection of anabolic agents.


Preparation and crystal structures of the beryllium ammines [Be(NH3)4]X2 (X = Br, I, CN, SCN, N3) and Be(NH3)2X'2 (X' = Cl, Br, I).
Tetraammineberyllium halides and pseudo-halides [Be(NH3)4]X2 (X = Cl, Br, I, CN, SCN, N3) as well as Be(NH3)2F2 have been prepared from beryllium metal and NH4X or NH4F in liquid ammonia at ambient temperature, respectively. Diammineberyllium halides Be(NH3)2X'2 (X' = Cl, Br, I) were synthesized at 300 °C from Be and NH4X'. The obtained compounds were characterised via X-ray diffraction, and IR and Raman spectroscopy and their thermal decomposition was studied by TGA.


Correlation-spectral characteristics of cortical potentials in a wide frequency range in dogs in the process of elaborating a lever-pressing alimentary conditioned response.
Power spectra (PS) and cross-correlation coefficients (CC) of the background electrical activity (2-100 Hz) in different neocortical areas were studied in dogs in the state of quiet wakefulness (QW) and after elaboration of motor (lever-pressing) alimentary conditioned responses (CR). Regional differences revealed that in all the frequency bands, including the high-frequency frequencies, there was a significant increase of power in the frequency band of 61-100 Hz which was not the same in different cortical areas after CR elaboration. This shows that not only their information value of high frequency bioelectrical processes but also their neuronal origin is essential. After elaboration of the same CR, individual EEG peculiarities observed in the QW became levelled and the functional state became characteristic for this type of conditioning and was reflected in the distributions of CC and PS of the background activity.


Myocardial G protein-coupled receptor kinases: implications for heart failure therapy.
The beta-adrenergic signaling cascade is an important regulator of myocardial function. Significant alterations of this pathway are associated with several cardiovascular diseases, including congestive heart failure (CHF). Included in these alterations is increased activity and expression of G protein-coupled receptor kinases (GRKs), such as the beta-adrenergic receptor kinase (beta ARK1), which phosphorylate and desensitize beta-adrenergic receptors (beta ARs). A body of evidence is accumulating that suggests that GRKs, in particular beta ARK1, are critical determinants of cardiac function under normal conditions and in disease states. Transgenic mice with myocardial-targeted alterations of GRK activity have shown profound changes in the in vivo functional performance of the heart. Included in these studies is the compelling finding that inhibition of beta ARK1 activity or expression significantly enhances cardiac function and potentiates beta AR signaling in failing cardiomyocytes. This article summarizes the advances made in the study of beta ARK1 in the heart and addresses its potential as a novel therapeutic target for CHF.


Gastric emptying of liquids and solids: roles of proximal and distal stomach.
The objective was to explore the hypothesis that the proximal stomach has a major role in gastric emptying of liquids and the distal stomach a major role in gastric emptying of solids. The results of experiments on the intact stomach and on the stomach after selective resections, denervations, and during hormonal infusions are, in general, consistent with the hypothesis.


Nerve growth factor and cyclic AMP: opposite effects on neuroblastoma-substrate adhesion.
Increased cellular adhesion has been postulated to be an early event required of neuroblasts undergoing neurite extension during differentiation. Nerve growth factor (NGF) induces neurite extension in a variety of cell types of neural crest origin. In the PC12 rat pheochromocytoma cell line, which has been proposed as a model for precursor cells to sympathetic neurons, NGF and dibutyryl cyclic AMP (dBcAMP) promote both neurite extension and an increased rate of cell-substrate adhesion. Since dBcAMP can substitute for NGF in this enhancement of adhesion rate in the PC12 cell line, cAMP has been suggested as a second messenger for NGF. We have shown that in two nearly diploid adrenergic like human neuroblastoma clones, the KA and SY5Y cell lines, which also extend neurites in response to both NGF and dBcAMP, only NGF enhances cellular adhesion, as defined by an increase in the number of cells cells prelabeled with 35S-methionine which attach to culture dishes at a given time. Incubation with monospecific antibodies directed against murine beta-NGF abolishes the NGF effect on adhesion. The NGF effect on human neuroblastoma is specific insofar as NGF does not facilitate adhesion of two glioma lines. Unlike the results obtained for PC12, in both SY5Y and KA lines, 1 mM dBcAMP decreases the rate of adhesion to levels significantly below those of controls. Adhesiveness of neuroblastoma cells treated with both NGF and dBcAMP is intermediate between that of cells treated with either agent alone. While theophylline mimics the dBcAMP effect, sodium butyrate has no such effect. At 22 degrees C, the effect of NGF on neuroblastoma substrate adhesion is observable within 5 minutes and persists for 2 hours; treatment of the KA line with NGF at 37 degrees C for 24 hours results in a more persistent enhancement of cell adhesion. Furthermore, both SY5Y and KA exhibit different morphologies when challenged with NGF, dBcAMP, or sodium butyrate. This study suggests that NGF and cyclic AMP do not share a common mechanism of action, but can in fact interact antagonistically in an adrenergic like neuroblastoma model system. Furthermore, the results suggest that increased cellular adhesiveness may not be an obligatory prerequisite for neurite extension by neuroblasts in development.


Stable and efficient transformation of apple.
Apple is one of precious fruit crop grown in temperate zone. In the post genomic era, the analysis of gene functions in horticultural crops such as apple is required for agricultural utilization. For analysis of such crops, the protocol establishment of tissue culture and transformation is essential. Although transformation efficiency in family Rosaceae is generally very low, some cultivars of Malus species have high transformation ability. Apple cultivars are usually clonally propagated by grafting on rootstocks, which can affect fruit quality and maturity and scion productivity. Apple rootstock cultivar Japan Morioka 2 (JM2) was produced at the Division of Apple Research, Institute of Fruit and Tea Science, NARO, in Japan. JM2, which was developed for dwarfing scions and improving disease resistance, is easily propagated by hardwood cutting. Furthermore, JM2 can be stably transformed at a high efficiency, which is better than other JM series rootstocks derived from the same parent. Leaflets of cultured shoots of JM2 have been transformed using Agrobacterium (Rhizobium) with a transducing gene. In this article, the JM2 transformation protocol is introduced in detail. Various genes and promoters have been confirmed to function as expected, with the resultant transformants exhibiting specific staining and fluorescent signals, and modified floral organ shapes, precious blooming and other characteristics. JM2 is thus a useful rootstock material for the enhancement of genetic research on apple and its relatives.


[Characteristics of adenohypophseal secretory activity in children with thymomegaly].
The radioimmunological method was applied in the study of ACTH, STH, and prolactin content in thymomegaly combined with pneumonia, and in practically healthy children. A comparative analysis of hormonal parameters depending on the functional condition of the thymus demonstrated a directly proportional correlation between the STH, prolactin level, and the thymus hyperplasia; there proved to be a reverse relationship between the ACTH level and thymomegaly. Hypoadrenocorticotropinemia, hypersomatotropinemia, and hyperprolactinemia could be used as diagnostic criteria in thymomegaly.


Structure and functional mechanism of porins.
Cellular organisms such as gram-negative bacteria are enclosed by a dual lipid bilayer system. The outer membranes of the dual bilayer envelopes predominantly contain large numbers of water-filled transmembrane protein channels known as porins. The recent availability of the molecular structures of several bacterial porins has provided the opportunity for comparing the results of a wide range of functional studies with the atomic level structural details of these membrane channels. Taken together, the structure and function data present the most comprehensive set of boundary conditions available for the evaluation of theory and models predicting the characteristics of solute transport through membrane protein channels. In this paper, we review the high-resolution structure data from the bacterial porins, as well as recent theoretical studies, in the context of biophysical and biochemical observations and discuss the molecular mechanisms responsible for the transport of solutes through porin channels. Particular emphasis has been placed on the features and roles of common structural elements, channel sterics and electrostatics, and voltage-dependent gating. A model for water-coordinated transport, providing a qualitative view of the porin transport mechanism, is also described.


The Decisions, Interventions, and Goals in ImplaNtable Cardioverter-DefIbrillator TherapY (DIGNITY) Pilot Study.
Implantable cardioverter-defibrillators (ICDs) are commonly implanted in older patients, including those with multiple comorbidities. There are few prospective studies assessing the clinical course and end-of-life circumstances for these patients. We prospectively followed 51 patients with ICDs for up to 18 months to longitudinally assess in terms of (1) advance care planning, (2) health status, (3) healthcare utilization, and (4) end-of-life circumstances through quarterly phone interviews and electronic medical record review. The mean age was 71.1±8.3, 74.5% were men, and 19.6% were non-white. Congestive heart failure was predominant (82.4%), as was chronic kidney disease (92%). At baseline, a total of 12% of subjects met criteria for major depression, and 78.4% met criteria for mild cognitive impairment. From this initial study cohort, 76% survived to 18 months and completed all follow-up interviews, 18% died, and 19% withdrew or were lost to follow-up. Though living will completion and healthcare proxy assignment were common (cumulative outcome at 18 months 88% and 98%, respectively), discussions of prognosis were uncommon (baseline, 9.8%; by 18 months, 22.7%), as were conversations regarding ICD deactivation (baseline, 15.7%; by 18 months, 25.5%). Five decedents with available data received shocks in the days immediately prior to death, including 3 of whom ultimately had their ICDs deactivated prior to death. We demonstrated the feasibility of prospective enrollment and follow-up of older, vulnerable ICD patients. Early findings suggest a high burden of cognitive and psychological impairment, poor communication with providers, and frequent shocks at the end of life. These findings will inform the design of a larger cohort study designed to further explore the experiences of living and dying with an ICD in this important patient population.


Global Retinoblastoma Presentation and Analysis by National Income Level.
Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.


The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets.
Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.


Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis.
The spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs), plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state. Using a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF₁₆₅-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia-dependent manner. Isoform-specific VEGF degradation provides a possible explanation for numerous examples of isoform specificity in VEGF patterning and examples of proteases relocation of VEGF upon release.


Exposure to Herbicides Prime P450-Mediated Detoxification of Helicoverpa armigera against Insecticide and Fungal Toxin.
With the long-term and large-scale use, herbicides have been well known to influence tritrophic interactions, particularly natural enemies of pests in agro-ecosystems. On the other hand, herbivorous insects, especially the generalist pests, have developed antagonistic interaction to different insecticides, toxic plant secondary metabolites, and even heavy metals. However, whether exposure to herbicides would affect resistance of insects against insecticides is largely unknown, especially in agricultural pests. Here, we first reported that pre-exposure to two widely used herbicides butachlor and haloxyfop-methyl for 48 h can prime the resistance of a generalist agricultural pest Helicoverpa armigera Hübner against insecticide methomyl and fungal toxin aflatoxin B1. In addition, there were no significant differences between control and herbicides-treated caterpillars on weight gain, pupal weight, and pupation rates, suggesting that exposure to herbicides induces resistance of H. armigera accompanied with no fitness cost. Moreover, by determining detoxifying enzyme activities and toxicity bioassay with additional inhibitor of cytochrome P450 piperonyl butoxide (PBO), we showed that exposure to herbicides might prime P450-mediated detoxification of H. armigera against insecticide. Based on these results, we propose that exposure to herbicides prime resistance of H. armigera against insecticide and fungal toxin by eliciting a clear elevation of predominantly P450 monooxygenase activities in the midgut and fat body.


Effects of Short-term Preoperative Topical Ketorolac on Pupil Diameter in Eyes Undergoing Femtosecond Laser-Assisted Capsulotomy.
To assess pupil diameter before and after femtosecond laser-assisted capsulotomy in patients who were pretreated with a short-term topical nonsteroidal anti-inflammatory drug (NSAID) (ketorolac) versus those without pretreatment. This prospective, randomized, observational case series included consecutive patients scheduled to undergo cataract extraction using the Catalys femtosecond laser platform (Abbott Medical Optics, Inc., Santa Ana, CA) to perform only capsulotomies. The same protocol for preoperative medical mydriasis was used for all patients, whereas pupil diameter was assessed using a surgical ruler immediately before and 3 minutes after femtosecond laser-assisted capsulotomy. The patients were divided into two groups: one received short-term topical ketorolac preoperatively and the other did not receive NSAID pretreatment (control). A total of 42 eyes of 42 patients (1 eye per patient) were included in the study. Mean pupillary miosis was 0.79 ± 1.08 and 1.57 ± 1.19 mm for the ketorolac and control groups, respectively. There was a statistically significant decrease in pupil diameter for both groups individually (P < .05). There was also a statistically significant difference between the two groups (P < .05) with the induced miosis in the eyes that did not receive topical NSAIDs prior to cataract extraction being twofold greater when compared with the miosis of the eyes that received ketorolac pretreatment. Short-term topical use of ketorolac prior to femtosecond laser-assisted cataract surgery seems to induce significantly less pupillary miosis in comparison to eyes that did not receive NSAID pretreatment. NSAID use is advised prior to femtosecond laser-assisted cataract surgery to minimize pupil miosis-related surgical difficulties or complications during cataract extraction. [J Refract Surg. 2017;33(4):230-234.].


Hepatic blood flow: morphologic aspects and physiologic regulation.
The study of the morphology of the hepatic circulation has given evidence that the liver consists of a large vascular delta formed by the confluence of the portal and arterial streams. Their arms, which subdivide the delta into lobar areas, start to run parallel and close to each other when they are still visible to the naked eye. Dwindled down to microscopic size, they become the scaffold of the parenchymal cell masses nestling between the microvessels. The arterioles, as they merge with the sinusoidal and portal channels, assume the role of organizing the microcirculation into units. These units are the vascular core of the structural and functional liver acini. It has now been demonstrated beyond doubt that a PO2 gradient exists in the hepatic vessels and tissues, decreasing from the site of the arteriolar rivulets joining the venous stream toward the site of their common egress via the terminal hepatic venules. The gradient permits the subdivision of the microscopic vascular units into three microcirculatory zones, each of them creating an appropriate microenvironment for specific enzymic and metabolic activity. The microcirculatory shifts in arterial flow from tide to ebb will cause change in the activity of the zones. These are essentially dynamic subdivisions of the metabolic activity in the large liver swamp. Here also start the tiny rivulets forming a green river, the bile stream, that runs in the opposite direction to the portal and hepatic arterial flow. It is to be expected that the quantity and quality of bile carrying important products back to the gastrointestinal area for digestion and absorption of fat are influenced by the tides in portal and arterial flow. All in all, it is evident that vascular morphology is the visual aspect of the dynamic blood flow, thus permitting us to perceive its functional orderliness, and to study the circulatory physiology in the hepatic delta. Means of measurement of hepatic blood flow have been reviewed and its methodological problems have been discussed. It was found that the term "estimated" hepatic blood flow is still justified. Also the relationship between hepatic blood flow and metabolism is not yet clear-cut. The role of the arterial and portal components of the hepatic circulation has been analyzed. There is a reciprocal relationship between arterial and portal volume flow; it is effectuated by the state of constriction or dilation of the mesenteric and hepatic arterioles, both under myogenic control. Portal blood delivers directly to the hepatocyte all water-soluble substances absorbed from the intestines or produced in the intestinal walls. The hepatic artery maintains an appropriate PO2 gradient between the acinar zones and flow of blood against increased tissue resistance; it assures a steady clearance of blood-borne substances, e.g., hormones and endogenous products. Regulation of arterial flow is less neural than neurohumoral; metabolites and bile salts exert additional effects on blood flow...


Abdominal compartment syndrome after ruptured abdominal aortic aneurysm.
Abdominal Compartment Syndrome (ACS) is an increasingly recognized syndrome of intra-abdominal hypertension and generalized physiological dysfunction in critically ill patients. Patients suffering a ruptured abdominal aortic aneurysm (rAAA) are at risk of developing ACS. The objective of the study was to compare the current views on the importance, prevalence and management of ACS after rAAA among Australian vascular surgeons and intensivists. A questionnaire was mailed to 116 registered vascular fellows from the Royal Australasian College of Surgeons and 314 registered fellows of the Joint Faculty of Intensive Care Medicine. Data were collected on the prevalence and importance of ACS after rAAA and whether prophylactic measures were or should be taken to prevent ACS. Hypothetical clinical scenarios representing a range of ACS after rAAA were also presented. The responses were compared using chi(2)-test and t-test. Sixty-seven per cent (78 of 116) of surgeons and 39% (122 of 314) of intensivists responded. Both groups estimated the prevalence of ACS after rAAA as between 10 and 30% and considered it an important entity. Only 30% of surgeons and 50% of intensivists suggested routine intra-abdominal pressure (IAP) monitoring. In patients with borderline IAP (18 mmHg), both groups believed that surgical intervention was unnecessary. Intensivists were more inclined to suggest surgical intervention for clinically deteriorating patients with an increased IAP (30 mmHg) compared with surgeons. Forty-three per cent of intensivists and 17% of surgeons suggested prophylactic (leaving the abdomen open) measures to prevent ACS in high-risk patients. Surgeons and intensivists have similar views on the prevalence and clinical importance of ACS after rAAA. Intensivists more frequently monitored IAP and suggested both early prophylactic and therapeutic intervention for ACS based on physiological and IAP findings.


Curtisians A-D, new free radical scavengers from the mushroom Paxillus curtisii.
In our continuous investigation for free radical scavengers from extracts of fruit body of basidiomycetes, we have isolated four new p-terphenyl compounds, designated as curtisians A-D, from the methanolic extract of the fruit body of Paxillus curtisii. These compounds were isolated by silica gel and Sephadex LH-20 column chromatographies, preparative-TLC and HPLC, consecutively. The structures of curtisians were assigned as p-terphenyls with substituents of acetyl, benzoyl, phenylbutyryl, 3-hydroxybutyryl and 3-acetoxybutyryl. Curtisians A, B, C and D exhibited inhibitory activity against lipid peroxidation with IC50, values of 0.15, 0.17, 0.24 and 0.14 microg/ml, respectively.


Advances in therapeutics for liver metastasis from colorectal cancer.
The evolution of chemotherapeutic regimens that include targeted molecular agents has resulted in a breakthrough in the management of advanced colorectal liver metastasis (CLM), improving the progression-free survival after liver resection, and rendering initially unresectable liver tumors resectable, with reported resection rates ranging from 13% to 51%. In addition, the criteria used for selecting patients for hepatectomy have been expanding because of advances in surgical techniques and improvements in chemotherapy. However, the increasing use of chemotherapy has raised concern about potential hepatotoxicities such as steatosis, chemotherapy-associated steatohepatitis, and sinusoidal obstruction syndrome, and their deleterious effects on postoperative outcome. The present review focuses on the advantages and disadvantages of chemotherapy, strategies for the prevention and diagnosis of chemotherapy-associated liver injury, and the adoption of more aggressive surgical approaches, which have changed the traditional paradigm for CLM.


Dual action of aldosterone on toad bladder: Na+ permeability and Na+ pump modulation.
The effects of aldosterone on the functional characteristics of the Na+ entry step across the apical membrane and on the Na+ exit step across the basolateral membrane of the urinary bladder of toads were examined using amiloride and ouabain as probes of the respective surfaces of the cell. Aldosterone stimulated Na+ transport with a concurrent increase in the transepithelial electrical conductance as did two other agents, vasopressin (ADH) and p-chloromercuriphenylsulfonate (PCMPS), primarily active on the apical membrane. Unlike the effects of ADH and PCMPS, however, the effect of aldosterone on Na+ conductance was blocked by actinomycin D and was associated with a decreased sensitivity of the apical Na+ channel to amiloride. In addition, aldosterone increased the sensitivity of the Na+ pump on the basolateral side to ouabain, an effect that was dependent on the metabolic state of the urinary bladder. These results support the inference of coordinate effects on Na+ permeability of the apical membrane and the Na+ pump of the basolateral membrane. Both effects of aldosterone appear to be dependent on the metabolic state of the transporting epithelium.


Assessing the role of tandem repeats in shaping the genomic architecture of great apes.
Ancestral reconstructions of mammalian genomes have revealed that evolutionary breakpoint regions are clustered in regions that are more prone to break and reorganize. What is still unclear to evolutionary biologists is whether these regions are physically unstable due solely to sequence composition and/or genome organization, or do they represent genomic areas where the selection against breakpoints is minimal. Here we present a comprehensive study of the distribution of tandem repeats in great apes. We analyzed the distribution of tandem repeats in relation to the localization of evolutionary breakpoint regions in the human, chimpanzee, orangutan and macaque genomes. We observed an accumulation of tandem repeats in the genomic regions implicated in chromosomal reorganizations. In the case of the human genome our analyses revealed that evolutionary breakpoint regions contained more base pairs implicated in tandem repeats compared to synteny blocks, being the AAAT motif the most frequently involved in evolutionary regions. We found that those AAAT repeats located in evolutionary regions were preferentially associated with Alu elements. Our observations provide evidence for the role of tandem repeats in shaping mammalian genome architecture. We hypothesize that an accumulation of specific tandem repeats in evolutionary regions can promote genome instability by altering the state of the chromatin conformation or by promoting the insertion of transposable elements.


Efficacy of cold plasma functionalised water for improving microbiological safety of fresh produce and wash water recycling.
Atmospheric cold plasma (ACP) is an effective method for microbiological decontamination. This study evaluated an alternative water-based decontamination approach for inactivation of bacterial population from fresh produce and in the wash water generated from fresh produce washing. The study characterised ACP inactivation of attached Listeria innocua and Pseudomonas fluorescens inoculated on lettuce in comparison to chlorine treatment. P. fluorescens was sensitive to ACP treatment and was reduced below detection limit within 3 min of treatment. L. innocua population was reduced by ∼2.4 Log10 CFU/g after 5 min of treatment; showing similar inactivation efficacy to chlorine treatment. The microbial load in wash water was continuously decreased and was below detection limits after 10 min of ACP treatment. Micro-bubbling along with agitation assisted the bacterial detachment and distribution of reactive species, thus increasing bacterial inactivation efficacy from fresh produce and wash water. A shift in pH of plasma functionalised water was observed along with high concentration of nitrate and ozone with a relative amount of nitrites which increased with plasma exposure time. Further, L. innocua treated at different independent pH conditions showed minimal or no effect of pH on ACP bacterial inactivation efficacy. Aqueous ACP treatment poses a promising alternative for decontamination of fresh produce and the associated wash-waters which could be applied in the food industry to replace continuous chlorine dosing of process waters.


Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG).
Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.


Effects of the Competitive Season on the Isokinetic Muscle Parameters Changes in World-Class Handball Players.
Maurelli, O, Bernard, PL, Dubois, R, Ahmaidi, S, and Prioux, J. Effects of the competitive season on the isokinetic muscle parameters changes in world-class handball players. J Strength Cond Res 33(10): 2778-2787, 2019-The aim of this study is to investigate the effects of the competitive season on isokinetic muscular parameters of the lower limbs in world-class handball players. Nineteen, male, world-class, handball players (age, 26.6 ± 5.4 years) participated in the study. Two bilateral isokinetic tests of knee joint flexors (H; hamstring) and extensors (Q; quadriceps) were performed in the beginning and end of the competitive season to determine the peak torque (PT), the mean power, and agonist-antagonist ratio, dominant-nondominant ratio (DNDR), and combined ratio. The results showed a significant decrease in PT values at low angular velocity (60°·s) in concentric mode for Q on dominant leg (p < 0.001). The other PT values for dominant and nondominant legs at low and high angular velocities (240°·s) and in eccentric mode (30°·s) were not significantly different for Q and H. For mean power, values did not change at 60°·s. At 240°·s, we found a significant decrease in H for dominant leg (p < 0.001) but not for nondominant leg. In eccentric mode, the results showed a significant increase on both legs (p < 0.001). For the ratios, values significantly decreased for DNDR at 60°·s for Q (p < 0.03) and for agonist/antagonist ratio at 240°·s for the dominant leg (p < 0.01). The present results highlight the importance of integrating regular strength training sessions during the competitive season in world-class handball players. Accordingly, this study should help trainers to modify their planning to maximize strength and power qualities of the lower limbs of their players in addition to avoiding injuries.


Digital Biomarkers of Gait and Balance in Diabetic Foot, Measurable by Wearable Inertial Measurement Units: A Mini Review.
People with diabetic foot frequently exhibit gait and balance dysfunction. Recent advances in wearable inertial measurement units (IMUs) enable to assess some of the gait and balance dysfunction associated with diabetic foot (i.e., digital biomarkers of gait and balance). However, there is no review to inform digital biomarkers of gait and balance dysfunction related to diabetic foot, measurable by wearable IMUs (e.g., what gait and balance parameters can wearable IMUs collect? Are the measurements repeatable?). Accordingly, we conducted a web-based, mini review using PubMed. Our search was limited to human subjects and English-written papers published in peer-reviewed journals. We identified 20 papers in this mini review. We found preliminary evidence of digital biomarkers of gait and balance dysfunction in people with diabetic foot, such as slow gait speed, large gait variability, unstable gait initiation, and large body sway. However, due to heterogeneities in included papers in terms of study design, movement tasks, and small sample size, more studies are recommended to confirm this preliminary evidence. Additionally, based on our mini review, we recommend establishing appropriate strategies to successfully incorporate wearable-based assessment into clinical practice for diabetic foot care.


Amphipols from A to Z.
Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep integral membrane proteins (MPs) water soluble. In this review, we discuss their structure and solution behavior; the way they associate with MPs; and the structure, dynamics, and solution properties of the resulting complexes. All MPs tested to date form water-soluble complexes with APols, and their biochemical stability is in general greatly improved compared with MPs in detergent solutions. The functionality and ligand-binding properties of APol-trapped MPs are reviewed, and the mechanisms by which APols stabilize MPs are discussed. Applications of APols include MP folding and cell-free synthesis, structural studies by NMR, electron microscopy and X-ray diffraction, APol-mediated immobilization of MPs onto solid supports, proteomics, delivery of MPs to preexisting membranes, and vaccine formulation.


Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up.
Three classic-type, small cell lung cancer cell lines (GLC-14, GLC-16, and GLC-19) have been established from one patient during longitudinal follow-up. During this period the tumor changed from sensitive to completely resistant to (chemo)therapy. A phenotypical and functional characterization of the different cell lines is given in combination with the matching clinical data. (a) The cell lines have been compared with the biopsies from which they were derived. There was a good match between the morphological, biochemical, and immunohistological findings in the cell lines as compared to those obtained in the biopsies. When the biopsy and cell line (GLC-14) obtained before the start of therapy were compared to the biopsies and cell lines (GLC-16 and GLC-19) acquired after the first and second reinduction therapy, respectively, no major changes could be observed. The only clear alteration was the loss of a neuroendocrine antigen (defined by monoclonal antibody MOC-51) in the posttherapy specimens. (b) The doxorubicin, melphalan, and etoposide sensitivity in vitro reflected the clinically observed development of resistance to treatment. The cell line (GLC-14) established before the start of therapy was more sensitive than the lines (GLC-16 and GLC-19) obtained after treatment. It is concluded that the cell lines described in this paper represent a well-characterized in vitro model in which the development of drug resistance in small cell lung cancer can be studied.


Automatic detection of anchor points for multiple sequence alignment.
determining beforehand specific positions to align (anchor points) has proved valuable for the accuracy of automated multiple sequence alignment (MSA) software. This feature can be used manually to include biological expertise, or automatically, usually by pairwise similarity searches. Multiple local similarities are be expected to be more adequate, as more biologically relevant. However, even good multiple local similarities can prove incompatible with the ordering of an alignment. we use a recently developed algorithm to detect multiple local similarities, which returns subsets of positions in the sequences sharing similar contexts of appearence. In this paper, we describe first how to get, with the help of this method, subsets of positions that could form partial columns in an alignment. We introduce next a graph-theoretic algorithm to detect (and remove) positions in the partial columns that are inconsistent with a multiple alignment. Partial columns can be used, for the time being, as guide only by a few MSA programs: ClustalW 2.0, DIALIGN 2 and T-Coffee. We perform tests on the effect of introducing these columns on the popular benchmark BAliBASE 3. we show that the inclusion of our partial alignment columns, as anchor points, improve on the whole the accuracy of the aligner ClustalW on the benchmark BAliBASE 3.


Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall.
Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and systemic inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that valsartan, an angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-salt diet were treated with vehicle or valsartan (1-10 mg/kg/day). The vehicle-treated rats developed hypertension, proteinuria, progressive kidney disease, and, 40 +/- 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day valsartan developed brain damage after 61 +/- 3 days (p <0.01 versus vehicle-treated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day. Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of monocyte chemoattractant protein-1, transforming growth factor-beta1, and interleukin-1beta, compared with vehicle-treated SHRSP. Urinary excretion of acute-phase proteins increased in the latter but remained negligible in the drug-treated animals. Furthermore, valsartan exerted protective effects also when given after established proteinuria. In SHRSP, blockade of AT1 receptor with valsartan prevents the development of proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions. Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.


Prevention of incisional hernia with retrorectus synthetic mesh versus biological mesh following loop ileostomy closure (Preloop trial).
The rate of incisional hernia after closure of a temporary loop ileostomy is significant. Synthetic meshes are still commonly avoided in contaminated wounds. The Preloop trial was a multicentre RCT designed to evaluate the benefits of synthetic mesh in incisional hernia prevention, and its safety for use in a contaminated surgical site compared with biological mesh. Study patients who underwent closure of a loop ileostomy after anterior resection for rectal cancer were assigned to receive either retrorectus synthetic or biological mesh to prevent incisional hernia. The primary outcomes were surgical-site infections within 30 days, and clinical or radiological incisional hernia incidence at 10 months. Secondary outcomes were reoperation rate, operating time, duration of hospital stay, other complications within 30 days of surgery, 5-year quality of life measured by RAND-36, and incisional hernia incidence within 5 years of follow-up. Between November 2018 and September 2021, 102 patients were randomised, of whom 97 received the intended allocation. At 10-month follow-up, 90 patients had undergone clinical evaluation and 88 radiological evaluation. One patient in each group (2 per cent) had a clinical diagnosis of incisional hernia (P = 0.950) and one further patient in each group had a CT-confirmed incisional hernia (P = 0.949). The number of other complications, reoperation rate, operating time, and duration of hospital stay did not differ between the study groups. Synthetic mesh appeared comparable to biological mesh in efficacy and safety for incisional hernia prevention at the time of loop ileostomy closure. NCT03445936 (http://www.clinicaltrials.gov).


Publications in epidemiology journals: Japanese perspectives.
This paper presents information on Japan's contribution to reputable epidemiologic journals as compared to other leading countries. Ten journals in the field of epidemiology with high impact factors were selected. Articles published in these journals during the period between 1991 and 2000 were searched for the authors' affiliation using Medline database. We found that Japan contributed only 1.1% of the total number of articles published and ranked 14th among all the countries. The United States of America contributed 56.3% of the total and ranked top followed by the United Kingdom (7.6%), Canada (4.1%), and the Netherlands (3.5%). In a time trend analysis, Japan's share of articles did not increase significantly in the last decade (p = 0.41). Barriers in conducting epidemiologic research in Japan should be identified and appropriate measures should be taken accordingly.


Complete posttranslational modification mapping of pathogenic Neisseria meningitidis pilins requires top-down mass spectrometry.
In pathogenic bacteria, posttranslationally modified proteins have been found to promote bacterial survival, replication, and evasion from the host immune system. In the human pathogen Neisseria meningitidis, the protein PilE (15-18 kDa) is the major building block of type IV pili, extracellular filamentous organelles that play a major role in mediating pathogenesis. Previous reports have shown that PilE can be expressed as a number of different proteoforms, each harboring its own set of PTMs and that specific proteoforms are key in promoting bacterial virulence. Efficient tools that allow complete PTM mapping of proteins involved in bacterial infection are therefore strongly needed. As we show in this study, a simple combination of mass profiling and bottom-up proteomics is fundamentally unable to achieve this goal when more than two proteoforms are present simultaneously. In a N. meningitidis strain isolated from a patient with meningitis, mass profiling revealed the presence of four major proteoforms of PilE, in a 1:1:1:1 ratio. Due to the complexity of the sample, a top-down approach was required to achieve complete PTM mapping for all four proteoforms, highlighting an unprecedented extent of glycosylation. Top-down MS therefore appears to be a promising tool for the analysis of highly posttranslationally modified proteins involved in bacterial virulence.


Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1.
Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern-recognition receptor that recognizes viruses and triggers anti-viral immune responses. Activation of intracellular RIG-I signalling is mediated through interferon-β (IFN-β) promoter stimulator-1 (IPS-1), an adaptor of RIG-I, which induces IFN regulatory factor (IRF) 3 activation and type I IFN expression. The phosphatidylinositol-3-kinase (PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG-I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG-I-mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG-I, led to IRF3 activation and IFN-β expression and these responses were attenuated by the PI3K inhibitor (LY294002) and an Akt dominant-negative mutant in the macrophage cell line(RAW264.7). IRF3 phosphorylation and dimerization as well as IFN-β expression induced by a synthetic RIG-I agonist, short poly(I:C), were suppressed by LY294002 or siRNA-Akt in bone marrow-derived macrophages. Suppression of PI3K and Akt using a dominant-negative mutant and siRNA knockdown resulted in attenuation of IRF3 activation and IFN-β expression induced by RIG-I itself or its adaptor, IPS-1. Association of Akt with IPS-1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase-recruitment domain in IPS-1. Collectively, our results show that PI3K and Akt are required downstream of IPS-1 for RIG-I-mediated anti-viral immune responses. The results describe a novel, interactive relationship between RIG-I downstream signalling molecules resulting in efficient anti-viral immunity.


Thermal stability study of crystalline and novel spray-dried amorphous nilotinib hydrochloride.
The thermal characteristics and the thermal degradation of crystalline and amorphous nilotinib hydrochloride (NH) were studied. The spray drying technique was successfully utilized for the amorphization of NH and was evaluated by spectroscopic techniques and differential scanning calorimetry (DSC). The ethanolic spray drying process yielded amorphous NH with a glass transition temperature (Tg) of 147°C. Thermal characterization of the amorphous phase was performed by heat capacity measurements using modulated DSC (mDSC). Thermal degradation was studied by thermogravimetric analysis (TGA). The derived thermodynamic properties of the amorphous NH indicate fragile behaviour and a low crystallization tendency. NH was found to be molecularly stable up to 193°C. After which, the thermal degradation displayed two phases. The values of the thermal degradation parameters were estimated using the Ozawa-Flynn-Wall and Friedman non-isothermal, model-free, isoconversional methods The results indicate the two phases to be single-step reactions. The examination of the physical stability of amorphous NH during storage and at elevated temperatures showed stability at 180°C for at least 5h and at 20-25°C/60% RH for at least 6 months. During these periods, no crystallization was observed. This study is the first to report the thermal characteristics of NH. Additionally, it is also the first to describe the full thermal analysis of a spray-dried amorphous drug. The thermal data may be used in the projection of future production processes and storage conditions of amorphous NH.


Health care costs of rheumatoid arthritis: A longitudinal population study.
Quantifying the contribution of rheumatoid arthritis to the acquisition of subsequent health care costs is an emerging focus of the rheumatologic community and payers of health care. Our objective was to determine the healthcare costs before and after diagnosis of rheumatoid arthritis (RA) from the public payer's perspective. The study design was a longitudinal observational administrative data-based cohort with RA cases from Ontario Canada (n = 104,933) and two control groups, matched 1:1 on year of cohort entry from 2001 to 2016. The first control group was matched on age, sex and calendar year of cohort entry (diagnosis year for those with RA); the second group added medical history to the match before RA diagnosis year. The main exposure was new onset RA. The secondary exposure was calendar year of RA diagnosis to compare attributable costs over the study observation window. Main outcomes were health care costs in 2015 Canadian dollars, overall and by cost category. We used attribution methods to classify costs into those associated with RA, those associated with comorbidities, and age/sex-related underlying costs. Health care costs associated with RA increased up to the year of diagnosis, where they reached $8,591: $4,142 in RA associated costs; $1,242 in RA comorbidity associated costs; and $3,207 in underlying costs. In the eighth-year post diagnosis, the RA costs declined to $2,567 while the RA comorbidity associated costs remained relatively constant at $1,142, and the underlying age/sex related cost increased to $4,426. RA patients had lower costs when diagnosed in later calendar years. Our results suggest a large proportion of disease related health care costs are a result of costs associated with RA comorbidities, which may appear many years before diagnosis.


Hearing and Tinnitus Evaluation in Music Teachers.
Music is an aesthetic whole consisting of sounds combined according to a certain purpose, method and understanding. Therefore, it also interacts with emotions in listeners. Music sounds are in the range of approximately 20-8000 Hz. This frequency range is within the frequency spectrum of the human cochlea. The aim of this research is to evaluate the hearing thresholds of music teachers and to determine whether they cause tinnitus. This research was conducted in Turgut Özal University Medical Faculty Hospital Audiology and Speech Disorders clinic. A total of 35 people (17 music teachers, 18 control groups) participated in the research. In this research, 17 music teachers (11 females, 6 males) aged 24-39, and 18 volunteers (12 females, 6 males) participated in the control group. After the otoscopic examination of all participants, pure tone audiometry (in the range of 125-16,000 Hz), immitansmetric examination and Distortion Product Otoacoustic Emission (DPOAE) tests were performed. Tinnitus Handicap Inventory (THI) was used in the evaluation of tinnitus. There was no statistically significant difference between the music teachers and the control group in all pure tone hearing threshold averages of 125-16,000 Hz (p>0.05). The Uncomfortable Level (UCL) average of music teachers was 104.12 ± 3.83 dB for the right ear, 108.33 ± 3.83 dB for the control group, 107.78 ± 4.28 dB for the left ear, and 103.53 ± 4.28 for the control group. DPOAE results were found statistically significant at 3000 Hz only for the right and left ears (p=0.036; p=0.015, respectively). Also, for DPOAE test, the control group's OAE values were higher than the music teachers. According to the Tinnitus Handicap Inventory in music teachers, 1st degree tinnitus has emerged. According to the findings obtained, the low UCL value in music teachers compared to the control group suggests the tolerance problem. Continuous exposure to the sound was thought to create a noise effect on the cochlea, and as a result, tinnitus susceptibility appeared in music teaching.


Powered versus manual toothbrushing for oral health.
Removing dental plaque may play a key role maintaining oral health. There is conflicting evidence for the relative merits of manual and powered toothbrushing in achieving this. This is an update of a Cochrane review first published in 2003, and previously updated in 2005. To compare manual and powered toothbrushes in everyday use, by people of any age, in relation to the removal of plaque, the health of the gingivae, staining and calculus, dependability, adverse effects and cost. We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 23 January 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE via OVID (1946 to 23 January 2014), EMBASE via OVID (1980 to 23 January 2014) and CINAHL via EBSCO (1980 to 23 January 2014). We searched the US National Institutes of Health Trials Register and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. Randomised controlled trials of at least four weeks of unsupervised powered toothbrushing versus manual toothbrushing for oral health in children and adults. We used standard methodological procedures expected by The Cochrane Collaboration. Random-effects models were used provided there were four or more studies included in the meta-analysis, otherwise fixed-effect models were used. Data were classed as short term (one to three months) and long term (greater than three months). Fifty-six trials met the inclusion criteria; 51 trials involving 4624 participants provided data for meta-analysis. Five trials were at low risk of bias, five at high and 46 at unclear risk of bias.There is moderate quality evidence that powered toothbrushes provide a statistically significant benefit compared with manual toothbrushes with regard to the reduction of plaque in both the short term (standardised mean difference (SMD) -0.50 (95% confidence interval (CI) -0.70 to -0.31); 40 trials, n = 2871) and long term (SMD -0.47 (95% CI -0.82 to -0.11; 14 trials, n = 978). These results correspond to an 11% reduction in plaque for the Quigley Hein index (Turesky) in the short term and 21% reduction long term. Both meta-analyses showed high levels of heterogeneity (I(2) = 83% and 86% respectively) that was not explained by the different powered toothbrush type subgroups.With regard to gingivitis, there is moderate quality evidence that powered toothbrushes again provide a statistically significant benefit when compared with manual toothbrushes both in the short term (SMD -0.43 (95% CI -0.60 to -0.25); 44 trials, n = 3345) and long term (SMD -0.21 (95% CI -0.31 to -0.12); 16 trials, n = 1645). This corresponds to a 6% and 11% reduction in gingivitis for the Löe and Silness index respectively. Both meta-analyses showed high levels of heterogeneity (I(2) = 82% and 51% respectively) that was not explained by the different powered toothbrush type subgroups.The number of trials for each type of powered toothbrush varied: side to side (10 trials), counter oscillation (five trials), rotation oscillation (27 trials), circular (two trials), ultrasonic (seven trials), ionic (four trials) and unknown (five trials). The greatest body of evidence was for rotation oscillation brushes which demonstrated a statistically significant reduction in plaque and gingivitis at both time points. Powered toothbrushes reduce plaque and gingivitis more than manual toothbrushing in the short and long term. The clinical importance of these findings remains unclear. Observation of methodological guidelines and greater standardisation of design would benefit both future trials and meta-analyses.Cost, reliability and side effects were inconsistently reported. Any reported side effects were localised and only temporary.


The Relationship between Adult Height and Blood Pressure.
Identification and modification of cardiovascular risk factors is paramount to reducing cardiovascular disease morbidity and mortality. Hypertension is a major risk factor for cardiovascular disease, but its association with height remains largely underrecognized. The objective of this manuscript is to review the evidence examining the association between blood pressure and human stature and to summarize the plausible pathophysiological mechanisms behind such an association. A systematic review of adult human height and its association with hypertension and coronary artery disease was undertaken. The literature evidence is summarized and tabulated, and an overview of the pathophysiological basis for this association is presented. Shorter arterial lengths found in shorter individuals may predispose to hypertension in a complex hemodynamic interplay, which is explained predominantly by summated arterial wave reflections and an elevated augmentation index. Our systemic review suggests that an inverse relationship between adult height and blood pressure exists. However, differences in the studied populations and heterogeneity in the methods applied across the various studies limit the generalizability of these findings and their clinical application. Physiological studies and epidemiological data suggest a potential inverse association between adult height and blood pressure. Further research is required to define the relationship more clearly between adult height and blood pressure and to assess whether antihypertensive therapeutic approaches and goals should be modified according to patients' heights.


H2M3wt-restricted, Listeria monocytogenes-immune CD8 T cells respond to multiple formylated peptides and to a variety of gram-positive and gram-negative bacteria.
A subset of H2M3wt-restricted, Listeria monocytogenes (LM)-immune CD8 effectors recognize antigen-presenting cells (APC) preincubated with heat-killed LM. The responsible product, which we have previously designated heat-killed Listeria-associated antigen (HAA), is extremely hydrophobic and resistant to proteolytic degradation. Despite the protease resistance of HAA, we now report that HAA-immune clones are uniformly responsive to fMIGWII, a formylated oligopeptide derived from the recently described LM product, lemA. While fMIGWII was by far the most potent peptide tested, over half our clones also responded to the LM-derived peptide fMIVII and cross-reactive responses to two other unrelated formylated peptides at concentrations of <1 microM were frequently observed. One of these peptides (fBlaZ) did not share any amino acid in common with fMIGWII except N-formyl methionine at position 1. Unformylated variants of the same peptides were inactive. HAA-immune CD8 cells also responded in an H2M3wt-restricted manner to APC pretreated with heat-killed or live preparations of other gram-positive and gram-negative bacteria such as Streptococcus pyogenes (SP) and Proteus vulgaris (PV). Unlike fMIGWII which is water soluble and protease sensitive, the native antigens extracted from SP and PV, like HAA, were very hydrophobic and proteinase K resistant, presumably reflecting in each case the association of cross-reactive polypeptides with bacterial lipid or phospholipid. Thus, HAA/lemA-immune, H2M3wt-restricted effectors can respond to a variety of formylated peptides and bacterial antigens in vitro. Similar cross-reactions in vivo might have physiologically significant implications.


Parasite killing in malaria non-vector mosquito Anopheles culicifacies species B: implication of nitric oxide synthase upregulation.
Anopheles culicifacies, the main vector of human malaria in rural India, is a complex of five sibling species. Despite being phylogenetically related, a naturally selected subgroup species B of this sibling species complex is found to be a poor vector of malaria. We have attempted to understand the differences between vector and non-vector Anopheles culicifacies mosquitoes in terms of transcriptionally activated nitric oxide synthase (AcNOS) physiologies to elucidate the mechanism of refractoriness. Identification of the differences between genes and gene products that may impart refractory phenotype can facilitate development of novel malaria transmission blocking strategies. We conducted a study on phylogenetically related susceptible (species A) and refractory (species B) sibling species of An. culicifacies mosquitoes to characterize biochemical and molecular differences in AcNOS gene and gene elements and their ability to inhibit oocyst growth. We demonstrate that in species B, AcNOS specific activity and nitrite/nitrates in mid-guts and haemolymph were higher as compared to species A after invasion of the mid-gut by P. vivax at the beginning and during the course of blood feeding. Semiquantitative RT-PCR and real time PCR data of AcNOS concluded that this gene is more abundantly expressed in midgut of species B than in species A and is transcriptionally upregulated post blood meals. Dietary feeding of L-NAME along with blood meals significantly inhibited midgut AcNOS activity leading to an increase in oocyst production in An. culicifacies species B. We hypothesize that upregulation of mosquito innate cytotoxicity due to NOS in refractory strain to Plasmodium vivax infection may contribute to natural refractoriness in An. culicifacies mosquito population. This innate capacity of refractory mosquitoes could represent the ancestral function of the mosquito immune system against the parasite and could be utilized to understand the molecular basis of refractoriness in planning effective vector control strategies.


Nickel-Tin Nanoalloy Supported ZnO Catalysts from Mixed-Metal Zeolitic Imidazolate Frameworks for Selective Conversion of Glycerol to 1,2-Propanediol.
The successful synthesis of finely tuned Ni1.5 Sn nanoalloy phases containing ZnO catalyst with a small particle size (6.7 nm) from a mixed-metal zeolitic imidazolate framework (MM-ZIF) is investigated. The catalyst was evaluated for the efficient production of 1,2-propanediol (1,2-PDO) from crude glycerol and comprehensively characterized using several analytical techniques. Among the catalysts, 3Ni1Sn/ZnO (Ni/Sn=3/1) showed the best catalytic performance and produced the highest yield (94.2 %) of 1,2-PDO at ~100 % conversion of glycerol; it also showed low apparent activation energy (15.4 kJ/mol) and excellent stability. The results demonstrated that the synergy between Ni-Sn alloy, finely dispersed Ni metallic sites, and the Lewis acidity of SnOx species-loaded ZnO played a pivotal role in the high activity and selectivity of the catalyst. The confirmation of acetol intermediate and theoretical calculations verify the Ni1.5 Sn phases provide the least energetic pathway for the formation of 1,2-PDO selectively. The reusability of solvent for successive ZIF synthesis, along with the excellent recyclability of the ZIF-derived catalyst, enables an overall sustainable process. We believe that the present synthetic protocol that uses MM-ZIF for the conversion of various biomass-derived platform chemicals into valuable products can be applied to various nanoalloy preparations.


Association of μ-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.
Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the μ-opioid receptor gene (OPRM1) might be associated with individual differences in opioid sensitivity, as well as with the incidence and severity of postoperative nausea and vomiting (PONV). The goal of the present study was to determine, in a cohort of Japanese surgical patients, genotypes and haplotypes of several SNPs in the OPRM1 gene, and their association with PONV during the early (first 24 h) postoperative period. We examined the incidence and severity of PONV, during the first 24 h after surgery, in 85 Japanese patients receiving intravenous patient-controlled analgesia fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene (rs1799971, A/G; rs510769, G/A; rs4870266, G/A; rs3798683, G/A; rs1323042, A/C; rs609623, C/T; rs9397685, A/G; and rs644261, C/G) were selected based on their minor allele frequency (>10%) and linkage disequilibrium strength (<80%), and genotyped for haplotype analysis and determination of associations with PONV. Only one out of eight investigated SNPs, rs9397685, in the intronic part of the OPRM1 gene was associated with differences in the occurrence and severity of PONV. We also found four common haplotypes with a frequency of >10% in the investigated patients, including GGGAACAC (33%), AGGGACAC (19%), GGGAACGC (12%), and AGAGACAC (10%). The severity of PONV in carriers of the GGGAACGC haplotype was significantly lower than in the carriers of the other haplotypes (P < 0.05). One intronic SNP, rs9397685, and haplotypes constructed from eight SNPs within the OPRM1 gene locus might be involved in the severity of PONV associated with general anesthesia and opioid administration. This novel finding, if validated and verified in larger and additional ethnic cohorts, might contribute to better knowledge of the contribution of the OPRM1 gene to PONV.


Decrease in serum protein carbonyl groups concentration and maintained hyperhomocysteinemia in patients undergoing bariatric surgery.
Human obesity is associated with oxidative stress but the factors contributing to the increase of reactive oxygen species (ROS) production remain unknown. We evaluated the association between serum homocysteine concentration, which may increase ROS production, and serum protein carbonyl groups concentration before and after bariatric surgery. Serum protein carbonyl groups and serum homocysteine concentrations, as well as obesity markers, were compared in 18 obese patients before and 6 months after bariatric surgery. Ten healthy individuals with normal body mass index (BMI) served as controls. Before bariatric surgery, obese patients displayed approximately 50% higher serum protein carbonyl groups concentration than control subjects. After surgery, serum protein carbonyl groups concentration decreased and matched values observed in controls. Serum homocysteine concentration was also elevated in obese patients, but in contrast to protein carbonyl groups, did not change after surgery. The body weight, BMI, HOMA-IR, serum leptin, triacylglycerols, LDL/HLD cholesterol ratio, insulin, and glucose concentrations were higher in obese patients as compared to controls, and decreased after bariatric surgery. This study demonstrates that bariatric surgery has protective effect on oxidative protein damage and improves several laboratory parameters including serum lipid concentration and insulin resistance. However, bariatric surgery does not cause a decrease in serum homocysteine concentration, a risk factor for the development of cardiovascular diseases. Collectively, the results presented in this paper suggest that serum homocysteine concentration is not directly associated with oxidative stress in obese patients after bariatric surgery.


Fell-Muir Lecture: Proteoglycans and more--from molecules to biology.
In this article the organization and functional details of the extracellular matrix, with particular focus on cartilage, are described. All tissues contain a set of molecules that are arranged to contribute structural elements. Examples are fibril-forming collagens forming major fibrillar networks in most tissues. The assembly process is regulated by a number of proteins (thrombospondins, LRR-proteins, matrilins and other collagens) that can bind to the collagen molecule and in many cases remain bound to the formed fibre providing additional stability and enhancing networking to other structural networks. One such network is formed by collagen VI molecules assembled to beaded filaments in the matrix catalysed by interactions with small proteoglycans of the LRR-family, which remain bound to the filament providing for interactions via a linker of a matrilin to other matrix constituents like collagen fibres and the large proteoglycans, e.g. aggrecan in cartilage. Aggrecan is contributing an extreme anionic charge density to the extracellular matrix, which by osmotic effects leads to water retention and strive to swelling, resisted by the tensile properties of the collagen fibres. Aggrecan is bound via one end to hyaluronan, including such molecules retained at the cell surface, to form very large molecular entities that interact with other constituents of the matrix, e.g. fibulins that can form their own network. Other important interactions are those with cell surface receptors such as integrins, heparan sulphfate proteoglycans, hyaluronan receptors and others. Many of the molecules with an ability to interact with these receptors can also bind to molecules in the matrix and provide a bridge from the matrix to the cell and induce various responses. In pathology, there is an imbalance in matrix turnover with often excessive proteolytic breakdown. This results in the formation of protein fragments, where cleavage provides information on the active enzyme. Those fragments released can be specifically detected employing antibodies specific to the cleavage site and used to diagnose and monitor e.g. joint disease at early stages.


Glycine metabolism in skeletal muscle: implications for metabolic homeostasis.
The review summarizes the recent literature on the role of glycine in skeletal muscle during times of stress. Supplemental glycine protects muscle mass and function under pathological conditions. In addition, mitochondrial dysfunction in skeletal muscle leads to increased cellular serine and glycine production and activation of NADPH-generating pathways and glutathione metabolism. These studies highlight how glycine availability modulates cellular homeostasis and redox status. Recent studies demonstrate that supplemental glycine effectively protects muscles in a variety of wasting models, including cancer cachexia, sepsis, and reduced caloric intake. The underlying mechanisms responsible for the effects of glycine remain unclear but likely involve receptor-mediated responses and modulation of intracellular metabolism. Future research to understand these mechanisms will provide insight into glycine's therapeutic potential. Our view is that glycine holds considerable promise for improving health by protecting muscles during different wasting conditions.


Subcutaneous microvascular responses to hemodilution with a red cell substitute consisting of polyethyleneglycol-modified vesicles encapsulating hemoglobin.
Phospholipid vesicles encapsulating purified hemoglobin [Hb vesicles (HbV); diameter 259 +/- 82 mm; oxygen affinity 31 mm Hg; [Hb] 5 and 10 g/dL] were developed to provide oxygen-carrying capacity to plasma expanders. Their function as a blood replacement was tested in the subcutaneous microvasculature of awake hamsters during severe hemodilution in which 80% of the red blood cell mass was substituted with suspensions of the vesicles in 5% human serum albumin (HSA) solution. Vesicles were tested with membranes that were unmodified (HbV/HSA) or conjugated with polyethyleneglycol (PEG) on the vesicular surface (PEG-HbV/HSA). The viscosity of 10 g/dL HbV/HSA was 8 cP at 358 s-1 owing to the intervesicular aggregation, while that of 10 g/dL PEG-HbV/HSA was 3.5 cP, since PEG chains inhibit aggregation. Both materials yielded normal mean arterial pressure, heart rate, and blood gas parameters at all levels of exchange, which could not be achieved with HSA alone. Subcutaneous microvascular studies showed that PEG-HbV/HSA significantly improved microhemodynamic conditions (flow rate, functional capillary density, vessel diameter, and oxygen tension) relative to unmodified HbV/HSA. Even though the enhancement of PEG modification did not achieve the functional characteristics of the blood-perfused microcirculation, PEG reduced vesicular aggregation and viscosity, improving microvascular perfusion relative to the unmodified type. These results highlight the significance of microvascular analysis in the design of red cell substitutes and the necessity of surface modification of HbV to prevent aggregation.