Alkali metal complexes of an enantiopure iminophosphonamide ligand with bright delayed fluorescence.
The enantiomerically pure ligand P,P-diphenyl-N,N'-bis((R)-1-phenylethyl)phosphinimidic amide (1; (R)-HPEPIA) was synthesized and subsequently deprotonated with alkali metal precursors to yield dimeric complexes [M2{(R)-PEPIA}2] (M = Li (2), Na (3), K (4), Rb (5)). The cesium compound [M{(R)-PEPIA}] (6) crystallized as a cocrystal composed of dimeric ([Cs2{(R)-PEPIA}2] (6d ) and 1D-polymeric ([Cs{(R)-PEPIA}] n ) (6p ) species in a 1 : 1 ratio. The coordination polymer 6p features a unique sinus-shaped configuration of repeating -Cs-N-P-N-Cs-N-P-N- units. Unusual photoluminescence (PL) properties were found for solid 1-6: in contrast to the fluorescent ligand 1, the alkali metal complexes show phosphorescence at low temperatures (<100 K) and thermally activated delayed fluorescence (TADF) above ∼150 K. The latter provides for PL quantum yields up to 36% (3) at ambient temperature. DFT calculations support that both 1 and 2-6d have similar singlet and triplet excited states with energy separations of a few tens of meV. The strongly enhanced intersystem crossing (ISC) in the metal complexes, resulting in TADF, is attributed to their dimeric structure. This suggests that the fluorophore dimerization may serve as a tool to effect ISC for the design of TADF emitters.


Long-term mortality trends in patients with traumatic brain injury.
Comparison of long-term mortality rates between patients with traumatic brain injury (TBI) and the general population has not been adequately investigated. This project aimed to obtain information on the long-term mortality rate of patients with TBI. Using a rehabilitation database of a major teaching hospital, the search identified 476 patients, of whom 27 were deceased. This mortality rate (5.7%) was compared with the expected mortality rate for an equivalent population without TBI (1.5%) using Australian Life Table data. It was found that patients with TBI had a significantly higher mortality rate than the general population (chi2 = 12.2, p < 0.001). Possible reasons for this finding are discussed.


Two isomers of HDTIC isolated from Astragali Radix decrease the expression of p16 in 2BS cells.
Astragali Radix, the root of Astragalus membranceus (Fish) Bunge Var. mongholicus (Bge), is a crude drug considered as one of the effective traditional Chinese anti-ageing material. The two isomers of 4-hydroxy-5-hydroxymethyl-[1, 3] dioxolan-2, 6'-spirane-5', 6', 7', 8'-tetrahydro-indolizine-3'-carbaldehyde (HDTIC), HDTIC-1 and HDTIC-2, were first extracted from the herb in 2002. We demonstrated previously that 0.1 micromol/L HDTIC-1 or 1.0 micromol/L HDTIC-2 strongly delay replicative senescence of human fetal lung diploid fibroblasts (2BS). In this study, we chose them to investigate their effects on the expression of senescence-associated genes to explore the mechanism of how HDTIC delays replicative senescence. The effects of HDTIC-1 and HDTIC-2 on the expression of p16 and p21 were observed in vitro by RT-PCR and Western blot. The anti-oxidative activities of the compounds were also observed by phenotype alteration after treatment with antioxidants. There was an obvious expression of p16 in the control senescent cells. However, in the 2BS cells, after 56 population doublings (PDs) grown from PD28 in 0.1 micromol/L HDTIC-1 or 1.0 micromol/L HDTIC-2, there was a weak mRNA expression of p16 and no protein expression of p16 was observed. The expression level of p21 increased with cell ageing. Moreover, there was no difference between the expression level of p21 in the control cells and that in the same PD cells cultured with HDTIC compounds. The results also showed that 2BS cells exposed to 100 micromol/L H2O2 for 5 minutes return to their non-senescent phenotype and continue to be confluent after incubating the damaged cells with HDTIC-1 (1.0 micromol/L ) or HDTIC-2 (10 micromol/L ) for 1 hour. Expression of p16 by 2BS cells was strongly inhibited by HDTIC compounds, which could contribute to their delayed replicative senescence by the way of p16(INK4a)/Rb/MAPK. The anti-oxidative activities of HDTIC-1 and HDTIC-2, described in this study for the first time, might be indirectly related to their inhibition of p16 expression.


Surgical Treatment of Epiblepharon Effectively Alleviates Keratopathy but Not Astigmatism: A Case-Control Study Utilizing Vector Analysis in East Asian Children.
To identify an appropriate surgical indication of epiblepharon by comparing keratopathy and astigmatism outcomes after surgical and medical treatments for epiblepharon in Asian children. Children diagnosed with epiblepharon (n = 82, age 5.93 ± 2.76 years) with >6 months of follow-up were enrolled. The clinical presentations and cycloplegic refractive status at the baseline and 3 and 6 months after treatment were compared between surgical (91 eyes from 47 children) and nonsurgical (67 eyes from 35 children) groups. The refractive and keratometric astigmatism at each time point were evaluated with vector analysis methods. For Thibos and Horner's method, the astigmatic power vector was decomposed into horizontal and oblique meridians (J 0 and J 45). However, the treatment-induced astigmatism (TIA) vectors were calculated by Alpins' method and depicted by the AstigMATIC software. In the surgical and nonsurgical groups, the baseline astigmatism magnitude was similar (2.22 ± 1.39 and 2.26 ± 1.46 D, p = 0.87). The rate of complete resolution of keratopathy at 6 months was 71.4% and 11.5%. The astigmatism magnitude in the surgical group differed among baseline and 3 months (2.25 ± 1.23 D) and 6 months postoperatively (1.97 ± 1.28 D) (p = 0.001). Power vector analyses confirmed a nuanced against-the-rule shift in the surgical group. This trend was especially observed in the subgroup of baseline astigmatism >2.0 D. However, the difference in the astigmatism magnitude between surgical and nonsurgical groups, even in highly astigmatic children, was not significant at 6 months. The improvement of keratopathy in the surgical group was greater than that in the nonsurgical group in consideration of the more advanced severity in the surgery group at baseline. Decreased with-the-rule astigmatism can be observed at 6 months postoperatively, particularly among those with greater baseline astigmatism. However, the amount of change is small, and the outcome does not differ significantly from the nonsurgical treatment. Therefore, surgical indications should majorly base on the severity of symptoms and keratopathy.


MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia.
In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34+ and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs.


High prevalence of interatrial septal aneurysm in young adults who were born preterm.
The cardiovascular vulnerability of young adults who were born preterm was first acknowledged over a decade ago. (1) To examine the echocardiographic characteristics of a group of young adults born preterm with an extremely low birthweight (<1000 g; ex-ELBW) in comparison with healthy controls born at term (C); (2) to identify a correlation between the potential echocardiographic abnormalities detected in ex-ELBW and their anthropometric parameters, age, presence of respiratory distress, patency of ductus arteriosus, length of stay in Neonatal Intensive Care Unit. Thirty-seven ex-ELBW (11 males, 26 females; mean age: 22.2 ± 1.8 years) were compared with 37 C (11 males, 26 females). Both groups underwent standard mono- and bi-dimensional transthoracic echocardiogram with color Doppler. No statistically significant differences were detected between the two groups regarding mono-dimensional echocardiography or Doppler measurements (p = ns). Conversely, a statistically significant difference was observed between the prevalence of interatrial septal aneurysm (ASA) in ex-ELBW compared to C (p = 0.0016). A significant association was likewise observed between ASA and the presence of both respiratory distress at birth (p < 0.05) and patency of the ductus arteriosus (p < 0.05). A significant prevalence of ASA was detected in ex-ELBW subjects compared to C, underlining a probable correlation with respiratory distress and patent ductus arteriosus. In view of the association between ASA and stroke in young adults devoid of other cerebrovascular risk factors, this unexpected observation suggests that all ex-preterm subjects should undergo transthoracic or transesophageal echocardiographic examination with the aim of detecting this potentially emboligenic cardiac abnormality.


Cystic Fibrosis Diagnostic Challenges over 4 Decades: Historical Perspectives and Lessons Learned.
Because cystic fibrosis (CF) can be difficult to diagnose, and because information about the genetic complexities and pathologic basis of the disease has grown so rapidly over the decades, several consensus conferences have been held by the US CF Foundation, and a variety of other efforts to improve diagnostic practices have been organized by the European CF Society. Despite these efforts, the application of diagnostic criteria has been variable and caused confusion. To improve diagnosis and achieve standardization in terms and definitions worldwide, the CF Foundation in 2015 convened a committee of 32 experts in the diagnosis of CF from 9 countries. As part of the process, all previous consensus-seeking exercises sponsored by the CF Foundation, along with the important efforts of the European CF Society, were comprehensively and critically reviewed. The goal was to better understand why consensus conferences and their publications have not led to the desired results. Lessons learned from previous diagnosis consensus processes and products were identified. It was decided that participation in developing a consensus was generally not inclusive enough for global impact. It was also found that many efforts to address sweat test issues were valuable but did not always improve clinical practices as CF diagnostic testing evolved. It also became clear from this review that premature applications of potential diagnostic tests such as nasal potential difference and intestinal current measurement should be avoided until validation and standardization occur. Finally, we have learned that due to the significant and growing number of cases that are challenging to diagnose, an associated continuing medical education program is both desirable and necessary. It is necessary but not sufficient to organize and publish CF diagnosis consensus processes. Follow-up implementation efforts and monitoring practices seem essential.


Histone hyperacetylation is involved in the quercetin-induced human leukemia cell death.
Quercetin (QU) is recognized as a promising anticancer drug, but its mechanism remains elusive. Here we found that QU induced human leukemia cell death in a dose-dependent manner. However, it did not show a dose-dependent inhibition on ROS generation (indicated by the level of malondialdehyde, MDA) in the same cells. QU showed similar antioxidant activity at concentrations of 50, 75 and 100 microM. Consistent with that, the antioxidant, N-acetyl-cysteine (NAC) could only further decrease the ROS generation and enhance the cell death triggered by QU at the concentrations less than 50 microM. These results indicate that an additional mechanism is involved in the anticancer activity of high concentrations of QU. When the effect of QU on histone acetylation was studied, QU induced significant histone hyperacetylation at 75 and 100 microM, indicating the possible involvement of histone hyperacetylation in the anticancer activity of high concentrations of QU. This conclusion was supported by the findings that when histone acetylation in the cells treated by QU was increased by different concentrations of TSA, the cell death was significantly enhanced. Our results thus provide the first evidence that QU can induce histone hyperacetylation and this induction of histone hyperacetylation may represent an unrevealed mechanism in its anticancer activity.


Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.
High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.


Long-term survival of dialysis patients with bacterial endocarditis in the United States.
The incidence of bacterial endocarditis is much greater in long-term dialysis patients compared with the general population, and chronic kidney disease has been postulated as an independent host-related risk factor. Limited data are available on the long-term survival of dialysis patients with endocarditis. Dialysis patients hospitalized for bacterial endocarditis between 1977 and 2000 were studied retrospectively using data from the US Renal Data System database. Long-term survival was estimated by means of the life-table method. A Cox proportional hazards model was used to identify the impact of demographic characteristics and comorbidity on outcome. A total of 13,130 dialysis patients with bacterial endocarditis were identified. The in-hospital mortality rate for the entire cohort was 23.5%. Survival rates at 1, 2, 3, and 5 years were 45.9%, 33.3%, 24.3%, and 14.7% for patients hospitalized between 1977 and 1991 and 41.0%, 29.1%, 20.6%, and 10.9% for those hospitalized between 1992 and 1996, respectively. Survival rates at 1, 2, and 3 years were 38.4%, 25.3%, and 18.3% for patients hospitalized between 1997 and 2000, respectively. The most powerful independent predictors of all-cause death were age, diabetes as cause of end-stage renal disease, and cerebrovascular accident or transient ischemic attack as a comorbid condition. Dialysis patients with bacterial endocarditis have poor long-term survival, even in the current treatment era, with survival rates changing little in the past 2 decades. Additional studies are needed to identify risk-reduction measures and develop additional treatment strategies for dialysis patients with endocarditis.


Phytochemical relationship of Euphorbia helioscopia and Euphorbia pulcherrima with Lactuca sativa.
Allelopathy is an important phenomenon that modifies the ecosystem. A plant can enhance or reduce the growth of other plant due to the presence of a number of allelochemicals in its different parts. Euphorbia helioscopia and Euphorbia pulcherrima are medicinal plant species. Both these species are collected from wild resources for various purposes. To reduce the pressure on wild population, it is important to bring them into cultivation. Therefore, the allelopathic effects of E. helioscopia and E. pulcherrima on the growth of lettuce seeds were studied. Three different concentrations (2%, 4% and 6%) of five different solvents (methanol, acetone, ethyl acetate, n-hexane and distilled water) were used to estimate the allelopathic potential of the above-mentioned Euphorbia species. Results indicated a non-significant growth inhibitory effect of both plants on lettuce seeds. Different extracts reduced the growth of test plant to some extent but this inhibition was not significant. From the observed results, it was concluded that the studied Euphorbia species, being medicinally important crops, can be introduced as intercrop with other cash crops.


Signal estimation and denoising using VC-theory.
Signal denoising is closely related to function estimation from noisy samples. The same problem is also addressed in statistics (non-linear regression) and neural network learning. Vapnik-Chervonenkis (VC) theory has recently emerged as a general theory for estimation of dependencies from finite samples. This theory emphasizes model complexity control according to Structural Risk Minimization (SRM) inductive principle, which considers a nested set of models of increasing complexity (called a structure), and then selects an optimal model complexity providing minimum error for future samples. This paper applies the framework of VC-theory to signal estimation/denoising. There are three factors important for accurate signal estimation from finite samples: (1) the type of (orthogonal) basis functions used (i.e. Fourier basis, wavelets etc.). (2) The choice of a structure, i.e. ordering of the basis functions according to their 'importance' for accurate signal estimation. This corresponds to the choice of a 'structure' under SRM formulation. (3) Selecting an optimal number of terms (basis functions) from the ordered sequence of basis functions (2), aka model selection or complexity control (in statistics). We propose a methodology for specifying appropriate orderings (2) and an analytic expression for model selection (3) for signal processing applications. We also present empirical comparisons between the proposed methodology and current state-of-the-art wavelet thresholding methods for univariate signals. These comparisons suggest that the prudent choice of a structure (2) and the use of VC-based model selection (3) are critical for accurate signal estimation with finite samples.


[The National Pharmacopoeia and the therapeutic status of flora in Mexican biomedicine].
The paper analyses the transformation of the Mexican pharmacopoeia, focusing on the presence of medicinal plants. Reflecting diverse processes, editions of the pharmacopoeia show a progressive modification in its content and profile. A text written to shape a Mexican materia medica, recognising empirical knowledge by the inclusion of popularly used resources and involving clinicians as authors and recipients, was transformed into a mainly industrial publication with no clinical references. The origin and implications of this process are explored.


PROMIS Global Health item nonresponse: is it better to impute missing item responses before computing T-scores?
Item response theory (IRT) scoring provides T-scores for physical and mental health subscales on the Patient-Reported Outcomes Measurement Information System Global Health questionnaire (PROMIS-GH) even when relevant items are skipped. We compared different item- and score-level imputation methods for estimating T-scores to the current scoring method. Missing PROMIS-GH items were simulated using a dataset of complete PROMIS-GH scales collected at a single tertiary care center. Four methods were used to estimate T-scores with missing item scores: (1) IRT-based scoring of available items (IRTavail), (2) item-level imputation using predictive mean matching (PMM), (3) item-level imputation using proportional odds logistic regression (POLR), and (4) T-score-level imputation (IMPdirect). Performance was assessed using root mean squared error (RMSE) and mean absolute error (MAE) of T-scores and comparing estimated regression coefficients from the four methods to the complete data model. Different proportions of missingness and sample sizes were examined. IRTavail had lowest RMSE and MAE for mental health T-scores while PMM had lowest RMSE and MAE for physical health T-scores. For both physical and mental health T-scores, regression coefficients estimated from imputation methods were closer to those of the complete data model. The available item scoring method produced more accurate PROMIS-GH mental but less accurate physical T-scores, compared to imputation methods. Using item-level imputation strategies may result in regression coefficient estimates closer to those of the complete data model when nonresponse rate is high. The choice of method may depend on the application, sample size, and amount of missingness.


Growth factors influencing bone development.
We have approached the study of growth factors affecting cartilage and bone development by investigating those factors present in bone which are able to initiate new cartilage and bone formation in vivo. This has led to the identification and molecular cloning of seven novel human factors which we have named BMP-1 through BMP-7. Six of these molecules are related to each other, and are also distantly related to TGF-beta. The presence of one of these molecules, recombinant human BMP-2 (rhBMP-2) is sufficient to produce the complex developmental system of cartilage and bone formation when implanted subcutaneously in a rat assay system. In this model, administration of rhBMP-2 ultimately results in the formation of a piece of trabecular bone, which is filled with mature bone marrow. While our studies demonstrate that rhBMP-2 by itself has the ability to induce cartilage and bone formation in vivo, we find other BMP molecules present along with BMP-2 in our highly purified nonrecombinant bone-inductive material. These results suggest that the bone inductive capacity of bone-derived proteins may reside in the combinatorial or synergistic activities of this set of BMP-2 related molecules.


case of autoimmune GFAP astrocytopathy with eosinophils in the cerebrospinal fluid.
Cerebrospinal fluid (CSF) eosinophilia is associated with a narrow differential, primarily including parasitic and fungal infections, neoplasm, and chemical meningitis. It has rarely been reported in neuroinflammatory conditions including as a finding of CSF cytology in two autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy cases. Here we describe a case of autoimmune GFAP astrocytopathy with classic clinical and radiographic features as well as presence of eosinophils in the CSF. This case highlights a potential association of eosinophils in the CSF with autoimmune GFAP astrocytopathy, which may suggest its inclusion in the differential diagnosis of eosinophilic meningitis, encephalitis, or myelitis.


Identification and molecular analysis of glycosaminoglycans in cutaneous lupus erythematosus and dermatomyositis.
Glycosaminoglycans (GAGs), also known histologically as dermal mucin, accumulate in several inflammatory skin conditions. Because different GAG species have distinct immunologic effects, the authors examined two GAGs, hyaluronan (HA) and chondroitin sulfate (CS), using specific stains in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). In the dermis of one CLE subtype, tumid LE (TLE), they found only increased HA, but both HA and CS were significantly elevated in another CLE subtype, discoid LE (DLE). DM lesional dermis accumulated mainly CS but not HA. The authors then used glycomic gene expression microarrays to assess the expression of HA- and CS-related genes in CLE skin. Real-time quantitative PCR confirmed significantly increased expression of HAS2, CHSY1, and C4ST1 in the combined groups of CLE lesions (n = 8) compared to healthy controls (n = 4). Thus, the increase in HA in CLE presumably results from upregulation of HAS2, whereas CHSY1 and C4ST1 appear to contribute to increased CS. Based on their known immunomodulatory effects in other systems, HA and CS may thus participate in the pathophysiology of these inflammatory skin conditions.


[Endoscopic ventriculostomy in the treatment of obstructive forms of hydrocephalus].
Third ventriculostomy creating a pathway for the CSF from the third ventricle to the interpeduncular cistern is a rational and sound alternative to the implantation of the shunting system, including Torkildsen shunts in managing obstructive hydrocephalus. Twenty four patients with hydrocephalus aged from 6 to 46 (mean 21 year) were operated. In 20 patients the occlusion was caused by small tumors in the aqueduct area, in 4 cases the occlusion was due to non-neoplastic process. In the majority of cases (19 patients) third ventriculostomy was the first operation for hydrocephalus. A rigid ventriculoscope (K. Storz, Germany) with an external diameter of 6 mm was used in all procedures. In 23 patients a rapid clinical improvement was observed along with resolution of intracranial hypertension. Median follow-up of 7 months duration was possible in 18 cases. 16 patients remain stable with no signs of hydrocephalus. Control MRI studies showed patent ventriculostomy. 5 patients after an endoscopic procedure were treated with irradiation for tumors. In 2 patients the opening in the ventricular floor fused and became nonfunctional. It happened 4 months after fenestration followed by surgical removal of tumors of the pineal region which caused occlusion. Complications were observed in 2 cases. In one patient ventriculitis developed shortly after the procedure and resolved completely by the end of the second postoperative week. Another patient was noted to have signs of transitory moderate diabetes insipidus.


International sore throats.
This paper reports on an international study of the diagnostic behaviour of doctors presented with patients complaining of a sore throat. Differences were found between individual doctors' predicted and actual behaviour, and between the behaviour of doctors in different countries.


PHAIR: a biosensor for pH measurement in air-liquid interface cell culture.
In many biological systems, pH can be used as a parameter to understand and study cell dynamics. However, measuring pH in live cell culture is limited by the sensor ion specificity, proximity to the cell surface, and scalability. Commercially available pH sensors are difficult to integrate into a small-scale cell culture system due to their size and are not cost-effective for disposable use. We made PHAIR-a new pH sensor that uses a micro-wire format to measure pH in vitro human airway cell culture. Tungsten micro-wires were used as the working electrodes, and silver micro-wires with a silver/silver chloride coating were used as a pseudo reference electrode. pH sensitivity, in a wide and narrow range, and stability of these sensors were tested in common standard buffer solutions as well as in culture media of human airway epithelial cells grown at the air-liquid interface in a 24 well cell culture plate. When measuring the pH of cells grown under basal and challenge conditions using PHAIR, cell viability and cytokine responses were not affected. Our results confirm that micro-wire-based sensors have the capacity for miniaturization and detection of diverse ions while maintaining sensitivity. This suggests the broad application of PHAIR in various biological experimental settings.


Qiliqiangxin inhibits the development of cardiac hypertrophy, remodeling, and dysfunction during 4 weeks of pressure overload in mice.
Qiliqiangxin (QL), a traditional Chinese medicine, has been used in the treatment of chronic heart failure. However, whether QL can benefit cardiac remodeling in the hypertensive state is unknown. We here examined the effects of QL on the development of cardiac hypertrophy through comparing those of losartan in C57BL/6 mice underlying transverse aorta constriction for 4 weeks. QL and losartan were administrated at 0.6 mg and 13.4 mg·kg·d, respectively. Cardiac hypertrophy, function, and remodeling were evaluated by echocardiography, catheterization, histology, and examination of specific gene expression and ERK phosphorylation. Cardiac apoptosis, autophagy, tumor necrosis factor α/insulin-like growth factor-1, and angiotensin II type 1 receptor expression and especially the proliferation of cardiomyocytes and phosphorylation of ErbB receptors were examined in vivo to elucidate the mechanisms. Transverse aorta constriction for 2 weeks resulted in a significant cardiac hypertrophy, which was significantly suppressed by either QL or losartan treatment. At 4 weeks after transverse aorta constriction, although the development of cardiac dysfunction and remodeling and the increases in apoptosis, autophagy, tumor necrosis factor α/insulin-like growth factor-1, and angiotensin II type 1 receptor expression were abrogated comparably between QL and losartan treatments, QL, but not losartan, enhanced proliferation of cardiomyocytes, which was paralleled with dowregulation of CCAAT/enhancer-binding protein β, upregulation of CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain 4, and increases in ErbB2 and ErbB4 phosphorylation. Furthermore, inhibition of either ErbB2 or CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain 4 abolished the cardiac protective effects of QL. Thus, QL inhibits myocardial inflammation and cardiomyocyte death and promotes cardiomyocyte proliferation, leading to an ameliorated cardiac remodeling and function in a mouse model of pressure overload. The possible mechanisms may involve inhibition of angiotensin II type 1 receptor and activation of ErbB receptors.


DNA methylation: a transcriptional mechanism co-opted by the developed mammalian brain?
Forming and maintaining behavioral memories is a complex process that involves, among other requirements, transcriptional regulation and systems communication. Here we review recent studies exploring the role of DNA methylation in these critical processes. Further, we suggest that, perhaps, the adult brain controls and utilizes the mechanism of DNA methylation in non-traditional ways that are waiting to be explored.


Significance of the nitric oxide cascade in erectile function.
In recent years, a significant body of experimental evidence has accumulated implicating nitric oxide as the central component of a novel signal transduction system that functions in the penis to mediate penile erection. The involvement of nitric oxide in erection physiology appears to be quite complex, involving multiple regulatory interactions: this gaseous molecule has been found to trigger several biochemical events that elicit erectile tissue responses, while a host of modulatory factors have been identified that influence its release and action in erectile tissue. Ongoing investigations in nitric oxide biology in other organ systems also suggest mechanisms which, while yet to be fully established in the penis, may operate significantly to determine the role of nitric oxide in this organ. Further elucidation of cellular and molecular interactions involving nitric oxide effects in the penis can be expected to reveal diverse targets that may serve as a basis for novel pharmacotherapeutic strategies for the future management of erectile dysfunction.


Towards a better understanding of the substrate specificity of the UDP-N-acetylglucosamine C4 epimerase WbpP.
WbpP is the only genuine UDP-GlcNAc (UDP-N-acetylglucosamine) C4 epimerase for which both biochemical and structural data are available. This represents a golden opportunity to elucidate the molecular basis for its specificity for N-acetylated substrates. Based on the comparison of the substrate binding site of WbpP with that of other C4 epimerases that convert preferentially non-acetylated substrates, or that are able to convert both acetylated and non-acetylated substrates equally well, specific residues of WbpP were mutated, and the substrate specificity of the mutants was determined by direct biochemical assays and kinetic analyses. Most of the mutations tested were anticipated to trigger a significant switch in substrate specificity, mostly towards a preference for non-acetylated substrates. However, only one of the mutations (A209H) had the expected effect, and most others resulted in enhanced specificity of WbpP for N-acetylated substrates (Q201E, G102K, Q201E/G102K, A209N and S143A). One mutation (S144K) totally abolished enzyme activity. These data indicate that, although all residues targeted in the present study turned out to be important for catalysis, determinants of substrate specificity are not confined to the substrate-binding pocket and that longer range interactions are essential in allowing proper positioning of various ligands in the binding pocket. Hence prediction or engineering of substrate specificity solely based on sequence analysis, or even on modelling of the binding pocket, might lead to incorrect functional assignments.


Proteomics meets blue biotechnology: a wealth of novelties and opportunities.
Blue biotechnology, in which aquatic environments provide the inspiration for various products such as food additives, aquaculture, biosensors, green chemistry, bioenergy, and pharmaceuticals, holds enormous promise. Large-scale efforts to sequence aquatic genomes and metagenomes, as well as campaigns to isolate new organisms and culture-based screenings, are helping to push the boundaries of known organisms. Mass spectrometry-based proteomics can complement 16S gene sequencing in the effort to discover new organisms of potential relevance to blue biotechnology by facilitating the rapid screening of microbial isolates and by providing in depth profiles of the proteomes and metaproteomes of marine organisms, both model cultivable isolates and, more recently, exotic non-cultivable species and communities. Proteomics has already contributed to blue biotechnology by identifying aquatic proteins with potential applications to food fermentation, the textile industry, and biomedical drug development. In this review, we discuss historical developments in blue biotechnology, the current limitations to the known marine biosphere, and the ways in which mass spectrometry can expand that knowledge. We further speculate about directions that research in blue biotechnology will take given current and near-future technological advancements in mass spectrometry.


Building a mechanistic understanding of predation with GPS-based movement data.
Quantifying kill rates and sources of variation in kill rates remains an important challenge in linking predators to their prey. We address current approaches to using global positioning system (GPS)-based movement data for quantifying key predation components of large carnivores. We review approaches to identify kill sites from GPS movement data as a means to estimate kill rates and address advantages of using GPS-based data over past approaches. Despite considerable progress, modelling the probability that a cluster of GPS points is a kill site is no substitute for field visits, but can guide our field efforts. Once kill sites are identified, time spent at a kill site (handling time) and time between kills (killing time) can be determined. We show how statistical models can be used to investigate the influence of factors such as animal characteristics (e.g. age, sex, group size) and landscape features on either handling time or killing efficiency. If we know the prey densities along paths to a kill, we can quantify the 'attack success' parameter in functional response models directly. Problems remain in incorporating the behavioural complexity derived from GPS movement paths into functional response models, particularly in multi-prey systems, but we believe that exploring the details of GPS movement data has put us on the right path.


FGF signaling controls caudal hindbrain specification through Ras-ERK1/2 pathway.
During early steps of embryonic development the hindbrain undergoes a regionalization process along the anterior-posterior (AP) axis that leads to a metameric organization in a series of rhombomeres (r). Refinement of the AP identities within the hindbrain requires the establishment of local signaling centers, which emit signals that pattern territories in their vicinity. Previous results demonstrated that the transcription factor vHnf1 confers caudal identity to the hindbrain inducing Krox20 in r5 and MafB/Kreisler in r5 and r6, through FGF signaling [1]. We show that in the chick hindbrain, Fgf3 is transcriptionally activated as early as 30 min after mvHnf1 electroporation, suggesting that it is a direct target of this transcription factor. We also analyzed the expression profiles of FGF activity readouts, such as MKP3 and Pea3, and showed that both are expressed within the hindbrain at early stages of embryonic development. In addition, MKP3 is induced upon overexpression of mFgf3 or mvHnf1 in the hindbrain, confirming vHnf1 is upstream FGF signaling. Finally, we addressed the question of which of the FGF-responding intracellular pathways were active and involved in the regulation of Krox20 and MafB in the hindbrain. While Ras-ERK1/2 activity is necessary for MKP3, Krox20 and MafB induction, PI3K-Akt is not involved in that process. Based on these observations we propose that vHnf1 acts directly through FGF3, and promotes caudal hindbrain identity by activating MafB and Krox20 via the Ras-ERK1/2 intracellular pathway.


Estrogen-induced up-regulation of gamma-aminobutyric acid receptors in the CNS of rodents.
Previous studies have identified an effect of estrogen administration on the number of central GABAergic binding sites of rat. We have further characterized this effect by performing a series of experiments in vitro where we analyzed the changes of gamma-aminobutyric acid (GABA) binding in slices of nervous tissue incubated in a physiological medium in presence of estradiol. The tissues were dissected from ovariectomized rats. In such a system, estrogen augmented the amount of [3H]muscimol binding within 3 h of incubation. The effect was dose-dependent and could be blocked by the addition of the anti-estrogen tamoxifen. The increase in [3H]muscimol binding could not be observed by addition of estradiol to broken membranes or by incubation of the slices with steroids deprived of estrogenic activity. Furthermore, the estrogen-induced increase of GABA binding sites could be prevented by addition of cycloheximide and alpha-amanitin in the incubation medium. Our data indicate that the estrogen may increase the number of GABA binding sites by direct interaction with the GABA receptor gene or genes involved in the metabolism of GABA receptor.


Respiratory compromise in French bulldogs presented with intervertebral disc extrusion.
French bulldogs hospitalised for the management of intervertebral disc extrusion (IVDE) are frequently affected by respiratory compromise, typically brachycephalic-associated upper respiratory obstruction and/or aspiration events. We evaluated the occurrence of such respiratory compromise events in French bulldogs presented to two referral hospitals. Clinical data for French bulldogs diagnosed with IVDE were retrospectively collated, including severity of neurological deficits, neuroanatomical localisation, diagnosis, details of respiratory compromise, treatment and outcome. A total of 306 dogs diagnosed with IVDE were included. Sixty dogs (19.6%) experienced respiratory compromise, of which 31 dogs (10.1%) progressed to cyanosis, collapse or respiratory arrest. The study was limited by its retrospective nature. Furthermore, the duration of hospitalisation was not evaluated and the decision for euthanasia was often multifactorial. One in five French bulldogs presented with IVDE experienced respiratory compromise. The detrimental welfare effects of this warrant further discussion.


Comparative reliability studies and analysis of Au, Pd-coated Cu and Pd-doped Cu wire in microelectronics packaging.
This paper compares and discusses the wearout reliability and analysis of Gold (Au), Palladium (Pd) coated Cu and Pd-doped Cu wires used in fineline Ball Grid Array (BGA) package. Intermetallic compound (IMC) thickness measurement has been carried out to estimate the coefficient of diffusion (Do) under various aging conditions of different bonding wires. Wire pull and ball bond shear strengths have been analyzed and we found smaller variation in Pd-doped Cu wire compared to Au and Pd-doped Cu wire. Au bonds were identified to have faster IMC formation, compared to slower IMC growth of Cu. The obtained weibull slope, β of three bonding wires are greater than 1.0 and belong to wearout reliability data point. Pd-doped Cu wire exhibits larger time-to-failure and cycles-to-failure in both wearout reliability tests in Highly Accelerated Temperature and Humidity (HAST) and Temperature Cycling (TC) tests. This proves Pd-doped Cu wire has a greater potential and higher reliability margin compared to Au and Pd-coated Cu wires.


High-intensity urban light installation dramatically alters nocturnal bird migration.
Billions of nocturnally migrating birds move through increasingly photopolluted skies, relying on cues for navigation and orientation that artificial light at night (ALAN) can impair. However, no studies have quantified avian responses to powerful ground-based light sources in urban areas. We studied effects of ALAN on migrating birds by monitoring the beams of the National September 11 Memorial & Museum's "Tribute in Light" in New York, quantifying behavioral responses with radar and acoustic sensors and modeling disorientation and attraction with simulations. This single light source induced significant behavioral alterations in birds, even in good visibility conditions, in this heavily photopolluted environment, and to altitudes up to 4 km. We estimate that the installation influenced ≈1.1 million birds during our study period of 7 d over 7 y. When the installation was illuminated, birds aggregated in high densities, decreased flight speeds, followed circular flight paths, and vocalized frequently. Simulations revealed a high probability of disorientation and subsequent attraction for nearby birds, and bird densities near the installation exceeded magnitudes 20 times greater than surrounding baseline densities during each year's observations. However, behavioral disruptions disappeared when lights were extinguished, suggesting that selective removal of light during nights with substantial bird migration is a viable strategy for minimizing potentially fatal interactions among ALAN, structures, and birds. Our results also highlight the value of additional studies describing behavioral patterns of nocturnally migrating birds in powerful lights in urban areas as well as conservation implications for such lighting installations.


Separation of stages in the development of the "T" cells involved in cell-mediated immunity.
Density distribution analysis in continuous gradients of albumin has been used to study the development of cytotoxic lymphocytes (CL), to separate and characterize the progenitors of CL, and to determine their relationship to subpopulations of T cells. CL progenitors in the thymus were a homogeneous, medium-density population, distinct from the typical, dense, thymus small-lymphocyte. Activity seemed to be associated with one minor subpopulation of cells with surface antigenic properties characteristic of peripheral T cells (high levels of H-2 antigen, low levels of theta-antigen). CL progenitors in the spleen differed from those in the thymus and normally had the high buoyant density of typical small T lymphocytes. In states of antigenic stimulation, some lighter-density CL progenitors were found in the spleen. The buoyant density of the CL population developing in the spleens of immunized animals showed progressive changes with time. Early, "immature" CL had the light-density characteristics of large, activated lymphocytes. As the response developed, the density of the CL population increased, and finally approached that of CL progenitors and of typical small lymphocytes. The data suggest that density subpopulations of T cells represent stages in the development of immunocompetent cells. Possible differentiation pathways of T lymphocytes in the thymus and in the spleen are discussed.


Myocardial injury in the mouse induced by transthoracic cauterization.
A simplified transthoracic procedure using electrocauterization was used to induce myocardial injury in mice. After a single small incision through the skin and dissection of the underlying musculature, a modified electrocautery probe consisting of an insulated 20-gauge blunt needle with a polyethylene sleeve was inserted through the interior intercostal muscle at the fourth intercostal space and positioned on the anterior surface of the heart. The placement of the probe on the heart was indicated by mechanical motion of the exterior section of the needle. Electrocautery was applied to the distal exposed end of the probe. Of 10 mice that underwent this procedure, nine survived. After 10 days, myocardial damage was assessed by visual and histologic examination of the heart. In eight of nine surviving mice, transmural injury was induced in the left ventricle. The region of myocardial tissue damage on the surface of the left ventricle was 4.6 +/- 0.5 mm in diameter. This method provides a simple, noninvasive technique using a transthoracic electrocautery procedure to induce myocardial injury in the mouse heart with a low incidence of postoperative mortality.


Counting ability in Down syndrome: The comprehension of the one-to-one correspondence principle and the role of receptive vocabulary.
The authors investigated whether children with Down's syndrome (DS) who have not started to produce number words understand the one-to-one correspondence principle (Experiment 1), and they looked at the relationship between number word knowledge and receptive vocabulary (Experiment 2). Sixteen children with DS who did not recite the count list participated in Experiment 1, along with 2 comparison groups: 1 of 16 children with DS who recited up to 10, paired by chronological age, and another of 16 typically developing children paired by their ability to recite the list. The understanding of the principle was evaluated by a preferential looking task. Children saw 1 of 2 conditions. In the number condition, they heard number words and in the beep condition they heard computerized beeps. In both conditions, children saw videos depicting counting events that were principle-consistent or principle-inconsistent. Experiment 2 evaluated 25 children with DS using the Give-a-Number task and the Receptive Vocabulary subtest of the Wechsler Preschool and Primary Scale of Intelligence-III. In Experiment 1, children in the number condition preferred principle-consistent videos, independent of their ability to recite the count list. Experiment 2 showed a strong correlation between number word knowledge and receptive vocabulary scores, independent of chronological age. The results suggest that the difficulty of children with DS in acquiring counting ability might not reflect a lack of understanding of the one-to-one correspondence principle, but might instead be related to vocabulary development. (PsycINFO Database Record


Ultrasound-Assisted Intraosseous Injection of Platelet-Rich Plasma for a Patient With Tibial Plateau Subchondral Bone Marrow Lesion: A Case Presentation and Technical Illustration.
The subchondral bone marrow lesion (BML) has been found to have a significant correlation with pain in osteoarthritis patients. The intraosseous injection with orthobiologics such as platelet-rich plasma (PRP) or bone marrow aspirate concentrate has shown a promising therapeutic effect on BML-related pain. Traditionally, the intraosseous injection was performed with a large caliber trocar to break into the subchondral bone under fluoroscopy guidance and the patient was usually sedated prior to the procedure. In this report, we presented a 55-year-old woman who suffered from refractory right lateral knee pain for three months. The MRI revealed a right lateral tibial plateau subchondral BML, tears of medial and lateral menisci, and a general osteoarthritic appearance. We used ultrasound (US) to guide a 21-gauge needle through a pre-existing cortical break on the Gerdy's tubercle for the intraosseous PRP injection. The contrast was confirmed to reach the subchondral bone of the lateral tibial plateau and the injection reproduced the patient's symptoms. Three weeks later, the patient had significant improvement in the visual analog scale and function. In conclusion, intraosseous injection with PRP is a possibly effective treatment for subchondral BML in knee osteoarthritis, and US can facilitate a smaller gauge needle placement without the need to sedate the patient.


Intensity-modulated fiber Bragg grating sensor system based on radio-frequency signal measurement.
An intensity-modulated, fiber Bragg grating (FBG) sensor system based on radio-frequency (RF) signal measurement is presented. The RF signal is generated at a photodetector by two modulated optical signals reflected from the sensing FBG and a reference FBG. Wavelength shift of the sensing FBG changes intensity of the RF signal through changing the delay between the two optical signals, with temperature effect being compensated automatically by the reference FBG. It also exhibits important features including potentially high-speed measurement, low cost, and adjustable sensitivity. In the experiment, strain measurement with a maximum sensitivity of -0.34 microV/micro epsilon has been achieved.


Green Synthesis for Carbon Quantum Dots via Opuntia ficus-indica and Agave maximiliana: Surface-Enhanced Raman Scattering Sensing Applications.
In this study, we present an alternative method for synthesizing carbon quantum dots (CQDs) using a green synthesis approach via extracts from Agave maximiliana and Opuntia ficus-indica(Ofi). The extracts from both plants were used as the carbon source for the CQDs. The synthesis method employs mesoporous zeolite 4A as a refractory for the thermal treatment of the samples. Transmission electron microscopy analysis established that the size of the CQDs shows a narrow distribution centered around 2 nm with a maximum size of less than 3 nm for both cases. The CQDs exhibit absorption bands associated with π-π* transitions located around 220 nm. In both cases, photoluminescence (PL) phenomenon was detected by irradiating the samples with a UV wavelength and detecting emissions close to the blue wavelength. Additionally, both kinds of CQDs were tested as surface-enhanced Raman scattering (SERS) substrates against methylene blue (MB), indicating an enhancement associated with ring deformation and stretching modes of the v(C-C) and v(C-N) bonds located around 1400 and 1620 cm-1, respectively. Complementarily, in the framework of density functional theory, H2nC2(2m+1) structures (with n = 3-5 and m = 1-3) were used as a theoretical representation of CQDs in interaction with the MB molecule. It is used for developing the analysis of charge transfer effects between both systems and for specifying elements that generate the SERS effect associated with the chemical enhancement mechanism.


Phosphatase and tensin homolog (PTEN) is down-regulated in human NK/T-cell lymphoma and corrects with clinical outcomes.
Nasal-type natural killer/T-cell (NK/T-cell) lymphoma is a more aggressive sub-group of non-Hodgkin lymphoma, which is more common in Asia. The phosphatase and tensin homolog (PTEN) was originally discovered as a candidate tumor suppressor mutated and lost in various cancers. However, its clinical value and role in NK/T-cell lymphoma remain to be further explored. In the present study, we analyzed PTEN protein expression in 60 cases of human NK/T-cell lymphoma tissues and 40 cases of control nasal mucosa tissues specimens by immunohistochemical analysis. As a result, positive rate of PTEN protein expression in NK/T-cell lymphoma tissues (33.3%) is significantly lower than that of control nasal mucosa tissues (85.0%) (P < .01). However, no significant association was found between PTEN protein expression and sex, age, tumor location, clinical staging (Ann Arbor staging), or serum lactate dehydrogenase level (P > .05). Instead, PTEN protein was inversely corrected with Ki-67 expression, indicating a functional role in PTEN in human NK/T-cell lymphoma (P < .05). For clinical outcomes, PTEN positive rate significantly increased in objective response group (CR+PR) (43.5%) compared with SD+PD group (18.9%). Furthermore, overexpression of PTEN contributed to chemotherapy sensitivity to different doses of cisplatin (DDP) in human NK/T-cell lymphoma SNK-6 cells. These results suggest that PTEN may regulate chemotherapy sensitivity of NK/T-cell lymphoma and contribute to clinical outcomes. These findings indicate PTEN to be a potential target anti-tumor therapeutics for NK/T-cell lymphoma.


The effectiveness of anti-TNF-alpha therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis.
To systematically review and meta-analyse evidence on the effectiveness of the TNF-α inhibitors when used sequentially. Systematic review of comparative and single-arm observational studies. Data were synthesized using random-effects meta-analysis. Treatment effects were estimated using four outcome measures from the included studies: European League Against Rheumatism (EULAR) and ACR20 response rates and mean improvement in disease activity score-28 (DAS-20) and HAQ. The effect of other factors was explored via meta-regression and sub-group analyses. Twenty studies comprising 2705 patients were included in the analysis. All studies were observational and most had no control group. Therefore, our primary analysis considered patient changes from baseline. The mean percentage of ACR20 responders was 60.8% (95% CI 53.8, 67.4), EULAR responders 70.5% (95% CI 63.7, 76.6), mean overall improvement in DAS-28 scores was 1.53 (95% CI 1.25, 1.80) and in HAQ scores was 0.25 (95% CI 0.11, 0.40). Four studies made comparisons with patients who received TNF-α inhibitors for the first time. Response rates associated with sequential TNF-α inhibitor treatment were lower than for first-time use. Sequential TNF-α inhibitor use is likely to lead to treatment benefit in terms of the signs and symptoms of disease and physical function. There is also some evidence to suggest that the probability of achieving a response is lower, and the average magnitude of response is lower than the first use. Further evidence from randomized controlled trials is required to confirm and further quantify the role specific anti-TNF-α agents have when used sequentially.


Two-port network analysis and modeling of a balanced armature receiver.
Models for acoustic transducers, such as loudspeakers, mastoid bone-drivers, hearing-aid receivers, etc., are critical elements in many acoustic applications. Acoustic transducers employ two-port models to convert between acoustic and electromagnetic signals. This study analyzes a widely-used commercial hearing-aid receiver ED series, manufactured by Knowles Electronics, Inc. Electromagnetic transducer modeling must consider two key elements: a semi-inductor and a gyrator. The semi-inductor accounts for electromagnetic eddy-currents, the 'skin effect' of a conductor (Vanderkooy, 1989), while the gyrator (McMillan, 1946; Tellegen, 1948) accounts for the anti-reciprocity characteristic [Lenz's law (Hunt, 1954, p. 113)]. Aside from Hunt (1954), no publications we know of have included the gyrator element in their electromagnetic transducer models. The most prevalent method of transducer modeling evokes the mobility method, an ideal transformer instead of a gyrator followed by the dual of the mechanical circuit (Beranek, 1954). The mobility approach greatly complicates the analysis. The present study proposes a novel, simplified and rigorous receiver model. Hunt's two-port parameters, the electrical impedance Ze(s), acoustic impedance Za(s) and electro-acoustic transduction coefficient Ta(s), are calculated using ABCD and impedance matrix methods (Van Valkenburg, 1964). The results from electrical input impedance measurements Zin(s), which vary with given acoustical loads, are used in the calculation (Weece and Allen, 2010). The hearing-aid receiver transducer model is designed based on energy transformation flow [electric→ mechanic→ acoustic]. The model has been verified with electrical input impedance, diaphragm velocity in vacuo, and output pressure measurements. This receiver model is suitable for designing most electromagnetic transducers and it can ultimately improve the design of hearing-aid devices by providing a simplified yet accurate, physically motivated analysis. This article is part of a special issue entitled "MEMRO 2012".


Stroke events, and case fatalities in Switzerland based on hospital statistics and cause of death statistics.
In Switzerland there is a shortage of population-based information on stroke incidence and case fatalities (CF). The aim of this study was to estimate stroke event rates and both in- and out-of-hospital CF rates. Data on stroke diagnoses, coded according to I60-I64 (ICD 10), were taken from the Federal Hospital Discharge Statistics database (HOST) and the Cause of Death database (CoD) for the year 2004. The number of total stroke events and of age- and gender-specific and agestandardised event rates were estimated; overall CF, in-hospital and out-of-hospital, were determined. Among the overall number of 13 996 hospital discharges from stroke (HOST) the number was lower in women (n = 6736) than in men (n = 7260). A total of 3568 deaths (2137 women and 1431 men) due to stroke were recorded in the CoD database. The number of estimated stroke events was 15 733, and higher in women (n = 7933) than in men (n = 7800). Men presented significantly higher age-specific stroke event rates and a higher age-standardised event rate (178.7/100 000 versus 119.7/100 000). Overall CF rates were significantly higher for women (26.9%) than for men (18.4%). The same was true of out-of-hospital CF but not of in-hospital CF rates. The data on estimated stroke events obtained indicate that stroke discharge rate underestimates the stroke event rate. Out-of-hospital deaths from stroke accounted for the largest proportion of total stroke deaths. Sex differences in both number of total stroke events and deaths could be explained by the higher proportion of women than men aged 55+ in the Swiss population.


Serum sex hormones and breast cancer risk factors in postmenopausal women.
Postmenopausal women with elevated serum estrogens and androgens are at an increased risk of breast cancer. We evaluated associations of serum estrogen and androgen levels with age, anthropometry, and reproductive history to assess whether these characteristics could potentially modify breast cancer risk through hormonal mechanisms. A cross-sectional study was conducted among 133 postmenopausal women who donated blood to the serum bank (Columbia, MO) and served as controls in a previous prospective nested case control study of serum hormones and breast cancer risk. Standard regression methods were used to calculate adjusted means and test for trends in relationships of serum hormone concentrations with breast cancer risk factors. All analyses were performed on the log(e) scale, and all models included assay batch, date, and time of blood collection. Serum levels of estradiol, non-sex hormone binding globulin bound estradiol, estrone, estrone sulfate, and testosterone increased significantly with increasing body mass index (BMI), whereas sex hormone binding globulin levels decreased. After adjusting for BMI, nulliparous women tended to have higher testosterone levels compared with parous women (P = 0.05), but there was no evidence of a trend of decreasing testosterone with increasing parity. Dehydroepiandrosterone, its sulfate, and androstenediol decreased significantly with increasing age. Although BMI and parity could potentially modify breast cancer risk through hormonal mechanisms, age-related increases in breast cancer incidence do not appear to be mediated through changes in serum levels of the hormones evaluated.


Gcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia.
Neurons and glia differentiate from multipotent precursors called neural stem cells (NSCs), upon the activation of specific transcription factors. In vitro, it has been shown that NSCs display very plastic features; however, one of the major challenges is to understand the bases of lineage restriction and NSC plasticity in vivo, at the cellular level. We show here that overexpression of the Gcm transcription factor, which controls the glial versus neuronal fate choice, fully and efficiently converts Drosophila NSCs towards the glial fate via an intermediate state. Gcm acts in a dose-dependent and autonomous manner by concomitantly repressing the endogenous program and inducing the glial program in the NSC. Most NSCs divide several times to build the embryonic nervous system and eventually enter quiescence: strikingly, the gliogenic potential of Gcm decreases with time and quiescent NSCs are resistant to fate conversion. Together with the fact that Gcm is able to convert mutant NSCs that cannot divide, this indicates that plasticity depends on temporal cues rather than on the mitotic potential. Finally, NSC plasticity involves specific chromatin modifications. The endogenous glial cells, as well as those induced by Gcm overexpression display low levels of histone 3 lysine 9 acetylation (H3K9ac) and Drosophila CREB-binding protein (dCBP) Histone Acetyl-Transferase (HAT). Moreover, we show that dCBP targets the H3K9 residue and that high levels of dCBP HAT disrupt gliogenesis. Thus, glial differentiation needs low levels of histone acetylation, a feature shared by vertebrate glia, calling for an epigenetic pathway conserved in evolution.


Recent advances in the medical and surgical treatment of multi-drug resistant tuberculosis.
Multi-drug resistant tuberculosis is a serious clinical problem. Extension of drug resistance to second-line anti-tuberculosis drugs in the form of the W-strain is cause for alarm. There is an urgent need for more rapid recognition of multi-drug resistant tuberculosis and newer therapeutic agents. This review summarizes the recent advances in the diagnosis and treatment of multi-drug resistant tuberculosis including surgery and new developments. Multidrug resistant tuberculosis therapy is characterized by prolonged treatment, high morbidity and mortality, and high relapse rates. New diagnostic procedures that include electrophoretic and molecular hybridization techniques will allow rapid diagnosis. Several new drugs are currently in various phases of development. Moxifloxacin, a respiratory fluoroquinolone, is currently in phase III clinical development. New classes of drugs such as nitroimidazopyrans (PA-824) and diarylquinolines (R-207910) are exciting based on phase I and II data. Immunomodulation with vaccines and interferon-gamma have been unhelpful. Surgery is reserved for selected cases only. Cure rates of over 90% with reasonable morbidity and mortality has been achieved with meticulous preoperative preparation, patient selection and careful surgical technique. Newer drugs and defined indications for surgery should provide improved cure rates, with reduced duration of treatment for multi-drug resistant tuberculosis.


Asterixis: one type of negative myoclonus.
Asterixis is a disorder of motor control characterized by irregular myoclonic lapses of posture affecting various parts of the body independently. These lapses are caused by involuntary 50- to 200-msec silent periods appearing in muscles (even antagonistic groups of muscles) which are tonically active. That is, the silent periods and postural lapses occur in muscles that have been contracting for a time whether or not there has been slow shortening or lengthening but probably do not occur during or immediately after a sudden movement at a joint. What constitutes a sudden as opposed to a slow movement remains to be defined. When bilateral asterixis is present, one cannot rule out the possibility of a focal lesion (see Table 2), but it is almost always due to a metabolic encephalopathy (with a wide variety of possible causes). Unilateral asterixis is due to a localized lesion, perhaps otherwise not clinically evident, in the contralateral cerebral hemisphere. This episodic dysfunction within neural circuits which are normally concerned with maintenance of sustained or tonic muscle contraction may be released by focal lesions only in specific CNS areas (such as ventrolateral thalamus) or by a more generalized neurochemical imbalance (metabolic encephalopathies of various kinds). The system, a lesion or metabolic dysfunction which produces asterixis, is presumably an anatomically and/or pharmacologically distinct one; asterixis is not the result of a nonspecific disorder any more than are seizures. Presumably, those aspects of each of the different factors (e.g., subdural hematomas, drugs, electrolyte imbalance, cerebrovascular accidents, intracerebral tumors) that may produce asterixis or a seizure are mediated through some fundamental neuronal or neural systems process. To label asterixis or seizures nonspecific results of CNS disorders or results of nonspecific CNS disorders may be simply to avoid confronting our ignorance of the specific pathophysiologic mechanisms involved. Although the anatomy, neurochemistry, and physiologic function of this asterixogenic system remain to be elucidated, observations that asterixis may be caused by discrete anatomic or pharmacologic (e.g., phenytoin) lesions should tell us something important about mechanisms underlying sustained muscle contraction in humans. Unfortunately clinicoanatomic correlations alone cannot provide precise answers because even those reasonably focal vascular lesions that cause asterixis are too gross to permit localization or identification of the neural systems involved.(ABSTRACT TRUNCATED AT 400 WORDS)


South Pole Telescope optics.
The South Pole Telescope is a 10 m diameter, wide-field, offset Gregorian telescope with a 966-pixel, millimeter-wave, bolometer array receiver. The telescope has an unusual optical system with a cold stop around the secondary. The design emphasizes low scattering and low background loading. All the optical components except the primary are cold, and the entire beam from prime focus to the detectors is surrounded by cold absorber.


2,4-Bis(o-tolyl)-3-azabicyclo
The crystal structure of the title compound, C(22)H(25)NO, confirms that the bicyclic ring system adopts the chair-chair conformation. The phenyl rings are equatorially disposed with respect to the bicyclic ring. There is a slight deviation from the chair conformation in the case of the cyclohexane ring.


[Use of clofelin in the prevention of perioperative myocardial dysfunction in patients with ischemic heart disease].
The purpose of this study was to evaluate the possibility of using clofeline in anesthesiological protocol for myocardial revascularization as a drug preventing hemodynamic disorders and perioperative myocardial dysfunction. In group 1 (27 pts.) clofelin was used in premedication (150 micrograms at night on the eve of surgery and before the operation), group 2 (29 pts.) was control. Clofelin improved the stability of the cardiovascular system, decreased the incidence of hyperdynamic reactions, episodes of myocardial ischemia, and cardiac arrhythmia during surgery. Use of clofelin for premedication decreased the need in inotropic support during the postperfusion period from 49 to 37% and ensured a higher cardiac production during transfer from artificial to spontaneous circulation.


Metastasis-associated protein 1 and its short form variant stimulates Wnt1 transcription through promoting its derepression from Six3 corepressor.
Although Wnt1 downstream signaling components have been well studied and activated in human cancer, the pathways that regulate Wnt1 itself have not been explored in depth. Here, we provide gain-of-function, loss-of function, and molecular evidence supporting functional interactions between metastasis-associated protein 1 short-form (MTA1s), metastasis-associated protein 1 (MTA1), and Wnt1 signaling components during mammary gland development and tumorigenesis. Using multiple model systems involving overexpression or knockdown of MTA1s or MTA1, we discovered that MTA1s and MTA1 hyperactivate the Wnt1 pathway due to increased expression of Wnt1 transcription. MTA1s and MTA1 physically interact with Six3 chromatin, a protein product of which is a direct histone deacetylase inhibitor-dependent repressor of Wnt1 transcription. Deletion of the MTA1s and MTA1 allele in murine embryonic fibroblasts resulted in the upregulation of Six3 and downregulation of Wnt signaling. In addition, mammary glands from the MTA1s/MTA1(-/-) mice exhibited increased recruitment of Six3 corepressor complex to the Wnt1 promoter and inhibition of Wnt1 pathway in mammary glands. These findings identify MTA1s and MTA1 as important upstream modifiers of the Wnt1 transcription, and consequently its functions, by directly inhibiting the transcription of Six3, allowing derepression of Wnt1 transcription.


[Plants associated to Abies guatemalensis (Pinaceae) forests in Western Guatemala].
The fragments of Abies guatemalensis forests in Western Guatemala are the reservoirs of plant species that have been poorly documented, missing the opportunity to expand the knowledge of the local flora and its use in conservation planning. To assess this, a floristic study was done in areas between 2 950-3 360masl in Western Guatemala between 2010-2011. Ten locations were sampled: in each a 500m2 plot was surveyed, and plants were classified in four strata by plant height (0.05-30m). A total of 119 species, 92 genera and 50 families in four divisions were found. The families with more species were Asteraceae, Poaceae, Rosaceae, Lamiaceae, Apiaceae and Solanaceae, and the most abundant genera were Salvia, Alchemilla and Bidens. The number of species found by strata was: 33 (low herbaceous), 49 (high herbaceous), 30 (shrubs) and seven in the tree strata. Regarding geographical distribution, the biggest species group detected was from central Mexico to Central America with 67%, which compared to the forests of A. guatemalensis in central and Southern Mexico, showed high floristic affinity, especially at the family and genus level. However, even having families and genera in common in the general structure of the fir forests, their floristic particularities should be taken into account when making management and conservation plans, because these are influenced by soil, latitude and microclimate conditions.


The Effect of School Psychologists and Social Workers on School Achievement and Failure: A National Multilevel Study in Chile.
School achievement and failure have become growing political and social concerns due to the negative consequences of school failure for individuals and society. The inclusive educational movement, which calls for equal access, permanence, participation, and promotion of all students worldwide, poses many challenges for schools and school systems. As a public policy strategy, some countries have provided additional funds for incorporating non-teaching professionals such as school psychologists and social workers in regular K-12 schools. However, there is lack of research on the effects of these psychosocial professionals on student outcomes. This national multilevel study explored the effect of psychologists (n = 8,469) and social workers (n = 3,524) on indicators of eighth-grade (n = 147,531) and 10th-grade (n = 106,347) students' academic achievement and dropout in Chile. A multilevel secondary analysis was performed using national records of non-teaching professionals working as school staff members, achievement scores on the national SIMCE test, and dropout rates based on official records. Results showed that after controlling for individual and school variables known to affect achievement and dropout, schools with psychologists and social workers working as staff members had lower short- and long-term dropout rates. The presence and higher number of school psychologists per school was positively associated with higher math achievement, with a reduced effect in low-SES schools. Lower-SES schools with more social workers had higher math scores. These results support policies that increase funding for school psychologists and social workers, since their incorporation partly explains better school achievement and less school failure when controlling for individual and school characteristics, but emphasize the need to further explore the mechanisms through which school achievement and failure are developed with the support of psychologists and social workers in schools. We discuss the need to regulate the type of prevention and intervention strategies from a whole-school, evidence-based approach, as well as to incorporate psychosocial training modules and comprehensive guidelines as part of professional training programs and as certified requisites for working in schools.


Analytical solution of the heat equation in a longitudinally pumped cubic solid-state laser.
Knowledge about the temperature distribution inside solid-state laser crystals is essential for calculation of thermal phase shift, thermal lensing, thermally induced birefringence, and heat-induced crystal bending. Solutions for the temperature distribution for the case of steady-state heat loading have appeared in the literature only for simple cylindrical crystal shapes and are usually based on numerical techniques. For the first time, to our knowledge, a full analytical solution of the heat equation for an anisotropic cubic cross-section solid-state crystal is presented. The crystal is assumed to be longitudinally pumped by a Gaussian pump profile. The pump power attenuation along the crystal and the real cooling mechanisms, such as convection, are considered in detail. A comparison between our analytical solutions and its numerical counterparts shows excellent agreement when just a few terms are employed in the series solutions.


Evolution of Alzheimer's disease related cortical lesions.
Alzheimer's disease is an immutably progressing dementing disorder. Its major pathologic hallmark is the gradual development of neurofibrillary changes in a few susceptible nerve cell types. The cortical changes do not occur inevitably with advancing age. Once the disease has begun, spontaneous recovery or remissions are not observed. The initial changes develop in poorly myelinated areas of the temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. Advanced age is not a prerequisite for the evolution of the lesions. Alzheimer's disease is thus an age-related, but not an age-dependent disease. The spread of the neurofibrillary changes resembles the process of cortical myelination, however in reverse order.


Composition and hydrothermal pretreatment and enzymatic saccharification performance of grasses and legumes from a mixed-species prairie.
Mixtures of prairie species (mixed prairie species; MPS) have been proposed to offer important advantages as a feedstock for sustainable production of fuels and chemicals. Therefore, understanding the performance in hydrothermal pretreatment and enzymatic hydrolysis of select species harvested from a mixed prairie is valuable in selecting these components for such applications. This study examined composition and sugar release from the most abundant components of a plot of MPS: a C3 grass (Poa pratensis), a C4 grass (Schizachyrium scoparium), and a legume (Lupinus perennis). Results from this study provide a platform to evaluate differences between grass and leguminous species, and the factors controlling their recalcitrance to pretreatment and enzymatic hydrolysis. Significant differences were found between the grass and leguminous species, and between the individual anatomical components that influence the recalcitrance of MPS. We found that both grasses contained higher levels of sugars than did the legume, and also exhibited higher sugar yields as a percentage of the maximum possible from combined pretreatment and enzymatic hydrolysis. Furthermore, particle size, acid-insoluble residue (AcIR), and xylose removal were not found to have a direct significant effect on glucan digestibility for any of the species tested, whereas anatomical composition was a key factor in both grass and legume recalcitrance, with the stems consistently exhibiting higher recalcitrance than the other anatomical fractions. The prairie species tested in this study responded well to hydrothermal pretreatment and enzymatic saccharification. Information from this study supports recommendations as to which plant types and species are more desirable for biological conversion in a mixture of prairie species, in addition to identifying fractions of the plants that would most benefit from genetic modification or targeted growth.


[About some features of formation of "spots of Vishnevsky" in general hypothermia].
The article describes the features of formation of "spots of Vishnevsky", in general hypothermia. It is proved that the wedge shape of hemorrhages in the gastric mucosa caused by swelling and discrepancy of the paries of stomach pits with the filling of forming wedge-shaped cavity with blood from the arrosive capillaries. It is noted that the dynamics of accumulation of PAS-positive material in the gastric pits in the gastric mucosa in case of total of hypothermia is directly dependent on the growth of intracellular acidosis and disintegration of plasmolemma of parietal cells.


Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: An EAACI statement.
The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded.


Neglected medium-term and long-term consequences of labour and childbirth: a systematic analysis of the burden, recommended practices, and a way forward.
Over the past three decades, substantial progress has been made in reducing maternal mortality worldwide. However, the historical focus on mortality reduction has been accompanied by comparative neglect of labour and birth complications that can emerge or persist months or years postnatally. This paper addresses these overlooked conditions, arguing that their absence from the global health agenda and national action plans has led to the misconception that they are uncommon or unimportant. The historical limitation of postnatal care services to the 6 weeks after birth is also a contributing factor. We reviewed epidemiological data on medium-term and long-term complications arising from labour and childbirth beyond 6 weeks, along with high-quality clinical guidelines for their prevention, identification, and treatment. We explore the complex interplay of human evolution, maternal physiology, and inherent predispositions that contribute to these complications. We offer actionable recommendations to change the current trajectories of these neglected conditions and help achieve the targets of Sustainable Development Goal 3. This paper is the third in a Series of four papers about maternal health in the perinatal period and beyond.


The surgical treatment of Rockwood grade III acromioclavicular dislocations.
The conservative or surgical treatment of Rockwood grade III acromioclavicular dislocations continues to be a controversial subject. Thus, the authors report their experience with 52 cases; long-term follow-up was obtained for 40 of these, paying close attention to the preoperative clinical and radiographic evaluation and to the results obtained in order to ascertain whether or not surgical repair is required. The results of surgical treatment, however satisfactory (90% excellent or very good), are nearly the same as those obtained when non surgical treatment is used as reported in the international literature. The authors conclude that the use of surgical treatment must be limited to carefully selected cases, should prolonged conservative treatment fail. Of the three surgical techniques used, temporary stabilization of the acromioclavicular joint using AO wires associated with restoration of the coracoclavicular connections has proven to be more effective than Dall-Miles metal wiring and tangential resection, with a lower incidence of complication.


Ultra-long-term results of the Chiari pelvic osteotomy in hip dysplasia patients: a minimum of thirty-five years follow-up.
The Chiari pelvic osteotomy was the first surgical procedure to address hip dysplasia by changing the position of the acetabulum by medialization, thus creating a bony roof and improving biomechanical conditions. The aim of this retrospective cohort study was to report on the very long-term results of this technique. Out of a consecutive series of 1536 hips, 504 in 405 patients were available for follow-up. The patients were assessed by physical and radiological examination. A Kaplan-Meier survival analysis with total hip arthroplasty as an endpoint was performed and stratified for age groups, pre-operative diagnosis, sex and osteoarthritis stage. The average follow-up was 36 ± 8.1 years (range, 35.2 to 54). The average pain level on the Visual Analogue Scale was 2.9 ± 2.6 (range 0 to 8.7). The average Harris Hip Score was 80.2 ± 17.4 (range 17.4 to 100). Correction of dysplasia was effective and remained stable over time. Osteoarthritis significantly increased over time with 53% Tönnis grade 3 at follow-up. The cumulative survivorship was 79.8% (95% confidence interval (CI), 76.1-83.2%) at 20 years, 57.1% (95% CI, 52.8-61.8%) at 30 years and 35% (95% CI, 30.3-40.3%) at 40 years. Young age, male sex and low osteoarthritis grade were positive prognostic factors. Although the Chiari pelvic osteotomy is considered a salvage procedure nowadays, it achieved excellent long-term results even in indications, which would be treated differently today. Young patients without osteoarthritis had the best outcome.


Tumor-secreted factors induce IL-1β maturation via the glucose-mediated synergistic axis of mTOR and NF-κB pathways in mouse macrophages.
Macrophages are one of the major cell types that produce IL-1β. IL-1β maturation occurs via inflammasome activation, and mature IL-1β is then released from the cell. Secreted IL-1β mediates inflammatory reactions in various pathological environments, such as those in infectious, autoimmune, and cancerous diseases. Although the mechanism of IL-1β production has been discovered in infectious and autoimmune diseases, its production mechanism in the tumor microenvironment is unclear. Therefore, the mechanism of IL-1β production in macrophages in the tumor microenvironment was investigated in this study. First, bone marrow-derived macrophages obtained from C57BL/6 mice were treated with B16F10 tumor-conditioned media (TCM) in vitro. TCM increased the levels of IL-1β via glucose-mediated activation of the inflammasome. Moreover, TCM enhanced the activation of both NF-κB and mTOR pathways in a glucose-dependent manner. In particular, the expression levels of mTORC1 component proteins were dependent on the TCM-induced activation of NF-κB signaling. In addition, TCM affected ASC-ASC interactions through increasing intracellular reactive oxygen species levels. Finally, glucose inhibition by inoculation with 2-deoxy-D-glucose in vivo decreased the IL-1β levels in both the blood and tumor region of B16F10-bearing C57BL/6 mice relative to those in PBS-injected tumor-bearing mice. These results suggest that glucose supplied from blood vessels might be important for IL-1β production in tumor-associated macrophages via the integrated signals of the NF-κB and mTOR pathways in the tumor microenvironment.


Dynamic contrast-enhanced CEST MRI using a low molecular weight dextran.
Natural and synthetic sugars have great potential for developing highly biocompatible and translatable chemical exchange saturation transfer (CEST) MRI contrast agents. In this study, we aimed to develop the smallest clinically available form of dextran, Dex1 (molecular weight, MW ~ 1 kDa), as a new CEST agent. We first characterized the CEST properties of Dex1 in vitro at 11.7 T and showed that the Dex1 had a detectable CEST signal at ~1.2 ppm, attributed to hydroxyl protons. In vivo CEST MRI studies were then carried out on C57BL6 mice bearing orthotopic GL261 brain tumors (n = 5) using a Bruker BioSpec 11.7 T MRI scanner. Both steady-state full Z-spectral images and single offset (1.2 ppm) dynamic dextran-enhanced (DDE) images were acquired before and after the intravenous injection of Dex1 (2 g/kg). The steady-state Z-spectral analysis showed a significantly higher CEST contrast enhancement in the tumor than in contralateral brain (∆MTRasym1.2 ppm = 0.010 ± 0.006 versus 0.002 ± 0.008, P = 0.0069) at 20 min after the injection of Dex1. Pharmacokinetic analyses of DDE were performed using the area under the curve (AUC) in the first 10 min after Dex1 injection, revealing a significantly higher uptake of Dex1 in the tumor than in brain tissue for tumor-bearing mice (AUC[0-10 min] = 21.9 ± 4.2 versus 5.3 ± 6.4%·min, P = 0.0294). In contrast, no Dex1 uptake was foundling in the brains of non-tumor-bearing mice (AUC[0-10 min] = -1.59 ± 2.43%·min). Importantly, the CEST MRI findings were consistent with the measurements obtained using DCE MRI and fluorescence microscopy, demonstrating the potential of Dex1 as a highly translatable CEST MRI contrast agent for assessing tumor hemodynamics.


O2 activation by nonheme iron complexes: A monomeric Fe(III)-Oxo complex derived from O2.
Iron species with terminal oxo ligands are implicated as key intermediates in several synthetic and biochemical catalytic cycles. However, there is a dearth of structural information regarding these types of complexes because their instability has precluded isolation under ambient conditions. The isolation and structural characterization of an iron(III) complex with a terminal oxo ligand, derived directly from dioxygen (O2), is reported. A stable structure resulted from placing the oxoiron unit within a synthetic cavity lined with hydrogen-bonding groups. The cavity creates a microenvironment around the iron center that aids in regulating O2 activation and stabilizing the oxoiron unit. These cavities share properties with the active sites of metalloproteins, where function is correlated strongly with site structure.


Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3.
The role of CTLA-4 in regulatory T cell (Treg) function is not well understood. We have examined the role of CTLA-4 and its relationship with the transcription factor FoxP3 using a model of Treg induction in human peripheral blood. Activation of human CD4(+)CD25(-) T cells resulted in the appearance of a de novo population of FoxP3-expressing cells within 48 h. These cells expressed high levels of CTLA-4 and cell sorting on expression of CTLA-4 strongly enriched for FoxP3(+)-expressing cells with suppressive function. Culture in IL-2 alone also generated cells with suppressive capacity that also correlated with the appearance of CTLA-4. To directly test the role of CTLA-4, we transfected resting human T cells with CTLA-4 and found that this method conferred suppression, similar to that of natural Tregs, even though these cells did not express FoxP3. Furthermore, transfection of FoxP3 did not induce CTLA-4 and these cells were not suppressive. By separating the expression of CTLA-4 and FoxP3, our data show that FoxP3 expression alone is insufficient to up-regulate CTLA-4; however, activation of CD4(+)CD25(-) T cells can induce both FoxP3 and CTLA-4 in a subpopulation of T cells that are capable of suppression. These data suggest that the acquisition of suppressive behavior by activated CD4(+)CD25(-) T cells requires the expression of CTLA-4, a feature that appears to be facilitated by, but is not dependent on, expression of FoxP3.


Participation of adrenoceptors in liver blood flow regulation in anesthetized dogs.
We evaluated involvement of adrenergic receptors in the responses of the hepatic vasculature to reduction either of portal venous flow or hepatic arterial inflow. Portal vein occlusion caused an increase in hepatic arterial blood flow (HAF) and decreases in hepatic arterial pressure (HAP) and hepatic arterial vascular resistance (HAR) in the intact group. After pretreatment with either yohimbine or prazosin, but not propranolol, occlusion of the portal vein produced a greater decrease in HAP as compared with that in the intact group. No significant changes in HAF, HAR, or hepatic tissue blood flow (HTF) occurred after the treatment. These results indicate that the compensatory response of the hepatic arterial vasculature to altered portal blood flow (PVF) is regulated independently of the intrahepatic adrenergic receptors. Hepatic arterial occlusion caused a significant decrease in portal venous pressure, PVF, and HTF. Portal venous vascular resistance (PVR) was reduced slightly, but not significantly. After pretreatment with either yohimbine or prazosin, but not propranolol, occlusion of the hepatic artery produced an opposite effect: to increase PVF and significantly decrease PVR. These results indicate that intrahepatic alpha-adrenoceptors participate in the regulation of portal vascular tone to maintain portal vein pressure at a steady level, when inflow from the hepatic artery is reduced.


Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells.
SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.


Wastewater treatment alters microbial colonization of microplastics.
Microplastics are ubiquitous contaminants in aquatic habitats globally, and wastewater treatment plants (WWTPs) are point sources of microplastics. Within aquatic habitats microplastics are colonized by microbial biofilms, which can include pathogenic taxa and taxa associated with plastic breakdown. Microplastics enter WWTPs in sewage and exit in sludge or effluent, but the role that WWTPs play in establishing or modifying microplastic bacterial assemblages is unknown. We analyzed microplastics and associated biofilms in raw sewage, effluent water, and sludge from two WWTPs. Both plants retained >99% of influent microplastics in sludge, and sludge microplastics showed higher bacterial species richness and higher abundance of taxa associated with bioflocculation (e.g. Xanthomonas) than influent microplastics, suggesting that colonization of microplastics within the WWTP may play a role in retention. Microplastics in WWTP effluent included significantly lower abundances of some potentially pathogenic bacterial taxa (e.g. Campylobacteraceae) compared to influent microplastics; however, other potentially pathogenic taxa (e.g. Acinetobacter) remained abundant on effluent microplastics, and several taxa linked to plastic breakdown (e.g. Klebsiella, Pseudomonas, and Sphingomonas) were significantly more abundant on effluent compared to influent microplastics. These results indicate that diverse bacterial assemblages colonize microplastics within sewage and that WWTPs can play a significant role in modifying the microplastic-associated assemblages, which may affect the fate of microplastics within the WWTPs and the environment.


Adding quantitative muscle MRI to the FSHD clinical trial toolbox.
To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum. Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures. The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients -0.845, 0.835, 0.791, -0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to -0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration. We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.