7,7′,8,8′-Tetra­meth­oxy-4,4′-dimethyl-3,5′-bichromene-2,2′-dione

In the title mol­ecule, C24H22O8, the mean planes of the two coumarin units are inclined to each other at a dihedral angle of 79.93 (3)°. The attached meth­oxy groups form torsion angles of 7.65 (19) and 78.36 (14)° with respect to one coumarin unit, and angles of 9.01 (16) and 99.08 (11)° with respect to the other coumarin unit. In the crystal structure, weak inter­molecular C—H⋯O hydrogen bonds connect pairs of mol­ecules to form dimers, generating R 2 2(16) and R 2 2(18) rings; the dimers are linked by further weak inter­molecular C—H⋯O hydrogen bonds, forming extended chains. Additional stabil­ization is provided by weak C—H⋯π inter­actions

Theory of mind in utterance interpretation: the case from clinical pragmatics

The cognitive basis of utterance interpretation is an area that continues to provoke intense theoretical debate among pragmatists. That utterance interpretation involves some type of mind-reading or theory of mind (ToM) is indisputable. However, theorists are divided on the exact nature of this ToM-based mechanism. In this paper, it is argued that the only type of ToM-based mechanism that can adequately represent the cognitive basis of utterance interpretation is one which reflects the rational, intentional, holistic character of interpretation. Such a ToM-based mechanism is supported on conceptual and empirical grounds. Empirical support for this view derives from the study of children and adults with pragmatic disorders. Specifically, three types of clinical case are considered. In the first case, evidence is advanced which indicates that individuals with pragmatic disorders exhibit deficits in reasoning and the use of inferences. These deficits compromise the ability of children and adults with pragmatic disorders to comply with the rational dimension of utterance interpretation

Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers

INTRODUCTION: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup. METHODS: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed. RESULTS: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification. CONCLUSION: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors

The effect of continuous ultrasound on chronic low back pain: protocol of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Chronic non-specific low-back pain (LBP) is one of the most common and expensive musculoskeletal disorders in industrialized countries. Similar to other countries in the world, LBP is a common health and socioeconomic problem in Iran. One of the most widely used modalities in the field of physiotherapy for treating LBP is therapeutic ultrasound. Despite its common use, there is still inconclusive evidence to support its effectiveness in this group of patients. This randomised trial will evaluate the effectiveness of continuous ultrasound in addition to exercise therapy in patients with chronic LBP.</p> <p>Methods and design</p> <p>A total of 46 patients, between the ages 18 and 65 years old who have had LBP for more than three months will be recruited from university hospitals. Participants will be randomized to receive continuous ultrasound plus exercise therapy or placebo ultrasound plus exercise therapy. These groups will be treated for 10 sessions during a period of 4 weeks. Primary outcome measures will be functional disability and pain intensity. Lumbar flexion and extension range of motion, as well as changes in electromyography muscle fatigue indices, will be measured as secondary outcomes. All outcome measures will be measured at baseline, after completion of the treatment sessions, and after one month.</p> <p>Discussion</p> <p>The results of this trial will help to provide some evidence regarding the use of continuous ultrasound in chronic LBP patients. This should lead to a more evidence-based approach to clinical decision making regarding the use of ultrasound for LBP.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2251">NTR2251</a></p

Does vimentin help to delineate the so-called 'basal type breast cancer'?

<p>Abstract</p> <p>Background</p> <p>Vimentin is one of the cytoplasmic intermediate filament proteins which are the major component of the cytoskeleton. In our study we checked the usefulness of vimentin expression in identifying cases of breast cancer with poorer prognosis, by adding vimentin to the immunopanel consisting of basal type cytokeratins, estrogen, progesterone, and HER2 receptors.</p> <p>Methods</p> <p>179 tissue specimens of invasive operable ductal breast cancer were assessed by the use of immunohistochemistry. The median follow-up period for censored cases was 90 months.</p> <p>Results</p> <p>38 cases (21.2%) were identified as being vimentin-positive. Vimentin-positive tumours affected younger women (p = 0.024), usually lacked estrogen and progesterone receptor (p < 0.001), more often expressed basal cytokeratins (<0.001), and were high-grade cancers (p < 0.001). Survival analysis showed that vimentin did not help to delineate basal type phenotype in a triple negative (ER, PgR, HER2-negative) group. For patients with 'vimentin or CK5/6, 14, 17-positive' tumours, 5-year estimated survival rate was 78.6%, whereas for patients with 'vimentin, or CK5/6, 14, 17-negative' tumours it was 58.3% (log-rank p = 0.227).</p> <p>Conclusion</p> <p>We were not able to better delineate an immunohistochemical definition of basal type of breast cancer by adding vimentin to the immunopanel consisted of ER, PgR, HER2, CK5/6, 14 and 17 markers, when overall survival was a primary end-point.</p

Actin- and Dynamin-Dependent Maturation of Bulk Endocytosis Restores Neurotransmission following Synaptic Depletion

Bulk endocytosis contributes to the maintenance of neurotransmission at the amphibian neuromuscular junction by regenerating synaptic vesicles. How nerve terminals internalize adequate portions of the presynaptic membrane when bulk endocytosis is initiated before the end of a sustained stimulation is unknown. A maturation process, occurring at the end of the stimulation, is hypothesised to precisely restore the pools of synaptic vesicles. Using confocal time-lapse microscopy of FM1-43-labeled nerve terminals at the amphibian neuromuscular junction, we confirm that bulk endocytosis is initiated during a sustained tetanic stimulation and reveal that shortly after the end of the stimulation, nerve terminals undergo a maturation process. This includes a transient bulging of the plasma membrane, followed by the development of large intraterminal FM1-43-positive donut-like structures comprising large bulk membrane cisternae surrounded by recycling vesicles. The degree of bulging increased with stimulation frequency and the plasmalemma surface retrieved following the transient bulging correlated with the surface membrane internalized in bulk cisternae and recycling vesicles. Dyngo-4a, a potent dynamin inhibitor, did not block the initiation, but prevented the maturation of bulk endocytosis. In contrast, cytochalasin D, an inhibitor of actin polymerization, hindered both the initiation and maturation processes. Both inhibitors hampered the functional recovery of neurotransmission after synaptic depletion. Our data confirm that initiation of bulk endocytosis occurs during stimulation and demonstrates that a delayed maturation process controlled by actin and dynamin underpins the coupling between exocytosis and bulk endocytosis

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells

We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1cdfcr-2J/dfcr-2J mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23

Maintenance Optimization and Inspection Planning of Wind Energy Assets: Models, Methods and Strategies

Designing cost-effective inspection and maintenance programmes for wind energy farms is a complex task involving a high degree of uncertainty due to diversity of assets and their corresponding damage mechanisms and failure modes, weather-dependent transport conditions, unpredictable spare parts demand, insufficient space or poor accessibility for maintenance and repair, limited availability of resources in terms of equipment and skilled manpower, etc. In recent years, maintenance optimization has attracted the attention of many researchers and practitioners from various sectors of the wind energy industry, including manufacturers, component suppliers, maintenance contractors and others. In this paper, we propose a conceptual classification framework for the available literature on maintenance policy optimization and inspection planning of wind energy systems and structures (turbines, foundations, power cables and electrical substations). The developed framework addresses a wide range of theoretical and practical issues, including the models, methods, and the strategies employed to optimise maintenance decisions and inspection procedures in wind farms. The literature published to date on the subject of this article is critically reviewed and several research gaps are identified. Moreover, the available studies are systematically classified using different criteria and some research directions of potential interest to operational researchers are highlighted