Synthesis,Molecular Structure,and Chiroptical Properties of Dibenzylidene Derivatives of Bicyclo[3.3.1]nonane and Brexane

Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0^3,7]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)‐(1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X‐ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7‐dibenzylidenebicyclo[3.3.1]nonanes, such as 2 and 7 , 8 , 9 , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the π→π* transitions in the CD spectra of monoenone 4 and tricyclic brexane acetate 11 was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. Chirality 27:728–737, 2015. © 2015 Wiley Periodicals, Inc.     

Peripheral and central fatigue after muscle-damaging exercise is muscle length dependent and inversely related

Healthy untrained men performed 10 series of 12 knee eccentric extension repetitions (EE) at 160°/s. The maximal voluntary isometric contraction force of the quadriceps muscle, the maximal rate of electrically induced torque development (RTD) and relaxation (RTR), isokinetic concentric torque at 30°/s, the electrostimulation-induced torque at 20 and 100 Hz frequencies were established before and after EE at shorter and longer muscle lengths. Besides, voluntary activation (VA) index and central activation ratio (CAR) were tested. There was more peripheral fatigue than central after EE. We established more central fatigue as well as low frequency fatigue at a shorter muscle length compared to the longer muscle length. Relative RTD as well as relative RTR, improved after EE and did not depend on the muscle length. Finally, central fatigue is inversely significantly related with the eccentric torque reduction during eccentric exercise and with the changes in muscle torque induced by low frequency stimulation.     

A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery

Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p_raw = 1.1×10⁻⁷, p_genome = 7.5×10⁻⁴). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD–mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders.     

Linear and Nonlinear Absorption Properties of Diamond-Like Carbon Doped With Cu Nanoparticles

Ultrafast relaxation processes in diamond-like carbon (DLC) thin films with embedded Cu nanoparticles (DLC:Cu nanocomposites) were investigated by means of transient absorption spectroscopy focusing on localized surface plasmon resonance (LSPR) of photoexcited Cu nanoparticles. Absorption spectra of the composite films correspond to the sum of absorption spectra of DLC matrix and Cu nanoparticles; however, Cu nanoparticles strongly dominate in the transient differential absorption. Excitations of DLC matrix and of Cu nanoparticles relax independently revealing no strong interaction. High sensitivity measurements enabled to obtain the hot electron relaxation dynamics in Cu nanoparticles in the low excitation intensity conditions. The relaxation time was found to be independent of the excitation intensity up to tens of microjoule per square centimeter per pulse and to increase at higher intensities. The relaxation time obtained at low excitation intensity was also found to increase by about 30 % in the samples with high Cu concentration, where larger nanoparticles were formed.     

Predictors of post-operative mortality following treatment for non-ruptured abdominal aortic aneurysm

The aim of this prospective study of patients undergoing repair of non-ruptured abdominal aortic aneurysm between 1999 and 2003 was to evaluate and compare risk factors for mortality after surgery, to determine a complex of informative factors for lethal outcome, and to define patient risk groups. Logistic regression analysis revealed a complex of informative factors, including female gender, previous myocardial infarction, age greater than 75 years, and clinical course of abdominal aortic aneurysm as important indicators for lethal outcome. A risk score model identified low-, moderate- and high-risk groups with mortality rates of 2.9%, 8.0% and 44.4%, respectively.     

Effect of Training and Match Loads on Hamstring Passive Stiffness in Professional Soccer Players

Objective:the purpose of this study was to identify differences in hamstring passive stiffness between the pre-season and in-season periods.Methods:Hamstring strength and passive stiffness were measured in professional male soccer players before and after the pre-season (4 weeks), and after the in-season (6 weeks) periods using an isokinetic dynamometer. Muscle passive stiffness was determined from the slope of the passive torque–angle relationship. External loads (acceleration and jumps) were monitored by GPS and internal loads by questionnaire.Results:Hamstring passive stiffness increased after 10 weeks of training and matches, without changes in passive peak torque and range of motion. The hamstring passive stiffness modifications were associated with the volume and intensity of accelerations and jumps. The individual data analysis also provided some support for the suppression of the biomechanical adaptation in the subjects with relatively large external load.Conclusions:Regular training and match workouts increase hamstring passive stiffness in professional soccer players but the adaptation of muscle-tendon unit passive elements might not occur if players experience excessive mechanical stress.     

Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10⁻¹⁰, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10⁻⁸, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10⁻¹¹, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.     

Prevalence of radiographic detectable intervertebral disc calcifications in Dachshunds surgically treated for disc extrusion

Background  

An association between the occurrence of calcified discs, visible on radiographic examination (CDVR), and disc extrusions has been suggested in published literature over the past 10-20 years, mainly from Nordic countries. It has also been postulated that dogs without CDVR would not develop disc extrusions. Furthermore, inheritance of CDVR has been calculated and it has been postulated that, by selecting dogs for breeding with few, or no CDVR, the prevalence of disc extrusions in the Dachshund population may be reduced.     

Investigation of readiness and perceived workload in junior female basketball players during a congested match schedule

This study aimed to: a) investigate the differences in workload and readiness between two junior female national basketball teams competing at different European Championships (EC); b) compare workload, readiness and match performance for players with longer and shorter playing times, and; c) examine the relationship between workload, readiness and match performance variables. Under-18 (U18) (n = 10, height = 179.9 ± 6.6 cm, body mass = 70.2 ± 5.1 kg) and under-20 (U20) female national basketball teams (n = 11, height = 178.4 ± 8.8 cm, body mass = 73.0 ± 9.7 kg) were monitored during congested match schedules encompassing 7 matches within 9 days. Daily workload was determined via the session rating of perceived exertion (sRPE workload); readiness was measured by heart-rate variability (HRV) and well-being (WB); and match performance was assessed using the efficiency statistic and playing time. Analysis of workload and readiness during the EC showed no statistically significant between-team differences in any variables except WB for the U18 team, which was lower on Day 8 compared to the U20 team (p = 0.03; effect size [ES] = large). Players accumulating longer playing time showed a higher sRPE workload (p = 0.01, ES = moderate) and efficiency statistic (p = 0.04, ES = moderate) while no readiness variable differed significantly (p > 0.05) compared to players with shorter playing time. Trivial-to-small correlations were observed between workload, readiness and match performance variables. The study shows that junior female basketball players were able to cope with a congested schedule of 7 matches in 9 days irrespective of the competition context or individual differences in workload. Finally, combining objective and subjective methods to assess workload and readiness is recommended due to the weak relationships observed between these methods.     

Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII

A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.