The embryonic genes Dkk3, Hoxd8, Hoxd9 and Tbx1 identify muscle types in a diet-independent and fiber-type unrelated way

<p>Abstract</p> <p>Background</p> <p>The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle type has a specific composition and distribution of the four fiber types. To find novel genes involved in specifying muscle types, we used microarray analysis to compare the gastrocnemius with the quadriceps from mice fed a low fat diet (LFD) or high fat diet (HFD) for 8 weeks. Additional qPCR analysis were performed in the gastrocnemius, quadriceps and soleus muscle from mice fed an LFD or HFD for 20 weeks.</p> <p>Results</p> <p>In mice fed the 8-week LFD 162 genes were differentially expressed in the gastrocnemius <it>vs</it>. the quadriceps. Genes with the strongest differences in expression were markers for oxidative fiber types (e.g. <it>Tnni1</it>) and genes which are known to be involved in embryogenesis (<it>Dkk3</it>, <it>Hoxd8</it>,<it>Hoxd9 </it>and <it>Tbx1</it>). Also <it>Dkk2, Hoxa5, Hoxa10, Hoxc9, Hoxc10, Hoxc6 </it>and <it>Tbx15 </it>were detectably, but not differentially expressed in adult muscle tissue. Expression of differentially expressed genes was not influenced by an 8-week or 20-week HFD. Comparing gastrocnemius, quadriceps and soleus, expression of <it>Hoxd8 </it>and <it>Hoxd9 </it>was not related with expression of markers for the four different fiber types. We found that the expression of both <it>Hoxd8 </it>and <it>Hoxd9 </it>was much higher in the gastrocnemius than in the quadriceps or soleus, whereas the expression of <it>Dkk3 </it>was high in quadriceps, but low in both gastrocnemius and soleus. Finally, expression of <it>Tbx1 </it>was high in quadriceps, intermediate in soleus and low in gastrocnemius.</p> <p>Conclusions</p> <p>We found that genes from the Dkk family, Hox family and Tbx family are detectably expressed in adult mouse muscle. Interestingly, expression of <it>Dkk3</it>, <it>Hoxd8, Hoxd9 </it>and <it>Tbx1 </it>was highly different between gastrocnemius, quadriceps and soleus. In fact, every muscle type showed a unique combination of expression of these four genes which was not influenced by diet. Altogether, we conclude that genes important for embryogenesis identify mouse muscle types in a diet-independent and fiber type-unrelated manner.</p

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics

A latent trait look at pretest-posttest validation of criterion-referenced test items

Since Cox and Vargas (1966) introduced their pretest-posttest validity index for criterion-referenced test items, a great number of additions and modifications have followed. All are based on the idea of gain scoring; that is, they are computed from the differences between proportions of pretest and posttest item responses. Although the method is simple and generally considered as the prototype of criterion-referenced item analysis, it has many and serious disadvantages. Some of these go back to the fact that it leads to indices based on a dual test administration- and population-dependent item p values. Others have to do with the global information about the discriminating power that these indices provide, the implicit weighting they suppose, and the meaningless maximization of posttest scores they lead to. Analyzing the pretest-posttest method from a latent trait point of view, it is proposed to replace indices like Cox and Vargas’ Dpp by an evaluation of the item information function for the mastery score. An empirical study was conducted to compare the differences in item selection between both methods

Cost-effectiveness of a structured progressive task-oriented circuit class training programme to enhance walking competency after stroke: The protocol of the FIT-Stroke trial

<p>Abstract</p> <p>Background</p> <p>Most patients who suffer a stroke experience reduced walking competency and health-related quality of life (HRQoL). A key factor in effective stroke rehabilitation is intensive, task-specific training. Recent studies suggest that intensive, patient-tailored training can be organized as a circuit with a series of task-oriented workstations.</p> <p>Primary aim of the FIT-Stroke trial is to evaluate the effects and cost-effectiveness of a structured, progressive task-oriented circuit class training (CCT) programme, compared to usual physiotherapeutic care during outpatient rehabilitation in a rehabilitation centre. The task-oriented CCT will be applied in groups of 4 to 6 patients. Outcome will be defined in terms of gait and gait-related ADLs after stroke. The trial will also investigate the generalizability of treatment effects of task-oriented CCT in terms of perceived fatigue, anxiety, depression and perceived HRQoL.</p> <p>Methods/design</p> <p>The multicentre single-blinded randomized trial will include 220 stroke patients discharged to the community from inpatient rehabilitation, who are able to communicate and walk at least 10 m without physical, hands-on assistance. After discharge from inpatient rehabilitation, patients in the experimental group will receive task-oriented CCT two times a week for 12 weeks at the physiotherapy department of the rehabilitation centre. Control group patients will receive usual individual, face-to-face, physiotherapy. Costs will be evaluated by having each patient keep a cost diary for the first 24 weeks after randomisation. Primary outcomes are the mobility part of the Stroke Impact Scale (SIS-3.0) and the EuroQol. Secondary outcomes are the other domains of SIS-3.0, lower limb muscle strength, walking endurance, gait speed, balance, confidence not to fall, instrumental ADL, fatigue, anxiety, depression and HRQoL.</p> <p>Discussion</p> <p>Based on assumptions about the effect of intensity of practice and specificity of treatment effects, FIT-Stroke will address two key aims. The first aim is to investigate the effects of task-oriented CCT on walking competency and HRQoL compared to usual face-to-face physiotherapy. The second aim is to reveal the cost-effectiveness of task-oriented CCT in the first 6 months post stroke. Both aims were recently recommended as priorities by the American Hearth Association and Stroke Council.</p> <p>Trial registration</p> <p>This study is registered in the Dutch Trial Register as NTR1534.</p

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]

Probing the Interplay between Quantum Charge Fluctuations and Magnetic Ordering in LuFe2O4

Ferroelectric and ferromagnetic materials possess spontaneous electric and magnetic order, respectively, which can be switched by the corresponding applied electric and magnetic fields. Multiferroics combine these properties in a single material, providing an avenue for controlling electric polarization with a magnetic field and magnetism with an electric field. These materials have been intensively studied in recent years, both for their fundamental scientific interest as well as their potential applications in a broad range of magnetoelectric devices [1, 2, 3, 4]. However, the microscopic origins of magnetism and ferroelectricity are quite different, and the mechanisms producing strong coupling between them are not always well understood. Hence, gaining a deeper understanding of magnetoelectric coupling in these materials is the key to their rational design. Here, we use ultrafast optical spectroscopy to show that quantum charge fluctuations can govern the interplay between electric polarization and magnetic ordering in the charge-ordered multiferroic LuFe2O4

Mortality after Hospitalization for Pneumonia among Individuals with HIV, 1995–2008: A Danish Cohort Study

BACKGROUND: HIV-infected persons are at increased risk of pneumonia, even with highly active antiretroviral treatment (HAART). We examined the impact of pneumonia on mortality and identified prognostic factors for death among HIV-infected. METHODOLOGY/PRINCIPAL FINDINGS: In a nationwide, population-based cohort of individuals with HIV, we included persons hospitalized with pneumonia from the Danish National Hospital Registry and obtained mortality data from the Danish Civil Registration System. Comparing individuals with and without pneumonia, we used Poisson regression to estimate relative mortality and logistic regression to examine prognostic factors for death following pneumonia. From January 1, 1995, to July 1, 2008, we observed 699 episodes of first hospitalization for pneumonia among 4,352 HIV patients. Ninety-day mortality after pneumonia decreased from 22.4% (95% confidence interval [CI]: 16.5%-28.9%) in 1995-1996 to 8.4% (95% CI: 6.1%-11.6%) in 2000-2008. Mortality remained elevated for more than a year after hospitalization for pneumonia: adjusted mortality rate ratio 5.38 (95% CI: 4.27-6.78), 1.80 (95% CI: 1.36-2.37), and 1.62 (95% CI: 1.32-2.00) for days 0-90, 91-365, and 366+, respectively. The following variables predicted mortality within 90 days following hospitalization for pneumonia (adjusted Odds Ratios): male sex (3.77, 95% CI: 1.37-10.4), Charlson Comorbidity Index score > or = 2 (3.86, 95% CI: 2.19-6.78); no current HAART (3.58, 95% CI: 1.83-6.99); history of AIDS (2.46, 95% CI: 1.40-4.32); age per 10 year increase (1.43, 95% CI: 1.11-1.85); and CD4+ cell count < or = 200 (2.52, 95% CI: 1.37-4.65). CONCLUSIONS/SIGNIFICANCE: The first hospitalization for pneumonia among HIV-infected individuals was associated with elevated risk of death up to more than a year later. Use of HAART decreased the risk, independent of current CD4+ cell count. Prognosis following pneumonia improved over calendar time

Kiadói és nyomdai tevékenység a szerbek körében a középkor végén és az újkor hajnalán

We study the properties of 30 spectroscopically identified pairs of galaxies observed during the peak epoch of star formation in the universe. These systems are drawn from the MOSFIRE Deep Evolution Field (MOSDEF) Survey at 1.4 ≤ z ≤ 3.8, and are interpreted as early-stage galaxy mergers. Galaxy pairs in our sample are identified as two objects whose spectra were collected on the same Keck/MOSFIRE spectroscopic slit. Accordingly, all pairs in the sample have projected separations R proj ≤ 60 kpc. The velocity separation for pairs was required to be Δv ≤ 500 km s -1 , which is a standard threshold for defining interacting galaxy pairs at low redshift. Stellar mass ratios in our sample range from 1.1 to 550, with 12 ratios closer than or equal to 3:1, the common definition of a "major merger." Studies of merging pairs in the local universe indicate an enhancement in star formation activity and deficit in gas-phase oxygen abundance relative to isolated galaxies of the same mass. We compare the MOSDEF pairs sample to a control sample of isolated galaxies at the same redshift, finding no measurable SFR enhancement or metallicity deficit at fixed stellar mass for the pairs sample. The lack of significant difference between the average properties of pairs and control samples appears in contrast to results from low-redshift studies, although the small sample size and lower signal-to-noise of the high-redshift data limit definitive conclusions on redshift evolution. These results are consistent with some theoretical works, suggesting a reduced differential effect of precoalescence mergers on galaxy properties at high redshift - specifically that precoalescence mergers do not drive strong starbursts

On the projection of future fire danger conditions with various instantaneous/mean-daily data sources

Fire danger indices are descriptors of fire potential in a large area, and combine a few variables that affect the initiation, spread and control of forest fires. The Canadian Fire Weather Index (FWI) is one of the most widely used fire danger indices in the world, and it is built upon instantaneous values of temperature, relative humidity and wind velocity at noon, together with 24 hourly accumulated precipitation. However, the scarcity of appropriate data has motivated the use of daily mean values as surrogates of the instantaneous ones in several studies that aimed to assess the impact of global warming on fire. In this paper we test the sensitivity of FWI values to both instantaneous and daily mean values, analyzing their effect on mean seasonal fire danger (seasonal severity rating, SSR) and extreme fire danger conditions (90th percentile, FWI90, and FWI>30, FOT30), with a special focus on its influence in climate change impact studies. To this aim, we analyzed reanalysis and regional climate model (RCM) simulations, and compared the resulting instantaneous and daily mean versions both in the present climate and in a future scenario. In particular, we were interested in determining the effect of these datasets on the projected changes obtained for the mean and extreme seasonal fire danger conditions in future climate scenarios, as given by a RCM. Overall, our results warn against the use of daily mean data for the computation of present and future fire danger conditions. Daily mean data lead to systematic negative biases of fire danger calculations. Although the mean seasonal fire danger indices might be corrected to compensate for this bias, fire danger extremes (FWI90 and specially FOT30) cannot be reliably transformed to accommodate the spatial pattern and magnitude of their respective instantaneous versions, leading to inconsistent results when projected into the future. As a result, we advocate caution when using daily mean data and strongly recommend the application of the standard definition for its calculation as closely as possible. Threshold-dependent indices derived from FWI are not reliably represented by the daily mean version and thus can neither be applied for the estimation of future fire danger season length and severity, nor for the estimation of future extreme events.The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 243888 (FUME Project). J.F. acknowledges nancial support from the Spanish R&D&I programme through grant CGL2010-22158-C02 (CORWES project). The ESCENA project (200800050084265) of the Spanish \Strategic action on energy and climate change" provided the WRF RCM simulation used in this study. We acknowledge three anonymous referees for their useful comments that helped to improve the original manuscript