To achieve the luminosity requirements of the Compact Linear Collider (CLIC) at the collision point, damping rings (DRs) equipped with superconducting wiggler magnets should be used to produce ...ultralow emittance with high bunch charge. Although Nb-Ti wigglers meet the specifications for CLIC DRs, the more challenging Nb 3 Sn technology could be used to increase the magnetic flux density amplitude in the gap and reduce the total length of wigglers in the DRs. To test the Nb 3 Sn technology, a small wiggler prototype is under design and will be built and tested at CERN. Magnetic calculations concerning the selection of the main wiggler's parameters are presented in this paper, which include the optimization of the main coil dimensions and the period length, in order to fulfill the normalized emittance and intrabeam scattering effect constraints, while decreasing the amount of wigglers in the DRs. Another advantage of using Nb 3 Sn, instead of Nb-Ti, as superconducting material is the possibility of increasing the working margin. Several scenarios well suited for CLIC damping wigglers, in which the working point is less than 80% of the magnet's current limit, are addressed in this work. In addition, the description of the manufacturing process and the current status of the Nb 3 Sn prototype fabrication are presented.
•A radial variable geometry turbine model is developed.•A quasi-bidimensional volute model is used to improve high frequency results.•The model is validated against CFD results.•The ...quasi-bidimensional volute is able to reproduce the evolution of the flow across the volute.
This paper presents the development and validation of a one-dimensional radial turbine model able to be used in automotive turbocharger simulations. The model has been validated using results from a numerical 3D CFD simulation of stationary and pulsating flow in a variable geometry radial turbine. As the CFD analysis showed, the main non-quasi-steady behavior of the turbine is due to the volute geometry, so special care was taken in order to properly model it while maintaining low computational costs. The flow in the volute has been decomposed in its radial and azimuthal direction. The azimuthal flow corresponds to the flow moving along the volute, while the radial flow is computed by coupling its flow with a stator model. Although the stator caused fewer accumulation effects than the volute, a small accumulation model has been used for it, which also allows to compute the evolution of the flow inside the turbine with lower costs. The flow in the moving rotor can be considered quasi-steady, so a zero-dimensional model for the rotor has been developed. Several losses models where implemented for both the stator and the rotor. The results show good agreement with the CFD computations.
During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational ...modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.
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•SIN3A deacetylase complex accumulates at stalled forks under replication stress•Depletion of SIN3A complex increases histone acetylation at stalled forks•In the absence of SIN3A complex, stalled forks undergo DNA breaks•SIN3A-depletion-mediated DNA breaks are caused by MUS81
Muñoz et al. show that the SIN3A deacetylase complex plays a role in DNA replication, preventing fork stalling and breakage. Under replication stress, histone tails are partially deacetylated by the SIN3A complex at stalled forks, and Sin3A depletion induces MUS81-mediated DNA breaks that promotes resection and genome instability.
To evaluate long-term visual and anatomical outcomes in neovascular age-related macular degeneration (nAMD) patients treated with anti-vascular endothelial growth factor (VEGF) agents depending on ...the time delay from confirmed diagnosis to treatment initiation.
Seventy-three nAMD patients (73 eyes) treated with anti-VEGF agents for 12 months using the pro re nata regimen were included in this retrospective longitudinal study. Patients were split into 3 groups according to the time from diagnosis to first anti-VEGF injection: < 48 h (group 1); 48 h-7 days (group 2); > 7 days (group 3). Decimal best-corrected visual acuity (VA) and macular thickness (MT) were recorded at baseline and 1–2-, 3–4-, 6- and 12-month later. Furthermore, age, gender as well as the applied treatment and number of injections after 12 months of treatment were also registered and compared.
Long-term effect of the treatment demonstrated enhanced VA in group 1 patients compared with the rest of groups after 1–2-, 6-, and 12-month follow-up (P < 0.05). Positive effects of early treatment were additionally corroborated by the augmented percentage of patients with normal VA in the group 1 respect to the rest of groups over studied time points (P < 0.05). Moreover, the VA gain in nAMD at group 1 was obtained with a mean of 3.7 intravitreal injections over 1-year follow-up period. Regarding MT, non-significant difference was observed among groups.
An early initial treatment with VEGF inhibitors is critical to achieve the best functional benefits of this therapy in new-onset nAMD patients.
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•Anti-VEGF therapy within 48 h from diagnosis leads to long-term visual gain in nAMD.•Visual gain is achieved with low IV injection number if early treatment is applied.•A prompt first anti-VEGF injection promotes long-term anatomical benefits in nAMD.
Mesenchymal stromal cells (MSCs) have been isolated from different tumors and it has been suggested that they support tumor growth through immunosuppression processes that favor tumor cell evasion ...from the immune system. To date, however, the presence of MSCs in cervical cancer (CeCa) and their possible role in tumor growth remains unknown. Herein we report on the presence of MSCs in cervical tissue, both in normal conditions (NCx-MSCs) and in CeCa (CeCa-MSCs), and described several biological properties of such cells. Our study showed similar patterns of cell surface antigen expression, but distinct differentiation potentials, when we compared both cervical MSC populations to MSCs from normal bone marrow (BM-MSCs, the gold standard). Interestingly, CeCa-MSCs were negative for the presence of human papilloma virus, indicating that these cells are not infected by such a viral agent. Also, interestingly, and in contrast to NCx-MSCs, CeCa-MSCs induced significant downregulation of surface HLA class I molecules (HLA-A*0201) on CaSki cells and other CeCa cell lines. We further observed that CeCa-MSCs inhibited antigen-specific T cell recognition of CaSki cells by cytotoxic T lymphocytes (CTLs). HLA class I downregulation on CeCa cells correlated with the production of IL-10 in cell cocultures. Importantly, this cytokine strongly suppressed recognition of CeCa cells by CTLs. In summary, this study demonstrates the presence of MSCs in CeCa and suggests that tumor-derived MSCs may provide immune protection to tumor cells by inducing downregulation of HLA class I molecules. This mechanism may have important implications in tumor growth.
Marjoram (Origanum majorana L.) is an herb traditionally used as a medicine in different countries, as Morocco and Iran, because of its beneficial cardiovascular effects. Some studies suggest that ...these effects are due, at least in part, to the presence of phenolic compounds such as rosmarinic acid (RA) and luteolin.
To analyze the possible cardiprotective effects of a marjoram extract (ME) reducing myocardial damage after coronary ischemia-reperfusion (IR) and its possible antihypertensive effects reducing the response of aorta segments to the vasoconstrictors noradrenaline (NA) and endothelin-1 (ET-1).
Male Wistar rats (300g) were used. After sacrifice, the heart was immediately removed and mounted in a perfusion system (Langendorff). The aorta was carefully dissected and cut in 2 mm segments to perform vascular reactivity experiments.
In the heart, ME perfusion after IR reduced heart rate and prevented IR-induced decrease of cardiac contractility, possibly through vasodilation of coronary arteries and through the upregulation of antioxidant markers in the myocardium that led to reduced apoptosis of cardiomyocytes. In the aorta, ME decreased the vasoconstrictor response to NA and ET-1 and exerted a potent anti-inflammatory and antioxidant effect. Neither RA nor 6-hydroxi-luteolin-O-glucoside, major compounds of this ME, were effective in improving cardiac contractility after IR or attenuating vasoconstriction to NA and ET-1 in aorta segments.
In conclusion, ME reduces the myocardial damage induced by IR and the contractile response to vasoconstrictors in the aorta. Thus, it may be useful for the treatment of cardiovascular diseases such as myocardial infarction and hypertension.
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Here we describe clinical and pathologic evidence of Chagas disease caused in dogs by circulating Trypanosoma cruzi from a newly recognized endemic area in Mexico. We show that the Zumpahuacan ...isolate, although less virulent than the Sylvio-X10 reference strain that caused acute myocarditis and death, was pathogenic in dogs. Dogs infected with the Zumpahuacan isolate exhibited electrocardiographic alterations, left- and right-ventricle dilation, and hydropericardium. Histologically, diffused perimysial and endomysial lymphoplasmacytic cell infiltration, cardiomyocyte necrosis, and amastigote nests were noted in Zumpahuacan-infected dogs. These findings suggest that the risk of T. cruzi infection and Chagas disease is present in the State of Mexico, and further research is needed to identify the T. cruzi bio-types circulating in southern State of Mexico.
Background
Some studies have reported that polyamine levels may influence immune system programming. The aim of this study was to evaluate the polyamine profile during gestation and its associations ...with maternal allergy and cytokine production in cord blood cells in response to different allergenic stimuli.
Methods
Polyamines were determined in plasma of pregnant women (24 weeks, N = 674) and in umbilical cord samples (N = 353 vein and N = 160 artery) from the Mediterranean NELA birth cohort. Immune cell populations were quantified, and the production of cytokines in response to different allergic and mitogenic stimuli was assessed in cord blood.
Results
Spermidine and spermine were the most prevalent polyamines in maternal, cord venous, and cord arterial plasma. Maternal allergies, especially allergic conjunctivitis, were associated with lower spermine in umbilical cord vein. Higher levels of polyamines were associated with higher lymphocyte number but lower Th2‐related cells in cord venous blood. Those subjects with higher levels of circulating polyamines in cord showed lower production of inflammatory cytokines, especially IFN‐α, and lower production of Th2‐related cytokines, mainly IL‐4 and IL‐5. The effects of polyamines on Th1‐related cytokines production were uncertain.
Conclusions
Spermidine and spermine are the predominant polyamines in plasma of pregnant women at mid‐pregnancy and also in umbilical cord. Maternal allergic diseases like allergic conjunctivitis are related to lower levels of polyamines in cord vein, which could influence the immune response of the newborn. Cord polyamine content is related to a decreased Th2 response and inflammatory cytokines production, which might be important to reduce an allergenic phenotype in the neonate.
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