The paper deals with the timetabling problem of a mixed multiple- and single-tracked railway network. Out of all the solutions minimizing the maximum relative travel time, the one minimizing the sum ...of the relative travel times is selected. User preferences are taken into account in the optimization problems, that is, the desired departure times of travellers are used instead of artificially planned departure times. To find the global optimum of the optimization problem, an algorithm based on the bisection rule is used to provide sharp upper bounds of the objective function together with one trick that allows us to drastically reduce the number of binary variables to be evaluated by considering only those which really matter. These two strategies together permit the memory requirements and the computation time to be reduced, the latter exponentially with the number of trains (several orders of magnitude for existing networks), when compared with other methods. Several examples of applications are presented to illustrate the possibilities and excellences of the proposed method. The model is applied to the case of the existing Madrid–Sevilla high-speed line (double track), together with several extensions to Toledo, Valencia, Albacete, and Málaga, which are contemplated in the future plans of the high-speed train Spanish network. The results show that the computation time is reduced drastically, and that in some corridors single-tracked lines would suffice instead of double-tracked lines.
Plant cells exhibit a high rate of mitochondrial DNA (mtDNA) recombination. This implies that before cytokinesis, the different mitochondrial compartments must fuse to allow for mtDNA intermixing. ...When and how the conditions for mtDNA intermixing are established are largely unknown. We have investigated the cell cycle-dependent changes in mitochondrial architecture in different Arabidopsis (Arabidopsis thaliana) cell types using confocal microscopy, conventional, and three-dimensional electron microscopy techniques. Whereas mitochondria of cells from most plant organs are always small and dispersed, shoot apical and leaf primordial meristematic cells contain small, discrete mitochondria in the cell periphery and one large, mitochondrial mass in the perinuclear region. Serial thin-section reconstructions of high-pressure-frozen shoot apical meristem cells demonstrate that during G1 through S phase, the large, central mitochondrion has a tentaculate morphology and wraps around one nuclear pole. In G2, both types of mitochondria double their volume, and the large mitochondrion extends around the nucleus to establish a second sheet-like domain at the opposite nuclear pole. During mitosis, approximately 60% of the smaller mitochondria fuse with the large mitochondrion, whose volume increases to 80% of the total mitochondrial volume, and reorganizes into a cage-like structure encompassing first the mitotic spindle and then the entire cytokinetic apparatus. During cytokinesis, the cage-like mitochondrion divides into two independent tentacular mitochondria from which new, small mitochondria arise by fission. These cell cycle-dependent changes in mitochondrial architecture explain how these meristematic cells can achieve a high rate of mtDNA recombination and ensure the even partitioning of mitochondria between daughter cells.
The polyoxometalate clusters with formula Gd(W5O18)29− and Gd(P5W30O110)12− each carry a single magnetic ion of gadolinium, which is the most widespread element among magnetic refrigerant materials. ...In an adiabatic demagnetization, the lowest attainable temperature is limited by the presence of magnetic interactions that bring about magnetic order below a critical temperature. We demonstrate that this limitation can be overcome by chemically engineering the molecules in such a way to effectively screen all magnetic interactions, suggesting their use as ultra‐low‐temperature coolers.
A novel hybrid plasmonic platform based on the synergetic combination of a molecularly imprinted polymer (MIP) thin film with Au nanoparticle (NPs) assemblies, noted as Au@MIP, was developed for ...surface-enhanced Raman scattering (SERS) spectroscopy recognition of polycyclic aromatic hydrocarbons (PAHs). While the MIP trapped the PAH close to the Au surface, the plasmonic NPs enhanced the molecule’s Raman signal. The Au@MIP fabrication comprises a two-step procedure, first, the layer-by-layer deposition of Au NPs on glass and their further coating with a uniform MIP thin film. Profilometry analysis demonstrated that the thickness and homogeneity of the MIP film could be finely tailored by tuning different parameters such as prepolymerization time or spin-coating rate. Two different PAH molecules, pyrene or fluoranthene, were used as templates for the fabrication of pyrene- or fluoranthene-based Au@MIP substrates. The use of pyrene or fluoranthene, as the template molecule to fabricate the Au@MIP thin films, enabled its ultradetection in the nM regime with a 100-fold improvement compared with the nonimprinted plasmonic sensors (Au@NIPs). The SERS data analysis allowed to estimate the binding constant of the template molecule to the MIP. The selectivity of both pyrene- and fluoranthene-based Au@MIPs was analyzed against three PAHs of different sizes. The results displayed the important role of the template molecule used for the Au@MIPs fabrication in the selectivity of the system. Finally, the practical applicability of pyrene-based Au@MIPs was shown by performing the detection of pyrene in two real samples: creek water and seawater. The design and optimization of this type of plasmonic platform will pave the way for the detection of other relevant (bio)molecules in a broad range of fields such as environmental control, food safety, or biomedicine.
Aim
The voltage‐gated Kv7.1 channel, in association with the regulatory subunit KCNE1, contributes to the IKs current in the heart. However, both proteins travel to the plasma membrane using ...different routes. While KCNE1 follows a classical Golgi‐mediated anterograde pathway, Kv7.1 is located in endoplasmic reticulum‐plasma membrane junctions (ER‐PMjs), where it associates with KCNE1 before being delivered to the plasma membrane.
Methods
To characterize the channel routing to these spots we used a wide repertoire of methodologies, such as protein expression analysis (i.e. protein association and biotin labeling), confocal (i.e. immunocytochemistry, FRET, and FRAP), and dSTORM microscopy, transmission electron microscopy, proteomics, and electrophysiology.
Results
We demonstrated that Kv7.1 targeted ER‐PMjs regardless of the origin or architecture of these structures. Kv2.1, a neuronal channel that also contributes to a cardiac action potential, and JPHs, involved in cardiac dyads, increased the number of ER‐PMjs in nonexcitable cells, driving and increasing the level of Kv7.1 at the cell surface. Both ER‐PMj inducers influenced channel function and dynamics, suggesting that different protein structures are formed. Although exhibiting no physical interaction, Kv7.1 resided in more condensed clusters (ring‐shaped) with Kv2.1 than with JPH4. Moreover, we found that VAMPs and AMIGO, which are Kv2.1 ancillary proteins also associated with Kv7.1. Specially, VAP B, showed higher interaction with the channel when ER‐PMjs were stimulated by Kv2.1.
Conclusion
Our results indicated that Kv7.1 may bind to different structures of ER‐PMjs that are induced by different mechanisms. This variable architecture can differentially affect the fate of cardiac Kv7.1 channels.
Background: To compare corneal densitometry (CD) patterns at the graft–host interface between Descemet Membrane Endothelial Keratoplasty (DMEK) and Descemet Stripping Automated Endothelial ...Keratoplasty (DSAEK). Corneal densitometry is a quantitative assessment that objectively evaluates corneal clarity and optical quality by measuring the light backscatter from the cornea. Methods: Fifty-one eyes that received DMEK or DSAEK surgery for corneal endothelium dysfunction were evaluated. The primary endpoint included CD patterns at the graft–host interface, which were assessed by the Pentacam HR device at the center point of the corneal horizontal meridian (CDcentral), and at six points on the central circumference of the cornea (with a total diameter of 4 mm) (CDI,II,III,IV,V,VI). Secondary endpoints included the best-corrected distance visual acuity (BCDVA), central corneal thickness (CCT), and graft thickness (GT). All of the evaluations were performed at follow-up appointments one, three, six and twelve months after the procedure. Results: DMEK showed a significant overall CD reduction of −7.9 ± 8.5 grayscale unit (GSU) compared to DSAEK (p < 0.001). In addition, the DMEK group showed significantly lower CDCentral,I,II,III,IV,V,VI values at follow-up appointments one, three, six and twelve months after the procedure compared to the DSAEK group (p < 0.001). BCDVA, CCT and GT were in favor of the DMEK group with a mean value of 0.39 ± 0.35 LogMar, 552.2 ± 71.1 µm and 11.03 ± 1.4 µm, respectively (p < 0.001). Conclusions: CD patterns at the graft–host interface seem to be different depending on the endothelial keratoplasty procedure. This provides specific insight into CD changes in this critical region of surgery, which may provide a better understanding of the postoperative evolution of these patients.
High CO 2 pneumoperitoneum pressure during laparoscopy adversely affects the peritoneal environment. This study hypothesized that low pneumoperitoneum pressure may be linked to less peritoneal damage ...and possibly to better clinical outcomes.
One hundred patients undergoing scheduled laparoscopic cholecystectomy were randomized 1:1 to low or to standard pneumoperitoneum pressure. Peritoneal biopsies were performed at baseline time and 1 hour after peritoneum insufflation in all patients. The primary outcome was peritoneal remodeling biomarkers and apoptotic index. Secondary outcomes included biomarker differences at the studied times and some clinical variables such as length of hospital stay, and quality and safety issues related to the procedure.
Peritoneal IL6 after 1 hour of surgery was significantly higher in the standard than in the low-pressure group (4.26±1.34 vs. 3.24±1.21; P =0.001). On the contrary, levels of connective tissue growth factor and plasminogen activator inhibitor-I were higher in the low-pressure group (0.89±0.61 vs. 0.61±0.84; P =0.025, and 0.74±0.89 vs. 0.24±1.15; P =0.028, respectively). Regarding apoptotic index, similar levels were found in both groups and were 44.0±10.9 and 42.5±17.8 in low and standard pressure groups, respectively. None of the secondary outcomes showed differences between the 2 groups.
Peritoneal inflammation after laparoscopic cholecystectomy is higher when surgery is performed under standard pressure. Adhesion formation seems to be less in this group. The majority of patients undergoing surgery under low pressure were operated under optimal workspace conditions, regardless of the surgeon's expertise.
Dysregulation of cholesterol homeostasis is associated with several pathologies including cardiovascular diseases and neurological disorders such as Alzheimer's disease (AD). MicroRNAs (miRNAs) have ...emerged as key post-transcriptional regulators of cholesterol metabolism. We previously established the role of miR-7 in regulating insulin resistance and amyloidosis, which represents a common pathological feature between type 2 diabetes and AD. We show here an additional metabolic function of miR-7 in cholesterol biosynthesis. We found that miR-7 blocks the last steps of the cholesterol biosynthetic pathway in vitro by targeting relevant genes including DHCR24 and SC5D posttranscriptionally. Intracranial infusion of miR-7 on an adeno-associated viral vector reduced the expression of DHCR24 in the brain of wild-type mice, supporting in vivo miR-7 targeting. We also found that cholesterol regulates endogenous levels of miR-7 in vitro, correlating with transcriptional regulation through SREBP2 binding to its promoter region. In parallel to SREBP2 inhibition, the levels of miR-7 and hnRNPK (the host gene of miR-7) were concomitantly reduced in brain in a mouse model of Niemann Pick type C1 disease and in murine fatty liver, which are both characterized by intracellular cholesterol accumulation. Taken together, the results establish a novel regulatory feedback loop by which miR-7 modulates cholesterol homeostasis at the posttranscriptional level, an effect that could be exploited for therapeutic interventions against prevalent human diseases.
•MiR-7 blocks DHCR24 and cholesterol synthesis•Cholesterol controls miR-7 levels•MiR-7 participates in a novel regulatory feedback loop of posttranscriptional regulation of cholesterol metabolism
The use of low‐density (LD) steels has become increasingly important due to the advantages they offer, such as high strength, high ductility, and principally weight reduction. However, there are few ...studies regarding their weldability by conventional processes due to the metallurgical complexity of these alloys, including kappa carbides precipitation and hot‐cracking associated with the high contents of Mn, Al, and C. Herein, the main objective is the characterization of the fusion zone and different heat‐affected zones of austenitic Fe–Mn–Al–C LD steels microalloyed with Ti/B and Ce/La. For this purpose, weld nuggets were prepared by autogenous gas tungsten arc welding process using heat inputs of 660 and 975 J. The weld nuggets were characterized metallographic, structural, and mechanically by light optical microscopy, scanning electron microscopy, X‐ray diffraction, and Vickers microhardness. In general, weld nuggets shows three well‐defined zones where γ‐austenite is the main phase and AlN and MnS particles act as nuclei of complex precipitated particles of microalloying elements such as TiC and (Ce, La)O. A considerable decrease in hot‐cracking was noticed in the microalloyed grades. A modulated structure of kappa‐carbide particles was responsible of the largest hardness values (≈450 Vickers microhardness) in the second heat‐affected zone.
Herein, weld nuggets of Fe–Mn–Al–C low‐density steels microalloyed with Ti/B and Ce/La obtained by gas tungsten arc welding process are microstructurally studied. Three well‐defined zones are noticed: a fusion zone and two heat‐affected zones. A significant decrease in hot‐cracking is observed in the microalloyed grades. κ‐carbide particles are responsible of the largest hardness values (≈450 Vickers microhardness).
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