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Synthesizing and exploring large-scale realistic urban road networks is beneficial to 3D content creation, traffic animation and urban planning. In this paper, we present an interactive tool that allows untrained users to design roads with complex realistic details and styles. Roads are generated by growing a geometric graph. During a sketching phase, the user specifies the target area and the examples. During a growing phase, two types of growth are effectively applied to generate roads in the target area; example-based growth uses patches extracted from the source example to generate roads that preserve some interesting structures in the example road networks; procedural-based growth uses the statistical information of the source example while effectively adapting the roads to the underlying terrain and the already generated roads. User-specified warping, blending and interpolation operations are used at will to produce new road network designs that are inspired by the examples. Finally, our method computes city blocks, individual parcels and plausible building and tree geometries. We have used our approach to create road networks covering up to 200 [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) represents a significant proportion of heart failure cases. Accurate diagnosis is challenging due to the heterogeneous nature of the disease and limitations in traditional echocardiographic parameters., Main Body: This review appraises the application of Global Longitudinal Strain (GLS) and Left Atrial Strain (LAS) as echocardiographic biomarkers in the diagnosis and phenotyping of HFpEF. Strain imaging, particularly Speckle Tracking Echocardiography, offers a superior assessment of myocardial deformation, providing a more detailed insight into left heart function than traditional metrics. Normal ranges for GLS and LAS are considered, acknowledging the impact of demographic and technical factors on these values. Clinical studies have demonstrated the prognostic value of GLS and LAS in HFpEF, especially in predicting cardiovascular outcomes and distinguishing HFpEF from other causes of dyspnea. Nevertheless, the variability of strain measurements and the potential for false-negative results underline the need for careful clinical interpretation. The HFA-PEFF scoring system's integration of these biomarkers, although systematic, reveals gaps in addressing the full spectrum of HFpEF pathology. The combined use of GLS and LAS has been suggested to define HFpEF phenogroups, which could lead to more personalized treatment plans., Conclusion: GLS and LAS have emerged as pivotal tools in the non-invasive diagnosis and stratification of HFpEF, offering a promise for tailored therapeutic strategies. Despite their potential, a structured approach to incorporating these biomarkers into standard diagnostic workflows is essential. Future clinical guidelines should include clear directives for the combined utilization of GLS and LAS, accentuating their role in the multidimensional assessment of HFpEF., (© 2024. The Author(s).)

Assessing left ventricular (LV) filling pressure (LVFP) is challenging in patients with coronary artery disease (CAD) and preserved LV ejection fraction (LVEF). We aimed to correlate left atrial strain (LAS) with two invasive complementary parameters of LVFP and compared its accuracy to other echocardiographic data to predict high LVFP. This cross-sectional, single-center study enrolled 81 outpatients with LVEF > 50% and significant CAD from a database. Near-simultaneous echocardiography and invasive measurements of both LV end-diastolic pressure (LVEDP) and LV pre-atrial contraction (pre-A) pressure were performed in each patient, based on the definition of LVEDP > 16 mmHg and LV pre-A > 12 mmHg as high LVFP. A moderate to strong correlation was observed between LAS reservoir (LASr), contractile strain, and LVEDP (r: 0.67 and 0.62, respectively; p < 0.001); the same was true for LV pre-A (r: 0.65 and 0.63, respectively; p < 0.001). LASr displayed good diagnostic performance to identify elevated LVFP, which was higher when compared to traditional parameters. Median value of LASr was higher for an isolated increase of LVEDP than for simultaneously high LV pre-A. The cutoff found to predict high LVFP was lower for LV pre-A than that one for LVEDP. In the current study, LASr did not provide an additional contribution to the 2016 diastolic function algorithm. LAS is a valuable tool for predicting LVFP in patients with CAD and preserved LVEF. The choice of LVEDP or LV pre-A as the representative marker of LVFP leads to different cutoffs to predict high pressures. The best strategy for adding this tool to a multiparametric algorithm requires further investigation., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and β-amyloid (Aβ), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Aβ oligomers have a much stronger affinity for fibrinogen than Aβ monomers, we tested whether amyloid aggregation inhibitors could block the Aβ-fibrinogen interaction and found that some Aβ aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the Aβ-fibrinogen interaction but also retained its potency toward the Aβ42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated Aβ42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the Aβ-fibrinogen interaction and Aβ aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as Aβ aggregation-driven pathology in AD.

Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 μM; and Bcl-xL, IC50 = 0.0037 μM).

A cationic rhodium(I)/Segphos complex catalyzes a [2 + 2 + 2] cycloaddition of internal 1,6-diynes with a phosphonate- or ester-substituted 1,3-butadiyne leading to C(2)-symmetric axially chiral biaryl diphosphonates or dicarboxylates, respectively, in high yields with outstanding ee's. The use of a phosphonate- or ester-substituted 1,3-butadiyne as a cycloaddition partner and Segphos as a ligand is crucial for the success of this transformation.

A convenient synthesis of perfluoroalkylated benzenes and pyridines has been achieved by a cationic Rh(I)/modified BINAP-complex-catalyzed chemo- and regioselective [2 + 2 + 2] cycloaddition of alkynes with a perfluoroalkylacetylene and a perfluoroalkylnitrile.

The destabilization of vesicles caused by interactions between lipid bilayers and proteins was studied by direct, real-time observation using high-intensity dark-field microscopy. We previously reported that talin, a cytoskeletal submembranous protein, can reversibly open stable large holes in giant liposomes made of neutral and acidic phospholipids. Talin and other proteins belonging to the band 4.1 superfamily have the FERM domain at their N-terminal and interact with lipid membranes via that domain. Here, we observed that band 4.1, ezrin and moesin, members of the band 4.1 superfamily, are also able to open stable holes in liposomes. However, truncation of their C-terminal domains, which can interact with the N-terminal FERM domain, impaired their hole opening activities. Oligomeric states of ezrin affected the capability of the membrane hole formation. Phosphatidylinositol bisphosphate (PIP2), which binds to the FERM domain and disrupts the interaction between the N and C termini of the band 4.1 superfamily, down-regulates their membrane opening activity. These results suggest that the intermolecular interaction plays a key role in the observed membrane hole formation.

[reaction: see text] We have established an enantioselective synthesis of both C2 symmetric and unsymmetric tetra-ortho-substituted axially chiral biaryls through rhodium-catalyzed double [2 + 2 + 2] cycloaddition (up to >99% ee). This method serves as an attractive new route to enantioenriched tetra-ortho-substituted axially chiral biaryls in view of the one-step access to substrate diynes and tetraynes starting from readily available alkynes.