DiffHopp: A Graph Diffusion Model for Novel Drug Design via Scaffold Hopping

Scaffold hopping is a drug discovery strategy to generate new chemical entities by modifying the core structure, the \emph{scaffold}, of a known active compound. This approach preserves the essential molecular features of the original scaffold while introducing novel chemical elements or structural features to enhance potency, selectivity, or bioavailability. However, there is currently a lack of generative models specifically tailored for this task, especially in the pocket-conditioned context. In this work, we present DiffHopp, a conditional E(3)-equivariant graph diffusion model tailored for scaffold hopping given a known protein-ligand complex

Selfishness, altruism and message spreading in mobile social networks

Many kinds of communication networks, in particular social and opportunistic networks, rely at least partly on on humans to help move data across the network. Human altruistic behavior is an important factor determining the feasibility of such a system. In this paper, we study the impact of different distributions of altruism on the throughput and delay of mobile social communication system. We evaluate the system performance using four experimental human mobility traces with uniform and community-biased traffic patterns. We found that mobile social networks are very robust to the distributions of altruism due to the nature of multiple paths. We further confirm the results by simulations on two popular social network models. To the best of our knowledge, this is the first complete study of the impact of altruism on mobile social networks, including the impact of topologies and traffic patterns.published_or_final_versio

Clinical reliability of complete-arch fixed prostheses supported by narrow-diameter implants to support complete-arch restorations

The aim of this study was to evaluate the clinical application of fixed screw-retained complete-arch rehabilitations supported by four narrow-diameter implants (NDIs). The records of patients treated with complete-arch prostheses screwed onto four NDIs treated with an immediate loading protocol between 2010 and 2020 with at least 1 year of follow-up after the positioning of the definitive restoration were reviewed. The implants were placed according to the final prosthetic design and were immediately loaded. The interim prostheses were replaced after the healing period by definitive acrylic resin titanium-supported prostheses. Patients were followed to evaluate treatment success, the implant survival rate (ISR), and the prosthetic survival rate (PSR). A total of 121 NDIs were positioned in 30 patients to restore 30 complete arches (18 maxilla and 12 mandible). One implant did not achieve osseointegration, resulting in an overall ISR of 99.2%. No prosthetic or implant failures occurred during the 1 to 11 years of follow-up. Three biological and four prosthetic complications occurred, resulting in a treatment rehabilitation survival of 94.1% and a PSR of 86.7%. Despite the limitations of the present retrospective study, such as the use of one single type of dental implant and patients treated in a single rehabilitation center, complete-arch rehabilitation with fixed prostheses supported by four NDIs seems to be a reliable treatment in the medium to long term

Clinical Reliability of Complete-Arch Fixed Prostheses Supported by Narrow-Diameter Implants to Support Complete-Arch Restorations

The aim of this study was to evaluate the clinical application of fixed screw-retained complete-arch rehabilitations supported by four narrow-diameter implants (NDIs). The records of patients treated with complete-arch prostheses screwed onto four NDIs treated with an immediate loading protocol between 2010 and 2020 with at least 1 year of follow-up after the positioning of the definitive restoration were reviewed. The implants were placed according to the final prosthetic design and were immediately loaded. The interim prostheses were replaced after the healing period by definitive acrylic resin titanium-supported prostheses. Patients were followed to evaluate treatment success, the implant survival rate (ISR), and the prosthetic survival rate (PSR). A total of 121 NDIs were positioned in 30 patients to restore 30 complete arches (18 maxilla and 12 mandible). One implant did not achieve osseointegration, resulting in an overall ISR of 99.2%. No prosthetic or implant failures occurred during the 1 to 11 years of follow-up. Three biological and four prosthetic complications occurred, resulting in a treatment rehabilitation survival of 94.1% and a PSR of 86.7%. Despite the limitations of the present retrospective study, such as the use of one single type of dental implant and patients treated in a single rehabilitation center, complete-arch rehabilitation with fixed prostheses supported by four NDIs seems to be a reliable treatment in the medium to long term

Polymorphisms of pro-inflammatory IL-6 and IL-1\u3b2 cytokines in ascending aortic aneurysms as genetic modifiers and predictive and prognostic biomarkers

Background: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. Methods: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. Results: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and-2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. Conclusions: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches

The Tychonoff uniqueness theorem for the G-heat equation

In this paper, we obtain the Tychonoff uniqueness theorem for the G-heat equation

Benchmarking Generated Poses: How Rational is Structure-based Drug Design with Generative Models?

Deep generative models for structure-based drug design (SBDD), where molecule generation is conditioned on a 3D protein pocket, have received considerable interest in recent years. These methods offer the promise of higher-quality molecule generation by explicitly modelling the 3D interaction between a potential drug and a protein receptor. However, previous work has primarily focused on the quality of the generated molecules themselves, with limited evaluation of the 3D molecule \emph{poses} that these methods produce, with most work simply discarding the generated pose and only reporting a "corrected" pose after redocking with traditional methods. Little is known about whether generated molecules satisfy known physical constraints for binding and the extent to which redocking alters the generated interactions. We introduce PoseCheck, an extensive analysis of multiple state-of-the-art methods and find that generated molecules have significantly more physical violations and fewer key interactions compared to baselines, calling into question the implicit assumption that providing rich 3D structure information improves molecule complementarity. We make recommendations for future research tackling identified failure modes and hope our benchmark can serve as a springboard for future SBDD generative modelling work to have a real-world impact

A Pilot Study on Prostate Cancer Risk and Pro-Inflammatory Genotypes: Pathophysiology and Therapeutic Implications

Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and treatment of PC, we have investigated the potential role of common SNPs of a gene cluster (TLR4, TLR2, PTGS2 and 5-Lo), involved in innate and inflammatory response, in PC cases, age-matched controls and centenarians from Sicily. Six SNPs were genotyped and their association with PC risk determined. Statistical analysis evidenced a significant association of some pro-inflammatory gene SNPs with an increased risk of PC. Furthermore, significant differences were observed comparing the three groups in the combined presence of a \u201chigh responder\u201d pro-inflammatory profile. Overall, the present results suggest the likely association of these SNPs and PC risk, clearly motivating the need of larger studies to confirm the role of these genes in PC development and/or progression

Repeated games for eikonal equations, integral curvature flows and non-linear parabolic integro-differential equations

The main purpose of this paper is to approximate several non-local evolution equations by zero-sum repeated games in the spirit of the previous works of Kohn and the second author (2006 and 2009): general fully non-linear parabolic integro-differential equations on the one hand, and the integral curvature flow of an interface (Imbert, 2008) on the other hand. In order to do so, we start by constructing such a game for eikonal equations whose speed has a non-constant sign. This provides a (discrete) deterministic control interpretation of these evolution equations. In all our games, two players choose positions successively, and their final payoff is determined by their positions and additional parameters of choice. Because of the non-locality of the problems approximated, by contrast with local problems, their choices have to "collect" information far from their current position. For integral curvature flows, players choose hypersurfaces in the whole space and positions on these hypersurfaces. For parabolic integro-differential equations, players choose smooth functions on the whole space