Molecular Simplification in Bioactive Molecules: Formal Synthesis of (+)-Muconin

7 páginas, 1 figura, 7 esquemas, 1 tabla.-- El PDF es la versión post-print.The concept of molecular simplification as a drug design strategy to shorten synthetic routes, while keeping or enhancing the biological activity of the lead drug, has been applied to (+)-muconin, an acetogenin with remarkable cytotoxicity. A novel approach that enables the stereoselective synthesis of such a natural compound or its enantiomer from a common precursor is described. An additional advantage of the method is complete stereochemical control and the decrease in the number of chemical steps required, thus providing an enhancement of the overall yield. Antiproliferative studies against the human solid tumor cell lines showed that the aliphatic chain-THF/THP fragment of (+)-muconin has modest cytotoxic activity. The strategy opens the way to preparing novel bioactive acetogenin analogues by shorter synthetic routes.The authors thank the MYCT (PPQ2002- 04361-C04-02) of Spain and the Canary Islands Government for supporting this research. F.R.P.C. thanks CajaCanarias for a FPI fellowship. R.C. thanks the Spanish MEC for a FPU fellowship. J.M.P. thanks ICIC for a postdoctoral fellowship.Peer reviewe

Updating the criteria for assessing the state of the railway track according to the data of track measuring equipment

Introduction. One of the consequences of the introduction of the Instructions for Assessing the Condition of the Rail Track (enacted on February 28, 2020 No. 436/r) was an increase in the number of newly detected deviations from the norm of track maintenance and their reassignment as malfunctions. As a result, the number of kilometres with limited train speeds has increased by up to 3 times, which may lead to significant losses in transportation and an increase in the cost of the immediate track maintenance.Materials and methods. Data from a special thoroughfare of a diagnostic complex along the operating lines of Russian Railways were used to analyse the actual distribution of types and magnitudes of malfunctions, the number and causes of the speed limits. The authors used computer simulations to determine the dynamic indicators of cars in accordance with the algorithm of the deterministic method for calculating the movement of cars along the railway track.Results. The consequences for assessing the state of the track from the standards specified in Instruction 436/r are analysed. The authors present the results of mathematical modelling of the rolling stock interaction with the track, confirming the feasibility of the proposed changes in the standards: increasing the permissible speeds of passenger trains, assessing the gauge widening in curved sections, clarifying the estimates of unbalanced acceleration.Discussion and conclusion. It is proposed to change a number of standards for assessing deviations from the norms of track maintenance in order to reduce the number of speed limits

СЛУЧАЙНЫЕ ПРОЦЕССЫ ВОЗМУЩЕНИЯ В ДИНАМИКЕ РЕЛЬСОВЫХ ЭКИПАЖЕЙ

Previous works contained correlation and spectral  analysis of the four-dimensional  disturbance  process in the form of vertical and horizontal irregularities of left and right rails, causing oscillations in rail vehicles. But when speed increases, the disturbance frequency range shifts to high frequencies and can go beyond natural frequencies of the system. Then disturbance almost ceases to excite a part of vibration frequencies and obtained results will be incorrect.The article considers requirements to the procedure of computer generating a multidimensional stationary random disturbance process, causing vibrations of rail vehicles.  Using  modeling,  computer  simulation,  and mathematical analysis it is shown that when the speed alters it is necessary to change terms of the composition of the random process of geometrical irregularities of the  track.  The  requirements  for  parameters  of  the probabilistic analysis are determined, examples of generating and the results of spectral analysis of irregularities generated for different speeds are shown.В статье рассмотрены требования к процедуре генерации на ЭВМ многомерного стационарного случайного процесса возмущения, вызывающего колебания рельсовых экипажей. Показано, что при изменении скорости движения необходимо менять состав слагаемых случайного процесса геометрических неровностей рельсового пути. Определены требования к параметрам вероятностного анализа, приведены примеры генерации и результаты спектрального анализа случайных неровностей для различных скоростей движения

Kinetic Control of Complexity in Multiple Dynamic Libraries

Multiple dynamic libraries of compounds are generated when more than one reversible reaction comes into play. Commonly, two or more orthogonal reversible reactions are used, leading to non-communicating dynamic libraries which share no building blocks. Only a few examples of communicating libraries have been reported, and in all those cases, building blocks are reversibly exchanged from one library to the other, constituting an antiparallel dynamic covalent system. Herein we report that communication between two different dynamic libraries through an irreversible process is also possible. Indeed, alkyl amines cancel the dynamic regime on the nucleophilic substitution of tetrazines, generating kinetically inert compounds. Interestingly, such amine can be part of another dynamic library, an imine-amine exchange. Thus, both libraries are interconnected with each other by an irreversible process which leads to kinetically inert structures that contain parts from both libraries, causing a collapse of the complexity. Additionally, a latent irreversible intercommunication could be developed. In such a way, a stable molecular system with specific host–guest and fluorescence properties, could be irreversibly transformed when the right stimulus was applied, triggering the cancellation of the original supramolecular and luminescent properties and the emergence of new ones.Grant PID2022-136566NB-I00 and PDC2022-133706-I00 funded by MCIN/AEI/10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR”. D. S. R. thanks Ministerio de Ciencia, Innovación y Universidades for his FPU fellowship. Y. P.-P. thanks Asociación Española contra el Cáncer (aecc) for a predoctoral fellowship. T. S. thanks ACIISI for a Catalina Ruiz fellowship. J. S. thanks Cabildo de Tenerife for the Agustín de Betancourt programme. All the authors would like to acknowledge the use of the HPLC, the Mass Spectrometry and the NMR Facilities at IPNA-CSIC, and they want to thank Nieves Rodríguez Paz for her unvaluable help. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Defects in Regulation of Local Immune Responses Resulting in Atherosclerosis

Atherosclerosis is nowadays generally accepted as an inflammatory disease but the mechanism of its origin and development have not yet been fully clarified. The present review focuses on the role of the local immune system as one of the key players in the pathogenesis of the complex process. Its part represented by vascular-associated lymphoid tissue (VALT) within the arterial wall participates directly in the vascular wall's homeostatis. Its inordinate activation during ontogenic development of an individual, this formerly defensive and physiologic mechanism transform into a pathological process resulting in an impairing inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious candidates for triggering these pathological changes. The principal role is played by anti-Hsp60 antibodies and by shear stress originating on the surface of endothelium due to blood flow. The experimental and clinical data supporting this immunological hypothesis of atherosclerosis are discussed

Tensor network Python (TeNPy) version 1

TeNPy (short for 'Tensor Network Python') is a python library for the simulation of strongly correlated quantum systems with tensor networks. The philosophy of this library is to achieve a balance of readability and usability for new-comers, while at the same time providing powerful algorithms for experts. The focus is on MPS algorithms for 1D and 2D lattices, such as DMRG ground state search, as well as dynamics using TEBD, TDVP, or MPO evolution. This article is a companion to the recent version 1.0 release of TeNPy and gives a brief overview of the package

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Crystal structures of self-assembled nanotubes from flexible macrocycles by weak interactions

8 páginas, 7 figuras, 2 tablas, 2 esquemas.Herein we report the crystal structures of tubular self-assemblies of flexible macrooligolides. The assembly is driven by the propensity of the macrocycles to create nearly flat structures displaying a void space within them and the cooperativity of weak directional interactions such as dipole–dipole interactions and CH***Ohydrogen bonds and non-directional interactions such as van der Waals contacts. The significance of the stereochemistry and the size of the cavity in the formation of the nanotubes are also studied.This research was supported by the Spanish MICINN-FEDER (CTQ2008-03334/BQU, CTQ2008-06806-C02-01/BQU and CTQ2008-06754-C04-01/PPQ), the MSC (RTICC RD06/0020/ 1046) and the Canary Islands FUNCIS (PI 01/06).Peer reviewe

A convenient and chemoselective one-pot oxidation/Wittig reaction for the C2-homologation of carbohydrate-derived glycols

3 pages, 2 tables.-- PMID: 16292846 [PubMed].-- Printed version published Nov 25, 2005.Supporting information available: Spectroscopic and analytical data for several compounds.-- Available at: http://pubs.acs.org/doi/suppl/10.1021/jo051566eErratum in: Journal of Organic Chemistry 71(3): 1288 (2006), doi: 10.1021/jo052606h.A simple and convenient one-pot protocol for the chemoselective C2-homologation of carbohydrate-derived glycols is described. The method comprises the chemoselective oxidation of the glycol to the corresponding hydroxyaldehyde and the subsequent Wittig alkenylation. In addition, the method does not need selective protective group manipulation, and it is safe, economical, fast (5 to 6 h), and bench-friendly. Its general utility is discussed.This research was supported by the Spanish Ministerio de Educación y Ciencia (PPQ2002-04361-C04-02 and PPQ2002-04361-C04-03). F.R.P.C. and R.C. thank CajaCanarias and the Spanish Ministerio de Educación y Ciencia for an FPI and FPU grant, respectively. F.G.T. thanks the Instituto Canario de Investigación del Cáncer for financial support (ICIC-PI. n° 07/2004; ISCiii, RTICCC C03/10)