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1.
J Org Chem ; 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39014960

RESUMEN

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

2.
Nat Commun ; 15(1): 5819, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38987287

RESUMEN

Hyperactivity mediated by synaptotoxic ß-amyloid (Aß) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aß peptides before Aß plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aß binding anticalin protein (Aß-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of ß-amyloidosis. Our results suggest that the sole targeting of Aß monomers is sufficient for the hyperactivity-suppressing effect of the Aß-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aß-anticalin-dependent depletion of naturally secreted Aß monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aß monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Modelos Animales de Enfermedad , Hipocampo , Ratones Transgénicos , Neuronas , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Ratones , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Placa Amiloide/metabolismo , Placa Amiloide/patología , Ácido Glutámico/metabolismo , Ratones Endogámicos C57BL , Femenino , Calcio/metabolismo , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos
3.
Life Sci Alliance ; 7(10)2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39009412

RESUMEN

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/ß, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration.


Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Ratones Transgénicos , Microglía , Proteínas Proto-Oncogénicas c-kit , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Ratones , Proteínas Proto-Oncogénicas c-kit/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Autofagia/efectos de los fármacos , Humanos , Péptidos beta-Amiloides/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Proteínas tau/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Masculino
4.
Chem Sci ; 15(25): 9438-9509, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38939157

RESUMEN

The research into adamantane-type compounds has gained momentum in recent years, yielding remarkable new applications for this class of materials. In particular, organic adamantane derivatives (AdR4) or inorganic adamantane-type compounds of the general formula [(RT)4E6] (R: organic substituent; T: group 14 atom C, Si, Ge, Sn; E: chalcogenide atom S, Se, Te, or CH2) were shown to exhibit strong nonlinear optical (NLO) properties, either second-harmonic generation (SHG) or an unprecedented type of highly-directed white-light generation (WLG) - depending on their respective crystalline or amorphous nature. The (missing) crystallinity, as well as the maximum wavelengths of the optical transitions, are controlled by the clusters' elemental composition and by the nature of the organic groups R. Very recently, it has been additionally shown that cluster cores with increased inhomogeneity, like the one in compounds [RSi{CH2Sn(E)R'}3], not only affect the chemical properties, such as increased robustness and reversible melting behaviour, but that such 'cluster glasses' form a conceptually new basis for their use in light conversion devices. These findings are likely only the tip of the iceberg, as beside elemental combinations including group 14 and group 16 elements, many more adamantane-type clusters (on the one hand) and related architectures representing extensions of adamantane-type clusters (on the other hand) are known, but have not yet been addressed in terms of their opto-electronic properties. In this review, we therefore present a survey of all known classes of adanmantane-type compounds and their respective synthetic access as well as their optical properties, if reported.

5.
Sci Total Environ ; 946: 173884, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-38885719

RESUMEN

Soft plastic lures (SPLs) are commonly used artificial lures in recreational angling. Anglers regularly lose SPLs while fishing and there is little knowledge about the environmental impacts of lost SPLs. As with other plastic items, SPLs contain phthalates and other persistent additives that may leach into water. In this study, 16 randomly chosen SPLs of common models were analyzed for the leaching of persistent, water-soluble plastic additives, including phthalates. The estrogenicity of sample extracts from a subsample of 10 SPLs was assessed using luciferase reporter gene bioassays. Over a period of 61 days, 10 of the 16 SPLs leached the targeted phthalates dimethyl phthalate (DMP), diethyl phthalate (DEP), benzyl butyl phthalate (BBP) and di-n-butyl phthalate (DnBP) at median detectable concentrations ranging from 10 ng/g sample BBP to a median of 1001 ng/g DMP as well as 45 persistent, mobile, and toxic (PMT) plastic additives. DEP was detected most frequently in 8 SPLs, followed by BBP (2 SPLs), DMP (2 SPLs) and DnBP (1 SPL). The extract from one SPL with comparatively low phthalate and PMT plastic additive levels was active in the bioassay, indicating high endocrine-disruptive potential, presumably due to unknown additives that were not among the target substances of the methodology used in this study. The study was supplemented by a mail survey among anglers, in which attitudes of anglers towards SPLs were investigated. The survey indicated that SPL loss is a common event during angling. Most participants were concerned about potential ecological impacts of SPLs, wanted the ingredients of SPLs to be labelled and supported legal restrictions concerning toxic ingredients of SPLs. The study shows that SPLs are a potential source of environmental pollution, may pose human health risks and need further investigation, considering the frequent use of SPLs in recreational angling.


Asunto(s)
Ácidos Ftálicos , Plásticos , Plásticos/análisis , Ácidos Ftálicos/análisis , Humanos , Monitoreo del Ambiente , Contaminantes Químicos del Agua/análisis , Recreación , Exposición a Riesgos Ambientales
6.
Angew Chem Int Ed Engl ; : e202409790, 2024 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-38880778

RESUMEN

A reaction-based optical relay sensing strategy that enables accurate determination of the concentration and enantiomeric ratio (er) of challenging chiral alcohols exhibiting stereocenters at the α-, ß-, γ- or even δ-position or hard-to-detect cryptochirality arising from H/D substitution is described. This unmatched application scope is achieved with a conceptually new sensing approach by which the alcohol moiety is replaced with an optimized achiral sulfonamide chromophore to minimize the distance between the covalently attached chiroptical reporter unit and the stereogenic center in the substrate. The result is a remarkably strong, red-shifted CD induction that increases linearly with the sample er. The CD sensing part of the tandem assay is seamlessly coupled to a redox reaction with a quinone molecule to generate a characteristic UV response that is independent of the enantiopurity of the alcohol and thus allows determination of the total analyte concentration. The robustness and utility of the CD/UV relay are further verified by chromatography-free asymmetric reaction analysis with small aliquots of crude product mixtures, paving the way toward high-throughput chiral compound screening workflows which is a highly sought-after goal in the pharmaceutical industry.

7.
PLoS One ; 19(4): e0300630, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38578754

RESUMEN

The destructive impact of fungi in agriculture and animal and human health, coincident with increases in antifungal resistance, underscores the need for new and alternative drug targets to counteract these trends. Cellular metabolism relies on many intermediates with intrinsic toxicity and promiscuous enzymatic activity generates others. Fuller knowledge of these toxic entities and their generation may offer opportunities of antifungal development. From this perspective our observation of media-conditional lethal metabolism in respiratory mutants of the opportunistic fungal pathogen Candida albicans was of interest. C. albicans mutants defective in NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain) exhibit normal growth in synthetic complete medium. In YPD medium, however, the mutants grow normally until early stationary phase whereupon a dramatic loss of viability occurs. Upwards of 90% of cells die over the subsequent four to six hours with a loss of membrane integrity. The extent of cell death was proportional to the amount of BactoPeptone, and to a lesser extent, the amount of yeast extract. YPD medium conditioned by growth of the mutant was toxic to wild-type cells indicating mutant metabolism established a toxic milieu in the media. Conditioned media contained a volatile component that contributed to toxicity, but only in the presence of a component of BactoPeptone. Fractionation experiments revealed purine nucleosides or bases as the synergistic component. GC-mass spectrometry analysis revealed acetal (1,1-diethoxyethane) as the active volatile. This previously unreported and lethal synergistic interaction of acetal and purines suggests a hitherto unrecognized toxic metabolism potentially exploitable in the search for antifungal targets.


Asunto(s)
Antifúngicos , Candida albicans , Animales , Humanos , Candida albicans/metabolismo , Antifúngicos/farmacología , Antifúngicos/metabolismo , Acetales/metabolismo , Complejo I de Transporte de Electrón/metabolismo
8.
J Clin Med ; 13(8)2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38673600

RESUMEN

Background: Patients with complex proximal tibial plateau fractures (TPFs) tend to overestimate the prognosis of their injury, potentially due to factors such as a limited understanding, optimism, and the influence of the pain intensity. Understanding the reasons behind this misperception is crucial for healthcare providers to effectively communicate with patients and establish realistic expectations for treatment outcomes. The purpose of this study was to analyze the outcomes of TPFs, with a particular focus on patient-reported outcome measures concerning functional recovery, pain levels, and overall satisfaction with treatment. The authors aim to provide valuable insights into the realistic expectations and potential limitations that patients may encounter during their recovery journey. Methods: In this retrospective single-center study, all surgically treated TPFs between January 2014 and December 2019 with a minimum follow-up of 12 months were included. Several patient-reported outcome measures were obtained, including the International Knee documentation Committee Score (IKDC), Lyholm score, Tegner score, and visual analog scale (VAS) for pain. Fractures were classified according to Schatzker, and then subgrouped into simple (Schatzker I-III) and complex (Schatzker IV-VI) fractures. Results: A total of 54 patients (mean age 51.1 ± 11.9 years, 59.3% female) with a mean follow-up time of 3.9 years were included. Schatzker II fractures were present in 48% (n = 26) of the cases, with Schatzker III in 6% (n = 3), Schatzker IV fractures in 6% (n = 3), and Schatker VI fractures in 41% (n = 22) of the cases. All outcome scores showed a significant improvement between the first year after surgery and the last follow-up (mean: 3.9 years). Simple fractures showed significantly lower patient-reported outcomes when compared to the preinjury state; however, good to excellent results were observed. Patient-reported outcomes of complex fractures showed no significant changes in the study period with good to excellent results. When it comes to the Lysholm score, there were no significant differences in the outcome between simple and complex fractures. Furthermore, there was a return-to-sports rate of 100%, with high rates of changing sporting activity in 25% (simple fractures) and 45% in complex fractures. Conclusions: The data from this study showed that both simple and complex tibial plateau fractures show favorable outcomes at the midterm follow-up, and that injury severity does not correlate with worse results. While patients may tend to overestimate the recovery speed, this research highlights the importance of long-term follow-up, demonstrating a substantial improvement between one year post-surgery and the final evaluation. Return-to-sports rates were high, with adjustments needed for certain activities. However, patients should recognize the need to shift to lower-impact sports and the lengthy recovery process.

9.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200208, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38662979

RESUMEN

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).


Asunto(s)
Relación Dosis-Respuesta a Droga , Esclerosis Múltiple Recurrente-Remitente , Humanos , Adulto , Masculino , Femenino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Persona de Mediana Edad , Adulto Joven , Método Doble Ciego , Adolescente
10.
J Org Chem ; 89(9): 6100-6105, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38619814

RESUMEN

Fluorooxindoles undergo asymmetric Michael addition to para-quinone methides under phase-transfer conditions with 10 mol% of a readily available cinchona alkaloid ammonium catalyst. This reaction affords sterically encumbered, multifunctional fluorinated organic compounds displaying two adjacent chirality centers with high yields, ee's and dr's.

11.
Angew Chem Int Ed Engl ; 63(26): e202404594, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38634562

RESUMEN

Piano stool complexes have been studied over many years and found widespread applications in organic synthesis, catalysis, materials and drug development. We now report the first examples of quantitative chiroptical molecular recognition of chiral compounds through click-like η6-arene coordination with readily available half sandwich complexes. This conceptually new approach to chirality sensing is based on irreversible acetonitrile displacement of [Cp*Ru(CH3CN)3]PF6 by an aromatic target molecule, a process that is fast and complete within a few minutes at room temperature. The metal coordination coincides with characteristic circular dichroism inductions that can be easily correlated to the absolute configuration and enantiomeric ratio of the bound molecule. A relay assay that decouples the determination of the enantiomeric composition and of the total sample amount by a practical CD/UV measurement protocol was developed and successfully tested. The introduction of piano stool complexes to the chiroptical sensing realm is mechanistically unique and extends the scope of currently known methods with small-molecule probes that require the presence of amino, alcohol, carboxylate or other privileged functional groups for binding of the target compound. A broad application range including pharmaceutically relevant multifunctional molecules and the use in chromatography-free asymmetric reaction analysis are also demonstrated.

12.
Angew Chem Int Ed Engl ; 63(19): e202400767, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38421186

RESUMEN

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high-throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer-generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi-well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small-molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high-throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

13.
Nat Commun ; 15(1): 1866, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38424080

RESUMEN

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing ß-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization.

14.
Chem Sci ; 15(4): 1498-1504, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38274061

RESUMEN

The analysis of mixtures of chiral compounds is a common task in academic and industrial laboratories typically achieved by laborious and time-consuming physical separation of the individual stereoisomers to allow interference-free quantification, for example using chiral chromatography coupled with UV detection. Current practice thus impedes high-throughput and slows down progress in countless chiral compound development projects. Here we describe a chemometric solution to this problem using a redox-responsive naphthoquinone that enables chromatography-free click chemistry sensing of challenging mixtures. The achiral probe covalently binds amino alcohols within a few minutes at room temperature and generates characteristic UVA and CDA spectra that are intentionally altered via sodium borohydride reduction to provide a second, strikingly different chiroptical data set (UVB and CDB). Chemometric partial least squares processing of the chiroptical outputs then enables spectral deconvolution and accurate determination of individual analyte concentrations. The success of this approach is demonstrated with 35 samples covering considerably varied total analyte amounts and stereoisomeric ratios. All chemicals and machine learning algorithms are readily available and can be immediately adapted by any laboratory.

15.
Psychol Sci ; 35(2): 191-201, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38252798

RESUMEN

To estimate object properties such as mass or friction, our brain relies on visual information to efficiently compute approximations. The role of sensorimotor feedback, however, is not well understood. Here we tested healthy adults (N = 79) in an inclined-plane problem, that is, how much a plane can be tilted before an object starts to slide, and contrasted the interaction group with observation groups who accessed involved forces by watching objects being manipulated. We created objects of different masses and levels of friction and asked participants to estimate the critical tilt angle after pushing an object, lifting it, or both. Estimates correlated with applied forces and were biased toward object mass, with higher estimates for heavier objects. Our findings highlight that inferences about physical object properties are tightly linked to the human sensorimotor system and that humans integrate sensorimotor information even at the risk of nonveridical perceptual estimates.


Asunto(s)
Percepción del Peso , Adulto , Humanos , Fricción , Encéfalo , Desempeño Psicomotor , Fuerza de la Mano
16.
Dis Aquat Organ ; 155: 21-33, 2023 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-37534719

RESUMEN

One possible reason for the European eel (Anguilla anguilla) population decline is the neozoan eel swim bladder nematode Anguillicola crassus. To investigate whether the prevalence of A. crassus and the associated swim bladder pathology is related to eel habitat, growth rate, and age, 728 yellow eels from 6 habitats differing in salinity and located along the German Baltic coast were examined between 2005 and 2009. The prevalence of A. crassus varied between habitats, ranging from 9 to 57%. Infection prevalence and the percentage of eels with a damaged swim bladder were significantly higher in inner coastal waters compared to more saline open coastal water. In infected eels, 1 to 32 adult and preadult individuals of A. crassus were observed. The mean infection intensity varied between habitats from 2 to 7 nematodes per eel but did not significantly differ between inner and open coastal waters. Infection prevalence and intensity decreased significantly with age when all open coastal waters and all habitats were combined. Both the lower prevalence of A. crassus and the swim bladder damage of older eels and of eels originating from open coastal water habitats suggest that these eels have a higher fitness for spawning migrations than eels from inner coastal waters. The present study underlines the importance of eel screening on a sufficiently small geographical scale for the accurate estimation of eel recruitment and the identification of priority areas that are likely to produce healthy silver eels.


Asunto(s)
Anguilla , Dracunculoidea , Enfermedades de los Peces , Animales , Vejiga Urinaria , Enfermedades de los Peces/epidemiología , Sacos Aéreos , Ecosistema , Agua
17.
Rev Fish Biol Fish ; : 1-17, 2023 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-37360579

RESUMEN

The global COVID-19 pandemic resulted in many jurisdictions implementing orders restricting the movements of people to inhibit virus transmission, with recreational angling often either not permitted or access to fisheries and/or related infrastructure being prevented. Following the lifting of restrictions, initial angler surveys and licence sales suggested increased participation and effort, and altered angler demographics, but with evidence remaining limited. Here, we overcome this evidence gap by identifying temporal changes in angling interest, licence sales, and angling effort in world regions by comparing data in the 'pre-pandemic' (up to and including 2019); 'acute pandemic' (2020) and 'COVID-acclimated' (2021) periods. We then identified how changes can inform the development of more resilient and sustainable recreational fisheries. Interest in angling (measured here as angling-related internet search term volumes) increased substantially in all regions during 2020. Patterns in licence sales revealed marked increases in some countries during 2020 but not in others. Where licence sales increased, this was rarely sustained in 2021; where there were declines, these related to fewer tourist anglers due to movement restrictions. Data from most countries indicated a younger demographic of people who participated in angling in 2020, including in urban areas, but this was not sustained in 2021. These short-lived changes in recreational angling indicate efforts to retain younger anglers could increase overall participation levels, where efforts can target education in appropriate angling practices and create more urban angling opportunities. These efforts would then provide recreational fisheries with greater resilience to cope with future global crises, including facilitating the ability of people to access angling opportunities during periods of high societal stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s11160-023-09784-5.

18.
Chirality ; 35(9): 619-624, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37129272

RESUMEN

Fluorinated oxindoles are frequently used building blocks in asymmetric synthesis and represent an important scaffold found in a variety of biologically relevant compounds. While it is understood that incorporation of fluorine atoms into organic molecules can improve their pharmacological properties, the impact on the configurational stability of chiral organofluorines is still underexplored. In this study, semipreparative HPLC enantioseparations of five oxindoles were carried out, and the resulting enantiomerically enriched solutions were used to investigate base promoted racemization kinetics at room temperature. It was found that incorporation of fluorine at the chiral center increases the configurational stability, while substitutions on the aromatic ring and at the lactam moiety also have significant effects on the rate of racemization, which generally follows reversible first-order reaction kinetics.

19.
Eur J Med Chem ; 251: 115244, 2023 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-36917882

RESUMEN

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia. They have also been shown to directly bind to CD99 and inhibit ES growth through a distinct mechanism. In the current study, we designed, synthesized and tested new ES specific derivatives of both drugs that would continue to target CD99 but with expected reduction in cellular membrane permeability and rendered unsuitable for inhibiting DNA synthesis. By using commercially available clofarabine and cladribine purine nucleoside analogs, we modified the primary alcohol moiety at the deoxyribose C-5' terminal site to suppress phosphorylation and thus inhibition of subsequent DNA synthesis pathways. In addition, we incorporated a variety of polar groups in the ribose and purine rings to reduce membrane permeability and investigated the effects of configurational changes in the sugar moiety. Among 26 new derivatives, we identified two compounds, BK50164 and BK60106, that cause cell death specifically in ES primarily due to inhibition of CD99 but not via inhibition of DNA synthesis. These findings provide a road map for the future development selective CD99 inhibitors for targeted treatment of ES.


Asunto(s)
Sarcoma de Ewing , Niño , Humanos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Moléculas de Adhesión Celular , Clofarabina/farmacología , Cladribina , ADN , Antígeno 12E7
20.
Eur J Trauma Emerg Surg ; 49(1): 401-409, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36057677

RESUMEN

PURPOSE: Mobility patterns of western societies have been changing due to ongoing demographic change. Therefore, continuously updated epidemiological data on fracture morphology and treatment strategies are needed. METHODS: This retrospective single-center study included all tibial plateau fractures (TPF) between January 2011 and December 2020 in a level-I trauma center in Central Europe. Epidemiology, trauma mechanism and fracture morphology were analyzed. Age- and sex-specific differences regarding fracture classification (Schatzker, AO/OTA, Moore) and changes during the study period are highlighted. RESULTS: A total of 607 patients (55.2% women, 44.8% men, mean age 52.9 years (± 17.9)) were included in the study, 462 (76.1%) thereof having undergone surgical treatment. Over the decade, an increase in mean age (+ 7.4 years; p = 0.10), incidence (+ 68%; p < 0.05) and low-energy trauma was observed, with the highest peak in elderly women. Within classifications, AO/OTA 41-B3 (24.9%), Schatzker II (26.8%) and Moore V (46.6%) fractures were the most common. CONCLUSION: Incidence (+ 68%), mean age and fractures with signs of knee dislocation of tibial plateau fracture increased over the last decade and low-energy trauma mechanism are more frequent. As the increase in incidence is mainly seen in older women, the comorbidities and need for immediate postoperative full weight-bearing have to be considered in treatment strategies.


Asunto(s)
Fracturas de la Tibia , Fracturas de la Meseta Tibial , Masculino , Humanos , Femenino , Anciano , Persona de Mediana Edad , Niño , Estudios Retrospectivos , Centros Traumatológicos , Fracturas de la Tibia/epidemiología , Fracturas de la Tibia/cirugía , Tomografía Computarizada por Rayos X/efectos adversos
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