Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a ...promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degrader-induced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern drug-induced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.
A new Y-based metal–organic framework (MOF) GR-MOF-6 with a chemical formula of {YL(DMF)2·(DMF)} n {H3L = 5-(4-carboxyphenyl)ethynyl isophthalic acid; DMF = N,N-dimethylformamide} has been prepared ...by a solvothermal route. Structural characterization reveals that this novel material is a three-dimensional MOF in which the coordination of the tritopic ligand to Y(III) metal ions leads to an intercrossing channel system extending over three dimensions. This material has proven to be a very efficient catalyst in the cyanosilylation of carbonyls, ranking second in catalytic activity among the reported rare earth metal-based MOFs described so far but with the lowest required catalyst loading. In addition, its electrophoretic behavior has been studied in depth, providing a zero-charge point between pH 4 and 5, a peak electrophoretic mobility of −1.553 μm cm V–1 s–1, and a ζ potential of −19.8 mV at pH 10.
Degraders hold the promise to efficiently inactivate previously intractable disease‐relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked ...proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS‐10, which shows preferential cytotoxicity against cells pan‐resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS‐10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.
The small molecule RBS‐10 exploits a novel synthetic lethal vulnerability in cancer cells that show widespread resistance to degraders.
The production of the aquaculture industry has increased to be equal to that of the world fisheries in recent years. However, aquaculture production faces threats such as infectious diseases. ...Betanodaviruses induce a neurological disease that affects fish species worldwide and is caused by nervous necrosis virus (NNV). NNV has a nude capsid protecting a bipartite RNA genome that consists of molecules RNA1 and RNA2. Four NNV strains distributed worldwide are discriminated according to sequence homology of the capsid protein encoded by RNA2. Since its first description over 30 years ago, the virus has expanded and reassortant strains have appeared. Preventive treatments prioritize the RGNNV (red-spotted grouper nervous necrosis virus) strain that has the highest optimum temperature for replication and the broadest range of susceptible species. There is strong concern about the spreading of NNV in the mariculture industry through contaminated diet. To surveil natural reservoirs of NNV in the western Mediterranean Sea, we collected invertebrate species in 2015 in the Alboran Sea. We report the detection of the RGNNV strain in two species of cephalopod mollusks (
and
), and in one decapod crustacean (
). According to RNA2 sequences obtained from invertebrate species and reported to date in the Mediterranean Sea, the strain RGNNV is predominant in this semienclosed sea. Neither an ecosystem- nor host-driven distribution of RGNNV were observed in the Mediterranean basin.
We report herein the first lithium anthraquinoid catalyst able to produce polylactide at room temperature starting from both
l
- and
rac
-lactide in the absence of any other initiator. The new ...lithium-based system is selective towards cyclic polymers, having narrow dispersity and weight-average molecular weights ranging from 49.5 to 137.6 kDa. The cyclic structure of the PLA generated from the lithium catalyst has been determined by a combination of
1
H NMR and DRIFT spectroscopy techniques and MALDI-TOF mass spectrometry. DFT calculations point to lithium aggregation as the key feature of the catalyst controlling the linear : cyclic polymer ratio. Molar mass distributions and dispersities were obtained through diffusion NMR experiments combined with inverse Laplace transform algorithms and compared with those obtained by SEC as the most established method.
We present herein the application of a lithium anthraquinoid in the catalytic synthesis of cyclic PLA, showing that the aggregation plays a critical role in cyclic
vs.
linear selectivity.
Abstract
Replication forks often stall at damaged DNA. To overcome these obstructions and complete the DNA duplication in a timely fashion, replication can be restarted downstream of the DNA lesion. ...In mammalian cells, this repriming of replication can be achieved through the activities of primase and polymerase PrimPol. PrimPol is stimulated in DNA synthesis through interaction with PolDIP2, however the exact mechanism of this PolDIP2-dependent stimulation is still unclear. Here, we show that PrimPol uses a flexible loop to interact with the C-terminal ApaG-like domain of PolDIP2, and that this contact is essential for PrimPol's enhanced processivity. PolDIP2 increases primer-template and dNTP binding affinities of PrimPol, which concomitantly enhances its nucleotide incorporation efficiency. This stimulation is dependent on a unique arginine cluster in PolDIP2. Since the polymerase activity of PrimPol alone is very limited, this mechanism, where the affinity for dNTPs gets increased by PolDIP2 binding, might be critical for the in vivo function of PrimPol in tolerating DNA lesions at physiological nucleotide concentrations.
We describe herein the synthesis and characterization of three novel lithium complexes (
2b-d
) bearing different hydrazonyl anthraquinonic backbones, which are tested in the ring-opening ...polymerization (ROP) of lactide and -caprolactone towards the synthesis of cyclic polymers. Various analytical methods, including multinuclear (
1
H,
13
C,
15
N,
7
Li) one- and two-dimensional, homo- and heteronuclear nOe and PGSE diffusion NMR, high-resolution MS spectrometry and FTIR spectroscopy, are used to fully identify the structures of the catalysts. The resulting cyclic polymers were characterized by means of MALDI-TOF, end-group NMR analysis and PGSE diffusion NMR coupled to inverse Laplace algorithms to unravel the weight-average molecular weight and dispersity. In comparison to the previously reported complex (
2a
), a clear difference in selectivity (linear
vs.
cyclic) is observed when using ligand backbones with different coordinative abilities and/or steric restrictions.
New lithium anthraquinoids
2b-d
active in the synthesis of cyclic PLA and cyclic PCL have been synthesized and fully characterized.
Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial ...transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.
Introduction
Electrical cardioversion (ECV) is a frequently used procedure for restoring sinus rhythm in atrial fibrillation (AF); however, the rate of recurrence is high. The identification of ...patients at high risk of recurrence could influence the decision‐making process. The present study evaluates the predictive value of risk scores in atrial fibrillation recurrence after elective electrical cardioversion.
Methods
Unicentric, observational, and prospective study of adult patients who have undergone an elective ECV as rhythm control strategy between July 2017 and September 2022.
Results
From the 283 analyzed patients (mean age 63.95 ± 10.76212, 74.9% male); 99 had paroxysmal AF (35%) and 159 (59%) presented AF recurrence during a follow‐up of 6 months. In patients with post‐ECV AF recurrence, the period of time from diagnosis until the performance of the procedure was longer (393 ± 891 vs. 195 ± 527, p = .02). No paroxysmal AF (71.3% vs. 57.8%, p = .02) and LA dilatation with >40 mL/m2 (35.9% vs. 23.3%, p = .02) volumes were more frequent within these patients. AF recurrence was more frequent in patients who had previous ECV (HR = 1.32; 95% CI: 1.12–2.35; p = .01) and more than 1 shock to recover sinus rhythm (HR = 1.62; 95% CI: 1.07–1.63; p = .01). The SLAC, ALARMEc, ATLAS, and CAAP‐AF scores were statistically significant, although with a moderate predictive capacity for post‐ECV recurrence.
Conclusions
Risk scores analyzed showed a modest value predicting AF recurrence after ECV. Previous ECV, and greater difficulty in restoring SR were independent predictors of recurrence.
The identification of patients at high risk of recurrence could influence the decision‐making process. The risk scores analyzed in the present study showed a modest predictive capacity for AF recurrence after ECV. Time in AF, previous CVE, and a greater difficulty in restoring SR were predictors of recurrence.
Pathogenic microorganisms select for a plethora of defensive mechanisms on their hosts. In males of some species, flashy traits might signal antimicrobial capacity and, thus, they might be favoured ...in scenarios of sexual selection. Antimicrobial capacity of individuals may predict reproductive success in males, and it could be adapted to changing environments. However, evidence for these associations is still scarce in females. Here, we evaluated antimicrobial capacity of spotless starling Sturnus unicolor females during the mating and nestling–provisioning phase. We did this by measuring 1) the blood plasma inhibition capacity against 12 bacterial strains (antagonistic index), 2) the constitutive innate humoral immunity (lysis and agglutination capacity, a non‐specific first barrier of protection of hosts against microbial parasites) and 3) the uropygial gland size and volume of secretion produced, relevant traits in the protection against, among others, feather‐degrading bacteria. We also measured colouration of throat and back feathers, and of leg and beak integuments. This information was collected during the pre‐laying and nestling stages to compare values from these two periods. We found an increase in the plasma antagonistic index from the pre‐laying to the nestling period, while a decrease on the plasma capacity of agglutination of foreign antigens. Both plasma antagonistic index and humoral immune response measured before breeding were positively related to future female reproductive success. In addition, the level of antimicrobial capacity was related to colouration of leg skin and beak integuments and of back feathers. These associations suggest that, similar to males, females might show through their physical appearance their capacity to fight microbial infections; information that could be evaluated by their potential partners and by female competitors.
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