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A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).

The objective of this article is to examine the role of doctors and health professionals in communicating the health impacts of climate change and exploring how achieving climate objectives is co-beneficial to public health objectives. This article identifies the main interpretative frameworks for climate change communication identified in the literature, contextualizes the challenge of climate communication in the field of public health, and analyses the element of trust, without which the communication process is likely to fail. Awareness-raising strategies must therefore create appropriate contexts that allow the public to perceive climate change as a relevant and immediate issue. Further, to be properly considered, such information must be issued from a source the public trusts. After providing a general framework within which to examine the role of doctors and health professionals in climate communication, message content is examined along with trust in message sources and in the medical profession, and the perceptions among and training of medical professionals concerning the climate challenge are considered.The literature reviewed in this article represents the body of climate change communication research related to the role of the doctor, an area of growing interest. This review provides a timely and complete analysis of the literature on the subject with the goal of starting a necessary, but too-long postponed, multidisciplinary dialogue.

Michela Massimi é professora de Filosofia da Ciência no Departamento de Filosofia da Universidade de Edimburgo, onde também é afiliada ao Higgs Centre for Theoretical Physics. Membro de importantes sociedades filosóficas e científicas, como a Royal Society of Edinburgh, a Royal Astronomical Society, e a Académie Internationale de Philosophie des Sciences (membro correspondente) é presidente eleita da PSA, Philosophy of Science Association, para o biênio 2023-2024. Massimi, com dupla nacionalidade, italiana e britânica, estudou na Sapienza Università di Roma, na London School of Economics, e lecionou História e Filosofia da Ciência na University College London antes de mudar-se para Edimburgo. Massimi trabalha com Filosofia da Ciência em uma abordagem marcada pelo recurso à pesquisa histórica. Seus interesses amplos abarcam a Filosofia da Cosmologia, o realismo científico, os estudos de ciências, as relações entre ciência e sociedade, entre outros tópicos. Tem se destacado por defender o que chama de Perspectival Realism, se afastando tanto do realismo tradicional, quanto do pragmatismo e do relativismo. Nessa entrevista dialogamos com Massimi sobre temas como o valor da ciência, a defesa da ciência em épocas de negacionismo e obscurantismo e as características de sua posição filosófica.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the loss of the cognitive functions and dementia. Several scientific evidences report that a central role in the pathogenesis of AD is played by the brain deposition of insoluble aggregates of β-amyloid protein (Aβ) proteins, thus causing neuronal cell death [1]. For this reason, one of the promising approach is to inhibit the aggregation of Aβ peptides. Because Aβ is self-assembling, one possible strategy to prevent this process is to use short peptide fragments homologous to the full-length wild-type Aβ protein. From this consideration, several short synthetic peptides were designed as beta-sheet breakers (BSB) [2]. In particular, the pentapetide Ac-LPFFD-NH2 (iAβ5p) exhibited a certain capability to inhibit Aβ fibrillogenesis [3]. iAβ5p analogs [4] were, then, designed by introducing N-Methylation at the amide bond nitrogen were also promising BSB. Here, we describe the methodological approach, which combines 3D GRID-based pharmacophore peptide screening with Well-Tempered Metadynamics simulations aimed to the discovery of novel N-Methylated BSB. This approach led us to identify two promising, cell permeable, N-Methylated peptides that were further evaluated for their BSB properties showing a significant improvement of the fibrillogenesis inhibition with respect to the lead iAβ5p.

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

The CHKB gene encodes choline kinase β, which catalyzes the first step in the biosynthetic pathway for the major phospholipid phosphatidylcholine. Homozygous loss-of-function variants in human CHKB are associated with a congenital muscular dystrophy. Dilated cardiomyopathy is present in some CHKB patients and can cause heart failure and death. Mechanisms underlying a cardiac phenotype due to decreased CHKB levels are not well characterized. We determined that there is cardiac hypertrophy in Chkb

Un semiconduttore bidimensionale puo accendere e spegnere un fascio di luce in un trilionesimo di secondo. Potrebbe essere usato per la trasmissione di dati ad alta velocita. Un semiconduttore bidimensionale puo accendere e spegnere un fascio di luce in un trilionesimo di secondo. Potrebbe essere usato per la trasmissione di dati ad alta velocita.

A two-dimensional semiconductor can be used to switch a beam of light on and off in only trillionth of a second. It could be used for high-speed transmission of data. A two-dimensional semiconductor can be used to switch a beam of light on and off in only trillionth of a second. It could be used for high-speed transmission of data.

A study finds that more than 40 per cent of fish that live around reefs would be threatened by rising water temperatures. A study finds that more than 40 per cent of fish that live around reefs would be threatened by rising water temperatures.

Uno studio mostra che piu del 40% delle specie di pesci che vivono intorno alle barriere coralline sarebbero minacciate dall'aumento della temperatura dei mari. Uno studio mostra che piu del 40% delle specie di pesci che vivono intorno alle barriere coralline sarebbero minacciate dall'aumento della temperatura dei mari.

Uno studio sui topi mostra che farmaci e dispositivi meccatronici possono essere combinati per aiutare il recupero dei movimenti dopo un ictus Uno studio sui topi mostra che farmaci e dispositivi meccatronici possono essere combinati per aiutare il recupero dei movimenti dopo un ictus

A study on mice shows that drugs and mechatronic devices could be combined to regain movement after a stroke A study on mice shows that drugs and mechatronic devices could be combined to regain movement after a stroke

CHKB encodes one of two mammalian choline kinase enzymes that catalyze the first step in the synthesis of the major membrane phospholipid, phosphatidylcholine (PC). In humans, inactivation of the CHKB gene causes a recessive form of a rostral-to-caudal congenital muscular dystrophy. Using Chkb knockout mice, we reveal that at no stage of the disease is PC level significantly altered. Instead, at early stages of the disease the level of mitochondrial specific lipids acylcarnitine (AcCa) and cardiolipin (CL) increase 15-fold and 10-fold, respectively. Importantly, these changes are only observed in affected muscle and contribute to the decrease in the skeletal muscle functional output in these mice. As the disease progresses, AcCa and CL levels normalize and there is a 12-fold increase in the neutral storage lipid triacylgycerol and a 3-fold increase in its upstream lipid diacylglycerol. Our findings indicate that the major changes in lipid metabolism upon loss of function of Chkb is not a change in PC level, but instead is an initial inability to utilize fatty acids for energy resulting in shunting of fatty acids into triacyglycerol.