Search

BACKGROUND: Falls are an impactful problem for people with Parkinson's disease (PwPD), impairing the functional capacity and quality of life. Although some predictors of fall risk have been evidenced, the investigation of functional capacity components individual and combined is needed to a more detailed approach to identify fall risk prediction. AIM: To verify the ability of individual and combined functional capacity components in predicting fall risk in PwPD. METHOD: Ninety-six individuals participated in this cohort study. Functional capacity was assessed by Berg Balance Scale, Timed Up and Go, Six-Minute Walk, and Sit-to-Stand tests. The participants who fell at least once during the prospective follow-up of 12 months were considered fallers. A trained evaluator registered the fall’s occurrence weekly. Mann-Whitney U, t-tests, and chi-square tests were used to compare fallers versus non-fallers. Receiver Operating Characteristics curves of functional capacity components (individual and combined) were performed to predict fall risk. RESULTS: Thirty-six (37.5%) PwPD were classified as fallers, being recorded 56 falls, and 60 (62.5%) as non-fallers. There are no differences in functional capacity components between groups. The combined functional capacity components were not able to predict fall risk in PwPD (area under the curve = 0.52; p = 0.77). These components were also unable to predict fall risk when analyzed individually. CONCLUSION: Our results indicated that functional capacity components, individual and combined, are not good predictors of fall risk in PwPD. The multifactorial characteristics of falls and the falls classification might affect the fall risk prediction and should be further investigated.

IntroductionThough in-hospital supplementation of the newborn is associated with decreased breastfeeding success, excessive neonatal weight loss is a medical indication for supplementation. Studies have theorized that maternal fluid intake during labor may impact neonatal weight loss, resulting in unnecessary supplementation. The purpose of this review was to synthesize evidence regarding the relationship between maternal fluid intake during labor and neonatal weight loss.MethodsLiterature searches were conducted in relevant databases using controlled vocabulary. The main findings and outcomes were compared across studies and calculations conducted to report the proportion of studies reporting significant findings.Results11 studies were included in the review. Overall, 7 studies (64%) identified a significant relationship between maternal fluid intake during labor and neonatal weight loss.ConclusionsGiven the risk to the newborn associated with excessive weight loss, it is not prudent to incorporate maternal fluid intake into supplementation guidelines based on existing evidence. Further research is needed before practice recommendations can be made.

The single-stranded RNA genome of SARS-CoV-2 contains some G-quadruplex-forming G-rich elements which are putative drug targets. Here, we performed a ligand-based pharmacophore virtual screening of FDA approved drugs to find candidates targeting such RNA structures. Further in silico and in vitro assays identified three drugs as emerging SARS-CoV-2 RNA G-quadruplex binders.

This thesis analyzes an analysis of the risk perception of Italian paediatricians and parents regarding the impact of climate change on pediatric health. The consequences of climate change are now before our eyes; the recent pandemic has highlighted the impact that the destruction of ecosystems and global warming can have on our health. Fragile subjects will pay the most for the consequences of this crisis: children, the elderly, pregnant women. According to the World Health Organization (WHO), 88% of the disease burden linked to climate change falls on children under the age of 5. Climate change poses a challenge of equity not only between different areas of the world but also between generations: the worst consequences will weigh on those who have not caused damage to the ecosystem. This study began by studying the risk perceptions of the two main caregivers who deal with the child's health: parents and paediatricians. The study analyzed a mixed methods approach, exploiting quantitative and qualitative approaches. Two surveys were carried out in collaboration with the Italian Society of Pediatrics (SIP) and AGE, the Italian Parents' Association, using a tool already consolidated in the literature and adapted according to the needs of the thesis. Sixty semi-structured interviews were then conducted with pediatricians of different age groups and different regions of Italy. The collected data were then compared with the literature on the subject, in order to understand differences and similarities. This work is part of a still rather scarce, but growing, field of literature and represents the first study of this type in Italy.

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out in our previous work for the most potent inhibitor 2-amino-3-chloropyridine amide (TPA14), we have investigated its non-competitive mechanism of action using molecular dynamics, thermodynamic integration and QM-MM/GBSA calculations. The computational studies highlighted the impact of mutations on the receptor binding pockets and elucidated the molecular basis of the non-competitive inhibition mechanism of TPA14, which prevents the endocannabinoid anandamide (AEA) from reaching its pro-active conformation. Our study provides a rationale for the design of non-competitive potent FAAH inhibitors for the treatment of neuropathic pain and chronic inflammation.

Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the parasite Trypanosoma brucei (T.b.). A validated target for the treatment of HAT is the parasitic T.b. cyclic nucleotide phosphodiesterase B1 (TbrPDEB1). Although nanomolar TbrPDEB1 inhibitors have been obtained, their activity against the off-target human PDE4 (hPDE4) is likely to lead to undesirable clinical side effects, such as nausea, emesis, and immune suppression. Thus, new and more selective TbrPDEB1 inhibitors are still needed. This retrospective study evaluated the free energy perturbation (FEP+) method to predict the affinity profiles of TbrPDEB1 inhibitors against hPDE4. We demonstrate that FEP+ can be used to accurately predict the activity profiles of these homologous proteins. Moreover, we show how FEP+ can overcome challenges like protein flexibility and high sequence conservation. This also implies that the method can be applied prospectively for the lead optimization campaigns to design new and more selective TbrPDEB1 inhibitors.

IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

In the last decade, researchers have focused on digital technologies within Industry 4.0. However, it seems the Industry 4.0 hype did not fulfil industry expectations due to many implementation challenges. Today, Industry 5.0 proposes a human-centric approach to implement digital sustainable technologies for smart quality improvement. One important aspect of digital sustainability is reducing the energy consumption of digital technologies. This can be achieved through a variety of means, such as optimizing energy efficiency, and data centres power consumption. Complementing and extending features of Industry 4.0, this research develops a conceptual model to promote Industry 5.0. The aim of the model is to optimize data without losing significant information contained in big data. The model is empowered by edge computing, as the Industry 5.0 enabler, which provides timely, meaningful insights into the system, and the achievement of real-time decision-making. In this way, we aim to optimize data storage and create conditions for further power and processing resource rationalization. Additionally, the proposed model contributes to Industry 5.0 from a social aspect by considering the knowledge, not only of experienced engineers, but also of workers who work on machines. Finally, the industrial application was done through a proof-of-concept using manufacturing data from the process industry, where the amount of data was reduced by 99.73% without losing significant information contained in big data.

This is a descriptive study using a quantitative approach which main objective aimed to assess and determine the entrepreneurial engagement of the grantees of the tertiary education subsidy (TES) in Central Philippines State University. This study specifically determined the demographic profile of respondents as to sex, campus they are enrolled, course/program they are taking, year level, and family source of income, the entrepreneurial engagement of the grantees and their satisfaction of the program. The researchers used both qualitative and quantitative approach in order to connect with the participants and to better understand their entrepreneurial engagement as a challenge in wise spending of their subsidy. Results revealed that in terms of demographic profile, female grantees outnumbered the male, most of those who responded in the survey were coming from the main campus, Cauayan, Hinigaran, Victorias and San Carlos extension campuses, the highest percentage of respondents were taking Bachelor in Elementary Education program and in third year and the source of income of most of them is farming. The respondents who indulge in entrepreneurial engagement mostly opted business enterprise such as sari-sari store, buy and sell and loading business, farm investments such as prenda or arendo and backyard raising such as carabao and hog raising, swine and cow fattening, poultry raising and raising of other backyard animals that are easy to raise. The respondents expressed that they are very satisfied with the Tertiary Education Subsidy program which conforms with the Agenda 21 (2002). Thus, the objective of the TES program is met.

An increasingly comprehension of the folding intermediate states of DNA G-quadruplexes (G4s) is currently an important scientific challenge, especially for the human telomeric (h-tel) G4s-forming sequences, characterized by a highly polymorphic nature. Despite the G-triplex conformation was proposed as one of the possible folding intermediates for the antiparallel and hybrid h-tel G4s, for the parallel h-tel topology with an all-anti guanine orientation, a vertical strand-slippage involving the G-triplets was proposed in previous works through microseconds-long standard molecular dynamics simulations (MDs). Here, in order to get further insights into the vertical strand-slippage and the folding intermediate states of the parallel h-tel G4s, we have carried out a Well-Tempered Metadynamics simulation (WT-MetaD), which allowed us to retrieve an ensemble of six G4s having two/G-tetrad conformations derived by the G-triplets vertical slippage. The insights highlighted in this work are aimed at rationalizing the mechanistic characterisation of the parallel h-tel G4 folding process.

[Image: see text] The design and synthesis of butyl chain derivatives at the indane ring 3-position of our lead CD4-mimetic compound BNM-III-170 that inhibits human immunodeficiency virus (HIV-1) infection are reported. Optimization efforts were guided by crystallographic and computational analysis of the small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120. Biological evaluation of 11–21 revealed that members of this series of CD4-mimetic compounds are able to inhibit HIV-1 viral entry into target cells more potently and with greater breadth compared to BNM-III-170. Crystallographic analysis of the binding pocket of 14, 16, and 17 revealed a novel hydrogen bonding interaction between His105 and a primary hydroxyl group on the butyl side chain. Further optimization of this interaction with the His105 residue holds the promise of more potent CD4-mimetic compounds.

The primary cilium is a microtubule‐based sensory organelle that dynamically links signalling pathways to cell differentiation, growth, and development. Genetic defects of primary cilia are responsible for genetic disorders known as ciliopathies. Orofacial digital type I syndrome (OFDI) is an X‐linked congenital ciliopathy caused by mutations in the OFD1 gene and characterized by malformations of the face, oral cavity, digits and, in the majority of cases, polycystic kidney disease. OFD1 plays a key role in cilium biogenesis. However, the impact of signalling pathways and the role of the ubiquitin‐proteasome system (UPS) in the control of OFD1 stability remain unknown. Here, we identify a novel complex assembled at centrosomes by TBC1D31, including the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1. We show that TBC1D31 is essential for ciliogenesis. Mechanistically, upon G‐protein‐coupled receptor (GPCR)‐cAMP stimulation, PKA phosphorylates OFD1 at ser735, thus promoting OFD1 proteolysis through the praja2‐UPS circuitry. This pathway is essential for ciliogenesis. In addition, a non‐phosphorylatable OFD1 mutant dramatically affects cilium morphology and dynamics. Consistent with a role of the TBC1D31/praja2/OFD1 axis in ciliogenesis, alteration of this molecular network impairs ciliogenesis in vivo in Medaka fish, resulting in developmental defects. Our findings reveal a multifunctional transduction unit at the centrosome that links GPCR signalling to ubiquitylation and proteolysis of the ciliopathy protein OFD1, with important implications on cilium biology and development. Derangement of this control mechanism may underpin human genetic disorders., OFD1 (oro‐facial digital type I syndrome protein) resides in a centrosomal complex that links GPCR signalling to ubiquitylation and degradation of OFD1, controlling cilium morphology and dynamics and vertebrate development.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.

Submitted by Lilian Teresa Gobbi (lilian.gobbi@unesp.br) on 2021-05-20T23:07:36Z No. of bitstreams: 1 Manuscript_accepted.pdf: 2005538 bytes, checksum: a08c00a8a6e0666817369b6853a61115 (MD5) Rejected by Marcia Correa Bueno Degasperi null (mcbueno@rc.unesp.br), reason: Prezado Gabriel, O documento enviado para a coleção Campus Unesp Rio Claro foi recusado pelo(s) seguinte(s) motivo(s): - É necessário o autor indicar o prazo de embargo para o artigo conforme normas da revista. Em consulta ao Sherpa Romeo, verificamos que o embargo para versão postprint é de 12 meses: https://v2.sherpa.ac.uk/id/publication/6992?template=romeo Tutorial para autoarquivamento de artigos preprint, postprint e publicados: https://www2.unesp.br/Home/cgb/tutorial-autoarquivamento-artigos-e-capitulos-de-livro-versao-1.0.pdf Em caso de dúvidas entre em contato pelos e-mails: stati.rc@unesp.br marcia.bueno@unesp.br WhatsApp (19) 3526-9666 Solicitamos que realize uma nova submissão seguindo as orientações destacadas. Agradecemos a compreensão. Atenciosamente, Márcia Correa Bueno Degasperi Biblioteca Campus Rio Claro Repositório Institucional UNESP https://repositorio.unesp.br on 2021-08-23T19:00:22Z (GMT) Submitted by Lilian Teresa Gobbi (lilian.gobbi@unesp.br) on 2021-08-23T20:10:19Z No. of bitstreams: 1 Manuscript_accepted.pdf: 2005538 bytes, checksum: a08c00a8a6e0666817369b6853a61115 (MD5) Approved for entry into archive by Marcia Correa Bueno Degasperi null (mcbueno@rc.unesp.br) on 2021-08-24T13:44:55Z (GMT) No. of bitstreams: 1 moraca_gag_postprint_rcla_center.pdf: 2005538 bytes, checksum: a08c00a8a6e0666817369b6853a61115 (MD5) Made available in DSpace on 2021-08-24T13:44:55Z (GMT). No. of bitstreams: 1 moraca_gag_postprint_rcla_center.pdf: 2005538 bytes, checksum: a08c00a8a6e0666817369b6853a61115 (MD5) Previous issue date: 2022-04-27 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Falls are associated with impairment in postural control in people with Parkinson's disease (PwPD). We aimed to predict the fall risk through models combining postural responses with clinical and cognitive measures. Also, we compared the center of pressure (CoP) between PwPD fallers and non-fallers after unpredictable external perturbations. We expected that CoP parameters combined with clinical and cognitive measures would predict fall risk. Seventy-five individuals participated in the study. CoP parameters were measured during postural responses through five trials with unpredictable translations of the support-surface in posterior direction. Range and peak of CoP were analyzed in two periods: early and late responses. Time to peak (negative peak) and recovery time were analyzed regardless of the periods. Models included the CoP parameters in early (model 1), late responses (model 2), and temporal parameters (model 3). Clinical and cognitive measures were entered into all models. Twenty-nine participants fell at least once, and 46 PwPD did not fall during 12 months following the postural assessment. Range of CoP in late responses was associated with fall risk (p = .046). However, although statistically non-significant, this parameter indicated low accuracy in predicting fall risk (area under the curve = 0.58). Fallers presented a higher range of CoP in early responses than non-fallers (p = .033). In conclusion, although an association was observed between fall risk and range of CoP in late responses, this parameter indicated low accuracy in predicting fall risk in PwPD. Also, fallers demonstrate worse postural control during early responses after external perturbations than non-fallers, measured by CoP parameters. Postprint Institute of Biosciences, Posture and Gait Studies Laboratory (LEPLO), São Paulo State University (Unesp), Rio Claro, Brazil Graduate Program in Movement Sciences, São Paulo State University (Unesp), Rio Claro, Brazil Center for Human Movement Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Neurology, Oregon Health & Science University, Portland, OR, USA FAPESP: 16/00503-0. FAPESP: 19/01203-9. CNPq: 429549/2018-0. CNPq: 309045/2017-7. CAPES: 001

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

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).

In mammalian cells, telomerase transcribes telomeres in large G-rich non-coding RNA, known as telomeric repeat-containing RNA (TERRA), which folds into noncanonical nucleic acid secondary structures called G-quadruplexes (G4s). Since TERRA G4 has been shown to be involved in telomere length and translation regulation, it could provide valuable insight into fundamental biological processes, such as cancer growth, and TERRA G4 binders could represent an innovative strategy for cancer treatment. In this work, the three best candidates identified in our previous virtual screening campaign on bimolecular DNA/RNA G4s were investigated on the monomolecular Tel DNA and TERRA G4s by means of molecular modelling simulations and in vitro and in cell analysis. The results obtained in this work highlighted the stabilizing power of all the three candidates on TERRA G4. In particular, the two compounds characterized by a chromene scaffold were selective TERRA G4 binders, while the compound with a naphthyridine core acted as a dual Tel/TERRA G4-binder. A biophysical investigation by circular dichroism confirmed the relative stabilization efficiency of the compounds towards TERRA and Tel G4s. The TERRA G4 stabilizing hits showed good antiproliferative activity against colorectal and lung adenocarcinoma cell lines. Lead optimization to increase TERRA G4 stabilization may provide new powerful tools against cancer.

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.