Įtampa tarp neįsivaizduojamų alternatyvų problemos ir episteminio instrumentalizmo

In this paper, I develop a critical assessment of epistemic instrumentalism as advocated by Kyle Stanford (2006). Epistemic instrumentalism is based on the claim that the criterion for the reliability of any theory is the absence of what Stanford calls ‘unconceived alternatives’. This means that the theory is reliable if and only if it does not admit of alternatives. Since most scientific theories do admit of unconceived alternatives, Stanford claims, they cannot be reliable. In contrast, ‘common sense’ claims are not exposed to unconceived alternatives, therefore they are reliable. Here, I analyse the definition of ‘common sense’ and argue that it is equally vulnerable to the ‘problem of unconceived alternatives’, pushing epistemic instrumentalism position to scepticism. The consequence is that the position of epistemic instrumentalist has nothing to stand on.Straipsnyje analizuojamas kritinis episteminio instrumentalizmo vertinimas, kurį išplėtojo Kyle’as Stanfordas (2006). Episteminis instrumentalizmas grindžiamas teiginiu, kad bet kurios teorijos patikimumo kriterijus yra nebuvimas to, ką Stanfordas vadina „neįsivaizduojamomis alternatyvomis“. Tai reiškia, kad teorija yra patikima tada ir tik tada, kai ji neleidžia alternatyvų. Pasak Stanfordo, kadangi dauguma mokslinių teorijų pripažįsta neįsivaizduojamas alternatyvas, jos negali būti patikimos; o „sveiko proto“ teiginiai, priešingai, esą patikimi, kadangi jiems nesiūlomos neįsivaizduojamos alternatyvos. Straipsnyje analizuojamas „sveiko proto“ apibrėžimas ir teigiama, kad jis yra lygiai taip pat pažeidžiamas „neįsivaizduojamų alternatyvų problemos“, o episteminio instrumentalizmo pozicija stumiama į skepticizmo glėbį. Autorė teigia, kad episteminio instrumentalisto pozicija neturi į ką atsiremti

Functional characterization of orbicularis oculi and extraocular muscles

The orbicularis oculi are the sphincter muscles of the eyelids and are involved in modulating facial expression. They differ from both limb and extraocular muscles (EOMs) in their histology and biochemistry. Weakness of the orbicularis oculi muscles is a feature of neuromuscular disorders affecting the neuromuscular junction, and weakness of facial muscles and ptosis have also been described in patients with mutations in the ryanodine receptor gene. Here, we investigate human orbicularis oculi muscles and find that they are functionally more similar to quadriceps than to EOMs in terms of excitation-contraction coupling components. In particular, they do not express the cardiac isoform of the dihydropyridine receptor, which we find to be highly expressed in EOMs where it is likely responsible for the large depolarization-induced calcium influx. We further show that human orbicularis oculi and EOMs express high levels of utrophin and low levels of dystrophin, whereas quadriceps express dystrophin and low levels of utrophin. The results of this study highlight the notion that myotubes obtained by explanting satellite cells from different muscles are not functionally identical and retain the physiological characteristics of their muscle of origin. Furthermore, our results indicate that sparing of facial and EOMs in patients with Duchenne muscular dystrophy is the result of the higher levels of utrophin expression

B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. The underlying feature of MH is a hypersensitivity of the calcium release machinery of the sarcoplasmic reticulum, and in many cases this is a result of point mutations in the skeletal muscle ryanodine receptor calcium release channel (RYR1). RYR1 is mainly expressed in skeletal muscle, but a recent report demonstrated the existence of this isoform in human B-lymphocytes. As B-cells can produce a number of cytokines, including endogenous pyrogens, we investigated whether some of the symptoms seen during MH could be related to the involvement of the immune system. Our results show that (i) Epstein-Barr virus-immortalized B-cells from MH-susceptible individuals carrying the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-chloro-m-cresol and (ii) their peripheral blood leukocytes produce more interleukin (IL)-1beta after treatment with the RYR activators caffeine and 4-chloro-m-cresol, compared with cells from healthy controls. Our result demonstrate that RYR1-mediated calcium signaling is involved in release of IL-1beta from B-lymphocytes and suggest that some of the symptoms seen during an MH episode may be due to IL-1beta production

Impatto di COVID-19 sulla relazione uomo-animale: indagine sierologica per la ricerca di anticorpi contro SARS-CoV-2 in furetti italiani

La recente pandemia di Coronavirus disease 19 (COVID-19) ha avuto un impatto enorme sulla salute umana e, fin dai primi mesi, positività al severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) sono state individuate anche tra gli animali. Come riportato in diversi paesi, numerose specie animali sono risultate suscettibili all’infezione, sia naturale che sperimentale e, tra queste, spiccano in modo particolare furetti e visoni. I furetti, già impiegati come modello animale nello studio di numerose patologie respiratorie dell’uomo, appaiono estremamente suscettibili all’infezione sperimentale da parte di SARS-CoV-2, mentre numerosi allevamenti di visoni sono stati duramente colpiti dall’infezione trasmessa dagli addetti ai lavori, con alcuni casi di successiva trasmissione del virus dagli animali all’uomo. Questi riscontri hanno costretto vari paesi a procedere con l’abbattimento degli animali negli allevamenti presenti sul territorio. In letteratura sono tuttavia disponibili informazioni ancora preliminari riguardo alla suscettibilità degli animali domestici a SARS-CoV-2 in ambiente naturale; le indagini svolte sulla specie furetto contano attualmente numeri irrisori e nessuno studio è stato ancora condotto per valutare la circolazione del virus in questa specie, in Italia. Durante il presente progetto di tesi, è stata ricercata la presenza di anticorpi contro SARS-CoV-2 in campioni di siero prelevati da furetti portati a visita presso ambulatori specialistici. I campioni sono stati testati con metodica ELISA e di sieroneutralizzazione, per conferma diagnostica e i risultati sono stati interpretati alla luce dei dati anamnestici relativi alla possibile esposizione a COVID-19 del nucleo familiare di provenienza dell’animale, raccolti attraverso un apposito questionario. Tutti i campioni sono risultati negativi, un dato in contrasto con l’ipotesi iniziale, avanzata in seguito agli studi sperimentali, che il furetto sia un animale estremamente suscettibile a SARS-CoV-2. Questo studio preliminare rappresenta la prima indagine sierologica sulla circolazione di SARS-CoV-2 in furetti italiani, sarà perciò interessante mettere in atto un campionamento strutturato, che possa contare su ampi numeri di animali e fornire risultati più solidi. In questo modo, sarà possibile acquisire dati che permettano di comprendere in modo approfondito l’interazione tra il virus, l’uomo e gli animali da compagnia, per controllare o ridurre il rischio che questa patologia rappresenta per una delle specie apparentemente più suscettibili tra i nostri “pets”

Role of the JP45-Calsequestrin Complex on Calcium Entry in Slow Twitch Skeletal Muscles

We exploited a variety of mouse models to assess the roles of JP45-CASQ1 (CASQ, calsequestrin) and JP45-CASQ2 on calcium entry in slow twitch muscles. In flexor digitorum brevis (FDB) fibers isolated from JP45-CASQ1-CASQ2 triple KO mice, calcium transients induced by tetanic stimulation rely on calcium entry via La3+- and nifedipine-sensitive calcium channels. The comparison of excitation-coupled calcium entry (ECCE) between FDB fibers from WT, JP45KO, CASQ1KO, CASQ2KO, JP45-CASQ1 double KO, JP45-CASQ2 double KO, and JP45-CASQ1-CASQ2 triple KO shows that ECCE enhancement requires ablation of both CASQs and JP45. Calcium entry activated by ablation of both JP45-CASQ1 and JP45-CASQ2 complexes supports tetanic force development in slow twitch soleus muscles. In addition, we show that CASQs interact with JP45 at Ca2+ concentrations similar to those present in the lumen of the sarcoplasmic reticulum at rest, whereas Ca2+ concentrations similar to those present in the SR lumen after depolarization-induced calcium release cause the dissociation of JP45 from CASQs. Our results show that the complex JP45-CASQs is a negative regulator of ECCE and that tetanic force development in slow twitch muscles is supported by the dynamic interaction between JP45 and CASQs

Effect of three anaesthetic techniques on isometric skeletal muscle strength

Background. Our aim was to quantify human involuntary isometric skeletal muscle strength during anaesthesia with propofol, sevoflurane, or spinal anaesthesia using bupivacaine. Methods. Thirty‐three healthy patients undergoing anaesthesia for elective lower limb surgery were investigated. Twenty‐two patients received a general anaesthetic with either propofol (n=12) or sevoflurane (n=10); for the remaining 11 patients spinal anaesthesia with bupivacaine was used. We used a non‐invasive muscle force assessment system before and during anaesthesia to determine the contractile properties of the ankle dorsiflexor muscles after peroneal nerve stimulation (single, double, triple, and quadruple stimulation). We measured peak torques; contraction times; peak rates of torque development and decay; times to peak torque development and decay; half‐relaxation times; torque latencies. Results. Males elicited greater peak torques than females, medians 6.3 vs 4.4 Nm, respectively (P=0.0002, Mann‐Whitney rank‐sum test). During sevoflurane and propofol anaesthesia, muscle strength did not differ from pre‐anaesthetic values. During spinal anaesthesia, torques were diminished for single‐pulse stimulation from 3.5 to 2.0 Nm (P=0.002, Wilcoxon signed rank test), and for double‐pulse from 7.6 to 5.6 Nm (P=0.02). Peak rates of torque development decreased for single‐pulse stimulation from 113 to 53 Nm s-1 and for double pulse from 195 to 105 Nm s-1. Torque latencies were increased during spinal anaesthesia. Conclusions. At clinically relevant concentrations, propofol and sevoflurane did not influence involuntary isometric skeletal muscle strength in adults, whereas spinal anaesthesia reduced strength by about 20%. Muscle strength assessment using a device such as described here provided reliable results and should be considered for use in other scientific investigations to identify potential effects of anaesthetic agents. Br J Anaesth 2004; 92: 367-7

The Corepressor NCoR1 Antagonizes PGC-1α and Estrogen-Related Receptor α in the Regulation of Skeletal Muscle Function and Oxidative Metabolism

Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases

CETICISMO E CRITICISMO: ALICERCES DE UMA FILOSOFIA CONTEMPORÂNEA

O presente artigo procura demonstrar, a partir de uma análise teórica e qualitativa, a diferença existente entre o significado dos conceitos de ceticismo e criticismo que muitas vezes foram empregados de forma inapropriada ao longo da tradição filosófica. O objetivo aqui é tentar desfazer certas confusões causadas pelo mal entendimento de tais concepções e, também, o de revelar o quanto estas duas linhas de pensamento foram responsáveis pelo surgimento da Teoria do Conhecimento (Epistemologia) por meio da reflexão de dois grandes filósofos críticos na história da filosofia. Através de uma investigação bibliográfica e de uma abordagem puramente teórica, este trabalho consiste em apresentar como pano de fundo um paralelo entre o pensamento crítico de Kant e de Wittgenstein a respeito do tema acima exposto. A intenção é de mostrar como as contribuições críticas destes dois grandes pensadores foram importantes no enfrentamento ao discurso cético para fundamentação epistemológica. Enfim, fica demonstrado neste artigo, também, o quanto os pensamentos céticos e críticos alicerçam tanto a Filosofia Contemporânea como a Epistemologia atual

Upstream stimulatory factors are involved in the P1 promoter directed transcription of the AbetaH-J-J locus

<p>Abstract</p> <p>Background</p> <p>Alternative splicing of the locus AβH-J-J generates functionally distinct proteins: the enzyme aspartyl (asparaginyl) β-hydroxylase (AAH), truncated homologs of AAH with a role in calcium homeostasis humbug and junctate and a structural protein of the sarcoplasmic reticulum membranes junctin. AAH and humbug are over expressed in a broad range of malignant neoplasms. We have previously reported that this locus contains two promoters, P1 and P2. While AAH and humbug are expressed in most tissues under the regulation of the P1 promoter, AAH, junctin and junctate are predominantly expressed in excitable tissues under the control of the P2 promoter. We previously demonstrated that Sp transcription factors positively regulate the P1 promoter.</p> <p>Results</p> <p>In the present study, we extended the functional characterization of the P1 promoter of the AβH-J-J locus. We demonstrated by quantitative Real-time RT-PCR that mRNAs from the P1 promoter are actively transcribed in all the human cell lines analysed. To investigate the transcription mechanism we transiently transfected HeLa cells with sequentially deleted reporter constructs containing different regions of the -661/+81 P1 nucleotide sequence. Our results showed that (i) this promoter fragment is a powerful activator of the reporter gene in HeLa cell line, (ii) the region spanning 512 bp upstream of the transcription start site exhibits maximal level of transcriptional activity, (iii) progressive deletions from -512 gradually reduce reporter expression.</p> <p>The region responsible for maximal transcription contains an E-box site; we characterized the molecular interactions between USF1/2 with this E-box element by electrophoretic mobility shift assay and supershift analysis. In addition, our USF1 and USF2 chromatin immunoprecipitation results demonstrate that these transcription factors bind the P1 promoter <it>in vivo</it>.</p> <p>A functional role of USF1/USF2 in upregulating P1-directed transcription was demonstrated by analysis of the effects of (i) <it>in vitro </it>mutagenesis of the P1/E-box binding site, (ii) RNA interference targeting USF1 transcripts.</p> <p>Conclusion</p> <p>Our results suggest that USF factors positively regulate the core of P1 promoter, and, together with our previously data, we can conclude that both Sp and USF DNA interaction and transcription activity are involved in the P1 promoter dependent expression of AAH and humbug.</p