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61.
Aladr D. Rnaszki Bettina K. Budai Barbara Csongrdy Rbert Stollmayer Krisztina Hagymsi Klra Werling Tams Fodor Anik Folhoffer Ildik Kalina Gabriella Gyri Pl Maurovich-Horvat Pl N. Kaposi 《Medicine》2022,101(33)
We aimed to assess the feasibility of ultrasound-based tissue attenuation imaging (TAI) and tissue scatter distribution imaging (TSI) for quantification of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We prospectively enrolled 101 participants with suspected NAFLD. The TAI and TSI measurements of the liver were performed with a Samsung RS85 Prestige ultrasound system. Based on the magnetic resonance imaging proton density fat fraction (MRI-PDFF), patients were divided into ≤5%, 5–10%, and ≥10% of MRI-PDFF groups. We determined the correlation between TAI, TSI, and MRI-PDFF and used multiple linear regression analysis to identify any association with clinical variables. The diagnostic performance of TAI, TSI was determined based on the area under the receiver operating characteristic curve (AUC). The intraclass correlation coefficient (ICC) was calculated to assess interobserver reliability.Both TAI (rs = 0.78, P < .001) and TSI (rs = 0.68, P < .001) showed significant correlation with MRI-PDFF. TAI overperformed TSI in the detection of both ≥5% MRI-PDFF (AUC = 0.89 vs 0.87) and ≥10% (AUC = 0.93 vs 0.86). MRI-PDFF proved to be an independent predictor of TAI (β = 1.03; P < .001), while both MRI-PDFF (β = 50.9; P < .001) and liver stiffness (β = −0.86; P < .001) were independent predictors of TSI. Interobserver analysis showed excellent reproducibility of TAI (ICC = 0.95) and moderate reproducibility of TSI (ICC = 0.73).TAI and TSI could be used successfully to diagnose and estimate the severity of hepatic steatosis in routine clinical practice. 相似文献
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Caterina Squarci Pasquale Bianco Massimo Reconditi Irene Pertici Marco Caremani Theyencheri Narayanan dm I. Horvth Andrs Mlnsi-Csizmadia Marco Linari Vincenzo Lombardi Gabriella Piazzesi 《Proceedings of the National Academy of Sciences of the United States of America》2023,120(9)
Titin is a molecular spring in parallel with myosin motors in each muscle half-sarcomere, responsible for passive force development at sarcomere length (SL) above the physiological range (>2.7 μm). The role of titin at physiological SL is unclear and is investigated here in single intact muscle cells of the frog (Rana esculenta), by combining half-sarcomere mechanics and synchrotron X-ray diffraction in the presence of 20 μM para-nitro-blebbistatin, which abolishes the activity of myosin motors and maintains them in the resting state even during activation of the cell by electrical stimulation. We show that, during cell activation at physiological SL, titin in the I-band switches from an SL-dependent extensible spring (OFF-state) to an SL-independent rectifier (ON-state) that allows free shortening while resisting stretch with an effective stiffness of ~3 pN nm−1 per half-thick filament. In this way, I-band titin efficiently transmits any load increase to the myosin filament in the A-band. Small-angle X-ray diffraction signals reveal that, with I-band titin ON, the periodic interactions of A-band titin with myosin motors alter their resting disposition in a load-dependent manner, biasing the azimuthal orientation of the motors toward actin. This work sets the stage for future investigations on scaffold and mechanosensing-based signaling functions of titin in health and disease.Contraction of the striated muscle is powered by the cyclical adenosine triphosphate (ATP)-fueled interactions of the motor protein myosin II, arranged in two bipolar arrays on thick filaments originating at the midpoint of each sarcomere (M-line), with the nearby thin, actin-containing filaments originating at the sarcomere extremities (Z-line, Fig. 1A). In the half-sarcomere, myosin motors are mechanically coupled as parallel force generators and the collective force depends on the number of motors available for actin attachment and thus on the degree of overlap between thick and thin filaments (Fig. 1B, black circles; ref. 1). The half-sarcomere is the basic functional unit in which the emergent properties from the arrays of myosin motors, the interdigitating thin filaments, and a “third” filament made by the cytoskeleton protein titin (Fig. 1C) account for the mechanical performance of muscle and its regulation.Open in a separate windowFig. 1.Structure–function of myofilaments and titin in relation to the length of the sarcomere. (A) Overview of the thick filament (blue), myosin motors (orange), and thin filament (yellow) at SL 2.2 μm (full overlap) and 3.0 μm (partial overlap). (B) Relation between SL and either active force at the plateau of the isometric tetanic contraction (black circles, linear fit to points at SL >2.2 μm, continuous line) or passive force (triangles, fitted with an exponential equation (red dashed line) and with the model (red circles) described in SI Appendix, Supporting Note 1 and Fig. S1). Data from ref. 2. (C) Protein disposition on the thin (yellow) and thick (light blue) filaments in the half-sarcomere at rest at 2.2 μm SL. M-line on the right and Z-line on the left. Inset: Overlap region on an enlarged scale to show with better resolution the ~38 nm axial periodicity of the troponin complex (gray) along the thin filament and the two motor domains (orange) of each myosin molecule tilted back on their tail (blue) in the OFF state (3, 4). The 49 crowns of motors are numbered starting from the M-line; thin filament with tropomyosin (brown) and troponin complex (gray); MyBP-C (green) aligned with myosin triplets from crowns 12 to 30. Titin (magenta) with PEVK segment identified by dark magenta. HBZ, half-bare zone. P-, C-, and D-zones, proximal, MyBP-C containing and distal zones. Only two of the six titin molecules and only one of the three series of MyBP-C molecules per htf are represented for clarity. (D) Straightening of the proximal tandem Ig segment by passive stretch to 3.0 μm SL.Titin is a giant protein (up to 4 MDa) that spans the half-sarcomere (Fig. 1C, magenta), first through the I-band, connecting the Z-line with the tip of the thick filament, and then through the A-band, associated with the thick filament (six molecules per thick filament; refs. 5, 6) up to the M-line at the center of the sarcomere (7–9). The titin I-band region acts as a spring able to transmit the stress also when no myosin motors are attached to actin. In the muscle fiber of the frog, in which there is no contribution from extracellular matrix components (10, 11), titin is responsible for the passive force when the muscle cell is stretched at rest (Fig. 1B, triangles; refs. 12–16). Within the I-band titin, the distal tandem immunoglobulin-like segment forms a stiff end-filament composed of the six titin molecules attaching to the tip of the thick filament (17, 18), while the other two segments account for titin extensibility: the proximal tandem Ig segment (hereinafter called tandem Ig segment) and the unique sequence rich in proline (P), glutamate (E), valine (V), and lysine (K) residues (PEVK segment). Both spring-like segments exhibit variable muscle-type specific lengths (7, 19), which account for the differences in passive force–sarcomere length (SL) relations (20). In situ studies using immunofluorescence and immunoelectron microscopy on skinned fibers and myofibrils from mammalian skeletal muscle demonstrated that the large extensibility of the muscle sarcomere at SL < 2.7 μm is enabled by straightening out of randomly bent elements of the tandem Ig segment. At longer SL, at which the tandem Ig segment approaches its contour length, the passive force increases more steeply, reflecting the PEVK segment stiffness (SI Appendix, Supporting Note 1 and Fig. S1; see refs. 21–25).Titin in the A-band is composed of Ig and fibronectin (Fn) domains each ~4 nm long, with two distinct domain superrepeats: 11 “C-type” superrepeats, each composed of 11 Ig-Fn domains, extending from about layer 3 to 37 of the myosin crowns, and 6 “D-type” superrepeats, each composed of seven Ig-Fn domains, extending from about layer 38 to the filament tip (Fig. 1C; refs. 7, 26–28). The A-band region of titin is made inextensible by its association to the other proteins in the thick filament, myosin, and the Myosin Binding Protein C (MyBP-C), an accessory protein that is bound with its C terminus to the central one-third of the half-thick filament (htf) (C-zone, from layer 12 to 30, Fig. 1C) and extends from the thick filament backbone to establish dynamic interactions with the thin filament (2, 29–31) with its N terminus.I-band titin transmits any pulling force exerted on the extremity of the half-sarcomere to the tip of the thick filament and in this way could play a role in thick filament mechanosensing that switches myosin motors ON (3, 32). Moreover, as an elastic element in parallel with motors, I-band titin could preserve the homogeneity of sarcomeres during contraction, by preventing the lengthening of weak half-sarcomeres. However, titin-dependent passive force typically rises steeply only at SL > 2.6 µm (Fig. 1B; refs. 2, 10, 11, 22, 24, 33), and thus I-band titin stiffness is too low for the above functions at physiological SL, unless it gets much larger during contraction.The mechanical definition of the I-band titin in situ in the active half-sarcomere is hampered by the presence of the in-parallel array of myosin motors with a stiffness that is more than one order of magnitude larger than titin stiffness (34). Here, we use para-nitro-blebbistatin (PNB; ref. 35) to inhibit actin–myosin interaction during tetanic stimulation of a frog muscle cell. In addition, 20 μM PNB suppresses in vitro actin-triggered ATPase activity of frog muscle myosin S1 and heavy meromyosin (HMM) (SI Appendix, Materials and Methods and Fig. S2 A and B) and the mechanical response of the muscle cell to tetanic stimulation (SI Appendix, Fig. S2 C–E), maintaining the motors in the OFF-state conformation, in which they lie tilted back on the surface of the thick filament (Fig. 1C and SI Appendix, Fig. S3) (4, 36). Previous studies noted that blebbistatin does not fully suppress the mechanical response and maintain the motor OFF-state upon Ca2+ activation in skinned rabbit psoas fibers (32, 37). This is likely a consequence of either the lower inhibitory power of blebbistatin as compared to PNB (SI Appendix, Fig. S2 A and B) or intrinsic limits of skinned preparations to fully preserve the motor OFF-structure (27, 38).Here, we used sarcomere-level mechanics and small-angle X-ray fiber diffraction to determine the titin-dependent mechanical and structural responses to a stepwise increase in load imposed on the muscle cell under PNB-inhibitory conditions. Length changes in units of nanometer per half-sarcomere (hereinafter referred to as nm) were measured with a striation follower in a population of ~500 sarcomeres. We discovered that upon stimulation at physiological SL, titin in the I-band switches from the OFF-state characterized by large extensibility to the ON-state in which it exhibits rectifying properties, allowing free shortening, while opposing stretching with a viscosity coefficient three orders of magnitude larger that underpins an effective stiffness of 3 pN nm−1. With the I-band titin in the ON-state, the periodic interactions between A-band titin and myosin motors are able to activate the thick filament by perturbing the resting disposition of motors on the surface of the thick filament in a load-dependent manner and biasing them toward the sixfold rotational symmetry of the thin filaments in the myofilament lattice. 相似文献
65.
Christophe Moderie Nicolas Nuez Allan Fielding Stefano Comai Gabriella Gobbi 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2022,25(6):479
BackgroundWomen are nearly twice as likely as men to suffer from major depressive disorder. Yet, there is a dearth of studies comparing the clinical outcomes of women and men with treatment-resistant depression (TRD) treated with similar augmentation strategies. We aimed to evaluate the effects of the augmentation strategies in women and men at the McGill University Health Center.MethodsWe reviewed health records of 76 patients (42 women, 34 men) with TRD, treated with augmentation strategies including antidepressants (AD) with mood stabilizers (AD+MS), antipsychotics (AD+AP), or in combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery-Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology (QIDS-C16), and Clinical Global Impression rating scale (CGI-S) at the beginning and after 3 months of an unchanged treatment. Changes in individual items of the HAMD-17 were also compared between the groups.ResultsWomen and men improved from beginning to 3 months on all scales (P < .001, η p2 ≥ 0.68). There was also a significant sex × time interaction for all scales (P < .05, η p2 ≥ 0.06), reflecting a greater improvement in women compared with men. Specifically, women exhibited greater improvement in early (P = .03, η p2 = 0.08) and middle-of-the-night insomnia (P = .01, η p2 = 0.09) as well as psychomotor retardation (P < .001 η p2 = 0.16) and psychic (P = .02, η p2 = 0.07) and somatic anxiety (P = .01, η p2 = 0.10).ConclusionsThe combination of AD+AP/MS generates a significantly greater clinical response in women compared with men with TRD, supporting the existence of distinct pharmacological profiles between sexes in our sample. Moreover, they emphasize the benefit of augmentation strategies in women, underscoring the benefit of addressing symptoms such as insomnia and anxiety with AP and MS. 相似文献
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Simone Perna Clara Gasparri Cinzia Ferraris Gaetan Claude Barrile Alessandro Cavioni Francesca Mansueto Zaira Patelli Gabriella Peroni Alice Tartara Marco Zese Mariangela Rondanelli 《Nutrients》2022,14(12)
Background: SARC-F is a simple sarcopenia screening tool. This study aimed to examine the validity of the Italian version of SARC-F. Methods: A total of 97 elderly individuals (37/60 males/females, 65 years and older) who met the study’s selection criteria were included. SARC-F was translated into the Italian language in a culturally responsive manner. The total score was calculated by adding the scores on the five items. The participants were divided into two groups according to the total score (SARC-F < 4 vs. SARC-F ≥ 4), and their associations with various factors (handgrip test, chair stand test, and Skeletal Muscle Index assessed by DXA) have been examined by gender. In addition, the tool’s validity was analyzed by comparing it with different international working group diagnostic criteria for sarcopenia. Results: The total prevalence of sarcopenia according to the SARC-F was 14.2% and, specifically, 12.8% among men and 14.3% in women. The sensitivity of the SARC-F was (male (M): 11–50% and female (F): 22–36%) medium-low compared with the European, international, and Asian criteria of sarcopenia; however, SARC-F showed a high specificity (M: 77.3–100% and F: 79.5–100%) and a moderate Cronbach’s alpha coefficient of (0.669 (CI95%: 0.358–0.830). The participants in the SARC-F ≥ 4 group had poorer handgrip for EWGSOP2 (p < 0.001) and chair stand (p < 0.001) than the participants in the SARC-F < 4 group. Conclusions: The Italian language version of SARC-F showed high specificity, moderate reliability, and good associations with other predictive tests. The Italian version of SARC-F appears to be a useful screening tool for the diagnosis of sarcopenia in Italian elderly populations. 相似文献
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Gabriella de M. Abreu Roberta M. Tarantino Ana Carolina P. da Fonseca Ritiele B. de Souza Camila A.P.D. Soares Pedro H. Cabello Melanie Rodacki Lenita Zajdenverg Verônica M. Zembrzuski Mário Campos Junior 《European journal of medical genetics》2021,64(5):104194
Maturity-Onset Diabetes of the Young type 4 is a rare form of diabetes mellitus, caused by mutations in the PDX1 gene. However, only a few mutations in this gene have been associated as a cause of monogenic diabetes up to date. It makes difficult to create a clinical manifestation profile of this disease and, consequently, to improve the therapeutic management for these patients. Here we report a normal weight woman, diagnosed with diabetes mellitus at 27 years old, during her first pregnancy. At the time of the recruitment, she was 40 years old and had a body mass index of 23.9 kg/m2, glycated hemoglobin level of 9.6%, and fasting plasma glucose (FPG) of 254 mg/dL. She presented no diabetic complications and she was being treated with insulin. She reported a family history of diabetes mellitus characteristic of an autosomal dominant mode of inheritance. Molecular analysis of the PDX1 gene revealed the missense variant c.532G > A (p.(Glu178Lys)) segregating from the patient to her son, reported as diabetic. It was absent in her healthy daughter. The c.532G > A seems to be a rare variant, absent in human variants databases, and among 86 normoglycemic controls. Eight in silico algorithms classified this variant as probably pathogenic. Additionally, analysis of the evolutionary conservation showed the glutamic acid in the position 178 of PDX-1 protein as conserved among several species. Our findings reinforce the importance of screening rare MODY genes among families with suspicion of monogenic diabetes to help better understand the clinical manifestations of this disease. 相似文献
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Behrens Frank Leage Soyi Liu Sapin Christophe El Baou Celine De La Torre Inmaculada Meszaros Gabriella Schett Georg Combe Bernard van den Bosch Filip Gossec Laure 《Clinical rheumatology》2021,40(12):4955-4956
Clinical Rheumatology - 相似文献
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