On Lyndon\u27s Equation in Some Lambda-Free Groups and HNN Extensions

In this paper we study Lyndon\u27s equation x(p)y(q)z(r) = 1, with x, y, z group elements and p, q, r positive integers, in HNN extensions of free and fully residually free groups, and draw some conclusions about its behavior in A-free groups

Regulation of mTORC1 by phosphatidic acid: mechanism and structural insight

The mammalian target of rapamycin (mTOR) is a Ser/Thr kinase with remarkable control over cellular status. As a master regulator, mTOR integrates a variety of intra- and extra-cellular signals in order to coordinate them with appropriate gene expression, protein synthesis, metabolism, cell migration, autophagy – the list goes on! mTOR signaling, with involvement in so many important cellular processes, can have detrimental physiological effects when dysregulated. Aberrant mTOR signaling is now known to contribute to a great number of the major pathologies we face today. Understanding how mTOR is normally regulated is, therefore, important for informing the development of effective and specific therapeutics for diseases like cancer and diabetes. Significant research efforts over the last two decades have informed our current understanding of the extensive mTOR signaling pathways, but many questions remain. In my dissertation work I have investigated longstanding mysteries of mTOR activation by mitogens and nutrients, with specific focus on the mechanism by which the lipid second messenger, phosphatidic acid, activates mTOR complex 1. The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. In collaboration with Dr. Mee Sup Yoon, I discovered that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation. We demonstrated that this mitogen stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and is recapitulated with the addition of the PLD product phosphatidic acid (PA). Parallel mass spectrometry analysis independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, I found that only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings, detailed in Chapter II reveal a mechanism of acute mTORC1 regulation that was previously unidentified and provide a molecular explanation for the exquisite specificity of PA function. In light of PA’s essential role in mTORC1 activation, I found it striking that mTOR proteins containing one of several point mutations have been reported to remain catalytically active in conditions when amino acids, and therefore PA, are absent. The existence of such hyperactive mTOR prompted me to ask whether a point mutation can render mTOR independent of regulation by PA and, if so, by what mechanism? In Chapter III, I describe how by examining the activity of several mTOR proteins each carrying a unique point mutation known to be associated with human cancer, I discovered that individual point mutations can confer varying degrees of PA-independent mTORC1 activity. My finding that an L1460P mutation in mTOR's FAT domain, S2215Y mutation in the kinase N-lobe, and E2419K in the kinase C-lobe all confer some mTORC1 activity in the absence of PA suggests that it is possible for PA-independent mTORC1 activity to result by more than one mechanism. Having identified that the activity of S2215Y mTOR is especially independent of PA and noting the implications of S2215Y for mTORC1’s structure, I propose that control of catalytic cleft access is a major aspect of mTORC1 activation by PA. My investigation also produced striking evidence that mTOR autophosphorylation, which is significantly hyperactivated by the R2505P mutation, does not necessarily correlate with PA-mediated mTORC1 phosphorylation of canonical substrates. Taken together, the experiments detailed in this chapter provide insight into the mechanism of mTORC1 activation by PA and carry significant therapeutic implications. Lastly, in Appendix A, I document several of my preliminary investigations of localization-dependent regulation of mTOR signaling. I have observed that both mTOR and raptor have a nuclear presence and that the proteins can localize there independently of each other. Additionally, I present evidence that nuclear mTORC1 phosphorylates the transcriptional repressor, Maf1, in a manner independent of the canonical mTORC1 pathway. Finally, I report for the first time that unsaturated PA species appear to recruit mTORC2 to detergent-sensitive cellular regions that I believe may be mitochondria-associated membranes

Evaluation of the influence of texture and microstructure of titanium substrates on TiO2 anodic coatings at 60 V

The current paper analyzes the influence of texture and microstructure of Ti substrates on morphology and color of titanium dioxide coatings obtained by anodic oxidation. Substrates of Ti grade 2 and Ti grade 5 with different thermo-mechanical histories were used in the shape of cylindrical bars cut in both longitudinal and transversal directions, and laminated sheets. The crystalline orientation of the surface grains in the substrate before oxidation, were determined by electron backscatter diffraction. The oxide coatings were analyzed by optical and scanning electron microscopy. The results show that different substrate grain orientations produce oxides with different colors, because of different thickness depending on their orientations. An oxide grown on a basal hcp plane, with higher atomic density is thinner than an oxide grown on a transversal hcp plane with lower atomic density. This effect is more pronounced on elongated grains. Different anodic oxidation process parameters and heat treatments of the substrate were applied in order to obtain a more uniform oxide thickness. A specific heat treatment of the substrate was the most efficient, starting from a favorable orientation of crystals, characteristic of rolling texture.Fil: Vera, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Materiales de Misiones. Universidad Nacional de Misiones. Facultad de Ciencias Exactas Químicas y Naturales. Instituto de Materiales de Misiones; ArgentinaFil: Avalos, Martina Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Rosenberger, Mario Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Materiales de Misiones. Universidad Nacional de Misiones. Facultad de Ciencias Exactas Químicas y Naturales. Instituto de Materiales de Misiones; ArgentinaFil: Bolmaro, Raul Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Schvezov, Carlos Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Materiales de Misiones. Universidad Nacional de Misiones. Facultad de Ciencias Exactas Químicas y Naturales. Instituto de Materiales de Misiones; ArgentinaFil: Ares, Alicia Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Materiales de Misiones. Universidad Nacional de Misiones. Facultad de Ciencias Exactas Químicas y Naturales. Instituto de Materiales de Misiones; Argentin

Erosion of materials used in heart valves prosthesis

Se estudia la erosión de materiales utilizados en la construcción de prótesis de válvulas cardíacas, Acero inoxidable 316 y Poli-metacrilato de metilo (PMMA) a niveles de desgaste bajos, esperados en estos dispositivos. Como material erosivo se utilizó SiC 220 mesh (65 μm de diámetro), en dos composiciones diferentes: 0,1 y 1 % en peso, suspendidas en una solución de glucosa al 50%P/P, (viscosidad de 0,01540 kg/(m.s)). Se usó un flujo de 2200 cm3/min y dos tamaños de boquillas de: 2,3 y 6,4 mm de diámetro, en dos ángulos de incidencia diferentes,60º y 90º. Los ensayos se realizaron por un período de 11 horas. Se partió de probetas de PMMA y Acero inoxidable 316 pulidas a espejo. Las escaras de desgaste se observaron al microscopio óptico. El tipo de fallas observadas en las probetas luego de los ensayos fueron: Puntos o cráteres (pequeños y grandes), Rayas largas, Rayas cortas y Rayas en forma de comas. En PMMA el desgaste se incrementó al aumentar la cantidad de partículas erosivas, tanto en los ensayos a 60º como a 90º. En cambio, no se observaron cambios en el nivel de con el ángulo de incidencia. En el acero inoxidable 316 se observó un incremento en el nivel de desgaste al reducir el ángulo de incidencia, de 90º a 60º.Erosion of poly-methil-metacrilate (PMMA) and 316 stainless steel, materials used in the fabrication of prosthetic heart valves, were studied. Particles of SiC, 65 μm in diameter (200 mesh), are used as erosive materials carried on a glucose solution as a carrier fluid. Two compositions of particles were used: 0.1 and 1 %wt. A flow rate of 2200 cm3 /min and two different outlet holes were used, the sample was located at 3 cm approximately of the outlet hole. The tests were performed for 11 hours. The initial surface of the PMMA and the stainless steel were polished up to a mirror like surface. The erosion scars were observed by optical microscopy. The types of failures found were: points or craters (smalls or larges), large scratches, short scratches and comma-like scratches. On the PMMA the wear increase when the amount of particles increase; however, no difference was observed when the incidence angle was changed. On the 316 stainless steel there the wear increased when the incidence angle change from 90º to 60 º.Fil: Rosenberger, Mario Roberto. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Guerrero, L. A.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Vera, Maria Laura. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Schvezov, Carlos Enrique. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; Argentin

Wear Resistance of Anodic Titanium Dioxide Films Produced on Ti-6Al-4V Alloy

Ti-6Al-4V alloy with TiO2 coating is the most commonly selected material to construct an aortic heart valve. Wear resistance is the main mechanical property to be evaluated for this purpose. In this paper, the wear resistance of TiO2 thin films obtained by anodic oxidation of Ti-6Al-4V is evaluated. Anodic oxidation was performed at 20 V to 70 V with a H2SO4 1 M electrolyte. The samples were thermally treated at 500°C for 1 h, and crystalline phases of TiO2 were obtained. The wear was performed in a ball-on-flat recip‐ rocating machine with a range of loads from 1 gf to 4 gf and times between 60 s and 1200 s, using a diamond sphere as counterface. The counterface oscillates at 0.5 Hz and 4 mm in amplitude. The wear is measured using a profilometer and is calculated as the worn volume. The wear resistance of the coated samples is larger than the substrate, and increases with thickness and with crystalline coating.Fil: Vera, Maria Laura. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Rosenberger, Mario Roberto. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Schvezov, Carlos Enrique. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; ArgentinaFil: Ares, Alicia Esther. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico Nordeste. Instituto de Materiales de Misiones; Argentin

Does Higher Intensity Increase the Rate of Responders to Endurance Training When Total Energy Expenditure Remains Constant? : A Randomized Controlled Trial

Background Standardized training prescriptions often result in large variation in training response with a substantial number of individuals that show little or no response at all. The present study examined whether the response in markers of cardiorespiratory ftness (CRF) to moderate intensity endurance training can be elevated by an increase in training intensity. Methods Thirty-one healthy, untrained participants (46±8 years, BMI 25.4±3.3 kg m−2 and V˙O2max 34±4 mL min−1 kg−1 ) trained for 10 weeks with moderate intensity (3 day week−1 for 50 min per session at 55% HRreserve). Hereafter, the allocation into two groups was performed by stratifed randomization for age, gender and VO2max response. CON (continuous moderate intensity) trained for another 16 weeks at moderate intensity, INC (increased intensity) trained energy-equivalent for 8 weeks at 70% HRreserve and then performed high-intensity interval training (4×4) for another 8 weeks. Responders were identifed as participants with VO2max increase above the technical measurement error. Results There was a signifcant diference in V˙O2max response between INC (3.4±2.7 mL kg−1 min−1 ) and CON (0.4±2.9 mL kg−1 min−1 ) after 26 weeks of training (P=0.020). After 10 weeks of moderate training, in total 16 of 31 participants were classifed as VO2max responders (52%). After another 16 weeks continuous moderate intensity training, no further increase of responders was observed in CON. In contrast, the energy equivalent training with increasing training intensity in INC signifcantly (P=0.031) increased the number of responders to 13 of 15 (87%). The energy equivalent higher training intensities increased the rate of responders more efectively than continued moderate training intensities (P=0.012). Conclusion High-intensity interval training increases the rate of response in VO2max to endurance training even when the total energy expenditure is held constant. Maintaining moderate endurance training intensities might not be the best choice to optimize training gains. Trial Registration German Clinical Trials Register, DRKS00031445, Registered 08 March 2023—Retrospectively registered, https://www.drks.de/DRKS0003144

Effects on cardiorespiratory fitness of moderate-intensity training vs. energy-matched training with increasing intensity

Introduction: The present study investigated the role of training intensity in the dose–response relationship between endurance training and cardiorespiratory fitness (CRF). The hypothesis was that beginners would benefit from an increase in training intensity after an initial training phase, even if the energy expenditure was not altered. For this purpose, 26 weeks of continuous moderate training (control group, CON) was compared to training with gradually increasing intensity (intervention group, INC) but constant energy expenditure. Methods: Thirty-one healthy, untrained subjects (13 men, 18 women; 46 ± 8 years; body mass index 25.4 ± 3.3 kg m−2 ; maximum oxygen uptake, VO2max 34 ± 4 ml min−1 kg−1 ) trained for 10 weeks with moderate intensity [3 days/ week for 50 min/session at 55% heart rate reserve (HRreserve)] before allocation to one of two groups. A minimization technique was used to ensure homogeneous groups. While group CON continued with moderate intensity for 16 weeks, the INC group trained at 70% HRreserve for 8 weeks and thereafter participated in a 4 × 4 training program (high-intensity interval training, HIIT) for 8 weeks. Constant energy expenditure was ensured by indirect calorimetry and corresponding adjustment of the training volume. Treadmill tests were performed at baseline and after 10, 18, and 26 weeks. Results: The INC group showed improved VO2max (3.4 ± 2.7 ml kg−1 min−1 ) to a significantly greater degree than the CON group (0.4 ± 2.9 ml kg−1 min−1 ) (P = 0.020). In addition, the INC group exhibited improved Vmax (1.7 ± 0.7 km h−1 ) to a significantly greater degree than the CON group (1.0 ± 0.5 km h−1 ) (P = 0.001). The reduction of resting HR was significantly larger in the INC group (7 ± 4 bpm) than in the CON group (2 ± 6 bpm) (P = 0.001). The mean heart rate in the submaximal exercise test was reduced significantly in the CON group (5 ± 6 bpm; P = 0.007) and in the INC group (8 ± 7 bpm; P = 0.001), without a significant interaction between group and time point

Endoluminal Negative-Pressure Therapy for Preventing Rectal Anastomotic Leaks: A Pilot Study in a Pig Model

Background: Anastomotic leak after rectal resection carries substantial morbidity and mortality. A diverting ileostomy is beneficial for high-risk anastomoses, but its creation and reversal carry a surgical risk in addition to that of resection itself. We sought an alternative method for managing complications of rectal anastomosis. Methods: We developed an endoluminal negative-pressure technology with a diverting proximal sump, and hypothesized that it would close anastomotic disruptions in pigs. We performed rectal resections on pigs, with primary anastomoses and the creation of an anastomotic defect. In animals in the treatment group we inserted an endoluminal negative-pressure device and kept it at a low level of continuous suction for 5 d. No device was inserted in a control group of animals. After the 5-d period of treatment we evaluated the anastomoses in both the treatment and control groups of animals for leakage, using contrast enemas. Specimens of anastomosed rectum were evaluated histologically for mucosal integrity and for the location and density of inflammatory responses. Results: Fourteen pigs were assigned to either the treatment (n=10) or control (n=4) group. Of the pigs in the treatment group, 90% had complete closure of their rectal defect, as compared with 25% of the animals in the control group (χ(2) test, p=0.04). The animals in the treatment group had only minimal mucosal and serosal inflammation, whereas those in the control group had extensive mucosal damage with associated serositis. Conclusions: Endoluminal negative-pressure therapy was well-tolerated and led to successful closure of 90% of the anastomic rectal defects in the treatment group of animals in the present study. Additional evaluation of this therapy is warranted