Wiring the adaptive response of mitochondria to metabolic transitions : a Mitofusin-2- dependent proteolytic elimination of OPA1 accompanies cristae and mitochondria-ER contacts remodelling in the postprandial mouse liver

Il est bien accepté dans des modèles en culture que les dynamiques mitochondriales et le remodelage des crêtes régulent le fonctionnement mitochondrial sous diverses conditions de stress, particulièrement l’apoptose et la famine. Malgré la quantité impressionnante de recherche effectuée dans ce domaine, on en connait encore très peu au sujet de l’importance des dynamiques mitochondriales et du remodelage de la structure mitochondriale sous des conditions physiologiques. Dans les années 1960, Hackenbrock a démontré que des mitochondries isolées adoptent des conformations internes distinctes selon l’état métabolique. D’après ses observations, il a prédit que les changements ultrastructurels de la mitochondrie régulent la production fonctionnelle de l’organite. Cependant, il n’est pas évident que ces changements ultrastructuraux suivent bien les changements métaboliques in vivo dans des conditions physiologiques. De plus, le métabolisme hépatique nécessite une adaptation constante de la production bioénergétique et biosynthétique de la mitochondrie suite aux changements de l’état anabolique/catabolique de la cellule hépatique. Toutefois, le fonctionnement de ce processus est encore largement inconnu. Dans cette étude, nous apportons les premières descriptions quantitatives in vivo de la réponse adaptative du réticulum mitochondrial aux transitions métaboliques du foie. Grâce à un modèle hépatique de souris postprandiale et une analyse cryo- microscopie électronique (cryo-EM) quantitative, nous montrons que, 5 heures après un repas, la voie mTORC1 est bloquée, le réseau mitochondrial se fragmente, la densité des crêtes diminue et la capacité respiratoire des mitochondries chute. Ces changements sont accompagnés d’une augmentation parallèle de la longueur des contacts mitochondrie-réticulum endoplasmique (MERCs), qui contrôle les échanges de calcium et de phospholipides entre les deux organites. De plus, ces évènements sont associés à l’expression transitoire de deux fragments C-terminaux (CTFs) inconnus jusqu’à présent provenant de la protéine Optic atrophy-1 (OPA1), une GTPase qui régule les dynamiques des crêtes mitochondriales et des mitochondries. Grâce à un protocole in vitro, nous montrons que ces CTFs proviennent d’un nouveau clivage d’OPA1, appellé clivage-C, qui élimine l’activité d’OPA1 en la coupant. Plus important encore, nous montrons que le clivage-C nécessite la présence de Mitofusin-2 (MFN2), une protéine clé dans la régulation de la fusion mitochondriale et dans la génèse des MERCs, mais pas la présence de l’homologue Mitofusin-1 (MFN1), ce qui confirme le lien entre le remodelage des crêtes et l’assemblage des MERCs.It is well established in cultured models that mitochondrial dynamics and cristae remodeling regulate mitochondrial function under different stress conditions, such as starvation and apoptosis. Despite the tremendous amount of research in this field, relatively little is known about the significance of mitochondrial dynamics and ultrastructure remodeling under normal physiological conditions in vivo. In the 1960’s, Hackenbrock demonstrated that isolated mitochondria adopt distinct internal conformations under different metabolic states. Based on these observations, he predicted that mitochondrial ultrastructural changes regulate the organelles functional output. However, whether these ultrastructural changes also accompany metabolic transitions in vivo, under physiological conditions, is not known. Further, hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely elusive. In this study, we provide the first in vivo quantitative description of the adaptive response of the mitochondrial reticulum to hepatic metabolic transitions. Using a postprandial mouse liver model and quantitative cryo-EM analysis we show that at 5 hours after feeding the mTORC1 signaling is blocked, the mitochondria network fragments, the cristae density decreases and the mitochondrial respiratory capacity drops. These changes are accompanied with a parallel increase in the mitochondria-ER contact (MERCs) lengths, which control calcium and phospholipids fluxes between the two organelles. Further, these events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy-1 (OPA1), a mitochondrial GTPase that regulates cristae and mitochondrial dynamics. Using an in vitro assay, we show that these CTFs originate from a novel OPA1 processing, termed C-cleavage that eliminates OPA1 activity by breaking off the GTPase. Importantly, we show that C-cleavage requires the presence of Mitofusin-2 (MFN2), a key regulator of mitochondria fusion and MERCs biogenesis, but not that of its homolog Mitofusin-1 (MFN1), thereby linking cristae remodeling to MERCs assembly

Investigation of regulation of stellar magnetism and rotation

Stellar rotation plays an important role in maintaining the magnetic fields inside the stellar interior through convection, and starspots are the most visible manifestation of the interplay between stellar rotation rate and magnetic fields. It is revealed through high end observations of evolution of magnetic fields and rotation rate of the Sun and other solar type stars that they exhibit a wide range of variation among their rotation rates yet there are some common ingredients such as rotational shear, turbulent transport and various nonlinear transport mechanisms which contribute towards the evolution and maintenance of the magnetic activity displayed by them. Also, these observations provide us with valuable information about the dependence of differential rotation and magnetic activity on rotation rate of stars with different ages and different rotation rates. Thus, the main challenge in dynamo theory is to explain these observations which is in fact a very strenuous problem and is challenging to do with full MHD simulations due to the various constraints such as expensive computations in terms of time and resolution. Therefore, it is useful to construct a simple parameterized model in order to understand the evolution of rotation rate and magnetic fields which can provide valuable insight into the various observations. This thesis discusses the modelling of solar dynamo and spindown of solar-type stars by using ODE and the effect of shear in kinematic dynamo in full MHD. We propose a simple parameterized model to understand the effect of nonlinear transport coefficients as well as mean/fluctuating differential rotation in the generation and destruction of magnetic fields and their capability in the working of dynamo near marginal stability. This model is then utilised to discuss detailed dynamics to understand the self-regulation of magnetic fields in solar/stellar dynamo. This work is further extended to understand the spindown of solar-type stars where the angular momentum loss is dynamically prescribed via equation of evolution of rotation rate and magnetic fields. The results obtained from this model are consistent with observations. Furthermore, regulatory behaviour of a kinematic dynamo by shear flow is investigated. Specifically, we study the induction equation by prescribing small scale velocity field to which a large scale radial/latitudinal shear is added in the direction of zonal flow. The results from numerical simulations are analysed and we conclude that the presence of large scale shear suppresses the small scale flows and results in quenching of a kinematic dynamo

Genetic Diversity of Genus \u3cem\u3eAvena\u3c/em\u3e in North Western-Himalayas assessed by Morphological Traits

Oat (Avena sativa L.) is a cool season, annual crop grown mainly in moist areas of temperate climates of the world serving as a food for mankind and forage for cattle. Oat is an important rabi fodder crop in India.In India, oat is also cultivated in Himalayan states like Kashmir, Himachal Pradesh and Uttarakhand. Oat in these regions have a wider adaptability, because of its excellent growing habitat, quick re-growth and better nutritional value (Misri, 2004). Oat breeding programme in Indian regions has not achieved much impetus due to a narrow genetic base of cultivated gene pool within the regionally adapted germplasm. The competition for utilization of land for food grains and fodder necessitates intensified efforts towards more efficient forage research and production, for which it is imperative to characterize and evaluate Avena species in order to identify donors for different traits and diversify primary oat gene pool. Historically, morphological traits have been important in the diversity analysis of crop species. The characterization of germplasm using morphological traits help the plant breeders to select the accessions to be utilized in hybridization programme. Considering the potential forage value of oats and limited genetic information available at morphological level, present study was aimed to assess the genetic diversity of genus Avena using morphological characterization. The information generated from this study will be helpful in characterizing the genus Avena germplasm and in the selection and utilization of diverse genotypes to enhance variability and productivity of commercial oat for future crop improvement endeavors in the Indian North-Western Himalayan region

Dynamical model for spindown of solar-type stars

After their formation, stars slow down their rotation rates by the removal of angular momentum from their surfaces, e.g., via stellar winds. Explaining how this rotation of solar-type stars evolves in time is currently an interesting but difficult problem in astrophysics. Despite the complexity of the processes involved, a traditional model, where the removal of angular momentum by magnetic fields is prescribed, has provided a useful framework to understand observational relations between stellar rotation, age, and magnetic field strength. Here, for the first time, a spindown model is proposed where loss of angular momentum by magnetic fields evolves dynamically, instead of being prescibed kinematically. To this end, we evolve the stellar rotation and magnetic field simultaneously over stellar evolution time by extending our previous work on a dynamo model which incorporates nonlinear feedback mechanisms on rotation and magnetic fields. We show that our extended model reproduces key observations and is capable of explaining the presence of the two branches of (fast and slow rotating) stars which have different relations between rotation rate Ω versus time (age), magnetic field strength $| B|$ versus rotation rate, and frequency of magnetic field ${\omega }_{\mathrm{cyc}}$ versus rotation rate. For fast rotating stars we find that: (i) there is an exponential spindown ${\rm{\Omega }}\propto {e}^{-1.35t}$, with t measured in Gyr; (ii) magnetic activity saturates for higher rotation rate; (iii) ${\omega }_{\mathrm{cyc}}\propto {{\rm{\Omega }}}^{0.83}$. For slow rotating stars we find: (i) a power-law spindown ${\rm{\Omega }}\propto {t}^{-0.52}$; (ii) that magnetic activity scales roughly linearly with rotation rate; (iii) ${\omega }_{\mathrm{cyc}}\propto {{\rm{\Omega }}}^{1.16}$. The results obtained from our investigations are in good agreement with observations. The Vaughan–Preston gap is consistently explained in our model by the shortest spindown timescale in this transition from fast to slow rotators. Our results highlight the importance of self-regulation of magnetic fields and rotation by direct and indirect interactions involving nonlinear feedback in stellar evolution

Proctitis following stereotactic body radiation therapy for prostate cancer

Background Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer. Methods Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT. Results The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT. Conclusions In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations

Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential

Dynamic model of dynamo (magnetic activity) and rotation

A dynamic model of dynamo and rotation is investigated to understand the observational data of the dependence of the magnetic activities and the differential rotation ΔΩ on the rotation rate Ω. Specifically, we propose a minimal seventh-order nonlinear dynamical system for magnetic fields and differential rotation ΔΩ by parameterizing the generation and destruction of magnetic fields by α-Ω effect and magnetic flux loss from stars and by including quenching of α-effect and differential rotation ΔΩ due to the Lorentz force. By examining different forms of α-quenching and flux loss, we study how the strength and frequency ω of magnetic fields and the differential rotation ΔΩ change with the rotation rate Ω through dynamo number. In particular, among the three cases with (i) α-quenching and no flux loss; (ii) flux loss and no α-quenching; (iii) α-quenching and flux loss, our results show that the best agreement with observations is obtained in case (iii) with equal amounts of α-quenching and poloidal and toroidal magnetic flux losses with quadratic nonlinear dependence on  |B|. Specifically, in this case, the frequency spectrum of the magnetic field has a well-localized frequency of the maximum intensity which scales as ω ∝ Ω0.80, in agreement with a previous observation. The magnetic field and mean differential rotation exhibit the tendency of saturation for high rotation. The implication of our results in light of necessary dynamic balance is discussed

Detailed mathematical and numerical analysis of a dynamo model

We investigate the role of nonlinear feedback by α-quenching, flux losses, and feedback by differential rotations in dynamo. Specifically, by studying the nonlinear dynamo model analytically and numerically, we unfold how frequency p of magnetic field, magnetic field strength |B|, and phase φ are influenced by different types of nonlinear feedback in the limit of a very weak mean and/or fluctuating differential rotation. We find that p and φ are controlled by both flux losses with no influence by α-quenching when there is no back reaction because of fluctuating differential rotation. We find a similar effect of poloidal flux loss and toroidal flux loss on p and |B| in the absence of a back reaction of shear. Their effect becomes totally different with the inclusion of this back reaction. Detailed investigations suggest that toroidal flux loss tends to have more influence than poloidal flux loss (with or without α-quenching) in the presence of fluctuating shear. Furthermore, the effect of α-quenching is boosted when combined with toroidal flux loss, indicating that the dynamic balance of dynamo is optimized in the presence of both α-quenching and flux loss. These results highlight the importance of nonlinear transport coefficients and differential rotation in the regulation of a dynamo

Principles of occlusion in implant dentistry

Dental implants require different biomechanical considerations from natural teeth. Also, with one of the criteria for long-term implant success being “occlusion,” it becomes imperative for the clinician to be well versed with the different concepts when rehabilitating with an implant prosthesis. All endeavors must be made to reduce the overload and noxious forces on implants during mandibular movements. The occlusal rehabilitation schemes for implant-supported prostheses are derivatives of the occlusal scheme for natural dentition. The implant-protected occlusion (IPO) scheme has been designed to ensure the longevity of both prosthesis and implant. The article reviews the concepts of IPO and their applicability in different clinical scenarios