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Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific.

Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.

The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (

Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+)-dependent metabolism during acute stress.

Background: Bladder exstrophy is a complex, rare congenital malformation with an incidence of 3.3 cases in every 100000 live births and is slightly more common in males. Primary surgical repair requires many hours of surgery with fluid and blood loss. Because of wide fluctuations in hemodynamics, a longer duration of surgery, smaller age, risk of hypothermia and post-operative intensive care may be required. We evaluated the use of continuous caudal epidural infusion of bupivacaine and fentanyl under general anesthesia for urinary bladder exstrophy-epispadias surgery in children. Aims and Objectives: Aim of the study was to evaluate the postoperative analgesia in patients undergoing surgery for bladder exstrophy. The primary objective was to assess the postoperative pain using FLACC scale and sedation score after successful caudal administration. Secondary objective was to assess the hemodynamic changes after caudal administration. Materials and Methods: A total of 13 patients aged between 9months and 13 years of either sex, weighing between 5kg to 30kg, belonging to ASA grade II to IV, underwent surgery for epispadias--exstrophy complex. Initial bolus 0.75ml/kg of 0.25% bupivacaine with fentanyl 1ug/kg was given through epidural. Postoperative analgesia was maintained by continuous infusion of 0.0625% bupivacaine @0.1ml/kg/hr in young children and 0.125% bupivacaine with fentanyl 1ug/ml in older children for 4-5 days with the help of ON-Q pump or infusion pump. Baseline hemodynamic parameters including MAP, heart rate and SpO2 was recorded at various time intervals. Postoperative pain was assessed using face, legs, activity, cry and consolability (FLACC) pain scale and sedation score was assessed by using ramsay sedation score. Results: There was a statistically significant decrease in mean pulse rate in the study group from baseline to thirty minutes after reversal (p<0.001). Similar observation was made for mean arterial pressure which also showed statistically significant decrease from baseline to thirty minutes after reversal (p<0.001). No change was observed in SpO2 from baseline to any other follow-up interval. Conclusion: Perioperative anesthetic and analgesic management of the bladder exstrophy patient can improve the success rate. Epidural bupivacaine with or without fentanyl infusions for short duration can provide safe analgesia. [ABSTRACT FROM AUTHOR]

The human lipidome comprises over tens of thousands of distinct lipid species in addition to total cholesterol and the other conventional lipid traits that are routinely measurable in the peripheral circulation. Of the lipid species considered to exhibit bioactive functions, sphingolipids are a class of molecules that have shown relevance to human disease risk and cardiovascular outcomes in particular. In this issue of theJCI, Poss et al. conducted targeted lipidomics in a case-control study involving over 600 individuals and found a sphingolipid profile that predicted coronary artery disease status. In the context of emerging evidence linking sphingolipid biology with cardiovascular pathophysiology, these results suggest the potential utility of serum sphingolipids as cholesterol-independent markers of risk and even future targets for optimizing cardiovascular health., Bioactive lipids The human lipidome comprises over tens of thousands of distinct lipid species, many of which have primarily structural or energetic functions and others of which play a variety [...]

This work proposes a two-degree-of-freedom factional order proportional-integral-derivative (2-DOF FOPID) controller for automatic voltage regulator (AVR) to mitigate the impact of voltage transients and set-point variations in any power system network. An inherent communication time delay is considered in the investigated AVR plant. This inherent time delay occurs due to the presence of amplifier, exciter, generator, and sensor, making the system unstable. Such an unstable AVR system is still unexplored and difficult to control. The suggested control structure of the 2-DOF FOPID is flexible enough from the perspective of tuning and provides enhanced performance of an AVR system at the cost of a large number of controller design parameters. Therefore, the proposed controller is optimized by an advanced meta-heuristic technique; squirrel search algorithm (SSA) which leads to SSA tuned 2-DOF fractional order PID (S2DFPID) controller. Moreover, selecting an appropriate meta-heuristic approach is a very tedious task for such unstable systems and advanced control architecture. Hence, a systematic statistical approach is also employed to select an optimization technique for the specified purpose, and a rigorous comparative assessment of seven state-of-the-art optimization techniques is also presented in this work. Investigation reveals the superior performance of S2DFPID controller compared to SSA-tuned fractional order PID (SFPID), and SSA-tuned traditional PID (SPID) controllers in the presence of set-point variations, external load disturbances and parametric uncertainties. [ABSTRACT FROM AUTHOR]

Graphical Abstract Effect of strain rate on the single tooth strength of nylon-based gear has been investigated using a newly designed testing fixture. An adjustable single tooth testing fixture has been designed and developed for the purposed of single tooth loading test which is able to accommodate the gear with varying thickness. Injection molded nylon-6 and SLS (selective laser sintering) printed glass filled nylon-6 standard involute and asymmetric gear tooth have been investigated for their single tooth loading test at three different strain rates of 0.0003, 0.003, and 0.01 per sec. Single tooth strength for both injection and printed gear is found to increase with the increase in strain rate. Injection molded single gear tooth undergone bending failure whereas SLS printed gear tooth shows fracture failure. Resistance to single tooth deflection at higher strain rate has drastically increased for injection molded standard involute (IS) gear tooth by 23% whereas, asymmetric gear tooth IA20 followed by IA34 shows slight increment. SLS printed asymmetric gear tooth PAG20/34 exhibits maximum single tooth strength among all three types of printed gears at all the three strain rates. At higher strain rate of 0.01 per sec, single tooth strength dominates by tooth profile geometry whereas, at lower strain rate of 0.0003 per sec, it dominates by tooth profile geometry and microstructure. [ABSTRACT FROM AUTHOR]