Stoicism, the physician, and care of medical outliers

BACKGROUND: Medical outliers present a medical, psychological, social, and economic challenge to the physicians who care for them. The determinism of Stoic thought is explored as an intellectual basis for the pursuit of a correct mental attitude that will provide aid and comfort to physicians who care for medical outliers, thus fostering continued physician engagement in their care. DISCUSSION: The Stoic topics of good, the preferable, the morally indifferent, living consistently, and appropriate actions are reviewed. Furthermore, Zeno's cardinal virtues of Justice, Temperance, Bravery, and Wisdom are addressed, as are the Stoic passions of fear, lust, mental pain, and mental pleasure. These concepts must be understood by physicians if they are to comprehend and accept the Stoic view as it relates to having the proper attitude when caring for those with long-term and/or costly illnesses. SUMMARY: Practicing physicians, especially those that are hospital based, and most assuredly those practicing critical care medicine, will be emotionally challenged by the medical outlier. A Stoic approach to such a social and psychological burden may be of benefit

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

Hydrodynamics of fossil fishes

Fromtheir earliest origins, fishes have developed a suite of adaptations for locomotion in water, which determine performance and ultimately fitness. Even without data from behaviour, soft tissue and extant relatives, it is possible to infer a wealth of palaeobiological and palaeoecological information. As in extant species, aspects of gross morphology such as streamlining, fin position and tail type are optimized even in the earliest fishes, indicating similar life strategies have been present throughout their evolutionary history. As hydrodynamical studies become more sophisticated, increasingly complex fluid movement can be modelled, including vortex formation and boundary layer control. Drag-reducing riblets ornamenting the scales of fast-moving sharks have been subjected to particularly intense research, but this has not been extended to extinct forms. Riblets are a convergent adaptation seen in many Palaeozoic fishes, and probably served a similar hydrodynamic purpose. Conversely, structures which appear to increase skin friction may act as turbulisors, reducing overall dragwhile serving a protective function. Here,we examine the diverse adaptions that contribute to drag reduction in modern fishes and review the few attempts to elucidate the hydrodynamics of extinct forms

Directing the evolution of Rubisco and Rubisco activase: first impressions of a new tool for photosynthesis research

During the last decade the practice of laboratory-directed protein evolution has become firmly established as a versatile tool in biochemical research by enabling molecular evolution toward desirable phenotypes or detection of novel structure–function interactions. Applications of this technique in the field of photosynthesis research are still in their infancy, but recently first steps have been reported in the directed evolution of the CO2-fixing enzyme Rubisco and its helper protein Rubisco activase. Here we summarize directed protein evolution strategies and review the progressive advances that have been made to develop and apply suitable selection systems for screening mutant forms of these enzymes that improve the fitness of the host organism. The goal of increasing photosynthetic efficiency of plants by improving the kinetics of Rubisco has been a long-term goal scoring modest successes. We discuss how directed evolution methodologies may one day be able to circumvent the problems encountered during this venture

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Chinese characters reveal impacts of prior experience on very early stages of perception

Visual perception is strongly determined by accumulated experience with the world, which has been shown for shape, color, and position perception, in the field of visuomotor learning, and in neural computation. In addition, visual perception is tuned to statistics of natural scenes. Such prior experience is modulated by neuronal top-down control the temporal properties of which had been subject to recent studies. Here, we deal with these temporal properties and address the question how early in time accumulated past experience can modulate visual perception

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN

Mutagenesis of the NaChBac sodium channel discloses a functional role for a conserved S6 asparagine

Asparagine is conserved in the S6 transmembrane segments of all voltage-gated sodium, calcium, and TRP channels identified to date. A broad spectrum of channelopathies including cardiac arrhythmias, epilepsy, muscle diseases, and pain disorders is associated with its mutation. To investigate its effects on sodium channel functional properties, we mutated the simple prokaryotic sodium channel NaChBac. Electrophysiological characterization of the N225D mutant reveals that this conservative substitution shifts the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability, as determined by synchrotron radiation circular dichroism spectroscopy studies of purified channels. Based on our analyses of high-resolution structures of NaChBac homologues, we suggest that the side-chain amine group of asparagine 225 forms one or more hydrogen bonds with different channel elements and that these interactions are important for normal channel function. The N225D mutation eliminates these hydrogen bonds and the structural consequences involve an enhanced channel inactivation