Mechanistic insight into the blocking of CO diffusion in [NiFe]-hydrogenase mutants through multiscale simulation

[NiFe]-hydrogenases are fascinating biological catalysts with potential application in biofuel cells. However, a severe problem in practical application is the strong sensitivity of hydrogenase to gaseous inhibitor molecules such as CO and O(2). Recently, a number of successful protein engineering studies have been reported that aimed at lowering the access of diatomic inhibitors to the active site pocket, but the molecular mechanism conferring increased resistance remained unclear. Here we use a multiscale simulation approach combining molecular dynamics with a master equation formalism to explain the steady drop in CO diffusion rate observed for the mutants V74M L122A, V74M L122M, and V74M of Desulfovibrio fructosovorans [NiFe]-hydrogenase. We find that diffusion in these variants is controlled by two gates, one between residues 74 and 476 and the other between residues 74 and 122. The existence of two control points in different locations explains why the reduction in the experimental diffusion rate does not simply correlate with the width of the main gas channel. We also find that in the more effective mutation (V74M) CO molecules are still able to reach the active site through transitions that are gated by the microsecond dihedral motions of the side chain of R476 and the thermal fluctuations of the width of the gas channel defined by M74 and L122. Reflecting on the molecular information gained from simulation, we discuss future mutation experiments that could further lower the diffusion rates of small ligands inhibiting [NiFe]-hydrogenase.     

Regeneration of whole fertile plants from 30,000-y-old fruit tissue buried in Siberian permafrost

Whole, fertile plants of Silene stenophylla Ledeb. (Caryophyllaceae) have been uniquely regenerated from maternal, immature fruit tissue of Late Pleistocene age using in vitro tissue culture and clonal micropropagation. The fruits were excavated in northeastern Siberia from fossil squirrel burrows buried at a depth of 38 m in undisturbed and never thawed Late Pleistocene permafrost sediments with a temperature of -7 °C. Accelerator mass spectrometry (AMS) radiocarbon dating showed fruits to be 31,800 ± 300 y old. The total γ-radiation dose accumulated by the fruits during this time was calculated as 0.07 kGy; this is the maximal reported dose after which tissues remain viable and seeds still germinate. Regenerated plants were brought to flowering and fruiting and they set viable seeds. At present, plants of S. stenophylla are the most ancient, viable, multicellular, living organisms. Morphophysiological studies comparing regenerated and extant plants obtained from modern seeds of the same species in the same region revealed that they were distinct phenotypes of S. stenophylla. The first generation cultivated from seeds obtained from regenerated plants progressed through all developmental stages and had the same morphological features as parent plants. The investigation showed high cryoresistance of plant placental tissue in permafrost. This natural cryopreservation of plant tissue over many thousands of years demonstrates a role for permafrost as a depository for an ancient gene pool, i.e., preexisting life, which hypothetically has long since vanished from the earth's surface, a potential source of ancient germplasm, and a laboratory for the study of rates of microevolution.     

The history of parkinsonism: Descriptions in ancient Indian medical literature

The clinical syndrome of parkinsonism was identified in ancient India even before the period of Christ and was treated methodically. The earliest reference to bradykinesia dates to 600 bc . Evidences prove that as early as 300 bc , Charaka proposed a coherent picture of parkinsonism by describing tremor, rigidity, bradykinesia, and gait disturbances as its components. The scenario was further developed by Madhava, Vagbhata, and Dalhana all through history. The 15th‐century classic “Bhasava rajyam” introduced the term kampavata, which may be regarded as an ayurvedic analogue of parkinsonism. The pathogenesis of kampavata centered on the concept of imbalance in the vata factor, which controls psychomotor activities. The essential element in therapy was the administration of powdered seed of Mucuna pruriens, or atmagupta, which as per reports, contains 4%?6% of levodopa. In addition to proving the existence and identification of parkinsonism in ancient India, the study points to the significance of ancient Indian Sanskrit works in medical history. © 2013 Movement Disorder Society     

Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections

Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.     

Mythos and logos in Hesiod's Theogony,circa 700 B.C.

Hesiod's Theogony, a completely preserved poem, is dated from about 700 B.C. It depicts partly a development, partly a situation that has arisen in the course of time in the world. It constitutes an attempt to understand the cosmos as the product of a genealogical evolution, which can be seen as a process of successive separation, differentiation, and hierarchization. In this attempted picture of the world myth and reality are inextricably interwoven. Observations of natural phenomena as far as of congenital malformations are accordingly exaggerated and undergone mythical transformation. Entities enumerated in this genealogical poem, no matter whether they stand for parts and concrete phenomena of the physical world or intellectual properties and abstract concepts, behave, think, and act, and are accordingly thought of, in anthropomorphic terms. Monogamy, polygamy, endogamy, exogamy, asexual and sexual reproduction, multiple conceptions and births, dominantly and recessively inherited traits, normal and abnormal offspring, and perceptions and notions on cosmogony, isogamy, and teratogenesis could be observed in the writing of the Theogony and interpreted by rational modern concepts. © 1996 Wiley-Liss, Inc.     

中西医并重之国策带来国医国药发展的春天

《中华人民共和国中医药法》体现了从团结中西医转轨为中西医并重的国策.习近平总书记称誉中医药是国之瑰宝,蕴育深邃的哲理,"传承精华、守正创新"为构建具有中国特色的、统一的医药学创造了良好的机遇.     

乔世举教授三期分治法治疗咳喘经验

咳喘是呼吸系统的难治性疾病。现代医学对咳喘病的治疗效果不令人满意,而传统医学有着诸多的优势。因此探求中医药治疗咳喘势在必行。咳喘病病位在肺肾而与五脏相关,应根据咳喘的不同阶段,分清在肺在脾在肾,辨清寒热虚实,而采用不同的治则和方药,进行系统调治,方可奏效。