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1.  EVOLUTION OF EPHEDRA AS THE SOMA OF RIGVEDA 
Ancient Science of Life  1982;2(2):93-97.
In Rigveda Soma is an evergreen plant, with thousand stalks yellow hued bestowing auspicious energy. Resembling yellow fibres of hemp ephedra was rained in Chlnoso Ho-Ma, Yellow-hemp. It was Sanskritized as Soma. Being an energizer-cum-euphoriant its juice was consumed thrice daily. Finally it became a drug of longevity, rejuvenation and resurrection even god Soma. As drug it was substituted by Rasayana promisiig rejuvenation but also salvation. Soma with Water and Fire constitutes the proto-cosmology of Rigveda.
PMCID: PMC3336717  PMID: 22556961
2.  EPHEDRA, THE OLDEST MEDICINAL PLANT WITH THE HISTORY OF AN UNINTERRUPTED USE 
Ancient Science of Life  1987;7(2):105-109.
Ephedra was a source of anti-fatigue drink. In later period it became a drink of immortality and longevity. The use of Soma as the first drink of a newly born child is mentioned in Rigveda. The author identifies the Soma of Rigveda with the Ephedra and established its use in ancient Rome and also highlights here its continuity among Zorostrains.
PMCID: PMC3331384  PMID: 22557597
3.  CATHA EDULIS (KHAT), A SEX DEPRESSANT, EUPHORIANT IN HISTORY 
Ancient Science of Life  1987;7(1):45-48.
This article traces the history of the Khat which is an intoxicant and also a sexual depressant. The author establishes that its origion is Abyssinia and it is brought to Arabia where it is commonly used even by Muslims. If Khat is consumed in excess it may impair the health but moderate quantity is beneficial.
PMCID: PMC3331378  PMID: 22557587
4.  Determination of Ephedrine Alkaloids in Botanicals and Dietary Supplements by HPLC-UV 
Journal of AOAC International  2004;87(1):1-14.
An international collaborative study was conducted of a high-performance liquid chromatography (HPLC)-UV method for the determination of the major (ephedrine [EP] and pseudoephedrine [PS]) and minor (norephedrine [NE], norpseudoephedrine [NP], methylephedrine [ME], and methylpseudoephedrine [MP]) alkaloids in selected dietary supplements representative of the commercially available products. Ten collaborating laboratories determined the ephedrine-type alkaloid content in 8 blind replicate samples. Five products contained ephedra ground herb or ephedra extract. These 5 products included ground botanical raw material of Ephedra sinica, a common powdered extract of Ephedra sinica, a finished product containing only Ephedra sinica ground botanical raw material, a complex multicomponent dietary supplement containing Ma Huang, and a high-protein chocolate flavored drink mix containing Ma Huang extract. In addition, collaborating laboratories received a negative control and negative control spiked with ephedrine alkaloids at high and low levels for recovery studies. Test extracts were treated to solid-phase extraction using a strong-cation exchange column to help remove interferences. The HPLC analyses were performed on a polar-embedded phenyl column using UV detection at 210 nm. Repeatability relative standard deviations (RSDr) ranged from 0.64–3.0% for EP and 2.0–6.6% for PS, excluding the high protein drink mix. Reproducibility relative standard deviations (RSDR) ranged from 2.1–6.6% for EP and 9.0–11.4% for PS, excluding the high protein drink mix. Recoveries ranged from 84.7–87.2% for EP and 84.6–98.2% for PS. The data developed for the minor alkaloids are more variable with generally unsatisfactory HORRATS(i.e., >2). However, since these alkaloids generally add little to the total alkaloid content of the products, the method gives satisfactory results in measuring total alkaloid content (RSDr 0.85–3.13%; RSDR 2.03–10.97%, HORRAT 0.69–3.23, exclusive of the results from the high protein drink). On the basis of these results, the method is recommended for Official First Action for determination of EP and PS in dietary supplements exclusive of the high protein drinks.
PMCID: PMC2584348  PMID: 15084081
5.  Determination of Ephedra Alkaloids by Liquid Chromatography/Tandem Mass Spectrometry 
Journal of AOAC International  2003;86(3):471-475.
In conjunction with an AOAC Task Group on dietary supplements, a liquid chromatography/tandem mass spectrometry (LC–MS/MS) method was validated for measurement of 6 major alkaloids in raw ephedra sinica herb, ephedra extracts, ephedra tablets, complex dietary supplements containing ephedra, and a high-protein drink mix containing ephedra. The amount of ephedrine-type alkaloids present was determined by LC with mass selective detection. Six replicates of each matrix were analyzed on 3 separate occasions. The presence of 6 ephedrine-type alkaloids was detected at a level >0.5 μg/g based on a 0.5 g sample. The standard curve range for this assay is from 0.02 to 1.0 μg/mL. Appropriate dilutions covered a wide range of specific alkaloid concentrations. The calibration curves for all 6 analytes had correlation coefficients >0.995.
PMCID: PMC2586890  PMID: 12852561
6.  A multi-compartment CNS neuron-glia co-culture microfluidic platform 
We present a novel multi-compartment neuron co-culture microsystem platform for in vitro CNS axon-glia interaction research, capable of conducting up to six independent experiments in parallel for higher-throughput. We developed a new fabrication method to create microfluidic devices having both micro and macro scale structures within the same device through a single soft-lithography process, enabling mass fabrication with good repeatability.
The multi-compartment microfluidic co-culture platform is composed of one soma compartment for neurons and six axon/glia compartments for oligodendrocytes (OLs). The soma compartment and axon/glia compartments are connected b y arrays of axon-guiding microchannels that function as physical barriers to confine neuronal soma in the soma compartment, while allowing axons to grow into axon/glia compartments. OLs loaded into axon/glia compartments can interact only with axons but not with neuronal soma or dendrites, enabling localized axon-glia interaction studies. The microchannels also enabled fluidic isolation between compartments, allowing six independent experiments to be conducted on a single device for higher throughput.
Soft-lithography using poly(dimethylsiloxane) (PDMS) is a commonly used technique in biomedical microdevices. Reservoirs on these devices are commonly defined by manual punching. Although simple, poor alignment and time consuming nature of the process makes this process not suitable when large numbers of reservoirs have to be repeatedly created. The newly developed method did not require manual punching of reservoirs, overcoming such limitations. First, seven reservoirs (depth: 3.5 mm) were made on a poly(methyl methacrylate) (PMMA) block using a micro-milling machine. Then, arrays of ridge microstructures, fabricated on a glass substrate, were hot-embossed against the PMMA block to define microchannels that connect the soma and axon/glia compartments. This process resulted in macro-scale reservoirs (3.5 mm) and micro-scale channels (2.5 µm) to coincide within a single PMMA master. A PDMS replica that served as a mold master was obtained using soft-lithography and the final PDMS device was replicated from this master.
Primary neurons from E16–18 rats were loaded to the soma compartment and cultured for two weeks. After one week of cell culture, axons crossed microchannels and formed axonal only network layer inside axon/glia compartments. Axons grew uniformly throughout six axon/glia compartments and OLs from P1–2 rats were added to axon/glia compartments at 14 days in vitro for co-culture.
doi:10.3791/1399
PMCID: PMC2774404  PMID: 19745806
Neuron culture; neuron-glia interaction; microfluidics; cell culture microsystem
7.  Components of SurA Required for Outer Membrane Biogenesis in Uropathogenic Escherichia coli 
PLoS ONE  2008;3(10):e3359.
Background
SurA is a periplasmic peptidyl-prolyl isomerase (PPIase) and chaperone of Escherichia coli and other Gram-negative bacteria. In contrast to other PPIases, SurA appears to have a distinct role in chaperoning newly synthesized porins destined for insertion into the outer membrane. Previous studies have indicated that the chaperone activity of SurA rests in its “core module” (the N- plus C-terminal domains), based on in vivo envelope phenotypes and in vitro binding and protection of non-native substrates.
Methodology/Principal Findings
In this study, we determined the components of SurA required for chaperone activity using in vivo phenotypes relevant to disease causation by uropathogenic E. coli (UPEC), namely membrane resistance to permeation by antimicrobials and maturation of the type 1 pilus usher FimD. FimD is a SurA-dependent, integral outer membrane protein through which heteropolymeric type 1 pili, which confer bladder epithelial binding and invasion capacity upon uropathogenic E. coli, are assembled and extruded. Consistent with prior results, the in vivo chaperone activity of SurA in UPEC rested primarily in the core module. However, the PPIase domains I and II were not expendable for wild-type resistance to novobiocin in broth culture. Steady-state levels of FimD were substantially restored in the UPEC surA mutant complemented with the SurA N- plus C-terminal domains. The addition of PPIase domain I augmented FimD maturation into the outer membrane, consistent with a model in which domain I enhances stability of and/or substrate binding by the core module.
Conclusions/Significance
Our results confirm the core module of E. coli SurA as a potential target for novel anti-infective development.
doi:10.1371/journal.pone.0003359
PMCID: PMC2556385  PMID: 18836534
8.  Combined Effects of Ephedrine-Containing Dietary Supplements, Caffeine, and Nicotine on Morphology and Ultrastructure of Rat Hearts 
Journal of Caffeine Research  2012;2(3):123-132.
Cigarette smokers have an increased risk for coronary artery disease. Nicotine present in cigarettes can adversely affect the cardiovascular system via stimulation of both sympathetic and parasympathetic neurons. Caffeine, another cardiovascular and central nervous system (CNS) stimulant, is commonly found in Ephedra and Ephedra-free dietary supplements. These caffeine-containing supplements also have been linked to cardiovascular toxicities. Although no longer on the U.S market, Ephedra-containing supplements are another source of cardiovascular and CNS stimulants, namely the ephedrine alkaloids. Together caffeine, nicotine, and ephedrine can individually stress the cardiovascular system, and an overlap of these agents is predicted in smokers and dieters. To understand the collective effects of these stimulants on the heart morphology and ultrastructure, rats were exposed to synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0–30 mg/kg/day), and/or caffeine (0–24 mg/kg/day) as well as an extract from a caffeine-containing Ephedra supplement (Metabolife 356). After exposure for 3 days, the hearts were removed and examined for hypersensitivity myocarditis and myocardial necrosis. None of the drugs tested alone affected heart tissue morphology, nor were atypical cardiac cells observed. However, in combination, significant interactions were found between caffeine and ephedrine; the interventricular septum was most susceptible, with a significant increase in atypical cardiac cells observed. Nicotine pretreatment caused greater susceptibility to cardiotoxicity associated with combinations of caffeine + ephedrine or Metabolife, particularly in the left ventricle wall. These results indicate that sympathomimetic combinations present in Ephedra supplements may have produced cardiotoxicity reported in consumers of these products. Moreover, the presence of nicotine exacerbates these toxic effects.
doi:10.1089/jcr.2012.0021
PMCID: PMC3621369  PMID: 24761270
9.  A BRIEF ACCOUNT OF THE FRACTIONS OF SOMA 
Ancient Science of Life  1990;9(4):207-208.
Soma was originally Sauma as the Sanskrit form of the Avesta name Haoma. It is a loan word from the Chinese term, Hao-Ma, fire coloured hempior fibrous items like hemp and also coloured yellow with a tinge of brown. The Aryans as hunters took its juice as anti-fatigue drink. It was extolled as panacea and even as drink of longevity. The plant and its stalks were crushed between stones to produce juice. There arose different fractions and these have been given in a regular chart here.
PMCID: PMC3331339  PMID: 22557699
11.  A New Euphoriant for Depressive Mental States 
British Medical Journal  1947;1(4512):918-922.
PMCID: PMC2053573  PMID: 20248139
13.  Letter: Euphoriant elixirs. 
British Medical Journal  1973;4(5891):552.
PMCID: PMC1587457  PMID: 4128000
14.  Euphoriant Effects of “Preludin” 
British Medical Journal  1957;2(5043):508-509.
PMCID: PMC1962212  PMID: 13460295
15.  Role of the Escherichia coli SurA Protein in Stationary-Phase Survival 
Journal of Bacteriology  1998;180(21):5704-5711.
SurA is a periplasmic peptidyl-prolyl isomerase required for the efficient folding of extracytoplasmic proteins. Although the surA gene had been identified in a screen for mutants that failed to survive in stationary phase, the role played by SurA in stationary-phase survival remained unknown. The results presented here demonstrate that the survival defect of surA mutants is due to their inability to grow at elevated pH in the absence of ςS. When cultures of Escherichia coli were grown in peptide-rich Luria-Bertani medium, the majority of the cells lost viability during the first two to three days of incubation in stationary phase as the pH rose to pH 9. At this time the surviving cells resumed growth. In cultures of surA rpoS double mutants the survivors lysed as they attempted to resume growth at the elevated pH. Cells lacking penicillin binding protein 3 and ςS had a survival defect similar to that of surA rpoS double mutants, suggesting that SurA foldase activity is important for the proper assembly of the cell wall-synthesizing apparatus.
PMCID: PMC107631  PMID: 9791122
16.  Determination of Ephedra Alkaloids in Urine and Plasma by HPLC-UV: Collaborative Study 
Journal of AOAC International  2004;87(1):15-24.
Ten collaborating laboratories determined the ephedra alkaloid content (ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, and methylpseudoephedrine) in 8 blind duplicates of human plasma and urine using high-performance liquid chromatography (HPLC) with UV detection. In addition to negative urine and plasma controls, urine samples were spiked with individual ephedra alkaloids ranging in concentration from about 1 to 5 μg/mL. Plasma samples were spiked with individual ephedra alkaloids ranging in concentration from about 100 to 400 ng/mL. Sample solutions were treated to solid-phase extraction using a strong-cation exchange column to help remove interferences. The HPLC analyses were performed on a polar-embedded phenyl column using UV detection at 210 nm. The ephedra alkaloids were not consistently detected in any of the spiked plasma samples. When ephedra alkaloids were detected in the plasma samples, reproducibility between blind replicate samples was very poor. Repeatability, reproducibility, and accuracy were also very poor for the spiked urine samples. On the basis of these re sults, the HPLC-UV method for the determination of ephedra alkaloids in human urine and plasma is not recommended for adoption as Official First Action.
PMCID: PMC2584345  PMID: 15084082
17.  Cardiotoxicity of Ma Huang/Caffeine or Ephedrine/Caffeine in a Rodent Model System 
Toxicologic pathology  2007;35(5):657-664.
Ma Huang (equivalent to 0, 12.5, 25, or 50 mg/kg ephedrine) or ephedrine (0, 6.25, 12.5, 25 mg/kg) were administered as one bolus oral dose to male F344 rats with and without caffeine. The herbal medicine Ma Huang (ephedra) in combination with caffeine caused rapid clinical signs of toxicity including salivation, hyperactivity, ataxia, and eventually lethargy, and failure to respond to stimuli. When this syndrome of clinical signs emerged, animals were moribund sacrificed, and a histological analysis for heart lesions performed. Cardiotoxicity included hemorrhage, necrosis, and degeneration in the ventricles or interventricular septum within 2–4 hours after treatment with Ma Huang (ephedra)/caffeine or ephedrine (the principal active component in Ma Huang)/caffeine. There was a steep dose response curve for cardiotoxicity with minimal toxicity seen at levels of Ma Huang (equivalent to 12.5 mg/kg ephedrine) with caffeine. However, cardiotoxic lesions occurred in 28% of animals with Ma Huang dosages equivalent to 25 mg/kg ephedrine with 15 or 30 mg/kg caffeine, and in 90% of animals at Ma Huang exposures equivalent to 50 mg/kg ephedrine with 15 or 30 mg/kg caffeine. Cardiotoxic lesions occurred in 47% of animals in the 25 mg/kg ephedrine groups with caffeine at 7.25, 15, or 30 mg/kg. There was no statistical difference in the occurrence of cardiotoxic lesions when 15 or 30 mg/kg caffeine was combined with Ma Huang equivalent to 25 or 50 mg/kg ephedrine; likewise there was no statistical difference in the occurrence of cardiotoxic lesions when 7.25, 15, or 30 mg/kg caffeine was combined with 25 mg/kg ephedrine. These results show that the cardiotoxic effects of the herbal medicine, Ma Huang, are similar to that of ephedrine, the principal active ingredient in the herbal medicine. The combination of Ma Huang or ephedrine with caffeine enhanced the cardiotoxicity over that with the herbal medicine or the active ingredient alone.
doi:10.1080/01926230701459978
PMCID: PMC2104562  PMID: 17676524
Cardiotoxicity; Ma Huang; ephedra; ephedrine; caffeine
18.  Genetic Analysis of 15 Protein Folding Factors and Proteases of the Escherichia coli Cell Envelope 
Journal of Bacteriology  2012;194(12):3225-3233.
Each cell hosts thousands of proteins that vary greatly in abundance, structure, and chemical properties. To ensure that all proteins are biologically active and properly localized, efficient quality control systems have evolved. While the structure, function, and regulation of some individual protein folding factors and proteases were resolved up to atomic resolution, others remain poorly characterized. In addition, little is known about which factors are required for viability under specific stress conditions. We therefore determined the physiological implications of 15 factors of the E. coli cell envelope by an integrated genetic approach comprising phenotypic analyses. Our data indicate that surA and tsp null mutations are a lethal combination in rich medium, that surA dsbA and surA dsbC double mutants are temperature sensitive, and that surA ptrA, surA yfgC, dsbA fkpA, degP tsp, degP ppiD, tsp ppiD, and degP dsbA double mutants are temperature sensitive in rich medium containing 0.5 M NaCl, while degP dsbA, degP yfgC, tsp ydgD, and degP tsp double mutants do not grow in the presence of SDS/EDTA. Furthermore, we show that in degP dsbA, degP tsp, and degP yfgC double mutants a subpopulation of LamB exists as unfolded monomers. In addition, dsbA null mutants expressed lower levels of the outer membrane proteins LptD, LamB, FhuA, and OmpW while FhuA levels were reduced in surA single and degP ppiD double mutants. Lower FhuA levels in degP ppiD strains depend on Tsp, since in a tsp degP ppiD triple mutant FhuA levels are restored.
doi:10.1128/JB.00221-12
PMCID: PMC3370860  PMID: 22505681
19.  Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy 
PLoS Computational Biology  2012;8(6):e1002545.
CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy.
Author Summary
Neurons receive information from other neurons via hundreds of contacts (synapses) spread across their dendritic branches. Input signals from synapses propagate along a dendrite to the cell body (soma), where the neuron decides whether or not to produce an action potential. Signals that travel further decay more. Were all synapses equally strong, a synapse far from the soma would have less influence on the decision than a synapse close by. However, neurons in the hippocampus, which are involved in learning and memory, have synapses far from the soma that are stronger than those close by, so that all synapses have an equal voice (“synaptic democracy”). But how can a synapse “know” how far it is from the soma? Using a computational model of a hippocampal neuron, we show that the action potential, which propagates from the soma back into the dendrites, contains information with which synapses can estimate their somatic distance. Specifically, the calcium concentration at the synapse, which is modulated by the backpropagating action potential, decreases with distance from the soma. We show that when the strength of a synapse is adapted in a self-organising manner based on calcium concentration, synaptic democracy is obtained.
doi:10.1371/journal.pcbi.1002545
PMCID: PMC3375220  PMID: 22719238
20.  Neuromuscular determinants of maximum walking speed in well-functioning older adults 
Experimental gerontology  2013;48(3):358-363.
Maximum walking speed may offer an advantage over usual walking speed for clinical assessment of age-related declines in mobility function that are due to neuromuscular impairment. The objective of this study was to determine the extent to which maximum walking speed is affected by neuromuscular function of the lower extremities in older adults. We recruited two groups of healthy, well functioning older adults who differed primarily on maximum walking speed. We hypothesized that individuals with slower maximum walking speed would exhibit reduced lower extremity muscle size and impaired plantarflexion force production and neuromuscular activation during a rapid contraction of the triceps surae muscle group (soleus (SO) and gastrocnemius (MG)).
All participants were required to have usual 10-meter walking speed >1.0 m/s. If the difference between usual and maximum 10m walking speed was < 0.6 m/s, the individual was assigned to the “Slower” group (n=8). If the difference between usual and maximum 10-meter walking speed was > 0.6 m/s, the individual was assigned to the “Faster” group (n=12). Peak rate of force development (RFD) and rate of neuromuscular activation (rate of EMG rise) of the triceps surae muscle group were assessed during a rapid plantarflexion movement. Muscle cross sectional area of the right triceps surae, quadriceps and hamstrings muscle groups was determined by magnetic resonance imaging.
Across participants, the difference between usual and maximal walking speed was predominantly dictated by maximum walking speed (r=.85). We therefore report maximum walking speed (1.76 and 2.17 m/s in Slower and Faster, p<.001) rather than the difference between usual and maximal. Plantarflexion RFD was 38% lower (p=.002) in Slower compared to Faster. MG rate of EMG rise was 34% lower (p=.01) in Slower than Faster, but SO rate of EMG rise did not differ between groups (p=.73). Contrary to our hypothesis, muscle CSA was not lower in Slower than Faster for the muscle groups tested, which included triceps surae (p=.44), quadriceps (p=.76) and hamstrings (p=.98). MG rate of EMG rise was positively associated with RFD and maximum 10m walking speed, but not usual 10m walking speed.
These findings support the conclusion that maximum walking speed is limited by impaired neuromuscular force and activation of the triceps surae muscle group. Future research should further evaluate the utility of maximum walking speed for use in clinical assessment to detect and monitor age-related functional decline.
doi:10.1016/j.exger.2013.01.010
PMCID: PMC3594593  PMID: 23376102
aging; walking; mobility; muscle; electromyography
21.  PpiD is a player in the network of periplasmic chaperones in Escherichia coli 
BMC Microbiology  2010;10:251.
Background
The inner membrane-anchored periplasmic folding factor PpiD is described as a parvulin-like peptidyl prolyl isomerase (PPIase) that assists in the maturation of the major beta-barrel outer membrane proteins (OMPs) of Escherichia coli. More recent work however, calls these findings into question. Here, we re-examined the role of PpiD in the E. coli periplasm by analyzing its functional interplay with other folding factors that influence OMP maturation as well as general protein folding in the periplasmic compartment of the cell, such as SurA, Skp, and DegP.
Results
The analysis of the effects of both deletion and overexpression of ppiD on cell envelope phenotypes revealed that PpiD in contrast to prior observations plays only a minor role, if any, in the maturation of OMPs and cannot compensate for the lack of SurA in the periplasm. On the other hand, our results show that overproduction of PpiD rescues a surA skp double mutant from lethality. In the presence of increased PpiD levels surA skp cells show reduced activities of both the SigmaE-dependent and the Cpx envelope stress responses, and contain increased amounts of folded species of the major OMP OmpA. These effects require the anchoring of PpiD in the inner membrane but are independent of its parvulin-like PPIase domain. Moreover, a PpiD protein lacking the PPIase domain also complements the growth defects of an fkpA ppiD surA triple PPIase mutant and exhibits chaperone activity in vitro. In addition, PpiD appears to collaborate with DegP, as deletion of ppiD confers a temperature-dependent conditional synthetic phenotype in a degP mutant.
Conclusions
This study provides first direct evidence that PpiD functions as a chaperone and contributes to the network of periplasmic chaperone activities without being specifically involved in OMP maturation. Consistent with previous work, our data support a model in which the chaperone function of PpiD is used to aid in the early periplasmic folding of many newly translocated proteins.
doi:10.1186/1471-2180-10-251
PMCID: PMC2956729  PMID: 20920237
22.  The Evolutionary Origin of Somatic Cells under the Dirty Work Hypothesis 
PLoS Biology  2014;12(5):e1001858.
Experimental evolution of digital organisms suggests that mutagenic side effects associated with performing valuable metabolic work can produce germ-soma differentiation in multicellular organisms.
Reproductive division of labor is a hallmark of multicellular organisms. However, the evolutionary pressures that give rise to delineated germ and somatic cells remain unclear. Here we propose a hypothesis that the mutagenic consequences associated with performing metabolic work favor such differentiation. We present evidence in support of this hypothesis gathered using a computational form of experimental evolution. Our digital organisms begin each experiment as undifferentiated multicellular individuals, and can evolve computational functions that improve their rate of reproduction. When such functions are associated with moderate mutagenic effects, we observe the evolution of reproductive division of labor within our multicellular organisms. Specifically, a fraction of the cells remove themselves from consideration as propagules for multicellular offspring, while simultaneously performing a disproportionately large amount of mutagenic work, and are thus classified as soma. As a consequence, other cells are able to take on the role of germ, remaining quiescent and thus protecting their genetic information. We analyze the lineages of multicellular organisms that successfully differentiate and discover that they display unforeseen evolutionary trajectories: cells first exhibit developmental patterns that concentrate metabolic work into a subset of germ cells (which we call “pseudo-somatic cells”) and later evolve to eliminate the reproductive potential of these cells and thus convert them to actual soma. We also demonstrate that the evolution of somatic cells enables phenotypic strategies that are otherwise not easily accessible to undifferentiated organisms, though expression of these new phenotypic traits typically includes negative side effects such as aging.
Author Summary
Cells within an organism are categorized as “germ” if they are able to grow into a whole new offspring organism or as “soma” if they contribute to the body's functionality but cannot produce an offspring themselves. From an evolutionary perspective, it is important to ask why and how a multicellular organism would demarcate the reproductive potential of its cells. Here we propose the “dirty work hypothesis,” which argues that germ–soma differentiation is an adaptation to allow metabolic work that damages a cell's DNA. Soma can afford to perform this “dirty work,” while germ cells must keep their DNA pristine for future multicellular offspring. We use digital organisms to provide experimental evidence in support of this hypothesis and present an unexpected evolutionary trajectory: multicellular organisms first evolve to confine damaging metabolic work to a subset of cells (which we label “pseudo-soma”) before more complex developmental patterns arise that allow for reproductive division of labor with a proper soma. Finally, we demonstrate that somatic cells allow organisms to evolve valuable functions that are otherwise too damaging to cells; however, they come with the side effect of rapid aging. Similar pressures may have produced reproductive division of labor in other contexts, such as the differentiation of reproductive queens and sterile workers in eusocial insect colonies.
doi:10.1371/journal.pbio.1001858
PMCID: PMC4019463  PMID: 24823361
23.  Study of Na+/H+ exchange-mediated pHi regulations in neuronal soma and neurites in compartmentalized microfluidic devices 
Regulation of intracellular pH (pHi) in neurons is crucial to maintain their physiological function. In the current study, newly-developed polydimethylsiloxane (PDMS) microfluidic devices were used to independently investigate pHi regulation in neuronal soma and neurites. Embryonic cortical neurons were cultured in PDMS microfluidic devices with soma growing in one chamber (seeded) and neurites extending through a set of perpendicular microchannels into the opposite parallel chamber (non-seeded). Neurons in the microchambers were characterized by the vital dye calcein-red, polarized mitochondria, neuronal specific β-tubulin (type-III), axonal Tau-1 protein, dendritic microtubule associated protein (MAP-2), and Na+/H+ exchanger isoform 1 (NHE-1). Neurites exhibited higher resting pHi than soma (7.16 ± 0.09 vs. 6.90 ± 0.15). The neurites had a proton extrusion rate 3.7-fold faster than in soma following NH4Cl prepulse-mediated acidification (p < 0.05). The difference in the pHi regulation rates between neurites and soma can be accounted for by the larger surface area to volume ratio in the neurites. Interestingly, inhibition of NHE-1 activity pharmacologically blocked the pHi regulation in soma and in neurites by ~ 70% (p < 0.05). Taken together, our study demonstrated that the microfluidic devices provide a useful tool to study neuronal pHi regulation in soma and their neurites. We conclude that NHE-1 plays an important role in regulation of pHi in both compartments.
doi:10.1039/b918440f
PMCID: PMC2875691  PMID: 20473413
pHi regulation; somata; dendrites; Na+/H+ exchanger; dendritic microtubule associated protein
24.  Development of a Brief Questionnaire to Assess Habitual Beverage Intake (BEVQ-15): Sugar-Sweetened Beverages and Total Beverage Energy Intake 
Introduction
Energy-containing beverages, specifically sugar-sweetened beverages (SSB), may contribute to weight gain and obesity development. Yet, no rapid assessment tools are available which quantify habitual beverage intake (grams, energy) in adults.
Objective
Determine the factorial validity of a newly developed beverage intake questionnaire (BEVQ) and identify potential to reduce items.
Methods
Participants from varying economic and educational backgrounds (n=1,596; age 43±12 yrs; BMI 31.5±0.2 kg/m2) completed a 19-item BEVQ (BEVQ-19). Beverages that contributed <10% to total beverage, or SSB, energy and grams were identified for potential removal. Factor analyses identified beverage categories that could potentially be combined. Regression analyses compared BEVQ-19 outcomes with the reduced version’s (BEVQ-15) variables. Inter-item reliability was assessed using Cronbach’s Alpha. Following BEVQ-15 development, a subsequent study (n=70; age 37±2 yrs; BMI 24.5±0.4 kg/m2) evaluated the relative validity of the BEVQ-15 through comparison of three 24-hour dietary recalls’ (FIR) beverage intake.
Results
Three beverage items were identified for elimination (vegetable juice, meal replacement drinks, mixed alcoholic drinks); beer and light beer were combined into one category. Regression models using BEVQ-15 variables explained 91–99% of variance in the four major outcomes of the BEVQ-19 (all P<0.001). Cronbach’s Alpha ranged 0.97–0.99 for all outcomes. In the follow-up study, BEVQ-15 and FIR variables were significantly correlated with the exception of whole milk; BEVQ-15 SSB (R2=0.69) and total beverage energy (R2=0.59) were more highly correlated with FIR than previously reported for the BEVQ-19. The BEVQ-15 produced a lower readability score of 4.8, which is appropriate for individuals with a fourth grade education or greater.
Conclusion
The BEVQ-19 can be reduced to a 15-item questionnaire. This brief dietary assessment tool will enable researchers and practitioners to rapidly (administration time of ~2 min) assess habitual beverage intake, and to determine possible associations of beverage consumption with health-related outcomes, such as weight status.
doi:10.1016/j.jand.2012.01.023
PMCID: PMC3379009  PMID: 22709811
Beverage intake; factor analysis; diet assessment; validity; questionnaire
25.  Ephedra and Its Application to Sport Performance: Another Concern for the Athletic Trainer? 
Journal of Athletic Training  2001;36(4):420-424.
Objective:
The ma huang herb, otherwise known as ephedra, has gained widespread popularity as an ergogenic supplement. With the sympathomimetic alkaloid ephedrine as its primary active ingredient, ma huang is marketed to reduce fatigue; increase strength, power, and speed; decrease reaction time; and improve body composition. Although numerous side effects have been associated with the use of ma huang, its popularity in athletes continues to grow. This review provides rationale for the ergogenic claims regarding ma huang and compares and contrasts those claims with data from scientifically controlled investigations.
Data Sources:
MEDLINE and SPORT Discus were searched from 1970 to 2000 using the key words ma huang, ephedra, and ephedrine in combination with humans, exercise, performance, and side effects.
Data Synthesis:
Ephedrine has been used alone or in combination with other drugs as an effective weight-loss agent. The weight loss has been attributed to thermogenic and lipolytic effects which, in combination with the central nervous system stimulating effects, have also resulted in its use as an ergogenic aid. Most of the scientific data, however, do not support manufacturers' ergogenic claims, and numerous side effects have been associated with ephedrine use. Thus, the safety and efficacy of ma huang as an ergogenic supplement must be questioned.
Conclusions/Recommendations:
It appears that the risks associated with the use of ma huang far outweigh any possible ergogenic benefits. Thus, it is extremely important that athletic trainers educate athletes on these issues so they can continue to perform at an optimum level in a safe and healthy manner.
PMCID: PMC155439  PMID: 16558668
ma huang; ephedrine; ergogenic aid; performance enhancement

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