2D Saturable Absorbers for Fibre Lasers

© 2015.Two-dimensional (2D) nanomaterials are an emergent and promising platform for future photonic and optoelectronic applications. Here, we review recent progress demonstrating the application of 2D nanomaterials as versatile, wideband saturable absorbers for Q-switching and mode-locking fibre lasers. We focus specifically on the family of few-layer transition metal dichalcogenides, including MoS2, MoSe2 and WS2

Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.Johdanto: Ihmisen immuunikatoviruksen (HIV) hoitoon käytetyt lääkeyhdistelmät ovat vähentäneet HIV-positiivisten henkilöiden sairastuvuutta ja kuolleisuutta. Yhdistelmähoitoon liittyy kuitenkin vakavia sivuvaikutuksia, jotka lisäävät potilaiden riskiä sairastua mm. diabetekseen ja sepelvaltimotautiin. Yksi leimaavimpia sivuvaikutuksia on lipodystrofia eli ihonalaisen rasvakudoksen häviäminen (lipoatrofia) kasvoista, raajoista ja vatsalta samalla kun rasvaa kertyy ylen määrin vatsaonteloon ja niskaan. Ilmiön syyt ovat epäselvät. Useiden HIV:ta vastaan suunnattujen lääkeaineiden on epäilty aiheuttavan lipodystrofiaa mm. tuhoamalla mitokondrioita, solujen energiatehtaita . Lipodystrofiaan ei ole tehokasta hoitoa, ellei HIV-lääkitystä muuteta, mutta esim. uridiini on ollut lupaava apu solumallitutkimusten valossa. Tavoitteet: Tutkia liittyykö yhdistelmähoitoon tai sen käyttöön liittyvään lipodystrofiaan verisuonien jäykistymistä, onko lipoatrofinen rasvakudos tulehtunutta verrattuna ei-lipoatrofiseen rasvakudokseen, eroaako lipoatrofinen ei-lipoatrofisesta rasvakudoksesta mm. mitokondriomäärän ja aineenvaihduntaan vaikuttavien geenien ilmentymisen suhteen sekä poikkeaako lipodystrofiassa paremmin säilyvä niskan rasva häviävästä vatsan ihonalaisrasvasta ja onko se mahdollisesti ruskeata rasvaa. Lisäksi tutkimme, voiko ravintolisänä käytetty uridiini parantaa lipoatrofiaa ja siihen liittyviä aineenvaihduntahäiriöitä, kuten rasvamaksaa ja heikentynyttä insuliiniherkkyyttä. Menetelmät: Tutkimuksiin osallistui 64 HIV-positiivista yhdistelmähoidettua potilasta, joista 45:lla oli ja 19:lla ei ollut kehittynyt lääkitykseen liittyviä rasvakudoksen muutoksia. Verisuonijäykkyys tutkittiin pulssiaaltoanalyysilla, kehon koostumus mitattiin kaksienergisella röntgenabsorptiometria- sekä magneettikuvaantamisella ja maksan rasvapitoisuus protonispektroskopialla. Rasvakudosnäytteet otettiin potilaiden vatsan ja niskan ihoalaisrasvasta ja niistä mitattiin eri geenien ilmentymistä sekä mitokondrioiden ja tulehdussolujen määrää mm. DNA:n monistustekniikalla ja kudosleikevärjäyksin. Uridiinin tehoa lipoatrofian hoidossa arvioitiin 3kk satunnaistetussa lumelääkekontrolloidussa tutkimuksessa, johon osallistui 20 HIV-positiivista yhdistelmähoidettua lipoatrofista henkilöä. Tulokset: HIV-lääkityksen kesto, mutta ei lipodystrofia, altistaa verisuonien jäykistymiselle iästä ja verenpainetasosta riippumatta. Lipoatrofisessa rasvakudoksessa tulehdukseen liittyvien geenien ilmentyminen ja tulehdussolujen määrä ovat lisääntyneet, kun taas mitokondriomäärä sekä rasvasolujen muodostumiseen ja toimintaan liittyvien geenien ilmentyminen vähentyneet verrattuna ei-lipoatrofiseen rasvakudokseen. Lipodystrofiassa säilyvä/lisääntyvä niskan rasva on vähemmän tulehtunutta kuin herkemmin häviävä vatsan ihonalaisrasva eikä se ole ruskeata rasvaa. Lipodystrofisten henkilöiden niskan rasvassa on vähemmän mitokondrioita kuin ei-lipodystrofisten henkilöiden niskan rasvassa, vaikka kudokset ovat ulkoisesti samannäköisiä. Niskan ja vatsan alueen ihonalaisrasva eroaa eniten ns. homeobox-geenien ilmentymisessä eli sellaisten geenien, jotka määrittelevät kudosten sijainnin ja ominaisuudet sikiökehityksen varhaisvaiheessa. Uridiini lisää ihonalaisrasvan määrää lipoatrofisilla potilailla, mutta ei vaikuta maksan rasvapitoisuuteen tai insuliiniherkkyyteen. Johtopäätökset: HIV:n hoitoon käytettyjen lääkkeiden pitkäaikaiskäyttö lisää verisuonien jäykkyyttä ja siten potilaiden riskiä sairastua sydän- ja verisuonitauteihin. Lipoatrofinen rasva on tulehtunut ja sen mitokondriovarannot vähentyneet. Koska mitokondrioiden vähyys on todettavissa niskarasvassa myös sellaisilla lipodystrofisilla henkilöillä, joilla se on säilynyt atrofialta, mitokondriokatoa ei voida pitää lipoatrofiaa suoraan aiheuttavana tekijänä. Niskan ja vatsan ihonalaisrasvan merkittävin ero on elinkehitystä ohjaavissa geeneissä, mikä voi selittää kudosten erilaisen alttiuden lääkkeiden sivuvaikutuksille. Uridiini on tehokas hoito HIV-potilaiden lipodystrofiaan muuttumattoman yhdistelmähoidon aikana

Input-output relations in biological systems: measurement, information and the Hill equation

Biological systems produce outputs in response to variable inputs. Input-output relations tend to follow a few regular patterns. For example, many chemical processes follow the S-shaped Hill equation relation between input concentrations and output concentrations. That Hill equation pattern contradicts the fundamental Michaelis-Menten theory of enzyme kinetics. I use the discrepancy between the expected Michaelis-Menten process of enzyme kinetics and the widely observed Hill equation pattern of biological systems to explore the general properties of biological input-output relations. I start with the various processes that could explain the discrepancy between basic chemistry and biological pattern. I then expand the analysis to consider broader aspects that shape biological input-output relations. Key aspects include the input-output processing by component subsystems and how those components combine to determine the system's overall input-output relations. That aggregate structure often imposes strong regularity on underlying disorder. Aggregation imposes order by dissipating information as it flows through the components of a system. The dissipation of information may be evaluated by the analysis of measurement and precision, explaining why certain common scaling patterns arise so frequently in input-output relations. I discuss how aggregation, measurement and scale provide a framework for understanding the relations between pattern and process. The regularity imposed by those broader structural aspects sets the contours of variation in biology. Thus, biological design will also tend to follow those contours. Natural selection may act primarily to modulate system properties within those broad constraints.Comment: Biology Direct 8:3

Unrelated toxin-antitoxin systems cooperate to induce persistence.

Persisters are drug-tolerant bacteria that account for the majority of bacterial infections. They are not mutants, rather, they are slow-growing cells in an otherwise normally growing population. It is known that the frequency of persisters in a population is correlated with the number of toxin-antitoxin systems in the organism. Our previous work provided a mechanistic link between the two by showing how multiple toxin-antitoxin systems, which are present in nearly all bacteria, can cooperate to induce bistable toxin concentrations that result in a heterogeneous population of slow- and fast-growing cells. As such, the slow-growing persisters are a bet-hedging subpopulation maintained under normal conditions. For technical reasons, the model assumed that the kinetic parameters of the various toxin-antitoxin systems in the cell are identical, but experimental data indicate that they differ, sometimes dramatically. Thus, a critical question remains: whether toxin-antitoxin systems from the diverse families, often found together in a cell, with significantly different kinetics, can cooperate in a similar manner. Here, we characterize the interaction of toxin-antitoxin systems from many families that are unrelated and kinetically diverse, and identify the essential determinant for their cooperation. The generic architecture of toxin-antitoxin systems provides the potential for bistability, and our results show that even when they do not exhibit bistability alone, unrelated systems can be coupled by the growth rate to create a strongly bistable, hysteretic switch between normal (fast-growing) and persistent (slow-growing) states. Different combinations of kinetic parameters can produce similar toxic switching thresholds, and the proximity of the thresholds is the primary determinant of bistability. Stochastic fluctuations can spontaneously switch all of the toxin-antitoxin systems in a cell at once. The spontaneous switch creates a heterogeneous population of growing and non-growing cells, typical of persisters, that exist under normal conditions, rather than only as an induced response. The frequency of persisters in the population can be tuned for a particular environmental niche by mixing and matching unrelated systems via mutation, horizontal gene transfer and selection

Deterministic functions of cortical acetylcholine

Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine ( AC h) release events occur on a fast, sub‐second to seconds‐long time scale (‘transients’). In rats performing a task requiring the detection of cues as well as the report of non‐cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue‐directed responding. Accordingly, ill‐timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying‐on‐task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems. Traditional descriptions of the basal forebrain cholinergic projection system to the cortex focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107385/1/ejn12515.pd

Enhancing Power Efficient Design Techniques in Deep Submicron Era

Excessive power dissipation has been one of the major bottlenecks for design and manufacture in the past couple of decades. Power efficient design has become more and more challenging when technology scales down to the deep submicron era that features the dominance of leakage, the manufacture variation, the on-chip temperature variation and higher reliability requirements, among others. Most of the computer aided design (CAD) tools and algorithms currently used in industry were developed in the pre deep submicron era and did not consider the new features explicitly and adequately. Recent research advances in deep submicron design, such as the mechanisms of leakage, the source and characterization of manufacture variation, the cause and models of on-chip temperature variation, provide us the opportunity to incorporate these important issues in power efficient design. We explore this opportunity in this dissertation by demonstrating that significant power reduction can be achieved with only minor modification to the existing CAD tools and algorithms. First, we consider peak current, which has become critical for circuit's reliability in deep submicron design. Traditional low power design techniques focus on the reduction of average power. We propose to reduce peak current while keeping the overhead on average power as small as possible. Second, dual Vt technique and gate sizing have been used simultaneously for leakage savings. However, this approach becomes less effective in deep submicron design. We propose to use the newly developed process-induced mechanical stress to enhance its performance. Finally, in deep submicron design, the impact of on-chip temperature variation on leakage and performance becomes more and more significant. We propose a temperature-aware dual Vt approach to alleviate hot spots and achieve further leakage reduction. We also consider this leakage-temperature dependency in the dynamic voltage scaling approach and discover that a commonly accepted result is incorrect for the current technology. We conduct extensive experiments with popular design benchmarks, using the latest industry CAD tools and design libraries. The results show that our proposed enhancements are promising in power saving and are practical to solve the low power design challenges in deep submicron era

Advanced space system concepts and their orbital support needs (1980 - 2000). Volume 3: Detailed data. Part 1: Catalog of initiatives, functional options, and future environments and goals

The following areas were discussed in relation to a study of the commonality of space vehicle applications to future national needs: (1) index of initiatives (civilian observation, communication, support), brief illustrated description of each initiative, time periods (from 1980 to 2000+) for implementation of these initiatives; (2) data bank of functional system options, presented in the form of data sheets, one for each of the major functions, with the system option for near-term, midterm, and far-term space projects applicable to each subcategory of functions to be fulfilled; (3) table relating initiatives and desired goals (public service and humanistic, materialistic, scientific and intellectual); and (4) data on size, weight and cost estimations