Transition probabilities for general birth-death processes with applications in ecology, genetics, and evolution

A birth-death process is a continuous-time Markov chain that counts the number of particles in a system over time. In the general process with $n$ current particles, a new particle is born with instantaneous rate $\lambda_n$ and a particle dies with instantaneous rate $\mu_n$. Currently no robust and efficient method exists to evaluate the finite-time transition probabilities in a general birth-death process with arbitrary birth and death rates. In this paper, we first revisit the theory of continued fractions to obtain expressions for the Laplace transforms of these transition probabilities and make explicit an important derivation connecting transition probabilities and continued fractions. We then develop an efficient algorithm for computing these probabilities that analyzes the error associated with approximations in the method. We demonstrate that this error-controlled method agrees with known solutions and outperforms previous approaches to computing these probabilities. Finally, we apply our novel method to several important problems in ecology, evolution, and genetics

Proton Magnetic Resonance Spectroscopy Reveals Neuroprotection by Oral Minocycline in a Nonhuman Primate Model of Accelerated NeuroAIDS

Background: Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury. Methodology/Principal Findings: Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocycline-treated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals. Conclusions/Significance: In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Endogenous laminin is required for human airway smooth muscle cell maturation

BACKGROUND: Airway smooth muscle (ASM) contraction underlies acute bronchospasm in asthma. ASM cells can switch between a synthetic-proliferative phenotype and a contractile phenotype. While the effects of extracellular matrix (ECM) components on modulation of ASM cells to a synthetic phenotype have been reported, the role of ECM components on maturation of ASM cells to a contractile phenotype in adult lung is unclear. As both changes in ECM components and accumulation of contractile ASM are features of airway wall remodelling in asthma, we examined the role of the ECM protein, laminin, in the maturation of contractile phenotype in human ASM cells. METHODS: Human ASM cells were made senescence-resistant by stable expression of human telomerase reverse transcriptase. Maturation to a contractile phenotype was induced by 7-day serum deprivation, as assessed by immunoblotting for desmin and calponin. The role of laminin on ASM maturation was investigated by comparing the effects of exogenous laminin coated on culture plates, and of soluble laminin peptide competitors. Endogenous expression of laminin chains during ASM maturation was also measured. RESULTS: Myocyte binding to endogenously expressed laminin was required for ASM phenotype maturation, as laminin competing peptides (YIGSR or GRGDSP) significantly reduced desmin and calponin protein accumulation that otherwise occurs with prolonged serum deprivation. Coating of plastic cell culture dishes with different purified laminin preparations was not sufficient to further promote accumulation of desmin or calponin during 7-day serum deprivation. Expression of α2, β1 and γ1 laminin chains by ASM cells was specifically up-regulated during myocyte maturation, suggesting a key role for laminin-2 in the development of the contractile phenotype. CONCLUSION: While earlier reports suggest exogenously applied laminin slows the spontaneous modulation of ASM to a synthetic phenotype, we show for the first time that endogenously expressed laminin is required for ASM maturation to the contractile phenotype. As endogenously expressed laminin chains α2, β1 and γ1 are uniquely increased during myocyte maturation, these laminin chains may be key in this process. Thus, human ASM maturation appears to involve regulated endogenous expression of a select set of laminin chains that are essential for accumulation of contractile phenotype myocytes

Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and duration of anticancer treatments

A quantitative synthesis of the medicinal ethnobotany of the Malinké of Mali and the Asháninka of Peru, with a new theoretical framework

<p>Abstract</p> <p>Background</p> <p>Although ethnomedically and taxonomically guided searches for new medicinal plants can improve the percentage of plants found containing active compounds when compared to random sampling, ethnobotany has fulfilled little of its promise in the last few decades to deliver a bounty of new, laboratory-proven medicinal plants and compounds. It is quite difficult to test, isolate, and elucidate the structure and mechanism of compounds from the plethora of new medicinal plant uses described each year with limited laboratory time and resources and the high cost of clinical trials of new drug candidates.</p> <p>Methods</p> <p>A new quantitative theoretical framework of mathematical formulas called "relational efficacy" is proposed that should narrow down this search for new plant-derived medicines based on the hypothesis that closely related plants used to treat closely related diseases in distantly related cultures have a higher probability of being effective because they are more likely to be independent discoveries of similar plant compounds and disease mechanisms. A prerequisite to this hypothesis, the idea that empirical testing in traditional medicine will lead to choosing similar medicinal plants and therefore the medicinal flora of two distant cultures will prove to be more similar than their general flora, is tested using resampling statistics on cross-cultural field data of the plants used by the Malinké of Mali and the Asháninka of Peru to treat the diseases malaria, African sleeping sickness, Chagas' disease, leishmaniasis, diabetes, eczema, asthma, and uterine fibroids.</p> <p>Results</p> <p>In this case, the similarity of the medicinal floras is found to be significantly greater than the similarity of the general floras, but only when the diseases in question are grouped into the categories of parasitic and autoimmune diseases.</p> <p>Conclusion</p> <p>If the central theoretical framework of this hypothesis is shown to be true, it will allow the synthesis of medicinal plant information from around the world to pinpoint the species with the highest potential efficacy to take into the laboratory and analyze further, ultimately saving much field and laboratory time and resources.</p> <p><b>Spanish abstract</b></p> <p>Las búsquedas que utilizan la etnomedicina y la taxonomía para descubrir nuevas plantas medicinales, pueden aumentar la probabilidad de éxito de encontrar compuestos químicos activos en plantas, en comparación con las búsquedas aleatorias. A pesar de lo anterior, en las últimas décadas, la etnobotánica no ha cumplido con las expectativas de proveer numerosas plantas medicinales y químicos nuevos una vez examinados en el laboratorio. Cada año se describen una plétora de plantas medicinales y sus usos, sin embargo las limitaciones de tiempo y recursos en los laboratorios, unidos al alto coste de los ensayos clínicos de las drogas potenciales, hacen muy difícil probar, aislar, y elucidar la estructura y el mecanismo de los compuestos de estas plantas. Se propone un nuevo marco teórico cuantitativo cuyo fin es focalizar la búsqueda de nueva plantas medicinales. Este marco teórico está basado en la hipótesis que las plantas cercanamente relacionadas, usadas para tratar enfermedades cercanamente relacionadas en culturas distantemente relacionadas, tienen una eficacia potencial más alta, debido a que es más probable que estos hallazgos sean descubrimientos independientes de compuestos químicos similares. Parte de esta hipótesis, que las escogencias racionales se hacen para elegir plantas medicinales similares y que la flora medicinal de dos culturas distantes es más similar que su flora general, se probó usando métodos estadísticos de remuestreo con datos de campo de la comunidad Malinké de Malí y de la Asháninka de Perú, y las enfermedades de paludismo, enfermedad africana del sueño, enfermedad de Chagas, leishmania, diabetes, eczema, asma, y fibromas uterinos. Se encontró, en este caso, que la similitud de las floras medicinales es significativamente mayor a la similitud de las floras generales, solamente cuando las enfermedades analizadas se agruparon en las categorías de enfermedades parasitarias y enfermedades autoinmunes. Si se demostrara que las otras partes de esta hipótesis son ciertas, se podría sintetizar la información sobre plantas medicinales alrededor del mundo, para establecer así las plantas potencialmente más eficaces para llevarlas al laboratorio y analizarlas más profundamente.</p> <p><b>French abstract</b></p> <p>Par rapport aux recherches menées de façon aléatoire, les recherches effectuées par des critères ethnobotaniques et taxonomiques ont de meilleures chances à découvrir de nouvelles plantes médicinales à produit chimique actifs. Pendant les dernières décennies pourtant, l'ethnobotanique a réalisé peu de ces promesses à révéler un grand nombre de plantes médicinales et de nouveaux produits chimiques, testés au laboratoire. Avec les ressources limitées pour la recherche au laboratoire et le coût élevé des épreuves cliniques pour trouver de nouveaux candidats aux médicaments, il est difficile d'étudier, d'isoler et d'élucider la structure et le mécanisme des produits chimiques de chacune des nombreuses plantes médicinales (et les utilisations de ces plantes) décrites chaque année. Nous proposons une nouvelle technique théorique et quantitative pour préciser la recherche de nouvelles plantes médicinales; elle est basée sur l'hypothèse que les plantes étroitement apparentées, employées pour traiter les maladies étroitement apparentées dans les cultures très éloignées les unes des autres, ont une potentialité d'efficacité supérieure parce qu'elles représentent la découverte indépendante des propriétés chimiques semblables des plantes. Une partie de cette hypothèse-qui démontre que la sélection des plantes médicinales semblables est un choix rationnel et qu'il y a davantage de ressemblance dans la flore médicinale de deux cultures éloignées que dans leur flore générale-est examinée par un re-échantillonnage des données de recherches effectuées parmi les Malinké au Mali et les Asháninka au Pérou, en particulier sur la malaria, la maladie africaine du sommeil, la maladie de Chagas, la leishmania, le diabète, l'eczéma, l'asthme et les fibromes utérins. Dans ces cas précis, la similitude de la flore médicinale s'avère sensiblement plus grande que la similitude de la flore générale, mais seulement quand les maladies en question sont regroupées ensemble comme maladies parasitaires et auto-immunitaires. Si cette hypothèse est prouvée, elle permettra la synthèse des informations recueillies sur les plantes médicinales du monde entier pour en sélectionner de façon plus précise celles qui sont les plus efficaces et qui méritent analyse plus approfondie au laboratoire.</p> <p><b>Asháninka abstract</b></p> <p>Aayiantyarori iròpero aavintane, ontzimatye ancovacovatero ayotero ovaqueraripaye incashi iyoyetziri ashaninka, ayotzityaro aajatzi iyotane viracocha paitachari "quimica" ancantero aaca oshintsinka inchashipaye. Atziri yotacotzirori cametsa, ishtoriajacotzirori iyotane ashaninkapaye te iroñàrantero maaroni ocaratzi yamenacotaqueri laboratorioki. Aaviantyarori cametsa, ayotacotero aavintarontsiyetatsiri osamani antzimaventero ishtoriatacotaro, aajatzi osheki opinata ampinaventero aparopaye inchashi, acoviriqui ayotacotero, osaretsikipaye. Tzimatsi ovaquerari quenquishiriantsitatsiri ero opinata osheki ashitoriatacotero aparopaye inchashi, asampiyetatyrey pashinipaye atziri saicatsiri intaina puitarika inchasshi yavintari, ajatzirica oshiyaro ayotzi aaca, quemetachari atziri saikatsiri nampitsiki malinke aajatzi ishiyari ashaninka saicatsiri peruki, tzimatsi inchashi aajatzi yaavintari osheki okamètsatzi aririka anteri mantsiyarentsi icantaitziri ompetarentsi catsirentsi, pochokirentsi, patsarontsi(matatsi) ashipetate maaroni, ampochavathate, ancainikentsite, oncatsithakite tsinani. Aririka añaker aajatzi ahiyaro inchashi yaavintayetari pashinipaye atziri intainasatzi irdotake ahitoriatacoperoteri anàashityard aavintarontsi ovamairiri shithanentsi, onàshitaavintarontsi tzicaacoventairi ero antane mantsiyarentsi. Omanperotatyarica iròperotzi avintarontsi, oshitovake laboratorioki aritaque iyoitanaquero maaroni quipatsiki iroperori avintarontsi.</p

Early detection of neuropathophysiology using diffusion-weighted magnetic resonance imaging in asymptomatic cats with feline immunodeficiency viral infection

HIV infection results in a highly prevalent syndrome of cognitive and motor disorders designated as HIV-associated dementia (HAD). Neurologic dysfunction resembling HAD has been documented in cats infected with strain PPR of the feline immunodeficiency virus (FIV), whereas another highly pathogenic strain (C36) has not been known to cause neurologic signs. Animals experimentally infected with equivalent doses of FIV-C36 or FIV-PPR, and uninfected controls were evaluated by magnetic resonance diffusion weighted imaging (DWMRI) and spectroscopy (MRS) at 17.5–18 weeks postinfection, as part of a study of viral clade pathogenesis in FIV-infected cats. The goals of the MR imaging portion of the project were to determine whether this methodology was capable of detecting early neuropathophysiology in the absence of outward manifestation of neurological signs and to compare the MR imaging results for the two viral strains expected to have differing degrees of neurologic effects. We hypothesized that there would be increased diffusion, evidenced by the apparent diffusion coefficient as measured by DW-MRI, and altered metabolite ratios measured by MRS, in the brains of FIV-PPRinfected cats relative to C36-infected cats and uninfected controls. Increased apparent diffusion coefficients were seen in the white matter, gray matter, and basal ganglia of both the PPR and C36-infected (asymptomatic) cats. Thalamic MRS metabolite ratios did not differ between groups. The equivalently increased diffusion by DW-MRI suggests similar indirect neurotoxicity mechanisms for the two viral genotypes. DW-MRI is a sensitive tool to detect neuropathophysiological changes in vivo that could be useful during longitudinal studies of FIV