Parsimony Analysis as a Specific Kind of Homology Estimation and the Implications for Character Weighting

“Remane-Hennigian systematists” still reject parsimony analysis for phylogenetics, because homology or apomorphy analyses are not included. In contrast, “pattern cladists” regard homology as a deductive concept after applying a parsimony test of character congruence. However, as in molecular phylogeny, selection of “good” characters is always done on the basis of ana priorihomology analysis. The distribution criterion of homology—“homologous characters have identical or hierarchical distribution”—is the basis of parsimony analysis. Because this criterion also might fail in cases of genealogical reticulation or concerted homoplasy, character congruence is not a strict test but another probabilistic criterion of homology. A synthetic approach is proposed for phenotypic analysis with application ofa prioricriteria of homology. The resultinga prioriprobabilities of homology serve as criteria for selection and weighting of characters (very low = not selected/poor/mediocre/good/Dollo characters). After application of a parsimony algorithm the final cladogram decides homology estimations.     

Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease

Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense “hypoxic” mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage.We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.     

A structural constitutive model considering angular dispersion and waviness of collagen fibres of rabbit facial veins

Background  

Structural constitutive models of vascular wall integrate information on composition and structural arrangements of tissue. In blood vessels, collagen fibres are arranged in coiled and wavy bundles and the individual collagen fibres have a deviation from their mean orientation. A complete structural constitutive model for vascular wall should incorporate both waviness and orientational distribution of fibres. We have previously developed a model, for passive properties of vascular wall, which considers the waviness of collagen fibres. However, to our knowledge there is no structural model of vascular wall which integrates both these features.     

Estrogens, progestins, and coronary artery reactivity in atherosclerotic monkeys

It has been known for many years that sex hormones modulate vasodilator responses of arteries supplying the uterus with blood. Recently, it has been shown that sex hormones such as estrogen modulate vasomotor responses of other arteries, including coronary arteries. It is thought that modulation of vasodilator and constrictor responses of coronary arteries may be one mechanism by which estrogen affects the risk of coronary heart disease. Although several studies have examined the effects (and potential mechanisms) of estrogen on vasodilator responses of nonatherosclerotic arteries, few have focused on estrogen's effects on atherosclerotic coronary arteries. In studies of ovariectomized atherosclerotic female cynomolgus monkeys, both long-term (2 years) and short-term (20 min) estradiol treatment augments dilator responses to acetylcholine, but not nitroglycerin. Presumably, this indicates an effect of estradiol on endothelium-mediated dilator responses of coronary arteries. Addition of the progestin medroxyprogesterone acetate diminishes the beneficial effect of conjugated equine estrogens on these dilator responses. This is significant because a progestin is usually added to estrogen replacement to reduce the risk of endometrial and breast cancer associated with unopposed estrogen therapy. However, it would seem that not all progestins act similarly on vascular reactivity. Studies in monkeys indicate that addition of progesterone or the progestin medroxyprogesterone acetate does not diminish the beneficial effects of estrogen on coronary dilator responses. Thus it would appear that different estrogen/progestin combinations may affect vascular reactivity in different manners, There is also an effort being made to examine the potential of different kinds of estrogens on cardiovascular risk. Studies in monkeys indicate that one of the estrogens found in conjugated equine estrogens (17 alpha-dihydroequilenin) has estrogen effects on vascular reactivity without having detrimental effects on uterine pathology. The isoflavones “plant estrogens” found in soy protein also have estrogenic effects on vascular reactivity and inhibition.     

Transvascular exchange of fluid and plasma proteins

A theoretical model of transvascular exchange of fluid and plasma proteins in the microcirculation is developed based on fundamental laws of the fluid mechanics and on phenomenological transport equations of the irreversible thermodynamics. Intravascular axial changes of the pressure, flow and plasma protein concentration are taken into account as well as axial gradients of vascular permeability. Proper nondimensionalization of the resulting equations leads to the identification of dimensionless parameters which combine the transport characteristics of the endothelial wall and the intravascular flow resistance. In the theory, the dependence of the reflection coefficient on the transport coefficients of the vascular wall and on the plasma protein concentration is established. The model is applied to the cat mesentery and the rat intestinal muscle. The numerical simulations indicate that taking into account vascular protein permeability yields considerable differences in the axial distribution of the plasma protein concentration and transvascular fluxes in comparison with the case of protein impermeability of the endothelial wall. The results show that the maximum of the transvascular fluid and plasma protein movement resides at the site of the small venules while a minimum of the exchange occurs at the site of the midcapillaries.     

Analytical studies of injury criteria for the thorax

The viscous criterion is a recently developed criterion to assess injury severity of the human thorax. In the viscous criterion, the peak viscous response, which is defined as the maximum product of deformation velocity and compression of an object, is proposed as a predictor of injury risk. However, the physical meaning of the criterion is not very clear. In this paper, the mathematical properties of the viscous criterion are analyzed. A mechanical thorax model is then used to relate the criterion to the physical quantities of the model using energy concepts. It is found that the so-called peak viscous response is strongly related to the peak energy storing rate of the thorax which is not related to the viscosity of the thorax. It is also shown that the viscous response of the thorax is given by the integral of the velocity squared with respect to time. The analysis is further expanded to a more general case to result in four criteria based upon the energy concepts. A hypothesis for injury assessment is proposed by using the four criteria.     

Cytoplasmic membrane damage and thromboplastinemia in hypercholesterolemia

Experiments on 67 rabbits were performed to examine the injured external cell membranes of the vascular wall, appearing in the blood flow in the course of the development of alimentary hypercholesterolemia. The time of the appearance in the blood plasma of the external cell membranes was judged from the activity of their specific marker, 5'-nucleotidase. An abrupt increase in 5'-nucleotidase activity was disclosed in the blood plasma at the height of hypercholesterolemia. The latter circumstance served as an objective criterion for injury to ther external cell membranes and might be regarded as a risk factor in thrombus formation.     

A Technique for the Combination of Clearing, Staining, and Injecting Small Mammals

A combined method for clearing soft tissues, staining cartilage and bone, and injecting the vascular system of small mammals was developed using Mus musculus (house mouse). Mammalian muscle tissue remains milky or even opaque after “clearing” by previous techniques due to the relatively high content of intramuscular fat. A method employing chloroform-ethanol successfully renders soft tissues of mammalian specimens translucent without damaging or bleeding color from the latex injected in the circulatory system. Resulting specimens yield an excellent view of the skeletal system and the injected vascular system without obstruction by opaque tissues or disruption by physical removal of connective tissue.     

Nowcasting the Spread of Chikungunya Virus in the Americas

Background

In December 2013, the first locally-acquired chikungunya virus (CHIKV) infections in the Americas were reported in the Caribbean. As of May 16, 55,992 cases had been reported and the outbreak was still spreading. Identification of newly affected locations is paramount to intervention activities, but challenging due to limitations of current data on the outbreak and on CHIKV transmission. We developed models to make probabilistic predictions of spread based on current data considering these limitations.

Methods and Findings

Branching process models capturing travel patterns, local infection prevalence, climate dependent transmission factors, and associated uncertainty estimates were developed to predict probable locations for the arrival of CHIKV-infected travelers and for the initiation of local transmission. Many international cities and areas close to where transmission has already occurred were likely to have received infected travelers. Of the ten locations predicted to be the most likely locations for introduced CHIKV transmission in the first four months of the outbreak, eight had reported local cases by the end of April. Eight additional locations were likely to have had introduction leading to local transmission in April, but with substantial uncertainty.

Conclusions

Branching process models can characterize the risk of CHIKV introduction and spread during the ongoing outbreak. Local transmission of CHIKV is currently likely in several Caribbean locations and possible, though uncertain, for other locations in the continental United States, Central America, and South America. This modeling framework may also be useful for other outbreaks where the risk of pathogen spread over heterogeneous transportation networks must be rapidly assessed on the basis of limited information.     

An anatomical basis for prognosis of malignant melanoma.

Clinical observations during surgery have led us to speculate that an anatomic basis may in fact exist for the poor prognosis associated with malignant melanoma arising in certain recognized "high-risk" areas. In our study we have treated and followed 45 patients with primary malignant melanoma for over 5 years. During the course of treatment, we identified variations in anatomic characteristics at the tumor sites. Criteria were established for high- and low-risk locations by the neurovascular structure encountered. We speculate that these sites that have neurovascular windows provide a readily accessible vascular pathway for the dissemination of malignant cells to deeper visceral structures and may account for the poor prognosis associated with primary lesions in these locations. Thirty patients were classified as being at high risk for developing metastasis, whereas 13 were classified as being at low risk; 2 patients were in a special-risk category. To date, 12 of the 30 patients with "high-risk" melanoma have gone on to develop metastatic disease, which represents 40 percent of that group, whereas none of the patients classified as "low risk" have developed metastases during the same period.     

A 3-D constrained mixture model for mechanically mediated vascular growth and remodeling

In contrast to the widely applied approach to model soft tissue remodeling employing the concept of volumetric growth, microstructurally motivated models are capable of capturing many of the underlying mechanisms of growth and remodeling; i.e., the production, removal, and remodeling of individual constituents at different rates and to different extents. A 3-dimensional constrained mixture computational framework has been developed for vascular growth and remodeling, considering new, microstructurally motivated kinematics and constitutive equations and new stress and muscle activation mediated evolution equations. Our computational results for alterations in flow and pressure, using reasonable physiological values for rates of constituent growth and turnover, concur with findings in the literature. For example, for flow-induced remodeling, our simulations predict that, although the wall shear stress is restored completely, the circumferential stress is not restored employing realistic physiological rate parameters. Also, our simulations predict different levels of thickening on inner versus outer wall locations, as shown in numerous reports of pressure-induced remodeling. Whereas the simulations are meant to be illustrative, they serve to highlight the experimental data currently lacking to fully quantify mechanically mediated adaptations in the vasculature.     

Carotid geometry effects on blood flow and on risk for vascular disease

It has been widely observed that atherosclerotic diseases occur at sites with complex hemodynamics, such as artery bifurcations, junctions, and regions of high curvature. These regions usually have very low or highly oscillatory wall shear stress (WSS). In the present work, 3D pulsatile blood flow through a model of the carotid artery bifurcation was simulated using a finite volume numerical method. The goal was to quantify the risk of atherogenesis associated with different carotid artery geometries. A risk scale based on the average WSS on the sinus wall of the internal carotid artery was proposed-a scale that can be used to quantify the effect of the carotid geometry on the relative risk for developing vascular disease. It was found that the bifurcation angle and the out-of-plane angle of the internal carotid artery affect the formation of low stress regions on the carotid walls. The main conclusions are: (a) larger internal carotid artery angles (theta(IC)) generally increase the frequency and the area of blood recirculation and lower the WSS on the sinus wall, hence increasing the risk of plaque build-up; (b) off-plane angles were found to lower the WSS on the sinus for geometries with theta(IC)25 degrees . Larger off-plane angles generally increase the danger of plague build-up; (c) for theta(IC) < 25 degrees , the off-plane angle does not have an obvious effect on the hemodynamic WSS; (d) symmetric bifurcations were found to increase the WSS on the sinus wall and ease the risk of vascular disease.     

Tempol attenuates atherosclerosis associated with metabolic syndrome via decreased vascular inflammation and NADPH-2 oxidase expression

Abstract

Oxidative stress is an important factor in the generation of vascular injury in atherosclerosis. Chronic administration of fructose in rodents is able to facilitate oxidative damage. In the present study we evaluated the role of Tempol, a superoxide dismutase mimetic, on the effect of high fructose intake in apolipoprotein E-deficient (ApoE-KO) mice. Rodents were fed with fructose overload (FF, 10% w/v) for 8 weeks and treated with Tempol 1 mg/kg/day the latest 4 weeks. Tempol revert the pro-oxidant effects caused by FF, diminished lipid peroxidation and impaired vascular NADPH oxidase system through the downregulation of p47phox expression in the vascular wall. Tempol inhibited the expression of vascular adhesion molecule 1 (VCAM-1) in aorta and reduced the development of atheroma plaques. Our results indicate that tempol attenuates oxidative stress by interfering with the correct assembly of Nox2 oxidase complex in the vascular wall and is able to reduce atherosclerosis. Thus tempol represents a potential therapeutic target for preventing risk factors associated with metabolic syndrome.     

Detectability and criterion measures in temporal generalization

Computer simulation of performance on “normal” and “episodic” temporal generalization tasks was used to examine the relations between the theoretical parameters of models which fit temporal generalization data (“timing sensitivity” and “threshold”), and the d′ (detectability) and beta (decision criterion) measures of signal-detection theory. In general, changes in timing sensitivity altered d′, whereas threshold changes affected beta, supporting the assertion that the two sorts of variables (“sensitivity/detectability” and “threshold/criterion”) were psychologically equivalent. Cases where temporal generalization gradients were apparently contaminated by “random responding” could be treated by changes in beta, but cases in which temporal generalization gradients were not peaked at the standard posed severe problems for a simple signal-detection account, although existing models of temporal generalization performance could deal with them.     

ACE inhibition and atherogenesis

Recent clinical studies such as HOPE, SECURE, and APRES show that angiotensin-converting enzyme (ACE) inhibitors like ramipril improve the prognosis of patients with a high risk of atherothrombotic cardiovascular events. Atherosclerosis, as a chronic inflammatory condition of the vascular system, can turn into an acute clinical event through the rupture of a vulnerable atherosclerotic plaque followed by thrombosis. ACE inhibition has a beneficial effect on the atherogenic setting and on fibrinolysis. Endothelial dysfunction is the end of a common process in which cardiovascular risk factors contribute to inflammation and atherogenesis. By inhibiting the formation of angiotensin II, ACE inhibitors prevent any damaging effects on endothelial function, vascular smooth muscle cells, and inflammatory vascular processes. An increase in the release of NO under ACE inhibition has a protective effect. Local renin-angiotensin systems in the tissue are involved in the inflammatory processes in the atherosclerotic plaque. Circulating ACE-containing monocytes, which adhere to endothelial cell lesions, differentiate within the vascular wall to ACE-containing macrophages or foam cells with increased local synthesis of ACE and angiotensin II. Within the vascular wall, angiotensin II decisively contributes to the instability of the plaque by stimulating growth factors, adhesion molecules, chemotactic proteins, cytokines, oxidized LDL, and matrix metalloproteinases. Suppression of the increased ACE activity within the plaque can lead to the stabilization and deactivation of the plaque by reducing inflammation in the vascular wall, thus lessening the risk of rupture and thrombosis and the resultant acute clinical cardiovascular events. The remarkable improvement in the long-term prognosis of atherosclerotic patients with increased cardiovascular risk might be the clinical result of the contribution made by ACE inhibition in the vascular wall.     

Automatic and label‐free identification of blood vessels in gliomas using the combination of multiphoton microscopy and image analysis

Currently, the targeted treatment of tumor based on the tumor microenvironment is newly developed. Blood vessels are the key parts in the tumor microenvironment, which is taken as a new visible target for tumor therapy. Multiphoton microscopy (MPM), based on the second harmonic generation and two‐photon excited fluorescence, is available to make the label‐free analysis on the blood vessels in human gliomas. MPM can reveal the vascular morphological characteristics in gliomas, including vascular malformation, intense vascular proliferation, perivascular collagen deposition, perivascular lymphocytes aggregation and microvascular proliferation. In addition, the image analysis algorithms were developed to automatically calculate the perivascular collagen content, vascular cavity area, lumen area, wall area and vessel number. Thus, the vascular morphology, the perivascular collagen deposition and intense vascular proliferation degree can be further quantitatively characterized. Compared with the pathological analysis, the combination of MPM and image analysis has potential advantages in making a quantitative and qualitative analyzing on vascular morphology in glioma microenvironment. As micro‐endoscope and two‐photon fiberscope are technologically improved, this combined method will be a useful imaging way to make the real‐time research on the targeting tumor microenvironment in gliomas.     

Cholesterol metabolism modulators and the future of atherosclerosis therapy

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).     

Aerosol influenza transmission risk contours: A study of humid tropics versus winter temperate zone

Background

In recent years, much attention has been given to the spread of influenza around the world. With the continuing human outbreak of H5N1 beginning in 2003 and the H1N1 pandemic in 2009, focus on influenza and other respiratory viruses has been increased. It has been accepted for decades that international travel via jet aircraft is a major vector for global spread of influenza, and epidemiological differences between tropical and temperate regions observed. Thus we wanted to study how indoor environmental conditions (enclosed locations) in the tropics and winter temperate zones contribute to the aerosol spread of influenza by travelers. To this end, a survey consisting of 632 readings of temperature (T) versus relative humidity (RH) in 389 different enclosed locations air travelers are likely to visit in 8 tropical nations were compared to 102 such readings in 2 Australian cities, including ground transport, hotels, shops, offices and other publicly accessible locations, along with 586 time course readings from aircraft.

Results

An influenza transmission risk contour map was developed for T versus RH. Empirical equations were created for estimating: 1. risk relative to temperature and RH, and 2. time parameterized influenza transmission risk. Using the transmission risk contours and equations, transmission risk for each country's locations was compared with influenza reports from the countries. Higher risk enclosed locations in the tropics included new automobile transport, luxury buses, luxury hotels, and bank branches. Most temperate locations were high risk.

Conclusion

Environmental control is recommended for public health mitigation focused on higher risk enclosed locations. Public health can make use of the methods developed to track potential vulnerability to aerosol influenza. The methods presented can also be used in influenza modeling. Accounting for differential aerosol transmission using T and RH can potentially explain anomalies of influenza epidemiology in addition to seasonality in temperate climates.