Mutual information analysis of mutation,nonlinearity, and triple interactions in proteins

Mutations are the cause of several diseases as well as the underlying force of evolution. A thorough understanding of their biophysical consequences is essential. We present a computational framework for evaluating different levels of mutual information (MI) and its dependence on mutation. We used molecular dynamics trajectories of the third PDZ domain and its different mutations. Nonlinear MI between all residue pairs are calculated by tensor Hermite polynomials up to the fifth order and compared with results from multivariate Gaussian distribution of joint probabilities. We show that MI is written as the sum of a Gaussian and a nonlinear component. Results for the PDZ domain show that the Gaussian term gives a sufficiently accurate representation of MI when compared with nonlinear terms up to the fifth order. Changes in MI between residue pairs show the characteristic patterns resulting from specific mutations. Emergence of new peaks in the MI versus residue index plots of mutated PDZ shows how mutation may change allosteric pathways. Triple correlations are characterized by evaluating MI between triplets of residues. We observed that certain triplets are strongly affected by mutation. Susceptibility of residues to perturbation is obtained by MI and discussed in terms of linear response theory.     

Serum MMP-9 activity as a diagnosing marker for the developing heart failure of post MI patients

Myocardial infarction (MI) is the result, in mostly cases, of the destabilization and rupture of atherosclerotic lesions. The destruction of cardiac tissue resulting from myocardial ischemia could further result in heart failure. It has been suggested that plaque instability may be mediated by matrix metalloproteinase (MMP) family. Studies have identified increased MMP-2 and MMP-9 in human platelets, and acute myocardial infarction patients with elevated MMP-2 and MMP-9 levels. However, the alteration of MMP-2 and MMP-9 from post MI left ventricle remodeling to heart failure remains to be clarified. The purpose of this study is to investigate the serum concentrations and activities of MMP-2 and MMP-9 in the developing heart failure from post MI patients. Twenty eight patients with MI without heart failure (Killip FC I) (group A; compensated) and twenty seven MI patients with heart failure (Killip II-III) (group B; decompensated) were collected to evaluate the serum levels and activities of MMP-2 and MMP-9 by ELISA and Zymography, respectively. It was observed that the both serum levels and activities of MMP-9 significantly increased (P < 0.01) in decompensated group compared to compensated group, but there was no significant difference of serum MMP-2 levels and activities between two groups. The highly elevated serum MMP-9 concentration of decompensated patients is not related with inflammatory or localized infarct area of myocardium and the real mechanisms remain to be revealed. We suggest that the increase of MMP-9 levels and activity may be used as a new marker to diagnose the development of heart failure in patients with post MI, and provide the therapeutic implications in the future.     

Exploratory Analysis on the Use of Statins with or without n-3 PUFA and Major Events in Patients Discharged for Acute Myocardial Infarction: An Observational Retrospective Study

BackgroundCombined treatment (CT) with statins and polyunsaturated fatty acids (n-3 PUFA) resulted in a reduction of death and major cardiovascular events when administered after a myocardial infarction (MI). However, recent data suggests that CT may be ineffective because patients are currently treated aggressively and the risk may not be further decreased. We aimed to study the prevalence and the results on major outcomes with CT among patients discharged with a MI in Italy.Conclusions/SignificanceAmong a representative sample of patients discharged with MI in Italy, we observed clinically significant synergism between the effects of statins and n-3 PUFA for most cardiovascular outcomes, including all cause mortality.     

Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators

Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is safe and may improve cardiac function and structural remodelling in patients following myocardial infarction (MI). Cardiovascular cell differentiation and paracrine effects to promote endogenous cardiac regeneration, neovascularization, anti-inflammation, anti-apoptosis, anti-remodelling and cardiac contractility, may contribute to MSC-based cardiac repair following MI. However, current evidence indicates that the efficacy of MSC transplantation was unsatisfactory, due to the poor viability and massive death of the engrafted MSCs in the infarcted myocardium. MicroRNAs are short endogenous, conserved, non-coding RNAs and important regulators involved in numerous facets of cardiac pathophysiologic processes. There is an obvious involvement of microRNAs in almost every facet of putative repair mechanisms of MSC-based therapy in MI, such as stem cell differentiation, neovascularization, apoptosis, cardiac remodelling, cardiac contractility and arrhythmias, and others. It is proposed that therapeutic modulation of individual cardiovascular microRNA of MSCs, either mimicking or antagonizing microRNA actions, will hopefully enhance MSC therapeutic efficacy. In addition, MSCs may be manipulated to enhance functional microRNA expression or to inhibit aberrant microRNA levels in a paracrine manner. We hypothesize that microRNAs may be used as novel regulators in MSC-based therapy in MI and MSC transplantation by microRNA regulation may represent promising therapeutic strategy for MI patients in the future.     

Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure

Strong expression of the inducible form of nitric oxide synthase (NOS II) has been shown in the myocardium of patients with myocardial infarction (MI). We hypothesized that NOS II plays an important role in the development of MI and subsequent heart failure and that inhibition of NOS II may beneficially alter the course of the disease. Long-term administration (2 mo) of the selective NOS II inhibitor S-methylisothiourea (SMT) to rats with MI significantly improved cardiac function. A significant drop in mortality, lung water content, infarct size, and cardiomyocyte hypertrophy was also associated with the use of SMT. Plasma concentration of nitrite and nitrate was also reduced by SMT. Short-term administration of SMT (first 2 wk only) significantly reduced infarct size; however, it did not improve cardiac dysfunction measured 2 mo after MI. These findings demonstrate that induction of NOS II during MI exerts negative effects on cardiac function and structure. Long-term administration of a selective NOS II inhibitor may prove to be beneficial in the treatment of MI and congestive heart failure.     

Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function

Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in rupture rate; however, patient data are controversial. We found a significantly higher rupture rate in testosterone-treated female mice within 1 wk after MI, whereas castration in males significantly reduced rupture. We hypothesized that testosterone may adversely affect remodeling after MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may be cardioprotective, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation on morphological and histological changes during early remodeling after MI in 4-wk-old male and female C57BL/6J mice and how these events could affect cardiac function. Females were randomly divided into 1) sham ovariectomy + placebo (s-ovx + P), 2) s-ovx + testosterone (T), 3) ovx + P, and 4) ovx + T; males were divided into 1) sham castration + P (s-cas + P), 2) s-cas + 17beta-estradiol (E), 3) cas + P, and 4) cas + E. At 6 wk after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle was weighed and sectioned for evaluation of MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day group before organ harvest. Cardiac rupture rate and IEI were significantly higher in testosterone-treated females and noncastrated males than in controls; these effects were accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and left ventricular dilatation. Ovariectomy in females and estrogen supplementation in males did not confer significant protection from cardiac rupture, IEI, or neutrophil infiltration. We concluded that, in mice, high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture, and possibly causing deterioration of cardiac function after MI, and, conversely, estrogen seems to have no significant protective effect in the acute phase after MI.     

Association of deoxyribonuclease I genetic polymorphisms with myocardial infarction in Han Chinese

Deoxyribonuclease I gene exhibits polymorphisms, including a single nucleotide polymorphism (A2317G) and a 56 bp variable number of tandem repeat, designated as HumDN1. G2317 was regarded as an independent risk factor for Japanese myocardial infarction (MI) patients. We investigated the association between either A2317G or HumDN1 polymorphism of deoxyribonuclease I gene and MI in Han Chinese population. A2317G and HumDN1 polymorphisms in 278 MI patients and 297 unrelated controls were detected by PCR and PCR-restriction fragment length polymorphism. Plasma lipids were measured in fasting state by biochemical methods. A new HumDN1 genotype -HumDN1 4/6 was found in Han Chinese MI patients. Genotype distributions and allele frequencies of A2317G and HumDN1 did not differ between MI patients and control group (all P > 0.05). In addition, none of estimated haplotypes significantly increased or decreased the risk of MI. In analysis of covariance, plasma total cholesterol was observed to be associated with HumDN1 genotypes in MI patients (P = 0.02). Our data suggest HumDN1 genotypes are related to total cholesterol levels in Han Chinese MI patients, but deoxyribonuclease I gene polymorphisms are not associated with susceptibility to MI in Han Chinese.     

Current molecular imaging of spinal tumors in clinical practice

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.     

Weed evolution after crop gene introgression: greater survival and fecundity of hybrids in a new environment

Crop-wild hybridization may produce offspring with lower fitness than their wild parents due to deleterious crop traits and outbreeding depression. Over time, however, selection for improved fitness could lead to greater invasiveness of hybrid taxa. To examine evolutionary change in crop-wild hybrids, we established four wild ( Raphanus raphanistrum ) and four hybrid radish populations ( R. raphanistrum  ×  Raphanus sativus ) in Michigan (MI), USA. Hybrid and wild populations had similar growth rates over four generations, and pollen fertility of hybrids improved. We then measured hybrid and wild fitness components in two common garden sites within the geographical range of wild radish [MI and California (CA)]. Advanced generation hybrids had slightly lower lifetime fecundity than wild plants in MI but exhibited c. 270% greater lifetime fecundity and c. 22% greater survival than wild plants in CA. Our results support the hypothesis that crop-wild hybridization may create genotypes with the potential to displace parental taxa in new environments.     

Approaches for missing covariate data in logistic regression with MNAR sensitivity analyses

Data with missing covariate values but fully observed binary outcomes are an important subset of the missing data challenge. Common approaches are complete case analysis (CCA) and multiple imputation (MI). While CCA relies on missing completely at random (MCAR), MI usually relies on a missing at random (MAR) assumption to produce unbiased results. For MI involving logistic regression models, it is also important to consider several missing not at random (MNAR) conditions under which CCA is asymptotically unbiased and, as we show, MI is also valid in some cases. We use a data application and simulation study to compare the performance of several machine learning and parametric MI methods under a fully conditional specification framework (MI-FCS). Our simulation includes five scenarios involving MCAR, MAR, and MNAR under predictable and nonpredictable conditions, where “predictable” indicates missingness is not associated with the outcome. We build on previous results in the literature to show MI and CCA can both produce unbiased results under more conditions than some analysts may realize. When both approaches were valid, we found that MI-FCS was at least as good as CCA in terms of estimated bias and coverage, and was superior when missingness involved a categorical covariate. We also demonstrate how MNAR sensitivity analysis can build confidence that unbiased results were obtained, including under MNAR-predictable, when CCA and MI are both valid. Since the missingness mechanism cannot be identified from observed data, investigators should compare results from MI and CCA when both are plausibly valid, followed by MNAR sensitivity analysis.     

脂肪干细胞治疗心肌梗死的机制与新策略

介绍脂肪干细胞（ADSCs）治疗心肌梗死机制及用于提高心肌梗死治疗效果的新策略。广泛查阅近年关于ADSCs用于治疗心肌梗死的基础与临床实验研究文献,并进行整理、综合与分析。ADSCs移植治疗心肌梗死的机制研究取得了一定的进展,其机制主要包括分化为心肌细胞、参与梗死区血管形成、通过旁分泌功能改善梗死区微环境等。对ADSCs进行缺氧耐受预处理、使用新型生物材料、联合细胞因子以及药物等,可以大大提高移植细胞的存活率,促进细胞的增殖与分化,改善心肌梗死治疗效果,加快心脏功能的恢复。ADSCs可能通过多种机制发挥治疗心肌梗死的作用,进一步提高移植细胞成活率和性能稳定性是增加ADSCs治疗心肌梗死效果的关键。随着研究的不断深入,ADSCs可能为未来心肌梗死的临床治疗带来新的希望。     

Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography

Molecular imaging (MI) with ultrasonography relies on microbubble contrast agents (MCAs) adhering to a ligand-specific target for applications such as characterizing tumor angiogenesis. It is projected that ultrasonic (US) MI can provide information about tumor therapeutic response before the detection of phenotypic changes. One of the limitations of preclinical US MI is that it lacks a comprehensive field of view. We attempted to improve targeted MCA visualization and quantification by performing three-dimensional (3D) MI of tumors expressing αvβ3 integrin. Volumetric acquisitions were obtained with a Siemens Sequoia system in cadence pulse sequencing mode by mechanically stepping the transducer elevationally across the tumor in 800-micron increments. MI was performed on rat fibrosarcoma tumors (n = 8) of similar sizes using MCAs conjugated with a cyclic RGD peptide targeted to αvβ3 integrin. US MI and immunohistochemical analyses show high microbubble targeting variability, suggesting that individual two-dimensional (2D) acquisitions risk misrepresenting more complex heterogeneous tissues. In 2D serial studies, where it may be challenging to image the same plane repeatedly, misalignments as small as 800 microns can introduce substantial error. 3D MI, including volumetric analysis of inter- and intra-animal targeting, provides a thorough way of characterizing angiogenesis and will be a more robust assessment technique for the future of MI.     

Taihangia rupestris,a Rare Herb Dwelling Cliff Faces: Responses to Irradiance

We studied the responses of gas exchange, leaf morphology, and growth to irradiance in Taihangia rupestris, a naturally rare herb inhabiting only vertical cliff faces. In low irradiance (LI, 10 % of full sun) T. rupestris had lower net photosynthetic rate (P _N) and produced much less leaves, total leaf area, and biomass than in high (HI, full sun) or medium irradiance (MI, 50 % of full sun). P _N of T. rupestris was higher in HI than in MI on August 8, but lower in HI than in MI on September 22. T. rupestris had shorter petioles and lower leaf area ratio, and produced more but smaller and thicker leaves in HI than in MI. In HI the fast production of new leaves may guarantee T. rupestris to maintain higher P _N at the whole plant level and thus accumulate more biomass at harvest, although the single-leaf P _N may become lower as found on September 22. Hence T. rupestris possesses a latent capacity to acclimate and adapt to full sun. Irradiance, therefore, may not be a responsible factor for the restricted distribution of T. rupestris on vertical cliffs.     

Spatial and temporal analyses of water quality and phytoplankton biomass in an urbanized versus a relatively pristine salt marsh estuary

The robust growth of coastal communities in the southeastern United States is putting unique pressures on estuarine resources. Urbanization of estuarine systems may alter ecosystem function and thus affect the spatial scale and magnitude of nutrient concentrations and primary production temporally and spatially. We examined the spatial and temporal patterns of nutrient and chlorophyll a (Chl a) concentrations in two shallow well-mixed estuaries, (1) a developed estuary, Murrells Inlet (MI), South Carolina, and (2) a relatively pristine estuary, North Inlet (NI), South Carolina. The summer chlorophyll a maximum in MI was characteristically higher than in NI, which may be indicative of eutrophication. Correlations between salinity and inorganic nutrients (N and P) suggest that nutrient import from upland sources may be more pronounced in MI during stochastic precipitation events. Although inorganic nutrient concentrations between the estuaries were similar overall, during a wet period, inorganic N concentration in MI was increased to a greater extent than in NI, while only minimal increases in inorganic P were observed in both estuaries. Chlorophyll a concentrations decreased from the dry to wet period. Geographic Information System (GIS) plots of intensive spatial sampling in MI indicated spatial gradients of nutrient concentrations within this estuary that appeared to be consistent over time. These observations were investigated in more detail using regression analyses to examine the influences of coastal dilution and nutrient sources on relationships between water quality constituents. Results indicate the importance of stochastic rain events in affecting the linkages of estuarine processes to upland runoff in the urbanized estuary, MI.     

Application of information theory to feature selection in protein docking

In the era of structural genomics, the prediction of protein interactions using docking algorithms is an important goal. The success of this method critically relies on the identification of good docking solutions among a vast excess of false solutions. We have adapted the concept of mutual information (MI) from information theory to achieve a fast and quantitative screening of different structural features with respect to their ability to discriminate between physiological and nonphysiological protein interfaces. The strategy includes the discretization of each structural feature into distinct value ranges to optimize its mutual information. We have selected 11 structural features and two datasets to demonstrate that the MI is dimensionless and can be directly compared for diverse structural features and between datasets of different sizes. Conversion of the MI values into a simple scoring function revealed that those features with a higher MI are actually more powerful for the identification of good docking solutions. Thus, an MI-based approach allows the rapid screening of structural features with respect to their information content and should therefore be helpful for the design of improved scoring functions in future. In addition, the concept presented here may also be adapted to related areas that require feature selection for biomolecules or organic ligands.     

Application of the fourth universal definition of myocardial infarction in clinical practice

Abstract

Purpose: The Fourth Universal Definition of Myocardial Infarction (MI) has highlighted the different pathophysiological mechanisms that may lead to ischaemic and non-ischaemic myocardial injury and has emphasised that the diagnosis of myocardial infarction requires the presence of acute myocardial ischaemia in the setting of acute myocardial injury. This case based review intends to illustrate basic principles on how to apply this new, revised definition in clinical practice.

Methods and Results: The distinction between different types of MIs (type 1 or type 2) and the delineation of MI from acute non-ischaemic myocardial injury may be challenging in individual patients, which is illustrated by presenting and discussing real-life routine cases.

Conclusions: Type 1?MI is a consequence of coronary plaque rupture or erosion with intracoronary thrombus formation that is usually apparent on coronary angiography. Plausible triggering mechanisms causing myocardial oxygen supply/demand mismatch must be identified for the diagnosis of type 2?MI and its treatment should focus initially on management of the underlying disease attributable to acute myocardial ischaemia.     

How monocular deprivation shifts ocular dominance in visual cortex of young mice

We used a chronic recording method to document the kinetics of ocular dominance (OD) plasticity induced by temporary lid closure in young mice. We find that monocular deprivation (MD) induces two separate modifications: (1) rapid, deprivation-induced response depression and (2) delayed, deprivation-enabled, experience-dependent response potentiation. To gain insight into how altering retinal activity triggers these cortical responses, we compared the effects of MD by lid closure with monocular inactivation (MI) by intravitreal injection of tetrodotoxin. We find that MI fails to induce deprived-eye response depression but promotes potentiation of responses driven by the normal eye. These effects of MI in juvenile mice closely resemble the effects of MD in adult mice. Understanding how MI and MD differentially affect activity in the visual system of young mice may provide key insight into how the critical period ends.     

Using information theory to search for co-evolving residues in proteins

MOTIVATION: Some functionally important protein residues are easily detected since they correspond to conserved columns in a multiple sequence alignment (MSA). However important residues may also mutate, with compensatory mutations occurring elsewhere in the protein, which serve to preserve or restore functionality. It is difficult to distinguish these co-evolving sites from other non-conserved sites. RESULTS: We used Mutual Information (MI) to identify co-evolving positions. Using in silico evolved MSAs, we examined the effects of the number of sequences, the size of amino acid alphabet and the mutation rate on two sources of background MI: finite sample size effects and phylogenetic influence. We then assessed the performance of various normalizations of MI in enhancing detection of co-evolving positions and found that normalization by the pair entropy was optimal. Real protein alignments were analyzed and co-evolving isolated pairs were often found to be in contact with each other. AVAILABILITY: All data and program files can be found at http://www.biochem.uwo.ca/cgi-bin/CDD/index.cgi