Cellular 3D structures, for example, organoids, are an excellent model for studying and developing treatments for various diseases, including hereditary ones. Therefore, they are increasingly being used in biomedical research. From the point of view of safety and efficacy, recombinant adeno‐associated viral (rAAV) vectors are currently most in demand for the delivery of various transgenes for gene replacement therapy or other applications. The delivery of transgenes using rAAV vectors to various types of organoids is an (...) urgent task, however, it is associated with a number of problems that are discussed in this review. Cellular heterogeneity and specifics of cultivation of 3D structures determine the complexity of rAAV delivery and are sometimes associated with low transduction efficiency. This review surveys the main ways to solve emerging problems and increase the efficiency of transgene delivery using rAAVs to organoids. A clear understanding of the stage of development of the organoid, its cellular composition and the presence of surface receptors will allow obtaining high levels of organoid transduction with existing rAAV vectors. (shrink)

Recombinant adeno‐associated viruses (rAAVs) are promising vectors for the delivery of various genetic constructs into eukaryotic cells. rAAVs have a number of properties that make it possible to successfully use them both in vitro and in vivo. Purification and concentration of rAAV vectors are critical for achieving high viral titer, stability, efficiency, and purity. This review systematically analyses all available purification approaches. The purification methods described in this work differ substantially from each other in mechanisms, (...) efficiency, labor time, and cost. Researchers have to choose a purification algorithm depending on the purpose of their work. We strive to simplify the choice of the necessary and sufficient technique based on the experimental needs and available resources of the laboratory. (shrink)

The concept of human gene therapy came on the heels of fundamental discoveries on the nature and working of the gene. However, realistic prospects to correct the underlying cause of recessive genetic disorders through the transfer of wild‐type alleles of defective genes had to wait for the arrival of recombinant DNA technology. These techniques permitted the isolation and insertion of genes into the first recombinant delivery systems. The realization that viruses are natural gene carriers provided inspiration for gene therapy and, (...) as engineered vectors, viruses became prominent gene delivery vehicles. Nonetheless, when put in the context of human and non‐human primate studies, all vectors fell short of success regardless of their viral or non‐viral origin. Recognition of issues such as inefficient gene transfer and short‐lived or scant expression in the relevant cell type(s) prompted researchers to refine and develop several gene delivery systems, in particular those based on retroviruses, adeno‐associated viruses and adenoviruses. Concomitantly, available technology was deployed to tackle disorders that require few genetically corrected cells to attain therapy. BioEssays 27: 506–517, 2005. © 2005 Wiley periodicals, Inc. (shrink)

Although 80–90% of adults are seropositive for antibodies against the human parvovirus adeno‐associated virus (AAV), infection has not been associated with either symptoms or disease. In cell culture, AAV infection is not productive unless there is a coinfection with a helper virus, either adenovirus or any type of herpes virus; in the absence of a helper virus coinfection the viral genome is integrated into the genome, usually at a specific site on chromosome 19q13.3‐qter. The integrated genome (...) can be activated and rescued by subsequent super infection by a helper virus. The high frequency of site‐specific integration by AAV and the lack of associated disease have encouraged the use of AAV as a vector for gene therapy. This review will focus on the molecular mechanisms involved in the establishment of, and rescue from, the latent state and their relevance to use of AAV as a vector. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors (...) and the transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

Aldehyde dehydrogenase 2 (ALDH2) deficiency constitutes one of the most common hereditary enzyme deficiencies, affecting 35% to 40% of East Asians and 8% of the world population. It causes the well-known Asian Alcohol Flush Syndrome, characterized by facial flushing, palpitation, tachycardia, nausea, and other unpleasant feelings when alcohol is consumed. It is also associated with a marked increase in the risk of a variety of serious disorders, including esophageal cancer and osteoporosis. Our recent studies with murine models have demonstrated (...) that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) will correct the deficiency state and prevent alcohol-induced abnormalities of the esophagus and bone. If successful in humans, such strategy would reduce the increased risk-associated disorders such as esophageal cancer and osteoporosis, but also prevent the Asian Alcohol Flush Syndrome. This treatment thus raises ethical concerns: although it would potentially prevent fatal disease, it could also allow affected individuals to drink alcohol without suffering the Asian Alcohol Flush Syndrome and, hence, potentially enable personal destructive behavior. Here we explore the ethical arguments against the development of a gene therapy for ALDH2 deficiency and we find them wanting. We contend that development of such treatments is ethically appropriate and should be part and parcel of the solutions offered against the condition. (shrink)

Viral modernity is a concept based upon the nature of viruses, the ancient and critical role they play in evolution and culture, and the basic application to understanding the role of information and forms of bioinformation in the social world. The concept draws a close association between viral biology on the one hand, and information science on the other – it is an illustration and prime example of bioinformationalism that brings together two of the most powerful forces that (...) now drive cultural evolution. The concept of viral modernity applies to viral technologies, codes and ecosystems in information, publishing, education and emerging knowledge systems. This paper traces the relationship between epidemics, quarantine, and public health management and outlines elements of viral-digital philosophy based on the fusion of living and technological systems. We discuss Covid-19 as a ‘bioinformationalist’ response that represents historically unprecedented level of sharing information from the sequencing of the genome to testing for a vaccination. Finally, we look at the US response to Covid-19 through the lens of infodemics and post-truth. The paper is followed by three open reviews, which further refine its conclusions as they relate to philosophy and the notion of the virus as Pharmakon. (shrink)

Viruses are major drivers of global biogeochemistry and the etiological agents of many diseases. They are also the winners in the game of life: there are more viruses on the planet than cellular organisms and they encode most of the genetic diversity on the planet. In fact, it is reasonable to view life as a viral incubator. Nevertheless, most ecological and evolutionary theories were developed, and continue to be developed, without considering the virosphere. This means these theories need to (...) be to reinterpreted in light of viral knowledge or we need to develop new theory from the viral point-of-view. Here we briefly introduce our viral planet and then address a major outstanding question in biology: why is most of life viral? A key insight is that during an infection cycle the original virus is completely broken down and only the associated information is passed on to the next generation. This is different for cellular organisms, which must pass on some physical part of themselves from generation to generation. Based on this premise, it is proposed that the thermodynamic consequences of physical information (e.g., Landauer’s principle) are observed in natural viral populations. This link between physical and genetic information is then used to develop the Viral Information Hypothesis, which states that genetic information replicates itself to the detriment of system energy efficiency (i.e., is viral in nature). Finally, we show how viral information can be tested, and illustrate how this novel view can explain existing ecological and evolutionary theories from more fundamental principles. (shrink)

Since the outbreak of the COVID-19 pandemic, there has been countless debate about the virus. The role discourse plays in this pandemic is tightly associated with the impact of pandemic on society....

This paper resists the virality of contemporary paranoia by turning to “French epistemology”, a philosophical ethos that embraces uncertainty and complexity by registering the transformative impact of scientific knowledge on thought. Despite its popular uses describing phenomena of communication today, the idea of virality comes from biomedicine. This paper, therefore, investigates the extent to which an epidemiological concept of viral transmission—the disease vector—can comprehend and encourage new possibilities of thought beyond paranoia. Briefly, I attempt to analyze thought as a (...) vector. I pursue this by examining Delaporte’s important, but neglected, study of the 1832 Parisian cholera epidemic. First elucidating his reconstruction of the ways tentative epistemological progress intertwined with and supported projects of working-class and colonial control. My vectorial analysis then considers how his argument infects contemporary readers with doubts that undo the bases of paranoia. I pursue this analysis further via a methodological examination of Delaporte’s study as both carrier of predecessors’ methods and host in which they alter, becoming newly infectious. I conclude by reflecting on this formulation of thought as disease vector and what Delaporte’s singular treatment of the problem of error reveals about an ethos committed to registering the impact of knowledge on thought. (shrink)

Critics of reliability theories of epistemic justificationoften claim that the `generality problem' is an insurmountabledifficulty for such theories. The generality problem is theproblem of specifying the level of generality at which abelief-forming process is to be described for the purposeof assessing its reliability. This problem is not asintractable as it seems. There are illuminating solutionsto analogous problems in the ethics literature. Reliabilistsought to attend to utilitarian approaches to choices betweeninfinite utility streams; they also ought to attend towelfarist approaches to social (...) choice situations that donot demand full aggregation of individual welfares.These analogies suggest that the traditional `single number'approach to reliability is misguided. I argue that a newapproach – the `vector reliability' approach – is preferable.Vector reliability theories associate target beliefs withreliability vectors – that is, structured collections ofreliability numbers – and construct criteria of epistemicjustification that appeal to these vectors. The bulk of thetheoretical labor involved in a reliability account of epistemicjustification is thus transferred from picking a uniquereliability number to constructing a plausible criterionof epistemic justification. (shrink)

Critics of reliability theories of epistemic justificationoften claim that the `generality problem' is an insurmountabledifficulty for such theories. The generality problem is theproblem of specifying the level of generality at which abelief-forming process is to be described for the purposeof assessing its reliability. This problem is not asintractable as it seems. There are illuminating solutionsto analogous problems in the ethics literature. Reliabilistsought to attend to utilitarian approaches to choices betweeninfinite utility streams; they also ought to attend towelfarist approaches to social (...) choice situations that donot demand full aggregation of individual welfares.These analogies suggest that the traditional `single number'approach to reliability is misguided. I argue that a newapproach – the `vector reliability' approach – is preferable.Vector reliability theories associate target beliefs withreliability vectors – that is, structured collections ofreliability numbers – and construct criteria of epistemicjustification that appeal to these vectors. The bulk of thetheoretical labor involved in a reliability account of epistemicjustification is thus transferred from picking a uniquereliability number to constructing a plausible criterionof epistemic justification. (shrink)

The cloning of eukaryotic genes by standard recombinant DNA techniques permits their structural characterization. However, analysis of the expression properties of these genes often requires their introduction into and replication within eukaryotic cells in culture. Certain viral vectors based on the papilloma viruses may prove to be especially important in such investigations. These ‘shuttle vectors’, capable of replication in both bacterial and eukaryotic cells, have already provided several findings of interest about the relationship between eukaryotic gene structure (...) and function. Further analysis of these vectors and their properties promises to enhance their use as investigative tools. (shrink)

Doping can be both of chemical and protein nature or may involve prohibited methods, such as illegal blood transfusions. The rapidly increasing number of genetic therapies as a promising new branch of regular medicine, has raised the issue whether these techniques might be abused in the field of sports. The risks involved in gene doping are several, and are related both to the vector protein used (DNA, chemical, viral) and to the encoded transgene. A concern in the athletic community (...) is that no one knows how easily gene doping can be detected. The DNA used for gene transfer is of human origin, and not different from that of the person applying gene doping. A combination of developing detection methods based on gene arrays or proteomics and a clear education program on the associated risks seems to be the most promising preventive method to counteract the possible application of gene doping. (shrink)

This article discusses the set of Harsanyi payoff vectors of a cooperative TU-game, also known as the Selectope. We reconsider some results on Harsanyi payoff vectors within a more general framework. First, an intuitive approach is used, showing that the set of Harsanyi payoff vectors is the core of an associated convex game. Next, the set of individual rational Harsanyi payoff vectors, the Harsanyi imputations in short, is considered. Existence conditions are provided, and if non-empty, (...) we provide a description as the core of a well-defined convex game, and show that it is an externally stable set. (shrink)

This article discusses the set of Harsanyi payoff vectors of a cooperative TU-game, also known as the Selectope. We reconsider some results on Harsanyi payoff vectors within a more general framework. First, an intuitive approach is used, showing that the set of Harsanyi payoff vectors is the core of an associated convex game. Next, the set of individual rational Harsanyi payoff vectors, the Harsanyi imputations in short, is considered. Existence conditions are provided, and if non-empty, (...) we provide a description as the core of a well-defined convex game, and show that it is an externally stable set. (shrink)

In this thesis, I give a metascientific account of causality in medicine. I begin with two historical cases of causal discovery. These are the discovery of the causation of Burkitt’s lymphoma by the Epstein-Barr virus, and of the various viral causes suggested for cervical cancer. These historical cases then support a philosophical discussion of causality in medicine. This begins with an introduction to the Russo- Williamson thesis (RWT), and discussion of a range of counter-arguments against it. Despite these, I (...) argue that the RWT is historically workable, given a small number of modifications. I then expand Russo and Williamson’s account. I first develop their suggestion that causal relationships in medicine require some kind of evidence of mechanism. I begin with a number of accounts of mechanisms and produce a range of consensus features of them. I then develop this consensus position by reference to the two historical case studies with an eye to their operational competence. In particular, I suggest that it is mechanistic models and their representations which we are concerned with in medicine, rather than the mechanism as it exists in the world. -/- I then employ these mechanistic models to give an account of the sorts of evidence used in formulating and evaluating causal claims. Again, I use the two human viral oncogenesis cases to give this account. I characterise and distinguish evidence of mechanism from evidence of difference-making, and relate this to mechanistic models. I then suggest the relationship between types of evidence presents us with a means of tackling the reference-class problem. This sets the scene for the final chapter. Here, I suggest the manner in which these two different classes of evidence become integrated is also reflected in the way that developing research programmes change as their associated causal claims develop. (shrink)

The versatile clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system has emerged as a promising technology for therapy and molecular diagnosis. It is especially suited for overcoming viral infections outbreaks, since their effective control relies on an efficient treatment, but also on a fast diagnosis to prevent disease dissemination. The CRISPR toolbox offers DNA‐ and RNA‐targeting nucleases that constitute dual weapons against viruses. They allow both the manipulation of viral and host genomes for therapeutic purposes and the detection (...) of viral nucleic acids in “Point of Care” sensor devices. Here, we thoroughly review recent advances in the use of the CRISPR/Cas system for the treatment and diagnosis of viral deleterious infections such as HIV or SARS‐CoV‐2, examining their strengths and limitations. We describe the main points to consider when designing CRISPR antiviral strategies and the scientific efforts to develop more sensitive CRISPR‐based viral detectors. Finally, we discuss future prospects to improve both applications. Also see the video abstract here: https://www.youtube.com/watch?v=C0z1dLpJWl4. (shrink)

Site‐specific or target‐specific mutagenesis of viral DNA genomes, using a selectable marker system is a powerful tool for the analysis of the function of specific regions of large DNA genomes. Through these techniques the construction of vectors capable of delivering vaccines for the prevention of infectious disease in humans and animals is possible.

Baculovirus vectors have proven useful in producing high levels of biologically active eukaryotic proteins and providing cellular fractions which are enriched in the protein of interest. Expression occurs in infected insect cells which also provide a suitable environment for posttranslational modification and folding of the protein product. Stable baculovirus vectors can be constructed rapidly with a minimum of viral manipulation.

The majority of human, animal and plant viral pathogens possess genomes composed of RNA. The strategies evolved for expression and replication of viral RNA genomes can differ significantly from those utilized for expression and replication of host‐cell genetic material. Consequently, knowledge of the molecular details of these strategies can lead to a clearer understanding of the origin, evolution and control of viral pathogens. We describe recent progress in identifying important structural and functional domains of the RNA genomes (...) and associated replicative enzymes for two very different viruses: vesicular stomatitis virus, which possesses a single‐stranded RNA genome of negative polarity, and wound tumor virus, which contains a genome composed of 12 discrete segments of double‐stranded RNA. (shrink)

Brock Macdonald1, Evi Vakiani2, Rhonda K Yantiss3, Jun Lee4, Robert S Brown Jr5, Samuel H Sigal61Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, CA, 2Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, 3Department of Pathology and Laboratory Medicine, New York Weill Cornell Medical College, New York, NY, 4Division of Nephrology, Department of Medicine, Weill Cornell Medical College, New York, NY, 5Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, (...) NY, 6Division of Gastroenterology and Hepatology, Department of Medicine, New York University, New York, NY, USA: The use of sirolimus as an alternative to calcineurin inhibitors for posttransplant immunosuppression is associated with a variety of inflammatory conditions. In this report, we describe the case of a 34-year-old man who developed abnormal liver tests 6 years after live-donor kidney transplantation and 5 years after initiation of sirolimus-based immunosuppression. Elevated aminotransferase levels persisted after withdrawal of potentially hepatotoxic medications, and serologic evaluation for viral hepatitis, autoimmune disease, and genetic disorders was unrevealing. Liver biopsy revealed prominent hepatocellular injury associated with a mixed inflammatory infiltrate and liver tests normalized within 2 weeks of discontinuation of sirolimus. In this report, we review previous reports of sirolimus hepatotoxicity and propose a unifying hypothesis for the various inflammatory conditions that have been attributed to sirolimus.Keywords: sirolimus, immunosuppression, transplant, inflammatory conditions, hepatotoxicity. (shrink)

We consider a representation of the state reduction which depends neither on its reality nor on the details of when and how it emerges. Then by means of the representation we find necessary conditions, even if not the sufficient ones, for a decomposition of the state vector space to be a solution to the basis problem. The conditions are that the decomposition should be Lorentz invariant and orthogonal and that the associated projections should be continuous. They are shown to (...) be able to determine a decomposition in each of a few examples considered if the other circumstances are taken into account together. (shrink)

The temperament of the body is an essential constituent for health conservancy and diagnosis of several diseases. Hence, general body temperament and uterine dystemperament with abnormal vaginal discharge need evaluation. In addition, we also applied a computational intelligence technique for enhancing scientific validity to classify the warm-cold and wet-dry temperaments. This trial included a total of 66 participants with a vaginal discharge of reproductive age. Data included demographic characteristics of the participants, symptoms associated with vaginal discharge, women’s general temperament, (...) and symptoms of uterine dystemperament. Correlation between general body temperament and age, abnormal vaginal discharge, and its associated symptoms was also performed. Additionally, we used the Support Vector Machine-Radial Basis Function model to classify the warm-cold and wet-dry temperaments. Warm general temperament was highly prevalent, followed by moderate on the warm-cold temperament scale. In wet-dry temperament, moderate general body temperament was more prevalent. In warm-cold and wet-dry scores, 78.78% and 74.24% had warm and wet uterine dystemperament, respectively. The age and symptoms were correlated with general temperament. A strong positive correlation was found between warm general temperament and warm dystemperament of the uterus. In addition, our SVM-RBF CV-5 classification model achieved the highest accuracy. Our results showed that vaginal discharge is more common in warm general temperament and warm-wet dystemperament of the uterus. The same has been proven by computational intelligence. Nevertheless, vaginal discharge can also happen in normal and other temperaments. (shrink)

Myelin oligodendrocyte glycoprotein antibody-associated disease is an immune-mediated demyelinating disease of the central nervous system that is present in both adults and children. The most common clinical manifestations are optic neuritis, myelitis, acute disseminated encephalomyelitis, and brainstem syndrome. Cerebral cortical encephalitis is a rare clinical phenotype of myelin oligodendrocyte glycoprotein antibody-associated disease, which usually begins with seizures, headaches, and fever, and may be misdiagnosed as viral encephalitis in the early stages. Herein, we report two typical MOG antibody (...) -positive patients presenting with CCE, both of whom presented with headache, fever, seizures, and who recovered completely after immunotherapy. In addition, we performed a systematic review of the present literature from the perspectives of population characteristics, clinical symptoms, MRI abnormalities, treatments, and prognosis. Among the patients reported in 25 articles, 33 met our inclusion criteria, with the age of onset ranging from 4 to 52 years. Most of the patients had seizures, headache, fever, and unilateral cortical lesions on brain MRI. For acute CCE, 30 patients were treated with high-dose intravenous methylprednisolone, and the symptoms of most patients were completely relieved after immunotherapy. This study reported our experience and lessons learned in the diagnosis and treatment of MOG-Ab-positive CCE and provides a systematic review of the literature to analyse this rare clinical phenotype. (shrink)

ABSTRACT Why did the popping of the housing bubble bring the financial system—rather than just the housing sector of the economy—to its knees? The answer lies in two methods by which banks had evaded regulatory capital requirements. First, they had temporarily placed assets—such as securitized mortgages—in off‐balance‐sheet entities, so that they did not have to hold significant capital buffers against them. Second, the capital regulations also allowed banks to reduce the amount of capital they held against assets that remained on (...) their balance sheets—if those assets took the form of AAA‐rated tranches of securitized mortgages. Thus, by repackaging mortgages into mortgage‐backed securities, whether held on or off their balance sheets, banks reduced the amount of capital required against their loans, increasing their ability to make loans many‐fold. The principal effect of this regulatory arbitrage, however, was to concentrate the risk of mortgage defaults in the banks and render them insolvent when the housing bubble popped. (shrink)

PurposeThe primary angle-closure glaucoma is an irreversible blinding eye disease in the world. Previous neuroimaging studies demonstrated that PACG patients were associated with cerebral changes. However, the effect of optic atrophy on local and remote brain functional connectivity in PACG patients remains unknown.Materials and MethodsIn total, 23 patients with PACG and 23 well-matched Health Controls were enrolled in our study and underwent resting-state functional magnetic resonance imaging scanning. The regional homogeneity method and functional connectivity method were used to evaluate (...) the local and remote brain functional connectivity. Moreover, support vector machine method was applied to constructing PACG classification model.ResultsCompared with the HC, PACG patients showed increased ReHo values in right cerebellum _8, left CER_4-5, and right CER_8. In contrast, PACG patients showed decreased ReHo values in the bilateral lingual gyrus /calcarine /superior occipital gyrus and right postcentral gyrus. The ReHo value exhibited an accuracy of 91.30% and area under curve of 0.95 for distinguishing the PACG patients from HC.ConclusionOur study demonstrated that the PACG patients showed abnormal ReHo value in the cerebellum, visual cortex, and supplementary motor area, which might be reflect the neurological mechanisms underlying vision loss and eye pain in PACG patients. Moreover, the ReHo values can be used as a useful biomarker for distinguishing the PACG patients from HCs. (shrink)

The well-known classifier support vector machine has many parameters associated with its various kernel functions. The radial basis function kernel, being the most preferred kernel, has two parameters to be optimized. The problem of optimizing these parameter values is called model selection in the literature, and its results strongly influence the performance of the classifier. Another factor that affects the classification performance of a classifier is the feature subset. Both these factors are interdependent and must be dealt with simultaneously. (...) Following the multiobjective definition of feature selection, we have applied a multiobjective genetic algorithm, NSGA II, to optimize the feature subset and model parameters simultaneously. Comparison of the proposed approach with the grid algorithm and GA-based method suggests that the MOGA-based approach performs better than the grid algorithm and is as good as the GA-based approach. Moreover, it provides multiple solutions instead of a single solution. The users can prefer one feature subset over the other as per their requirement and available resources. (shrink)

We present an annotated bibliography of peer reviewed scientific research highlighting the human health, animal welfare, and environmental risks associated with genetic modification. Risks associated with the expression of the transgenic material include concerns over resistance and non-target effects of crops expressing Bt toxins, consequences of herbicide use associated with genetically modified herbicide-tolerant plants, and transfer of gene expression from genetically modified crops through vertical and horizontal gene transfer. These risks are not connected to the technique of (...) genetic modification as such, but would be present for any conventionally produced crops with the same heritable traits. In contrast, other risks are a direct consequence of the method used in gene manipulation. These come about because of the unstable nature of the transgene and vectors used to insert it, and because of unpredictable interactions between the transgene and the host genome. The debate over the release of genetically modified organisms is not merely a scientific one; it encompasses economics, law, ethics, and policy. Any discussion on these levels does, however, need to be informed by sound science. We hope that the scientific references provided here will provide a useful starting point for further debate. (shrink)

In this article we show that it is possible to completely classify the degrees of r.e. bases of r.e. vector spaces in terms of weak truth table degrees. The ideas extend to classify the degrees of complements and splittings. Several ramifications of the classification are discussed, together with an analysis of the structure of the degrees of pairs of r.e. summands of r.e. spaces.

Aim: To evaluate health-related quality of life of chronic hepatitis B and hepatitis B virus related cirrhosis patients and analyzed specific differences in all dimensions of HRQoL.Methods: A total of 349 patients met selection criteria were enrolled. The 36-Item Short-Form Health Survey was adopted.Results: Results showed that the physiological HRQoL of the cirrhotic group was significantly lower than that of the non-cirrhotic group, the psychological HRQoL was also lower. HRQoL was significantly negatively correlated with liver stiffness. We further evaluated the (...) risk factors associated with poor HRQoL in HBV-related cirrhosis patients. Results showed that positive HBV DNA viral load and HCC family history were independent factors associated with HRQoL in HBV-related cirrhosis. For better risk stratification of patients, multivariable analyses were conducted to explore the independent factors that affected specific physiological and psychological HRQoL. In specific physiological HRQoL, results show that marital status, positive HBV DNA viral load and antiviral drugs were independent factors associated with physiological HRQoL in cirrhosis patients. In psychological HRQoL, only HCC family history was independent risk factors associated with psychological HRQoL.Conclusion: We found that the impaired HRQoL dimensions of HBV related cirrhosis patients differ between the various subpopulations. According to our results, risk stratification, medical decision making and personalizing interventions could be made. (shrink)

We review the relativistic classical and quantum mechanics of Stueckelberg, and introduce the compensation fields necessary for the gauge covariance of the Stueckelbert–Schrödinger equation. To achieve this, one must introduce a fifth, Lorentz scalar, compensation field, in addition to the four vector fields with compensate the action of the space-time derivatives. A generalized Lorentz force can be derived from the classical Hamilton equations associated with this evolution function. We show that the fifth (scalar) field can be eliminated through the (...) introduction of a conformal metric on the spacetime manifold. The geodesic equation associated with this metric coincides with the Lorentz force, and is therefore dynamically equivalent. Since the generalized Maxwell equations for the five dimensional fields provide an equation relating the fifth field with the spacetime density of events, one can derive the spacetime event density associated with the Friedmann–Robertson–Walker solution of the Einstein equations. The resulting density, in the conformal coordinate space, is isotropic and homogeneous, decreasing as the square of the Robertson–Walker scale factor. Using the Einstein equations, one see that both for the static and matter dominated models, the conformal time slice in which the events which generate the world lines are contained becomes progressively thinner as the inverse square of the scale factor, establishing a simple correspondence between the configurations predicted by the underlying Friedmann–Robertson–Walker dynamical model and the configurations in the conformal coordinates. (shrink)

Charles Eisenmann, dans un compte-rendu critique de la Pensée juridique, publié dans la Revue de droit public en 1961, écrivait : " On voudrait proclamer d'abord sans réserves, les rares qualités de l'ouvrage, qui en rendent la lecture très recommandable, en particulier pour ceux qui, jeunes ou juristes déjà formés, n'ont pas encore ou n'ont plus commerce très assidu avec la théorie ou la philosophie du droit. Ils prendront contact avec une pensée vivante et chaude, qui cherche avec ardeur, souplesse (...) et agilité." Les qualités qui ont conduit la Pensée juridique à être un des ouvrages de base de la formation théorique de toute une génération de juristes, celle des décennies 60-70, demeurent encore aujourd'hui intactes. C'est pourquoi il nous a paru souhaitable d'ouvrir la nouvelle collection des introuvables des éditions Panthéon- Assas par une réédition de l'ouvrage de Michel Virally. (shrink)

Here we discuss the hypothesis that the RNA components of the Ro ribonucleoproteins (RNPs), the Y RNAs, can be processed into microRNAs (miRNAs). Although Ro RNPs, whose main protein components Ro60 and La are targeted by the immune system in several autoimmune diseases, were discovered many years ago, their function is still poorly understood. Indeed, recent data show that miRNA-sized small RNAs can be generated from Y RNAs. This hypothesis leads also to a model in which Ro60 acts as a (...) modulator in the Y RNA-derived miRNA biogenesis pathway. The implications of these Y RNA-derived miRNAs, which may be specifically produced under pathological circumstances such as in autoimmunity or during viral infections, for the enigmatic function of Ro RNPs are discussed. (shrink)

A new method of multiattribute decision making is proposed based on the max-min and min-max gray association degree. The gray association coefficients between the alternative, positive ideal solution and negative ideal solution are defined. Here, we construct a bi-objective programming model that maximizes the minimum gray association degree and minimizes the maximum gray association degree simultaneously. By using the linear weighted summation method, the bi-objective programming model is transformed into a linear programming model. Thus, we can obtain the weight vector (...) of attributes by solving the linear programming model. The ranking order of alternatives is generated according to the relative closeness. A numerical example is examined to demonstrate the applicability and implementation process of the decision method proposed in this paper. (shrink)

PurposeThyroid-associated ophthalmopathy is a vision threatening autoimmune and inflammatory orbital disease, and has been reported to be associated with a wide range of structural and functional abnormalities of bilateral hemispheres. However, whether the interhemisphere functional connectivity of TAO patients is altered still remain unclear. A new technique called voxel-mirrored homotopic connectivity combined with support vector machine method was used in the present study to explore interhemispheric homotopic functional connectivity alterations in patients with TAO.MethodsA total of 21 TAO patients (...) and 21 wellmatched healthy controls, respectively, underwent functional magnetic resonance imaging scanning in the resting state. We evaluated alterations in the resting state functional connectivity between hemispheres by applying VMHC method and then selected these abnormal brain regions as seed areas for subsequent study using FC method. Furthermore, the observed changes of regions in the VMHC analysis were chosen as classification features to differentiate patients with TAO from HCs through support vector machine method.ResultsThe results showed that compared with HCs, TAO patients showed significantly lower VMHC values in the bilateral postcentral gyrus, lingual gyrus, calcarine, middle temporal gyrus, middle occipital gyrus and angular. Moreover, significantly decreased FC values were found between the right postcentral gyrus/lingual gyrus/calcarine and left lingual gyrus/cuneus/superior occipital gyrus, left postcentral gyrus/lingual gyrus/calcarine and right lingual gyrus/ middle temporal gyrus, right middle temporal gyrus and left cerebellum-8/lingual gyrus/middle occipital gyrus/supplementary motor area, left middle temporal gyrus and right middle occipital gyrus, right middle occipital gyrus/angular and left middle temporal pole. The SVM classification model achieved good performance in differentiating TAO patients from HCs.ConclusionThe present study revealed that the altered interhemisphere interaction and integration of information involved in cognitive and visual information processing pathways including the postcentral gyrus, cuneus, cerebellum, angular, widespread visual cortex and temporal cortex in patients with TAO relative to HC group. VMHC variability had potential value for accurately and specifically distinguishing patients with TAO from HCs. The new findings may provide novel insights into the neurological mechanisms underlying visual and cognitive disorders in patients with TAO. (shrink)

The quantum state of a d-dimensional system can be represented by a probability distribution over the d 2 outcomes of a Symmetric Informationally Complete Positive Operator Valued Measure (SIC-POVM), and then this probability distribution can be represented by a vector of $\mathbb {R}^{d^{2}-1}$ in a (d 2−1)-dimensional simplex, we will call this set of vectors $\mathcal{Q}$ . Other way of represent a d-dimensional system is by the corresponding Bloch vector also in $\mathbb {R}^{d^{2}-1}$ , we will call this set (...) of vectors $\mathcal{B}$ . In this paper it is proved that with the adequate scaling $\mathcal{B}=\mathcal{Q}$ . Also we indicate some features of the shape of $\mathcal{Q}$. (shrink)

The concept of “nonlocalization” associated with the gravitational field, which is carried by the internal variable (θ) annexed to each point, is considered in connection with the geometrical theory of gauge fields. Two concrete examples of “nonlocalization” are proposed by taking θ as a vector and a spinor, respectively.

Herpes simplex virus type 2 is the most prevalent sexually transmitted infection in the world, despite the availability of effective anti-viral treatments. A mathematical model to explore the association between gender and HSV-2 treatment adherence is developed. Threshold parameters are determined and stabilities analyzed. Sensitivity analysis of the reproduction number and the numerical simulations suggest that treatment adherence for both females and males are equally important in keeping the reproduction as low as possible. The basic model is then extended (...) to incorporate time-dependent intervention strategies. The Pontryagin’s Maximum Principle is used to characterize the optimal level of the controls, and the resulting optimality system is solved numerically. (shrink)

Summary Principles Timely support for patients and people close to them, and effective, sensitive communication are essential. Decisions must be based on the individual patient's circumstances and reviewed regularly. Sensitive advance discussion should always be encouraged, but not forced. Information about CPR and the chances of a successful outcome needs to be realistic. Practical matters Information about CPR policies should be displayed for patients and staff. Leaflets should be available for patients and people close to them explaining about CPR, how (...) decisions are made and their involvement in decisions. Decisions about attempting CPR must be communicated effectively to relevant health professionals. In emergencies If no advance decision has been made or is known, CPR should be attempted unless: the patient has refused CPR; the patient is clearly in the terminal phase of illness; or the burdens of the treatment outweigh the benefits. Advance decision making Competent patients should be involved in discussions about attempting CPR unless they indicate that they do not want to be. Where patients lack competence to participate, people close to them can be helpful in reflecting their views. Legal issues Patients' rights under the Human Rights Act must be taken into account in decision making. Neither patients nor relatives can demand treatment which the health care team judges to be inappropriate, but all efforts will be made to accommodate wishes and preferences. In England, Wales and Northern Ireland relatives and people close to the patient are not entitled in law to take health care decisions for the patient. In Scotland, adults may appoint a health care proxy to give consent to medical treatment. Health professionals need to be aware of the law in relation to decision making for children and young people.IntroductionWhy policies are neededCardiopulmonary resuscitation can be attempted on any person whose cardiac or respiratory functions cease. Failure of these functions is part of dying and thus …. (shrink)

1. Aim of the guidelines2. Principles of good practice3. Circumcision for medical purposes4. Non-therapeutic circumcision 4.1. The law 4.1.1. Summary: the law 4.2. Consent and refusal 4.2.1. Children’s own consent 4.2.2. Parents’ consent 4.2.3. Summary: consent and refusal 4.3. Best interests 4.3.1. Summary: best interests 4.4. Health issues 4.5. Standards 4.6. Facilities 4.7. Charging patients 4.8. Conscientious objection5. Useful addresses.