Characteristics of the Internal Representation of the Probability Structure of the Environment in Certain Mental Illnesses

In 1935, Pavlov advanced the hypothesis that certain depressive states might be traceable to the subject's incorrect assessment of the probability that some threatening event, for example, a bolt of lightning, would occur.* Recent attempts to verify this hypothesis empirically and to apply it clinically by distinguishing the interacting influences of the real probability and the biological significance of an event have encountered considerable difficulties of a methodological nature. One possible approach to the solution of this problem and to working out equivalent assessments of these two factors is to compare the speed with which conditioned responses to various appropriate ecological stimuli are developed and extinguished (D. A. Biryukov) when the probability of the reinforcement is adequate (D. N. Menitskii, 1964). Another approach is to compare motor reaction times (I. M. Feigenberg). Moreover, the process of decision making and the overall reaction of the organism can be regarded as two discrete steps: (1) construction of a probability model of the environment (perception), and (2) evaluation of the "utility function" (motivation). The two steps are effected by different neurological mechanisms.     

Thermodynamics of the Human Brain

The human brain may be regarded as an irreversible system which is constrained by a fixed inflow of free energy in the form of chemical nourishment from within the body and information from the environment. The evolution of the internal spontaneous process may be described as a path on the saddle surface of entropy production rate in the configuration space of the process variables. From any initial state of high entropy production the system evolves towards the saddle point by a series of regessions to temporary minima alternating with fluctuations which introduce new internal constraints and open new channels for regression. The spontaneous regression steps of the process are to be associated with the learning process and the deductive processes of thought since information is necessarily being stored, whereas the fluctuation or nucleation steps are to be associated with the inductive or creative part of the thought process. The state of consciousness is to be associated with the system undergoing regression. If, under certain boundary conditions, the system attains the stable saddle point, a state of unconsciousness is attained in which no change of state variables occurs in time. The stability of this state is indicated by its resistance to perturbation.     

Treatment of effluents polluted by nitrogen with new biological technologies based on autotrophic nitrification-denitrification processes

In recent years, various technologies have been developed for the removal of nitrogen from wastewater that is rich in nitrogen but poor in organic carbon, such as the effluents from anaerobic digesters and from certain industries. These technologies have resulted in several patents. The core of these technologies is some of the processes and patents described in this paper: Aerobic denitrification, Sharon, Anammox, OLAND, CANON, NOx process, DEMON. More specifically, one of the first innovative options described for removing nitrogen include partial nitrification under aerobic conditions (partial Sharon process) followed by autotrophic anaerobic oxidation (Anammox process). The partial Sharon-Anammox process can be performed under alternating oxic and anoxic conditions in the same bioreactor or in two steps in two separate bioreactors. This overview focuses on the technical and biological aspects of these new types of treatment system, and compares them to other technologies. Given the fact that nitrification is a sensitive process, special attention is paid to conditions such as temperature, dissolved oxygen, hydraulic retention time, free ammonia, nitrous acid concentration, and pH. A discussion of the pros and cons of such treatment systems is also included since autotrophic nitrogen removal has advantages as well as drawbacks. The paper concludes with a discussion of future research that could improve these systems by enhancing performance and reducing costs.     

Direct cloning by covalent attachment of probe DNA to target DNA.

A novel cloning procedure which makes use of covalent attachment of probe DNA to specific target DNA is reported. We show that specific gene fragments found in complex genomes such as the human genome can be cloned directly from a pool of genomic DNA with very high efficiency. This direct cloning method totally eliminates certain steps in current cloning procedures such as construction of DNA libraries and colony (plaque) hybridization. The resulting process has made cloning methods simpler and more time efficient, while achieving high cloning efficiency due to the stable nature of the probe-target DNA complex through covalent bonding. Most importantly, since clones are directly obtained from a pool of genomic DNA, the isolated clones are considered to be faithful copies of the original genes. This has apparently solved the problem of isolating clones with misincorporated bases or chimeric DNA, both of which are often encountered in cloning processes using PCR or other methods involving in vitro DNA synthesis.     

Specificity of interferon action in protein synthesis.

Inhibitors of elongation steps in protein synthesis such as cycloheximide and anisomycin mimic interferon treatment in that they specifically inhibit the synthesis of certain viral proteins. These specific effects are seen only at very low concentrations of the antibiotics, under conditions where host cellular protein synthesis, as well as cell viability, are not severely reduced. A qualitatively as well as quantitatively close correlation between the effects of the two types of agents has been established for encephalomyocarditis virus, vesicular stomatitis virus and murine leukemia virus protein synthesis. It is concluded that one of the primary mechanisms of interferon action may be a nonspecific retardation of one or more elongation steps, and that this may be sufficient to account for its effects on the replication of certain viruses such as encephalomyocarditis and vesicular stomatitis viruses.     

A framework for the implementation of new radiation therapy technologies and treatment techniques in low-income countries

We present a practical, generic, easy-to-use framework for the implementation of new radiation therapy technologies and treatment techniques in low-income countries. The framework is intended to standardize the implementation process, reduce the effort involved in generating an implementation strategy, and provide improved patient safety by reducing the likelihood that steps are missed during the implementation process. The 10 steps in the framework provide a practical approach to implementation. The steps are, 1) Site and resource assessment, 2) Evaluation of equipment and funding, 3) Establishing timelines, 4) Defining the treatment process, 5) Equipment commissioning, 6) Training and competency assessment, 7) Prospective risk analysis, 8) System testing, 9) External dosimetric audit and incident learning, and 10) Support and follow-up. For each step, practical advice for completing the step is provided, as well as links to helpful supplementary material. An associated checklist is provided that can be used to track progress through the steps in the framework. While the emphasis of this paper is on addressing the needs of low-income countries, the concepts also apply in high-income countries.     

Mathematical analysis of multiscale models for hepatitis C virus dynamics under therapy with direct-acting antiviral agents

Chronic hepatitis C virus (HCV) infection remains a world-wide public health problem. Therapy with interferon and ribavirin leads to viral elimination in less than 50% of treated patients. New treatment options aiming at a higher cure rate are focused on direct-acting antiviral agents (DAAs), which directly interfere with different steps in the HCV life cycle. In this paper, we describe and analyze a recently developed multiscale model that predicts HCV dynamics under therapy with DAAs. The model includes both intracellular viral RNA replication and extracellular viral infection. We calculate the steady states of the model and perform a detailed stability analysis. With certain assumptions we obtain analytical approximations of the viral load decline after treatment initiation. One approximation agrees well with the prediction of the model, and can conveniently be used to fit patient data and estimate parameter values. We also discuss other possible ways to incorporate intracellular viral dynamics into the multiscale model.     

NanoStore: a concept for logistical improvements of compound handling in high-throughput screening

Small molecule screening, the systematic encounter of biology space with chemical space, has provoked the emergence of a whole industry that recreates itself by constant iterative improvements to this process. The authors describe an approach to tackle the problem for one of the most time-consuming steps in the execution of a screening campaign, namely, the reformatting of high-throughput screening test compounds from master plates to daughter assay plates used in the execution of the screen. Through an engineered storage procedure, they prepare plates ahead of the screening process with the respective compounds in a ready-to-use format. They show the biological inertness of the method and how it facilitates efficient recovery of compound activity. This uncoupling of normally interconnected processes provides time and compound savings, avoids repeated freeze-thaw cycles of compound solutions, and removes the problems associated with the DMSO sensitivity of certain assays types.     

Continuous Virus Inactivation: How to Generate a Plug Flow

To realize continuous integrated manufacturing of biopharmaceuticals, all steps of production have to be operated in a continuous mode. Virus inactivation is a crucial step in this process, and due to standard procedures and a fixed residence time, it is particularly challenging to realize. Two articles in this issue present possible solutions to this problem.     

Adaptive weighted learning for unbalanced multicategory classification

Summary .  In multicategory classification, standard techniques typically treat all classes equally. This treatment can be problematic when the dataset is unbalanced in the sense that certain classes have very small class proportions compared to others. The minority classes may be ignored or discounted during the classification process due to their small proportions. This can be a serious problem if those minority classes are important. In this article, we study the problem of unbalanced classification and propose new criteria to measure classification accuracy. Moreover, we propose three different weighted learning procedures, two one-step weighted procedures, as well as one adaptive weighted procedure. We demonstrate the advantages of the new procedures, using multicategory support vector machines, through simulated and real datasets. Our results indicate that the proposed methodology can handle unbalanced classification problems effectively.     

Functional gastrointestinal disturbances; recognition and treatment

The recognition of functional gastrointestinal diseases depends essentially on certain positive features characteristic of them. When there are evidences of associated functional disturbances in other organ systems or in the patient as a whole, or characteristic clinical syndromes are present, and there is lack of symptomatic or objective evidence of organic disease on careful examination, the diagnosis of functional gastrointestinal disorder is likely. Treatment of functional gastrointestinal disturbances rests fundamentally on the art of medicine in the treatment of the patient and not on the science of medicine in the treatment of a disease. The essential steps in successful treatment include convincing the patient of the diagnosis, improving and relieving symptoms and avoiding or adequately controlling recurrences.Psychotherapy is a keystone in the treatment of functional gastrointestinal disorders. Not often, however, are the services of a psychiatrist necessary. Given, as needed, mild sedatives, certain forms of specific treatment in specific conditions, general measures and good hygiene and sympathetic understanding, the patient may be expected to recover or improve.     

Maturation of Autophagic Vacuoles in Mammalian Cells

The autophagic process was first described in mammalian cells several decades ago. After their formation as double-membraned vacuoles containing cytoplasmic material, autophagic vacuoles or autophagosomes undergo a stepwise maturation including fusion with both endosomal and lysosomal vesicles. However, the molecular mechanisms regulating these fusion steps have begun to emerge only recently. The list of newly discovered molecules that regulate the maturation of autophagosomes to degradative autolysosomes includes the AAA ATPase SKD1, the small GTP binding protein Rab7, and possibly also the Alzheimer-linked presenilin 1. This review combines previous data on the endo/lysosomal fusion steps during autophagic vacuole maturation with recent findings on the molecules regulating these fusion steps. Interestingly, autophagic vacuole maturation appears to be blocked in certain human diseases including neuronal ceroid lipofuscinosis and Danon disease. This suggests that autophagy has important housekeeping or protective functions, because a block in autophagic maturation causes a disease.     

Rapid sodium channel conductance changes during voltage clamp steps in squid giant axons.

The sodium conductance of the membrane of the giant axon of squid was isolated by the use of potassium-free solutions and voltage-clamped with pulses containing three levels of depolarization. The conductance appears to undergo rapid changes during certain repolarizing clamp steps whose voltage reach at least partially overlaps the gating range. The percentage change in conductance increases with time of depolarization from approximately 0 to approximately 25-30% at 7 ms for a potential step from +70 to -30 mV. Conductance steps were also observed for voltage steps from various depolarized levels to -70 mV. All observed shifts were in the direction of a decreased conductance. The conductance steps appear to be a weak function of the concentration of external calcium, which also acts as a voltage-dependent channel blocker for inwardly directed sodium currents. A number of possible mechanisms are suggested. One of these is discussed in some detail and postulates a voltage- and time-dependent molecular process that does not itself yield open or closed channel conformations, but that affects the magnitude of the rate constants that do connect open and closed state conformations.     

RNA Unwinding by NS3 Helicase: A Statistical Approach

The study of double-stranded RNA unwinding by helicases is a problem of basic scientific interest. One such example is provided by studies on the hepatitis C virus (HCV) NS3 helicase using single molecule mechanical experiments. HCV currently infects nearly 3% of the world population and NS3 is a protein essential for viral genome replication. The objective of this study is to model the RNA unwinding mechanism based on previously published data and study its characteristics and their dependence on force, ATP and NS3 protein concentration. In this work, RNA unwinding by NS3 helicase is hypothesized to occur in a series of discrete steps and the steps themselves occurring in accordance with an underlying point process. A point process driven change point model is employed to model the RNA unwinding mechanism. The results are in large agreement with findings in previous studies. A gamma distribution based renewal process was found to model well the point process that drives the unwinding mechanism. The analysis suggests that the periods of constant extension observed during NS3 activity can indeed be classified into pauses and subpauses and that each depend on the ATP concentration. The step size is independent of external factors and seems to have a median value of 11.37 base pairs. The steps themselves are composed of a number of substeps with an average of about 4 substeps per step and an average substep size of about 3.7 base pairs. An interesting finding pertains to the stepping velocity. Our analysis indicates that stepping velocity may be of two kinds- a low and a high velocity.     

Maturation of autophagic vacuoles in Mammalian cells

The autophagic process was first described in mammalian cells several decades ago. After their formation as double-membraned vacuoles containing cytoplasmic material, autophagic vacuoles or autophagosomes undergo a stepwise maturation including fusion with both endosomal and lysosomal vesicles. However, the molecular mechanisms regulating these fusion steps have begun to emerge only recently. The list of newly discovered molecules that regulate the maturation of autophagosomes to degradative autolysosomes includes the AAA ATPase SKD1, the small GTP binding protein Rab7, and possibly also the Alzheimer-linked presenilin 1. This review combines previous data on the endo/lysosomal fusion steps during autophagic vacuole maturation with recent findings on the molecules regulating these fusion steps. Interestingly, autophagic vacuole maturation appears to be blocked in certain human diseases including neuronal ceroid lipofuscinosis and Danon disease. This suggests that autophagy has important housekeeping or protective functions because a block in autophagic maturation causes a disease.     

Process considerations and economic evaluation of two-step steam pretreatment for production of fuel ethanol from softwood

To increase the overall ethanol yield from softwood, the steam pretreatment stage can be carried out in two steps. The two-step pretreatment process was evaluated from a techno-economic standpoint and compared with the one-step pretreatment process. The production plants considered were designed to utilize spruce as raw material and have a capacity of 200,000 tons/year. The two-step process resulted in a higher ethanol yield and a lower requirement for enzymes. However, the two-step process is more capital-intensive and has a higher energy requirement. The estimated ethanol production cost was the same, 4.13 SEK/L (55.1 cent /L) for both alternatives. For the two-step process different energy-saving options were considered, such as a higher concentration of water-insoluble solids in the filter cake before the second step, and the possibility of excluding the pressure reduction between the steps. The most optimistic configuration, with 50% water-insoluble solids in the filter cake in the feed to the second pretreatment step, no pressure reduction between the pretreatment steps, and 77% overall ethanol yield (0.25 kg EtOH/kg dry wood), resulted in a production cost of 3.90 SEK/L (52.0 cent /L). This shows the potential for the two-step pretreatment process, which, however, remains to be verified in pilot trials.     

Rechnergestützte führung von fermentationsprozessen Teil I

The industrial continuous fermentation for the production of microbial protein is like any real process subject to disturbances. The considerable social expenditures involved in production make it necessary to restrict the negative consequences of these disturbances to a minimum by means of suitable measures. One such measure is the computer-aided adaptation of the static optimum. For the reaction on nonmeasurable disturbing inputs an algorithm is given containing the steps data filtering, adaption of process model and optimization, and the solution of the data-filtering problem in the widest sense by spline functions is discussed. The application of this algorithm to a specific problem of process control is demonstrated in [1].     

Reconcentration of poliovirus from sewage.

Virus can be adsorbed from effluents of sewage treatment plants on large-surface membranes. Subsequent elution of virus requires large volumes, which in turn requires reconcentration of virus for assay. However, reconcentration of such viral eluates on small adsorbent surfaces is difficult because certain soluble sewage components are adsorbed along with the virus on the initial virus adsorbent and are removed along with the virus by the eluent. Upon acidification of the initial eluate to reconcentrate the virus on smaller membrane surfaces, flocs are formed that interfere with the reconcentration process. To circumvent this problem, the interfering sewage components can be removed by activated carbon and ion-exchange resins. The virus is then readily reconcentrated on small membranes.     

Reconcentration of poliovirus from sewage.

Virus can be adsorbed from effluents of sewage treatment plants on large-surface membranes. Subsequent elution of virus requires large volumes, which in turn requires reconcentration of virus for assay. However, reconcentration of such viral eluates on small adsorbent surfaces is difficult because certain soluble sewage components are adsorbed along with the virus on the initial virus adsorbent and are removed along with the virus by the eluent. Upon acidification of the initial eluate to reconcentrate the virus on smaller membrane surfaces, flocs are formed that interfere with the reconcentration process. To circumvent this problem, the interfering sewage components can be removed by activated carbon and ion-exchange resins. The virus is then readily reconcentrated on small membranes.     

Assessing the Effect of the Best Treatment. A Non-parametric Inference Problem

For patients of a certain type, a number of treatments are available. The effect of each such treatment is assumed to be described by a shift model; it is, however, admitted that there may be an interaction between patient and treatment, meaning in particular that the treatment which is best for one patient is not necessarily best for another. The problem is the following: if each patient is given the treatment which is optimal for that particular patient, will this produce a significant effect and, if so, how large is the effect?