An emerging field of plasma medicine is discussed, where non-equilibrium plasmas are shown to be able to initiate, promote, control, and catalyze various complex behaviors and responses in biological systems. More importantly, it will be shown that plasma can be tuned to achieve the desired medical effect, especially in medical sterilization and treatment of different kind of skin diseases. Wound healing and tissue regeneration can be achieved following various types of plasma treatment in a multitude of wound pathologies. Non-equilibrium plasmas will be shown to be non-destructive to tissue, safe, and effective in inactivation of various parasites and foreign organisms.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ppap.200700154

Applied Plasma Medicine

This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases.

The role of autophagy in neurodegenerative disease

The Heat Shock Response: Life on the Verge of Death

This introductory review on plasma health care is intended to provide the interested reader with a summary of the current status of this emerging field, its scope, and its broad interdisciplinary approach, ranging from plasma physics, chemistry and technology, to microbiology, biochemistry, biophysics, medicine and hygiene. Apart from the basic plasma processes and the restrictions and requirements set by international health standards, the review focuses on plasma interaction with prokaryotic cells (bacteria), eukaryotic cells (mammalian cells), cell membranes, DNA etc. In so doing, some of the unfamiliar terminology—an unavoidable by-product of interdisciplinary research—is covered and explained. Plasma health care may provide a fast and efficient new path for effective hospital (and other public buildings) hygiene— helping to prevent and contain diseases that are continuously gaining ground as resistance of pathogens to antibiotics grows. The delivery of medically active 'substances' at the molecular or ionic level is another exciting topic of research through effects on cell walls (permeabilization), cell excitation (paracrine action) and the introduction of reactive species into cell cytoplasm. Electric fields, charging of surfaces, current flows etc can also affect tissue in a controlled way. The field is young and hopes are high. It is fitting to cover the beginnings in New Journal of Physics, since it is the physics (and non- equilibrium chemistry) of room temperature atmospheric pressure plasmas that have made this development of plasma health care possible.

/pdf/plasma-medicine-an-introductory-review-16ncxlrbef.pdf

Plasma medicine: an introductory review

Reconstructing gene regulatory networks from high-throughput data is a long-standing challenge. Through the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we performed a comprehensive blind assessment of over 30 network inference methods on Escherichia coli, Staphylococcus aureus, Saccharomyces cerevisiae and in silico microarray data. We characterize the performance, data requirements and inherent biases of different inference approaches, and we provide guidelines for algorithm application and development. We observed that no single inference method performs optimally across all data sets. In contrast, integration of predictions from multiple inference methods shows robust and high performance across diverse data sets. We thereby constructed high-confidence networks for E. coli and S. aureus, each comprising ∼1,700 transcriptional interactions at a precision of ∼50%. We experimentally tested 53 previously unobserved regulatory interactions in E. coli, of which 23 (43%) were supported. Our results establish community-based methods as a powerful and robust tool for the inference of transcriptional gene regulatory networks.

Wisdom of crowds for robust gene network inference

As part of their life cycle, neutralophilic bacteria are often exposed to varying environmental stresses, among which fluctuations in pH are the most frequent. In particular, acid environments can be encountered in many situations from fermented food to the gastric compartment of the animal host. Herein, we review the current knowledge of the molecular mechanisms adopted by a range of Gram-positive and Gram-negative bacteria, mostly those affecting human health, for coping with acid stress. Because organic and inorganic acids have deleterious effects on the activity of the biological macromolecules to the point of significantly reducing growth and even threatening their viability, it is not unexpected that neutralophilic bacteria have evolved a number of different protective mechanisms, which provide them with an advantage in otherwise life-threatening conditions. The overall logic of these is to protect the cell from the deleterious effects of a harmful level of protons. Among the most favoured mechanisms are the pumping out of protons, production of ammonia and proton-consuming decarboxylation reactions, as well as modifications of the lipid content in the membrane. Several examples are provided to describe mechanisms adopted to sense the external acidic pH. Particular attention is paid to Escherichia coli extreme acid resistance mechanisms, the activity of which ensure survival and may be directly linked to virulence.

Coping with low pH: molecular strategies in neutralophilic bacteria

Protein folding in the cell, long thought to be a spontaneous process, in fact often requires the assistance of molecular chaperones. This is thought to be largely because of the danger of incorrect folding and aggregation of proteins, which is a particular problem in the crowded environment of the cell. Molecular chaperones are involved in numerous processes in bacterial cells, including assisting the folding of newly synthesized proteins, both during and after translation; assisting in protein secretion, preventing aggregation of proteins on heat shock, and repairing proteins that have been damaged or misfolded by stresses such as a heat shock. Within the cell, a balance has to be found between refolding of proteins and their proteolytic degradation, and molecular chaperones play a key role in this. In this review, the evidence for the existence and role of the major cytoplasmic molecular chaperones will be discussed, mainly from the physiological point of view but also in relationship to their known structure, function and mechanism of action. The two major chaperone systems in bacterial cells (as typified by Escherichia coli) are the GroE and DnaK chaperones, and the contrasting roles and mechanisms of these chaperones will be presented. The GroE chaperone machine acts by providing a protected environment in which protein folding of individual protein molecules can proceed, whereas the DnaK chaperones act by binding and protecting exposed regions on unfolded or partially folded protein chains. DnaK chaperones interact with trigger factor in protein translation and with ClpB in reactivating proteins which have become aggregated after heat shock. The nature of the other cytoplasmic chaperones in the cell will also be reviewed, including those for which a clear function has not yet been determined, and those where an in vivo chaperone function has still to be proven, such as the small heat shock proteins IbpA and IbpB. The regulation of expression of the genes of the heat shock response will also be discussed, particularly in the light of the signals that are needed to induce the response. The major signals for induction of the heat shock response are elevated temperature and the presence of unfolded protein within the cell, but these are sensed and transduced differently by different bacteria. The best characterized example is the sigma 32 subunit of RNA polymerase from E. coli, which is both more efficiently translated and also transiently stabilized following heat shock. The DnaK chaperones modulate this effect. However, a more widely conserved system appears to be typified by the HrcA repressor in Bacillus subtilis, the activity of which is modulated by the GroE chaperone machine. Other examples of regulation of molecular chaperones will also be discussed. Finally, the likely future research directions for molecular chaperone biology in the post-genomic era will be briefly evaluated.

Microbial molecular chaperones.

Resistance against currently used antitubercular therapeutics increasingly undermines efforts to contain the worldwide tuberculosis (TB) epidemic. Recently, benzothiazinone (BTZ) inhibitors have shown nanomolar potency against both drug-susceptible and multidrug-resistant strains of the tubercle bacillus. However, their proposed mode of action is lacking structural evidence. We report here the crystal structure of the BTZ target, FAD-containing oxidoreductase Mycobacterium tuberculosis DprE1, which is essential for viability. Different crystal forms of ligand-free DprE1 reveal considerable levels of structural flexibility of two surface loops that seem to govern accessibility of the active site. Structures of complexes with the BTZ-derived nitroso derivative CT325 reveal the mode of inhibitor binding, which includes a covalent link to conserved Cys387, and reveal a trifluoromethyl group as a second key determinant of interaction with the enzyme. Surprisingly, we find that a noncovalent complex was formed between DprE1 and CT319, which is structurally identical to CT325 except for an inert nitro group replacing the reactive nitroso group. This demonstrates that binding of BTZ-class inhibitors to DprE1 is not strictly dependent on formation of the covalent link to Cys387. On the basis of the structural and activity data, we propose that the complex of DrpE1 bound to CT325 is a representative of the BTZ-target complex. These results mark a significant step forward in the characterization of a key TB drug target.

/pdf/structural-basis-of-inhibition-of-mycobacterium-tuberculosis-1j7coq7fut.pdf

Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors

Mechanisms of plasma-induced microbial inactivation have commonly been studied with physicochemical techniques. In this letter, Escherichia coli K-12 and its Delta recA, Delta rpoS, and Delta soxS mutants are employed to discriminate effects of UV photons, OH radicals, and reactive oxygen species produced in atmospheric discharges. This microbiological approach exploits the fact that these E. coli mutants are defective in their resistance against various external stresses. By interplaying bacterial inactivation kinetics with optical emission spectroscopy, oxygen atoms are identified as a major contributor in plasma inactivation with minor contributions from UV photons, OH radicals, singlet oxygen metastables, and nitric oxide. (c) 2007 American Institute of Physics.

Probing bactericidal mechanisms induced by cold atmospheric plasmas with Escherichia coli mutants

A significant proportion of bacteria express two or more chaperonin genes. Chaperonins are a group of molecular chaperones, defined by sequence similarity, required for the folding of some cellular proteins. Chaperonin monomers have a mass of c. 60 kDa, and are typically found as large protein complexes containing 14 subunits arranged in two rings. The mechanism of action of the Escherichia coli GroEL protein has been studied in great detail. It acts by binding to unfolded proteins and enabling them to fold in a protected environment where they do not interact with any other proteins. GroEL can assist the folding of many proteins of different sizes, sequences, and structures, and homologues from many different bacteria can functionally replace GroEL in E. coli. What then are the functions of multiple chaperonins? Do they provide a mechanism for cells to increase their general chaperoning ability, or have they become specialized to take on specific novel cellular roles? Here I will review the genetic, biochemical, and phylogenetic evidence that has a bearing on this question, and show that there is good evidence for at least some specificity of function in multiple chaperonin genes.

Peter A. Lund

Papers

Coping with low pH: molecular strategies in neutralophilic bacteria

Microbial molecular chaperones.

Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors

Probing bactericidal mechanisms induced by cold atmospheric plasmas with Escherichia coli mutants

Multiple chaperonins in bacteria--why so many?