Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co‐factor for the Fe+2‐containing α‐ketoglutarate‐dependent Jumonji‐C domain‐containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4−CD8−) T cells to double positive (CD4+CD8+) T cells and of T‐helper cells to different (...) effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water‐soluble vitamin and a safe micro‐nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system. (shrink)

Uric acid has increasingly been associated with insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus. Diabetic patients who are hyperuricemic have a risk of developing diabetic complications. Pathogenesis of uric acid may decrease nitric oxide bioavailability in vascular smooth muscle, endothelial cells and direct scavenging of nitric oxide by uric acid. A decrease in endothelial nitric oxide production by uric acid has also been associated with endothelial dysfunction and insulin resistance. This study aims to determine the relationship between uric acid (...) and glucose levels in patients with type 2 diabetes mellitus. The study included 161 Libyan patients (67 males and 94 females) diagnosed with type 2 diabetes mellitus. Both levels of serum uric acid and hemoglobin A1c (HbA1c) were determined. The patients were divided into two groups. The controllable diabetic group with HbA1c of less than 06.0% and the uncontrollable diabetic group with HbA1c of more than 06.0%. Patients who are suffering from type 2 diabetes mellitus without complications were included whereas patients with smoking, alcoholism, nephrotic disease, malignancy, hepatitis, and renal failure or kidney disease were excluded. The mean and standard deviation of uric acid, HbA1c and Pearson correlation coefficient test were considered. In the controllable diabetic group, serum uric acid mean was found to be 4.807±1.39 and HbA1c was found to be 5.032±1.39. In the uncontrollable diabetic group, serum uric acid was 4.897±1.66 and HbA1c was 8.396±1.65. Uric acid level has significantly been correlated with HBA1C in controlled and uncontrolled diabetic patients (p<0.05). In addition, the uric acid level was found to be higher in the uncontrolled diabetic group than that in the controlled group (p<0.05). A possible relationship between serum uric acid and the incidence of type 2 diabetes mellitus was noted. Thus, uric acid can be used as a potential biomarker to indicate impaired glucose metabolism. (shrink)

Retinoic acid (RA), a derivative of vitamin A, is essential for normal mammalian development. Developmental abnormalities induced by RA excess and vitamin A deficiency are different even though they affect the same organ systems, and it is clear that there are intraembryonic tissue differences in the requirement for RA. The developmental functions of RA are mediated by its effects on gene expression. In the nucleus, two different forms of RA bind to and activate two families of nuclear receptors, which themselves (...) co‐operate in initiating the transcription of target genes. In this article I propose that the amount of RA reaching the nucleus in different embryonic tissues is modulated by a mechanism involving three cytoplasmic binding proteins for retinol (CRBP I) and retinoic acid (CRABP I and II). Abnormalities of craniofacial development resulting from exposure of early neural plate stage embryos to RA excess have been studied in some detail; their initial stages involve alteration of both morphological development and the segment‐specific pattern of gene expression in the early hindbrain and its derived neural crest. This system is ideal for studying the relationships between retinoic acid receptors, retinoid binding proteins, and the development of genetic and morphological pattern. (shrink)

Insulin is stored within the pancreas in an inactive Zn2+‐bound hexameric form prior to release. Similarly, clinical insulins contain Zn2+ and form multimeric complexes. Upon release from the pancreas or upon injection, insulin only becomes active once Zn2+ disengages from the complex. In plasma and other extracellular fluids, the majority of Zn2+ is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn2+. The Zn2+‐binding properties of HSA are attenuated by (...) non‐esterified fatty acids (NEFAs) also transported by HSA. Elevated NEFA concentrations are associated with obesity and type 2 diabetes. Here we present the hypothesis that higher NEFA levels in obese and/or diabetic individuals may contribute to insulin resistance and affect therapeutic insulin dose‐response profiles, through modulation of HSA/Zn2+ dynamics. We envisage this novel concept to have important implications for personalized treatments and management of diabetes‐related conditions in the future. (shrink)

The exploration of plant behavior on a cellular scale in a minimal invasive manner is key to understanding plant adaptations to their environment. Plant hormones regulate multiple aspects of growth and development and mediate environmental responses to ensure a successful life cycle. To monitor the dynamics of plant hormone actions in intact tissue, we need qualitative and quantitative tools with high temporal and spatial resolution. Here, we describe a set of biological instruments (reporters) for the analysis of the distribution and (...) signaling of various plant hormones. Furthermore, we provide examples of their utility for gaining novel insights into plant hormone action with a deeper focus on the drought hormone abscisic acid. (shrink)

Are acids natural kinds? Or are they merely relevant kinds? Although acidity has been one of the oldest and most important concepts in chemistry, surprisingly little ink has been spilled on the natural kind question. I approach the question from the perspective of microstructural essentialism. After explaining why both Brønsted acids and Lewis acids are considered functional kinds, I address the challenges of multiple realization and multiple determination. Contra Manafu and Hendry, I argue that the stereotypical properties (...) of acids are not multiply realized. Instead, given the equivalence between the proton-donating and electron-accepting mechanisms of Brønsted and Lewis, respectively, I show that acidity as a property type can be identified with a unique microstructural property, namely the presence of a LUMO or other low energy empty orbital. In doing so, I defend the view that the Lewis theory encompasses Brønsted–Lowry, and that all Brønsted acids are also Lewis acids. Contra Hacking and Chang, I thus maintain that the different concepts of acidity do not crosscut, and that the hierarchy requirement is met. Finally, by characterizing natural kinds as powerful objects and by adopting a dispositional view of functions, I illustrate how the microessentialist can make sense of the latent and relational character of most acids. In sum, I contend that acids are genuine natural kinds, even for the microstructural essentialist. (shrink)

Acidity provides an interesting example of an everyday concept that developed fully into a scientific one; it is one of the oldest concepts in chemistry and remains an important one. However, up to now there has been no unity to it. Currently two standard theoretical definitions coexist ; the standard laboratory measure of acidity, namely the pH, only corresponds directly to the Br⊘nsted-Lowry concept. The lasting identity of the acidity concept in modern chemistry is based on the persistence of the (...) quotidian concept. This is suggestive for considerations of other scientific concepts. (shrink)

Henry Knowles Beecher, an icon of human research ethics, and Timothy Francis Leary, a guru of the counterculture, are bound together in history by the synthetic hallucinogen lysergic acid diethylamide. Beecher was a U.S. Army Lieutenant Colonel who received five battle stars, was inducted into the Legion of Merit, held the first endowed chair in his discipline, wrote at least three path-breaking papers, and is honored by two prestigious ethics awards in his name. Leary was a West Point dropout who (...) was obliged to leave a research assistant professorship, was convicted of violating the Marihuana Tax Act, was sentenced to 20 years in prison and broke out with the... (shrink)

The study of haemopoiesis enables us to address one of the central questions of developmental biology, concerning the molecular mechanisms by which a multipotent cell develops into distinct differentiated progeny. Recent work(1) suggests specific roles for retinoic acid receptors at two distinct stages of haemopoiesis. Continuous cell lines of lymphohaemopoietic progenitors were established by infection with a retrovirus containing a dominant negative retinoic acid receptor. The cell lines depend on stem cell factor for their proliferation and can be induced to (...) diffentiate into B‐lymphocytes, erythrocytes, neutrophils, monocytes, mast cells and megakaryocytes. Since lymphohaemopoietic progenitors represent less than 0.01% of nucleated marrow cells, immortalised progenitors provide a valuable system with which to study haemopoiesis on a molecular level. (shrink)

How vertebrates evolved different traits for acid excretion to maintain body fluid pH homeostasis is largely unknown. The evolution of Na+/H+ exchanger (NHE)‐mediated NH4+ excretion in fishes is reported, and the coevolution with increased ammoniagenesis and accompanying gluconeogenesis is speculated to benefit vertebrates in terms of both internal homeostasis and energy metabolism response to acidic stress. The findings provide new insights into our understanding of the possible adaptation of fishes to progressing global environmental acidification. In human kidney, titratable H+ and (...) NH4+ comprise the two main components of net acid excretion. V‐type H+‐ATPase‐mediated H+ excretion may have developed in stenohaline lampreys when they initially invaded freshwater from marine habitats, but this trait is lost in most fishes. Instead, increased reliance on NHE‐mediated NH4+ excretion is gradually developed and intensified during fish evolution. Further investigations on more species will be needed to support the hypothesis. Also see the video abstract here https://youtu.be/vZuObtfm-34. (shrink)

Enzymes that degrade nucleic acids are emerging as important players in the pathogenesis of inflammatory disease. This is exemplified by the recent identification of four genes that cause the childhood inflammatory disorder, Aicardi‐Goutières syndrome (AGS). This is an autosomal recessive neurological condition whose clinical and immunological features parallel those of congenital viral infection. The four AGS genes encode two nucleases: TREX1 and the hetero‐trimeric Ribonuclease H2 (RNase H2) complex. The biochemical activity of these enzymes was initially characterised 30 years (...) ago but a role in neurological inflammation was entirely unanticipated until they were found to be mutated in AGS. This has led to a hypothesis that accumulation of intracellular nucleic acids occurs as a consequence of mutation in these enzymes and triggers an inflammatory response through activation of innate immune pattern recognition receptors. ©2007 Wiley Periodicals, Inc BioEssays 30:833–842, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The initial relationships between organisms leading to endosymbiosis and the first eukaryote are currently a topic of hot debate. Here, I present a theory that offers a gradual scenario in which the origins of phagocytosis and mitochondria are intertwined in such a way that the evolution of one would not be possible without the other. In this scenario, the premitochondrial bacterial symbiont became initially associated with a protophagocytic host on the basis of cooperation to kill prey with symbiont‐produced toxins and (...) reactive oxygen species (ROS). Subsequently, the cooperation was focused on the digestion stage, through the acidification of the protophagocytic cavities via exportation of protons produced by the aerobic respiration of the symbiont. The host gained an improved phagocytic capacity and the symbiont received organic compounds from prey. As the host gradually lost its membrane energetics to develop lysosomal digestion, respiration was centralized in the premitochondrial symbiont for energy production for the consortium. (shrink)

Tackling impaired bioenergetics in multiple sclerosis has been recently recognized as an innovative approach with therapeutic potential. Guanidinoacetic acid is an experimental nutrient that plays a significant role in high-energy phosphate metabolism. The preliminary trials suggest beneficial effects of supplemental GAA in MS, with GAA augments biomarkers of brain energy metabolism and improves patient-reported features of the disease. GAA can also impact other metabolic footprints of MS, including demyelination, oxidative stress, and GABA-glutamate imbalance. In this mini-review article, we summarize studies (...) evaluating GAA effectiveness in MS, explore mechanisms of GAA action, and discuss the challenges of using dietary GAA as an element of MS therapy. (shrink)

Acid attacks on women are increasing at alarming rates in Bangladesh, but the government has failed to provide medical care to the victims. Easily available sulfuric acid, which can mutilate a human face in moments, has emerged as a weapon used to disfigure a woman’s body. By the mid-1990s, activists had documented acid attacks, and urban protests were followed by demands for better medical care. I show how the interaction between local and international-level civil society organizations made international resources available (...) to local feminist groups engaged in domestic social struggles and helped to improve medical care for acid victims of Bangladesh. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, arachidonic (...) acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

There is growing evidence of evolutionary genome plasticity. The evolution of repetitive DNA elements, the major components of most eukaryotic genomes, involves the amplification of various classes of mobile genetic elements, the expansion of satellite DNA, the transfer of fragments or entire organellar genomes and may have connections with viruses. In addition to various repetitive DNA elements, a plethora of large and small RNAs migrate within and between cells during individual development as well as during evolution and contribute to changes (...) of genome structure and function. Such migration of DNA and RNA molecules often results in horizontal gene transfer, thus shaping the whole genomic network of interconnected species. Here, we propose that a high evolutionary dynamism of repetitive genome components is often related to the migration/movement of DNA or RNA molecules. We speculate that the cytoplasm is probably an ideal compartment for such evolutionary experiments. (shrink)

Nucleic acid hybridization is being increasingly used in viral diagnosis. Most of the assays described so far for this purpose require the use of radioactive probes. Their replacement by Non‐radioactive assays has many advantages and makes the technique feasible in routine diagnostic work. Non‐radioactive assays have had limited use but their diagnostic value has been demonstrated for a number of virus infections. They have the main advantages of employing stable probes, of avoiding safety hazards and of being easy and rapid (...) to perform with limited laboratory facilities. Their main disadvantage compared to radioactive assays is in having relatively low sensitivity. Improvements in probe construction, in labelling and detecting methods, in sample treatment and in hybridization conditions may well increase their usefulness. (shrink)

Extracellular nucleic acids are found in different biological fluids in the organism and in the environment: DNA is a ubiquitous component of the organic matter pool in the soil and in all marine and freshwater habitats. Data from recent studies strongly suggest that extracellular DNA and RNA play important biological roles in microbial communities and in higher organisms. DNA is an important component of bacterial biofilms and is involved in horizontal gene transfer. In recent years, the circulating extracellular nucleic (...) acids were shown to be associated with some diseases. Attempts are being made to develop noninvasive methods of early tumor diagnostics based on analysis of circulating DNA and RNA. Recent observations demonstrated the possibility of nucleic acids exchange between eukaryotic cells and extracellular space suggesting their participation in so far unidentified biological processes. BioEssays 29:654–667, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This paper uses scientific perspectivism as a lens for understanding acid experiments from the Chemical Revolution. I argue that this account has several advantages over several recent interpretations of this period, interpretations that do not neatly capture some of the historical experiments on acids. The perspectival view is distinctive in that it avoids discontinuity, allows for the rational resolution of disagreement, and is sensitive to the historical epistemic context.

For a period of several years the philosopher of science Hasok Chang has promoted various inter-related views including pluralism, pragmatism, and an associated view of natural kinds. He has also argued for what he calls the persistence of everyday terms in the scientific view. Chang claims that terms like phlogiston were never truly abandoned but became transformed into different concepts that remain useful. On the other hand, Chang argues that some scientific terms such as acidity have suffered a form of (...) “rupture”, especially in the case of the modern Lewis definition of acids. Chang also complains that the degree of acidity of a Lewis acid cannot be measured using a pH meter and seems to regard this as a serious problem. The present paper examines some of these views, especially what Chang claims to be a rupture in the definition of acidity. It is suggested that there has been no such rupture but a genuine generalization, on moving from the Brønsted-Lowry theory to the Lewis theory of acidity. It will be shown how the quantification and measurement of Lewis acidity can easily be realized through the use of equilibrium theory and the use of stability constants. (shrink)

We consider the evidence that RA†, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: (1) the stimulation of axon outgrowth in particular neuronal sub‐types; (2) the migration of the neural crest; and (3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA‐induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; (...) the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system. (shrink)

Among the many vivid metaphors in Darwin’s Dangerous Idea, one stands out. The understanding of how cumulative natural selection gives rise to adaptations is, Dennett says, like a “universal acid”—an idea so powerful and corrosive of conventional wisdom that it dissolves all attempts to contain it within biology. Like most good ideas, this one is very simple: Once replicators (material objects that are faithfully copied) come to exist, some will replicate more rapidly than others, leading to adaptation by natural selection. (...) The great power of the idea is that the resulting adaptations can be understood by asking what leads to efficient, rapid replication. Given that ideas seem to replicate, it is natural that Dawkins (1976, 1982), Dennett (1992), and others have explored the possibility of using this idea to explain cultural evolution. (shrink)

Wana Manitpisitkul1, Sabrina Lee2, Matthew Cooper31Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD, USA; 2Solid Organ Transplant Program, University of Utah Health Care, Salt Lake City, UT, USA; 3Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA: Addition of mycophenolate mofetil to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological (...) and gastrointestinal side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.Keywords: enteric-coated mycophenolate sodium, mycophenolate mofetil, kidney transplant, efficacy, gastrointestinal tolerability. (shrink)

The acid rain issue came into prominence because scientists kept telling the world of acid rain's potential devastating effects. Yet, the acid rain debate was marked by mistrust between American and Canadian scientists. The signing of the Air Quality Accord in 1991 appears to have quelled this divisiveness and promises to bring about a new era of scientific cooperation. Using surveys of acid rain scientists in the United States and Canada across three time periods, this study finds both similarities and (...) differences between how Canadian and American scientists view many of the issues surrounding the acid rain debate. (shrink)

In vertebrate development, the HOX genes act to specify cell identity along much of the anterior‐posterior axis of the embryonic central nervous system. In all vertebrates examined to date, the vitamin A metabolite retinoic acid is implicated in the patterning of the anterior posterior axis and the induction of HOX gene expression. Two recent papers have extended the study of retinoic acid induction of HOX genes to the closest relatives of the vertebrates, amphioxus and tunicates(1,2). In both these species, exogenous (...) retinoic acid is able to induce ectopic expression of HOX 1 genes in the anterior central nervous system. This suggests that retinoic acid control of anterior‐posterior axis formation and HOX induction is not specific to vertebrates. However, in the more distantly related echinoderms and arthropods, retinoic acid does not seem to act in the same way. Thus the role of retinoic acid in anterior‐posterior axis specification may be a chordate innovation, perhaps linked to the evolution of another chordate character, the dorsal neural tube. (shrink)

The hypothalamus is a specialized area in the brain that integrates the control of energy homeostasis. More than 70 years ago, it was proposed that the central nervous system sensed circulating levels of metabolites such as glucose, lipids and amino acids and modified feeding according to the levels of those molecules. This led to the formulation of the Glucostatic, Lipostatic and Aminostatic Hypotheses. It has taken almost that much time to demonstrate that circulating long‐chain fatty acids act as (...) signals of nutrient surplus in the hypothalamus. Moreover, pharmacological and/or genetic inhibition of fatty acid synthase, AMP‐activated protein kinase and carnitine palmitoyltransferase 1 results in profound decrease in feeding and body weight in rodents. The molecular mechanism behind these actions depends on changes in the cellular pool of malonyl‐CoA and fatty acyl‐CoAs. Current evidence also suggests that this pathway may play a major role in the physiological regulation of feeding, by integrating hormonal and nutrient‐derived signals in the hypothalamus. Here, we summarize what is known about hypothalamic fatty acid metabolism and feeding control and provide future directions for research. Understanding these molecular mechanisms could provide new targets for the treatment of obesity and related disorders. BioEssays 29: 248–261, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Upon separation of the protein from the nucleic acid component of tobacco mosaic virus by phenol, using a fast and gentle procedure, the nucleic acid is infective in assays on tobacco leaves. A series of qualitative and quantitative control experiments demonstrates that the biological activity cannot depend on residual proteins in the preparation, but is a property of isolated nucleic acid which is thus the genetic material of the virus.

Among the many vivid metaphors in Darwin’s Dangerous Idea, one stands out. The understanding of how cumulative natural selection gives rise to adaptations is, Dennett says, like a “universal acid”—an idea so powerful and corrosive of conventional wisdom that it dissolves all attempts to contain it within biology. Like most good ideas, this one is very simple: Once replicators (material objects that are faithfully copied) come to exist, some will replicate more rapidly than others, leading to adaptation by natural selection. (...) The great power of the idea is that the resulting adaptations can be understood by asking what leads to efficient, rapid replication. Given that ideas seem to replicate, it is natural that Dawkins (1976, 1982), Dennett (1992), and others have explored the possibility of using this idea to explain cultural evolution. (shrink)

Despite its biological importance, the mechanism of formation of cutin, the polymeric matrix of plant cuticles, has not yet been fully clarified. Here, for the first time, we show the participation in the process of lipid vesicles formed by the self‐assembly of endogenous polyhydroxy fatty acids. The accumulation and fusion of these vesicles (cutinsomes) at the outer part of epidermal cell wall is proposed as the mechanism for early cuticle formation. BioEssays 30:273–277, 2008. © 2008 Wiley Periodicals, Inc.

Bacteria have a significant impact on human production and life, endangering human life and health, so rapid detection of infectious agents is essential to improve human health. Aptamers, which are pieces of oligonucleotides (DNA or RNA) have been applied to biosensors for bacteria detection due to their high affinity, selectivity, robust chemical stability, and their compatibility with various signal amplification and signal transduction mechanisms. In this review, we summarize the different bacterial aptamers selected in recent years using SELEX technology and (...) discuss the differences in optical and electrochemical bacterial aptamer sensors. In addition the technological developments and innovations in bacterial aptamer sensor technology are introduced. Combining new materials and methods, the efficiency and stability of the sensors have also been improved. This review summarizes the progress of current bacterial aptamer sensors based on their practical application status and provides an outlook on their future development. (shrink)

The acidity function is a thermodynamic quantitative measure of acid strength for non-aqueous and concentrated aqueous Brønsted acids, with acid strength being defined as the extent to which the acid protonates a base of known basicity. The acidity function, which was developed, both theoretically and experimentally, by Louis P. Hammett of Columbia University during the 1930s, has proven useful in the area of physical organic chemistry where it has been used to correlate rates of acid-catalyzed reactions and to quantitate (...) the acidity of superacids, acids with protonating abilities greater than pure sulfuric acid. All Brønsted acids can now be compared using a common measure. Karl Popper’s seminal idea of theory falsification does not apply here because of the many successful applications of the acidity function. Likewise, Thomas Kuhn’s idea of a paradigm shift does not apply here, even though the acidity function concept was revolutionary, because the acidity function is commensurate with classical concepts of acidity. (shrink)

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle‐mediated transport, peroxisome assembly, 26S protease (...) function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non‐exclusive) such possibilities are: (1) ATP‐dependent proteasome function and (2) ATP‐dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP‐dependent protein clamp. (shrink)

Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram negative bacilli to control and treat. One of the major challenges that the pathogenic bacteria face in their host is the scarcity of freely available iron. To survive under such conditions, bacteria express new proteins on their outer membrane and also secrete iron chelators called siderophores. Antibodies directed against these proteins associated with iron uptake exert a bacteriostatic or bactericidal effect against A. baumanii in vitro, by blocking (...) siderophore mediated iron uptake pathways. Attempts should be made to discover peptides that could mimic protein epitopes and possess the same immunogenicity as the whole protein. Subsequently, theoretical methods for epitope prediction have been developed leading to synthesis of such peptides that are important for development of immunodiagnostic tests and vaccines. The present study was designed to in silico resolving the major obstacles in the control or in prevention of the diseases caused by A. baumannii. We exploited bioinformatic tools to better understand and characterize the Baumannii acinetobactin utilization structure of A. baumannii and select appropriate regions as effective B cell epitopes. In conclusion, amino acids 26–191 of cork domain and 321–635 of part of the barrel domain including L4–L9, were selected as vaccine candidates. These two regions contain functional exposed amino acids with higher score of B cell epitopes properties. Majority of amino acids are hydrophilic, flexible, accessible, and favorable for B cells from secondary structure point of view. (shrink)

Correspondence analysis of 28 proteomes selected to span the entire realm of prokaryotes revealed universal biases in the proteins’ amino acid distribution. Integral Inner Membrane Proteins always form an individual cluster, which can then be used to predict protein localisation in unknown proteomes, independently of the organism’s biotope or kingdom. Orphan proteins are consistently rich in aromatic residues. Another bias is also ubiquitous: the amino acid composition is driven by the GþC content of the first codon position. An unexpected bias (...) is driven, in many proteomes, by the AANbox of the genetic code, suggesting some functional biochemical relationship between asparagine and lysine. Less-significant biases are driven by the rare amino acids, cysteine and tryptophan. Some allow identification of species-specific functions or localisation such as surface or exported proteins. Errors in genome annotations are also revealed by correspondence analysis, making it useful for quality control and correction. (shrink)

Fatty acids (FAs) are well known to serve as substrates for reactions that provide cells with membranes and energy. In contrast to these metabolic reactions, the physiological importance of FAs themselves known as free FAs (FFAs) in cells remains obscure. Since accumulation of FFAs in cells is toxic, cells must develop mechanisms to detoxify FFAs. One such mechanism is to sequester free polyunsaturated FAs (PUFAs) into a droplet‐like structure assembled by Fas‐Associated Factor 1 (FAF1), a cytosolic protein. This sequestration (...) limits access of PUFAs to Fe2+, thereby preventing Fe2+‐catalyzed PUFA peroxidation. Consequently, assembly of the FAF1‐FFA complex is critical to protect cells from ferroptosis, a cell death pathway triggered by PUFA peroxidation. The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex should open new directions to explore signaling pathways by which FFAs regulate cellular physiology. (shrink)

This paper examines the issue of acid mine drainage in South Africa and environmental decision making processes that could be taken to mitigate the problem in the context of both conventional risk assessment and the precautionary principle. It is argued that conventional risk assessment protects the status quo and hence cannot be entirely relied upon as an effective tool to resolve environmental problems in the context of South Africa, a developing country with complex environmental health concerns. The complexity of the (...) environmental issues is discussed from historical and political perspectives. An argument is subsequently made that the precautionary principle is an alternative tool, and its adoption can be used to empower local communities. This work, therefore, adds to new knowledge by problematising conventional risk assessment and proposing the framing of the acid mine drainage issues in a complex and contextual scenario of a developing country—South Africa. (shrink)

In amblyopia, abnormal visual experience during development leads to an enduring loss of visual acuity in adulthood. Physiological studies in animal models suggest that intracortical GABAergic inhibition may mediate visual deficits in amblyopia. To better understand the relationship between visual cortical γ-aminobutyric acid (GABA) and perceptual suppression in persons with amblyopia (PWA), we employed magnetic resonance spectroscopy (MRS) to quantify GABA levels in both PWA and normally-sighted persons (NSP). In the same individuals, we obtained psychophysical measures of perceptual suppression for (...) a variety of ocular configurations. In PWA, we found a robust negative correlation between the depth of amblyopia (the difference in visual acuity between the amblyopic and non-amblyopic eyes) and GABA concentration that was specific to visual cortex and was not observed in a sensorimotor cortical control region. Moreover, lower levels of visual cortical GABA were associated with weaker perceptual suppression of the fellow eye by the amblyopic eye and stronger suppression of the amblyopic eye by the fellow eye. Taken together, our findings provide evidence that intracortical GABAergic inhibition is an important component of the pathology of human amblyopia and suggest possible therapeutic interventions to restore vision in the amblyopic eye through enhancement of visual cortical GABAergic signaling in PWA. (shrink)

In January 2014, a letter and original research article were published in Nature describing a process whereby somatic mouse cells could be converted into stem cells by subjecting them to stress. These “stimulus-triggered acquisition of pluripotency” cells were shown to be capable of contributing to all cell types of a developing embryo, and extra-embryonic tissues. The lead author of the publications, Haruko Obokata, became an overnight celebrity in Japan, where she was dubbed the new face of Japanese science. However, in (...) the weeks that followed publication of the research, issues arose. Other laboratories and researchers found that they were unable to replicate Obokata et al.’s work. Closer scrutiny of the papers by the scientific community also suggested that there was manipulation of images that had been published, and Obokata was accused of misconduct. Those who should have been supervising her work were also heavily criticised. The STAP cell saga of 2014 is used as an example to highlight the importance of trust and replication in twenty-first century biological science. The role of trust in the scientific community is highlighted, and the effects on interactions between science and the public examined. Similarly, this essay aims to highlight the importance of replication, and how this is understood by researchers, the media, and the public. The expected behaviour of scientists in the twenty-first century is now more closely scrutinised. (shrink)

This essay responds to Hirstein, Sifferd and Fagan’s book, Responsible Brains, which claims that executive function is the guiding mechanism that supports both responsible agency and the necessity for some excuses. In contrast, I suggest that executive function is not the universal acid and the neuroscience at present contributes almost nothing to the necessary psychological level of explanation and analysis. To the extent neuroscience can be useful, it is virtually entirely dependent on well-validated psychology to correlate with the neuroscientific variables (...) under investigation. The essay considers what executive function is and what the neuroscience adds to our understanding of it. Then it addresses moral and legal responsibility generally, and specific doctrines. Executive function is seldom found to be the most perspicuous approach to any of the general or specific moral and legal questions. (shrink)