Minireview Series Research Articles

Exploring the Hidden Potential of Bacteriophages 3-Part Miniseries

Bacteriophages are viruses that specifically infect bacteria. They can be found everywhere: in the oceans, on plants, and within the human microbiome. Bacteriophage fall into two categories: lytic and lysogenic. Lytic phages have been used for the treatment of various bacterial infections. Lysogenic phages have the potential to act as a vector for bacterial genetic manipulation through the introduction of key genes via horizontal gene transfer. This process would result in the introduction of engineered genetic material to bacterial hosts, for instance to change the behavior of gut bacteria without impacting the human host or requiring complex procedures. Therefore, bacteriophage could be used for the targeted treatment of a multitude of complex diseases, including antibiotic-resistant bacterial infections, sexually transmitted infections, bacterial dysbiosis, cancer treatment, and potentially hormone/ metabolite replacement therapy. Similarly, bacteriophages are in use for the prevention and eradication of agricultural pests and offer relief from antibiotic overuse by the meat industry. These organisms could even be used to stave off parasite-induced honeybee colony collapse. Indeed, genetic manipulations of bacteriophage could be employed as a novel method to increase oceanic carbon capture, methane fixation, and plastic degradation to reduce the levels of pollution contributing to environmental toxicity and climate change. This three-part mini review series highlights phage biological processes and the correlated potential areas of application, making an argument for an increase in phage research while presenting the field’s current limitations and the future of innovative solutions for some of the most pressing problems of the 21st century.

An Overview of Clinical Oncology and Impact on Oral Health.

As the incidence of cancer continues to increase, so too will the use of various forms of cancer therapeutics and their associated oral and dental complications. Although many of the acute and chronic oral toxicities of cancer therapy are largely unavoidable, appropriate and timely management of these complications has the potential to alleviate morbidity and improve outcomes. Undoubtedly, the substantial short- and long-term impacts of cancer therapy on the health of the oral cavity requires increased awareness, prevention, and treatment by multidisciplinary healthcare teams consisting of medical oncologists, dentists, and other oral healthcare specialists. This mini review provides a brief purview of the current state of clinical oncology and its impact on oral health. The topics introduced here will be further investigated throughout the remainder of the “Oral Complications in Cancer Patients” mini-review series.

Androgen deprivation therapy and its modulation of PSMA expression in prostate cancer: mini review and case series of patients studied with sequential [68Ga]-Ga-PSMA-11 PET/CT

Androgen deprivation therapy and its modulation of PSMA expression in prostate cancer: mini review and case series of patients studied with sequential [68Ga]-Ga-PSMA-11 PET/CT

From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function.

Chemokine receptors CXCR4 and atypical chemokine receptor 3 (ACKR3/CXCR7) are highly expressed in a range of tumors. Yet, their role in cancer progression is not well understood. This minireview series encompasses seven comprehensive reviews focusing on modulators (small molecules, pepducins, antibodies), structural aspects, spatio-temporal signaling properties, and phosphorylation/interactome of CXCR4 and ACKR3. Moreover, different (patho)physiologic aspects and roles of these receptors in immunologic and oncogenic processes are discussed. SIGNIFICANCE STATEMENT: CXCR4 and atypical chemokine receptor 3 are two oncogenic G protein-coupled receptors that are highly upregulated in various tumors. Insight into the signalling properties of these receptors and the availability of modulators targeting these receptors are essential to assess their role in cancer.

Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Non-coding RNAs in vascular disease - from basic science to clinical applications: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.

Non-coding RNAs are increasingly recognized not only as regulators of various biological functions but also as targets for a new generation of RNA therapeutics and biomarkers. We hereby review recent insights relating to non-coding RNAs including microRNAs (e.g. miR-126, miR-146a), long non-coding RNAs (e.g. MIR503HG, GATA6-AS, SMILR), and circular RNAs (e.g. cZNF292) and their role in vascular diseases. This includes identification and therapeutic use of hypoxia-regulated non-coding RNAs and endogenous non-coding RNAs that regulate intrinsic smooth muscle cell signalling, age-related non-coding RNAs, and non-coding RNAs involved in the regulation of mitochondrial biology and metabolic control. Finally, we discuss non-coding RNA species with biomarker potential.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Issue Cover (November 2017)

Front cover: This Cover introduces the mini Review series ‘Beyond Amyloid’, in which the authors provide insights into various aspects of Alzheimer disease that go beyond the commonly discussed aspects of the disease.Guest editor: Christian Behl, Johannes Gutenberg University Mainz, Germany. Email: cbehl@uni-mainz.de.Sporadic Alzheimer's disease (AD) is a complex disease. Describing its totality is reminiscent of the story of the blind men trying to describe an elephant. As we probe the mysteries of the creature, sightless as to its full extent, we are drawn to its most obvious part – the giant trunk in the case of the elephant, β-amyloid plaques in the case of AD. There are other blind men trying to be heard, however, as they describe other parts of the elephant and other features of the disease. Many functions decline with age (black line). Yet, our overemphasis on amyloid deposition (red line) has distracted us from the study of these other age-related changes (gray matter – green line; white matter – purple line). In this issue, we blind men and women have joined together to describe the features of Alzheimer's disease that lie beyond the amyloid cascade hypothesis, and explore alternatives from the perspectives of evolution, bioenergetics, microtubules, and DNA damage in the brain. Read the full article ‘Re-imagining Alzheimer's disease – the diminishing importance of amyloid and a glimpse of what lies ahead’ by K.-H. Tse and K. Herrup (J. Neurochem. 2017, vol. 143(4), pp. 432–444) on doi: 10.1111/jnc.14079

Beyond Amyloid - Widening the View on Alzheimer's Disease.

For 25years, the amyloid cascade hypothesis, based on the finding that mutations in the amyloid precursor protein are closely linked to familial forms of Alzheimer's disease (AD), dominated the research on this disease. Recent failures of clinical anti-amyloidogenic trials, however, substantially support the reasoning (i) that the pathomechanisms that trigger familial AD, namely the generation, aggregation, and deposition of amyloid beta, cannot necessarily be extrapolated to sporadic cases and (ii) that amyloid beta represents a prominent histopathological feature in AD but not its exclusive causative factor. In autumn 2016, the Volkswagen Foundation hosted the Herrenhausen Symposium 'Beyond Amyloid - Widening the View on Alzheimer's Disease' in Hannover, Germany, to bring together current knowledge on cellular and molecular processes that contribute to AD pathogenesis independent of or alongside with the amyloid biochemistry. The following mini review series was authored by key speakers at the meeting, and highlights some of the mechanisms potentially involved in AD etiology that provide alternative viewpoints and mechanisms beyond the amyloid cascade hypothesis. This article is part of the series "Beyond Amyloid".

Reconstructed ancestral enzymes reveal that negative selection drove the evolution of substrate specificity in ADP-dependent kinases

One central goal in molecular evolution is to pinpoint the mechanisms and evolutionary forces that cause an enzyme to change its substrate specificity; however, these processes remain largely unexplored. Using the glycolytic ADP-dependent kinases of archaea, including the orders Thermococcales, Methanosarcinales, and Methanococcales, as a model and employing an approach involving paleoenzymology, evolutionary statistics, and protein structural analysis, we could track changes in substrate specificity during ADP-dependent kinase evolution along with the structural determinants of these changes. To do so, we studied five key resurrected ancestral enzymes as well as their extant counterparts. We found that a major shift in function from a bifunctional ancestor that could phosphorylate either glucose or fructose 6-phosphate (fructose-6-P) as a substrate to a fructose 6-P-specific enzyme was started by a single amino acid substitution resulting in negative selection with a ground-state mode against glucose and a subsequent 1,600-fold change in specificity of the ancestral protein. This change rendered the residual phosphorylation of glucose a promiscuous and physiologically irrelevant activity, highlighting how promiscuity may be an evolutionary vestige of ancestral enzyme activities, which have been eliminated over time. We also could reconstruct the evolutionary history of substrate utilization by using an evolutionary model of discrete binary characters, indicating that substrate uses can be discretely lost or acquired during enzyme evolution. These findings exemplify how negative selection and subtle enzyme changes can lead to major evolutionary shifts in function, which can subsequently generate important adaptive advantages, for example, in improving glycolytic efficiency in Thermococcales.

Introduction to the Special Issue on Malaria.

This minireview series highlights recent developments in malaria research. The reviews cover diverse topics, from conventional antimalarial therapies and the strategies used to circumvent the emergence of drug resistance, to the latest approaches for the discovery and validation of new druggable targets and for the development of effective antimalarial vaccines.

Commentary on Myths and Methodologies: Making sense of exercise mass and water balance.

The article by Drs Cheuvront & Montain (2017) kicks off a Mini Review Series on Myths and Methodologies, which explores the underlying principles of a selected methodology, considers appropriate and inappropriate uses and outlines best practice in physiology for particular methods or equipment. Their review concisely summarizes water and body mass balances during exercise, with explanation as to why these differ and therefore when such differences might become problematic. The sources of water and mass exchanges are well contextualized. As water generated from oxidative metabolism offsets that lost from ventilation, body water loss approximates that lost from the skin (i.e. eqn 4; or sweat loss) if ingestion and excretion are accounted for. In turn, body water loss and sweat loss approximate body mass loss minus 48 g (mJ energy expended)−1 (∼eqn 9). This equation is applied to quantify dehydration (eqn 11), before other applications are addressed, including worked examples for a marathon run by two individuals of different fitness. The matter of chemiosmotically bound water being released from macronutrients during their metabolism is then addressed because of its relevance to practical applications of these equations and its potential to affect the validity of (some) consensus fluid replacement guidelines. The net effect of liberating this existing water is concluded to be small, e.g. <200 ml water exchanged between compartments for energy expenditures up to 2000 kcal (approximately a marathon). Thus, the efficacy of drinking during exercise is considered to be synonymous with percentage dehydration. This conclusion is appealing but belies physiological and methodological complexities that remain unresolved and are beyond the scope of this short review that otherwise does an excellent job of summarizing issues of water and mass balances. Physiologically or functionally, efficacious hydration behaviour in exercise concerns not only body water balance but also its composition and distribution. Whether these are impacted meaningfully by glycogen metabolism will depend on the mass of water liberated and its potassium content, both of which remain to be clarified and are likely to vary (e.g. Maughan et al. 2007; King et al. 2008). Cheuvront & Montain (2017) also point out that glycogen is not the only substrate oxidized or releasing water during exercise (Candlish, 1981). That is true, but glycogen would usually be most important not only because it binds the most water (one to four times its own mass) but also because it is the major substrate mass oxidized in most endurance and team sports, while also fuelling the glycolysis that predominates in team sports. Glycolysis permits the release of more water relative to energy expenditure and is coincident with high heat strain and thus rate of dehydration. Of course, if the liberated water is low in volume or high in potassium it will have little effect (systemically at least), as concluded by Cheuvront & Montain (2017), but more research is needed to elucidate its role and importance.

The role of drebrin in neurons.

Drebrin is an actin-binding protein that changes the helical pitch of actin filaments (F-actin), and drebrin-decorated F-actin shows slow treadmilling and decreased rate of depolymerization. Moreover, the characteristic morphology of drebrin-decorated F-actin enables it to respond differently to the same signals from other actin cytoskeletons. Drebrin consists of two major isoforms, drebrin E and drebrin A. In the developing brain, drebrin E appears in migrating neurons and accumulates in the growth cones of axons and dendrites. Drebrin E-decorated F-actin links lamellipodium F-actin to microtubules in the growth cones. Then drebrin A appears at nascent synapses and drebrin A-decorated F-actin facilitates postsynaptic molecular assembly. In the adult brain, drebrin A-decorated F-actin is concentrated in the central region of dendritic spines. During long-term potentiation initiation, NMDA receptor-mediated Ca2+ influx induces the transient exodus of drebrin A-decorated F-actin via myosin II ATPase activation. Because of the unique physical characteristics of drebrin A-decorated F-actin, this exodus likely contributes to the facilitation of F-actin polymerization and spine enlargement. Additionally, drebrin reaccumulation in dendritic spines is observed after the exodus. In our drebrin exodus model of structure-based synaptic plasticity, reestablishment of drebrin A-decorated F-actin is necessary to keep the enlarged spine size during long-term potentiation maintenance. In this review, we introduce the genetic and biochemical properties of drebrin and the roles of drebrin in early stage of brain development, synaptic formation and synaptic plasticity. Further, we discuss the pathological relevance of drebrin loss in Alzheimer's disease. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

60th Anniversary of the Japanese Society for Neurochemistry.

To welcome the 60th anniversary of the Japanese Society for Neurochemistry (JSN), in this issue, we publish five articles from leading groups of the JSN in the Journal of Neurochemistry. These five reviews are regarding molecular base-investigation of neuronal regulation, and the research styles and its destination are exhibiting the characteristics that identify our society. Here, we introduce what we have archived in the neurochemical fields of research, including Ca2+ neurobiology, synaptic plasticity, neurogenesis and neuroregeneration. With the achievements in the past decades in mind, we will continue to contribute to the development of neurochemistry from now on too. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

Calmodulin kinases: essential regulators in health and disease.

Neuronal activity induces intracellular Ca2+ increase, which triggers activation of a series of Ca2+ -dependent signaling cascades. Among these, the multifunctional Ca2+ /calmodulin-dependent protein kinases (CaMKs, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated CaMKs for these roles in neuronal functions are CaMKI, CaMKII, CaMKIV and we will shed light on these neuronal CaMKs' functions in this review. Catalytically active members of CaMKs currently are CaMKI, CaMKII, CaMKIV and CaMKK. Although they all necessitate the binding of Ca2+ and calmodulin complex (Ca2+ /CaM) for releasing autoinhibition, each member of CaMK has distinct activation mechanisms-autophosphorylation mediated autonomy of multimeric CaMKII and CaMKK-dependent phosphoswitch-induced activation of CaMKI or CaMKIV. Furthermore, each CaMK shows distinct subcellular localization that underlies specific compartmentalized function in each activated neuron. In this review, we first summarize these molecular characteristics of each CaMK as to regulation and subcellular localization, and then describe each biological function. In the last section, we also focus on the emerging role of CaMKs in pathophysiological conditions by introducing the recent studies, especially focusing on drug addiction and depression, and discuss how dysfunctional CaMKs may contribute to the pathology of the neuropsychological disorders. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

Mechanisms of neuronal migration in the adult brain.

Adult neurogenesis was first observed nearly 60years ago, and it has since grown into an important neurochemistry research field. Much recent research has focused on the treatment of brain diseases through neuronal regeneration with endogenously generated neurons. In the adult brain, immature neurons called neuroblasts are continuously generated in the ventricular-subventricular zone (V-SVZ). These neuroblasts migrate rapidly through the rostral migratory stream to the olfactory bulb, where they mature and are integrated into the neuronal circuitry. After brain insult, some of the neuroblasts in the V-SVZ migrate toward the lesion to repopulate the injured tissue. This notable migratory capacity of V-SVZ-derived neuroblasts is important for efficiently regenerating neurons in remote areas of the brain. As these neurons migrate for long distances through adult brain tissue, they are supported by various guidance cues and structures that act as scaffolds. Some of these mechanisms are unique to neuroblast migration in the adult brain, and are not involved in migration in the developing brain. Here, we review the latest findings on the mechanisms of neuroblast migration in the adult brain under physiological and pathological conditions, and discuss various issues that still need to be resolved. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

Applications of induced pluripotent stem cell technologies in spinal cord injury.

Numerous basic research studies have suggested the potential efficacy of neural precursor cell (NPC) transplantation in spinal cord injury (SCI). However, in most such studies, the origin of the cells used was mainly fetal tissue or embryonic stem cells, both of which carry potential ethical concerns with respect to clinical use. The development of induced pluripotent stem cells (iPSCs) opened a new path toward regenerative medicine for SCI. iPSCs can be generated from somatic cells by induction of transcription factors, and induced to differentiate into NPCs with characteristics of cells of the central nervous system. The beneficial effect of iPSC-derived NPC transplantation has been reported from our group and others working in rodent and non-human primate models. These promising results facilitate the application of iPSCs for clinical applications in SCI patients. However, iPSCs also have issues, such as genetic/epigenetic abnormalities and tumorigenesis because of the artificial induction method, that must be addressed prior to clinical use. The selection of somatic cells, generation of integration-free iPSCs, and characterization of differentiated NPCs with thorough quality management are all needed to address these potential risks. To enhance the efficacy of the transplanted iPSC-NPCs, especially at chronic phase of SCI, administration of a chondroitinase or semaphorin3A inhibitor represents a potentially important means of promoting axonal regeneration through the lesion site. The combined use of rehabilitation with such cell therapy approaches is also important, as repetitive training enhances neurite outgrowth of transplanted cells and strengthens neural circuits at central pattern generators. Our group has already evaluated clinical grade iPSC-derived NPCs, and we look forward to initiating clinical testing as the next step toward determining whether this approach is safe and effective for clinical use. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

IP3 receptor mutations and brain diseases in human and rodents

The inositol 1,4,5-trisphosphate receptor (IP3 R) is a huge Ca2+ channel that is localized at the endoplasmic reticulum. The IP3 R releases Ca2+ from the endoplasmic reticulum upon binding to IP3 , which is produced by various extracellular stimuli through phospholipase C activation. All vertebrate organisms have three subtypes of IP3 R genes, which have distinct properties of IP3 -binding and Ca2+ sensitivity, and are differently regulated by phosphorylation and by their associated proteins. Each cell type expresses the three subtypes of IP3 R in a distinct proportion, which is important for creating and maintaining spatially and temporally appropriate intracellular Ca2+ level patterns for the regulation of specific physiological phenomena. Of the three types of IP3 Rs, the type 1 receptor (IP3 R1) is dominantly expressed in the brain and is important for brain function. Recent emerging evidence suggests that abnormal Ca2+ signals from the IP3 R1 are closely associated with human brain pathology. In this review, we focus on the recent advances in our knowledge of the regulation of IP3 R1 and its functional implication in human brain diseases, as revealed by IP3 R mutation studies and analysis of human disease-associated genes. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".

Matrix pathobiology-central roles for proteoglycans and heparanase in health and disease.

This thematic minireview series highlights new concepts in matrix pathobiology. The reviews in this series cover the roles of the two matrix proteoglycans, decorin and biglycan, in inflammation and autophagy, the various functions of syndecans in cancer development and prognosis and the recently discovered mechanisms underlying the multiple roles of heparanase in cancer progression, inflammation, and autophagy.

Hippocampal GABAergic transmission: a new target for adenosine control of excitability.

Physiological network functioning in the hippocampus is dependent on a balance between glutamatergic cell excitability and the activity of diverse local circuit neurons that release the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Tuners of neuronal communication such as adenosine, an endogenous modulator of synapses, control hippocampal network operations by regulating excitability. Evidence has been recently accumulating on the influence of adenosine on different aspects of GABAergic transmission to shape hippocampal function. This review addresses how adenosine, through its high-affinity A1 (A1 R) and A2A receptors (A2A R), interferes with different GABA-mediated forms of inhibition in the hippocampus to regulate neuronal excitability. Adenosine-mediated modulation of phasic/tonic inhibitory transmission, of GABA transport mechanisms and its interference with other modulatory systems are discussed together with the putative implications for neuronal function in physiological and pathological conditions. This article is part of a mini review series: 'Synaptic Function and Dysfunction in Brain Diseases'.