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Osteoarthritis (OA) is a prevalent debilitating age-related skeletal disease. The hallmark of OA is the degradation of articular cartilage that cushions the joint during movement. It is characterized by chronic pain and disability. Magnesium, a critical trace element in the human body, plays a pivotal role in metabolism homeostasis and the energy balance. Humans obtain magnesium mainly from the diet. However, inadequate magnesium intake is not uncommon. Moreover, the magnesium status deteriorates with ageing. There has been a growing body of clinical studies pointing to an intimate relationship between dietary magnesium and OA although the conclusion remains controversial. As reported, the magnesium ion concentration is essential to determine cell fate. Firstly, the low-concentration magnesium ions induced human fibroblasts senescence. Magnesium supplementation was also able to mitigate chondrocyte apoptosis, and to facilitate chondrocyte proliferation and differentiation. In this literature review, we will outline the existing evidence in animals and humans. We will also discuss the controversies on plasma or intracellular level of magnesium as the indicator of magnesium status. In addition, we put forward the interplay between dietary magnesium intake and intestinal microbiome to modulate the inflammatory milieu in the conjecture of OA pathogenesis. This leads to an emerging hypothesis that the synergistic effect of magnesium and probiotics may open a new avenue for the prevention and treatment of OA., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The circadian clock coordinates the physiological responses of a biological system to day and night rhythms through complex loops of transcriptional/translational regulation. It can respond to external stimuli and adjust generated circadian oscillations accordingly to maintain an endogenous period close to 24 h. However, the interaction between nutritional status and circadian rhythms in plants is poorly understood. Magnesium (Mg) is essential for numerous biological processes in plants, and its homeostasis is crucial to maintain optimal development and growth. Magnesium deficiency in young Arabidopsis thaliana seedlings increased the period of circadian oscillations of the CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) promoter (pCCA1:LUC) activity and dampened their amplitude under constant light in a dose-dependent manner. Although the circadian period increase caused by Mg deficiency was light dependent, it did not depend on active photosynthesis. Mathematical modeling of the Mg input into the circadian clock reproduced the experimental increase of the circadian period and suggested that Mg is likely to affect global transcription/translation levels rather than a single component of the circadian oscillator. Upon addition of a low dose of cycloheximide to perturb translation, the circadian period increased further under Mg deficiency, which was rescued when sufficient Mg was supplied, supporting the model's prediction. These findings suggest that sufficient Mg supply is required to support proper timekeeping in plants., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

COVID-19 has resulted in an ongoing global pandemic, which spread largely among people who have had close contact with the infected person. The immunopathology of the SARS-CoV-2 virus includes the production of an excess amount of pro-inflammatory cytokines "a cytokine-storm". The respiratory system (main), cardiovascular system and the gastrointestinal tract are the most affected body systems during viral infection. It has been found that most of the patients who require admission to hospital are elderly or have chronic underlying diseases. Higher cases of malnutrition and co-morbidities like diabetes mellitus and cardiovascular diseases are reported in elderly patients due to which, the immune system weakens and hence, the response to the virus is diminished in magnitude. A deficiency of micronutrients results in impaired immune responses leading to improper secretion of cytokines, alterations in secretory antibody response and antibody affinity which increases susceptibility to viral infection. The deficiency of various micronutrients in COVID-19 patient can be treated by appropriate nutritional supplements, prescribed after evaluating the patients' nutritional status. Here we aim to highlight the role of a few particular nutrients namely Vitamin D, Vitamin C, Omega-3 fatty acids, Zinc and Magnesium along with the synergistic roles they play in enhancing immunity and thus, maintaining homeostasis., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Several changes of magnesium (Mg) metabolism have been reported with aging, including diminished Mg intake, impaired intestinal Mg absorption and renal Mg wasting. Mild Mg deficits are generally asymptomatic and clinical signs are usually non-specific or absent. Asthenia, sleep disorders, hyperemotionality, and cognitive disorders are common in the elderly with mild Mg deficit, and may be often confused with age-related symptoms. Chronic Mg deficits increase the production of free radicals which have been implicated in the development of several chronic age-related disorders. Numerous human diseases have been associated with Mg deficits, including cardiovascular diseases, hypertension and stroke, cardio-metabolic syndrome and type 2 diabetes mellitus, airways constrictive syndromes and asthma, depression, stress-related conditions and psychiatric disorders, Alzheimer's disease (AD) and other dementia syndromes, muscular diseases (muscle pain, chronic fatigue, and fibromyalgia), bone fragility, and cancer. Dietary Mg and/or Mg consumed in drinking water (generally more bioavailable than Mg contained in food) or in alternative Mg supplements should be taken into consideration in the correction of Mg deficits. Maintaining an optimal Mg balance all through life may help in the prevention of oxidative stress and chronic conditions associated with aging. This needs to be demonstrated by future studies.

Magnesium (Mg 2+ ) is an essential mineral for the functioning and maintenance of the body. Disturbances in Mg 2+ intracellular homeostasis result in cell-membrane modification, an increase in oxidative stress, alteration in the proliferation mechanism, differentiation, and apoptosis. Mg 2+ deficiency often results in inflammation, with activation of inflammatory pathways and increased production of proinflammatory cytokines by immune cells. Immune cells and others that make up the blood system are from hematopoietic tissue in the bone marrow. The hematopoietic tissue is a tissue with high indices of renovation, and Mg 2+ has a pivotal role in the cell replication process, as well as DNA and RNA synthesis. However, the impact of the intra- and extracellular disturbance of Mg 2+ homeostasis on the hematopoietic tissue is little explored. This review deals specifically with the physiological requirements of Mg 2+ on hematopoiesis, showing various studies related to the physiological requirements and the effects of deficiency or excess of this mineral on the hematopoiesis regulation, as well as on the specific process of erythropoiesis, granulopoiesis, lymphopoiesis, and thrombopoiesis. The literature selected includes studies in vitro, in animal models, and in humans, giving details about the impact that alterations of Mg 2+ homeostasis can have on hematopoietic cells and hematopoietic tissue.

Magnesium plays important roles in the nervous system. An increase in the Mg 2+ concentration in cerebrospinal fluid enhances neural functions, while Mg 2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg 2+ due to the release of Mg 2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg 2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg 2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg 2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg 2+ release from mitochondria and Mg 2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg 2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg 2+ regulation in neuronal survival under excitotoxicity.

Periodontal diseases are mainly the results of infections and inflammation of the gum and bone that surround and support the teeth. In this study, the alveolar bone destruction in periodontitis is hypothesized to be treated with novel Mg-Cu alloy grafts due to their antimicrobial and osteopromotive properties. In order to study this new strategy using Mg-Cu alloy grafts as a periodontal bone substitute, the in vitro degradation and antibacterial performance were examined. The pH variation and Mg 2+ and Cu 2+ release of Mg-Cu alloy extracts were measured. Porphyromonas gingivalis ( P. gingivalis ) and Aggregatibacter actinomycetemcomitans ( A. actinomycetemcomitans ), two common bacteria associated with periodontal disease, were cultured in Mg-Cu alloy extracts, and bacterial survival rate was evaluated. The changes of bacterial biofilm and its structure were revealed by scanning electron microscopy (SEM) and transmission electronic microscopy (TEM), respectively. The results showed that the Mg-Cu alloy could significantly decrease the survival rates of both P. gingivalis and A. actinomycetemcomitans . Furthermore, the bacterial biofilms were completely destroyed in Mg-Cu alloy extracts, and the bacterial cell membranes were damaged, finally leading to bacterial apoptosis. These results indicate that the Mg-Cu alloy can effectively eliminate periodontal pathogens, and the use of Mg-Cu in periodontal bone grafts has a great potential to prevent infections after periodontal surgery., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xue Zhao et al.)

Photosynthesis provides food, fibre and fuel that support our society; understanding the mechanisms controlling dynamic changes in this process helps identify new options to improve photosynthesis. Photosynthesis shows diel changes, which have been largely attributed to external light/dark conditions, as well as internal gene expression and the post-translational modification of critical enzymes. Here we report diel fluctuations of magnesium (Mg) in rice (Oryza sativa) chloroplasts, which may function as a rhythm regulator contributing to the post-translational regulation of photosynthetic CO 2 assimilation in rice. We found that a chloroplast-localized Mg 2+ transporter gene, OsMGT3, which is rhythmically expressed in leaf mesophyll cells, partly modulates Mg fluctuations in rice chloroplasts. Knockout of OsMGT3 substantially reduced Mg 2+ uptake, as well as the amplitude of free Mg 2+ fluctuations in chloroplasts, which was closely associated with a decrease in ribulose 1,5-bisphosphate carboxylase activity in vivo and a consequent decline in the photosynthetic rate. In addition, the mesophyll-specific overexpression of OsMGT3 remarkably improved photosynthetic efficiency and growth performance in rice. Taken together, these observations demonstrate that OsMGT3-dependent diel Mg fluctuations in chloroplasts may contribute to Mg-dependent enzyme activities for photosynthesis over the daily cycle. Enhancing Mg 2+ input to chloroplasts could be a potential approach to improving photosynthetic efficiency in plants.

Introduction: Magnesium is an essential cation involved in many functions within the central nervous system, including transmission and intracellular signal transduction. Several studies have shown its usefulness in neurological and psychiatric diseases. Furthermore, it seems that magnesium levels are lowered in the course of several mental disorders, especially depression., Objectives: In this study, we wish to evaluate the presence of a relationship between the levels of magnesium and the presence of psychiatric pathology as well as the effectiveness of magnesium as a therapeutic supplementation., Methods: A systematic search of scientific records concerning magnesium in psychiatric disorders published from 2010 up to March 2020 was performed. We collected a total of 32 articles: 18 on Depressive Disorders (DD), four on Anxiety Disorders (AD), four on Attention Deficit Hyperactivity Disorder (ADHD), three on Autism Spectrum Disorder (ASD), one on Obsessive-Compulsive Disorder (OCD), one on Schizophrenia (SCZ) and one on Eating Disorders (ED)., Results: Twelve studies highlighted mainly positive results in depressive symptoms. Seven showed a significant correlation between reduced plasma magnesium values and depression measured with psychometric scales. Two papers reported improved depressive symptoms after magnesium intake, two in association with antidepressants, compared to controls. No significant association between magnesium serum levels and panic or Generalized Anxiety Disorder (GAD) patients, in two distinct papers, was found. In two other papers, a reduced Hamilton Anxiety Rating Scale (HAM-A) score in depressed patients correlated with higher levels of magnesium and beneficial levels of magnesium in stressed patients was found. Two papers reported low levels of magnesium in association with ADHD. Only one of three papers showed lower levels of magnesium in ASD. ED and SCZ reported a variation in magnesium levels in some aspects of the disease., Conclusion: The results are not univocal, both in terms of the plasma levels and of therapeutic effects. However, from the available evidence, it emerged that supplementation with magnesium could be beneficial. Therefore, it is necessary to design ad hoc clinical trials to evaluate the efficacy of magnesium alone or together with other drugs (antidepressants) in order to establish the correct use of this cation with potential therapeutic effects., Competing Interests: Page: 18 The authors declare no conflict of interest

The study was designed to determine the impact of magnesium (Mg 2+ ) on bovine embryo development. We found that two commercially available sources of bovine serum albumin (BSA) and fetal bovine serum (FBS) contained different amounts of Mg 2+ residue: 4 ppm in ICPbio BSA, 114 ppm in Sigma BSA, and 44 ppm in FBS. When CR1 was used as basal medium, PVA and ICPbio BSA produced the lowest blastocyst yield (2.2-2.3%), whereas Sigma BSA increased blastocyst yield to 18.9% (P < 0.05). Supplementation of 1.4 mM MgCl 2 into the medium increased the blastocyst rate in the ICPbio BSA group (29.4%) but not in the PVA group (5.4%; P < 0.05) to a level comparable to that of the FBS group (33.7%; P > 0.05). We next found that increasing concentrations of MgCl 2 in the culture medium (ICPbio BSA) elevated blastocyst rate from 2.6% (0 mM), 38.4% (0.35 mM) to 50.2% (1.4 mM; P < 0.05), further maintained at 44.9% (2.1 mM) and 43.4% (2.8 mM) (P > 0.05). However, blastocyst rate was reduced to 31.4% (4.2 mM) and 29.4% (5.6 mM) when MgCl 2 supplement was increased (P < 0.05). Comparable blastocyst development was achieved in both ICPbio BSA (30.0-33.1%) and Sigma BSA (37.4-38.7%) groups when 1.4 mM Mg 2+ was supplemented regardless of its source (MgCl 2 vs. MgSO 4 ; P > 0.05). In embryo transfer experiments, higher rates of pregnancy (54.3 vs. 41.5%) and calving (44.3 vs. 32.5%) were achieved in the CR1-Mg 2+ -supplemented BSA group compared with the FBS group with co-culture, respectively (P < 0.05). These results demonstrate that Mg 2+ is a key ion that promotes competent blastocyst and term development. Therefore, a simple and efficient defined medium (CR1-Mg 2+ -BSA) can successfully replace complex serum and somatic cell co-culture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The circadian clock controls 24-h biological rhythms in our body, influencing many time-related activities such as sleep and wake. The simplest circadian clock is found in cyanobacteria, with the proteins KaiA, KaiB, and KaiC generating a self-sustained circadian oscillation of KaiC phosphorylation and dephosphorylation. KaiA activates KaiC phosphorylation by binding the A-loop of KaiC, while KaiB attenuates the phosphorylation by sequestering KaiA from the A-loop. Structural analysis revealed that magnesium regulates the phosphorylation and dephosphorylation of KaiC by dissociating from and associating with catalytic Glu residues that activate phosphorylation and dephosphorylation, respectively. High magnesium causes KaiC to dephosphorylate, whereas low magnesium causes KaiC to phosphorylate. KaiC alone behaves as an hourglass timekeeper when the magnesium concentration is alternated between low and high levels in vitro. We suggest that a magnesium-based hourglass timekeeping system may have been used by ancient cyanobacteria before magnesium homeostasis was established.

Riboswitches are cis-acting regulatory RNA biosensors that rival the efficiency of those found in proteins. At the heart of their regulatory function is the formation of a highly specific aptamer-ligand complex. Understanding how these RNAs recognize the ligand to regulate gene expression at physiological concentrations of Mg2+ ions and ligand is critical given their broad impact on bacterial gene expression and their potential as antibiotic targets. In this work, we used single-molecule FRET and biochemical techniques to demonstrate that Mg2+ ions act as fine-tuning elements of the amino acid-sensing lysC aptamer's ligand-free structure in the mesophile Bacillus subtilis. Mg2+ interactions with the aptamer produce encounter complexes with strikingly different sensitivities to the ligand in different, yet equally accessible, physiological ionic conditions. Our results demonstrate that the aptamer adapts its structure and folding landscape on a Mg2+-tunable scale to efficiently respond to changes in intracellular lysine of more than two orders of magnitude. The remarkable tunability of the lysC aptamer by sub-millimolar variations in the physiological concentration of Mg2+ ions suggests that some single-aptamer riboswitches have exploited the coupling of cellular levels of ligand and divalent metal ions to tightly control gene expression., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose of Review: Vascular calcification is a major contributor to increased cardiovascular mortality in chronic kidney disease (CKD). Recently, calciprotein particles (CPP) were identified to drive the calcification process. CPP may explain the effects of high phosphate on vascular calcification. Magnesium is a promising novel therapeutic approach to halt vascular calcification, because it inhibits CPP maturation and is associated with reduced cardiovascular mortality in CKD. We aim to examine the current evidence for the role of CPP in the calcification process and to explain how magnesium prevents calcification., Recent Findings: A recent meta-analysis concluded that reducing high phosphate levels in CKD patients does not associate with lowering cardiovascular mortality. Inhibition of CPP formation prevents phosphate-induced calcification in vitro. Consequently, delaying CPP formation and maturation may be a clinical approach to reduce calcification. Magnesium inhibits CPP maturation and vascular calcification. Clinical pilot studies suggest that magnesium is a promising intervention strategy against calcification in CKD patients., Summary: CPP induce vascular calcification and are modulated by serum phosphate and magnesium concentrations. Magnesium is a strong inhibitor of CPP maturation and therefore, a promising therapeutic approach to reduce vascular calcification in CKD. Currently, several studies are being performed to determine the clinical outcomes of magnesium supplementation in CKD.

Prokaryotic (6-4) photolyases branch at the base of the evolution of cryptochromes and photolyases. Prototypical members contain an iron-sulphur cluster which was lost in the evolution of the other groups. In the Agrobacterium (6-4) photolyase PhrB, the repair of DNA lesions containing UV-induced (6-4) pyrimidine dimers is stimulated by Mg 2+ . We propose that Mg 2+ is required for efficient lesion binding and for charge stabilization after electron transfer from the FADH - chromophore to the DNA lesion. Furthermore, two highly conserved Asp residues close to the DNA-binding site are essential for the effect of Mg 2+ . Simulations show that two Mg 2+ bind to the region around these residues. On the other hand, DNA repair by eukaryotic (6-4) photolyases is not increased by Mg 2+ . In these photolyases, structurally overlapping regions contain no Asp but positively charged Lys or Arg. During the evolution of photolyases, the role of Mg 2+ in charge stabilization and enhancement of DNA binding was therefore taken over by a postiviely charged amino acid. Besides PhrB, another prokaryotic (6-4) photolyase from the marine cyanobacterium Prochlorococcus marinus, PromaPL, which contains no iron-sulphur cluster, was also investigated. This photolyase is stimulated by Mg 2+ as well. The evolutionary loss of the iron-sulphur cluster due to limiting iron concentrations can occur in a marine environment as a result of iron deprivation. However, the evolutionary replacement of Mg 2+ by a positively charged amino acid is unlikely to occur in a marine environment because the concentration of divalent cations in seawater is always sufficient. We therefore assume that this transition could have occurred in a freshwater environment., (© 2019 Federation of European Biochemical Societies.)

Soil microelement deficiency and heavy metal contamination affects plant growth and development, but improving trace element uptake and reducing heavy metal accumulation by genetic breeding can help alleviate this. Cell number regulator 2 (TaCNR2) from common wheat (Triticum aestivum) are similar to plant cadmium resistance proteins, involved with regulating heavy metal translocation. Our aim was to understand the effect of TaCNR2 on heavy metal tolerance and translocation. In this study, real-time quantitative PCR indicated TaCNR2 expression in the wheat seedlings increased under Cd, Zn and Mn treatment. Overexpression of TaCNR2 in Arabidopsis and rice enhanced its stress tolerance to Cd, Zn and Mn, and overexpression in rice improved Cd, Zn and Mn translocation from roots to shoots. The grain husks in overexpressed rice had higher Cd, Zn and Mn concentrations, but the brown rice accumulated less Cd but higher Mn than wild rice. The results showed that TaCNR2 can transport heavy metal ions. Thus, this study provides a novel gene resource for increasing nutrition uptake and reducing toxic metal accumulation in crops.

Magnesium (Mg 2+ ) is an endogenous cation that is involved in many essential biological reactions. Abnormal Mg 2+ metabolisms in the body affect important physiological and pathological processes. However, most endogenous Mg 2+ markers fail to represent body Mg 2+ status; they are disadvantageous in terms of representational capacity, applied range, operational convenience, etc. In this article, we evaluated some of the most popular Mg 2+ marker candidates. A logical model of the blood Mg 2+ compartments was established, which consisted of unstable Mg 2+ pools, representative Mg 2+ pools, and conserved Mg 2+ pools. These pools were based on the metabolic efficiency of Mg 2+ in an acute Mg 2+ intake test. The results of this study showed that only the erythrocyte intracellular ionized Mg 2+ (RBC [Mg 2+ ] i ), a representative Mg 2+ pool, could effectively represent abnormal body Mg 2+ metabolisms in various conditions, including dietary Mg 2+ adjustments, aging and metabolic syndrome. These results suggest that RBC [Mg 2+ ] i might be a widely applicable marker of body Mg 2+ levels. On unified technology platform and evaluation system, this research compared the representative capacities of RBC [Mg 2+ ] i , plasma Mg 2+ concentration (plasma [Mg 2+ ]), erythrocyte intracellular total Mg (RBC [Mg] total ) and Mg retention in rats and mice under various Mg 2+ -metabolism-related physiological and pathological conditions. Our technique for the direct quantitative analysis of RBC [Mg 2+ ] i may prove valuable for basic physiological research, dietary Mg 2+ regulation, as well as clinical monitoring/intervention of Mg 2+ -metabolism-related pathology.

The aim of this study was to gain an understanding on the collective cellular effects of magnesium (Mg) corrosion products on the behaviour of cells responsible for bone formation and remodelling. The response of mesenchymal stem cells (MSCs) and osteoclast cells to both soluble (Mg ions) and insoluble (granule) corrosion products were recapitulated in vitro by controlling the concentration of the corrosion products. Clearance of corrosion granules by MSCs was also inspected by TEM analysis at sub-cellular level. The effect of Mg corrosion products varied depending on the state of differentiation of cells, concentration and length of exposure. The presence of the corrosion products significantly altered the cells' metabolic and proliferative activities, which further affected cell fusion/differentiation. While cells tolerated higher than physiological range of Mg concentration (16 mM), concentrations below 10 mM were beneficial for cell growth. Furthermore, MSCs were shown to contribute to the clearance of intercellular corrosion granules, whilst high concentrations of corrosion products negatively impacted on osteoclast progenitor cell number and mature osteoclast cell function.

Cell-free systems are widely used to study mechanisms and regulation of translation, but the use of in vitro transcribed (IVT) mRNAs as translation substrates limits their efficiency and utility. Here, we present an approach for in vitro translation of messenger ribonucleoprotein (mRNP) complexes affinity purified in association with tagged mRNAs expressed in mammalian cells. We show that in vitro translation of purified mRNPs is much more efficient than that achieved using standard IVT mRNA substrates and is compatible with physiological ionic conditions. The high efficiency of affinity-purified mRNP in vitro translation is attributable to both copurified protein components and proper mRNA processing and modification. Further, we use translation inhibitors to show that translation of purified mRNPs consists of separable phases of run-off elongation by copurified ribosomes and de novo initiation by ribosomes present in the translation extracts. We expect that this in vitro system will enhance mechanistic studies of eukaryotic translation and translation-associated processes by allowing the use of endogenous mRNPs as translation substrates under physiological buffer conditions., (Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near-atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils ( i ) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and ( ii ) the critical participation of the Cwf19 protein in displacing the intron lariat/U2 branch helix. These findings provide unprecedented details on the SPL functional dynamics, thus contributing to move a step forward toward a thorough understanding of eukaryotic pre-mRNA splicing., Competing Interests: The authors declare no conflict of interest.

Magnesium is the most abundant intracellular divalent cation and essential for maintaining normal cellular physiology and metabolism, acting as a cofactor of numerous enzymes, regulating ion channels and energy generation. In the heart, magnesium plays a key role in modulating neuronal excitation, intracardiac conduction, and myocardial contraction by regulating a number of ion transporters, including potassium and calcium channels. Magnesium also has a role in regulating vascular tone, atherogenesis and thrombosis, vascular calcification, and proliferation and migration of endothelial and vascular smooth muscle cells. As such, magnesium potentially has a major influence on the pathogenesis of cardiovascular disease. As the kidney is a major regulator of magnesium homeostasis, kidney disorders can potentially lead to both magnesium depletion and overload, and as such increase the risk of cardiovascular disease. Observational data have shown an association between low serum magnesium concentrations or magnesium intake and increased atherosclerosis, coronary artery disease, arrhythmias, and heart failure. However, major trials of supplementation with magnesium have reported inconsistent benefits and also raised potential adverse effects of magnesium overload. As such, there is currently no firm recommendation for routine magnesium supplementation except when hypomagnesemia has been proven or suspected as a cause for cardiac arrhythmias., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Magnesium (Mg 2+ ) is a mineral with the ability to influence cell proliferation and to modulate inflammatory/immune responses, due to its anti-inflammatory properties. In addition, mesenchymal stem cells (MSCs) modulate the function of all major immune cell populations. Knowing that, the current work aimed to investigate the effects of Mg 2+ enrichment, and its influence on the immunomodulatory capacity of MSCs. Murine C3H/10T1/2 MSCs were cultivated in media with different concentrations of Mg 2+ (0, 1, 3 and 5 mM), in order to evaluate the effects of Mg 2+ on MSC immunomodulatory properties, cell proliferation rates, expression of NFκB and STAT-3, production of IL-1β, IL-6, TGF-β, IL-10, PGE2 and NO, and TRPM7 expression. The results showed that TRPM7 is expressed in MSCs, but Mg 2+ , in the way that cells were cultivated, did not affect TRPM7 expression. Additionally, there was no difference in the intracellular concentration of Mg 2+ . Mg 2+ , especially at 5 mM, raised proliferation rates of MSCs, and modulated immune responses by decreasing levels of IL-1β and IL-6, and by increasing levels of IL-10 and PGE2 in cells stimulated with LPS or TNF-α. In addition, MSCs cultured in 5 mM Mg 2+ expressed lower levels of pNFκB/NFκB and higher levels of pSTAT-3/STAT-3. Furthermore, conditioned media from MSCs reduced lymphocyte and macrophage proliferation, but Mg 2+ did not affect this parameter. In addition, conditioned media from MSCs cultured at 5 mM of Mg 2+ modulated the production profile of cytokines, especially of IL-1β and IL-6 in macrophages. In conclusion, Mg 2+ is able to modulate some immunoregulatory properties of MSCs., (Copyright © 2018. Published by Elsevier Inc.)

Magnesium is an essential ion in the human body, playing an important role in practically every major metabolic and biochemical process, supporting and maintaining cellular processes critical for human life. Magnesium plays an important physiological role, particularly in the brain, heart, and skeletal muscles. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Magnesium has been implicated in and used as treatment of several diseases. Although the importance of magnesium is widely acknowledged, routine serum magnesium levels are not routinely evaluated in clinical medicine. This review provides a discussion as to where magnesium is stored, handled, absorbed, and excreted. We discuss approaches for the assessment of magnesium status., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Hypertension is an important public health challenge because of its high prevalence and strong association with cardiovascular disease and premature death. Hypertension is a major cause of CKD, is present in more than 80% of CKD patients, and contributes to CKD progression. Risk factors for hypertension include, but are not limited to, age, race, family history, obesity, physical inactivity, tobacco use, and inadequate intake of minerals such as calcium, potassium, and magnesium. Magnesium is the second most abundant intracellular cation in the human body and plays an important role in insulin and adenosine triphosphate metabolism. Low dietary magnesium intake has been associated with an increased risk of developing hypertension in prospective cohort studies. Moreover, clinical trials suggest that magnesium supplementation has blood pressure-lowering effects. In addition, emerging data reveal potential mechanisms by which magnesium may influence blood pressure. Here, we will review these mechanisms, using a physiology-based approach, focusing on the effects of magnesium on total peripheral resistance and cardiac output., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Nutrients usually act in a coordinated manner in the body. Intestinal absorption and subsequent metabolism of a particular nutrient, to a certain extent, is dependent on the availability of other nutrients. Magnesium and vitamin D are 2 essential nutrients that are necessary for the physiologic functions of various organs. Magnesium assists in the activation of vitamin D, which helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. All of the enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys. Deficiency in either of these nutrients is reported to be associated with various disorders, such as skeletal deformities, cardiovascular diseases, and metabolic syndrome. It is therefore essential to ensure that the recommended amount of magnesium is consumed to obtain the optimal benefits of vitamin D.

Magnesium, as a physiological calcium antagonist, plays a vital role in the bone metabolism and the balance between magnesium and calcium is crucial in bone physiology. We recently demonstrated that matrix mineralization in human bone marrow-derived mesenchymal stem cells (hBMSCs) can be suppressed by high Mg 2+ . However, a complete understanding of the mechanisms involved still remains to be elucidated. As mitochondrial calcium phosphate granules depletion manifests concurrently with the appearance of matrix vesicles (MVs) and autophagy are associated with matrix mineralization, we studied the effect of high extracellular Mg 2+ on these pathways. Our results first demonstrated that high Mg 2+ has a significant inhibitory effect on the generalization of extracellular mineral aggregates and the expression of collagen 1 along which the mineral crystals grow. Transmission electron microscope results showed that less amount of MVs were observed inside hBMSCs treated with high Mg 2+ and high Mg 2+ inhibited the release of MVs. In addition, high Mg 2+ significantly suppressed mitochondrial Ca 2+ accumulation. Autophagy is promoted as a response to osteogenesis of hBMSCs. High Mg 2+ inhibited the level of autophagy upon osteogenesis and autophagy inhibitor 3-MA significantly suppressed mineralization. Exogenous ATP can reverse the inhibitory effect of high Mg 2+ by increasing the level of autophagy. Taken together, our results indicate that high Mg 2+ may modulate MVs-mediated mineralization via suppressing mitochondrial Ca 2+ intensity and regulates autophagy of hBMSCs upon osteogenesis, resulting in decreased extracellular mineralized matrix deposition. Our results contribute to the understanding of the role of magnesium homeostasis in osteoporosis and the design of magnesium alloys., (© 2017 International Federation for Cell Biology.)

Divalent metal ions, usually Mg2+, are required for both DNA synthesis and proofreading functions by DNA polymerases (DNA Pol). Although used as a non-reactive cofactor substitute for binding and crystallographic studies, Ca2+ supports DNA polymerization by only one DNA Pol, Dpo4. Here, we explore whether Ca2+-driven catalysis might apply to high-fidelity (HiFi) family B DNA Pols. The consequences of replacing Mg2+ by Ca2+ on base pairing at the polymerase active site as well as the editing of terminal nucleotides at the exonuclease active site of the archaeal Pyrococcus abyssi DNA Pol (PabPolB) are characterized and compared to other (families B, A, Y, X, D) DNA Pols. Based on primer extension assays, steady-state kinetics and ion-chased experiments, we demonstrate that Ca2+ (and other metal ions) activates DNA synthesis by PabPolB. While showing a slower rate of phosphodiester bond formation, nucleotide selectivity is improved over that of Mg2+. Further mechanistic studies show that the affinities for primer/template are higher in the presence of Ca2+ and reinforced by a correct incoming nucleotide. Conversely, no exonuclease degradation of the terminal nucleotides occurs with Ca2+. Evolutionary and mechanistic insights among DNA Pols are thus discussed., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Study Objectives: The correlated activation of pre- and postsynaptic neurons is essential for the NMDA receptor-mediated Ca2+ influx by removing Mg2+ from block site and NMDA receptors have been implicated in phase resetting of circadian clocks. So we assessed rest:activity rhythms in Mg2+ block defective animals., Methods: Using Drosophila locomotor monitoring system, we checked circadian rest:activity rhythms of different mutants under constant darkness (DD) and light:dark (LD) conditions. We recorded NMDA receptor-mediated currents or Ca2+ increase in neurons using patch-clamp and Ca2+ imaging techniques., Results: We found that Mg2+ block defective mutant flies were completely arrhythmic under DD. To further understand the role of Mg2+ block in daily circadian rest:activity, we observed the mutant files under LD cycles, and we found severely reduced morning anticipation and advanced evening peak compared to control flies. We also used tissue-specific expression of Mg2+ block defective NMDA receptors and demonstrated pigment-dispersing factor receptor (PDFR)-expressing circadian neurons were implicated in mediating the circadian rest:activity deficits. Endogenous functional NMDA receptors are expressed in most Drosophila neurons, including in a subgroup of dorsal neurons (DN1s). Subsequently, we determined that the uncorrelated extra Ca2+ influx may act in part through Ca2+/Calmodulin (CaM)-stimulated PDE1c pathway leading to morning behavior phenotypes., Conclusions: These results demonstrate that Mg2+ block of NMDA receptors at resting potential is essential for the daily circadian rest:activity rhythms and we propose that Mg2+ block functions to suppress CaM-stimulated PDE1c activation at resting potential, thus regulating Ca2+ and cyclic AMP oscillations in circadian and sleep circuits., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg 2+ -sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg 2+ -insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Magnesium balance is infrequently discussed in the dialysis population, and the clinical consequences of derangements in magnesium homeostasis are incompletely understood. There is an association between hypomagnesemia and adverse outcomes including increases in cardiovascular disease and mortality, while elevated magnesium levels have also been linked with complications such as osteomalacia. In this review, we discuss the features of magnesium physiology relevant to dialysis patients and provide an updated summary of the literature linking magnesium derangements with bone disease, cardiovascular disease, sudden cardiac death, and mortality., (© 2017 Wiley Periodicals, Inc.)

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg 2+ ) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg 2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg 2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg 2+ wasting, as evidenced by an inappropriately high fractional Mg 2+ excretion. Familial renal Mg 2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg 2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg 2+ supplementation, it has contributed enormously to our understanding of Mg 2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.

Magnesium is an essential chemical element in all organisms, intervening in most cellular enzymatic reactions; thus, its importance in homeostasis and as a therapeutic tool in highly challenging patients such as pediatrics. The primary purpose of this paper was to review the role of magnesium sulfate as an adjuvant drug in pediatric anesthesia. This compound already has the scientific backing in certain aspects such as analgesia or muscle relaxation, but only theoretical or empirical backing in others such as organ protection or inflammation, where it seems to be promising. The multitude of potential applications in pediatric anesthesia, its high safety, and low cost make magnesium sulfate could be considered a Super Adjuvant., (© 2017 John Wiley & Sons Ltd.)

Adipose tissue is considered an endocrine organ that promotes excessive production of reactive oxygen species when in excess, thus contributing to lipid peroxidation. Magnesium deficiency contributes to the development of oxidative stress in obese individuals, as this mineral plays a role as an antioxidant, participates as a cofactor of several enzymes, maintains cell membrane stability and mitigates the effects of oxidative stress. The objective of this review is to bring together updated information on the participation of magnesium in the oxidative stress present in obesity. We conducted a search of articles published in the PubMed, SciELO and LILACS databases, using the keywords 'magnesium', 'oxidative stress', 'malondialdehyde', 'superoxide dismutase', 'glutathione peroxidase', 'reactive oxygen species', 'inflammation' and 'obesity'. The studies show that obese subjects have low serum concentrations of magnesium, as well as high concentrations of oxidative stress marker in these individuals. Furthermore, it is evident that the adequate intake of magnesium contributes to its appropriate homeostasis in the body. Thus, this review of current research can help define the need for intervention with supplementation of this mineral for the prevention and treatment of disorders associated with this chronic disease.

Experiments on the action of glutamate on mammalian and amphibian nervous systems started back in the 1950s but decades passed before it became widely accepted that glutamate was the major excitatory neurotransmitter in the CNS. The pace of research greatly accelerated in the 1980s when selective ligands that identified glutamate receptor subtypes became widely available, and voltage clamp techniques, coupled with rapid perfusion, began to resolve the unique functional properties of what cloning subsequently revealed to be a large family of receptors with numerous subtypes. More recently the power of X-ray crystallography and cryo-EM has been applied to the study of glutamate receptors, revealing their atomic structures, and the conformational changes that underlie their gating. In this review I summarize the history of this field, viewed through the lens of a career in which I spent 3 decades working on the structure and function of glutamate receptor ion channels. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'., (Published by Elsevier Ltd.)

Magnesium is the second intracellular cation and the fourth most abundant mineral in the body. Low levels of magnesium have been associated with insulin resistance and type-2 diabetes mellitus, asthma, osteoporosis and chronic kidney disease (CKD). The use of proton pump inhibitors (PPIs) represents the most common cause of hypomagnesemia. The risk of hypomagnesemia, and consequently worsening of the renal function, is increased when diuretics are added to therapy in subjects treated with PPIs. Interestingly, diuretics and PPIs are two of the most used drugs in subjects with CKD. In this review, we described the mechanisms at the basis of the hypomagnesemia and the effect of this electrolyte disturbance in subjects with CKD.

The manner in which mitochondria take up and store Ca(2+) remains highly debated. Recent experimental and computational evidence has suggested the presence of at least two modes of Ca(2+) uptake and a complex Ca(2+) sequestration mechanism in mitochondria. But how Mg(2+) regulates these different modes of Ca(2+) uptake as well as mitochondrial Ca(2+) sequestration is not known. In this study, we investigated two different ways by which mitochondria take up and sequester Ca(2+) by using two different protocols. Isolated guinea pig cardiac mitochondria were exposed to varying concentrations of CaCl2 in the presence or absence of MgCl2. In the first protocol, A, CaCl2 was added to the respiration buffer containing isolated mitochondria, whereas in the second protocol, B, mitochondria were added to the respiration buffer with CaCl2 already present. Protocol A resulted first in a fast transitory uptake followed by a slow gradual uptake. In contrast, protocol B only revealed a slow and gradual Ca(2+) uptake, which was approximately 40 % of the slow uptake rate observed in protocol A. These two types of Ca(2+) uptake modes were differentially modulated by extra-matrix Mg(2+). That is, Mg(2+) markedly inhibited the slow mode of Ca(2+) uptake in both protocols in a concentration-dependent manner, but not the fast mode of uptake exhibited in protocol A. Mg(2+) also inhibited Na(+)-dependent Ca(2+) extrusion. The general Ca(2+) binding properties of the mitochondrial Ca(2+) sequestration system were reaffirmed and shown to be independent of the mode of Ca(2+) uptake, i.e. through the fast or slow mode of uptake. In addition, extra-matrix Mg(2+) hindered Ca(2+) sequestration. Our results indicate that mitochondria exhibit different modes of Ca(2+) uptake depending on the nature of exposure to extra-matrix Ca(2+), which are differentially sensitive to Mg(2+). The implications of these findings in cardiomyocytes are discussed.

Chronic kidney disease is highly prevalent worldwide and is associated with important cardiovascular morbidity and mortality. The search for new prognostic factors and therapeutic targets is therefore essential. There has been recently an increased interest about magnesium, poorly studied yet in that context. In this article, we review the most recent studies looking at the associations between magnesium, cardiovascular and chronic kidney disease. According to the available data, hypomagnesemia seems to alter negatively cardiovascular and renal prognosis. Maintaining normal magnesium levels could then be protective. However, studied populations are heterogeneous, most of the data is only observational and residual confounding factors still need to be considered. All those issues limit currently any definitive therapeutic recommendations.

MgtE is predicted to be a Rhizobium leguminosarum channel and is essential for growth when both Mg²⁺ is limiting and the pH is low. N₂was only fixed at 8% of the rate of wild type when the crop legume Pisum sativum was inoculated with an mgtE mutant of R. leguminosarum and, although bacteroids were present, they were few in number and not fully developed. R. leguminosarum MgtE was also essential for N₂fixation on the native legume Vicia hirsuta but not when in symbiosis with Vicia faba. The importance of MgtE and the relevance of the contrasting phenotypes is discussed.

This study aimed to investigate the intracellular Mg(2+) regulation of the L-type Ca(2+) channels in guinea pig ventricular myocytes. By adopting the inside-out configuration of the patch clamp technique, single channel currents of the L-type Ca(2+) channels were recorded at different intracellular Mg(2+) concentrations ([Mg(2+)]i). At free [Mg(2+)]i of 0, 10(-9), 10(-7), 10(-5), 10(-3), and 10(-1) M, 1.4 μM CaM + 3 mM ATP induced channel activities of 44%, 117%, 202%, 181%, 147%, and 20% of the control activity in cell-attached mode, respectively, showing a bell-shaped concentration-response relationship. Moreover, the intracellular Mg(2+) modulated the Ca(2+) channel gating properties, accounting for alterations in channel activities. These results imply that Mg(2+) has a dual effect on the L-type Ca(2+) channels: facilitation and inhibition. Lower [Mg(2+)]i maintains and enhances the basal activity of Ca(2+) channels, whereas higher [Mg(2+)]i inhibits channel activity. Taken together, our data from the application of an [Mg(2+)]i series suggest that the dual effect of Mg(2+) upon the L-type Ca(2+) channels exhibits long open-time dependence., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Small RNA silencing is mediated by the effector RNA-induced silencing complex (RISC) that consists of an Argonaute protein (AGOs 1-4 in humans). A fundamental step during RISC assembly involves the separation of two strands of a small RNA duplex, whereby only the guide strand is retained to form the mature RISC, a process not well understood. Despite the widely accepted view that 'slicer-dependent unwinding' via passenger-strand cleavage is a prerequisite for the assembly of a highly complementary siRNA into the AGO2-RISC, here we show by careful re-examination that 'slicer-independent unwinding' plays a more significant role in human RISC maturation than previously appreciated, not only for a miRNA duplex, but, unexpectedly, for a highly complementary siRNA as well. We discovered that 'slicer-dependency' for the unwinding was affected primarily by certain parameters such as temperature and Mg(2+). We further validate these observations in non-slicer AGOs (1, 3 and 4) that can be programmed with siRNAs at the physiological temperature of humans, suggesting that slicer-independent mechanism is likely a common feature of human AGOs. Our results now clearly explain why both miRNA and siRNA are found in all four human AGOs, which is in striking contrast to the strict small-RNA sorting system in Drosophila., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Toxin-antitoxin (TA) systems play important roles in bacterial physiology, such as multidrug tolerance, biofilm formation, and arrest of cellular growth under stress conditions. To develop novel antimicrobial agents against tuberculosis, we focused on VapBC systems, which encompass more than half of TA systems in Mycobacterium tuberculosis. Here, we report that theMycobacterium tuberculosis VapC30 toxin regulates cellular growth through both magnesium and manganese ion-dependent ribonuclease activity and is inhibited by the cognate VapB30 antitoxin. We also determined the 2.7-Å resolution crystal structure of the M. tuberculosis VapBC30 complex, which revealed a novel process of inactivation of the VapC30 toxin via swapped blocking by the VapB30 antitoxin. Our study on M. tuberculosis VapBC30 leads us to design two kinds of VapB30 and VapC30-based novel peptides which successfully disrupt the toxin-antitoxin complex and thus activate the ribonuclease activity of the VapC30 toxin. Our discovery herein possibly paves the way to treat tuberculosis for next generation., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Disorders of magnesium homeostasis are very common in dialysis patients but have received scant attention. In this review, we address measurement of plasma magnesium, magnesium balance and the factors that affect magnesium flux during dialysis, the prevalence of hypo- and hypermagnesemia in dialysis patients, and the potential clinical significance of hypo- and hypermagnesemia in dialysis patients. Many factors can affect plasma magnesium concentration, including diet, nutritional status (including plasma albumin level), medications (such as proton pump inhibitors), and dialysis prescription. Further interventional studies to determine the effect of normalization of plasma magnesium concentration on clinical outcomes are needed. At the present time, we recommend that predialysis plasma magnesium be measured on a regular basis, with the dialysate magnesium concentration adjusted to maintain plasma magnesium concentration within the normal range., (Published by Elsevier Inc.)

Magnesium is actively involved in a number of metabolic reactions as an important co-factor, with special emphasis on carbohydrate metabolism. After a brief overview of the regulation of intra- and extracellular magnesium, the present review first describes the regulatory role of magnesium in important metabolic pathways involved in energy metabolism and glycaemic control. Next the clinical significance of hypomagnesaemic conditions with regard to the management of glucose in prediabetic stages, such as insulin resistance/impaired glucose tolerance and in type 2 diabetes mellitus are characterized. Cross-sectional as well as longitudinal studies suggest that a reduced dietary magnesium intake serves as a risk factor for the incidence of both impaired glucose regulation and type 2 diabetes. Mechanisms that might be responsible for diabetes-associated hypomagnesaemia are discussed. Furthermore, the role of hypomagnesaemia in the development and progression of chronic diabetic complications are addressed. Finally, the available literature on the effects of magnesium supplementation on glycaemic control parameters during prediabetic conditions (preventive approach) as well as type 2 diabetes mellitus (therapeutic approach) are reviewed systematically. There is considerable evidence that chronic magnesium supplementation may delay the progression from impaired glucose regulation to type 2 diabetes; however, the effects of oral magnesium supplementation as an adjunct therapy for type 2 diabetes are quite heterogeneous with respect to the various measures of glycaemic control. The results of this review suggest a requirement for critical consideration of the pros and cons of magnesium replacement therapy, based on variables such as magnesium status, stage of disease and glycaemic control., (© 2015 John Wiley & Sons Ltd.)

Mg+2/Mn+2-dependent type 2C protein phosphatases (PP2Cs) are ubiquitous in eukaryotes, mediating diverse cellular signaling processes through metal ion catalyzed dephosphorylation of target proteins. We have identified a distinct PP2C sequence class ("PP2C7s") which is nearly universally distributed in Eukaryotes, and therefore apparently ancient. PP2C7s are by far most prominent and diverse in plants and green algae. Combining phylogenetic analysis, subcellular localization predictions, and a distillation of publically available gene expression data, we have traced the evolutionary trajectory of this gene family in photosynthetic eukaryotes, demonstrating two major sequence assemblages featuring a succession of increasingly derived sub-clades. These display predominant expression moving from an ancestral pattern in photosynthetic tissues toward non-photosynthetic, specialized and reproductive structures. Gene co-expression network composition strongly suggests a shifting pattern of PP2C7 gene functions, including possible regulation of starch metabolism for one homologue set in Arabidopsis and rice. Distinct plant PP2C7 sub-clades demonstrate novel amino terminal protein sequences upon motif analysis, consistent with a shifting pattern of regulation of protein function. More broadly, neither the major events in PP2C sequence evolution, nor the origin of the diversity of metal binding characteristics currently observed in different PP2C lineages, are clearly understood. Identification of the PP2C7 sequence clade has allowed us to provide a better understanding of both of these issues. Phylogenetic analysis and sequence comparisons using Hidden Markov Models strongly suggest that PP2Cs originated in Bacteria (Group II PP2C sequences), entered Eukaryotes through the ancestral mitochondrial endosymbiosis, elaborated in Eukaryotes, then re-entered Bacteria through an inter-domain gene transfer, ultimately producing bacterial Group I PP2C sequences. A key evolutionary event, occurring first in ancient Eukaryotes, was the acquisition of a conserved aspartate in classic Motif 5. This has been inherited subsequently by PP2C7s, eukaryotic PP2Cs and bacterial Group I PP2Cs, where it is crucial to the formation of a third metal binding pocket, and catalysis.