Nutritional genomics has exploded in the last decade, yielding insights—both nutrigenomic and nutrigenetic—into the physiology of dietary interactions and our genes. Among these are insights into the regulation of magnesium transport and homeostasis and mechanisms underlying magnesium’s role in insulin and glucose handling. Recent observational evidence has attempted to examine some promising research avenues on interaction between genetics and dietary magnesium in relation to diabetes and diabetes risk factors. This brief review summarizes the recent evidence on dietary magnesium’s role in diabetes and related traits in the presence of underlying genetic risk, and discusses future potential research directions. The insights of the last decade into the genetics of type 2 diabetes and impaired glucose and insulin metabolism have yielded dozens of replicated risk loci. The genome-wide association (GWA) era has uncovered additional and novel genetic associations with disease risk that were beyond the purview of the previous genetic era’s linkage or candidate gene studies. However, researchers are now more than aware that GWA and prior approaches have their limitations and, moreover, that our current understanding of the contributions of genetics to complex and multifactorial diseases such as type 2 diabetes must steadily move into ever greater complexity to include gene-gene/gene-environment interactions, epigenetics, whole exome/genome approaches, and beyond.versus metformin on diabetes risk in those at risk, in the context of a well-known single nucleotide polymorphism (SNP) at TCF7L2 (rs7903146) . TObservational studies and clinical trials have shown that dietary magnesium has relatively consistent beneficial associations with type 2 diabetes and related traits  or sequeRecently, a handful of investigations have delved into possible genetic interactions between magnesium intake and loci that may be responsible for impaired magnesium metabolism and homeostasis, or impaired glucose and insulin metabolism. These studies have turned up promising and not-so promising research avenues regarding interactions between genetics and dietary magnesium in relation to diabetes and diabetes risk factors.In this brief review, we summarize the underlying mechanisms thought to drive magnesium’s role in insulin and glucose homeostasis and metabolism, the epidemiologic evidence to date on dietary magnesium in relation to diabetes and related traits, and some recent evidence on magnesium’s role in diabetes in the presence of underlying genetic risk. This review ends with a discussion of research needs and future directions in the magnesium field.r = 0.05) between self-reported dietary intake of magnesium and levels in serum , rather than obesity, per se, was associated with hypomagnesaemia [Prospective studies ,45,47,48nesaemia . Evidencnesaemia .i.e., >5 years). One prospective investigation of magnesium intake in 1036 US adults (56.4% women) participating in the Insulin Resistance Atherosclerosis Study who were free of initial and incident type 2 diabetes, estimated that the optimal magnesium intake in relation to insulin sensitivity was at least 325 mg/day [Few studies have prospectively evaluated magnesium intake and insulin sensitivity or resistance over the long term . Interestingly, neither fasting glucose nor fasting insulin concentrations were significantly changed by this low magnesium diet [A small body of clinical evidence supports a role for magnesium supplementation in glucose and insulin metabolism . A meta-trations , suggesttrations ,32,37. Iium diet .TRPM), members 6 (TRPM6) or 7 (TRPM7), which encode magnesium transporters: TRPM6 expression occurring mainly in the kidney and intestine, where it is critical for reabsorption, while TRPM7 expression occurs ubiquitously [TRPMs, additional mutations involved in familial hypomagnesemia , such as mutations in CLDN16 and CLDN19 (which encode tight junction proteins claudin-16 and claudin-19 and regulate aspects of ion reabsorption in the kidney) [SLC12A3—encoding a sodium/choride transporter) and 41 , among others. Functional and experimental studies on a number of these genes are extensive, and have been expertly reviewed by several authors [Despite magnesium’s tight homeostatic regulation, surprisingly little is known about the mechanisms that are broadly regulating total body magnesium in humans, perhaps owing to the complexity and ubiquity of magnesium and its roles in the body. Nevertheless, among the most investigated of the known genes implicated in magnesium transport and homeostasis are the variants in transient receptor potential cation channel, subfamily M (uitously . After t kidney) , mutatioic women ), magnes authors ,72,73.MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1). Nevertheless, because the top six polymorphisms seem to involve magnesium transport and homeostasis, it is plausible to hypothesize that they may also modify individual risk for magnesium-related conditions—including diabetes—in the face of differential magnesium intake.Two additional studies in humans, both published in 2010, have spurred ongoing interest in the genetics of magnesium. One of these was a meta-analysis of genome-wide association studies (GWAS) of serum magnesium (as well as serum potassium and sodium), originally designed to evaluate the contribution of common genetic variation to the normal physiologic variation in serum concentrations . No signHsd11b2). In the offspring of magnesium-deficient dams, hepatic Hsd11b2 CpG promoters showed substantial hyper-methylation, likely pointing to downstream down-regulated gene expression [HSD11B1 gene deficiency  and HSDWhile many genetic interaction studies, such as the ones we discuss in greater detail below, are “nutrigenetic” in that they reveal how or whether polymorphisms modify how we use nutrients, “nutrigenomics” studies such as the cross-over trial above reveal broader genetic response to magnesium supplementation as an environmental stimulus, revealing the complexity of our responses to environmental exposures. Hence the latter are hypothesis-generating, while results from the former may perhaps be more amenable to dictating personalized approaches to health and disease management.et al. [TRPM6 and 5 common SNPs in TRPM7 for their association with diabetes risk. They reported that two common non-synonymous TRPM6 coding region variants—Val1393Ile in exon 29 (rs3750425) and Lys1584Glu in exon 30 (rs2274924)—might confer susceptibility to type 2 diabetes in women with low magnesium intake. Women who were carriers of the two rare alleles of rs3750425 and rs2274924 had nearly five times the odds of type 2 diabetes compared to women who were non-carriers, only when their magnesium intake was <250 mg/day. Two amino acid changes by these polymorphisms are located between the coiled region and kinase near the C-terminal and may reduce TRPM6 channel activity by changing protein conformation. However, the other three studies to date which have investigated such relationships have found that magnesium-related variants did not individually modify either risk of type 2 diabetes [et al. [TRPM6 rs2274924 variant and elevated total glycosylated hemoglobin and greater prevalence of gestational diabetes in 997 women following delivery. They also conducted functional testing to explore the functionality of this SNP. The authors reported that the insulin signaling cascade is unable to activate the phosphorylation of the amino acid adjacent to the substituted amino acid resulting from the polymorphism, thereby rendering the variant TRPM6 channel insensitive to the activating effects of insulin.In humans, only four studies have thus far specifically investigated associations between loci in many of the candidate genes discussed above and diabetes or glycemic traits ,68,83,84et al. [TRMP6, TRPM7, CNNM2 and MUC1) was significantly associated with either fasting glucose or fasting insulin, and none of the eight magnesium-locus × dietary-magnesium interactions were statistically significant. However, the authors observed suggestive inverse association of rs2274924 and rs3750425 in TRPM6 with fasting glucose, the same loci associated with risk of diabetes in women when in haplotype [TRPM6 in glycemia and diabetes. It is possible that in these studies, all of which have been observational, there is some unknown or uncontrolled for confounder which is obscuring a more clear relationship between the loci and the glycemia-related outcomes.Hruby et al.  reportedaplotype , and witaplotype . The nonCNNM2. CNNM2 encodes a membrane protein required for renal magnesium handling and the G allele at this locus was associated with lower serum magnesium [versus the C allele. This interaction potentially indicates a higher dietary magnesium requirement in those with a propensity for lower serum magnesium, for beneficial effects on fasting glucose.In this meta-analysis, one suggestive interaction between magnesium intake and fasting glucose, was observed with rs3740393 in agnesium . If replType 2 diabetes is a complex, multifactorial disorder, heavily influenced by both genetic and environmental determinants. Yet neither genetics nor environmental factors alone explain why some develop the disease while others don’t, thus paving the way for hypotheses on environment-gene interactions, most notably interactions involving modifiable lifestyle factors such as physical activity and diet.Findings from dietary magnesium-gene investigations conducted to date have generally failed to yield consistent and robust results. Interaction analyses have suffered from a number of limitations that may hamper the accumulation of unequivocal evidence. As has been frequently noted by those working in the field of nutrigenetics/nutrigenomics  at the eTRPMs as well as familial hypomagnesaemia, and how supplementation in these individuals differentially affects biomarkers of magnesium status relative to those without the mutations. Such a study would do much to not only assess the magnitude of the impact of serum magnesium-lowering alleles in the presence of equivalent dietary intake in non-carriers, but also the underlying mechanisms.Future well-designed mechanistic studies, which would lend themselves to our basic understanding of magnesium homeostasis, are warranted. Among these is a relatively straightforward study of magnesium supplementation in carriers of rare variants associated with magnesium homeostasis and transport, notably the A second and equally obvious trial is that of magnesium supplementation as primary prevention for diabetes. To date, such a study has been unfeasible owing to length-of-follow-up and costs associated with long-term randomized trials. Hampering this and other studies of single supplemental nutrients is the historicity of the single-nutrient approach in the context of the randomized trial: many have notoriously not wrought the fruit suggested they would by observational literature. Nevertheless, other observational approaches designed to advance our understanding of magnesium-gene interactions are underway, including a genome-wide interaction study of magnesium intake involving over 20 observational cohorts in the US and Europe. In the interim, then, these and functional and mechanistic studies, coupled with smaller trials in genetically or physiologically at-risk individuals will continue to be the norm, and will hopefully lend themselves to the incremental insights needed to truly understand the myriad roles of this fascinating and yet relatively underappreciated mineral.


Here, we examine the evolutionary history of one such transporter, the Sarco(endo)plasmic reticulum calcium ATPase (SERCA), which maintains calcium homeostasis in the cell by actively pumping Ca2+ into the sarco(endo)plasmic reticulum. Our protein-based phylogenetic analyses across Eukaryotes revealed two monophyletic clades of SERCA proteins, one containing animals, fungi, and plants, and the other consisting of plants and protists. Our analyses suggest that the three known SERCA proteins in vertebrates arose through two major gene duplication events after the divergence from tunicates, but before the separation of fishes and tetrapods. In plants, we recovered two SERCA clades, one being the sister group to Metazoa and the other to Apicomplexa clade, suggesting an ancient duplication in an early eukaryotic ancestor, followed by subsequent loss of one copy in Opisthokonta, the other in protists, and retention of both in plants. We also report relatively recent and independent gene duplication events within invertebrate taxa including tunicates and the leech Helobdella robusta. Thus, it appears that both ancient and recent gene duplication events have played an important role in the evolution of this ubiquitous gene family across the eukaryotic domain.Investigating the phylogenetic relationships within physiologically essential gene families across a broad range of taxa can reveal the key gene duplication events underlying their family expansion and is thus important to functional genomics studies. P-Type II ATPases represent a large family of ATP powered transporters that move ions across cellular membranes and includes Na Many evolutionary events such as gene duplication are important drivers of the expansion of gene families but can also confound functional genomics and gene expression studies that focus on orthologous genes. Consequently, a solid phylogeny of the genes of interest, especially multiple-copy genes, is needed before performing gene expression or comparative studies. The availability of many sequenced genomes greatly facilitates the investigation of the evolutionary history of many environmentally relevant gene families, such as the P-type II ATPases. This family of cation transporters plays a key role in the adaptation of organisms to variable environments, including variation in cation concentrations, due to their shared specificities for Ca2+ concentrations, SERCA uses ATP to actively pump calcium into the sarco(endo)plasmic reticulum for storage Scarco(endo)plasmic Reticulum Calcium-ATPase (SERCA) is a key player in calcium signalling SERCA. Three genes are present in vertebrates (ATP2A1-3), coding for three SERCA isoforms, SERCA 1-3 Schistosoma mansoni, which has at least two Artemia franciscana and Caenorhabditis elegansGiven the importance of the SERCA proteins to both cellular and organismal physiology, changes in the function, location, and expression of SERCA constitute significant evolutionary events. Previous genetic studies revealed that several gene duplication events occurred in the evolution of the Arabidopsis has 46 known P-type ATPase genes with multiple isoforms in each family; comparatively humans have about 36 genes. Several hypotheses have been proposed to explain the evolution of this complex gene family. First, multiple isoforms could have evolved to be expressed in different cell types, and would have tissue specific regulation The P-type ATPases show a complex history of gene duplication events. For example, 2+ ATPase” and “SERCA”. In addition, BLAST searches were conducted based on annotated sequences. If multiple splice variants of the protein were reported, the canonical sequence was used.A total of 81 SERCA amino acid sequences of vertebrate, invertebrate, plant, fungi, and other unicellular eukaryotes such as protists and ciliated protozoans were retrieved from Genbank, Uniprot, Ensembl, and JGI . Sequenc2+ ATPase (ATP2B1), Secretory Pathway Ca2+ ATPase (ATP2C1 and ATP2C2), Na+/K+-transporting ATPase (ATP4A1), K+-transporting ATPase (ATP4A), as well as the fungi-specific Na+/K+ ATPase (ACU1) and Na+ transport ATPase (ENA1) The amino acid sequence alignment was performed using ClustalW The SERCA alignment consisted of 81 sequences (61 unique taxa) spanning 1575 amino acids and contained 220 conserved and 818 parsimony-informative sites. Both the BI and NJ analyses returned highly congruent tree topologies. There were two major monophyletic clades. The first group contains clades A, B and C, which consist of metazoan, fungal, and plant sequences, respectively . The secATP2A1-3, respectively) form highly supported monophyletic groups. This pattern indicates that the three SERCA isoforms arose through two rounds of gene (or whole genome) duplication events after divergence from the tunicates but before the separation of fishes and tetrapods. Furthermore, ATP2A1 and 2 are sister groups and likely arose from a more recent duplication event than the one leading to ATP2A3. Our findings do not support the previous suggestion that SERCA2 is the most ancestral of the three isoforms Within metazoans, the SERCA sequences of the chordates form a well supported monophyletic group that includes two sister clades, corresponding to the vertebrates and tunicates. In vertebrates, each of the three SERCA isoforms . This suggests that SMA1 and 2 are likely paralogs that arose from an ancient gene duplication event. Furthermore, Helobdella robusta also possesses three SERCA genes. While SERCA A and B group with other annelid sequences SERCA C is highly divergent and basal to the animal clade. Thus, SERCA C likely arose due to an ancient gene duplication event, while SERCA A and B are the result of a relatively recent gene duplication event. This is consistent with findings of several other gene duplications within the H. robusta genome, across a variety of unrelated gene families Our study reveals that invertebrates also have experienced several instances of gene duplication events leading to multiple 2+ to respond to different stimuli, the temporal and spatial patterns of the signals must vary Arabidopsis is known to have four Endoplasmic Ca2+ ATPases (coded by genes ECA 1-4) ECA 1, 2, and Arabidopsis ECA4 genes and is sister to the clade formed by apicomplexan sequences. However, Plant2, which contains the ECA 3 genes, is sister to metazoan sequences. The presence of two divergent clades of SERCA genes in plants indicates a possible ancient duplication early in eukaryotic evolution followed by the loss of ECA 3-like protein from the protists and the loss of the other duplicate in the lineage leading to animals and fungi, whereas the plants retained both copies. Alternatively, lateral gene transfer (LGT) between protists and plants could have resulted in the Plant1 group. However, LGT events are rare and their prevalence in eukaryotes is unclear ECA 3 encoded protein serves to pump calcium into both the Golgi and endoplasmic reticulum ECA 3 encoded protein to the Golgi may have played a role in its evolution and maintenance in plant genomes and warrants further investigation. The evolution of complex calcium signalling in plants was likely facilitated by duplication of Ca2+ ATPase genes which diverged in their patterns of regulation and localization.Plants are particularly reliant on calcium signalling to control many vital physiological processes and stress responses SERCA genes gain novel functions; this is especially apparent in the three vertebrate SERCA genes that exhibit tissue specific expression patterns likely resulting from divergence in regulation of these genes following the duplication events. Evidence of both ancient and recent gene duplication events in many taxa demonstrates the capacity of SERCA genes to multiply and retain functional significance.Gene duplication events are an essential part of the evolutionary process as they generate novel gene functions and families. The initial increased dosage of gene products resulting from a gene duplication event may be beneficial or detrimental to the organism. The function of the new gene will be retained through stabilizing selection if the increased dosage is beneficial or lost through purifying selection if it is detrimental Panulirus argus, Procambarus clarkii, and Porcellio scaber are sister to the hexapods, and not to the clade formed by the branchiopods Daphnia pulex and Artemia franciscana. This observation is consistent with other molecular and morphological based studies that support the monophyly of Pancrustacea, including all members Crustacea and Hexapoda If we ignore the major ancient gene duplication events, the overall phylogenetic pattern recovered was consistent with that of the combined protein data of α-tubulin, β-tubulin, actin, and elongation factor 1–alpha SERCA genes. Notably, gene duplication events have resulted in proteins with new function and expression patterns in plants and vertebrates. Our results have refined the understanding of the complex evolutionary history of this gene family and will greatly facilitate gene expression and comparative studies that focus on SERCA genes.Overall, our phylogenetic analyses reveal several recent and ancient gene duplication events across different taxonomic levels during the evolution of Table S1List of protein sequences used for phylogenetic analyses.(DOCX)Click here for additional data file.


Myzus persicae, commonly known as the green peach aphid (GPA), is an important pest of a large variety of plants that includes Arabidopsis thaliana. This review summarizes recent studies that have exploited the compatible interaction between Arabidopsis and GPA to understand the molecular and physiological mechanisms utilized by plants to control aphid infestation, as well as genes and mechanisms that contribute to susceptibility. In addition, recent efforts to identify aphid-delivered elicitors of plant defenses and novel aphid salivary components that facilitate infestation are also discussed.The phloem provides a unique niche for several organisms. Aphids are a large group of Hemipteran insects that utilize stylets present in their mouthparts to pierce sieve elements and drink large volumes of phloem sap. In addition, many aphids also vector viral diseases.  The phloem, which provides a conduit for resource distribution and signaling, also provides a niche for some organisms. However, for these organisms the phloem also provides several challenges in that the phloem sap is under high pressure, has a high C:N ratio and a high osmolarity due to elevated sugar content. Furthermore, when ruptured or punctured the sieve elements are prone to occlusion. Aphids (Hemiptera: Aphididae) constitute a large group of “piercing-sucking” class of insects that have adapted to feeding from sieve elements Pollard, . Nearly Brevicoryne brassicae) and the mustard aphid (Lipaphis erysimi) have a limited host range that is restricted to cruciferous plants. In contrast, as described below, a generalist like the green peach aphid  , and horticultural crops in the Brassicaceae, Solanaceae and Cucurbitaceae families , Canadian plum (P. nigra), black cherry (P. serotina), and dwarf Russian almond (P. tenella)  reproduction. Asexual reproduction is characterized by a telescopic generation in which an adult female contains embryos that themselves contain embryos. In nature, the GPAs life cycle includes primary and secondary hosts. The sexual cycle is completed on the primary host, which comprise stone fruits like peach  silencing of the homologous C002 gene had detrimental effects on the insect's ability to colonize plants  and PIntO2 are two other putative salivary protein-encoding GPA genes that have been suggested to facilitate GPA colonization on Arabidopsis. Compared to non-transgenic plants, the number of nymphs produced was larger on transgenic plants expressing PIntO1 or PIntO2 from the phloem-specific AtSUC2 promoter  were similarly expressed in Arabidopsis  leucine-rich-repeat (LRR) protein confers resistance against certain biotypes of Macrosiphum euphorbiae (potato aphid) and Meloidogyne sp. (root-knot nematodes)   is conferred by the Nr gene, in soybean resistance against Aphis glycines (soybean aphid) is conferred by the RAG1 and RAG2 genes, in apple the Sd1 gene confers resistance against some biotypes of Dysaphis devecta (rosy leaf curling aphid)  have been identified in rye, wheat or Tausch's goatgrass that confer resistance against Diuraphis noxia (Russian wheat aphid)  mutants suggest that this increase in sucrose in GPA-infested leaves is likely not detrimental to GPA. Quite to the contrary, GPA population was larger on the tps11 mutant, despite sucrose content being 40% higher in the GPA-infested leaves of the tps11 mutant compared to the wild type (WT) plants  mutant  is observed in GPA-infested Arabidopsis  gene, which resulted in the attenuation of the GPA infestation-induced premature leaf senescence phenotype, was accompanied by improved performance of the GPA. Senescence is accompanied by changes in redox status   infestation  in response to penetration of sieve elements by stylets of Acyrthosiphon pisum (pea aphid) -infested faba bean leaves by burning of leaf-tips, changes were observed in insect feeding behavior. EPG analysis showed that the insect switched from phloem sap ingestion to secretion of water saliva, presumably to reverse phloem occlusion  genes were required for the increased antibiosis observed in the ssi2 mutant  contribute to Arabidopsis defense to the GPA. Oxidation of polyunsaturated fatty acid  is the first step in the synthesis of oxylipins  gene, which for long has been used as a molecular marker for the activation of SA signaling, and the PDF1.2 gene, which is a marker for the activation of JA and ethylene signaling, were upregulated in GPA-infested leaves  gene, which is involved in the synthesis of SA in Arabidopsis, was also upregulated in response to GPA infestation , which is required for SA synthesis, was also induced in GPA-infested plants , a key SA signaling regulator and a putative SA receptor  methyl ester (BTH), a synthetic functional analog of SA, also did not curtail GPA colonization on Arabidopsis  mutant, which contains higher levels of JA than the WT plant, was more resistant to GPA than the WT plant. They further showed that exogenously applied MeJA also promoted resistance to GPA in Arabidopsis  mutant compared to the WT plant , wheat infested with Schizaphis graminum (greenbug), and barley infested with Rhopalosiphum padi (oat aphid) and Russian wheat aphid  GPA population size was larger than on plants expressing WT PAD4, thus suggesting that S118 and D178 are critical for PAD4's involvement in defense against GPA  .In pathogen-infected Arabidopsis, PAD4 functioning along with its interacting protein EDS1 (ENHANCED DISEASE SUSCEPTIBILITY 1), regulates its own expression and functions in a feed-positive SA amplification loop with EDS1 to regulate expression of defense genes  mutant, which accumulates elevated levels of trehalose due to deficiency in the ability to degrade trehalose  has a wider role in plant stress response.Arabidopsis contains more than 20 genes putatively involved in trehalose metabolism , HYL1 (HYPONASTIC LEAVES 1), HEN1 (HUA ENHANCER1), SE (SERRATE), and HST (HASTY) genes, which are involved in miRNA generation, processing or transport, and in the AGO1 (ARGONAUTE1) gene, which is one of the slicer in the miRNA pathway. Expression of the CYP83B1 and CYP81F2 genes, which are involved in the synthesis of indolic glucosinolates, and the CYP79B2 gene, which is involved in the synthesis of indole-3-acetaldoxime, a precursor for indolic glucosinolates as well as auxin and camalexins, was constitutively higher in the dcl1 mutant. In addition, PAD3 induction and camalexin accumulation in response to GPA infestation were higher in the dcl1 mutant than the WT plant. GPA fecundity was significantly higher on the dcl1 pad3 double mutant compared to the dcl1 mutant plant, thus suggesting that increased PAD3 activity contributes to the dcl1-conferred reduction in GPA fecundity.Small RNAs, which are 20–40 nucleotide-long non-coding RNAs, regulate gene expression at the transcriptional and post-transcriptional level. In plants, small RNAs are known to regulate JA and ethylene signaling, and influence defense against microbes and herbivores  inhibits anti-viral miRNA silencing mechanisms, as well as interferes with JA and SA signaling  infestation, is also suggested to be synthesized in the roots from where it is transported to the shoots  expression in roots. LOX5 encodes a 9-LOX, which is involved in the oxidation of fatty acids to yield oxylipins that can be further modified to yield a variety of biologically active lipids. Levels of 9-LOX-derived oxylipins also increased in roots, shoots and petiole exudates of plants that had GPA on their shoots. Loss of LOX5 function resulted in reduced colonization of the lox5 mutant by GPA. Insects reared on the lox5 mutant had significantly lower water content compared to insects reared on the WT plant. Irrigation with 9-LOX products restored water content and restored insect colonization on the lox5 mutant, suggesting that a 9-LOX lipid or product thereof is required for facilitating GPA colonization on WT plants. EPG monitoring of insect feeding behavior indicated that on the lox5 mutant, GPA spent less time feeding from sieve elements and drinking from the xylem, thus accounting for the reduced water content in the insects. Grafting experiments in which the WT shoots were grafted on lox5 roots and vice-versa indicated that LOX5 function is required in roots to promote GPA colonization on Arabidopsis shoots  and the recent development of plant delivered RNAi approaches to silence GPA gene expression should now facilitate understanding the function of GPA genes in this interaction, as well.Although for quite some time Arabidopsis has been utilized as a model plant to understand the molecular basis of plant growth, development and response to pathogens, it is only in the last 10 years that significant progress has been made on utilizing Arabidopsis to study plant interaction with phloem-sap consuming insects. The compatible interaction between Arabidopsis and GPA has provided new insights on the physiological and molecular adaptations that contribute to controlling the severity of infestation. In addition, this interaction has also begun to provide information on how the insect targets host mechanisms to facilitate colonization. The near completion of the GPA genome sequence (AphidBase; The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Based on these findings, we reviewed the functions of OXT and its properties with respect to the development of therapies for human social behavior impairments in psychological diseases. In addition, preliminary studies of continuous nasal OXT administration on subjects with autism spectrum disorders are described.The nine amino acid peptide oxytocin (OXT) has been directly associated with different types of behavioral reactions. The formation and maintenance of social relationships in youth and middle age are important components of human mental health. A deficit in healthy behavioral formation leads to social isolation and limitation of well-being. Mice are social animals and are therefore useful for investigating the neurobiological mechanisms of cognitive process control, including the development of social relationships and social skills. Studies in mice may broaden our understanding of the human condition. The multifunctional protein CD38/ADP-ribosyl cyclase is highly expressed in the brain, plays an important role in central OXT release, and regulates social memory. In this review article, we discuss the mechanisms of social behavior affected by the dysregulation of brain OXT function as a consequence of a lack of CD38. OXT bound to OXT receptors initiates autoregulatory positive feedback of OXT release in the hypothalamus and posterior pituitary. OXT bio-behavioral positive feedback is usually implicated in female reproductive systems, but can also be observed in social behavior. Exogenous stimuli (OXT treatment  The nine amino acid peptide oxytocin (OXT) plays a dual role with peripheral and central effects in the regulation of many physiological and pathophysiological processes, including penile erection and ejaculation  from ryanodine-sensitive Ca2+ pools, resulting in increases of cytosolic free Ca2+ concentrations ([Ca2+]i). Therefore, it is postulated that some cellular events such as secretion or cell migration depend on the formation of cADPR.With respect to OXT, we reported that CD38, a type II transmembrane protein, which controls leukemia malignancy in blood cells  of the human CD38 gene in relation to autism spectrum disorders (ASDs) and repetitive treatment of ASD patients with nasal administration of OXT.Oxytocin is involved in different types of mammalian social behavior from rodents to humans in both sexes , ASDs, eating disorders, addiction, schizophrenia, and posttraumatic stress disorder (PTSD) show dysregulation of OXT levels  displayed deficits in social recognition  emitted fewer ultrasonic vocalizations (USV), had higher levels of aggression, and showed social memory impairment (the latter of which could be abolished by OXT administration) compared to wild-type littermates  show impairment of glucose-induced increases in cADPR, Ca2+ concentration, and insulin secretion in pancreatic β-cells and the absence of Ca2+ oscillations in T cells  and supraoptic nucleus (SON), stored in Herring bodies and released into systemic circulation from the posterior pituitary , neurotransmitters, and hormones responsible for establishing parental behavior can activate many receptor complexes. For example, social  experience coincides with the efficiency of OXTR binding  and how this mechanism is related to social recognition or social behavior in the in vitro experiments with the hypothalamus and posterior pituitary of adult male mice ]. Reproduction-related stimuli cause positive feedback release of OXT within the brains of lactating rats  experience activates OXT neurons, increases hypothalamic CD38/ADP ribosyl cyclase activity, stimulates OXT release from the axons and potentially from the dendrites, and induces OXT autoregulation . In −/−Cd38 mice, ADP-ribosyl cyclase activity was markedly lower in the hypothalamus and pituitary from the first postnatal day and was consistently lower thereafter until the adult stage in comparison with Cd38/++ mice  OXT levels were significantly lower in −/−Cd38 postpartum mice under stressful conditions, such as pup–dam separation , resulting in the pups becoming scattered in different places. However, after reunion, −/−Cd38 dams fed the pups sufficiently for them to grow to the same weight as the controls  behavior in −/−Cd38 mice  mice  and duration (∼60 ms). The number of USVs was significantly (1.6-fold) lower in −/−Cd38 pups than in Cd38/++ pups. Reduced USVs in mice are a useful parameter relevant to the second diagnostic symptom of autism, impaired communication  permeability for OXT or some other pathways  lines obtained from subjects with ASD and their “unaffected” parents demonstrated significant reduction of expression in affected subjects (Lerer et al., CD38 expression, VABS score and IQ in humans (Riebold et al., CD38, or human OXTR SNP variants and parenting behavior have been observed between human mothers and fathers (Feldman et al., CD38 expression was not confined to the trust-related condition. Therefore, they suggested a role of CD38 in basal OXT release rather than OXT release associated with emotional events in humans (Kiss et al., Indeed, positive feedback of OXT-induced OXT release was recently observed in human males. OXT was shown to enhance visual scanning of faces, particularly the eye region, as compared to a placebo. Plasma or salivary OXT levels are significantly increased after intranasal OXT administration (Andari et al., In summary, recent data suggest novel mechanisms underlying social behavior and confirm new molecular targets for pharmacological corrections of behavioral changes associated with neurodevelopmental disorders. The plasma OXT level is a reliable marker reflecting central oxytocinergic functions in humans. Rodent models are useful in this research field to investigate the molecular mechanisms underlying the disturbance of central and peripheral OXT regulation and to develop new perspectives in the therapy of human diseases characterized by social behavior deficits.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Several possible biomarkers representing biological modifications during specific phenomena as simile-inflammatory process, bone resorption and formation, periodontal ligament changes, and vascular and neural responses are proposed. Citations to potentially published trials were conducted by searching PubMed, Cochrane databases, and scientific textbooks. Additionally, hand searching and contact with experts in the area were undertaken to identify potentially relevant published and unpublished studies. Selection criteria were as follows: animal models involving only mice and rats undergoing orthodontic treatment; collection of gingival crevicular fluid (GCF) as a noninvasively procedure for humans; no other simultaneous treatment that could affect experimental orthodontic movement. The data suggest that knowledge of the remodeling process occurring in periodontal tissues during orthodontic and orthopedic therapies may be a clinical usefulness procedure leading to proper choice of mechanical stress to improve and to shorten the period of treatment, avoiding adverse consequences. The relevance for clinicians of evaluating the rate of some substances as valid biomarkers of periodontal effects during orthodontic movement, by means of two models of study,  Tooth movement by orthodontic force application is dependent on remodeling in periodontal ligament and alveolar bone. Orthodontic movement should be described as a continual and balanced process characterized by bone deposition and bone resorption, respectively, on pressure and tension sites . OrthodoTo identify the degree of remodeling occurring in the periodontal tissues during orthodontic or orthopedic retention by monitoring the levels of certain biochemical mediators may be a clinically useful procedure, because of their important roles in tooth movement and even in tissue damage.In this paper, the importance of evaluating the levels of substances as valid biomarkers of periodontal effects of an orthodontic treatment is emphasized, through an accurate description of the specific role of each of them.Citations to potentially published trials were conducted by searching PubMed, Cochrane databases, and scientific textbooks. Additionally, hand searching and contact with experts in the area were undertaken to identify potentially relevant published and unpublished studies. Selection criteria were as follows: animal models involving only mice and rats undergoing orthodontic treatment; collection of gingival crevicular fluid (GCF) as a noninvasively procedure for humans; no other simultaneous treatment that could affect experimental orthodontic movement.Only studies on mice and rats have been considered as animal models , whereasmice and men, the clinical usefulness of some biomarkers in orthodontics is properly analyzed.Thus, by means of the two models of study, Biological mechanisms that control the shift from the stimulus, consisting of a continuous force application, to the reaction, represented by tooth displacement in periodontal space, can be evaluated by considering the theory of the pressure tension, according to which cell differentiation and subsequent tooth movement are controlled by chemical signals. The sequence of events following orthodontic tooth movement can be characterized using suitable biomarkers.β (IL-1β) is one of the most potent cytokines in periodontal environment during the initial stage of orthodontic tooth movement [β during tooth movement include cells such as fibroblasts, macrophages, cementoblasts, cementoclasts, osteoblasts, and osteoclasts [β [β is secreted by osteoclasts as an immediate response to mechanical stress during the initial stage of orthodontic treatment, and at later stages by macrophages, whose accumulation has been observed in compressed areas. Since survival, fusion, and activation of osteoclasts correlate with IL-1β, this Interleukin also determines the amount of tooth movement dependently on the efficiency of alveolar bone remodeling process [β mRNA in rats' periodontal ligament after orthodontic force loading is increased within 3 h, particularly on pressure side [β when compared to the experimental tooth movement of vehicle treated mice, indicating a reduction of the number of osteoclasts on pressure side of periodontal tissues after histological characterization and a consequent downregulation of orthodontic tooth displacement rate in mice treated with IL-RA therapy [β gene cluster polymorphisms evaluated in GCF [In experimental tooth movement, the presence of neuroimmune interactions may be of primary importance in the initial inflammatory response . Interlemovement . The poteoclasts . In the lasts [β . Particu process . The conure side . An induure side . In fact therapy . Moreoved in GCF .β is also considered to be a powerful inducer of Interleukin-6 (IL-6) production; it overlaps with IL-6 and Tumor Necrosis Factor-α (TNF-α) in their actions  role in stimulating bone resorption [2, specially, is able to mediate inflammatory responses and induces bone resorption by activating osteoclastic cells [2 reflect the biologic activity in periodontium during orthodontic tooth movement, and it is significantly higher in both tension and compression sides [Clinical and animal studies by various authors have identified prostaglandins E  are specific glycoproteins, which interact to regulate production, maturation, and function of monocyte-macrophages (M-CSF) as well as granulocytes (G-CSF). They might have implications in bone remodeling and thereby during tooth movement . An impoin vivo during experimental tooth movement in rat periodontal tissues with immunohistochemical analysis. VEGF immunoreactivity was found in vascular endothelial cells, in fibroblasts adjacent to hyalinized tissue, a local necrotic area in compressed zone, in osteoblasts and osteoclasts, and in mononuclear cells. Kaku et al. detected VEGF mRNA in fibroblasts and osteoblasts in tension area of mice periodontal ligament during experimental tooth orthodontic movement [Vascular endothelial growth factor (VEGF) is a cytokine involved in tissue neoformation, since it increases vascular permeability and mediates angiogenesis . During movement , 32. TheDuring orthodontic tooth movement the increased concentration of biologically active proteins contributes to neurogenic inflammation occurring in periodontium. Somatosensory neurons transmit signals from periodontal peripheral nerve fibers to the central nervous system. With application of physiologic orthodontic force, periodontal peripheral nerve fibers release calcitonin gene related peptide (CGRP) and substance P. In addition to acting as neurotransmitters, CGRP and substance P serve as vasodilators, increasing vascular flow and permeability (diapedesis) and stimulating plasma extravasation and leukocyte migration into tissues (transmigration).CGRP induces bone formation through osteoblast proliferation and osteoclast inhibition. CGRP receptors are found on osteoblasts, monocytes, lymphocytes, and mast cells, and receptor activation results in amplified intercellular communication, promoting cytokine (inflammatory mediator molecules) synthesis and release.2 production [Normal periodontal and alveolar bone innervations are essential to orthodontic tooth movement-associated periodontal remodeling. Healthy innervation promotes maximum blood flow during orthodontic tooth movement, whereas denervation reduces blood flow and bone formation . Substanoduction .β and other proinflammatory cytokines. Caspase-1 mRNA expression is increased in a rat model undergoing orthodontic treatment, and its rate changes with different temporal phases of orthodontic tooth displacement [β-glucuronidase (βG). Increased levels of this enzyme have been found in the GCF of adolescents treated with rapid maxillary expander. Moreover, βG, as other biochemical mediators like IL-1β, responds to direct and indirect application of mechanical force to teeth, with an increased level that is higher than following stronger forces [Generally, a high enzyme activity is suggestive of a greater cellular activity . An apoplacement . Some stlacement , 38. A br forces .Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities in GCF have been measured to confirm the biological activity which occurs in the periodontium during orthodontic treatment. They are soluble enzymes normally confined to the cytoplasm of cells then released to the extracellular environment after cell necrosis. The GCF AST activity is significantly elevated in both tension and compression sites at days 7 and 14. This rise is explained as a consequence of a controlled trauma which produces cell death as a consequence of mechanical force exerted on alveolar bone and periodontal ligament. A low increase of GCF AST activity reflects the application of orthodontic force on teeth, particularly in dental sites undergoing pressure, while an occlusal trauma leads to a higher amount of enzymatic level . It posiThe biological response incident to orthodontic tooth movement ultimately involves alterations in the surrounding bone architecture . Bone meVarious investigations consider the duration of an orthodontic cycle of 21 days, to identify and understand the enzymatic changes occurring during early stages of orthodontic force application in coincidence with initial and lag phases of tooth movement. It was observed that ALP activity peaked on the 14th day in most patients, followed by a sharp fall by the 21st day. The fall in activity is related to removal of the hyalinized zone. In hard bony tissues ALP is implicated in mineralization process because of the intense staining reaction given by active osteoblasts and osteocytes. No enzyme activity is found in bone matrix, except in close association with matrix synthesizing cells. The osteogenic cells in the periodontal ligament respond to tensional forces with an increase in the maturation rate. In periodontal ligament fibroblast and collagen proliferation are shown to increase under tension stress. ALP activity is low in the compressed hyalinized zones of the periodontal ligament; conversely ACP activity is higher. A late phase of bone deposition (7–14 days) occurs in both tension and pressure sites of the alveolar wall.Thus, the predominant bone remodeling activity at the early times in a bone remodeling cycle is resorptive with increased acid phosphatase activity, but in the later phase resorption and deposition become synchronous. High levels of ALP have been described after 7 days, when bone deposition begins, and a significant peak occurs on day 14. It is obvious that, as a forerunner to bone formation, the number of fibroblasts and osteoblasts raise in tension areas. This amount occurs as a result of the increase in cell number by mitotic cell division. In histologic studies it has been observed that in marginal tensional areas cell proliferation occur between 36 and 50 hrs and lasts for 10 days or 3 weeks. On the compression side bone resorption would occur and osteoclastic activity would be high with little or no osteoblastic activity.In conclusion, the analysis of the association between ALP and bone metabolism, under healthy gingival conditions, is a suggestive indicator of histological and biochemical changes in bone turnover and therefore of the amount of tooth movement.Finally, specific properties of GCF ALP activity render this enzyme an interesting diagnostic tool in orthodontics.When exposed to varying degrees of magnitude, frequency, and duration of mechanical loading, alveolar bone and adjacent periodontal tissues show extensive macroscopic and microscopic changes.Mechanical loading also alters periodontal tissue vascularity and blood flow, resulting in the local synthesis and release of various molecules, such as cytokines, growth factors, colony-stimulating factors, enzymes, and neurotransmitters. On the basis of sequential reactions and released substances, several of these biologically active molecules have been proposed as biomarkers to better understand the biological process involved in orthodontic tooth movement, to improve treatment and reduce adverse side effects . A biomaPotential biological markers can be collected by means of different experimental and clinical methods, respectively, in animal and in living human models. GCF analysis, especially, has offered several advantages for its simple, quick, and noninvasive collection and for the wide variety of molecules detected in his volume .Knowledge of the ongoing process occurring in periodontal tissues during orthodontic and orthopedic therapies can lead to proper choice of mechanical loading with the aim of shortening the period of treatment and avoiding adverse consequences associated with orthodontic treatment, such as root resorption or bone loss.


Research evidence is not always being disseminated to healthcare providers who need it to inform their clinical practice. This can result in the provision of ineffective services and an inefficient use of resources, the implications of which might be felt particularly acutely in low- and middle-income countries. Malaria prevention is a particularly compelling domain to study evidence/practice gaps given the proven efficacy, cost-effectiveness and disappointing utilization of insecticide-treated nets (ITNs).This study compares what is known about ITNs to the related knowledge and practices of healthcare providers in four low- and middle-income countries. A new questionnaire was developed, pilot tested, translated and administered to 497 healthcare providers in Ghana (140), Laos (136), Senegal (100) and Tanzania (121). Ten questions tested participants' knowledge and clinical practice related to malaria prevention. Additional questions addressed their individual characteristics, working context and research-related activities. Ordinal logistic regressions with knowledge and practices as the dependent variable were conducted in addition to descriptive statistics.The survey achieved a 75% response rate (372/497) across Ghana (107/140), Laos (136/136), Senegal (51/100) and Tanzania (78/121). Few participating healthcare providers correctly answered all five knowledge questions about ITNs (13%) or self-reported performing all five clinical practices according to established evidence (2%). Statistically significant factors associated with higher knowledge within each country included: 1) training in acquiring systematic reviews through the Cochrane Library ; and 2) ability to read and write English well or very well . Statistically significant factors associated with better clinical practices within each country include: 1) reading scientific journals from their own country ; 2) working with researchers to improve their clinical practice or quality of working life ; 3) training on malaria prevention since their last degree ; and 4) easy access to the internet .Improving healthcare providers' knowledge and practices is an untapped opportunity for expanding ITN utilization and preventing malaria. This study points to several strategies that may help bridge the gap between what is known from research evidence and the knowledge and practices of healthcare providers. Training on acquiring systematic reviews and facilitating internet access may be particularly helpful. There is growing awareness and concern among educators, researchers, practitioners and policymakers that what is known from research evidence is often not being put into action ,2. An exEfforts to address malaria are particularly implicated by this "know-do" gap given the proven effectiveness of insecticide-treated nets (ITNs) in preventing the disease -6, this community members about their knowledge and practices relating to malaria prevention [This study seeks to probe the gap between what is known globally through research evidence about malaria prevention interventions  and the related knowledge and practices of healthcare providers in low- and middle-income countries. While many studies have asked evention -39, noneevention -44. In cevention -50, and evention -60, dehyevention -68 and pevention -73. A beThis inquiry is part of a larger study sponsored by the World Health Organization that examined the link between research, practice and policy. Other elements of this global effort have focused on whether and how healthcare providers use research evidence ,75 and tThe development, translation, pilot-testing, reliability and validity of the questionnaire administered in this study has been described elsewhere . In summThe questionnaire was administered locally between October 2004 and December 2005 by country teams in Ghana, Laos, Senegal and Tanzania with each aiming to obtain complete responses from 100 healthcare providers. These four low- and lower-middle-income countries differ in population size, per capita income, health expenditures, life expectancy, coverage for ITNs, and computer and internet access (Table vs. private) and then selected randomly for inclusion. 140 healthcare providers were approached representing 48 different facilities. In Laos, a sampling frame was constructed based on existing lists of providers from the Ministry of Health and four provincial health departments. A stratified random sampling process was similarly applied to select 136 healthcare providers who worked at different types of facilities  in Borikhamsay, Savannakheth and Vientiane. In Senegal, a sampling frame was developed from lists of providers working at eight Dakar- or Thiès-based institutions and a list of clinician-scientists they had previously constructed. Simple random sampling was used to select 100 healthcare providers. Finally, in Tanzania, country investigators used purposive sampling to identify 121 regional or district medical officers who were attending a meeting for malaria and the integrated management of childhood illness. These variations in sampling frames and methodology, and the limited sample size, preclude meaningful between-country comparisons.In Ghana, the country team constructed a sampling frame of appropriate healthcare providers from lists of government and private health facilities obtained from the Ministry of Health and the Society of Private Medical & Dental Practitioners respectively. A stratified cluster random sampling process was used with the facilities stratified by region (Greater Accra and Ashanti) and governance . The scale was inverted for the one practice which is contrary to recommended practice. All questions were weighted equally such that individual practice scores were integers ranging from five to 25. Both knowledge and practice scores were transformed into quintiles (within each country) and used as ordinal variables. Independent variables for both models included healthcare providers' 1) use of particular sources of evidence, 2) views and activities related to improving clinical practice, and 3) individual and practice characteristics. Multiple imputation (using 100 imputations) was used to fill in missing values using multivariate normal regressions. This approach was selected because it accommodates arbitrary missing-value patterns . ObservaIn the analysis, systematic reviews (and the Cochrane Library as the single most comprehensive source) are emphasized because they are widely recognized as the best available approach to the synthesis of global research evidence, they efficiently provide summary information to inform decision-making, and they are widely-available and internationally authoritative on clinical interventions -99, incl372 healthcare providers participated in this study out of the 497 providers approached, yielding an overall response rate of 75% .A majority of the respondents were male (56%), trained as primary care physicians (67%), could read and write English (63%), and worked in rural areas (56%), government-operated facilities (86%) and hospitals 82%). On average, the respondents were 42 years old and spent the greatest percentage of their time on clinical practice (59%) rather than research (8%), teaching (10%) or administrative duties (18%). Few had easy access to a computer with a CD ROM (24%) or the internet (22%), had earned master's or doctorate degrees (15%), and worked with researchers (44%). Few of the respondents had training on acquiring, assessing or adapting research evidence since their last degree although a substantial number received training related specifically to malaria prevention (45%). There were also few respondents that self-reported using the electronic Cochrane Library at least once a month (11%), but relatively more that self-reported reading electronic or paper versions of clinical practice guidelines, protocols or decision-support tools (59%), scientific journals from either their own country (55%) or high-income countries (36%), and summaries of articles, reports and reviews from public or non-profit organizations (57%). Almost half of the participating healthcare providers reported that research performed in their own country was of above average or excellent quality (48%) , whether from Ghana (10%), Laos (0%), Senegal (4%) or Tanzania (33%). The overall percentage of correct responses to individual questions ranged from 43% on the effectiveness of torn ITNs (question 1) to 68% on the protective effect of ITNs for non-users in the same house (question 2), with variation greatest within Senegal (8%-98%) and least within Tanzania (70%-85%). Approximately half of all participating healthcare providers knew that using untreated nets can divert extra biting to sleepers without nets in the same houses (48%), that ITNs need regular re-treatment to remain effective while long-lasting ITNs do not (57%), and that ITNs have been demonstrated to reduce the number of malaria episodes in communities with stable malaria (57%) , whether from Ghana (1%), Laos (1%), Senegal 4%) or Tanzania (5%). Approximately half of providers often or very often reported that they enquired about young children's home-use of ITNs (52%), recommended to caregivers that young children use them (56%) and advised caregivers on the need to regularly re-treat them (46%). A quarter of the participating healthcare providers reported often or very often giving ITNs to the caretakers of young children and pregnant women (26%). More than one-third of the respondents self-reported that they often or very often incorrectly informed caretakers that torn ITNs are worse than no ITNs (37%)  training in acquiring systematic reviews through the Cochrane Library since completing their last degree ; and 2) the ability to read and write English well or very well . The second ordinal logistic model highlighted several factors associated with healthcare providers following better practices relating to malaria prevention, namely: 1) reading scientific journals from their own country ; 2) working with researchers to improve their clinical practice or quality of working life ; 3) training on malaria prevention since their last degree ; and 4) easy access to the internet   informed patients that torn ITNs are worse than no ITNs. These gaps in knowledge and practices on the prevention of malaria align with other gaps that have been well-documented among households on the same issue -39 and hself-report that these journals lead to changes in their clinical practice, as previous studies have found [This study also found various alterable factors that were associated with higher knowledge and better practices. For example, healthcare providers that had access to the internet and training in malaria prevention reported better practices relating to malaria prevention than those who did not. This study also indicates that healthcare providers who read journals from their own country not only ve found ,80, but ve found ,124. ThiThe logistic models suggest that higher knowledge and better practices may be associated with different factors. While it may be the case that these factors influence knowledge and practices differently, these divergent results could also be explained by social desirability bias which presumably would affect self-reports of practices much more than it would affect answers to knowledge-testing questions. Alternatively, the models may lack sufficient power, the dependent variables may not adequately reflect respondents' real "knowledge" and "practice", or there may be confounding variables affecting the analysis.Improving healthcare providers' knowledge and practices is an untapped opportunity for expanding ITN coverage and preventing malaria. Not only are healthcare providers the main source through which people learn about and use health interventions , but theSpecifically, this study's results point to several possible areas in which interventions may be effective in helping healthcare providers attain greater knowledge on malaria prevention and evidence-based practices. First, the low proportion of healthcare providers who received training in acquiring, assessing and adapting research evidence suggests such training is an opportunity for improvement--especially if it covers systematic reviews. Indeed, whereas graduate degrees and clinical specialization were not associated with greater knowledge on malaria prevention, training in acquiring systematic reviews through the Cochrane Library was. Second, improving access to computers and the internet may be fruitful. While only 11% of the total sample used the Cochrane Library (which is free in most low-income countries), this doubles to 25% for those who have easy access to the internet. Third, the fact that English language abilities were associated with higher knowledge suggests that the best health knowledge and/or training opportunities may not be available to healthcare providers in their local languages. Efforts to disseminate translated research syntheses may be helpful. Fourth, supporting interaction between healthcare providers and researchers may also be an effective strategy for improving clinical practice. Finally, access to scientific journals from healthcare providers' own country can be facilitated, especially as the studies they contain would be among the most applicable to their local context.This study has five main strengths. First, it examines malaria, a disease prioritized in the Millennium Development Goals and which has a proven intervention for prevention that is not universally utilized . Second, the study's questionnaire was built on existing questionnaires, pilot tested, and assessed for reliability and validity . Third, This study has four main limitations. First, the survey relies on self-reported data to assess healthcare providers' practices which increases the risk of social desirability bias and may differ from actual performance. One review of studies conducted between 1980-1996 suggests self-reports of practices overestimate actual behaviour  by up to 27% . Second,Increased attention is necessary to help bridge the gap between what is known from research evidence about preventing malaria and the knowledge and practices of healthcare providers in low- and middle-income countries. Until serious and multi-pronged efforts are implemented, we may never be able to fully capitalize on existing evidence-based and cost-effective interventions like ITNs for reducing the burden of malaria, addressing inequities and improving health globally. Those policymakers, civil society leaders, donors and international organizations who are working to prevent malaria should at least consider strategies to enhance healthcare provider' knowledge and evidence-based practice, such as offering training on acquiring systematic reviews, facilitating access to the internet, translating research syntheses to local languages, encouraging interactions with researchers, making ITNs available at healthcare facilities, and supporting the dissemination of local scientific journals. Further studies are necessary to both confirm these exploratory findings and more precisely inform future policy directions.The authors declare that they have no competing interests.SJH, GEG, JNL, GDN, EJAO, MFS and BB contributed substantially to the study concept and design, the acquisition of data, or the analysis and interpretation of data, and revised the article critically for important intellectual content. SJH led the drafting of the paper, GEG led the data analysis, and JNL led the overall study design. All authors gave their approval for this paper to be published.Funding for this project was provided by the Alliance for Health Policy & Systems Research and the Global Development Network and supplemented with substantial in-kind support of staff time and other resources from McMaster University and the World Health Organization. John Lavis receives salary support as the Canada Research Chair in Knowledge Transfer and Exchange. The views expressed in this paper are those of the authors and do not represent the views of their affiliated organizations.


The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders. The presence of ROS produced profound consequences for life on earth, both beneficial and deleterious. For example, a wealth of evidence suggests that high levels of ROS are intimately linked to the appearance of neuronal death in various neurological disorders. These include chronic diseases (Parkinson's disease or Alzheimer's disease) [The earth began its life without free oxygen in its atmosphere . Oxygen disease) , acute idisease) , 6, or pdisease) .An increase in oxidative and nitrooxidative stress and a decrease in the antioxidant capacity of the brain are key factors involved in the etiology of neuropsychiatric diseases . In the 2−∙), through its derivative, the hydroxyl radical (∙OH), plays an essential role in cell physiology by stimulating the activation of guanylate cyclase and formation of the “second messenger” cGMP in cells and activation of the transcription factor nuclear factor kB (NF-kB) by hydrogen peroxide in mammalian cells [Even though ROS are involved in a number of diseases, they are also very pertinent mediators of several normal physiological processes. All of the good ROS are products of turnover in the mitochondrial respiratory chain. The highly reactive nature of singlet oxygen can even be exploited to make reactive peroxides that can serve as antimicrobial agents . Most ofan cells . Under n2−, which along with other ROS destroy the engulfed bacteria (oxidative burst) [2− in modulating synaptic plasticity, memory formation, and learning is altered by age [In the inflammatory response, macrophages and neutrophils are attracted by activated T lymphocytes and IL-2 and produce high levels of Oe burst) . In braie burst)  by modifd by age .Activated oxygen species, especially those that share electronic orbital features with singlet oxygen, are highly reactive, and therefore the evolutionary adaptation by organisms to make oxygen wholly beneficial has never been complete. Consequently, there are many deleterious effects associated with excessive, activated ROS. ROS are thereby capable of producing membrane damage, changes in the inner proteins affecting their structure and function, lipids denaturation, and structural damage to DNA. In the brain, those effects appear when ROS are in excessive concentrations and thus the ability of antioxidant mechanisms of neurons to counterbalance the damaging reactions is diminished .The brain is especially susceptible to the assaults perpetrated by ROS. This is because the brain as an organ is a major metabolizer of oxygen (20% of the body consumption) and yet has relatively feeble protective antioxidant mechanisms. Thus it is especially vulnerable to oxidative stress. The brain contains a large amount of polyunsaturated peroxidizable fatty acids along with high levels of iron that act as a prooxidant and sometimes induce autophagic cell death in hemorrhagic stroke. Synaptic transmission involving dopamine and glutamate oxidation may also occur in the brain –15. In aAt the DNA level, oxidative modifications may cause rapid depletion of intracellular energy by activating DNA repair enzymes. Energy scarcity after stroke will cause in turn endonuclease-mediated DNA fragmentation, the key mechanism that leads to DNA-damage .The mitochondria is the cellular powerhouse that generates ATP and therefore is a key participant in all physiological and pathological events. Following ischemia-associated excitotoxicity and other neurodegenerative insults, mitochondria will take up calcium which leads to an increased production of reactive oxygen species (ROS). As a result, neuronal cells face excessive amounts of ROS . The mec2+ stored in the mitochondrial matrix. Furthermore, since the mitochondrial matrix is negatively charged, K+ can enter through the pore and cause osmotic swelling [Once opened, the pore can cause the collapse of the proton gradient. This promotes collapse of respiratory control as well as release of Caswelling . A bioenswelling . If the An increasing number of studies report the prevalence of oxidative stress and mitochondrial abnormalities in numerous neuropsychiatric disorders –30. A spDefects in the electron transport chain (ETC) system and especially the mitochondrial complex dysfunctions have been reported to be involved in autism , 40 and Recent findings suggest that neuroinflammation is an important player in the pathophysiology of neuropsychiatric diseases such as stroke, depression, Alzheimer's diseases, or schizophrenia , 44.After the onset of cerebral ischemia, oxidative stress plays a major role in neuroinflammatory reactions , 46. In κB [κB mediated proinflammatory reactions and innate immune responses are prominent features in cerebral ischemic conditions [Redox-mediated increase in free radicals in the postischemic brains notably leads to augmented expression of several proinflammatory genes whose expression is mediated through the transcription factor nuclear factor-kappa-B or NF-κB . Importanditions –52. Althnditions , neuronanditions –57.2− and NO free radicals [2− radicals that could in turn lead to neuronal loss in Parkinson's disease [In Parkinson's disease (PD), a considerable body of evidence suggests that both dopaminergic and nondopaminergic cells undergo degeneration –60. The radicals . Dopaminradicals . Additio disease . Similar disease .The involvement of microglial activation most likely attracts lymphocytes to the site of injury. Subsequent pathophysiological sequelae involve damage to the integrity of the blood brain barrier (BBB), and then increased shedding of several inflammatory cytokines into the cerebral spinal fluid (CSF) of PD patients , 63. As The research findings from Reynolds and colleagues implicate the role of adaptive immunity functions during microglial inflammation in Parkinson's disease . On the Major events associated with oxidative stress could exacerbate inflammation-related pathologies in Alzheimer's disease (AD) –69. ReceThe important role conferred to Toll-like receptors (TLR2 and TLR4) in AD as peripheral biomarkers  of AD paThe demyelination and axonal damage triggered by oxidative stress and inflammatory reactions are widely reported in multiple sclerosis (MS) . The subEpidemiological studies on prenatal exposure to infection during the developmental period suggests that the immune system plays an important role in a number of disorders such as schizophrenia, depression, or cognitive impairment . The innThe vulnerability to develop psychiatric diseases later in life  involves not only the immune response of the brain, but also the changes in glial cell function , 90. ThuMajor depressive disorders are often associated with an increased inflammatory response of the brain. A study employing the serotonin transporter (SERT) mutant rats has shown that deletion of the SERT gene is associated with an increased level of proinflammatory cytokines and an increased number of activated microglia suggesting that the serotonin transporter dysfunction plays an important role in the pathogenesis of depressive disorders via an increased glial response to inflammatory agents , 93. MorThe progression of bipolar disorders is multifactorial and include the interaction between the neurotransmitters, neuropeptides, oxidative and nitrosative stress and cytokines, and neurotrophins including BDNF , 97. Mosin vivo  1H-MRS that was used to evaluate the postinjury evolution of 20 individual neurochemicals after traumatic brain injury (TBI) revealed a dramatic depletion of glutathione (GSH) and ascorbate (Asc), two endogenous antioxidants with the highest concentration in the central nervous system [The levels of several growth factors and metabolites are altered in cerebral tissue, cerebrospinal fluid (CSF), and serum of patients exposed to oxidative stress and can be used to assess risk factors or as potential biomarkers. Similarly, longitudinal s system . The folAlthough many of the cognitive and behavioral features of autism spectrum disorders (ASD) are associated with dysfunctions of the central nervous system, ASD also appears to be associated with systemic metabolic abnormalities such as oxidative stress and mitochondrial dysfunction –102. GluA recent meta-analysis of oxidative stress in schizophrenia suggests that red blood cells (RBC) SOD levels and to a lesser extent RBC catalase and plasma nitrites, were significantly decreased in acutely relapsed inpatients, first-episode psychosis, and stable medicated outpatients .Several markers of lipid peroxidation including the ubiquitous lipid peroxidation product, malondialdehyde (MDA), have been found to be significantly increased in ADHD patients. The study comprised 20 adult-ADHD patients and 21 healthy volunteers, to whom malondialdehyde levels were measured in plasma. The study evaluated indirectly the level of ROS and found that the mean plasma MDA levels of patients having adult-ADHD were significantly higher than those of the control group. The results suggest a relation between oxidative metabolism and adult ADHD .Studies conducted on postmortem tissue from depressed patients have shown reduced levels of hippocampal, an anatomical structure involved in anxiety and depressive behaviors, as well as cortical BDNF . In addiIn the periphery, a meta-analysis provided strong evidence that BDNF levels in serum of depressed subjects are lower as compared to those of the healthy controls. Further, the antidepressant treatment restored BDNF to normal levels .After adipose tissue, the organ with the highest lipid content is the brain and elevated serum levels of lipid peroxidation products have been often reported in bipolar disorders. Because the axonal membranes and myelin sheaths of the brain are rich in lipids, it has been proposed that lipid peroxidation products may be promising peripheral biomarkers of underlying white matter abnormalities in bipolar disorders (BP). A recent study combined diffusion tensor imaging and biochemical analysis of serum to examine relationships between measures of white matter integrity as measured by fractional anisotropy, radial diffusivity, and peripheral measures of lipid peroxidation, the lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE. The study suggests that serum LPH may be useful in the development of a clinically relevant assay for peripheral biomarkers of BD .Similarly, lipofuscin granule accumulation has been described in biopsies from patients suffering from major depressive disorder (MDD) indicating the impact of oxidative stress on neurovascular abnormalities in these patients .Mitochondrial dysfunction can also be detected in peripheral tissues. Although erythrocytes are considered as passive “reporter cells” for the oxidative status of the whole organism, decreased glutathione peroxidase activity (GPx) in RBC may be considered as a new peripheral marker for AD . SeveralOther classical markers of oxidative stress in plasma of early stage AD patients include thiobarbituric acid reactive substances (TBARS) as an index of lipid peroxidation, protein carbonyl content as an index of protein oxidation, the enzymatic activities of GPx, catalase (CAT), and superoxide dismutase (SOD) as well as the plasma levels of total glutathione (reduced GSH plus oxidized glutathione (GSSG) .Similarly, 4-hydroxynonenal (4-HNE), an alpha, beta-unsaturated hydroxyalkenal produced by peroxidation of polyunsaturated fatty acids, is widely recognized as a specific marker of oxidative stress both centrally and in the CSF and serum of PD patients –127.Likewise, several markers of lipid peroxidation including the ubiquitous lipid peroxidation product, malondialdehyde (MDA), have been found to be significantly increased in PD brains –131. TheOxidative stress and neuroinflammation are key factors contributing to aging of the brain. Many studies highlighted the importance of antioxidative defenses in the aging process , 137, buThe nuclear factor erythroid 2 related factor (Nrf2) is a dimer of the p45 protein and a member of the small Maf family proteins involved in the modulation of both antioxidant and anti-inflammatory signaling .in vitro study on primary cortical cultures has recently shown that prolonged expression of the transcription factor NF-E2-related factor 2 (Nrf2) induced by hypoxia and oxidative stress acts neuroprotectively against oxygen glucose deprivation. By inserting the Nrf2 gene in an inducible gene construct, a controlled, neuroprotective effect can be achieved by overexpressing Nrf2 not only during hypoxia but also after reperfusion [As cells are permanently exposed to a variety of oxidative stressors they must be able to trigger antioxidative signaling pathways in order to maintain redox homeostasis. To this end Nrf2 is activated, via phosphorylation, while under oxidative stress (such as in hypoxia/ischemia reperfusion or in neurodegenerative diseases) it is shuttled to the nucleus where it builds up a dimer with the small Maf. The activated complex in turn promotes the transcription of genes involved in neuroprotection. An erfusion .The key trigger to this neuroprotective cascade is the binding of Nrf2 to the antioxidant response elements (AREs) –142. TheInterestingly, recent studies have also shown that Nrf2/Hmox activation may enhance cell proliferation and survival in the subventricular zone (SVZ) of aged brains by reverting microglial phenotype into the proneurogenic phenotype , 148. WeOf these, omega-3 polyunsaturated fatty acid (PUFA) is one of the few compounds that are able to modulate the expression of genes involved in cell signaling, division, apoptosis, and oxidative stress . MountinA recent study investigated the antioxidant effect of alpha linolenic acid in adults and children with ADHD, DCD, and autism. Omega-3 polyunsaturated fatty acids were given as supplements to patients diet, and the changes in hyperactivity, attention, and other disruptive behaviors were analyzed. The patients who received flax oil  did show a significant improvement in the symptoms of ADHD reflected by a reduction in total hyperactivity scores . HoweverVitamins have also been used in clinical trials. A study was performed on patients over 70 years old, who were diagnosed with dementia and other cognitive dysfunctions . An imprIn human and animal models, the cognitive decline in vascular dementia is dependent on the hippocampal function. Recently, peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists were shown to diminish oxidative stress, inflammation, and apoptosis in the central nervous system , 158. PeTelmisartan is a special angiotensin II receptor blocker (ARB) and a partial agonist of the (PPAR-gamma). A recent study asked if telmisartan protects against cognitive decline in a rat model of vascular dementia. Indeed, it was found that telmisartan acts neuroprotectively against cognitive decline after cerebral ischemia by promoting anti-inflammatory and antioxidant effects , 160. InThiazolidinediones (TZDs) are still another potent synthetic agonists of PPAR-gamma that have been successfully used to diminish inflammation after cerebral ischemia . SimilarThe first study that used hyperbaric oxygen therapy to treat autistic children showed a significant level of improvement of autistic symptoms in 75% of patients . The res2S) is another gas recently used in several neuroprotective studies. H2S is a mild inhibitor of oxidative phosphorylation and can protect neurons after a stroke [Hydrogen sulfide  and in a rat model with permanent focal cerebral ischemia , respectively [α and malondialdehyde) and inflammatory cytokines (TNF-α and IL-6) was decreased [Two further studies showed that indeed hydrogen-rich saline can benefit the brain in a ectively , 170. Thecreased , 170.Healthy volunteers treated with lithium for a period of 2–4 weeks showed decreased superoxide dismutase levels and superoxide dismutase/catalase ratio as well as diminished hydrogen peroxide concentrations. Therefore, lithium has a potential role for neuroprotection in bipolar disorders and even in neurodegenerative diseases. Lithium seems to be the gold standard due to its ability to prevent/or reverse DNA damage, lipid peroxidation, and free radical formation . In addiA mechanism that implicates the oxidative stress in the appearance of depressive symptoms is the metabolism of the nitric oxide (NO). NO is generated by nitric oxide synthase (NOS) that catalyzes the metabolism of L-arginine to L-citrulline and nitric oxide (∙NO) in the presence of molecular oxygen and NADPH. NO is a gas that acts as second messenger in a number of organs, including the brain, and is also a free radical involved in the etiology and progression of many diseases.−) and thus may result in neuronal death due to increased nitrative/nitrosative stress. NOS can also generate superoxide when levels of the natural substrates L-arginine and tetrahydrobiopterin decrease [Neuronal NOS (nNOS) is a Ca2+-calmodulin-dependent isoform of NOS that is constitutively expressed in neuronal cells. A persistent expression of nNOS may result in an increased production of reactive nitrogen species (RNS), such as ∙NO and peroxynitrite  is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product uric acid is a powerful antioxidant. By examining the activity of XO in the occipital cortex and thalamus of patients with psychosis, the authors found a decreased activity of XO suggesting a downregulation of cellular defence mechanisms in schizophrenia .The available drugs currently in use either for research or therapeutic purposes for several brain diseases are shown in Here we reviewed many aspects of therapeutic strategies aimed to improve the neuroprotection and the function of the brain. Many preclinical models showed an increased neuroprotection to stressors like hypoxia. Although many promising drugs, in particular antioxidants, have been developed and shown to be beneficial to experimental animal models, the results of recent clinical trials investigating these promising drugs have been largely negative. As alluded to previously, the oxidative stress is a key contributor to neurodegeneration. Therefore, the antioxidant therapy is a novel therapeutic strategy and neuroscientists are increasingly interested in the participation of ROS towards the pathology involved in neurodegenerative disorders. It is, however, difficult to determine targets for treatment and to distinguish between what may be harmful or beneficial for the brain, without precise knowledge of the pathways involved in the progression of neuronal diseases .β, TNF-α, and COX-2 [Modulation of prooxidant-antioxidant balance plays an important role in mitochondrial dysfunction and provides an additional therapeutic option which can be used to improve neuroprotection and cognitive functions in response to oxidative stress. Anti-ROS drugs could probe pathological pathways associated with neurodegeneration psychiatric disorders. However, there are only few well-established drugs of such a kind and the risks and benefits are still not fully clarified. Most likely, multiple distinct pathways should be targeted for an efficient therapeutic purpose. Therefore it is not surprisingly that many drugs exert their beneficial effects on neurotransmission indirectly by modulating inflammation, oxidative stress, or apoptosis . Meta-annd COX-2 . However


Plant hormones are small molecules derived from various metabolic pathways and are important regulators of plant development. The most recently discovered phytohormone class comprises the carotenoid-derived strigolactones (SLs). For a long time these compounds were only known to be secreted into the rhizosphere where they act as signaling compounds, but now we know they are also active as endogenous plant hormones and they have been in the spotlight ever since. The initial discovery that SLs are involved in the inhibition of axillary bud outgrowth, initiated a multitude of other studies showing that SLs also play a role in defining root architecture, secondary growth, hypocotyl elongation, and seed germination, mostly in interaction with other hormones. Their coordinated action enables the plant to respond in an appropriate manner to environmental factors such as temperature, shading, day length, and nutrient availability. Here, we will review the current knowledge on the crosstalk between SLs and other plant hormones—such as auxin, cytokinin, abscisic acid (ABA), ethylene (ET), and gibberellins (GA)—during different physiological processes. We will furthermore take a bird's eye view of how this hormonal crosstalk enables plants to respond to their ever changing environments. Plant hormones are small molecules derived from various essential metabolic pathways. They play critical roles during all developmental stages in plants, from early embryogenesis to senescence. Research on plant hormones started as early as the beginning of the last century and has resulted in the discovery of auxins, ethylene (ET), cytokinins (CK), gibberellins (GA), abscisic acid (ABA), brassinosteroids (BRs), jasmonic acid (JA), salicylic acid (SA), and the recently identified strigolactones (SLs). The biosynthetic pathways of these plant hormones have been mostly elucidated, with some minor exceptions, such as some missing steps in SL biosynthesis. Generally, plant hormones exert their effect locally at or near the site of biosynthesis or are mobile between different tissues. The mechanisms of hormone crosstalk can be diverse. Hormone signaling pathways are known to interact at the level of gene expression. A common crosstalk strategy is to control specific key components of signaling pathways of other hormones  and broomrapes (Orobanche and Phelipanche spp.) since the sixties of last century . It was suggested that ABA may regulate SL biosynthesis . The A and B rings vary due to different side groups, while the C and D rings are highly conserved and seem to play an essential role in biological activity  in Arabidopsis , ramosus (rms) in pea (Pisum sativum), dwarf (d) or high-tilleringdwarf (htd) in rice (Oryza sativa), and decreased apical dominance (dad) in petunia (Petunia hybrida). All these mutants are defective in SL biosynthesis or signaling. They form the basis for the discovery of genes involved in the SL biosynthetic and downstream signaling pathways. Key catalytic enzymes in the SL biosynthetic pathway include DWARF27 (D27) /DAD3  shown increased transcript levels of the PIN1/3/4/6 genes and an increased auxin transport capacity in the primary stem when compared to wild type plants , and transport inhibitor resistant3 (tir3)  while a higher GR24 concentration (0.1–1 μM) reduced branching , is particularly expressed in the vasculature and nodal tissues near the axillary buds   Figure . ControvPsBRC1 mostly occurred in the axillary buds and was up-regulated by application of GR24 and down-regulated by CK treatment  in rice could only partially rescue the tillering phenotype of the SL signaling mutant d3  has evolved independent from SL signaling which may be explained by the fact that maize domestication is associated with a gain-of-function mutation in the TB1 gene  root (PR) and several orders of lateral roots (LR) . This is a complex region of the root tip including a stem cell niche (SCN), a proximal meristem (PM), and a distal meristem (DM) Figure . Cell dimax1, max3, and max4) and SL signaling mutant (max2) is shorter than in wild-type plants  located opposite of the xylem poles in the basal meristem (BM) of the parental root   and SL-insensitive (max2) mutants shown increased density of LRs compared with wild type  mutant and ET-resistant mutant aux1 exhibited decreased RH length  show reduced sensitivity to GR24, suggesting that SL signaling is not necessary for the ET response but ET signaling is involved in the SL response  shows reduced sensitivity to GR24 compared with the wild type upon RH elongation. Therefore, the effect of SLs on RH elongation is dependent on both auxin and ET biosynthesis and signaling while ET signaling also directly interacts with the auxin pathway , results in increased numbers of ARs (crown roots) as well as active crown root formation in the elongated node of the stem, suggesting that increased auxin production promotes AR development from both callus and stem  show that SLs negatively regulate AR formation , the AR formation is restored to the wild type level. This is consistent with the fact that MAX2 is expressed in vasculature tissues throughout the plant. The authors suggest that SL signaling in the xylem is sufficient to mediate the formation of pericycle-derived AR. Interestingly, etiolation is known to induce AR formation in hypocotyls and this process is stimulated in all max mutants. The expression of MAX3 and MAX4 in wild type hypocotyls is induced upon light exposure, suggesting that local SL biosynthesis is involved in the regulation of AR formation during the process of de-etiolation , results in a reduction in AR number even in the presence of elevated auxin levels (such as in 35S: YUC1 plants). The auxin response mutant auxin resistant 1 (axr1) and the axr1max1-4 double mutants hardly form ARs. Auxin application  increases the number of ARs in max mutants  displays reduced secondary growth  mutant seeds are insensitive to GR24. It was suggested that there is a butenolide-based signaling mechanism via KAI2 which is distinct from SL signaling, providing an adaptive response to smoke . During this response, plants are able to detect a decrease in the R:FR and initiate morphological changes that help plants to compete with their neighbors , which is suppressed by light-activated PHYB. COP1 not only controlled the transcription of PIN1 and the capacity of the PAT stream in the hypocotyls but also affected PIN1 and PIN2 intracellular distribution in the root tip thus affecting root elongation. This suggests that COP1 efficiently coordinates both root and shoot growth under changing light conditions , for example, is one of the essential macronutrients required by plants but only the inorganic phosphate (Pi) is the phosphorus form which is accessible for plants. As roots are the main site for Pi acquisition, plant roots usually cope with Pi-limiting conditions by investing more energy into root growth, resulting in reduced shoot/root ratio (including inhibited shoot branching), inhibited PR elongation and enhanced LR and RH growth  mutant, displaying reduced inhibition of PR growth and reduced LR and RH growth under Pi-limited conditions, shown less sensitivity to auxin and enhanced ability to sustain auxin response in the root tip than wild type plants under low Pi, suggesting that low Pi can increase the sensitivity of roots to auxin  by agricultural crops. Improved PUE is a highly desirable trait to which also root architecture contributes. Since SLs are involved in different plant developmental processes leading to plant architectural changes, including root architecture, more knowledge about their role, particularly under phosphate limiting conditions, is highly desirable. This includes the low phosphate mediated regulation of SL transport within the plant and the exudation to the rhizosphere as well as the local regulation of SL biosynthesis and transport in close vicinity to the buds.SL crosstalk with other plant hormones is still a research area in its infancy, certainly at the cellular and genetic level. As we have pointed out in this review, a common target for many plant hormones is the regulation of auxin levels and gradients through their effect on PINs. The exact mechanism of how SLs do this however still needs to be resolved. Because different hormonal and environmental signals also interact with each other this is very complex. Computational modeling and simulations may facilitate the interpretation of complicated datasets, leading to predictions or the establishment of new models.Finally, the intriguing structural diversity in SLs observed in plants and its relevance for differential regulation of various plant developmental processes is of great interest. Improved knowledge about SL perception and downstream signaling mechanisms will shed more light on the biological relevance of this structural diversity. The discovery of genetic variation and favorable alleles of genes involved in SL diversification and downstream signaling processes would be an interesting asset to future breeding programs as it will help to fine-tune SL action in such a way that maximum benefit is obtained in agriculture , without negative side effects (germination of parasitic weeds).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.