The purpose of this study was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease. For this review, a search was performed using several pre-defined keyword combinations and their equivalents: “diabetes kidney disease” and “renal failure” in combination with “diabetes treatment” and “oral antidiabetic drugs” or “oral hypoglycemic agents.” The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Diabetes treatment in patients with diabetic kidney disease is challenging, in part because of progression of renal failure-related changes in insulin signaling, glucose transport and metabolism, favoring both hyperglycemic peaks and hypoglycemia. Additionally, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions. The management of hyperglycemia in patients with diabetic kidney disease is even more difficult, requiring adjustment of antidiabetic agents and insulin doses. The health team responsible for the follow-up of these patients should be vigilant and prepared to make such changes; however, unfortunately, there are few guidelines addressing the nuances of the management of this specific population. Approximately 20–30% of patients with type 2 diabetes mellitus (T2DM) have renal impairment, classified as moderate-to-severe CKD (glomerular filtration rate (GFR) <60 mL/min/1.73 mGlycemic control in patients with kidney failure faces special challenges. According to the progression of CKD, changes in insulin signaling, glucose transport and metabolism are associated with accumulation of uremic toxins, inflammatory factors and oxidative stress, inducing insulin resistance and the response of target tissues to insulin signaling The management of hyperglycemia in patients with CKD is especially difficult, in part because of the treatment complexity and in part due to insufficient convincing data supporting the benefits of tight glycemic control in this subset of patients. Furthermore, inherent risks, including severe hypoglycemia and increased cardiovascular risk, should be considered when formulating therapeutic strategies The aim of this review article was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease (DKD).For this review, a search was performed using several pre-defined keyword combinations and their equivalents: “diabetes kidney disease” and “renal failure” in combination with “diabetes treatment” and “oral antidiabetic drugs” (OADs) or “oral hypoglycemic agents.” The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Only full-text manuscripts published in English were included in the study.Traditionally, insulin has been considered the safe choice for treating diabetic patients with kidney injury. Recently, new oral drug options have become good potential alternatives and traditional medications used in diabetes treatment have had their prescriptions and dosages reviewed.2, with dose reduction advised at 45 mL/min/1.73 m2in vivo; and also improving the free-radical defense system Usually, metformin is the initial pharmacological agent for type 2 diabetes treatment Sulfonylureas (SUs) are drugs that stimulate endogenous insulin secretion by pancreatic β cells. These drugs may potentially cause hypoglycemia, especially in association with high doses; omission or reduction of carbohydrate intake; alcohol abuse; hepatic dysfunction; heart failure; malnutrition; advanced age; and interactions with certain drugs that displace SUs from their plasma protein-binding sites 2Both repaglinide and nateglinide belong to a class of glinides, which are Su-like agents that stimulate insulin secretion but are rapidly absorbed, with a short duration of action, thus contributing to reducing postprandial hyperglycemia. Nateglinide (but not repaglinide) is hepatically metabolized, with renal excretion of active metabolites that are retained in DKD, so it should be used with caution in patients with advanced renal injury Alpha-glucosidase inhibitors reduce the rate of digestion and intestinal absorption of carbohydrates, resulting in mild reduction of glycated hemoglobin (A1C). Acarbose is metabolized nearly completely within the gastrointestinal tract, so less than 2% of an oral dose is recovered as the active drug or its metabolites in the urine. The other drug in this class, or miglitol, is absorbed systemically and excreted unchanged in the urine. Given their modest efficacy in glycemic control and the lack of long-term trials in patients with kidney disease, these medications should be avoided in CKD stages 4 and 5 Post hoc analysis from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) identified a greater decline in the eGFR with pioglitazone (between-group difference of 0.8 mL/min per 1.73 m(2)/yr) than with placebo Pioglitazone is a thiazolidinedione (TZD) antidiabetic agent that is a potent and highly selective agonist of peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action, such as the adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. The pharmacokinetic profile of pioglitazone was found to be similar between healthy subjects and patients with moderately or severely impaired renal function who did not require dialysis 2), without dose adjustments Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones by DPP-4, enhancing glucose-dependent insulin secretion. There are five available DPP-4 inhibitors, also known as “gliptins” , and despite their common mechanism of action, these agents have structural heterogeneity that translates into different pharmacological properties and different metabolism and excretion pathways The safety of this therapeutic class has been questioned after the release of a phase 4 trial showing increase in hospitalization for HF. Certain risk factors are associated with this higher HF rate, such as previous HF, a GFR of <60 mL/ min and increased levels of N-terminal pro-B-type natriuretic peptide (BNP) Incretin mimetics include glucagon-like peptide 1 (GLP1) analogs and agonists , which increase insulin secretion and suppress glucagon secretion in a glucose-dependent manner, with reduced risk of hypoglycemia. These mimetics also slow gastric emptying and suppress appetite via central nervous system modulations, resulting in a reduced body weight. However, the main side effects are nausea and vomiting. Exenatide is predominantly eliminated by glomerular filtration and its clearance is mildly reduced in patients with mild or moderate renal impairment, whereas in subjects with ESRD, its removal is significantly reduced. Lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation, resulting in smaller peptides and amino acids that are introduced into protein metabolism. However, data from patients with kidney disease are limited. In persons without diabetes, mild-to-moderate renal impairment did not appear to affect the drug's pharmacokinetics or safety, but drug exposure was increased in persons with severe renal impairment, suggesting the need for dose adjustment in this population. Finally, liraglutide is metabolized in a manner similar to that for large proteins and its elimination is not related to a specific organ. Currently, its prescription in patients beyond mild-stage renal disease is limited and there are no recommendations that support its use in the moderate and severe stages 2. To date, however, just canagliflozin has been evaluated, showing safety and efficacy in a subset of patients with stage 3 CKD The sodium-glucose cotransporter 2 (SGLT2) protein, expressed in the kidney proximal tubules, is able to reabsorb approximately 90% of glucose filtered through the glomeruli. A new generation of drugs called SGLT2 inhibitors act by lowering plasma glucose by promoting glycosuria and osmotic diuresis, thus directly reducing plasma glucose concentrations in patients with hyperglycemia. This therapeutic class has been approved for the treatment of patients with T2DM with an eGFR of ≥45 mL/min/1.73 mThe kidney also plays an important role in insulin clearance from the systemic circulation by distinct pathways. The first route involves glomerular filtration and subsequent absorption of insulin by proximal tubular cells through endocytosis. The second includes insulin diffusion through the peritubular capillaries and its binding to the contraluminal tubular membrane of cells and especially those located in the distal half of the nephron. As a result, insulin is transported by lysosomes and is metabolized into amino acids that are released into the peritubular vessels by diffusion, after which the final degradation products are reabsorbed Few studies have examined the pharmacokinetics of long-acting insulin in diabetic patients with CKD. Although patients with impaired kidney function have lower insulin requirements, no dose adjustment is required if the GFR is >50 mL/min Neutral protamine Hagedorn insulin (NPH) is known as an intermediate-acting insulin. Its time-action profile shows a typical peak within 4–7 hours after subcutaneous injection, and it is usually administered twice or three times daily Because of its pharmacokinetics and stable half-life, insulin glargine has a time-action profile of approximately 24 hours and should be prescribed as a once-daily medication Another long-acting insulin analog that is commercially available is insulin detemir, which has an onset of action of 1 hour and a time-action profile of 12–24 hours, and, depending on patients' sensibility, it can be administered once daily A new-generation basal insulin with an ultra-long duration of action, insulin degludec, was approved to be commercialized, but there has been just one study in patients with different GFRs Insulin lispro, insulin aspart and insulin glulisine are short-acting insulin analogs with very similar pharmacokinetic profiles. They are present either in monomeric or in very weakly bound hexameric forms, which are rapidly absorbed following subcutaneous injection. These insulin analogs usually reach their plasmatic concentration after approximately 60–90 minutes and have a duration of action of 3–4 hours The search for the combination of keywords related to short- and long-acting insulin analogs yielded a few studies in patients with renal insufficiency. However, one study that enrolled hospitalized patients with the objective of evaluating insulin doses and hypoglycemia frequency showed that after initial reduction of glargine/glulisine insulin weight-based dosing, there was a notable decline in hypoglycemic events, or a 50% reduction, without compromising glycemic control Intensive glucose control decreases the risk of microalbuminuria and macroalbuminuria, but evidence is lacking as to whether intensive glycemic control reduces the risk of clinically significant renal outcomes, such as doubling of creatinine, ESRD or death from renal disease during the years of follow-upDespite efforts to prevent morbidity and mortality in diabetes through guidelines and recommendations, a significant portion of the diabetic population still does not receive adequate care, as described by several reports auditing the quality of care The individualization of therapy, taking into account factors such as the presence of complications and other diseases, disease management capabilities, the CKD stage, the duration of disease, and previous glycemic control, among other factors, should be evaluated and may be considered as a safe and effective strategy for these patients The management of hyperglycemia in patients with DKD is even more difficult as a result of reduced glomerular filtration and its interference with glucose metabolism in many ways, favoring both hyperglycemic peaks and hypoglycemia. Additionally, renal failure impairs the clearance and metabolism of antidiabetic agents and insulin, thus frequently necessitating reassessment of prescriptions or adjustment of doses The dilemma of treating hyperglycemia in advanced kidney disease is how to balance tight glycemic control and harmful effects on the patient's safety. In other words, keeping glycemia within the normal narrow range to reduce the progression of the disease, improving quality of life, and minimizing comorbidities should be balanced, especially to avoid hypoglycemia, which is associated with increased cardiovascular risks. However, to date, the real benefits and impact of tight glycemic control in patients with long-standing diabetes and advanced CKD in particular are not yet fully known.Betônico CR conceived and designed the study and was responsible for the data acquisition. Titan SM, Correa-Giannela ML and Nery M were responsible for the data acquisition. Queiroz MS was responsible for the manuscript drafting, critical revision of the manuscript for important intellectual content and approval of the final version of the manuscript. All authors read and approved the final version of the manuscript.


Iron (Fe) is very abundant in most soils but its availability for plants is low, especially in calcareous soils. Plants have been divided into Strategy I and Strategy II species to acquire Fe from soils. Strategy I species apply a reduction-based uptake system which includes all higher plants except the Poaceae. Strategy II species apply a chelation-based uptake system which includes the Poaceae. To cope with Fe deficiency both type of species activate several Fe deficiency responses, mainly in their roots. These responses need to be tightly regulated to avoid Fe toxicity and to conserve energy. Their regulation is not totally understood but some hormones and signaling substances have been implicated. Several years ago it was suggested that ethylene could participate in the regulation of Fe deficiency responses in Strategy I species. In Strategy II species, the role of hormones and signaling substances has been less studied. However, in rice, traditionally considered a Strategy II species but that possesses some characteristics of Strategy I species, it has been recently shown that ethylene can also play a role in the regulation of some of its Fe deficiency responses. Here, we will review and discuss the data supporting a role for ethylene in the regulation of Fe deficiency responses in both Strategy I species and rice. In addition, we will review the data about ethylene and Fe responses related to Strategy II species. We will also discuss the results supporting the action of ethylene through different transduction pathways and its interaction with other signals, such as certain Fe-related repressive signals occurring in the phloem sap. Finally, the possible implication of ethylene in the interactions among Fe deficiency responses and the responses to other nutrient deficiencies in the plant will be addressed. Under Fr Figure . For thir Figure .Once adequate Fe has been absorbed, Fe deficiency responses need to be down regulated to avoid toxicity and to conserve energy. The regulation of these responses is not fully understood but several hormones and signaling substances have been proposed to participate in their activation, like auxin , ACS (ACC synthases) and ACO , the kinase CTR1 phosphorylates EIN2 , preventing the cleavage and translocation of the EIN2 C-terminal fragment into the nucleus. In the presence of ethylene, CTR1 is inactivated, resulting in dephosphorylation of EIN2 and its cleavage. The EIN2 C-terminal fragment is then translocated into the nucleus, where it participates in stabilization of the transcription factor EIN3 and downstream gene activation , EIN2, EIN3, EILs, and ERFs  and Fe2+ uptake capacity (due to increased expression of AtIRT1-like genes) , which contributes to Fe solubilisation , playing an opposite role to AtPYE  and dgl mutants. Upon treatment with ethylene inhibitors, these mutants lower Fe uptake and, consequently, avoid Fe toxicity symptoms  and the Fe2+ uptake capacity (depending on AtIRT1-like genes) can be regulated by ethylene through AtFIT, AtbHLH38, and AtbHLH39. Similarly, the acidification capacity  and other genes involved in phenolic synthesis, are dependent on the transcription factor AtMYB72  proteins participate in the synthesis of NA (nicotianamine), which is a chelating agent implied in the long-distance transport of Fe  and that facilitates the transport of Fe through the phloem to sink organs  show constitutive activation of Fe responses, even when grown under Fe-sufficient conditions  and AtFRD3 genes  to Fe-sufficient plants promoted them  in complete nutrient solution; however, neither of these mutants have full constitutive activation of Fe physiological responses .From the results above, several conclusions can be drawn. First, morphological and physiological responses can be differently regulated by ethylene. Second, for some morphological responses, like root hairs, ethylene acts through a signaling pathway including ETR1, CTR1, and EIN2 Figure . Third, ctr1 and ein2 mutants respond to both ACC  moving through the phloem, which could negatively interact with ethylene signaling to regulate Fe physiological responses  in Arabidopsis  from rice and the PS efflux transporter HvTOM1 from barley. The Fe3+-PS are taken up into root cells by Fe3+-PS transporters, like ZmYS1 (YELLOW STRIPE 1) and YSL (YELLOW STRIPE 1–like) transporters , of the MA (Mugineic Acid) family, which are synthesized from SAM  as well as genes implicated in PS efflux (TOM1) and Fe3+-PS uptake , several hormones  have been implicated in the regulation of its Fe deficiency responses  dependent manner, being induced higher in Cu-deficient spl7 mutant plants than in the wild type . This latter cross talk suggests that responses to biotic and abiotic stresses can share some common regulatory components. ISR is a mechanism by which selected plant growth-promoting bacteria and fungi in the rhizosphere prime the whole plant body for defense against a broad range of pathogens and insect herbivores (Pieterse et al., The participation of ethylene in the activation of most of the morphological and physiological responses to Fe deficiency in Strategy I species implies that it acts as a general coordinator of their control. Nonetheless, morphological and physiological responses seem to be regulated by ethylene through different signaling pathways. Additionally, several results suggest that ethylene acts in conjunction with other positive signals, like auxin and NO, and with negative signals, e.g., probable Fe-related repressive signals moving through the phloem. Ethylene has also been implicated in the regulation of some Fe responses in rice, that possesses combined characteristics of both Strategy I and Strategy II species. In Strategy II species, the few existing data do not support an important role for ethylene in the regulation of their Fe deficiency responses. The common involvement of ethylene in the regulation of responses to other nutrient deficiencies and in the regulation of the ISR, could partially explain the cross talk between Fe deficiency responses and responses to other deficiencies, and Fe deficiency responses and the ISR.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.


HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study  was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD.The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an  The default mode network (DMN) is a coherent network of spontaneous neural activity that is enhanced during tasks involving internal mentation such as autobiographical memory, self-referential thinking and mind-wandering . Analyses revealed significant negative associations between levels of 5-HT1A heteroreceptors and BOLD signal in the dorsal medial prefrontal cortex (mPFC) and PCC suggesting a modulatory influence of these receptors on DMN connectivity in these regions. Another study found that peripheral platelet serotonin uptake velocity  was negatively correlated with DMN activity in the mPFC , but only two previous studies have examined the association between the genetic variation within this system and DMN connectivity. Wiggins et al. , while others have found positive associations  and Reuveni et al., N = 20 or a mixed pattern . Given the foregoing evidence for the modulatory influence of genes and serotonin on the DMN, we wondered if some of the variability in results observed across studies might relate to previously unaccounted for genetic variation in serotonin signaling and hypothesized that serotonin receptor gene SNPs would moderate associations between PTSD and DMN connectivity. We recently examined the effects of blast exposure and mild traumatic brain injury (mTBI) on DMN connectivity using the cohort on which this report was based (N = 134) and found blast exposure to be associated with reduced connectivity in the bilateral primary somatosensory and motor cortices; however, associations between PTSD and DMN connectivity were not thoroughly examined . Most veterans had served in the Army (63.7%), but the Marines (23%), Air Force (8.9%), Navy (3.7%), and Coast Guard (0.7%) were also represented. Additional clinical characteristics can be found in Robinson et al. , and unstable psychological diagnosis that would interfere with accurate data collection. Additional MRI exclusion criteria included pregnancy and having a metal implant, shrapnel, aneurysm clip, or pacemaker. Of those who were genotyped and had DMN data, 154 were of self-reported White non-Hispanic (WNH) ancestry. Ancestry was confirmed via genetic principal components (PC) analysis of genome-wide SNP data  and eight subjects were dropped because they had PC values > 6 standard deviations away from the mean for WNH subjects. An additional 11 subjects were omitted from analysis due to excessive motion during the restating state scan. Of the remaining 135 participants, 124 (91.9%) were male and their mean age was 31.39  from each hemisphere. These were: bilateral isthmus of the cingulate, angular gyrus, middle temporal gyrus (MTG), and medial pre-frontal cortex  who also had DMN and clinical data available for analysis. DNA was isolated from blood on a Qiagen AutoPure instrument using Qiagen reagents and samples were normalized using PicoGreen assays (Invitrogen). Genotyping was based on the Illumina HumanOmni2.5-8 microarray and scanned using an Illumina iScan System . Of the 7 candidate SNPs implicated in meta-analyses of relevant psychiatric traits, 4 were on the Omni2.5 chip  and the other three  were imputed from 1000 Genomes . For these analyses, all genotyped SNPs within 5 kb of the gene boundaries were analyzed. Additional details on genotype call rates, evaluation of biological sex and imputation are available in the Supplementary MaterialGenetic association analyses were conducted using a subset of ancestrally homogenous participants  along with the covariates age, sex, and the first two genetic PCs. The SNPs were evaluated individually in a second block and each phenotype × SNP interaction (with corresponding main effects included in the model) was examined in a third. Both nominal (uncorrected) significance and multiple-testing corrected significance  for main effects and interactions were determined using Monte-Carlo null simulation with 10,000 replicates in which the SNP data were randomly permuted between subjects. This analysis imposed strict multiple-testing control while taking into account the correlations between SNPs and between the eight DMN variables. Analyses of potential confounding variables were examined in post-hoc analyses using the same model.All variables were screened for outliers. This process identified one multivariate outlier that was >3.0 Descriptive statistics for the primary study variables are listed in Table p < 0.002) and within the PCC-left MTG circuit  with women showing greater DMN connectivity in both components compared to men but no PTSD main effect . When the seven candidate SNPs were entered in the second block of the analysis, results showed a significant main effect of rs130058 (HTR1B) on connectivity between the PCC and right angular gyrus with carriers of the A (minor) allele tending to show reduced connectivity within this region compared to others (see Table HTR2A) and both the right mPFC  and right MTG components . We then examined the generalizability of the rs7997012 × PTSD severity effect to a clinical diagnosis of PTSD by repeating the analysis using this one SNP and a dichotomous current PTSD diagnosis variable and found a significant interaction involving the right MTG component that survived multiple testing correction across the 8 DMN components . Decomposition of the rs7997012 × PTSD severity interaction revealed no significant simple effects, though there was a non-significant trend toward a negative correlation between PTSD severity and right mPFC connectivity  among individuals who were homozygous for the G-allele.In the first block of the genetic association analysis, the eight DMN variables were regressed onto age, sex, the two genetic PCs and PTSD severity. Results showed a significant main effect of sex on connectivity between the PCC and the left mPFC  insufficient for meaningful post-hoc analysis, we then repeated the original analysis using data from men only and found the same pattern of results with similar multiple-testing corrected effects. We also examined the effects of potential confounding variables by repeating the rs7997012 × PTSD severity analysis using the PCC-right mPFC component as the sole dependent variable with blast exposure, current major depression, antidepressant medication status, and combat exposure included as covariates. None of these covariates contributed significantly to the model and the rs7997012 × PTSD severity interaction term remained significant (p = 6 × 10−5). Finally, in a separate analysis controlling for age, sex and the two PCs, we examined the association between these seven SNPs and PTSD and found no significant SNP effects.Given the main effect of sex observed in the first block of the initial analysis, but a female subsample size (HTR1B SNPs and 88 HTR2A SNPs) using the same approach. This analysis revealed two PTSD × SNP interactions that survived correction for multiple testing across the 99 SNPs and 8 DMN components included in the analysis. Specifically, HTR2A SNPs rs977003 and rs7322347 moderated the association between PTSD severity and reduced connectivity of the PCC-right MTG component (Table pcorrected = 0.0503), while the interaction involving the right MTG component fell farther out of range.  but not controls . Finally, as with the candidate SNP analysis, we then performed a separate analysis examining the association between each of the 99 SNPs and PTSD and found no multiple testing-corrected effects.Because rs977003 and rs7322347 are in high LD (p = 0.00375) and in the same direction as the PTSD × rs977003 effect. However, when both interaction terms were entered into the same model, the PTSD interaction remained significant  while the depression interaction did not .In light of prior evidence (reviewed earlier) for the influence of close-range blast exposure, anti-depressant medication use and major depression on DMN connectivity, we then examined the specificity of the rs977003 × PTSD interaction by substituting each of these variables, in turn, for PTSD as the interaction term of the model in separate analyses. Neither blast exposure nor anti-depressant medication showed significant main effects or interactions with rs977003 in predicting right MTG connectivity. In the major depression model, the diagnosis × rs977003 interaction was significant  emerged as significant moderators of the association between PTSD and DMN such that individuals with PTSD who were homozygous for the minor allele of these SNPs showed reduced connectivity within the PCC-right MTG component of the DMN.This study examined the hypothesis that serotonin receptor gene variants moderate the association between PTSD and DMN connectivity and, to our knowledge, was the largest DMN study of PTSD conducted to date, as well as the first to examine associations between serotonin receptor genes and DMN connectivity in any sample. On the basis of prior evidence for a modulatory role of the serotonergic system on DMN activity, we began by examining candidate SNPs in the *D; Peters et al., rs7997012 is the best-known of the 3 SNPs implicated in this study and has been the focus of ~1 dozen studies of anti-depressant medication response  that moderated the association between PTSD and DMN connectivity in the The primary DMN component implicated in this study was connectivity between the PCC and right MTG. Structurally, these regions are inter-connected by white matter fiber bundles . This showed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was strongest within portions of the middle and inferior temporal gyri. Unexpectedly, this analysis revealed a new cluster in the occipital cortex, showing the opposite effect, which was not found in the original analyses because it is not part of the DMN . These regions have well-established roles in the processing of visual stimuli, yet in the context of a resting state scan the functional significance of connectivity in this region is not obvious. However, one theoretical process that could potentially account for this finding is These findings should be considered in light of several study limitations including the cross-sectional assessment and ancestrally homogenous and predominantly male sample. The DMN component implicated in our findings was functionally and anatomically distinct from the region where we reported associations with close-range blast exposure in a prior study using the same cohort (i.e., the somatosensory and motor cortices; Robinson et al., 2A receptor on DMN connectivity. More broadly, they contribute to an extensive literature on the role of the 5-HT2A receptor in neural mechanisms of cognitive control and the modulation of anxiety (Aznar and Klein, In conclusion, research on the genetics and neurobiology of PTSD has historically focused largely on identifying risk factors that give rise to the syndrome through their interaction with trauma exposure. In this study, we focused instead on identifying genetic variants that modify the association between a hypothesized endophenotype of PTSD and the clinical diagnosis with the hope that doing so will advance our understanding of sources of individual variability in the association between the putative biomarker and the phenotype. Results add to a growing body of research suggesting a modulatory influence of the 5-HTMM and ES designed the study, analyzed the data, interpreted the results, and wrote up the findings. MR, NS, EW, JH, ML, SS, AS, WM, and RM helped interpret the results, revised the work, and approved the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.ES, MR, NS, EW, JH, ML, SS, AS, WM, and RM 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. MM owns stock in Illumina, Inc.


Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. Frontotemporal dementia (FTD) is the second most common cause of dementia in the presenile age group (<65 years of age), and accounts for 5–15% of all cases of dementia, with a prevalence of 10–15 per 100,000 subjects in the age group of 45–65 years , the agrammatic variant of primary progressive aphasia (avPPA), and the semantic variant of PPA (svPPA) Mesulam, . MoreoveMAPT) gene on chromosome 17 were identified in families with FTD and parkinsonism  gene .In 2006, the second FTD-related gene on chromosome 17 was discovered in the progranulin (C9orf72) gene  gene, which cause inclusion body myopathy with Paget disease of bone and FTD  gene, involved in the endosomal–lysosomal pathway        genes  , characterized by the relative selective degeneration of the frontal and temporal lobes, is used to describe the pathological hallmarks of the disease. Abnormal intracellular accumulation of insoluble proteins have been identified with immunohistochemical techniques and, according to the predominant neuronal inclusions, FTLD cases have been categorized into several types  inclusions were identified as the predominant hallmark of the originally identified ubiquitin positive inclusions, which were termed FTLD-U  have been proposed based on the location of these inclusions  or three isoforms with three repeats each (3R), respectively   often shows reduced frontal and/or temporal hypometabolism, which resembles the patterns observed in sporadic FTD  is altered in MAPT mutation has demonstrated a classic frontotemporal distribution characteristic of inherited tauopathies  , and ALS, concluding that rs5848 was associated with an increased risk of AD and PD in the homozygous and recessive models but not with FTLD  and in a single case of limb onset sporadic ALS (p.T182M)  , hypoperfusion of the hippocampus and that of the cingulate gyrus have been observed, denoting the association of these regions with the pathogenesis of GRN group, differences were observed between carriers and non-carriers in the insula at 15 years before expected onset, then in the temporal and parietal lobes at 10 years before expected onset, with the earliest subcortical area affected being the striatum at 5 years before expected onset. GRN mutation carriers also showed significantly greater asymmetry than non-carriers at 5 years before expected onset  was associated with decreased connectivity within the ventral salience network  and the left frontoparietal network   affected by FTD-ALS, with the intuition that the repeat expansion, which was identified in the parents but not in the affected children by using fluorescent PCR, was too large to be amplified by the PCR method and could only be identified by repeated-primed PCR assay and Southern blot analysis  proteins which are the result of the bidirectional translation of the non-coding GGGGCC expansion repeat through a mechanism of non-ATG-initiated translation, termed RAN translation , or might even lack TDP-43 pathology  and antisense (GGCCCC) repeat RNA and DPR proteins, the relative contribution to these mechanisms and the molecular pathways that lead to neurodegeneration are yet to be elucidated  carriers , and comparable in frequency to GRN mutations in familial FTD cases , with about 50% patients affected by age 60 and with a penetrance reaching 90% at age 70. Disease duration is also variable, ranging from 1 to 22 years, with the development of ALS as a strong negative prognostic factor   family of proteins and is involved in multiple cellular processes, including protein degradation via both proteasome and autophagy pathways, in membrane fusion, transcriptional activation, apoptosis, and molecular chaperoning  is a ubiquitously expressed and highly conserved ribonucleoprotein, encoded by the TARDBP gene as causative for both familial and sporadic ALS provided additional proofs for the pathogenic role of TDP-43 in neurodegeneration  on the second exon of TREM2 mutations as risk factor in FTD patients, confirming that the Q33X, R47H, and T66M mutations were significantly associated with the disease and absent in healthy subjects  and FTLD-TDP , although it is occasionally associated with FTLD-FUS (found in FUS mutations only in MND/ALS), FTLD-U (found in CHMP2B mutations) and the newly identified FTLD-DPR in C9orf72 mutations.Neuropathology is variably associated with two predominant hallmarks, namely FTLD-tau , which is variably associated with MND/ALS. MAPT mutation carriers often present with a very early age of onset bvFTD, associated with parkinsonism, which is a common feature later in the disease course in all types of genetic FTLD. GRN mutations carriers frequently present with bvFTD, avPPA, and concomitant CBS at onset. TARDBP sequencing should be performed in familial or sporadic C9orf72 negative FTD-MND/ALS cases. The association of inclusion body myopathy and Paget’s disease are indicative of VCP mutations (Rohrer and Warren, As previously outlined, frequently there is poor correspondence between the type of mutation or neuropathological feature and the clinical phenotype; indeed, neuropathology is predicable only in known genetic defects and few clinical or neuroanatomical features have a specific molecular association (Rohrer et al., GRN mutations, while relative symmetric atrophy with particular involvement of the anterior temporal lobes is indicative of MAPT mutations (Rohrer et al., C9orf72 mutation carriers tend to have a more generalized and symmetrical atrophy (Rohrer et al., In addition to these distinct clinical features, from a neuroimaging perspective, strikingly asymmetric interhemispheric atrophy with frontoparietal involvement is indicative of in vivo biomarker that can accurately predict the underlying neuropathology and consequently point out which gene should be analyzed, but a clear-cut association between clinical or neuroradiological features and characteristic histological inclusions has not been yet established (Kim et al., GRN mutations, and should be performed before GRN sequencing (Finch et al., 181 to total-tau ratio appears to predict FTLD-TDP pathology with high accuracy, thus leading to the search of genes associated with TDP-43 neuropathology (Hu et al., Numerous attempts have been made to identify an in vivo biomarkers is mandatory for guiding genetic screening, for defining distinctive therapeutic approaches and helping in patients’ selection in future clinical trials.Considering the vast clinical, genetic, and pathological heterogeneity associated with this disease, the development of accurate 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.


Salmonella enterica serovar Typhimurium  by bacterial lipopolysaccharide (LPS) and recognition of bacterial peptidoglycan by NOD1 and NOD2 , 10. TLRM. tuberculosis and Salmonella Typhimurium inhibit autophagy initiation signaling upstream autophagosome formation .Xenophagy is a defense mechanism of the infected cell against invading bacteria, but intracellular pathogens have evolved mechanisms to inhibit or modulate the autophagy response of the host. For example, ormation , 15, whe surface  . These bacteria show defective replication in autophagy-deficient cells, and treatment of host cells with autophagy activators promotes bacterial replication. This observation raises the question, why a pathogen would increase a host defense mechanism like autophagy? In uninfected cells, augmentation of the autophagy rate is used to increase the intracellular pool of basic nutrients, to build new cellular structures. During infection, some intracellular bacteria have developed mechanisms to hijack the autophagosomes and redirect the by-products of the autophagic degradation toward microbial replication rather than for the use by the host cell , which accumulates autophagy markers  are decorated with the autophagy proteins LC3, Beclin1, and Rab24, and overexpression of LC3 or Beclin1 increases the number and size of the CRVs . BCVs hijack autophagosome initiation factors, such as ULK1 or Beclin1, and become autophagosome-like compartments  that recruits vesicles emerging from the endoplasmic reticulum (ER) and acquires autophagy markers like LC3, showing that LCVs rapidly become autophagosomes , and pyrazinamide (PZA), although able to kill the bacteria directly in vitro  and a host-deleterious “metabolic-related” induction of autophagy by invading bacteria for nutritional theft of host energy resources. Results of clinical trials using autophagy modulators and a more profound understanding of the role of autophagy during infection are thus needed to correctly use autophagy modulators in the fight against infectious diseases.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Aphis glycines Matsumura) is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of “metabolic hijacking” by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor.The soybean aphid ( Plants deploy biochemical and molecular strategies to deter feeding by insect herbivores. The plant hormones salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) coordinate the deployment of biochemical defense against pathogens, insect pests and abiotic stresses . SA is mHerbivores that feed on phloem, such as members of the insect order Hemiptera (including aphids), avoid triggering defense responses related to mechanical damage. Salivary effectors are able to inhibit occlusion of sieve elements . In addiAphis glycines Matsumura) is a significant pest of soybean in North America that can reduce yield by up to 40% if left untreated [Rag1 resistance gene, and a slower response in susceptible plants, with a strong SA-dependent response observed in both cases [The soybean aphid , feth cases . An analth cases . Moreoveth cases . A biointh cases , 19.Metabolome analyses have also provided some insight into the metabolic changes that occur when SBA and soybean interact. Soybean plants produced a series of volatile compounds after colonization by SBA, including methyl salicylate that attracts predators of the SBA . Thus, Sα-DOX1expression is induced in response to aphid colonization in Arabidopsis and tomato, and α-DOX1 knock-down results in increased susceptibility to aphids in both plants [SSI2 gene, which encodes a plastidyl stearoyl acyl-carrier protein desaturase that catalyzes the synthesis of oleic acid (18:1), causes enhanced resistance against Myzus persicae [ssi2-dependent resistance also requires the activity of MYZUS PERSICAE-INDUCED LIPASE1 (MPL1), an estearase/lipase that is induced by aphid infestation in Arabidopsis [Plant lipids are an important component of the response to aphid attacks (reviewed in ). Linoleh plants . In addipersicae . This ssbidopsis . DespiteHeterodera glycines) and brown stem rot (Cadophora gregata). Heterodera glycines, a parasitic nematode that colonizes soybean roots, is the leading yield-reducing pathogen of soybean [Cadophora gregata is a common fungal pathogen of soybean that infects the root system and later moves to the stem, causing the brown stem rot disease and a reduction in the movement of nutrients [H. glycines and C. gregata have been shown to undergo plant-mediated interactions with SBA when soybean is infected with all three pests [Due to its economic importance, the interaction between soybean and SBA is an attractive model for the study of plant-aphid interactions. Our objective was to characterize the effects of SBA infestations on the fatty acid metabolism of soybeans. To determine the specificity of those effects, the impact of SBA was compared to the plant’s response to two other soybean pests, the soybean cyst nematode  to SBA infestations in a field environment. There were six different treatments: 1) aphid infestation where the population was left to develop without limit (SBA:unlimited); 2) aphid infestation where the population was left to grow to 250 aphids per plant and then sprayed with insecticide to simulate recommended management practices (SBA:250); 3) infestation of soybean plants with only the soybean cyst nematode via the soil (SCN); 4) infection with only brown stem rot fungus via the soil (BSR); 5) a combination of the SBA:unlimited, SCN, and BSR treatments (SBA:SCN:BSR); and 6) control, where plants were left untreated and free of all pests. Estimates of SBA and SCN populations and BSR disease severity ratings are shown in The youngest fully-developed leaf from plants exposed to each treatment were collected near the peak of aphid infestation, when plants were at late reproductive (R4-R5) growth stage, and fatty acid composition was determined. Multivariate analysis of fatty acid data for soybean leaves collected over the two seasons (2008 and 2009) revealed a significant (P<0.05) treatment effect on fatty acid levels . There wMultivariate analysis indicated that there were significant correlations among leaf fatty acid levels. In particular, palmitic acid and linolenic acid showed a strong and significant negative correlation. Palmitic acid also showed smaller but significant negative correlations with stearic and linoleic acids. A small significant positive correlation between stearic and linoleic acids was also observed. These results illustrated that the levels of individual fatty acids are not independent variables .Aphid infestation had a strong effect on the relative levels of fatty acid of soybean leaves . UnlimitWe also wanted to know if plants that had been infested with aphids early in the season and then treated with insecticide, following integrated pest management (IPM) recommendations, would still show symptoms of aphid infestation at the metabolic level when seeds start developing. To address this question, plants infested with aphids were treated with insecticide when aphid populations reached 250 aphids per plant (SBA:250). These insecticide applications occurred before leaves were removed from the plant for fatty acid analysis, and these plants were kept free of aphids with additional insecticide applications as needed. Fatty acid analyses of leaves collected at the R4 stage (i.e. beginning pod fill) showed that this treatment, unlike uncontrolled aphid colonization, had no statistically significant effect on any fatty acid level .Changes in leaf fatty acid profiles could be an aphid-specific response or part of a general defense mechanism against pests. To test these possibilities, we analyzed the fatty acid profiles of plants infected with the fungal pathogen causing brown stem rot (BSR) disease or the soybean cyst nematode (SCN). Neither the BSR fungus nor SCN had a significant effect on leaf fatty acids .We also analyzed the effect of a multiple pest combination (SBA:BSR:SCN) on fatty acids. There was a significant increase in palmitic acid level in leaves of plants subjected to the three treatment combination compared to the control . In the Soybean oil is an important economic resource, and its fatty acid composition has been the target of traditional breeding and biotechnology approaches aimed at improving its quality and usability for food and non-food applications , 34. SinUnlimited aphid infestation resulted in a significant decrease in the levels of linoleic and linolenic acids in seeds similar to the effect observed in leaves , althougRoot colonization by SCN and BSR fungus infections had no significant effect on the composition of seed fatty acids . The comOur analysis of fatty acid composition revealed that palmitic acid in the leaves increased significantly when the plants were infested with aphids  while thAs expected, a correlation of PUFA content versus palmitic acid in the leaves revealed a very strong, negative relationship with a correlation coefficient of -0.99 . This giIn seeds, there was a strong negative correlation between PUFAs and both stearic acid and oleic acid. Correlation of PUFAs with oleic acid was consistently observed each year and showed a coefficient of -0.88 , with 77Based on these results, it is possible to hypothesize that, following aphid infestation, a block in the production of linoleic and linolenic acids results in the increase in palmitic acid in leaves; while a block in the same pathway results in an increase in stearic and oleic acids in seeds.Fatty acids are a group of biomolecules that play important roles in all living organisms. They are major components of cellular membranes, where they confer fluidity and selective permeability, and they also serve as a source of reserve energy . Free faHeliothis virescens) feeding on tall goldenrod, Solidago altissima, caused an increase in the levels of linoleic and linolenic acid in damaged leaves compared to the undamaged controls [fad3-2 fad7-2 fad8) defective in linolenic acid production was highly susceptible to the larvae of the fungus gnat Bradysia impatiens compared to the wild type plants that contained normal linolenic acid levels [DHS1, PAL1 and AtVSP, genes involved in plant defense and wound response [In this study, we found that long-term aphid infestation results in a significant reduction in the amount of PUFAs in the leaves of soybean. The reduction in relative levels of PUFAs after long-term aphid colonization is different from the effects observed in other plant-insect interactions. For example, a generalist tobacco budworm caterpillar  or desaturation of oleic acid to linoleic acid in the endoplasmic reticulum and chloroplast . The desaturases FAD2 and FAD6 are structurally similar ; hence i-1; and “SBA: 250”, where the population was left to increase to 250 aphids plant-1 and then sprayed with lambda-cyhalothrin  to simulate the recommendations for soybean aphid management [The experiment was conducted during 2008 and 2009 at the Iowa State University Horticulture Research Station north of Ames, in Story Co. Iowa. A detailed description of the field experiment is reported in McCarville et al. . Brieflynagement . In bothnagement ). Once tLeaf samples were collected six weeks after aphid infestation when aphid populations were peaking inside the cages. By this time, the plants were at the R4-R5 growth stage  and we hLeaf and seed samples from individual plants for each treatment (6 replicates for 2008 and 5 replicates for 2009) were finely ground using a mortar and pestle in liquid nitrogen prior to fatty acid extraction. Fatty acid extraction was based on a general method described by Hammond and Fehr  and HammFatty acid data were analyzed using multivariate analysis of variance (MANOVA) , with a confidence interval of 95%. Individual fatty acids were then analyzed using analysis of variance (ANOVA) with Bonferroni correction to account for multiple comparisons, thus using a confidence interval of 99%. Means comparisons were carried out using Tukey’s range test .S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S3 Appendix(PDF)Click here for additional data file.S4 Appendix(PDF)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.


The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA  and vWF concentrations . In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients. Several recent studies have shown that BH4 levels may be modified by genetic variability of the GTP-cyclohydrolase 1 (GCH1) gene located on chromosome 14 in humans and encoding a rate limiting enzyme in the complex process of tetrahydrobiopterin synthesis Atherosclerosis and its clinical manifestations, such as myocardial infarction and stroke, are the major causes of mortality in type 2 diabetes mellitus (T2DM) patients The study population consisted of 182 consecutive patients diagnosed with T2DM and followed up in an outpatient setting at the Department of Metabolic Diseases, University Hospital, Krakow, Poland. During patient recruitment, the WHO definitions and criteria of diabetes diagnosis were used Endothelial function was assessed by flow mediated dilation (FMD) measurement as described and validated by our laboratory before Measurement of IMT was performed as previously described MDA in plasma was determined using liquid chromatography with mass detection . These tests were performed at the Department of Pharmacology JUMC by a modified method described by Sim et al. Polymorphisms in the GCH1 gene were selected for genotyping based on the existing literature Polymorphisms rs10483639, rs841, rs3783641, rs10137071, and rs8007267 were determined using commercially available kits ABI TaqMan SNP Genotyping pre-designed assays . End-point fluorescence was determined using Applied Biosystems 7900HT Fast Real-Time PCR System .Data for statistical analysis were analyzed with SAS ver. 9.3 . Deviations of genotype frequencies of studied polymorphisms from Hardy-Weinberg equilibrium were tested using a modified Chi-square test, implemented in the SAS Genetics module. An extent of LD between the studied polymorphisms was calculated and presented graphically with Haploview ver. 4.1. Patients with different genotypes were compared for differences in continuous variables using the Wilcoxon test and in categorical variables using Chi-square or Fisher's exact test. To compare the effect of polymorphisms and haplotype blocks on quantitative outcome variables, we used PLINK ver. 1.06 with association tests based on Wald statistic. Univariate tests of association were used for individual polymorphisms and haplotype blocks, multivariate tests for combinations of polymorphisms and clinical variables. The following clinical variables, potential confounders of association between genetic factors and outcome variables, were tested: age and sex of patients, characteristics of T2DM, risk factors of atherosclerosis and medication used. P values of less than 0.05 were considered statistically significant.Clinical characteristics of patients are summarized in The physical location of 5 genotyped polymorphisms on chromosome 14 is described in We next studied the associations between each of the 5 genotyped SNPs, as well as each of the 2 haplotype blocks formed by these SNPs, with outcome variables . PolymorAssociation of each of the two described above haplotype blocks with studied outcome variables was determined using omnibus haplotype association tests with studied variables .Haplotype analysis showed that MDA concentration was associated with both haplotype blocks while vWF concentration was associated only with the first haplotype block. This is in line with the analysis of associations of individual polymorphisms with outcome variables. In addition, we observed that association of both haplotype blocks with MDA concentration was less significant than the ones of individual polymorphisms. However, in case the of vWF concentration, the association of the first haplotype block was more significant than that of any individual polymorphism. There was no significant association between the haplotype blocks and FMD values.In addition to single polymorphism analyses and haplotype block analyses, we have also tested whether clinical covariates, described in the Statistical Analysis paragraph of the In the present study we have found that polymorphisms in the GCH1 gene, that can affect tetrahydrobiopterin synthesis, are associated with markers of endothelial dysfunction and oxidative stress. This is important, as both endothelial dysfunction and oxidative stress in T2DM patients are the major mechanisms for the development of both micro- and macro-angiopathy. Further studies are required to determine if the same association of polymorphisms is true for patients with type 1 diabetes. Expanding this study to include a group of healthy, non-diabetic control subjects could also verify whether the described associations of polymorphisms with endothelial dysfunction and oxidative stress also remain significant during normoglycemia or are specific to diabetic patients only.GCH1 gene locus have been initially shown in relation to the role of BH4 in catecholamine and serotonin synthesis GCH1 lead to hyperphenylalaninemia Functional effects of polymorphisms located in the A number of studies have looked at cardiovascular disease in relation to the GCH1 genetic variation. Zhang et al. In the present project, we have studied 5 polymorphisms spread throughout the gene, which has allowed us to look at variation in the GCH1 gene. Careful examination of the structure of LD in the Polish cohort of T2DM patients showed that these polymorphisms belong to two separate haplotype blocks, in agreement with our analysis of HapMap data. A previous study reported the existence of various numbers of haplotype blocks in the GCH1 locus, depending on the population studied We found that only one of the polymorphisms, rs841, was associated with impaired endothelium dependent vascular dilatation while no relationship was observed with non-endothelium dependent responses. This is in agreement with previous reports of the functional effects of this polymorphism on vascular function in T2DM. Subsequently, we found that three polymorphisms, which form the first haplotype block, were also associated with biomarker plasma vWF concentration, which clearly confirms the functional importance of the GCH1 gene variability in the regulation of vascular function in T2DM.The major mechanism through which the GCH1 gene could affect endothelial function is eNOS uncoupling, which is directly linked to oxidative stress. Four polymorphisms, three constituting the first haplotype block and one from the second haplotype block, are associated with MDA plasma concentration. Moreover, the first haplotype block was even more strongly associated with this variable than any of the analyzed SNPs. This finding suggests that the first haplotype block may contain a non-genotyped polymorphism affecting MDA concentration. Therefore, this would be a stronger association than any of the polymorphisms previously genotyped by our group. An alternative explanation to this finding could be an epigenetic interaction between studied polymorphisms or other polymorphisms in haplotype block 1, modifying the presence of CpG islands in this locus, thereby affecting methylation pattern and expression of GCH1. Such a possibility was demonstrated at other loci We also tested whether associations defined in this study could have been confounded by clinical factors. The only clinical variable associated with the outcome variables of MDA and vWF concentrations (but not with FMD), was the current smoking status. However, further statistical analysis has shown that the association of SNPs with outcome variables was not confounded by smoking, renal dysfunction, or diabetes duration. In summary, GCH1 polymorphisms or haplotype blocks are associated with FMD, malondialdehyde, and von Willebrand factor concentrations, independently of other clinical characteristics in Polish T2DM patients.Interestingly, in our T2DM study group we did not observe an association between GCH1 genetic variation and IMT, which has been reported previously Macrovascular complications are responsible for mortality excess and lower quality of life in T2DM patients. Their occurrence may be accelerated and exacerbated by a deficiency in NO production Apart from the correction of NO availability, another important strategy for preventing complications in diabetic patients could be to reverse endothelial progenitor cell dysfunction In summary, the results of our study indicate that functional polymorphisms of the GTP cyclohydrolase I gene, which directly affect tetrahydrobiopterin synthesis, are associated with endothelial dysfunction and oxidative stress in T2DM patients.


In this review, we compare knowledge about the recently discovered strigolactone signaling pathway and the well established gibberellin signaling pathway to identify gaps of knowledge and putative research directions in strigolactone biology.Communication between and inside cells is integral for the vitality of living organisms. Hormonal signaling cascades form a large part of this communication and an understanding of both their complexity and interactive nature is only beginning to emerge. In plants, the strigolactone (SL) signaling pathway is the most recent addition to the classically acting group of hormones and, although fundamental insights have been made, knowledge about the nature and impact of SL signaling is still cursory. This narrow understanding is in spite of the fact that SLs influence a specific spectrum of processes, which includes shoot branching and root system architecture in response, partly, to environmental stimuli. This makes these hormones ideal tools for understanding the coordination of plant growth processes, mechanisms of long-distance communication and developmental plasticity. Here, we summarize current knowledge about SL signaling and employ the well-characterized gibberellin (GA) signaling pathway as a scaffold to highlight emerging features as well as gaps in our knowledge in this context. GA signaling is particularly suitable for this comparison because both signaling cascades share key features of hormone perception and of immediate downstream events. Therefore, our comparative view demonstrates the possible level of complexity and regulatory interfaces of SL signaling. SLs have a long research history in the context of interactions between plants and other organisms. They were identified in 1966 as plant-derived molecules used by parasitic plants to interact with their hosts , GA3, GA4, GA5, GA6 and GA7 are biologically active. These GAs show different affinities to their receptors  but a higher bioactivity. This is presumably due to increased GA3 stability caused by a double bond at the C2 position , the identification of the active forms 5DS as well as its unnatural enantiomer GR24ent−5DS -dependent pathway inducing germination after wildfires  is involved in SL secretion into the rhizosphere  in Arabidopsis  ubiquitin ligase (E3) complex via the F-box protein SLEEPY1 (SLY1), which provides substrate specificity to the complex  show much milder phenotypic alterations than gid1a/b/c mutants do, although they accumulate comparable or even higher levels of DELLAs. Intriguingly, overexpression of the GID1 receptor suppresses these alterations  , which does not contribute to SL or KAR responsiveness  in rice . D3 is the rice ortholog to MORE AXILLARY GROWTH2 (MAX2) from Jatropha curcas , the only DELLA protein found in rice  essential for binding to GID1 , REPRESSOR OF GA1-3 (RGA), RGA-LIKE1 (RGL1), RGL2 and RGL3 carry such a domain  and an amino acid substitution that changes a positively charged Arg into a Thr  was identified in sis Fig. . The smaO-GlcNAcylation catalyzed by the GlcNAc transferase SPINDLY (SPY) promotes DELLA activity  gene and to the RGA protein , a co-chaperone required for tubulin folding, translocates after GA-induced DELLA degradation and increases the amount of active tubulin subunits promoting cell expansion  providing plenty of opportunities for interactions with other molecules. Indeed, D53/SMXL proteins carry a putative ethylene-responsive element binding factor-associated amphiphilic repression (EAR) domain that can interact with TOPLESS (TPL)  from entering the nucleus and degrading the light-responsive protein LONG HYPOCOTYL5 (HY5) (Tsuchiya et al. Apart from being secreted by plant roots and their role in biotic interactions (Xie and Yoneyama in planta and unwrap their distinct adaptive values. The spatio-temporal dynamics of SL signaling is another interesting aspect for which hardly any information is available. Do all cells have the capacity to sense SLs or is this mainly restricted to vascular tissues? Does sensitivity change over time or in different environments? The identification of events downstream of D53/SMXL proteolysis will certainly provide important insights and tools for addressing these questions. The dissimilarity of D53/SMXL proteins to any other group of known developmental regulators suggests the existence of unique molecular mechanisms and argues for surprising findings in the future.Due to recent fundamental breakthroughs in SL biology research, we expect the unfolding of another complex signaling network in plants soon. In particular, the identification of the D53/SMXL protein family as repressors of SL signaling and direct targets of SL-dependent proteolysis opens up novel avenues to core events in the signaling cascade. Their characterization will be tremendously helpful for integrating the SL pathway into known regulatory networks and for understanding primary effects of SL signaling. Comparisons to other signaling cascades, like GA signaling, are certainly helpful as a first guideline in this regard. Such a comparison demonstrates the degree of complexity possible on the level of transport, perception, and targeted processes and emphasizes experimental pitfalls to be taken into consideration. For example, it will be essential to decipher the roles of the different SLs EW, VL and TG wrote the manuscript. All authors read and approved the manuscript.


In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors.The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca Glioma is a major tumor involving glial cells in the central nervous system, and accounting for 35–50% of intracranial tumors in adults. Among them grade IV glioblastoma multiform (GBM) has the highest incidence and shortest patient survival, with approximately three cases per 100,000 person-years and median survival of only approximately 10 months. The longest survival is achieved in patients who undergo resection followed by radiotherapy and chemotherapy, yet the median survival with this combined treatment is still only 20 months Holland, . Increas+ and Cl− channels generates transmembrane fluxes of the respective ions supporting membrane potential changes as well as cell volume changes promoted by the osmotically driven water flux. Volume changes are in turn strongly required for a number of basic cell functions, such as cell division and growth, migration and death  Are there GBM ion channels involved in the control of certain aspects of cell aggressiveness that are also regulated by hypoxia? (ii) For these specific channels, do experiments performed in GBM or in other preparations have highlighted a hypoxic-mediated modulation of their expression or activity? This undertaking has been made bearing in mind the rational that ion channels would be involved in the hypoxia-induced aggressiveness of GBM.Among the chemotherapics most used in the treatment of GBM there are temozolomide (TMZ), carmustine  and doxorubicin (DOXO), all DNA alkylating agents causing DNA damage and cell death. Although the use of chemotherapics plays an important role in the combined treatment of GBM, it remains a challenge because of tumor chemoresistance  in cerebellar granule neurons . In GBM cells hypoxia increases Notch1 activation, which induces the expression of TRPC6, resulting in an increased basal intracellular Ca2+ concentration and activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway . K2+ influx, DNA fragmentation, externalization of phosphatidilserine, mitochondrial transmembrane potential dissipation, and activation of caspase 3 and p38 MAPK (Amantini et al., 2+ channels are over-expressed and their activity is correlated with tumor proliferation and progression. Valerie et al. (2+ channel leads to apoptotic cell death by inhibiting mTOR/Akt pro-survival signaling pathways. We have already discussed the ability of hypoxia to modulate T-type Ca2+ channels. As for TRPV1 channel, in pulmonary artery smooth muscle cells, the TRPV1 gene and protein are upregulated by chronic hypoxia (Wang et al., 2+ channels may thus potentially be involved in the hypoxia-induced resistance to apoptosis in GBM cells.In U373 glioma cell line, capsaicin stimulation of TRPV1 channels induced a rapid Cae et al.  showed tIn this perspective we have taken several examples of GBM aggressiveness and showed how they strictly relate to hypoxia and ion channels. Namely, we provided evidence that hypoxia promotes GBM aggressive phenotypes, that several types of ion channel are deeply involved in driving GBM aggressiveness, and that hypoxia heavily modulates these very channels promoting GBM aggressiveness. These lines of evidence are in our view more than a circumstantial coincidence. On the contrary they appear strong indications to put forward the working hypothesis that hypoxia promotes the various forms of GBM aggressiveness through mechanisms involving also ion channels as relevant players. This working hypothesis could be taken as a basis to direct future research.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.


Mature seeds of most of the higher plants harbor dormant embryos and go through the complex process of germination under favorable environmental conditions. The germination process involves dynamic physiological, cellular and metabolic events that are controlled by the interplay of several gene products and different phytohormones. The small non-coding RNAs comprise key regulatory modules in the process of seed dormancy and germination. Recent studies have implicated the small RNAs in plant growth in correlation with various plant physiological processes including hormone signaling and stress response. In this review we provide a brief overview of the regulation of seed germination or dormancy while emphasizing on the current understanding of the role of small RNAs in this regard. We have also highlighted specific examples of stress responsive small RNAs in seed germination and discussed their future potential. The seeds of higher plants contain the dormant embryos, as miniature new plants, along with adequate food reserves to sustain the growing seedlings until they establish themselves as self-sufficient, autotrophic organisms Figure . Germinaviviparous (vp), tomato sitiens (sit), and Arabidopsis ABA-deficient (aba), and ABA-insensitive (abi) mutants  has added a new dimension to the understanding of the regulation of cellular environment . They hamiRNA biogenesis is a multistep process that is mainly resistricted to the nucleus in plants. Briefly, the miRNA gene is transcribed into a capped and poly-adenylated primary miRNA (pri-miRNA) by enzyme RNA polymerase II . The priOne strand of the duplex is loaded into RISC (RNA-induced silencing complex) containing AGO1. The strand selection widely depends on the relative stability of the two ends of the duplex . It is oArabidopsis, namely TAS1, TAS2, TAS3, TAS4  have also been implicated in plant development thereby attracting major research interest for many plant biologists . ta-siRNS3, TAS4 . For theocessing .CUC1/CUC2 and NAC1 transcripts by miR164 to affect reproductive and root development  and regulate various aspects of plant development such as vegetative to reproductive phase changes, leaf polarity and lateral root development in Arabidopsis  genes like LEC2 and FUS3. Whereas the negative regulators or repressors of early embryo maturation are ASIL1, ASIL2, and HDA6/SIL1  and ethylene insensitive2 (ein2) or, enhanced response to aba3 (era3) show upregulation of ABA responsive genes and delay in seed germination  family members, which are cell wall loosening proteins that can indirectly influence seed germination , which is involved in DNA demethylation, an epigenetic regulatory process of plants in various stress conditions (Parallel studies have shown that the small RNA biogenesis pathway mutants, that show high expression of ABA, are highly sensitive to salt and osmotic stresses , therebynditions . Over exthaliana . Similarnditions . miR402 nditions . miR417 nditions . HoweverAgriculture exclusively depends on growing crops; so the success of cultivation as well as productivity largely depends on seed viability, seed germination and efficiency of seed development. Small RNAs play critical roles in regulation of gene expression in developing and germinating seeds . In thisThe 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.


Protein complexes involved in epigenetic regulation of transcription have evolved as molecular strategies to face environmental stress in plants. SAGA (Spt–Ada–Gcn5 Acetyltransferase) is a transcriptional co-activator complex that regulates numerous cellular processes through the coordination of multiple post-translational histone modifications, including acetylation, deubiquitination, and chromatin recognition. The diverse functions of the SAGA complex involve distinct modules that are highly conserved between yeast, flies, and mammals. In this review, the composition of the SAGA complex in plants is described and its role in gene expression regulation under stress conditions summarized. Some of these proteins are likely involved in the regulation of the inducible expression of genes under light, cold, drought, salt, and iron stress, although the functions of several of its components remain unknown. Transcriptional coactivators are multi-protein complexes that can recognize histone markers, modify chromatin, and recruit the transcriptional machinery to control gene expression  module contains the General Control Non-depressible 5 (GCN5) acetyltransferase in complex with ADA2, ADA3, and SGF29. This module is completely conserved in several photosynthetic organisms Table . The GCNSPT8 gene are also absent in the genomes of metazoans  with specific transcriptional activators , yielding mostly vascular tissue preferential expression  module comprises four proteins: UBP8, SGF11, SUS1, and SGF73. This module is conserved in plants with the exception of SGF73 Table . A homolThe protein CHD1 has been identified as a component of the SAGA complex in yeast , which constitutes the TFIID complex involved in PIC assembly. The constitutive expression of TAF10 enhances seed tolerance to salt stress during germination, and the knocked-down mutant is more sensitive to salt stress , which demonstrates an increased tolerance to salt and osmotic stress in comparison to wild-type plants during seed germination  genes  and light-activated gene expression under different light wavelengths  and cryptochromes (CRY) that direct adaptive changes in gene expression in response to environmental signals. Ultimately, these light signals are integrated by downstream DNA-binding transcription factors, which bind to several light responsive elements (LRE) present in the promoters of light-inducible genes (Reviewed in Casal and Yanovsky, FRD3, a key gene in iron homeostasis, and modulates the H3K9/14 global acetylation levels under iron deficient conditions, suggest that GCN5 plays a critical role in iron homeostasis through the regulation of target genes (Xing et al., Recently a report demonstrated that a mutation in GCN5 resulted in accumulation of manganese, zinc, and iron in the roots (Xing et al., The protein complexes involved in chromatin remodeling and epigenetic modifications are highly conserved in eukaryotes. The SAGA complex is no exception, and although highly conserved in plants, the physical and functional relationships between its different modules remain to be elucidated. Additional study is needed to identify the target genes of the SAGA complex in different environmental conditions and developmental stages, as well as which transcription factors interact with these complexes. Further characterization of the SAGA complex presents the opportunity to identify new actors that participate in the control of gene expression in plants.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.


Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological characteristic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecular genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequencing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid metabolism and organelle structures, which represent in fact a relatively small number of cellular processes that could help to find common curative approaches, which are still lacking.The online version of this article (doi:10.1007/s00439-015-1536-7) contains supplementary material, which is available to authorized users. Hereditary spastic paraplegia (HSP) refers to a group of neurological diseases caused by corticospinal tract degeneration .The exploration of rare genetic disorders is an important issue since some diseases associated with spasticity are treatable. In particular, spastic paraparesis can be one of the multiple presentations of inborn errors of metabolism in children and adults and in some cases the symptom spastic paraparesis remains the only symptom for years; therefore, these metabolic causes should be included in the general diagnostic approach to sporadic spastic paraparesis due to treatment options  (Tanyel and Mancano SPAST (SPG4) and KIAA1840 (SPG11) (see below). All classical modes of transmission can be found and there are at least 67 genes that, when mutated, can account for these diseases . Up to now, the clinical phenotype and age at onset were critical to prioritize molecular testing because of the heterogeneity of these diseases at the clinical and genetic levels . More than 25 novel causative genes have been reported in 2013–2014 due to next-generation sequencing methods, making this genetic workflow time-consuming , ATL1 (SPG3), KIF5A (SPG10) and REEP1 (SPG31) are described as being responsible for around 50 % of all cases  forms of HSP are mainly pure forms with ages at onset that can range from infancy to late adulthood. Mutations in ses Fig. . SPAST pCYP7B1 (SPG5), SPG7, KIAA1840 (SPG11) and ZFYVE26 (SPG15) genes are among the most frequently found but their relative frequencies vary according to the geographical origin  have been shown to account for approximately 20 % of AR-HSP  forms appear to be particularly prevalent where consanguinity is common such as in the Middle East or Mediterranean countries , a myelin component. SPG2 can also account for late-onset cases in women , in which missense homozygous mutations located in the kinesin motor domain account for a relatively pure HSP  (Supplementary Table 2), suggesting a toxic gain of function effect resulting in a dominant inheritance pattern. In contrast, biallelic mutations affect the capacity of TFG to self-assemble and then probably lead to a loss of function , which have been found in patients with spastic ataxia associated with cataract, having ataxia , Boucher-Neuhäuser syndrome , isolated cerebellar ataxia and isolated spastic paraplegia (SPG39)  mutations may mimic ALS5 when muscle wasting is marked in absence of other complicated signs, or complex HSP in presence of cerebellar and cognitive signs  and ALS-like presentations  encoding the methionyl-tRNA synthase essential for protein biosynthesis  or spastic paraplegia  and EXOSC3  patients    result in a toxic gain of function by ER-stress-mediated cell death responsible for motor neuron diseases, including SPG17 and hereditary motor neuropathy type V  , KIF1A (SPG30) and KIF1C (SAX2/SPAX2/SPG58), which are motor proteins (kinesins) involved in organelle/vesicle trafficking. In KIF5A, heterozygous missense mutations in the motor domain are associated with a reduced velocity along microtubules in gliding assays  due to IBA57 mutations  and spastizin (SPG15) account for proteins involved in the formation of lysosomes  . SPG5 physiopathology may result from an accumulation of toxic substrates and the absence of neurosteroids   and SPG4 human embryonic stem cells indicated that microtubule-binding agents might have therapeutic value  in a continuum with other neurological diseases and that the phenotype of a given patient will depend on multiple factors, including the mutated gene, the nature of the mutation and its location in the protein, the zygosity of the mutation, modifier variants and the environment. When considering all factors, it becomes clear that the dogma linking one gene to one phenotype has to be replaced by one patient—one disease, which will fit with personalized medicine in the future. On the other hand, there is indication for a possible unification of genetic forms from the cell biological and, thus, potentially therapeutic point of view. In particular, the functions of several recently identified HSP proteins suggest that they may participate in the same molecular pathway of lipid metabolism, which may lead to common therapies. Interestingly, disturbances in lipid metabolism also offered the unprecedented opportunity to identify biomarkers for HSP, as in SPG5 (25 and 27 hydroxy-cholesterol) Below is the link to the electronic supplementary material.