Furthermore, we describe how the recently characterized H3 3 dyna

Furthermore, we describe how the recently characterized H3.3 dynamics associated buy CB-839 with gastrulation, myogenesis, or neurogenesis underline the role of chromatin changes in cell differentiation. Finally, we discuss the challenges of maintaining centromeric identity through propagation of the centromeric CenH3 variant in different cell types. Future challenges will be to gain a comprehensive picture of H3 variants and their chaperones during development and differentiation.”
“Phosphatase and actin regulators (Phactrs) are a novel family of proteins expressed in the brain,

and they exhibit both strong modulatory activity of protein phosphatase 1 and actin-binding activity. Phactrs are comprised of four family members (Phactr1-4), but their detailed expression patterns during embryonic and postnatal development are not well understood. AG-120 solubility dmso We found that these family members exhibit different spatiotemporal mRNA expression patterns. Phactr4 mRNA was found in neural stem cells in the developing and adult brains, whereas Phactr1 and 3 appeared to be expressed in post-mitotic neurons. Following traumatic brain injury which promotes neurogenesis in the neurogenic region and gliogenesis in the injury penumbra, the mRNA expression of phactr2

and 4 was progressively increased in the injury penumbra, and phactr4 mRNA and protein induction was observed in reactive astrocytes. These differential expression patterns of phactrs imply specific functions for each protein during development, and the importance of Phactr4 in the reactive gliosis following brain injury. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Increasing evidence indicates favourable effects of the Mediterranean diet, partly associated to its monounsaturated fatty acids (MUFA) content on both obesity and diabetes. However, neither the underlying mechanisms by which the Mediterranean diet exerts Ibrutinib chemical structure its protective

effect, nor the interplay with other environmental factors (i.e. physical activity), are fully characterised. In this review, we examined recent data on how the metabolic fate of MUFA and saturated fatty acids (SFA) differs. Because of differential packaging into lipoproteins, hydrolysis of triacylglycerol-rich lipoproteins by lipoprotein lipase and transport into oxidative tissues, MUFA are oxidised more than SFA. This high MUFA oxidation favour lipid oxidation and according to the oxidative balance concept reduces the risk of obesity. It also improves the intra-muscular triacylglycerol turnover, which mitigates the SFA-induced accumulation of diacylglycerol and ceramides, and thus protects the insulin sensitivity and cell viability. Finally, physical activity through its action on the energy turnover differentially regulates the metabolism of SFA and MUFA.

To our knowledge, this is the first report on global peptide sequ

To our knowledge, this is the first report on global peptide sequencing and quantification of protein in PA and IVF embryos by LC-MS/MS that may be useful as a reference map for future studies.”
“The number of personalized medicines and companion diagnostics in use in the United States has gradually increased over the past decade, from a handful of medicines and tests in 2001 to several dozen in 2011. However, the numbers have not reached the potential hoped for when the human genome project was completed in 2001. Significant clinical, regulatory, and economic barriers exist and persist. From a regulatory perspective, therapeutics and companion diagnostics are ideally developed simultaneously,

with the clinical significance of the diagnostic established using data from the clinical development program of the corresponding therapeutic. Nevertheless, this is AZD1480 clinical trial not (yet) happening. Most personalized medicines are personalized post hoc,

that is, a companion diagnostic is developed separately and approved after the therapeutic. This is due in part to a separate and more complex regulatory process for diagnostics coupled with a lack of clear regulatory guidance. More importantly, payers have placed restrictions on reimbursement of personalized medicines and their companion diagnostics, given the lack of evidence on the clinical utility of many tests. To achieve increased clinical adoption of diagnostics and targeted therapies through more favorable reimbursement and incorporation

in clinical Nutlin3a practice guidelines, regulators will need to provide unambiguous guidance and manufacturers will need to bring more and better clinical evidence to the market place.”
“Retinoid X receptors (RXRs) form a distinct and unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Recent advances reveal that RXRs are important regulators of macrophages, key players in inflammatory and metabolic disorders. This review outlines the versatility of RXR action in the control of macrophage gene transcription through its heterodimerization with other NRs or through RXR homodimerization. We also highlight the potential Venetoclax mouse of RXR-controlled transcriptional programs as targets for the treatment of pathologies associated with altered macrophage function, such as atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration.”
“Here, we report for the first time a comparative phosphoproteomic analysis of distinct tumor cell lines in the presence or absence of the microtubule-interfering agent nocodazole. In total, 1525 phosphorylation sites assigned to 726 phosphoproteins were identified using LC-MS-based technology following phosphopeptide enrichment.

ECGs were classified as ischemic or nonischemic The primary outc

ECGs were classified as ischemic or nonischemic. The primary outcome was death at 1 year after the vascular operation. Independent predictors of long-term mortality were determined by Cox proportional hazards regression analysis.

Results: The most common vascular problem was an expanding abdominal aortic aneurysm (n = 185 [55%]). With regard to cTnI, 53 patients (16%) were classified as high (+) and 82 (24%) as low (+). The ECG in 21 patients (6%) showed evidence of myocardial ischemia. An increase in 1-year mortality of 3% for normal, 11% for low (+), and 17% for high (+) (P < .01) was seen with incremental

cTn values. Independent predictors of long-term mortality were age (odds ratio [OR], 1.05, 95% confidence interval [CI], 1.02-1.07; P < .01), stratified troponin (OR, 1.62; 95% YAP-TEAD Inhibitor 1 in vitro CI, 1.25-2.10; https://www.selleckchem.com/products/idasanutlin-rg-7388.html P < .01), tissue loss (OR, 3.30; 95% CI, 1.72-6.33; P < .01), stratified

Revised Cardiac Risk Index (OR, 1.32; 95% CI, 0.97-1.81; P < .07), and statin use (OR, 0.62; 95% CI, 0.40-0.98; P = .04). The presence of ischemia on ECG was not a predictor of long-term mortality.

Conclusions: In the presence of an elevated cTn I, the ECG is not an independent predictor of long-term mortality after vascular surgery. These results support a strategy of routine surveillance of cTns after vascular surgery for the detection of cardiac events and postoperative risk stratification. (J Vasc Surg 2013;57:166-72.)”
“Luciferase exhibits a broad range of emitting frequencies. Light emission from the bioluminescence of luciferase makes it an excellent tool for monitoring DOK2 gene expression,

thus the control of its bioluminescence color has great bio-analytical applications. Here I use an elastic network model to examine how the sequence distribution of luciferase is related to bioluminescence multicolor emission. Based on the open and closed forms of crystal structures for luciferase, several computational analysis tools are applied to characterize the functionally relevant dynamical features within luciferase, and probe the dynamical mechanisms underlying the interactions between luciferin (a light-emitting substrate) and luciferase. Perturbation-based correlation analysis is used to identify hot-spot residues that are dynamically coupled to the active site of luciferase, and the results show that the sequence region of subdomain B of luciferase is largely responsible for determining the emitting color of bioluminescence. Moreover, the mode decomposition analysis reveals that the lowest frequency mode is the major contributor to the dynamical couplings between the hot-spot residues and the binding site in luciferase.”
“Objective: We examined the hypothesis that a 1 C reduction in body temperature would reduce gray and white matter injury induced by spinal cord ischemia in rats.

Neuropsychopharmacology (2012) 37, 2233-2243; doi:10 1038/npp 201

Neuropsychopharmacology (2012) 37, 2233-2243; doi:10.1038/npp.2012.74; Savolitinib in vitro published online 16 May 2012″
“Cohesins are mutated in a significant number of tumors of various types making them attractive targets for chemotherapeutic intervention.

However, cohesins have a spectrum of cellular roles including sister chromatid cohesion, transcription, replication, and repair. Which of these roles are central to cancer biology and which roles can be exploited for therapeutic intervention? Genetic interaction networks in yeast have identified synthetic lethal interactions between mutations in cohesin and replication fork mediators. These interactions are conserved in worms and in human cells suggesting that inhibition of replication fork stability mediators such as poly (ADP-ribose) polymerase (PARP) could result in the specific killing of tumors with cohesin Wortmannin purchase mutations. These findings also highlight the utility of genetic interaction networks in model organisms for the identification of clinically relevant interactions. Here, we review this type of approach, emphasizing the power of synthetic lethal interactions to reveal new avenues for developing cancer therapeutics.”
“We have developed an Escherichia coli expression vector that is particularly useful for construction and production of fusion proteins. Based on the synthetic biology pSB1C3 platform, the resulting

vector offers a combination of useful features: the strong T7 promoter combined with lac operator, OmpA signal sequence, a selection of cloning sites located at convenient positions and a 3′-terminal His-10 tag. Each of these regions is flanked by a restriction site that allows for easy vector modification, including removal of the signal sequence without perturbation of the reading frame. All the elements were assembled by stepwise addition of three cassettes for which the design was made de nova. To prove the efficiency of the new vector, named pMD204, we successfully produced a cysteine proteinase inhibitor variant in the periplasm and in 6-phosphogluconolactonase the cytoplasm of E.

coli, in both cases as a soluble and active protein. (C) 2008 Elsevier Inc. All rights reserved.”
“Background/Aims: The role of vitamin D in the process of vascular calcification is unclear in patients with chronic kidney disease. We investigated whether serum 25-hydroxyvitamin D [25(OH)D] is associated with vascular calcification in predialysis and dialysis patients. Methods: We included 86 predialysis and 139 dialysis patients. The simple vascular calcification score (SVCS) was evaluated by examining plain Xrays of the pelvis and hands as described previously. The carotid-to-femoral pulse wave velocity (CF-PWV) was assessed with a commercially available device. Results: We found a high prevalence of vitamin D deficiency in our population (78.2%). Vascular calcification was present in 46.2% of all patients.

Mechanistically, sorafenib-induced

cell death is preceded

Mechanistically, sorafenib-induced

cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of Selleck Verteporfin the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy. Leukemia (2011)

25, 838-847; doi: 10.1038/leu.2011.2; published online 4 February 2011″
“Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also BIBF 1120 order induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8(+) cytotoxic T cells (CTLs) established by weekly stimulation

with alloantigen-expressing antigenpresenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal C-X-C chemokine receptor type 7 (CXCR-7) GVHD is dependent on the presence of either CD4(+) or CD8(+) T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-gamma and TNF-alpha or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8(+) T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction. Leukemia (2011) 25, 848-855; doi: 10.1038/leu.2011.16; published online 18 February 2011″
“BACKGROUND AND IMPORTANCE: Chordomas are relatively rare tumors that arise from the neuraxis. Most often, chordomas are single lesions that metastasize late.


“A 19-year-old woman presented with a 4-day history of abd


“A 19-year-old woman presented with a 4-day history of abdominal pain in the right upper quadrant and epigastrium, with occasional radiation to her back. She also noted profound fatigue and a 13.6-kg weight loss during the preceding months. ForewordIn this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing Anlotinib price his or her reasoning with the reader (regular

type). The authors’ commentary follows.StageA 19-year-old woman presented to a community hospital with a 4-day history of abdominal pain, located in the right upper quadrant and epigastrium, with occasional radiation to her back. She described the pain as intermittent and variable in intensity, associated with nausea, and occurring independently of oral intake or body position. A review of systems was notable Epoxomicin datasheet for profound fatigue and a 13.6-kg (30-lb) weight loss during the preceding months, which she attributed to stress in the wake of her parents’ recent divorce. She reported no fever, sweats, jaundice, dyspnea, vomiting, diarrhea, constipation, urinary abnormalities,

joint aches, or rash.”
“Communication Deviance (CD) in rearing parents is a known indicator of a psychopathology risk in the offspring, but the direction of the effects of these two factors on each other has remained an unresolved question. The purpose of the present study was to clarify this issue by assessing the relationship of CD in adoptive parents with certain attributes of the adoptee and adoptive parents themselves. The subjects were 109 adoptees at a high or low risk of Alanine-glyoxylate transaminase schizophrenia-spectrum

disorders and their adoptive parents. Communication Deviance was measured in individual, spouse and family Rorschach situations. Thought disorders in the adoptees were assessed using the Thought Disorder Index. The variability of CD in the adoptive parents in individual Rorschach situations was not significantly explained by any characteristics of the child. The variability in parental CD in family Rorschach situations was most closely associated with the characteristics of the parents themselves. The results strongly support the hypotheses that the frequency of Communication Deviance is an enduring trait rather than a fluctuating state and that frequent CD in parent’s speech may impair the growing child’s cognitive development and predispose him/her to schizophrenia-spectrum disorders. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2 on an antigen-specific CD8(+) T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8(+) T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death during in vitro division.

(c) 2013 Elsevier Ltd All rights reserved “
“A large and gr

(c) 2013 Elsevier Ltd. All rights reserved.”
“A large and growing number of studies support the notion that arousing positive emotional states expand, and that arousing negative states constrict, the scope of attention on both the perceptual and conceptual levels. However, these studies have predominantly involved the manipulation or measurement of conscious emotional experiences (e.g., subjective feelings of happiness or anxiety). This raises the question: Do cues that are merely associated with benign versus threatening situations but do not elicit conscious feelings of positive or negative emotional arousal independently expand or contract attentional scope? Integrating

theoretical advances in affective neuroscience, positive psychology, and social cognition, the authors propose that rudimentary intero- and exteroceptive BAY 1895344 nmr stimuli may indeed become associated with the onset of arousing positive or negative emotional states and/or with appraisals that the environment is benign or threatening and thereby come to moderate the scope of attention in the absence of conscious emotional experience. Ferroptosis inhibitor Specifically, implicit “”benign situation”" cues are posited to broaden, and implicit “”threatening situation”" cues to narrow, the range of both perceptual and conceptual attentional selection. An extensive array of research findings involving

a diverse set of such implicit affective cues (e.g., enactment of approach and avoidance behaviors, incidental exposure to colors signaling safety vs. danger) is marshaled in support of this proposition. Potential alternative explanations for and moderators of these attentional tuning effects, as well as their higher level neuropsychological underpinnings, are also discussed along with prospective extensions to a range of other situational cues and domains of social cognitive processing.”
“Controversy

surrounds whether crossed and/or uncrossed fibers carry taste information from tongue to cortex and whether there is hemispheric specialization for gustatory processing. The current study examined these issues in 14 patients with unilateral insula lesions, seven with right-sided and seven with left-sided damage, and in 42 healthy controls. Olopatadine Two tasks were carried out, with tastants applied unilaterally to the tongue tip: (1) taste discrimination; and (2) stimulus sampling followed by judgments of quality, intensity, hedonics and name-recognition, for sweet, salty, bitter and sour tastants. Controls were better at discriminating tastants applied to their right tongue tip relative to their left, and better at taste quality judgments when tastants were applied to their left tongue tip relative to their right. Insula lesions to the left or right side resulted in bilateral impairments in discrimination, quality judgments and naming, when compared to controls.

Preferences among three high-carbohydrate diets were determined i

Preferences among three high-carbohydrate diets were determined in female selleck kinase inhibitor Wistar rats (n = 16). Adolescent rats (n = 162) received the following weekly diet schedules: (1) continuous regular chow (7 days/week), (2) chow (5 days/week) followed by a more preferred diet (2 days/week), or (3) chow (5 days/week) followed

by a less preferred chow (2 days/week). Some animals were yoke-restricted (75% calories) when provided chow to increase its rewarding properties. Diurnal locomotor activity was measured in a familiar environment, and anxiety-like behavior was assessed in the elevated plus-maze and defensive withdrawal tests. Rats withdrawn from the preferred diet showed hypophagia, anxiogenic-like behavior, increased locomotion, and weight loss. Chow hypophagia was progressive, individuat-specific in magnitude, (partly) non-homeostatic in nature, and blunted by previous chow restriction. Despite eating less, rats cycled Lenvatinib with the preferred diet became heavier, fatter, and diurnally less active, with greater feed efficiency and proinflammatory adipokine levels than chow controls. The present diet cycling procedure may model consummatory, anxiety-related, and metabolic effects of qualitative dieting in humans. (C) 2008

Elsevier Ltd. All rights reserved.”
“Rapamycin is a U.S. Food and Drug Administration-approved drug for the prevention of immunorejection following organ transplantation. Pharmacological studies suggest a potential new application of rapamycin in attenuating cardiomyopathy, but the potential for this application is not yet supported by genetic studies of genes in target

of rapamycin (TOR) signaling in rodents. Recently, supporting genetic evidence was presented in zebra fish using two adult cardiomyopathy models. By characterizing a heterozygous zebrafish target of Non-specific serine/threonine protein kinase rapamycin (ztor) mutant, the therapeutic effect of long-term TOR signaling inhibition was demonstrated. Dose- and stage-dependent functions of TOR signaling provide an explanation for the seemingly contradictory results obtained in genetic studies of TOR components in rodents. The results from the zebra fish studies, together with the supporting preliminary clinical studies, suggested that TOR signaling inhibition should be further pursued as a novel therapeutic strategy for cardiomyopathy. Future directions for developing TOR-based therapy include assessing the long-term benefits of rapamycin as a candidate drug for heart failure patients, defining the dynamic activity of TOR, exploring the impacts of TOR signaling manipulation in different models of cardiomyopathies, and elucidating the downstream signaling branches that confer the therapeutic effects of TOR signaling inhibition.

By focusing on different aspects of JNK signaling, it becomes inc

By focusing on different aspects of JNK signaling, it becomes increasingly obvious that the JNK cascade is intricately regulated and intensely dependent on the availability and functionality of its single components and their intracellular localization. Our review also emphasizes, that JNKs are indispensable for neuronal cell death as well as many physiological functions in the brain. Finally, we

discuss pharmacological strategies which target pathological Adavosertib in vivo JNK activities without affecting their physiological functions. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“We present three models of how transcription factors (TFs) bind to their specific binding sites on the DNA: a model based on statistical physics, a Markov-chain model and a computational simulation. Comparison of these models suggests

that the effect of non-specific binding can be significant. We also investigate possible mechanisms for cooperativity. The simulation model suggests that direct interactions between TFs are unlikely to be the main source of cooperativity between specific binding sites, because such interactions tend to lead to the formation Of Clusters on the DNA with Selleckchem Vactosertib undesirable side-effects. (C) 2008 Elsevier Ltd. All rights reserved.”
“Photic responses of the circadian system are mediated through light-induced clock gene expression in the suprachiasmatic nucleus (SCN). In nocturnal rodents, depending on the timing of light exposure, Per1 and Per2 gene expression Staurosporine order shows distinct compartmentalized patterns that correspond to the behavioral responses.

Whether the gene- and region-specific induction patterns are unique to nocturnal animals, or are also present in diurnal species is unknown. We explored this question by examining the light-induced Per1 and Per2 gene expression in functionally distinct SCN sub-regions, using diurnal grass rats Arvicanthis niloticus. Light exposure during nighttime induced Per1 and Per2 expression in the SCN, showing unique spatiotemporal profiles depending on the phase of the light exposure. After a phase delaying light pulse (LP) in the early night, strong Per1 induction was observed in the retinorecipient core region of the SCN, while strong Per2 induction was observed throughout the entire SCN. After a phase advancing LP in the late night, Per1 was first induced in the core and then extended into the whole SCN, accompanied by a weak Per2 induction. This compartmentalized expression pattern is very similar to that observed in nocturnal rodents, suggesting that the same molecular and intercellular pathways underlying acute photic responses are present in both diurnal and nocturnal species. However, after an LP in early subjective day, which induces phase advances in diurnal grass rats, but not in nocturnal rodents, we did not observe any Per1 or Per2 induction in the SCN.

023) Our results indicate that sex modulates the interactive eff

023). Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S’-allele is associated with hippocampal volume independent

of CA in women, men only have smaller hippocarnpi if they carry the risk allele and experienced severe CA. Neuropsychopharmacology (2012) 37, 1848-1855; doi:10.1038/npp.2012.32; published online 21 March 2012″
“The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate

Bleomycin with pro-cognitive capacities.

This study was performed: (1) to assess the learn more pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine.

Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15-4 mg/kg MTC; 0.1-0.5 mg/kg rivastigmine) in mono or combination treatment.

Scopolamine treatment prevented spatial BCKDHA learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (> 0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments.

In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism

by minimising side effects at lower doses.”
“Reactive oxygen species (ROS), particularly hydrogen peroxide, and the proteins that regulate them play important roles in the migration and adhesion of cells. Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, which relay signals from the cell surface to key signaling proteins inside the cell. ROS act within cells to promote migration and also in nonmigrating cells to influence the behavior of migrating cells. Hydrogen peroxide has also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds. We discuss recent progress made towards understanding how organisms use ROS, and to what degree they depend on them, during the related processes of cell migration and adhesion.