Kidney International (2011) 79, 452-463; doi:10.1038/ki.2010.438; published online

27 October 2010″
“Elevated urinary albumin excretion in GSK461364 supplier patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression learn more and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria

in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy. Kidney International (2011) 79, 464-470; doi:10.1038/ki.2010.404; published online 27 October 2010″
“Cystatin C is being considered as a replacement for serum creatinine in the estimation of the glomerular filtration rate (GFR); however, its plasma levels might be affected by factors other than the GFR, such as protein intake. We performed a post hoc analysis of the data in the Modification of Diet in Renal Disease study, in Sclareol which we compared serum creatinine and cystatin C levels in 741 patients

with available estimates of protein intake at baseline prior to their randomization to diets containing various amounts of protein, and at 2 years of follow-up in 426 of these patients in whom a cystatin C measurement was available. The 503 patients in study A (GFR 25-55 ml/min per 1.73 m(2)) had been assigned a low (0.58 g/kg per day) or a usual (1.3 g/kg per day) protein intake, and the 238 participants in study B (GFR 13-24 ml/min per 1.73 m(2)) were assigned a very low (0.28 g/kg per day) or the low protein intake. In either study group, lowering the dietary protein intake reduced the change in creatinine, but did not have a significant change in cystatin C. Thus, in patients with moderate-to-severe chronic kidney disease, serum cystatin C unlike serum creatinine was not affected by dietary protein intake independent of changes in GFR.

(C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Increasing evidence shows that calpain-mediated proteolytic processing of a selective number of proteins plays an important role in neuronal apoptosis. Study of calpain-mediated cleavage events and related functions may contribute to a better understanding of neuronal apoptosis and neurodegenerative diseases. We, therefore, investigated the

role of calpain substrates in potassium deprivation-induced apoptosis of cerebellar granule neurons (CGNs). Twelve previously known and seven novel candidates of calpain substrates were identified by 2-D DIGE and MALDI-TOF/TOF MS analysis. Further, the identified novel calpain substrates were validated by Western blot analysis. Moreover, we focused on the collapsin response mediator proteins (CRMP-1, -2, -3 and -4 isoforms) and FG-4592 chemical structure found that CRMPs were proteolytically processed by calpain but not by caspase, both in vivo and in vitro. To clarify the properties of the calpain-mediated proteolysis of CRMPs, we constructed the deletion mutants of CRMPs for additional biochemical studies.

In vitro cleavage assays revealed that CRMP-1, -2 and -4 were truncated by calpain at the C-terminus, whereas CRMP-3 was cleaved BV-6 at the N-terminus. Finally, we assessed the role of CRMPs in the process of potassium deprivation-triggered neuronal apoptosis by overexpressing the truncated CRMPs in CGNs. Our data clearly showed that the truncated CRMP-3 and -4, but not CRMP-1 and -2, significantly induced neuronal apoptosis. These findings demonstrated that calpain-truncated CRMP-3 and -4 act as pro-apoptotic players when CGNs undergo apoptosis.”
“The present study used a rat model with bile duct ligation to examine the effect of cholestasis, to the localization of occludin in brain capillary endothelium by means of electronic microscopy. The results demonstrated a dislocation of occludin away from the tight junction sites of brain endothelial cells. A significant increase of the occludin-interendothelial cleft distance was demonstrated in the midbrain

and the cerebellum samples but not in the frontal Morin Hydrate cortex, compared to the control group samples. These findings imply a brain region selective derangement of occludin in response to liver disease. (C) 2012 Published by Elsevier Ireland Ltd.”
“We have developed a proteome database (DB), BiomarkerDigger (http://biomarkerdigger.org) that automates data analysis, searching, and metadata-gathering function. The metadata-gathering function searches proteome DBs for protein-protein interaction, Gene Ontology, protein domain, Online Mendelian Inheritance in Man, and tissue expression profile information. and integrates it into protein data sets that are accessed through a search function in BiomarkerDigger.

The 5-HT(1A) receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 degrees C water), without

increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT(2A) receptor agonists increase the potency of morphine for antinociception at doses that have no MK-0518 ic50 effect on the rate of operant responding, 5-HT(1A) receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT

receptor subtypes could help to improve the use of opioids for treating pain. Neuropsychopharmacology (2011) 36, 940-949; doi:10.1038/npp.2010.232; published online 5 January 2011″
“Organisms can respond to variation in temperature through the direct effect of temperature on phenotypes (phenotypic plasticity), or through long-term adaptation to temperature (and thus evolution of either mean size or thermal reaction norm). We examined the effects of various temperatures (of 20 and 30 degrees C) on development PS 341 time, adult body size (body length and body width) and pre-adult survivorship in six populations of Chrysomya megacephala, collected at different latitudes. We found that temperature changes induced substantial plasticity in terms of development time, body size and pre-adult survivorship. indicating that developmental temperature significantly affects growth and life history traits of C. megacephala. We also detected genetic differences among populations for body size and development time, and these two traits exhibited highly significant variations in the responses of different populations to various temperature conditions, indicating genetic differences among populations in terms of thermal reaction norms. The latitude

of origin of the different populations (and hence mean temperature regimes in the environments from where the populations originated) did not appear to fully explain these genetic differences. In short, changes in development Oxygenase time and body size in C. megacephala can be regarded as adaptations to changing thermal regimes. (C) 2010 Elsevier Ltd. All rights reserved.”
“Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers.

We examined dopamine D1 receptor (D1DR) binding in the cerebral cortex and striatum of 12 adolescents (mean age 13.5 +/- 1.8 years) and 18 young adults (25 +/- 2.3 years) using positron emission tomography

(PET) and radioligand [(11)C]SCH23390. Over the age span of 10-30 years [(11)C]SCH23390 binding (binding potential, BP) declined in all brain regions. The rate of BP decline was age-segment and brain region dependent. Most pronounced decline in BP was observed in the cortical regions during adolescence (mean BP in adults lower by 14-26% as compared to adolescents, P<0.0001). Significantly slower rate of decline in BP was observed in two cortical regions (orbitofrontal and posterior cingulate cortices) and striatal regions. The present PET-study provides new evidence on the development https://www.selleckchem.com/products/pifithrin-alpha.html of D1DR in humans in vivo which is of critical importance for understanding of the biology of neurodevelopmental disorders. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Cholestatic liver injury following extra- or intrahepatic bile duct obstruction causes nonparenchymal cell proliferation and matrix deposition leading to end-stage liver disease and cirrhosis. In cholestatic conditions, nitric oxide (NO) is mainly produced by a hepatocyte-inducible NO synthase SCH772984 in vivo (iNOS) as a result of enhanced inflow of endotoxins

to the liver and also by accumulation of bile salts in hepatocytes and subsequent hepatocellular injury. This study was aimed to investigate the role of NO and S-nitrosothiol (SNO) homeostasis in the development of hepatocellular injury during cholestasis induced by bile duct ligation (BDL) in rats. Male Wistar rats (200-250 g) were divided into four groups (n – 10 each), including sham-operated (SO), bile duct-ligated (BDL), tauroursodeoxycholic acid (TUDCA, 50 mg/kg) and S-methylisothiourea (SMT, 25 mg/kg) treated. old After 7 days, BDL rats showed elevated serum levels of gamma-glutamiltranspeptidase, aspartate aminotransferase, alanine aminotransferase, LDH,

and bilirubin, bile duct proliferation and fibrosis, compared with the SO group. TUDCA treatment did not significantly alter these parameters, but the iNOS inhibitor SMT ameliorated hepatocellular injury, as shown by lower levels of circulating hepatic enzymes and bilirubin, and a decreased grade of bile duct proliferation and fibrosis. Both TUDCA and SMT treatments reversed Mrp2 canalicular pump expression to control levels. However, only SMT treatment significantly lowered the increased levels of plasma NO and S-nitrosation (S-nitrosylation) of liver proteins in BDL rats. Moreover, BDL resulted in a reduction of the S-nitrosoglutathione reductase (GSNOR/Adh5) enzymatic activity and a downregulation of the GSNOR/Adh5 mRNA expression that was reverted by SMT, but not TUDCA, treatment.

Our results indicate that the main role of negations in conditional rules is to focus attention on the negated constituent but also suggest that there

is some inter-individual differences in the way participants apprehend such negations, as indicated by a correlation between N2 amplitude and participants’ reaction times. Overall, these findings emphasize how overcoming perceptual features plays a role in the mismatching effect and extend the mismatch-related effects of the N2 into a reasoning task. (C) 2008 Elsevier Ltd. All rights reserved.”
“Rift Valley Fever (RVF) is an important viral zoonosis Idasanutlin in Africa affecting animals and humans. Since no protective vaccines or effective treatments are available for human use, accurate and reliable diagnostic methods are essential for surveillance of the disease in order to implement adequate public health actions. To study the kinetics of the

RVF Virus (RVFV) infection, a SYBR Green-based quantitative real-time RT-PCR assay was developed. By using primers targeting the S-segment of RVFV, the detection limit of this assay was estimated to 30 RNA templates. Blood and organs of experimentally infected mice were sampled at different Necrostatin-1 order time points and RVFV RNA was quantified. High amounts of RVFV RNA were found in blood, brain, and liver samples shortly after infection with a 1-4 days post infection window for viral RNA detection. Mice developed symptoms after the appearance of serum antibodies, indicating that the host response plays an important role in the outcome of the disease.

The RVFV quantitative RT-PCR proved to be a valuable diagnostic tool during the first days of infection, before detectable antibody levels and visual symptoms of RVF were observed. (c) 2008 Elsevier B.V. All rights reserved.”
“A well-documented feature of Huntington’s disease (HID) is disproportionate Epothilone B (EPO906, Patupilone) impairment in the ability to recognise the emotional expression of disgust. However, this finding has been challenged by studies that report no differential disgust impairment and attribute apparent differences across emotions to task difficulty. The present study sought to shed light on disparities in findings through a comparative study of emotion recognition in HD and frontotemporal dementia (FTD). Ten HD, 12 FTD patients and 12 healthy controls were administered 10 tasks assessing facial and vocal recognition of emotions and comprehension of emotion terms. The findings were not consistent with either the ‘selective disgust impairment’ or ‘task difficulty’ view. Both HID and FTD groups were impaired compared to controls, deficits in HID being less severe. Impairments in FTD were elicited for all emotions whereas in HD they were demonstrated predominantly for negative emotions of fear, disgust and anger.

Children who passed this challenge at 24 months were placed on a diet

with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months.

RESULTS

After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific selleck compound IgG4 antibody levels selleck kinase inhibitor were associated with passing the oral food challenge at 24 months.

CONCLUSIONS

These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically

significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.)”
“Background: Postthrombotic syndrome (PTS) is a common complication after iliofemoral venous thrombosis, often resulting in poor quality of life (QOL) among the affected patients. This study assessed development of PTS and its effect on QOL among patients treated for iliofemoral venous thrombosis by catheter-directed thrombolysis.

Methods: Patients admitted with an iliofemoral venous thrombosis and treated with catheter-directed thrombolysis at Gentofte University Hospital from 1999 to 2008 were invited to participate. Duplex ultrasound imaging was used

to assess venous patency and valve function. Each patient completed the generic Short-Form 36-item (SF-36) health survey assessment, producing physical component (PCS) and mental component summary (MCS) scores, and the disease-specific Venous Insufficiency Epidemiological and Economic Study (VEINES)-Quality of Life (QOL)/Symptoms (Sym), questionnaires to assess QOL. PTS was assessed cAMP using the Villalta scale.

Results: The study included 109 patients. Median follow-up was 71 months. PTS developed in 18 patients (16.5%) and of those, initial thrombolysis was successful in 13. Patients with PTS had significantly worse mean +/- standard deviation scores than patients without PTS on VEINES-QOL (34.2 +/- 9.6 vs 53.1 +/- 6.6; P < .0001), VEINES-Sym (34.0 +/- 8.8 vs 53.2 +/- 6.6; P < .0001), SF-36 MCS (44.2 +/- 15.5 vs 52.3 +/- 11.0; P = .005), and SF-36 PCS (42.3 +/- 9.1 vs 53.5 +/- 7.8; P < .0001) subscales. Patients with reflux or chronic occlusions, or both, had significantly lower mean +/- SD scores than patients with patent veins without reflux on VEINES-QOL (43.5 +/- 14.3 vs 51.0 +/- 8.8; P = .044) and SF-36 PCS (47.2 +/- 10.9 vs 52.4 +/- 8.

We review recent studies investigating the combined actions of guidance cues present at the same choice points. Two main scenarios are emerging from Cl-amidine chemical structure these studies: parallel signaling and crosstalk between guidance systems. In the first case, cues act in an additive manner, whereas in the second case the outcome

is non-additive and differs from the sum of individual effects, suggesting more complex signal integration in the growth cone. Some of the molecular mechanisms underlying these interactions are beginning to be unraveled.”
“We describe the rapid isolation of single-domain recombinant antibodies in VHH format from a pre-immune llama library created in our laboratory. Such naive library has demonstrated to be a versatile tool and enabled the isolation of several different antibodies LY411575 order for any of the six proteins panned in parallel. The binders specific for human fibroblast growth factor receptor 1 (FGFR1) were successively analyzed in more detail and resulted suitable for both western blot and immunofluorescence analyses. Several milligrams per liter of antibodies were purified by affinity chromatography and used for kinetic and thermodynamic characterization. Their K(D) was in the nanomolar range and they apparently bound a

FGF receptor 1 domain not overlapping the region recognized by its physiological ligand FGF. Altogether, the collected data indicate that the new library can enable the recovery of binders of high affinity, specificity and functionality in the conventional immunological tests, avoiding the necessity MycoClean Mycoplasma Removal Kit of further maturation steps. Such results confirmed recent reports of high affinity pre-immune IgNARs and supported the choice of using large single-domain recombinant antibody naive libraries as an alternative

to the preparation of immune libraries for selecting monoclonal antibodies, at convenient cost and time conditions.”
“Chronic inhalation of quartz-containing dust produces reversible inflammatory changes in lungs resulting in irreversible fibrotic changes termed pneumoconiosis. Due to the inflammatory process in the lungs, highly reactive substances are released that may be detoxified by glutathione S-transferases. Therefore, 90 hard coal miners with pneumoconiosis as a recognized occupational disease (in Germany: Berufskrankheit BK 4101) were genotyped for glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) according to standard methods. Furthermore, occupational exposure and smoking habits were assessed by questionnaire. Changes in a chest x-ray were classified according to ILO classification 2000. Of the investigated hard coal miners 43% were GSTM1 negative whereas 57% were GSTM1 positive. The arithmetic mean of the age at time of investigation was 74.2 yr (range: 42-87 yr).

Deletion mutagenesis and coprecipitation assays mapped the vIL-6-binding domain (vBD) of VKORC1v2 to TM-proximal residues 31 to 39. However, while sufficient to confer vIL-6 binding to a heterologous protein, vBD was unable to induce vIL-6 secretion when fused to (secreted) hIL-6, suggesting a VKORC1v2-independent mechanism of vIL-6 ER retention. In functional assays, overexpression of ER-directed vBD led to suppression of

PEL cell proliferation and viability, effects also mediated by VKORC1v2 depletion and, as reported previously, by vIL-6 suppression. The growth-inhibitory and proapoptotic effects of VKORC1v2 depletion could be rescued by transduced wild-type VKORC1v2 but not by a vIL-6-refractory vBD-altered variant, AG-014699 datasheet indicating the functional relevance of the vIL-6-VKORC1v2 interaction. Notably, gp130 signaling was unaffected

by VKORC1v2 or vBD overexpression or by VKORC1v2 depletion, suggesting an alternative pathway of vIL-6 activity via VKORC1v2. Combined, our data identify a novel and functionally significant interaction BIBF 1120 purchase partner of vIL-6 that could potentially be targeted for therapeutic benefit.”
“The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and its receptors (PAC1 and VPAC2) are expressed in the ventral tegmental area and nucleus accumbens, raising the possibility that PACAP could be a potential modulator of the mesolimbic dopaminergic system.

The present study was designed to determine if PACAP 5-carboxymethyl-2-hydroxymuconate Delta-isomerase plays

a role in acute motor stimulatory and rewarding actions of morphine.

The effect of intracerebroventricular PACAP administration (0, 0.03, 0.3, 1.0, or 3.0 mu g/3 mu L) was studied on basal motor activity as well as on morphine (5 mg/kg)-stimulated motor activity. Motor stimulation and conditioned place preference (CPP) induced by morphine (5 or 10 mg/kg) were also determined in mice lacking PACAP and their wild-type controls.

Intracerebroventricular PACAP dose-dependently suppressed basal motor activity and PACAP-deficient mice exhibited higher basal motor activity than control mice, providing evidence that the action of endogenous PACAP on basal motor activity is inhibitory. Paradoxically, low doses of PACAP which did not alter basal motor activity were found to enhance the motor stimulatory action of morphine. Furthermore, morphine-induced motor stimulation was blunted in PACAP-deficient mice. Additionally, morphine-induced CPP following a single, but not repeated, alternate-day saline/morphine (10 mg/kg) conditioning was blunted in PACAP-deficient mice compared to their wild-type littermates/controls.

The present results suggest that endogenous PACAP, at low doses, positively modulates the acute motor stimulatory and rewarding actions of morphine.

The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (+/- SE) was higher among patients who received early transplantation than among those who did not (77 +/- 8% vs. 23 +/- 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation.

Conclusions Early liver transplantation can improve survival in patients with a first episode

of severe alcoholic hepatitis not responding to medical therapy. (Funded by Societe Nationale Francaise de Gastroenterologie.)”
“Objectives: In 2005, the time-based waiting list for lung transplantation was replaced by an illness/benefit lung allocation score (LAS). Although short-term outcomes after transplantation have been

reported to be similar before Liproxstatin1 and after CBL0137 research buy the new system, little is known about long-term results. The objective of this study was to evaluate the impact of LAS on the development of bronchiolitis obliterans syndrome as well as on overall 3-year and bronchiolitis obliterans syndrome-related survival.

Methods: Data obtained from the United Network for Organ Sharing were used to review 8091 patients who underwent lung transplantation from 2002 to 2008. Patients were stratified according to time of transplantation into those treated before initiation of the LAS (pre-LAS group, January 2002-April 2005, n = 3729) and those treated after implementation of the score (post-LAS group, May 2005-May 2008, n = 4362). Overall, 3-year survivals for patient groups were compared using a univariate analysis, Cox proportional hazards model to generate a relative risk, and Kaplan-Meier curve analyses.

Results: During the 3-year follow-up period, bronchiolitis

obliterans syndrome developed in 22% of lung transplant recipients (n = 1801). Although Metformin research buy the incidence of postoperative bronchiolitis obliterans syndrome development was similar between groups, post-LAS patients incurred fewer bronchiolitis obliterans syndrome-free days (609 +/- 7.5 vs 682 +/- 9; P <.0001; log-rank test P = .0108) than did pre-LAS patients. Overall 3-year survival was lower in post-LAS patients and approached statistical significance (P = .05). Similarly, bronchiolitis obliterans syndrome-related survival was worse for patients in the post-LAS group (log-rank test P = .01).

Conclusions: In the current LAS era, lung transplant recipients have significantly fewer bronchiolitis obliterans syndrome-free days after 3-year follow-up. Compared with the pre-LAS population, overall and bronchiolitis obliterans syndrome-related survival appears worse in the post-LAS era. Limitation of known risk factors for development of bronchiolitis obliterans syndrome-may prove even more important in this patient population.

Crown Copyright (C) 2008 Published by Elsevier Ltd. All rights reserved.”
“The purpose of the present study was to investigate the behavioral outcomes of all-trans retinoic acid (RA) treatment in the period spanning gestational day (GD) 8-10. A sublethal dose (2.5 mg/kg b.w.) compatible

with high neonatal Pritelivir nmr survival, sufficient to supply male offspring for later behavioral testing, was used. Indeed, the mortality rate at birth was 7.8%. Reproduction parameters (body weight gain of dams during gestation, number of dams giving birth, pregnancy length, litter size at birth), offspring body weight gain and the development of their somatic characteristics (ear unfolding, auditory conduit opening, eyes opening, hair growth) were not altered by RA. Instead, the onset of righting reflex and negative geotaxis were delayed by 2 days, suggesting vestibular involvement and abnormal functioning of the cerebellum. Then, the performance of RA-treated rats on open field and rotarod/accelerod tasks was assessed from postnatal day (PND) 21 to 90. Similar to the previously investigated GD 11-13 RA treatment, the GD 8-10 RA treatment impaired the open field activity and

rotarod/accelerod performance in young adult rats, thus suggesting a task-specific rather than a stage-specific effect of low-dose retinoids during brain development. The delayed appearance of these outcomes underlines the relevance of longitudinal studies to sort out specific RA-targeted neurochemical-behavioral pathways that could be labelled as having no phenotype based on standard examination

ACY-1215 manufacturer at birth. (c) 2008 Elsevier Inc. All rights reserved.”
“We obtained several structural features of an NK fitness landscape by analytical approach. Particularly, we focused on spatial distributions of “”ascending slopes”", “”highlands”", “”nearly neutral networks”", and “”local optima”" along the fitness coordinate W, from the viewpoint of adaptive walks with step-width d, where d is the number of mutated sites (Hamming distance) after a generation. The parameter k governs the degree of the ruggedness on the NK landscape, and we handled cases where k is moderate against the sequence length. From the foot LIP to the middle region on the Methylitaconate Delta-isomerase landscape, many ascending slopes exist (high evolvability) and these slopes extend up near the “”highland”", which is mathematically defined as the specific region W = W(d)* where the expectation of the fitness increment becomes zero. Denoting the standard deviation of the fitness change at W = W(d)*; by SD*, we considered the existence of “”nearly neutral networks”", which percolate in the fitness band between W – SD* and W + SD*. Our results suggest that the highland corresponds to a phase-transition threshold of the formation of the nearly neutral networks.