Ykl-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

Background: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results: YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around beta-amyloid plaques, and surrounding vessels with beta-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Conclusions: Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component

Unbiased pattern analysis reveals highly diverse responses of cytoskeletal systems to cyclic straining

In mammalian cells, actin, microtubules, and various types of cytoplasmic intermediate filaments respond to external stretching. Here, we investigated the underlying processes in endothelial cells plated on soft substrates from silicone elastomer. After cyclic stretch (0.13 Hz, 14% strain amplitude) for periods ranging from 5 min to 8 h, cells were fixed and double-stained for microtubules and either actin or vimentin. Cell images were analyzed by a two-step routine. In the first step, micrographs were segmented for potential fibrous structures. In the second step, the resulting binary masks were auto- or cross-correlated. Autocorrelation of segmented images provided a sensitive and objective measure of orientational and translational order of the different cytoskeletal systems. Aligning of correlograms from individual cells removed the influence of only partial alignment between cells and enabled determination of intrinsic cytoskeletal order. We found that cyclic stretching affected the actin cytoskeleton most, microtubules less, and vimentin mostly only via reorientation of the whole cell. Pharmacological disruption of microtubules had barely any influence on actin ordering. The similarity, i.e., cross-correlation, between vimentin and microtubules was much higher than the one between actin and microtubules. Moreover, prolonged cyclic stretching slightly decoupled the cytoskeletal systems as it reduced the cross-correlations in both cases. Finally, actin and microtubules were more correlated at peripheral regions of cells whereas vimentin and microtubules correlated more in central regions

Reorientation dynamics and structural interdependencies of actin, microtubules and intermediate filaments upon cyclic stretch application

Any cell within a tissue is constantly confronted with a variety of mechanical stimuli. Sensing of these diverse stimuli plays an important role in cellular regulation. Besides shear stress, cells of the vascular endothelium are particularly exposed to a permanent cyclic straining originating from the interplay of outwards pushing blood pressure and inwards acting contraction by smooth musculature. Perpendicular alignment of cells as structural adaptation to this condition is a basic prerequisite in order to withstand deformation forces.Here, we combine live cell approaches with immunocytochemical analyses on single cell level to closely elucidate the mechanisms of cytoskeletal realignment to cyclic strain and consolidate orientation analyses of actin fibres, microtubules (MTs) and vimentin. We could show that strain‐induced reorientation takes place for all cytoskeletal systems. However, all systems are characterized by their own, specific reorientation time course with actin filaments reorienting first followed by MTs and finally vimentin. Interestingly, in all cases, this reorientation was faster than cell body realignment which argues for an active adaptation mechanism for all cytoskeletal systems. Upon actin destabilization, already smallest alterations in actin kinetics massively hamper cell morphology under strain and therefore overall reorientation. Depolymerization of MTs just slightly influences actin reorientation velocity but strongly affects cell body reorientation

Ykl-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

Background: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results: YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around beta-amyloid plaques, and surrounding vessels with beta-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Conclusions: Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component

Ykl-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

Background: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results: YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around beta-amyloid plaques, and surrounding vessels with beta-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Conclusions: Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component

MODELI ZA PROCJENU NEIZRAVNE ČVRSTOĆE VAPNENCA U SATURIRANOM STANJU

There are a number of methods of estimating physical and mechanical characteristics. Principally, the most widely used is the regression, but recently the more sophisticated methods such as neural networks has frequently been applied, as well. This paper presents the models of a simple and a multiple regression and the neural networks – types Radial Basis Function and Multiple Layer Perceptron, which can be used for the estimate of the Brazilian indirect tensile strength in saturated conditions. The paper includes the issues of collecting the data for the analysis and modelling and the overview of the performed analysis of the efficacy assessment of the estimate of each model. After the assessment, the model which provides the best estimate was selected, including the model which could have the most wide-spread application in the engineering practice.Potreba za procjenom neizravne vlačne čvrstoće koju inače određujemo brazilskim testom može se javiti pri idejnim rješenjima podzemnih radova u sredinama gdje je prisutna podzemna voda. Pregledom dostupne literature iz relevantnih izvora, koja se bavi utjecajem zasićenja na neizravnu vlačnu čvrstoću stijena koja se određuje brazilskim testom, utvrđeno je da se samo nekoliko radova bavi procjenom neizravne vlačne čvrstoće kod vapnenaca i pri tome se ne bave zasićenjem vodom. Isto tako, autori ovoga rada pregledom dostupne literature iz relevantnih izvora nisu naišli na rad koji bi se bavio procjenjivanjem neizravne vlačne čvrstoće vapnenca pomoću neuronskih mreža koje bi primjenjivale samo dva ulazna parametra, neizravnu vlačnu čvrstoću u suhome stanju i/ili šupljikavosti, stoga je bio razumljiv znanstveni interes za izradu i primjenu modela takva tipa. Skup podataka na temelju kojega je modelirano izrađen je jednim djelom od prikupljenih podataka iz objavljene literature gdje su navedeni rezultati ispitivanja poroznosti, indirektne vlačne čvrstoće u suhome i zasićenome stanju miocenskoga vapnenca, a drugi dio početnoga skupa bazira se na istraživanjima koja su provedena u Geomehaničkome laboratoriju RGN fakulteta u Zagrebu na vapnencima iz kamenoloma „Podberam” kod Pazina. U obama slučajevima ispitivanja su obavljena prema preporuci Međunarodnoga društva za mehaniku stijena pa je objedinjavanje bilo moguće. Na temelju prikupljenih podataka pomoću programskoga paketa Statistica 12 ukupno je napravljeno pet modela za procjenu neizravne vlačne čvrstoće. Modeli jednostruke regresije nose oznaku SR_1 (temelji se na jednostavnoj regresiji s poroznošću) i SR_2 koji je napravljen pomoću neizravne vlačne čvrstoće u suhome stanju. Model višestruke regresije nazvan je MR, a u njemu su nezavisne varijable šupljikavosti i neizravne vlačne čvrstoće u suhome stanju. Model neuronskih mreža s radijalnom baznom funkcijom nazvan je NN_RBF, a model tipa višeslojna mreža nosi oznaku NN_MLP. Uobičajeno se izrađeni modeli evaluiraju pomoću niza koeficijenata koji služe u tu svrhu: koeficijent koleracije (R), koeficijent determinacije (R2 ), korigirani R2 (R2 Adj) i korijen srednje kvadratne pogreške (RMSE). Prema parametrima ocjene najbolji je model NN_MLP, zatim slijedi model NN_RBF pa model MR te model SR_2 i na kraju model SR_1. Iako model NN_MLP najbolje procjenjuje neizravnu vlačnu čvrstoću u saturiranome stanju jer ima R = 0,987348; R2 = 0,974856; R 2 Adj = 0,974382 i RMSE = 0,272791, ipak prema mogućnosti šire primjene u inženjerskoj praksi model višestruke regresije najviše obećava jer za njegovu primjenu nisu potrebni složeni programski paketi. Modele iz ovoga rada treba primjenjivati samo kada su ulazni parametri u rasponu za indirektnu vlačnu čvrstoću u suhome stanju od 0,07 do 7,381 MPa

Additional file 1: of YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

Summary of human brain cases and regions analyzed with qPCR, western blot and immunohistochemical analysis. Number of cases, age (mean ± SD) and gender (number of females and males) are indicated. (TIFF 93 kb