Does human capital compensate for population decline?

Fertility rates have been falling persistently over the past 50 years in most rich countries. Simultaneously, the trend of outward migration from poorer to richer countries has been steady. These two forces contributed to population aging, and – in an increasing number of countries – even to population decline. In this paper, we quantify the effect of decreasing fertility on the aggregate human capital stock. In doing so we take into account that parents with fewer children may raise investments in their children's education and health. We find that the human capital impact of declining fertility is partly compensated through such responses when including the full set of countries in our regressions. For the subset of countries that experience population decline, the compensatory effect is weaker and, in many specifications, even insignificant

Astrocyte-Derived Tissue Transglutaminase Interacts with Fibronectin: A Role in Astrocyte Adhesion and Migration?

An important neuropathological feature of neuroinflammatory processes that occur during e.g. Multiple Sclerosis (MS) is the formation of an astroglial scar. Astroglial scar formation is facilitated by the interaction between astrocytes and extracellular matrix proteins (ECM) such as fibronectin. Since there is evidence indicating that glial scars strongly inhibit both axon growth and (re)myelination in brain lesions, it is important to understand the factors that contribute to the interaction between astrocytes and ECM proteins. Tissue Transglutaminase (TG2) is a multifunctional enzyme with an ubiquitous tissue distribution, being clearly present within the brain. It has been shown that inflammatory cytokines can enhance TG2 activity. In addition, TG2 can mediate cell adhesion and migration and it binds fibronectin with high affinity. We therefore hypothesized that TG2 is involved in astrocyte-fibronectin interactions. Our studies using primary rat astrocytes show that intracellular and cell surface expression and activity of TG2 is increased after treatment with pro-inflammatory cytokines. Astrocyte-derived TG2 interacts with fibronectin and is involved in astrocyte adhesion onto and migration across fibronectin. TG2 is involved in stimulating focal adhesion formation which is necessary for the interaction of astrocytes with ECM proteins. We conclude that astrocyte-derived TG2 contributes to the interaction between astrocytes and fibronectin. It might thereby regulate ECM remodeling and possibly glial scarring

Calcineurin Inhibition at the Clinical Phase of Prion Disease Reduces Neurodegeneration, Improves Behavioral Alterations and Increases Animal Survival

Prion diseases are fatal neurodegenerative disorders characterized by a long pre-symptomatic phase followed by rapid and progressive clinical phase. Although rare in humans, the unconventional infectious nature of the disease raises the potential for an epidemic. Unfortunately, no treatment is currently available. The hallmark event in prion diseases is the accumulation of a misfolded and infectious form of the prion protein (PrPSc). Previous reports have shown that PrPSc induces endoplasmic reticulum stress and changes in calcium homeostasis in the brain of affected individuals. In this study we show that the calcium-dependent phosphatase Calcineurin (CaN) is hyperactivated both in vitro and in vivo as a result of PrPSc formation. CaN activation mediates prion-induced neurodegeneration, suggesting that inhibition of this phosphatase could be a target for therapy. To test this hypothesis, prion infected wild type mice were treated intra-peritoneally with the CaN inhibitor FK506 at the clinical phase of the disease. Treated animals exhibited reduced severity of the clinical abnormalities and increased survival time compared to vehicle treated controls. Treatment also led to a significant increase in the brain levels of the CaN downstream targets pCREB and pBAD, which paralleled the decrease of CaN activity. Importantly, we observed a lower degree of neurodegeneration in animals treated with the drug as revealed by a higher number of neurons and a lower quantity of degenerating nerve cells. These changes were not dependent on PrPSc formation, since the protein accumulated in the brain to the same levels as in the untreated mice. Our findings contribute to an understanding of the mechanism of neurodegeneration in prion diseases and more importantly may provide a novel strategy for therapy that is beneficial at the clinical phase of the disease

Hippocampal neurophysiology is modified by a disease-associated C-terminal fragment of tau protein

The accumulation of cleaved tau fragments in the brain is associated with several tauopathies. For this reason, we recently developed a transgenic mouse that selectively accumulates a C-Terminal 35 kDa human tau fragment (Tau35). These animals develop progressive motor and spatial memory impairment, paralleled by increased hippocampal glycogen synthase kinase 3b activity. In this neurophysiological study, we focused on the CA1 subfield of the hippocampus, a brain area involved in memory encoding. The accumulation of Tau35 results in a significant increase of short-term facilitation of the synaptic response in the theta frequency range (10 Hz), without affecting basal synaptic transmission and long-term synaptic plasticity. Tau35 expression also alters the intrinsic excitability of CA1 pyramidal neurons. Thus, Tau35 presence is associated with increased and decreased excitability at hyperpolarized and depolarized potentials, respectively. These observations are paralleled by a hyperpolarization of the voltage-sensitivity of noninactivating Kþ currents. Further investigation is needed to assess the causal link between such functional alterations and the cognitive and motor impairments previously observed in this model

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype

Porphyrins as SERRS spectral probes of chemically functionalized Ag nanoparticles

International audienceThe results of surface-enhanced resonance Raman scattering (SERRS) spectral probing of citrate- and/or citric acid-modified Ag nanoparticles by selected free-base porphyrins, namely a tetracationic 5,10,15,20-tetrakis(1-methyl-4-pyridiniumyl)porphine and neutral 5,10,15,20-tetra(pyridyl)porphine (H2TPyP) and 5,10,15,20-tetrakis(4-aminophenyl)porphine (H2TAPP) are reported, along with a novel procedure of the functionalized Ag nanoparticle hydrosols preparation by laser ablation of a Ag target in aqueous sodium citrate and/or citric acid solutions of various concentrations. SERRS spectra obtained from the Ag nanoparticle hydrosol/porphyrin system were analyzed using the spectral marker bands of free-base, Ag metallated and diacid forms. In freshly prepared SERRS-active systems, adsorbed citrate was found to function as an efficient molecular spacer for positively charged porphyrin species both in the pH-neutral and in the acidic media, allowing for SERRS spectral detection of not only cationic, but also additionally protonized neutral porphyrins in the native free-base (and/or, at low pH, in the diacid) form without denaturation by Ag incorporation. Furthermore, a substantial increase of the SERRS signal observed for H2TPyP and H2TAPP in systems with Ag nanoparticles prepared by laser ablation in 1 × 10−2 M citric acid solutions is attributed to both the electromagnetic enhancement increase stemming from the presence of hot spots in compact aggregates of touching and intergrown Ag nanoparticles (visualized by /HR/-TEM), and from the molecular resonance enhancement increase originating from a close match between the Soret band of the diacid form (440 nm) and the 457.9 nm excitation. For H2TAPP, the large SERRS enhancement manifests itself in the 1 × 10−10 M SERRS spectral detection limit

Alpha-synuclein deficiency in the C57BL/6JOlaHsd strain does not modify disease progression in the ME7-model of prion disease

We previously detailed how intrahippocampal inoculation of C57BL/6J mice with murine modified scrapie (ME7) leads to chronic neurodegeneration (Cunningham C, Deacon R, Wells H, Boche D, Waters S, Diniz CP, Scott H, Rawlins JN, Perry VH (2003) Eur J Neurosci 17:2147–2155.). Our characterization of the ME7-model is based on inoculation of this murine modified scrapie agent into C57BL/6J mice from Harlan laboratories. This agent in the C57BL/6J host generates a disease that spans a 24-week time course. The hippocampal pathology shows progressive misfolded prion (PrPSc) deposition, astrogliosis and leads to behavioural dysfunction underpinned by the early synaptic loss that precedes neuronal death. The Harlan C57BL/6J, although widely used as a wild type mouse, are a sub-strain harbouring a spontaneous deletion of ?-synuclein with the full description C57BL/6JOlaHsd. Recently ?-synuclein has been shown to ameliorate the synaptic loss in a mouse model lacking the synaptic chaperone CSP-?. This opens a potential confound of the ME7-model, particularly with respect to the signature synaptic loss that underpin the physiological and behavioural dysfunction. To investigate if this strain-selective loss of a candidate disease modifier impacts on signature ME7 pathology, we compared cohorts of C57BL/6JOlaHsd (?-synuclein negative) with the founder strain from Charles Rivers (C57BL/6JCrl, ?-synuclein positive). There were subtle changes in behaviour when comparing control animals from the two sub-strains indicating potentially significant consequences for studies assuming neurobiogical identity of both strains. However, there was no evidence that the absence of ?-synuclein modifies disease. Indeed, accumulation of PrPSc, synaptic loss and the behavioural dysfunction associated with the ME7-agent was the same in both genetic backgrounds. Our data suggest that ?-synuclein deficiency does not contribute to the compartment specific processes that give rise to prion disease mediated synaptotoxicity and neurodegeneration

MALAT1 in Liquid Biopsy: The Diagnostic and Prognostic Promise for Colorectal Cancer and Adenomas?

Klara Cervena,1,2 Anna Siskova,1,2 Jiri Jungwirth,3,4 Marin Volari&cacute;,5 Jan Kral,6 Pavel Kohout,7 Miroslav Levy,8 Veronika Vymetalkova1,2,9 1Institute of Experimental Medicine, Czech Academy of Sciences, Prague, 142 00, Czech Republic; 2Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, 128 00, Czech Republic; 3Institute of Physiology, 1st Faculty of Medicine Charles University, Prague, 121 08, Czech Republic; 4Department of Surgery, Weiden Clinic, Weiden in der Oberpfalz, 92637, Germany; 5Laboratory for Non-Coding DNA, Ru&dstrok;er Boškovi&cacute; Institute, Zagreb, 10000, Croatia; 6Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, 140 21, Czech Republic; 7Department of Internal Medicine, 3rd Faculty of Medicine Charles University and Faculty Thomayer Hospital Prague, Prague, 140 00, Czech Republic; 8Department of Surgery, First Faculty of Medicine, Charles University and Thomayer Hospital Prague, Prague, 140 59, Czech Republic; 9Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, 323 00, Czech RepublicCorrespondence: Klara Cervena, Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague, 142 00, Czech Republic, Email [email protected]: The development of colorectal cancer (CRC) is a multistep process accompanied by the accumulation of mutations that start from specific precancerous lesion – colorectal adenomas (CA). CRC incidence and mortality can be reduced by the early identification of these neoplasm. Colonoscopy is the most widely used screening method for CRC identification. Nowadays, clinical research interest is shifting to the use of liquid biopsy that may help with the early diagnosis of CA and CRC. In our previous study, we identified long non-coding RNA MALAT1 gene amplification associated with the development of CA.Methods: This study aimed to describe the potential of MALAT1 expression levels in the adenoma tissue of patients used in the previous study by real-time qPCR. Furthermore, we analysed the plasma samples of an independent group of patients with CA (n=97), CRC (n=101), and cancer-free individuals (CFI, n=48).Results: There was no difference in the MALAT1 expression level between CA patients with or without MALAT1 amplification. However, the plasma MALAT1 expression levels were significantly upregulated in patients with CRC and CA compared to CFI (for both p< 0.001). Moreover, a correlation between MALAT1 expression and histological types of adenomas was identified– high-CRC-risk adenomas also displayed the highest MALAT1 expression levels. Furthermore, in CRC patients, MALAT1 levels were associated with a response to therapy.Conclusion: MALAT1 expression levels could serve as a promising circulating biomarker for early CA and CRC diagnosis, and even as a predictor of therapy response in CRC patients.Keywords: MALAT1, colorectal adenomas, colorectal cancer, plasma, liquid biops