1,722,272 research outputs found
Families of Calabi-Yau elliptic fibrations in P(L^a + L^b + O_B)
Full text linkLet B be a smooth projective surface, and let L be an ample line bundle on B. The aim of this paper is to study the families of elliptic Calabi-Yau threefolds sitting in the bundle P(L a L b O B ) as anticanonical divisors. We will show that the number of such families is finite
Targeting the post-translational proteome with intrabodies
Full text linkThe complexity of the proteome exceeds that of the genome. Post-translational modifications (PTMs) and conformational changes of proteins trigger new molecular interactions whose systematic elucidation is hampered by the lack of specific tools. PTMs are particularly relevant for epigenetic regulation of gene expression; a field of translational interest. However, state-of-the-art inhibitors used in epigenetic studies and therapies target modifier enzymes such as acetylases and deacetylases, rather than a single PTM protein per se. The systematic development of anti-PTM intrabodies, which allow targeting of intracellular proteins in the context of living cells, will help reaching a new level of precision and specificity in the description of epigenetics, paving the way to new therapeutic opportunities
Complex symplectic structures and the del-delbar-lemma
Full text linkIn this paper, we study complex symplectic manifolds, i.e., compact complex manifolds X which admit a holomorphic (2, 0)-form σ which is d-closed and non-degenerate, and in particular the Beauville–Bogomolov–Fujiki quadric Qσ associated with them. We will show that if X satisfies the -lemma, then Qσ is smooth if and only if h2 , 0(X) = 1 and is irreducible if and only if h1 , 1(X) > 0
Getting Into the Brain: The Intranasal Approach to Enhance the Delivery of Nerve Growth Factor and Its Painless Derivative in Alzheimer’s Disease and Down Syndrome
No full textThe neurotrophin Nerve Growth Factor (NGF) holds a great potential as a therapeutic candidate for the treatment of neurological diseases. However, its safe and effective delivery to the brain is limited by the fact that NGF needs to be selectively targeted to the brain, to avoid severe side effects such as pain and to bypass the blood brain barrier. In this perspective, we will summarize the different approaches that have been used, or are currently applied, to deliver NGF to the brain, during preclinical and clinical trials to develop NGF as a therapeutic drug for Alzheimer’s disease. We will focus on the intranasal delivery of NGF, an approach that is used to deliver proteins to the brain in a non-invasive, safe, and effective manner minimizing systemic exposure. We will also describe the main experimental facts related to the effective intranasal delivery of a mutant form of NGF [painless NGF, human nerve growth factor painless (hNGFp)] in mouse models of Alzheimer’s disease and compare it to other ways to deliver NGF to the brain. We will also report new data on the application of intranasal delivery of hNGFp in Down Syndrome mouse model. These new data extend the therapeutic potential of hNGFp for the treatment of the dementia that is progressively associated to Down Syndrome. In conclusion, we will show how this approach can be a promising strategy and a potential solution for other unmet medical needs of safely and effectively delivering this neuroprotective neurotrophin to the brain
∂∂ ̄-lemma and p-Kähler structures on families of solvmanifolds
No full textWe provide families of compact (n+1)-dimensional complex non Kähler manifolds satisfying the ∂∂ ̄-Lemma, with holomorphically trivial canonical bundle, carrying a balanced metric and with no p-Kähler structures. Such a construction extends to the completely solvable case in any dimension Nakamura’s construction of low-dimensional holomorphically parallelizable solvmanifolds
Sotto il Torchio. Libri e monete antiche dalle raccolte della Biblioteca Universitaria di Padova e del Museo Bottacin
Full text link
Painless Nerve Growth Factor: A TrkA biased agonist mediating a broad neuroprotection via its actions on microglia cells
No full textNerve Growth Factor (NGF) is a therapeutic candidate for Alzheimer's disease, based on its well known actions on basal forebrain cholinergic neurons. However, because of its pro-nociceptive activity, in current clinical trials NGF has to be administered intraparenchymally into the brain by neurosurgery via cell or gene therapy approaches. To prevent the NGF pain-inducing collateral effects, thus avoiding the necessity for local brain injection, we developed painless NGF (hNGFp), based on the human genetic disease Hereditary Sensory and Autonomic Neuropathy type V (HSAN V). hNGFp has similar neurotrophic activity as wild type human NGF, but its pain sensitizing activity is tenfold lower. Pharmacologically, hNGFp is a biased receptor agonist of NGF TrkA receptor. The results of recent studies shed new light on the neuroprotective mechanism by hNGFp and are highly relevant for the planning of NGF-based clinical trials. The intraparenchymal delivery of hNGFp, as used in clinical trials, was simulated in the 5xFAD mouse model and found to be inefficacious in reducing Aβ plaque load. On the contrary, the same dose of hNGFp administered intranasally, which was rather widely biodistributed in the brain and did not induce pain sensitization, blocked APP processing into amyloid and restored synaptic plasticity and memory in this aggressive neurodegeneration model. This potent and broad neuroprotection by hNGFp was found to be mediated by hNGFp actions on glial cells. hNGFp increases inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. Independent work has shown that NGF has a potent anti-inflammatory action on microglia and steers them towards a neuroprotective phenotype. These studies demonstrate that microglia cells are a new target cell of NGF in the brain and have therapeutic significance: i) they establish that the neuroprotective actions of hNGFp relies on a widespread exposure of the brain, ii) they identify a new anti-neurodegenerative pathway, linking hNGFp to inflammatory chemokines and cytokines via microglia, a common target for new therapeutic opportunities for neurodegenerative diseases, iii) they extend the neuroprotective potential of hNGFp beyond its classical cholinergic target, thereby widening the range of neurological diseases for which this neurotrophic factor might be used therapeutically, iv) they help interpreting the results of current NGF clinical trials in AD and the design of future trials with this new potent therapeutic candidate
A continuous model of physiological prion aggregation suggests a role for Orb2 in gating long-term synaptic information.
Full text linkThe regulation of mRNA translation at the level of the synapse is believed to be fundamental in memory and learning at the cellular level. The family of cytoplasmic polyadenylation element binding (CPEB) proteins emerged as an important RNA-binding protein family during development and in adult neurons. Drosophila Orb2 (homologue of mouse CPEB3 protein and of the neural isoform of Aplysia CPEB) has been found to be involved in the translation of plasticity-dependent mRNAs and has been associated with long-term memory. Orb2 protein presents two main isoforms, Orb2A and Orb2B, which form an activity-induced amyloid-like functional aggregate, thought to be the translation-inducing state of the RNA-binding protein. Here we present a first two-states continuous differential model for Orb2A-Orb2B aggregation. This model provides new working hypotheses for studying the role of prion-like CPEB proteins in long-term synaptic plasticity. Moreover, this model can be used as a first step to integrate translation- and protein aggregation-dependent phenomena in synaptic facilitation rules
Dolbeault-Massey triple products of low degree
Full text linkLet A=(A•,•,∂-A) be a differential bigraded algebra. We characterize non-vanishing Dolbeault-Massey triple products of low degree (see Theorems 3.1 and 3.2). We give some applications for the Dolbeault complex on a compact complex manifold
- …
