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Abstract Background Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer’s disease (AD), contributing to progressive memory loss and cognitive decline. Reduced levels of the nucleoporin 153 (Nup153), a key epigenetic regulator of NSC stemness, characterize the neural stem cells isolated from a mouse model of AD (3×Tg) (AD-NSCs) and determine their altered plasticity and gene expression. Methods Nup153-regulated mechanisms contributing to NSC function were investigated: (1) in cultured NSCs isolated from AD and wild type (WT) mice by proteomics; (2) in vivo by lentiviral-mediated delivery of Nup153 or GFP in the hippocampus of AD and control mice analyzing neurogenesis and cognitive function; (3) in human iPSC-derived brain organoids obtained from AD patients and control subjects as a model of neurodevelopment. Results Proteomic approach identified Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. Gene ontology (GO) analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism, nuclear import and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration, mitochondrial dysfunction, proteasomal processing and RNA degradation. Furthermore, recovery of Nup153 levels in AD-NSCs reduced the levels of oxidative stress markers and recovered proteasomal activity. Lentiviral-mediated delivery of Nup153 in the hippocampal niche of AD mice increased the proliferation of early progenitors, marked by BrdU/DCX and BrdU/PSANCAM positivity and, later, the integration of differentiating neurons in the cell granule layer (BrdU/NeuN+ cells) compared with GFP-injected AD mice. Consistently, Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD-GFP mice at 1 month after virus delivery assessed by Morris Water Maze. To validate the role of Nup153 in neurogenesis we took advantage of brain organoids derived from AD-iPSCs characterized by fewer neuroepithelial progenitor loops and reduced differentiation areas. The upregulation of Nup153 in AD organoids recovered the formation of neural-like tubes and differentiation. Conclusions Our data suggest that the positive effect of Nup153 on neurogenesis is based on a complex regulatory network orchestrated by Nup153 and that this protein is a valuable disease target.

Aesthetic aspects of drinking water, such as Taste and Odor (T&O), have significant effects on consumer perceptions and acceptability. Solving unpleasant water T&O episodes in water supplies is challenging, since it requires expertise and know-how in diagnosis, evaluation of impacts and implementation of control measures. We present gaps, challenges and perspectives to advance water T&O science and technology, by identifying key areas in sensory and chemical analysis, risk assessment and water treatment, as articulated by WaterTOP (COST Action CA18225), an interdisciplinary European and international network of researchers, experts, and stakeholders.

Antiviral hydrophobic cellulose-based cotton or non-woven fabrics containing mesoporous TiO2 particles were developed for potential use in healthcare and in other contaminated environments. Hydrosols made with the sol-gel method using two different amounts of the Ti precursor were applied to cotton and non-woven fabrics and their virucidal effect on Murine Coronavirus (MHV-3) and Human Adenovirus (HAdV-5) was evaluated under indoor light irradiation. The results show 90% reduction of HAdV-5 and up to 99% of MHV-3 in non-woven fabric, and 90% reduction of MHV-3 and no reduction of HAdV-5 in cotton fabric. The antiviral activity was related to the properties of the TiO2 powders and coatings characterized by BET surface area, DRX, DLS, FTIR, DRS, SEM, TEM and water contact angle. The hydrophobic characteristic of the treated fabrics and the high surface area of the TiO2 particles favor interaction with the virus, especially MHV-3. These results demonstrate that non-woven fabric and cotton, coated with TiO2, can be highly effective in preventing contamination with MHV-3 and HAdV-5 viruses, particularly for applications in healthcare indoor environments.

Abstract Background The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models. Results Here, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia. Conclusions Targeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.

Abstract We aim to explore the connections between structural network inequalities and bank’s customer spending behaviours, within an entire national ecosystem made of natural persons (i.e., an individual human being) and legal entities (i.e., private or public organisations), different business sectors, and supply chains that span distinct geographical regions. We focus on Italy, that is among the wealthiest nations in the world, and also an example of a complex economic system. In particular, we had access to a large subset of anonymised and GDPR-compliant wire transfer data recorded from Jan 2016 to Dec 2017 by Intesa Sanpaolo, a leading banking group in the Eurozone, and the most important one in Italy.Intesa Sanpaolo wire transfers network exhibits a strong heavy-tailed behaviour and a giant component that grows continuously around the same core of the 1% highest degree nodes, and it also shows a general disassortative pattern, even if some ranges of degrees’ values stand out from the trend. Structural heterogeneity is explored further by means of a bow-tie analysis, that shows clearly that the majority of relevant, in terms of transferred amount, transactions is settled between a smaller set of nodes that are associated to legal entities and that mostly belong to the strongly connected component. This observation brings to a more comprehensive inspection of differences between Italian regions and business sectors, that could support the detection and the understanding of the interplay between supply chains.Our results suggest that there is a general flow of money that seems to stream down from higher degree legal entities to lower degree natural persons, crossing Italian regions and connecting different business sectors, and that is finally redistributed through expenses sharing within families and smaller communities. We also describe a reference dataset and an empirical contribution to the study on financial networks, focusing on finer-grained information concerned about spending behaviour through wire transfers.

A Disintegrin and Metalloprotease 10, also known as ADAM10, is a cell surface protease ubiquitously expressed in mammalian cells where it cuts several membrane proteins implicated in multiple physiological processes. The dysregulation of ADAM10 expression and function has been implicated in pathological conditions, including Alzheimer’s disease (AD). Although it has been suggested that ADAM10 is expressed as a zymogen and the removal of the prodomain results in its activation, other potential mechanisms for the ADAM10 proteolytic function and activation remain unclear. Another suggested mechanism is post-translational modification of the cytoplasmic domain, which regulates ADAM10-dependent protein ectodomain shedding. Therefore, the precise and temporal activation of ADAM10 is highly desirable to reveal the fine details of ADAM10-mediated cleavage mechanisms and protease-dependent therapeutic applications. Here, we present a strategy to control prodomain and cytosolic tail cleavage to regulate ADAM10 shedding activity without the intervention of small endogenous molecule signaling pathways. We generated a series of engineered ADAM10 analogs containing Tobacco Etch Virus protease (TEV) cleavage site (TEVcs), rendering ADAM10 cleavable by TEV. This strategy revealed that, in the absence of other stimuli, the TEV-mediated removal of the prodomain could not activate ADAM10. However, the TEV-mediated cleavage of the cytosolic domain significantly increased ADAM10 activity. Then, we generated ADAM10 with a minimal constitutively catalytic activity that increased significantly in the presence of TEV or after activating a chemically activatable TEV. Our results revealed a bioengineering strategy for controlling the ADAM10 activity in living cells, paving the way to obtain spatiotemporal control of ADAM10. Finally, we proved that our approach of controlling ADAM10 promoted α-secretase activity and the non-amyloidogenic cleavage of amyloid-β precursor protein (APP), thereby increasing the production of the neuroprotective soluble ectodomain (sAPPα). Our bioengineering strategy has the potential to be exploited as a next-generation gene therapy for AD.

Abstract Background Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area. Methods Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections. Results Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E2 (PGE2) and prostacyclin (PGI2), but not PGF2α, evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H1, PGE2 (EP4), and PGI2 (IP) receptors, respectively. Conclusions The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE2, PGI2), or do not provoke (VIP and PGF2α), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.