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Abstract Background Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of pathological proteins and synaptic dysfunction. This study aims to investigate the molecular and functional differences between human induced pluripotent stem cells (hiPSCs) derived from patients with sporadic AD (sAD) and age-matched controls (healthy subjects, HS), focusing on their neuronal differentiation and synaptic properties in order to better understand the cellular and molecular mechanisms underlying AD pathology. Methods Skin fibroblasts from sAD patients (n = 5) and HS subjects (n = 5) were reprogrammed into hiPSCs using non-integrating Sendai virus vectors. Through karyotyping, we assessed pluripotency markers (OCT4, SOX2, TRA-1–60) and genomic integrity. Neuronal differentiation was evaluated by immunostaining for MAP2 and NEUN. Electrophysiological properties were measured using whole-cell patch-clamp, while protein expression of Aβ, phosphorylated tau, Synapsin-1, Synaptophysin, PSD95, and GluA1 was quantified by western blot. We then focused on PAK1-LIMK1-Cofilin signaling, which plays a key role in regulating synaptic structure and function, both of which are disrupted in neurodegenerative diseases such as AD. Results sAD and HS hiPSCs displayed similar stemness features and genomic stability. However, they differed in neuronal differentiation and function. sAD-derived neurons (sAD-hNs) displayed increased levels of AD-related proteins, including Aβ and phosphorylated tau. Electrophysiological analyses revealed that while both sAD- and HS-hNs generated action potentials, sAD-hNs exhibited decreased spontaneous synaptic activity. Significant reductions in the expression of synaptic proteins such as Synapsin-1, Synaptophysin, PSD95, and GluA1 were found in sAD-hNs, which are also characterized by reduced neurite length, indicating impaired differentiation. Notably, sAD-hNs demonstrated a marked reduction in LIMK1 phosphorylation, which could be the underlying cause for the changes in cytoskeletal dynamics that we found, leading to the morphological and functional modifications observed in sAD-hNs. To further investigate the involvement of the LIMK1 pathway in the morphological and functional changes observed in sAD neurons, we conducted perturbation experiments using the specific LIMK1 inhibitor, BMS-5. Neurons obtained from healthy subjects treated with the inhibitor showed similar morphological changes to those observed in sAD neurons, confirming that LIMK1 activity is crucial for maintaining normal neuronal structure. Furthermore, administration of the inhibitor to sAD neurons did not exacerbate the morphological alterations, suggesting that LIMK1 activity is already compromised in these cells. Conclusion Our findings demonstrate that although sAD- and HS-hiPSCs are similar in their stemness and genomic stability, sAD-hNs exhibit distinct functional and structural anomalies mirroring AD pathology. These anomalies include synaptic dysfunction, altered cytoskeletal organization, and accumulation of AD-related proteins. Our study underscores the usefulness of hiPSCs in modeling AD and provides insights into the disease's molecular underpinnings, thus highlighting potential therapeutic targets.

“Una Salud” es un enfoque multidisciplinario que integra la salud animal, humana y ambiental, por medio de estrategias para la detección temprana de enfermedades, como la vigilancia de salud en fauna silvestre. El objetivo de este trabajo fue emplear estas estrategias en tres Parques Nacionales de Argentina y sus zonas de interfaz. Se realizaron muestreos oportunistas de animales muertos y/o enfermos hallados durante recorridas o reportados por la comunidad local, complementando el registro de casos con la aplicación móvil “Marandu”. En paralelo se realizaron muestreos sistemáticos de microroedores, murciélagos, artrópodos vectores y matrices ambientales. Las muestras fueron analizadas mediante técnicas específicas para la detección de patógenos y plaguicidas. Se muestrearon 119 mamíferos muertos de diferentes especies, 406 microroedores y 279 murciélagos vivos, y se colectaron 629 artrópodos y 263 muestras ambientales. Los diagnósticos revelaron la presencia de Trypanosoma sp., T. evansi, T. theileri, Anaplasma marginale, Theileria cervi y más de 15 plaguicidas en ambiente y en tejidos animales. Estos resultados subrayan la importancia de una vigilancia continua e integrada para prevenir y controlar enfermedades emergentes y escenarios de contaminación ambiental.

ABSTRACT Extracellular vesicles (EV), key players in cell-to-cell communication, may contribute to disease propagation in several neurodegenerative diseases, including Alzheimer’s disease (AD), by favoring the dissemination of neurotoxic proteins within the brain. Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htauGFP), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtauGFP. Finally, we exploited an in vivo model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer’s disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.

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.

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of pathological proteins and synaptic dysfunction. This study aims to investigate the molecular and functional differences between human induced pluripotent stem cells (hiPSCs) derived from patients with sporadic AD (sAD) and age-matched controls (healthy subjects, HS), focusing on their neuronal differentiation and synaptic properties in order to better understand the cellular and molecular mechanisms underlying AD pathology. Methods: Skin fibroblasts from sAD patients (n = 5) and HS subjects (n = 5) were reprogrammed into hiPSCs using non-integrating Sendai virus vectors. Through karyotyping, we assessed pluripotency markers (OCT4, SOX2, TRA-1–60) and genomic integrity. Neuronal differentiation was evaluated by immunostaining for MAP2 and NEUN. Electrophysiological properties were measured using whole-cell patch-clamp, while protein expression of Aβ, phosphorylated tau, Synapsin-1, Synaptophysin, PSD95, and GluA1 was quantified by western blot. We then focused on PAK1-LIMK1-Cofilin signaling, which plays a key role in regulating synaptic structure and function, both of which are disrupted in neurodegenerative diseases such as AD. Results: sAD and HS hiPSCs displayed similar stemness features and genomic stability. However, they differed in neuronal differentiation and function. sAD-derived neurons (sAD-hNs) displayed increased levels of AD-related proteins, including Aβ and phosphorylated tau. Electrophysiological analyses revealed that while both sAD- and HS-hNs generated action potentials, sAD-hNs exhibited decreased spontaneous synaptic activity. Significant reductions in the expression of synaptic proteins such as Synapsin-1, Synaptophysin, PSD95, and GluA1 were found in sAD-hNs, which are also characterized by reduced neurite length, indicating impaired differentiation. Notably, sAD-hNs demonstrated a marked reduction in LIMK1 phosphorylation, which could be the underlying cause for the changes in cytoskeletal dynamics that we found, leading to the morphological and functional modifications observed in sAD-hNs. To further investigate the involvement of the LIMK1 pathway in the morphological and functional changes observed in sAD neurons, we conducted perturbation experiments using the specific LIMK1 inhibitor, BMS-5. Neurons obtained from healthy subjects treated with the inhibitor showed similar morphological changes to those observed in sAD neurons, confirming that LIMK1 activity is crucial for maintaining normal neuronal structure. Furthermore, administration of the inhibitor to sAD neurons did not exacerbate the morphological alterations, suggesting that LIMK1 activity is already compromised in these cells. Conclusion: Our findings demonstrate that although sAD- and HS-hiPSCs are similar in their stemness and genomic stability, sAD-hNs exhibit distinct functional and structural anomalies mirroring AD pathology. These anomalies include synaptic dysfunction, altered cytoskeletal organization, and accumulation of AD-related proteins. Our study underscores the usefulness of hiPSCs in modeling AD and provides insights into the disease's molecular underpinnings, thus highlighting potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: Management of renal cell carcinoma (RCC) with inferior vena cava (IVC) extension is one of the greatest challenges in urology. The gold standard treatment includes extracorporeal circulation and deep hypothermic circulatory arrest (DHCA). However, this surgical treatment has an impact on survival and prognosis. We aim to present a less invasive surgical approach for the treatment of level III and IV IVC thrombi in RCC. Methods: We identified all patients undergoing radical nephrectomy and thrombectomy at our Institution between 2016 and 2020. Patients with level IV thrombi were treated with a combined thoracic and abdominal procedure: beating heart surgery with normothermic cardiopulmonary bypass (CPB) was used for thrombus retrieval. Level III thrombi were approached exclusively through an abdominal access. Results: We identified 12 patients treated with radical nephrectomy and thrombectomy among 243 patients undergoing radical nephrectomy for RCC. Mean age was 69.3 years, most patients were in T3c clinical stage, without lymph-node involvement (75%) and no metastases (66.7%); 58.3% of patients had Mayo III thrombus classification. Median intensive care unit stay was 2 days and total in-hospital stay 10.5 days. In-hospital mortality was 0%, with a 66.6% survival rate at 2 years. Conclusions: Beating heart surgery with normothermic CPB can be considered a less invasive method for radical resection of Mayo level IV IVC thrombi. This surgical approach is safe and feasible, with good in-hospital and short-term outcomes. [ABSTRACT FROM AUTHOR]

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.

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.