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Ilaria Ottonelli,1,* Elisa Adani,2,* Andrea Bighinati,2 Sabrina Cuoghi,1 Giovanni Tosi,1,3 Maria Angela Vandelli,1 Barbara Ruozi,1 Valeria Marigo,2,3 Jason Thomas Duskey1 1Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Center for Neuroscience and Neurotechnology, Modena, Italy*These authors contributed equally to this workCorrespondence: Jason Thomas Duskey, Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, Modena, MO, Italy, 41125, Tel +390592058573, Email jtduskey@unimore.it Valeria Marigo, Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 287, Modena, MO, 41125, Italy, Tel +390592055392, Email vmarigo@unimore.itPurpose: In recent years, microfluidic technologies have become mainstream in producing gene therapy nanomedicines (NMeds) following the Covid-19 vaccine; however, extensive optimizations are needed for each NMed type and genetic material. This article strives to improve LNPs for pDNA loading, protection, and delivery, while minimizing toxicity.Methods: The microfluidic technique was optimized to form cationic or neutral LNPs to load pDNA. Classical “post-formulation” DNA addition vs “pre” addition in the aqueous phase were compared. All formulations were characterized (size, homogeneity, zeta potential, morphology, weight yield, and stability), then tested for loading efficiency, nuclease protection, toxicity, and cell uptake.Results: Optimized LNPs formulated with DPPC: Chol:DOTAP 1:1:0.1 molar ratio and 10 μg of DOPE-Rhod, had a size of 160 nm and good homogeneity. The chemico-physical characteristics of cationic LNPs worsened when adding 15 μg/mL of pDNA with the “post” method, while maintaining their characteristics up to 100 μg/mL of pDNA with the “pre” addition remaining stable for 30 days. Interestingly, neutral LNPs formulated with the same method loaded up to 50% of the DNA. Both particles could protect the DNA from nucleases even after one month of storage, and low cell toxicity was found up to 40 μg/mL LNPs. Cell uptake occurred within 2 hours for both formulations with the DNA intact in the cytoplasm, outside of the lysosomes.Conclusion: In this study, the upcoming microfluidic technique was applied to two strategies to generate pDNA-LNPs. Cationic LNPs could load 10x the amount of DNA as the classical approach, while neutral LNPs, which also loaded and protected DNA, showed lower toxicity and good DNA protection. This is a big step forward at minimizing doses and toxicity of LNP-based gene therapy.Keywords: gene therapy, lipid nanoparticles, microfluidics, lipoplexes, DNA delivery

This study aimed to compare the percentage of bioceramic sealer penetration and maximum penetration sealer depending on the fluorescent staining method when evaluated with confocal laser scanning microscopy (CLSM). In total, 42 single-rooted premolars were instrumented. Two groups of 20 teeth each were filled using the single cone technique. TotalFill BC Sealer® mixed with Rhodamine B was used for the first group and TotalFill BC Sealer® mixed with Fluo-3 for the second group. Two teeth made up the control group. All teeth were sectioned at 3 and 6 mm from the apex and were analyzed with CLSM. The canal perimeter where the tubular penetration happened and the maximum penetration of each sample were calculated. There were no significant differences between the two groups in either the apical or medial sections. In terms of maximum penetration, Rhodamine B had greater tubular penetration in the apical sections, and it had similar results to Fluo-3 in the medial sections. TotalFill BC Sealer® has a higher tubular penetration in the medial slices than in the apical slices regardless of the fluorescent stain used. Rhodamine B has higher results than Fluo-3 in terms of the percentage of sealer penetration and maximum penetration.

Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise.

Abstract Alpha-melanocyte stimulating hormone (α-MSH) and its receptor, melanocortin 1 receptor (MC1R), have been proposed as potential target for anti-cancer strategies in melanoma research, due to their tissue specific expression and involvement in melanocyte homeostasis. However, their role in prevention and treatment of melanoma is still debated and controversial. Although a large body of evidence supports α-MSH in preventing melanoma development, some preclinical findings suggest that the α-MSH downstream signalling may promote immune escape and cancer resistance to therapy. Additionally, in metastatic melanoma both MC1R and α-MSH have been reported to be overexpressed at levels much higher than normal cells. Furthermore, targeted therapy (e.g. BRAF inhibition in BRAFV600E mutant tumours) has been shown to enhance this phenomenon. Collectively, these data suggest that targeting MC1R could serve as an approach in the treatment of metastatic melanoma. In this review, we explore the molecular biology of α-MSH with particular emphasis into its tumor-related properties, whilst elaborating the experimental evidence currently available regarding the interplay between α-MSH/MC1R axis, melanoma and antitumor strategies.

Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.

This article traces the main lines of the evolution of the ideas that have prevailed and the choices that have been made in modelling the fracture of materials for a century. In particular, the emphasis is on the creation and development of damage mechanics with its primary ambition to remedy the shortcomings of Griffith’s fracture theory. We underline the successes of this enterprise and the advances it has allowed by insisting on the key role played by the variational approach, but we also show its limits.

This article reviews some important steps in the development and application of the variational approach to fracture. It emphasizes the essential role played by the permanent dialogue between mechanicians and applied mathematicians in bringing about this new paradigm and ensuring its undeniable success.

We present NIRCam and NIRISS modules for DOLPHOT, a widely used crowded-field stellar photometry package. We describe details of the modules including pixel masking, astrometric alignment, star finding, photometry, catalog creation, and artificial star tests. We tested these modules using NIRCam and NIRISS images of M92 (a Milky Way globular cluster), Draco II (an ultrafaint dwarf galaxy), and Wolf–Lundmark–Mellote (a star-forming dwarf galaxy). DOLPHOT’s photometry is highly precise, and the color–magnitude diagrams are deeper and have better definition than anticipated during original program design in 2017. The primary systematic uncertainties in DOLPHOT’s photometry arise from mismatches in the model and observed point-spread functions (PSFs) and aperture corrections, each contributing ≲0.01 mag to the photometric error budget. Version 1.2 of WebbPSF models, which include charge diffusion and interpixel capacitance effects, significantly reduced PSF-related uncertainties. We also observed minor (≲0.05 mag) chip-to-chip variations in NIRCam’s zero-points, which will be addressed by the JWST flux calibration program. Globular cluster observations are crucial for photometric calibration. Temporal variations in the photometry are generally ≲0.01 mag, although rare large misalignment events can introduce errors up to 0.08 mag. We provide recommended DOLPHOT parameters, guidelines for photometric reduction, and advice for improved observing strategies. Our Early Release Science DOLPHOT data products are available on MAST, complemented by comprehensive online documentation and tutorials for using DOLPHOT with JWST imaging data.

The initial–final mass relation (IFMR) plays a crucial role in understanding stellar structure and evolution by linking a star’s initial mass to the mass of the resulting white dwarf. This study explores the IFMR in the initial mass range 0.8 ≤ M _ini / M _⊙ ≤ 4 using full PARSEC evolutionary calculations supplemented with COLIBRI computations to complete the ejection of the envelope and obtain the final core mass. Recent works have shown that the supposed monotonicity of the IFMR is interrupted by a kink in the initial mass range M _ini ≈ 1.65–2.10 M _⊙ , due to the interaction between recurrent dredge-up episodes and stellar winds in carbon stars evolving on the thermally pulsing asymptotic giant branch phase. To reproduce the IFMR nonmonotonic behavior we investigate the role of convective overshooting efficiency applied to the base of the convective envelope ( f _env ) and to the borders of the pulse-driven convective zone ( f _pdcz ), as well as its interplay with mass loss. We compare our models to observational data and find that f _env must vary with initial mass in order to accurately reproduce the IFMR’s observed kink and slopes. We find some degeneracy between the overshooting parameters when only the IFMR information is used. Nonetheless, this analysis provides valuable insights into the internal mixing processes during the TP-AGB phase.

We calculate new evolutionary models of rotating primordial very massive stars, with initial mass from 100 M _⊙ to 200 M _⊙ , for two values of the initial metallicity Z = 0 and Z = 0.0002. For the first time in this mass range, we consider stellar rotation and pulsation-driven mass loss, along with radiative winds. The models evolve from the zero-age main sequence until the onset of pair-instability. We discuss the main properties of the models during their evolution and then focus on the final fate and the possible progenitors of jet-driven events. All tracks that undergo pulsational-pair instability produce successful gamma-ray bursts (GRB) in the collapsar framework, while those that collapse directly to black holes (BH) produce jet-driven supernova events. In these latter cases, the expected black hole mass changes due to the jet propagation inside the progenitor, resulting in different models that should produce BH within the pair-instability black hole mass gap. Successful GRBs predicted here from zero metallicity, and very metal-poor progenitors, may be bright enough to be detected even up to redshift ∼20 using current telescopes such as the Swift-BAT X-ray detector and the JWST.

Age-related muscle loss poses a significant health concern in an aging population. This study aimed to assess the impact of a home Full-Body in-Bed Gym protocol on quality of life, pain and risk of sarcopenia in elderly subjects. A total of 22 subjects with a median age of 71.90 years were included in the study. Patients participating in the Full-Body in-Bed Gym program, with a frequency of three times a week for two months, demonstrated a significant enhancement in their quality of life, as indicated by the 12-Item Short Form Health Survey (SF-12) Mental Component Summary (p = 0.04), and an improvement in pain levels (p = 0.03). Although not statistically significant, there was also an improvement in sarcopenia risk. Patients were given the freedom to decide whether to continue treatment after the evaluation of outcomes. Patient compliance with the exercise protocol over six months indicated its feasibility and sustainability, even in the long term. These findings suggest that the Full-Body in-Bed Gym protocol may play a valuable role in mitigating age-related muscle loss, emphasizing the importance of further investigation into such rehabilitation and prevention strategies.

Hemotropic Mycoplasma spp. (hemoplasmas) are uncultivable bacteria that infect mammals, including humans. We detected a potentially novel hemoplasma species in blood samples from wild river dolphins in the Amazon River Basin, Brazil. Further investigation could determine pathogenicity and zoonotic potential of the detected hemoplasma.

Na América Latina ainda persistem os fatores de risco de câncer relacionados com a pobreza; ao mesmo tempo, já estão presentes aqueles decorrentes do desenvolvimento. A tendência temporal das taxas de mortalidade revela que apenas o Uruguai, a Argentina, a Região Sul do Brasil e Cuba têm índices de mortalidade proporcional próximos aos países desenvolvidos, isto é, 20%. No sexo masculino prevalecem ainda os cânceres de pulmão e estômago, sem grandes diferenças regionais. No sexo feminino o câncer de útero é o primeiro da lista nas regiões menos desenvolvidas, como Venezuela, México e Nordeste do Brasil, e o de mama, nas mais desenvolvidas, como Uruguai, Argentina e Sul do Brasil. A localização colorretal está assumindo características epidêmicas em algumas dessas regiões mais desenvolvidas, em ambos os sexos. São também importantes a ocorrência do câncer de vesícula biliar em mulheres nos países do Oeste, principalmente Chile, e do esôfago em homens nos países do Sul, quais sejam Uruguai, Argentina e extremo Sul do Brasil. Considerando-se que em várias regiões a melhoria da expectativa de vida contrapõe-se à permanência da pobreza em outras, fica evidente para as próximas décadas considerável aumento de morbidade e mortalidade por câncer na América Latina.

The autosomal dominant form of retinitis pigmentosa (adRP) is a blindness-causing conformational disease largely linked to mutations of rhodopsin. Molecular simulations coupled to the graph-based protein structure network (PSN) analysis and in vitro experiments were conducted to determine the effects of 33 adRP rhodopsin mutations on the structure and routing of the opsin protein. The integration of atomic and subcellular levels of analysis was accomplished by the linear correlation between indices of mutational impairment in structure network and in routing. The graph-based index of structural perturbation served also to divide the mutants in four clusters, consistent with their differences in subcellular localization and responses to 9-cis retinal. The stability core of opsin inferred from PSN analysis was targeted by virtual screening of over 300,000 anionic compounds leading to the discovery of a reversible orthosteric inhibitor of retinal binding more effective than retinal in improving routing of three adRP mutants.

Abstract River dolphins are a highly threatened polyphyletic group comprised of four odontocete families: Iniidae, Pontoporiidae, Lipotidae, and Platanistidae, the first two endemic to South America. To address the knowledge gap regarding infectious agents in this cetacean group, we surveyed the presence of herpesviruses by PCR in skin and/or blood samples of live-captured Amazon (Inia geoffrensis, n = 25) and Bolivian (Inia boliviensis, n = 22) river dolphins of the Amazon basin and in selected tissue samples of franciscanas (Pontoporia blainvillei, n = 27) stranded or bycaught in southeastern Brazil. Additionally, available franciscana tissue samples were examined by histopathology. Herpesvirus DNA was amplified in 13 Bolivian river dolphins (59.1%, 95% CI 38.5–79.6%) and 14 franciscanas (51.9%, 95% CI 33.0–70.7%). All Amazon river dolphins were herpesvirus-negative. Two different herpesviruses were found in Bolivian river dolphins: a previously known gammaherpesvirus detected in blood and/or skin samples of all positive individuals and a novel alphaherpesvirus in the skin of one animal. A new gammaherpesvirus was found in several franciscana samples—the first herpesvirus recorded in Pontoporiidae. Intranuclear inclusion bodies consistent with herpesvirus were observed in the lymph node of one franciscana. The high divergence among the obtained herpesviruses and those previously described can be explained by viral-host coevolution, and by the fact that these populations are fairly isolated.

Summary: Aortic endothelial cell dysfunction is an early trigger of atherosclerosis, the major cause of the cardiovascular disease (CVD). Nanomedicines targeting vascular endothelium and lesions hold great promise as therapeutic solutions to vascular disorders. This study investigates the vascular delivery efficacy of polyurethane-polyurea nanocapsules (Puua-NCs) with pH-synchronized shell cationization and redox-triggered release. Fluorescent lipophilic dye DiI was encapsulated into Puua-NCs of variable sizes and concentrations. In vitro cellular uptake studies with human aortic endothelial cells showed that these Puua-NCs were taken up by cells in a dose-dependent manner. In apolipoprotein E-deficient mice fed a Western diet, a model of atherosclerosis, circulating Puua-NCs were stable and accumulated in aortic endothelium and lesions within 24 hours after intravenous administration. Treatment with thiol-reducing and oxidizing reagents disrupted the disulfide bonds on the surface of internalized NCs, triggering disassembly and intracellular cargo release. Ultimately, Puua-NCs are a potential redox-controllable cardiovascular drug delivery system.

En este artículo se aborda el rol que ha tenido el Estado local, a través de las políticas públicas urbanas, en configuración socio urbana de Bariloche y cuáles han sido las principales estrategias en relación a la problemática de acceso al suelo y la vivienda en la post convertibilidad. Para ello analizamos las principales normativas locales, las políticas de planificación, las herramientas de gestión del suelo y las políticas habitacionales que se han desarrollado. A través de entrevistas, fuentes secundarias y el análisis crítico de la normativa mencionada, se concluye que a pesar de que la ciudad cuenta con una gran cantidad de herramientas de gestión del suelo y que la cuestión habitacional se ha puesto en la agenda pública como consecuencia de la emergencia habitacional oficialmente declarada en distintos años, no se ha logrado abordar de manera estructural la problemática de la producción y circulación de acceso al suelo. La densificación y crecimiento de los barrios populares, los miles de lotes con servicio que no logran ser finalizados y los cientos de viviendas llave en mano que excluyen a los sectores populares son una muestra de ello.

Con el propósito de cumplir con el objetivo general del dossier, el cual supone analizar el rol del Estado en los procesos de conformación del hábitat popular en tres ciudades patagónicas, enfocándonos en las principales políticas de suelo y de vivienda, consideramos necesario generar un apartado dedicado a caracterizar cada una de las localidades que componen el estudio. De tal modo, el presente texto se organiza en torno a información sobre la ubicación de Comodoro Rivadavia, San Carlos de Bariloche y Cipolletti, la historia y el perfil productivo de estas ciudades, datos demográficos como la tasa de crecimiento poblacional, los flujos migratorios, el nivel de desempleo, pobreza o de necesidades básicas insatisfechas, etc. En tal sentido, destacamos la evolución de las estadísticas ligadas con el déficit habitacional, así como establecemos una primera aproximación sobre la presencia de asentamientos en cada localidad. En la introducción general de la publicación detallamos sobre las estrategias metodológicas implementadas, pero cabe resaltar para esta sección que las mismas se basaron en fuentes como los censos nacionales de población elaborados por el Instituto Nacional de Estadísticas, al igual que en entrevistas a referentes de los gobiernos locales y habitantes de asentamientos populares.

El presente texto da inicio a un dossier centrado en el análisis de las principales políticas de suelo y de vivienda llevadas adelante en Cipolletti, San Carlos de Bariloche (provincia de Río Negro) y Comodoro Rivadavia (provincia de Chubut) durante la etapa caracterizada como “postconvertibilidad” (2003-2015); en concreto, nos interesa examinar las intervenciones estatales ligadas con las tomas de tierras y la conformación de asentamientos populares. En tal sentido, la introducción del dossier ha sido organizada en base a los siguientes títulos. En “Urbanización popular y asentamientos informales en América Latina”, indagamos el peso que la ciudad informal en general, y las tomas de tierras en particular, han tenido en la historia urbana de nuestro continente. En el segundo título, denominado “Precisiones conceptuales sobre las políticas urbanas”, explicitamos la perspectiva teórica que adoptamos para examinar las políticas públicas urbanas. El tercer apartado gira en torno a ciertas tendencias históricas en materia de política habitacional en nuestro país; el mismo nos permite dar paso a una nueva sección, centrada en las dificultades de acceso al suelo durante la etapa que privilegiamos en nuestro análisis (la cual denominamos como postconvertilidad). El último apartado explicita la metodología y fuentes de investigación priorizadas a lo largo del estudio.

Failure of a protein to achieve its functional structural state and normal cellular location contributes to the etiology and pathology of heritable human conformational diseases. The autosomal dominant form of retinitis pigmentosa (adRP) is an incurable blindness largely linked to mutations of the membrane protein rod opsin. While the mechanisms underlying the noxious effects of the mutated protein are not completely understood, a common feature is the functional protein conformational loss. Here, the wild type and 39 adRP rod opsin mutants were subjected to mechanical unfolding simulations coupled to the graph theory-based protein structure network analysis.A robust computational model was inferred and in vitro validated in its ability to predict endoplasmic reticulum retention of adRP mutants, a feature linked to the mutation-caused misfolding. The structure-based approach could also infer the structural determinants of small chaperone action on misfolded protein mutants with therapeutic implications.The approach is exportable to conformational diseases linked to missense mutations in any membrane protein.

In this study we compute the equation of state and Rosseland mean opacity from temperatures of T ≃ 30,000 K down to T ≃ 400 K, pushing the capabilities of the Æ SOPUS code into the regime where solid grains can form. The GGchem code is used to solve the chemistry for temperatures less than ≃3000 K. Atoms, molecules, and dust grains in thermodynamic equilibrium are all included in the equation of state. To incorporate monochromatic atomic and molecular cross sections, an optimized opacity sampling technique is used. The Mie theory is employed to calculate the opacity of 43 grain species. Tables of Rosseland mean opacities for scaled-solar compositions are provided. Based on our computing resources, opacities for other chemical patterns, as well as various grain sizes, porosities, and shapes, can be easily computed upon user request to the corresponding author.

We present the JWST Resolved Stellar Populations Early Release Science (ERS) program. We obtained 27.5 hr of NIRCam and NIRISS imaging of three targets in the Local Group (Milky Way globular cluster M92, ultrafaint dwarf galaxy Draco II , and star-forming dwarf galaxy WLM), which span factors of ∼10 ^5 in luminosity, ∼10 ^4 in distance, and ∼10 ^5 in surface brightness. We describe the survey strategy, scientific and technical goals, implementation details, present select NIRCam color–magnitude diagrams (CMDs), and validate the NIRCam exposure time calculator (ETC). Our CMDs are among the deepest in existence for each class of target. They touch the theoretical hydrogen-burning limit in M92 (

We present new evolutionary models of primordial very massive stars with initial masses ranging from 100 to 1000 M _⊙ that extend from the main sequence to the onset of dynamical instability caused by the creation of electron–positron pairs during core C, Ne, or O burning, depending on the star’s mass and metallicity. Mass loss accounts for radiation-driven winds, as well as pulsation-driven mass loss on the main sequence and during the red supergiant phase. After examining the evolutionary properties, we focus on the final outcome of the models and associated compact remnants. Stars that avoid the pair instability supernova channel should produce black holes with masses ranging from ≈40 to ≈1000 M _⊙ . In particular, stars with initial masses of about 100 M _⊙ could leave black holes of ≃85–90 M _⊙ , values consistent with the estimated primary black hole mass of the GW190521 merger event. Overall, these results may contribute to explaining future data from next-generation gravitational-wave detectors, such as the Einstein Telescope and Cosmic Explorer, which will have access to an as-yet-unexplored black hole mass range of ≈10 ^2 –10 ^4 M _⊙ in the early universe.

Abstract Background Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. Results The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. Conclusions We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy.

Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells. Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases. The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients. Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation. One of these targets is the increase of intracellular calcium ions, that has been detected in several murine models of inherited retinal degeneration. Recently, neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration. Here, we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches, such as the neuroprotective activity of the Pigment epithelium-derived factor. The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches. We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.

Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME. In tumors, TIM expansion and differentiation is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by cancer and immune cells. Nevertheless, the role of GM-CSF in tumors has not yet been fully elucidated. In this study, we show that GM-CSF activity is significantly affected by RNS-triggered post-translational modifications. The nitration of a single tryptophan residue in the sequence of GM-CSF nourishes the expansion of highly immunosuppressive myeloid subsets in tumor-bearing hosts. Importantly, tumors from colorectal cancer patients express higher levels of nitrated tryptophan compared to non-neoplastic tissues. Collectively, our data identify a novel and selective target that can be exploited to remodel the TME and foster protective immunity against cancer.

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments.