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Abstract Spatial information is encoded by location-dependent hippocampal place cell firing rates and sub-second, rhythmic entrainment of spike times. These rate and temporal codes have primarily been characterized in low-dimensional environments under limited cognitive demands; but how is coding configured in complex environments when individual place cells signal several locations, individual locations contribute to multiple routes and functional demands vary? Quantifying CA1 population dynamics of male rats during a decision-making task, here we show that the phase of individual place cells’ spikes relative to the local theta rhythm shifts to differentiate activity in different place fields. Theta phase coding also disambiguates repeated visits to the same location during different routes, particularly preceding spatial decisions. Using unsupervised detection of cell assemblies alongside theoretical simulation, we show that integrating rate and phase coding mechanisms dynamically recruits units to different assemblies, generating spiking sequences that disambiguate episodes of experience and multiplexing spatial information with cognitive context.

Abstract Social recognition is essential for the formation of social structures. Many times, recognition comes with lesser exploration of familiar animals. This lesser exploration has led to the assumption that recognition may be a habituation memory. The underlying memory mechanisms and the thereby acquired cortical representations of familiar mice have remained largely unknown, however. Here, we introduce an approach directly examining the recognition process from volatile body odors among male mice. We show that volatile body odors emitted by mice are sufficient to identify individuals and that more salience is assigned to familiar mice. Familiarity is encoded by reinforced population responses in two olfactory cortex hubs and communicated to other brain regions. The underlying oxytocin-induced plasticity promotes the separation of the cortical representations of familiar from other mice. In summary, neuronal encoding of familiar animals is distinct and utilizes the cortical representational space more broadly, promoting storage of complex social relationships.

Summary: The zona incerta (ZI), a subthalamic area connected to numerous brain regions, has raised clinical interest because its stimulation alleviates the motor symptoms of Parkinson’s disease. To explore its coordinative nature, we studied the assembly formation in a dataset of neural recordings in mice and quantified the degree of functional coordination of ZI with other 24 brain areas. We found that the ZI is a highly integrative area. The analysis in terms of “loop-like” motifs, directional assemblies composed of three neurons spanning two areas, has revealed reciprocal functional interactions with reentrant signals that, in most cases, start and end with the activation of ZI units. In support of its proposed integrative role, we found that almost one-third of the ZI’s neurons formed assemblies with more than half of the other recorded areas and that loop-like assemblies may stand out as hyper-integrative motifs compared to other types of activation patterns.

Abstract The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulation of brain homeostatic functions, shaping synaptic neuronal transmission and neurotransmitter levels with effects on mice behavior. In detail, the interferon-γ plays a role in the formation of non-spatial memory, tuning the frequency of GABAergic neurotransmission on cortical pyramidal neurons, while the acetylcholine is a mediator involved in the modulation of brain circuitries that regulate anxiety-like behavior. These findings disclose mechanisms of immune-to-brain communication that modulate brain functions under physiological conditions.

Abstract Objective The scope of this work is to evaluate an operative protocol for emergency C-section to improve teamwork and reduce surgical setup time. Methods Sixty-six health care operators working together in the delivery ward (gynecologists, midwives, anesthesiologists) simulated an emergency scenario applying a “five actions for each operator” protocol. For each simulation, the decision to delivery interval was considered and the perception of each operator as a team worker was analyzed with specific tests. Results The “five actions for five people” protocol significantly reduces the decision to delivery interval (p

Manna, a well-known herbal drug has multiple traditional and pharmaceutical uses and the entire composition, sugar derivatives and polyphenols, gives rise to a very interesting bioactive complex with versatile therapeutic and benefic properties such as antioxidant and anti-inflammatory activities. The aim of this research was to investigate a F. ornus manna extract loaded in a pectin hydrogel as a synergic vehicle to evaluate the potential use of the complex for cosmetic and dermatological applications. In particular, the study set out to disclose manna properties as a wound healing agent with antimicrobial and reparative activity on infected tissues. Moreover, considering the correlation between antioxidant activity and antiaging potential, the extract was investigated in regard to the anti-elastase activity and skin whitening potential. The total phenolic content of each extract was also determined and a safe profile by in vitro cytotoxicity studies was verified. The hydrogel complex, containing the manna extract and pectin as the gelling agent, exhibited suitable properties in terms of pH (from 5.50 to 6.80), rheological behavior and ability of preserving the antioxidant activity of the manna exudate (around 10%). All the peculiarities that make the pectin hydrogels ideal systems for skin disease, as wound dressings and for antiaging cosmetic formulations.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1–4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4). All new derivatives 1–4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure–activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10–22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure–activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Graphene oxide and its magnetic nanoparticle-based composites are a well-known tool to remove heavy metals from wastewater. Unfortunately, one of the major issues in handling such small particles consists of their difficult removal from treated wastewater (even when their magnetic properties are exploited), due to their very small diameter. One possible way to overcome this problem is to embed them in a macroscopic biopolymer matrix, such as alginate or chitosan beads. In this way, the adsorbent becomes easier to handle and can be used to build, for example, a packed column, as in a traditional industrial adsorber. In this work, the removal performances of two different embedded magnetic nanocomposite adsorbents (MNAs) are discussed. The first type of MNA is based on ferrite magnetic nanoparticles (MNPs) generated by coprecipitation using iron(II/III) salts and ammonium hydroxide, while the second is based on a 2D material composed of MNP-decorated graphene oxide. Both MNAs were embedded in cross-linked alginate beads and used to treat artificial water contaminated with chromium(III), nickel(II), and copper(II) in different concentrations. The yield of removal and differences between MNAs and non-embedded magnetic nanomaterials are also discussed. From the results, it was found that the time to reach the adsorption equilibrium is higher when compared to that of the nanomaterials only, due to the lower surface/volume ratio of the beads, but the adsorption capacity is higher, due to the additional interaction with alginate.

Liposomal amphotericin B (Ambisome®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital.

Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacological modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the pro-differentiating effects of SIRT6 silencing, as the levels of Keratin 1, Keratin 10 and Loricrin were upregulated compared to controls. Next, the effects of SIRT6 pharmacological modulation were evaluated in a DMBA-TPA-induced skin cancer mouse model. Mice treated with the inhibitor S6 in a preventive approach, i.e. at the beginning of the promotion stage, presented reduced number and size of papillomas, compared to the controls. The epidermal hyperproliferation marker Keratin 6 and the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed compared to untreated lesions. In a therapeutic approach, i.e. treatment starting after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated mice displayed an opposite trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, with a higher E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results confirm that SIRT6 plays a role in skin carcinogenesis and suggest SIRT6 pharmacological inhibition as a promising strategy in cSCC.

Conservation of the neural code across subjects is crucial for training brain-computer interfaces. Through alignment of neural manifolds, the authors show cross-subject generalization in the decoding of unconstrained behavior from sensorimotor cortex.

In the framework of sustainability, proposing new technologies to improve the current linear economy system is one of the most challenging aspects for both academics and industries. In this context, the optimization of wastewater recovery and re-use are among the most crucial aspects to improve; in fact, contaminated waters come from a wide range of industries: cooking, refineries, food, pharmaceuticals, textile and agriculture. Heavy metals are among the most critical pollutants, being widely spread (especially in the textile sector) and difficult to remove. In this work, two different sets of Magnetic Nanostructured Adsorbents (MNAs) to clean wastewaters containing Chromium (III), Nickel (II) and Copper (II) ions were studied and compared. The first type of MNA was a 2-D nanosheet structure generated using iron (II/III) salts and sodium (or ammonium) hydroxide solution to decorate a dispersion of graphene oxide (GO) in water. The second type of adsorbent was a 3-D structure composed of GO-MNAs embedded in cross-linked alginate beads. Performed experiments (in a wide range of metal ions concentrations) showed very promising results in terms of removal efficiencies (almost complete abatement could be achieved using a proper amount of MNAs) with respect to all tested contaminants, highlighting better performances of the beads with respect to the corresponding 2-D structure.

Natural deep eutectic solvents (NaDES) represent a new generation of green, non-flammable solvents, useful as an efficient alternative to the well-known ionic liquids. They can be easily prepared and exhibit unexpected solubilizing power for lipophilic molecules, although those of a hydrophilic nature are mostly used. For their unique properties, they can be recommend for different cosmetic and pharmaceutical applications, ranging from sustainable extraction, obtaining ready-to-use ingredients, to the development of biocompatible drug delivery responsive systems. In the biomedical field, NaDES can be used as biopolymer modifiers, acting as delivery compounds also known as “therapeutic deep eutectic systems”, being able to solubilize and stabilize different chemical and galenical formulations. The aim of this review is to give an overview of the current knowledge regarding natural deep eutectic solvents specifically applied in the cosmetic and pharmaceutical fields. The work could help to disclose new opportunities and challenges for their implementation not only as green alternative solvents but also as potential useful pathways to deliver bioactive ingredients in innovative formulations.

Where and how the brain learns from experience is not fully understood. Here the authors use a hierarchical approach from behavioural modelling to systems fMRI to cellular coding reveals brain mechanisms for history informed updating of future predictions.

Aiming at developing a dermal formulation against melanoma, the synthesized imidazo-pyrazoles 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (3-methoxy-4-phenoxy-benzylidene)-hydrazide (4G) and 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (4-benzyloxy-3-methoxy-benzylidene)-hydrazide (4I) were screened on patient-isolated melanoma cells (MEOV NT) and on Vemurafenib (PLX4032)-resistant (MEOV PLX-R) ones. Since 4I on MEOV PLX-R cells was 1.4-fold more effective than PLX, a hydrogel formulation containing 4I (R4HG-4I) was prepared in parallel with an empty R4-based hydrogel (R4HG) using a synthesized antibacterial resin (R4) as gelling agent. Thanks to its high hydrophilicity, porosity (85%), and excellent swelling capability (552%), R4 allowed to achieve R4HG and R4HG-4I with high equilibrium degree of swelling (EDS) and equilibrium water content (EWC). Chemometric-assisted ATR-FTIR analyses confirmed the chemical structure of swollen and fully dried (R4HG-D and R4HG-4I-D) hydrogels. The morphology of R4HG-D and R4HG-4I-D was examined by optical microscopy and SEM, while UV–vis analyses were carried out to obtain the drug loading (DL%) and the encapsulation efficiency (EE%) of R4HG-4I. Potentiometric titrations were performed to determine the equivalents of NH3+ in both R4HG and R4HG-4I. The swelling and water release profiles of both materials and related kinetics were assessed by equilibrium swelling rate and water loss studies, respectively, while their biodegradability over time was assessed by in vitro degradation experiments determining their mass loss. Rheological experiments established that both R4HG and R4HG-4I are shear-thinning Bingham pseudoplastic fluids with low yield stress, thus assuring easy spreadability in a future topical application. Release studies evidenced a sustained and quantitative release of 4I governed mainly by diffusion. Upon favorable results from further experiments in a more realistic 3D model of melanoma, R4HG-4I could represent a starting point to develop new topical therapeutic options to adjuvate the treatments of melanoma cells also when resistant to currently available drugs.

The potential of perinatal tissues to provide cellular populations to be used in different applications of regenerative medicine is well established. Recently, the efforts of researchers are being addressed regarding the evaluation of cell products (secreted molecules or extracellular vesicles, EVs) to be used as an alternative to cellular infusion. The data regarding the effective recapitulation of most perinatal cells’ properties by their secreted complement point in this direction. EVs secreted from perinatal cells exhibit key therapeutic effects such as tissue repair and regeneration, the suppression of inflammatory responses, immune system modulation, and a variety of other functions. Although the properties of EVs from perinatal derivatives and their significant potential for therapeutic success are amply recognized, several challenges still remain that need to be addressed. In the present review, we provide an up-to-date analysis of the most recent results in the field, which can be addressed in future research in order to overcome the challenges that are still present in the characterization and utilization of the secreted complement of perinatal cells and, in particular, mesenchymal stromal cells.

Abstract Transthyretin amyloid cardiomyopathy (ATTR‐CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is associated with various cardiac symptoms, such as progressive heart failure, conduction disturbance, and arrhythmia. The implementation of 99mtechnetium (99mTc)‐labelled bone radiotracer scintigraphy for diagnosing ATTR‐CM has enabled accurate diagnosis of the disease with high sensitivity and specificity and positioned this diagnostic modality as an integral part of disease diagnostic algorithms. In 2020, 99mTc‐pyrophosphate scintigraphy received exceptional approval for Japanese national health insurance reimbursement as a diagnostic method of ATTR‐CM. Nevertheless, the utility of 99mTc‐labelled bone radiotracer scintigraphy and the importance of an early diagnosis of suspected ATTR‐CM using this technique have yet to be internalized as common practice by general cardiologists, and guidance on daily clinical scenarios to consider this technique for a diagnosis of suspected ATTR‐CM is warranted. In this review, we discuss the utility of 99mTc‐labelled bone radiotracer scintigraphy for the early diagnosis of ATTR‐CM based on published literature and the outcomes of an advisory board meeting. This review also discusses clinical scenarios that could support early diagnosis of suspected ATTR‐CM as well as common pitfalls, correct implementation, and future perspectives of 99mTc‐labelled bone radiotracer scintigraphy in daily clinical practice. The clinical scenarios to consider 99mTc‐labelled bone radiotracer scintigraphy in daily practice may include, but are not limited to, patients with a family history of the hereditary type of disease; elderly patients (aged ≥60 years) with unexplained cardiac findings (e.g. cardiac hypertrophy associated with abnormalities on an electrocardiogram, heart failure with preserved ejection fraction associated with unexplained left ventricular hypertrophy, and heart failure with reduced ejection fraction associated with atrial fibrillation and left ventricular hypertrophy); and patients with cardiac hypertrophy associated with diastolic dysfunction, right ventricular/interatrial septum/valve thickness, left ventricular sparkling, or apical sparing. Cardiac hypertrophy and persistent elevation in cardiac troponin in elderly patients are also suggestive of ATTR‐CM. 99mTc‐labelled bone radiotracer scintigraphy is also recommended in patients with characteristic cardiac magnetic resonance findings (e.g. diffuse subendocardial late gadolinium enhancement patterns, native T1 increase, and increase in extracellular volume) or patients with cardiac hypertrophy and bilateral carpal tunnel syndrome.

Objective This systematic review aims to update the evidence on Duchenne muscular dystrophy (DMD) in Italy, describing the epidemiology, quality of life (QoL) of patients and caregivers, treatment adherence, and economic impact of DMD. Methods Systematic searches were conducted in PubMed, Embase and Web of Science up to January 2023. Literature selection process, data extraction and quality assessment were performed by two independent reviewers. Study protocol was registered in PROSPERO (CRD42021245196). Results Thirteen studies were included. The prevalence of DMD in the general population is 1.7–3.4 cases per 100,000, while the birth prevalence is 21.7–28.2 per 100,000 live male births. The QoL of DMD patients and caregivers is lower than that of healthy subjects, and the burden for caregivers of DMD children is higher than that of caregivers of children with other neuromuscular disorders. The compliance of real-world DMD care to clinical guidelines recommendations in Italy is lower than in other European countries. The annual cost of illness for DMD in Italy is € 35,000–46,000 per capita while, adding intangible costs, the total cost amounts to € 70,000. Conclusion Although it is a rare disease, DMD represents a significant burden in terms of quality of life of patients and their caregivers, and economic impact.

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery.

Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the “cytokine storm”, that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.

Abstract Objective evaluation of technical skills of the operators during the obstetrical device application for operative vaginal delivery, named kiwi-cup in a simulation training program. Methods Thirty-five residents in obstetrics and gynecology of the University of Pisa, Italy were recruited and evaluated with an assessment scale on technical skills from 0 to 55 points. They performed various operative vaginal delivery simulations with kiwi-cup and were evaluated at time 0 by a tutor. After 8 weeks, simulation training was repeated and trainees were re-evaluated by the same tutor. Results after 8 weeks from the first simulation session, trainees have been shown to increase technical skills (46.27 ± 4.6 with p-value

Fenretinide (4-HPR), a retinoid derivative, has shown high antitumor activity, a low toxicological profile, and no induction of resistance. Despite these favorable features, the variability in oral absorption due to its low solubility combined with the high hepatic first pass effect strongly reduce clinical outcomes. To overcome the solubility and dissolution challenges of poorly water-soluble 4-HPR, we prepared a solid dispersion of the drug (4-HPR-P5) using a hydrophilic copolymer (P5) previously synthesized by our team as the solubilizing agent. The molecularly dispersed drug was obtained by antisolvent co-precipitation, an easy and up-scalable technique. A higher drug apparent solubility (1134-fold increase) and a markedly faster dissolution were obtained. In water, the colloidal dispersion showed a mean hydrodynamic diameter of 249 nm and positive zeta potential (+41.3 mV), confirming the suitability of the formulation for intravenous administration. The solid nanoparticles were also characterized by a high drug payload (37%), as was also evidenced by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. The 4-HPR-P5 exhibited antiproliferative activity, with IC50 values of 1.25 and 1.93 µM on IMR-32 and SH-SY5Y neuroblastoma cells, respectively. Our data confirmed that the 4-HPR-P5 formulation developed herein was able to increase drug apparent aqueous solubility and provide an extended release over time, thus suggesting that it represents an efficient approach to improve 4-HPR bioavailability.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) serve as a potential cell-based therapy for degenerative disease. They provide immunomodulatory and anti-inflammatory properties, multipotent differentiation potential and are harvested with no ethical concern. It is unknown whether MSCs collected from different areas of the human umbilical cord elicit more favorable effects than others. Three MSC populations were harvested from various regions of the human umbilical cord: cord lining (CL-MSCs), perivascular region (PV-MSCs), and Wharton's jelly (WJ-MSCs). Mesenchymal markers (CD90 and CD73) were expressed by all three cell populations. Stemness marker (OCT4), endothelial cell adhesion molecular marker (CD146), and monocyte-macrophage marker (CD14) were expressed by WJ-MSCs, PV-MSCs, and CL-MSCs, respectively. Stroke presents with oxygen and glucose deprivation and leads to dysfunctional mitochondria and consequently cell death. Targeting the restoration of mitochondrial function in the stroke brain through mitochondrial transfer may be effective in treating stroke. In vitro exposure to ambient and OGD conditions resulted in CL-MSCs number decreasing the least post-OGD/R exposure, and PV-MSCs exhibiting the greatest mitochondrial activity. All three hUC-MSC populations presented similar metabolic activity and survival in normal and pathologic environments. These characteristics indicate hUC-MSCs potential as a potent therapeutic in regenerative medicine.

It is not entirely understood how network plasticity produces the coding of predicted value during stimulus-outcome learning. Here, the authors reveal a reinforcing loop in distributed limbic circuits, transforming sensory stimuli into reward prediction coding broadcasted by dopamine neurons to the brain.

Abstract The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow‐derived NCS‐01 cells. Coculture with NCS‐01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS‐01 cells displayed dose‐dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri‐infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS‐01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS‐01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin‐6, but equally importantly we observed for the first time the formation of filopodia by NCS‐01 cells under stroke conditions, characterized by cadherin‐positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia‐mediated mechanism of action provide solid lab‐to‐clinic evidence supporting the use of NCS‐01 cells for treatment of stroke in the clinical setting.

Water pollution from dyes is harmful to the environment, plants, animals, and humans and is one of the most widespread problems afflicting people throughout the world. Adsorption is a widely used method to remove contaminants derived from the textile industry, food colorants, printing, and cosmetic manufacturing from water. Here, aiming to develop new low-cost and up-scalable adsorbent materials for anionic dye remediation and water decontamination by electrostatic interactions, two cationic resins (R1 and R2) were prepared. In particular, they were obtained by copolymerizing 4-ammonium methyl and ethyl styrene monomers (M1 and M2) with dimethylacrylamide (DMAA), using N-(2-acryloylamino-ethyl)-acrylamide (AAEA) as cross-linker. Once characterized by several analytical techniques, upon their dispersion in an excess of water, R1 and R2 provided the R1- and R2-based hydrogels (namely R1HG and R2HG) with equilibrium degrees of swelling (EDS) of 900% and 1000% and equilibrium water contents (EWC) of 90 and 91%, respectively. By applying Cross’ rheology equation to the data of R1HG and R2HG’s viscosity vs. shear rate, it was established that both hydrogels are shear thinning fluids with pseudoplastic/Bingham plastic behavior depending on share rate. The equivalents of -NH3+ groups, essential for the electrostatic-based absorbent activity, were estimated by the method of Gaur and Gupta on R1 and R2 and by potentiometric titrations on R1HG and R2HG. In absorption experiments in bulk, R1HG and R2HG showed high removal efficiency (97–100%) towards methyl orange (MO) azo dye, fluorescein (F), and their mixture (MOF). Using F or MO solutions (pH = 7.5, room temperature), the maximum absorption was 47.8 mg/g in 90′ (F) and 47.7 mg/g in 120′ (MO) for R1, while that of R2 was 49.0 mg/g in 20′ (F) and 48.5 mg/g in 30′ (MO). Additionally, R1HG and R2HG-based columns, mimicking decontamination systems by filtration, were capable of removing MO, F, and MOF from water with a 100% removal efficiency, in different conditions of use. R1HG and R2HG represent low-cost and up-scalable column packing materials that are promising for application in industrial wastewater treatment.

In the effort to obtain multitarget compound interfering with inflammation, oxidative stress, and tumorigenesis, we synthesized a small library of pyrazole compounds, selecting 4a, 4f, and 4g as the most noteworthy being IC50 against platelet ROS production induced by thrombin of about 10 µM. The in vitro antioxidant potential of the three molecules was evaluated, and since they show a remarkable antioxidative activity, their effect on several parameter indicative of oxidative status and on the efficiency of the aerobic metabolism was tested. The three molecules strongly inhibit superoxide anion production, lipid peroxidation, NADPH oxidase activity and almost restore the oxidative phosphorylation efficiency in thrombin-stimulated platelet, demonstrating a protective effect against oxidative stress. This effect was confirmed in endothelial cell in which 4a, 4f, and 4g show an interesting inhibition activity on H2O2-stimulated EA.hy926 cells. At last, antiproliferative activity of 4a, 4f, and 4g was submitted to a large screening at the NCI. The molecules show interesting anticancer activity, among them the most remarkable is 4g able to strongly inhibit the proliferation of both solid tumor and leukemia cells lines. In conclusion, all the three newly synthetized pyrazoles show remarkable antioxidant and antiproliferative effect worthy of further study.

Here, to develop new topical antibacterial formulations to treat staphylococcal infections, two pyrazoles (3c and 4b) previously reported as antibacterial agents, especially against staphylococci, were formulated as hydrogels (R1-HG-3c and R1HG-4b) using a cationic polystyrene-based resin (R1) and here synthetized and characterized as gelling agents. Thanks to the high hydrophilicity, high-level porosity, and excellent swelling capabilities of R1, R1HG-3c and R1HG-4b were achieved with an equilibrium degree of swelling (EDS) of 765% (R1HG-3c) and 675% (R1HG-4b) and equilibrium water content (EWC) of 88% and 87%, respectively. The chemical structure of soaked and dried gels was investigated by PCA-assisted attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy, while their morphology was investigated by optical microscopy. Weight loss studies were carried out with R1HG-3c and R1HG-4b to investigate their water release profiles and the related kinetics, while their stability was evaluated over time both by monitoring their inversion properties to detect possible impairments of the 3D network and by PCA-assisted ATR-FTIR spectroscopy to detect possible structural changes. The flow and dynamic rheological characterization of the gels was assessed by determining their viscosity vs. shear rate, applying the Cross rheological equation to achieve the curves of shear stress vs. shear rate, and carrying out amplitude and frequency sweep experiments. Finally, their content in NH3+ groups was determined by potentiometric titrations. Due to their favorable physicochemical characteristic and the antibacterial effects of 3c and 4b possibly improved by the cationic R1, the pyrazole-enriched gels reported here could represent new weapons to treat severe skin and wound infections sustained by MDR bacteria of staphylococcal species.

NK cells are innate lymphoid cells endowed with cytotoxic capacity that play key roles in the immune surveillance of tumors. Increasing evidence indicates that NK cell anti-tumor response is shaped by bidirectional interactions with myeloid cell subsets such as dendritic cells (DCs) and macrophages. DC-NK cell crosstalk in the tumor microenvironment (TME) strongly impacts on the overall NK cell anti-tumor response as DCs can affect NK cell survival and optimal activation while, in turn, NK cells can stimulate DCs survival, maturation and tumor infiltration through the release of soluble factors. Similarly, macrophages can either shape NK cell differentiation and function by expressing activating receptor ligands and/or cytokines, or they can contribute to the establishment of an immune-suppressive microenvironment through the expression and secretion of molecules that ultimately lead to NK cell inhibition. Consequently, the exploitation of NK cell interaction with DCs or macrophages in the tumor context may result in an improvement of efficacy of immunotherapeutic approaches.

Objects touched by patients and healthcare workers in hospitals may harbor pathogens, including multi-drug resistant (MDR) staphylococci, enterococci (VRE), Escherichia coli, Acinetobacter, and Pseudomonas species. Medical devices contaminated by these pathogens may also act as a source of severe and difficult-to-treat human infections, thus becoming a critical public health concern requiring urgent resolutions. To this end, we recently reported the bactericidal effects of a cationic copolymer (CP1). Here, aiming at developing a bactericidal formulation possibly to be used either for surfaces disinfection or to treat skin infections, CP1 was formulated as a hydrogel (CP1_1.1-Hgel). Importantly, even if not cross-linked, CP1 formed the gel upon simple dispersion in water, without requiring gelling agents or other additives which could be skin-incompatible or interfere with CP1 bactericidal effects in possible future topical applications. CP1_1.1-Hgel was characterized by attenuated-total-reflectance Fourier transform infrared (ATR-FTIR) and UV-Vis spectroscopy, as well as optic and scanning electron microscopy (OM and SEM) to investigate its chemical structure and morphology. Its stability was assessed by monitoring its inversion properties over time at room temperature, while its mechanical characteristics were assessed by rheological experiments. Dose-dependent cytotoxicity studies performed on human fibroblasts for 24 h with gel samples obtained by diluting CP_1.1-Hgel at properly selected concentrations established that the 3D network formation did not significantly affect the cytotoxic profile of CP1. Also, microbiologic investigations carried out on two-fold serial dilutions of CP1-gel confirmed the minimum inhibitory concentrations (MICs) previously reported for the not formulated CP1.Selectivity indices values up to 12 were estimated by the values of LD50 and MICs determined here on gel samples.

Here, a new two-component hydrogel (CP1OP2-Hgel) was developed, simply by dispersing in water two cationic bactericidal polymers (CP1 and OP2) effective against several multidrug-resistant (MDR) clinical isolates of the most relevant Gram-positive and Gram-negative species. Interestingly, while OP2 acts only as an antibacterial ingredient when in gel, CP1 works as both an antibacterial and a gelling agent. To verify whether it would be worthwhile to use CP1 and OP2 as bioactive ingredients of a new hydrogel supposed for a future treatment of skin infections, dose-dependent cytotoxicity studies with CP1 and OP2 were performed on human fibroblasts for 24 h, before preparing the formulation. Although a significant cytotoxicity at concentrations > 2 µM was evidenced for both polymers, selectivity indices (SIs) over 12 (CP1) and up to six (OP2) were determined, due to the powerful antibacterial properties of the two polymers, thus supporting the rationale for their formulation as a hydrogel. The chemical structure and morphology of CP1OP2-Hgel were investigated by PCA-assisted attenuated total reflectance (ATR) Fourier-transform infrared (FTIR) analysis and scanning electron microscopy (SEM), while its rheological properties were assessed by determining its dynamic viscosity. The cumulative weight loss and swelling percentage curves, the porosity, and the maximum swelling capability of CP1OP2-Hgel were also determined and reported. Overall, due to the potent bactericidal effects of CP1 and OP2 and their favorable selectivity indices against several MDR pathogens, good rheological properties, high porosity, and strong swelling capability, CP1OP2-Hgel may, in the future, become a new weapon for treating severe nosocomial skin infections or infected chronic wounds. Further investigations in this sense are currently being carried out.

Extracellular vesicles (EVs) constitute one of the main mechanisms by which cells communicate with the surrounding tissue or at distance. Vesicle secretion is featured by most cell types, and adult mesenchymal stromal cells (MSCs) of different tissue origins have shown the ability to produce them. In recent years, several reports disclosed the molecular composition and suggested clinical indications for EVs derived from adult MSCs. The parental cells were already known for their roles in different disease settings in regulating inflammation, immune modulation, or transdifferentiation to promote cell repopulation. Interestingly, most reports also suggested that part of the properties of parental cells were maintained by isolated EV populations. This review analyzes the recent development in the field of cell-free therapies, focusing on several adult tissues as a source of MSC-derived EVs and the available clinical data from in vivo models.

Abstract Background Simulation in laparoscopic surgery is nowadays recognized as a valid instrument for learning and training surgeons in different procedures. However, its role as evaluation test and self-assessment tool to verify basic surgical skills is still under discussion. Methods Thirty-three residents in obstetrics and gynecology at University of Pisa, Italy were recruited, and they received a simulation program consisting of 5 tasks. They had to perform basic laparoscopic surgery maneuvers as creating pneumoperitoneum, positioning trocars under vision, demonstrating the appropriate use of dominant and non-dominant hand and making single stitch and knot. They were evaluated with a modified OSATs scale. Results Senior trainees had better score than junior trainees (p value

Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms of the disease, surgical removal of the entire globe and its intraocular contents (enucleation) is, unfortunately, necessary, whereas in other cases, conventional chemotherapy is normally used. To overcome the side-effects and reduced efficacy of traditional chemotherapic drugs, nanodelivery systems that ensure a sustained drug release and manage to reach the target site have more recently been developed. This review takes into account the current use and advances of nanomedicine in the treatment of retinoblastoma and discusses nanoparticulate formulations that contain conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed.

Valve leaflets and chordae structurally normal characterize functional mitral regurgitation (FMR), which in heart failure (HF) setting results from an imbalance between closing and tethering forces secondary to alterations in the left ventricle (LV) and left atrium geometry. In this context, FMR impacts the quality of life and increases mortality. Despite multiple medical and surgical attempts to treat FMR, to date, there is no univocal treatment for many patients. The pathophysiology of FMR is highly complex and involves several underlying mechanisms. Left ventricle dyssynchrony may contribute to FMR onset and worsening and represents an important target for FMR management. In this article, we discuss the mechanisms of FMR and review the potential therapeutic role of CRT, providing a comprehensive review of the available data coming from clinical studies and trials.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

Rosa x damascena Mill. essential oil is mainly used in the cosmetics and perfumery industry, but it also finds application in the food industry as a flavoring agent. The chemical composition of essential oils is affected by environment, soil, harvesting technique, storage condition, and extraction methods. Nowadays, the study and design of greener, more efficient, and sustainable extractive procedures is the main and strategic focus in the chemical research and development of botanical derivatives, especially as regards fragrances and essential oils. Several technologies are available, and the best method to use depends on the desired chemicals, but conventional extractive processes are often laborious and time-consuming, involve large amounts of solvents, and may cause the partial loss of volatiles, affecting the quality of the final product. In the last decade, microwave irradiation has been successfully applied to classical techniques, often improving the general extractive efficiency and extract quality. In the present paper, as a preliminary analytical screening approach, two microwave-mediated techniques, Solvent-Free Microwave Extraction (SFME) and Microwave Hydrodiffusion and Gravity (MHG), and two conventional procedures, Hydrodistillation (HD) and Steam Distillation (SD), were applied and compared for the extraction of volatile compounds from R. x damascena fresh petals to highlight differences and advantages of the selected procedure and of the obtained extracts useful in a cosmetic context as fragrances or active ingredients. The chemical composition of the extracts was investigated by GC-MS and GC-FID. Sixty-one components, distributed in the four techniques, were identified. SD and HD are dominated by oxygenated terpenes (59.01% and 50.06%, respectively), while MHG and SFME extracts are dominated by alcohols (61.67% and 46.81%, respectively). A relevant variability in the composition of the extracts relating to the extraction techniques used was observed. To point out the correlation between the process and composition of the obtained natural products, principal component analysis (PCA) of the data extracted from GC-FID was used. Taking into account a cosmetic application, SFME shows several advantages when compared with the other procedures. The extract (obtained in a significantly higher amount) contains a meaningful lower level of potential fragrance allergenic compounds and quite a double amount of benzyl alcohol and 2-phenyl ethanol that can also enhance the preservative action in personal care products.

The production of olive oil generates olive mill wastewater (OMW) which essentially derives from the processing, treatment and pressing of olives in mills. Traditional milling processes require a quantity of water varying between 40 and 120 L per quintal of pressed olives, generating a considerable amount of wastewater. It is thus necessary to reduce process water and enhance its use to implement the concept of a circular economy. To this end, our preliminary work was dedicated to water purification by means of suitable and efficient filtration systems. The microfiltered OMW was firstly concentrated through reverse osmosis. Then, an additional concentration step was carried out via vacuum membrane distillation using hydrophobic hollow fiber membranes. The application of the membrane-based processes allowed the recovery of a purified water and the concentration of valuable polyphenols in a smaller volume. The different fractions obtained from the purification have been tested for the determination of the antioxidant power (DPPH assay) and dosage of polyphenols (Folin–Ciocalteu assay) and were characterized using IR spectroscopy. All samples showed relevant antioxidant activity (percentage range: 10–80%) and total phenolic content in the 1.5–15 g GAE/L range. The obtained fractions were tested for their antimicrobial effect on numerous clinical isolates of Gram-positive and Gram-negative species, resistant and multi-resistant to current antibiotic drugs. OMW samples showed widespread activity against the considered (phyto)pathogens (MIC range 8–16 mg/mL) thus supporting the value of this waste material in the (phyto)pharmaceutical field.

Stroke is a debilitating disease that remains as a significant unmet need. Although our understanding of the disease pathology has advanced over the years, treatment options for stroke are limited. Recent studies have implicated the important role of healthy mitochondria in neuroprotection against stroke. Under the stroke pathological condition, transfer of healthy mitochondria is observed from astrocytes to ischemic neurons. However, without additional therapeutic intervention, such astrocyte-to-neuron transfer of mitochondria may not sufficiently afford a robust and stable therapeutic effect against the devastating primary insult and progressive neurodegeneration associated with stroke. We now explore the concept that transplantation of exogenous stem cells may serve as efficacious sources of healthy mitochondria for ischemic cells, not only neurons but also endothelial cells. This review captures the recent advances on the therapeutic potential of mitochondrial transfer as a novel stroke treatment. This paper is a review article. Referred literature in this article has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit – a communication framework between neurons, their supply microvessels along with glial cells – underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.