Electronics and Detectors for the Stellar Intensity Interferometer of the ASTRI Mini-Array Telescopes.

The ASTRI Mini-Array is an international collaboration led by the Italian National Institute for Astrophysics (INAF) that will operate nine telescopes to perform Cherenkov and optical stellar intensity interferometry (SII) observations. At the focal plane of these telescopes, we are planning to install a stellar intensity interferometry instrument. Here we present the selected design, based on Silicon Photomultiplier (SiPM) detectors matching the telescope point spread function together with dedicated front-end electronics.

Curcumin I-SMA nanomicelles as promising therapeutic tool to tackle bacterial infections.

Renewed interest towards natural substances has been pushed by the widespread diffusion of antibiotic resistance. Curcumin I is the most active and effective constituent of curcuminoids extracted from Curcuma longa and, among other beneficial effects, attracted attention for its antimicrobial potential. Since the poor pharmacokinetic profile hinders its efficient utilization, in the present paper, we report encapsulation of curcumin I in poly(styrene-co-maleic acid) (SMA-CUR) providing a nanomicellar system with improved aqueous solubility and bioavailability. SMA-CUR was characterized by means of size, zeta potential, polydispersity index, atomic force microscopy (AFM), drug release studies, spectroscopic properties and stability. SMA-CUR nanoformulation displayed exciting antimicrobial properties compared to free curcumin I towards Gram-positive and Gram-negative clinical isolates.

New Isolation of Ponticelli III Virus (Bunyavirales: Phenuiviridae) in Emilia-Romagna Region, Italy.

The number of newly described sandfly-borne phleboviruses has been steadily growing in recent years. Some phleboviruses are human pathogens, but their health relevance is largely uncharacterized. We aimed to investigate the circulation of these viruses in the Emilia-Romagna region where several have already been described. A total of 482 sandflies were collected in a site in Reggio Emilia in 2019 and 2020. Sandflies collected in 2020 were grouped in 21 pools with a maximum of 25 sandflies per pool, submitted to real time PCR, and isolated in Vero cell culture. Complete genome sequencing showed the isolation of a strain of a Ponticelli III virus. This virus, which belongs to the species Adana phlebovirus, differed in the M segment from the Ponticelli I and Ponticelli II viruses. Analysis performed on the genomic segments of the newly isolated virus compared with other phleboviruses highlighted a strong purifying selection in the L segments, and different substitution saturation, highest in the M segments. Future research should address the ecological processes driving the occurrence of these novel phleboviruses and their possible impact on public health.

Discovery of SI 1/20 and SI 1/22 as Mutual Prodrugs of 5-Fluorouracil and Imidazole-Based Heme Oxygenase 1 Inhibitor with Improved Cytotoxicity in DU145 Prostate Cancer Cells.

In this work, we extend the concept of 5-fluorouracil/heme oxygenase 1 (5-FU/HO-1) inhibitor hybrid as an effective strategy for enhancing 5-FU-based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1/20 and SI 1/22, in which the two active parent drugs (i. e., 5-FU and an imidazole-based HO-1 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and in silico ADMET predictions were indicative of good drug-likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5-FU and HO-1 inhibitor administered alone or in combination. Interestingly, both compounds showed statistically significant lower toxicity, than 5-FU at the same dose, against non-tumorigenic human benign prostatic hyperplasia (BPH-1) cell line. Moreover, the newly synthesized mutual prodrugs inhibited the HO-1 activity both in a cell-free model and in vitro, as well as downregulated the HO-1 expression and increased the reactive oxygen species (ROS) levels.

Science of the Van Allen Probes Science Operations Centers.

The Van Allen Probes mission operations materialized through a distributed model in which operational responsibility was divided between the Mission Operations Center (MOC) and separate instrument specific SOCs. The sole MOC handled all aspects of telemetering and receiving tasks as well as certain scientifically relevant ancillary tasks. Each instrument science team developed individual instrument specific SOCs proficient in unique capabilities in support of science data acquisition, data processing, instrument performance, and tools for the instrument team scientists. In parallel activities, project scientists took on the task of providing a significant modeling tool base usable by the instrument science teams and the larger scientific community. With a mission as complex as Van Allen Probes, scientific inquiry occurred due to constant and significant collaboration between the SOCs and in concert with the project science team. Planned cross-instrument coordinated observations resulted in critical discoveries during the seven-year mission. Instrument cross-calibration activities elucidated a more seamless set of data products. Specific topics include post-launch changes and enhancements to the SOCs, discussion of coordination activities between the SOCs, SOC specific analysis software, modeling software provided by the Van Allen Probes project, and a section on lessons learned. One of the most significant lessons learned was the importance of the original decision to implement individual team SOCs providing timely and well-documented instrument data for the NASA Van Allen Probes Mission scientists and the larger magnetospheric and radiation belt scientific community.

Odontogenic keratocystic can be misdiagnosed for a lateral periodontal cyst when the clinical and radiographical findings are similar.

Lateral periodontal cyst (LPC) and odontogenic keratocystic (OK) are two osteolytic lesions of the jaw with different local invasiveness and percentage of recurrence. The aim of this study was to highlight the attention on the differential diagnosis of these lesions that sometimes can have unexpected location and can lead doubts on diagnosis, therapy, and follow-up. A 34-year-old man presented to our department with a complaint of soft pain in the vestibular aspect of left mandibular second premolar and left mandibular first molar. Vital teeth in the left mandible, no mucosal swelling, and no drainage were observed. The CBCT showed a well circumscribed hypodensity area, extending between 3.5 and the apex of mesial root of 3.6. No displacement and no resorption of the roots were notified. Upon clinical and radiographical examination, a provisional diagnosis of LPC was made and enucleation of the lesion and histological examination were planned. Histologically, a cystic wall partially lined by a keratinizing squamous epithelium was observed. Surrounding and within the lesion, there was a chronic inflammatory infiltrate also of granulomatous type and with cholesterol clefts. Based on these findings, the diagnosis of odontogenic keratocystic was done. Radiolucent lesions in the premolar and canine region are frequently clinically and radiographically misdiagnosed. The identification of keratocyst in a location preoperatively favoring a lateral periodontal cyst should be suspected and biopsy must be considered in all cases to establish the nature of the lesion, the best surgical treatment, and the follow-up appointments.

Ejaculation Sparing Thulium Laser Enucleation of the Prostate: An Observational Prospective Study.

Benign prostatic hypertrophy (BPH) is a condition that appears with advancing age and affects 1/3 of men over 50 years, resulting in filling and emptying symptoms. One of the main limitations of endoscopic techniques for BPH is the occurrence of retrograde ejaculation. The purpose of this prospective observational study is to evaluate the efficacy and feasibility of ejaculation-sparing thulium laser enucleation of the prostate (ES-ThuLEP) in the treatment of BPH-related LUTS and the preservation of ejaculation. Sexually active patients with BPH were enrolled and followed up with at 3, 6, and 12 months after surgery. Personal and pharmacological histories were collected, while three standardized questionnaires­the International Index of Erectile Function short form (IIEF-5), the International Consultation on Incontinence Questionnaire for Male Sexual Matters Associated with Lower Urinary Tract Symptoms Module (ICIQ­MLUTSsex), and the International Prostatic Symptom Score (IPSS)­were administered. In addition, all patients underwent uroflowmetry and an assessment of post-void residual volume (PVR). A total of 53 patients were enrolled. A statistically significant improvement in the IPSS score, maximum flow (Qmax), and post-void volume (PVR) at 3 months, 6 months, and 12 months after surgery was found (p < 0.05), while no statistically significant differences were reported between IIEF-5 scores before and after surgery. A total of 48 patients (88.6%) had preserved ejaculation at 3 months, while 92.4% and 94.3% of patients reported preserved ejaculation at 6 and 12 months, respectively. Nevertheless, some degree of hypoposia was referred, at 3, 6, and 12 months, by 43.7%, 30.6%, and 13.2% of patients, respectively. The ES-ThuLEP technique successfully preserved ejaculation in over 90% of patients, representing an ejaculation-sparing alternative in the treatment of BPH.

Structure-activity relationships of mixed σ1R/σ2R ligands with antiproliferative and anticancer effects.

The overexpression of σ receptors (σRs) in various types of tumors has prompted a deep investigation of their role in cancer pathophysiology. Consequently, σR ligands have been widely studied in vitro and in vivo for their antiproliferative effects as a novel potential class of chemotherapeutic agents, both alone and in combination with other anticancer drugs. A growing body of evidence highlights that σR ligands can inhibit cancer cells' survival, migration, and proliferation, thanks to the modulation of a wide panel of tumorigenic pathways. In addition to their antitumor activity, σR ligands are gaining momentum as radiotracers for PET and SPECT imaging applications. The purpose of this review is to report on recent advances in the development of σR ligands. In particular, herein, we describe the structure-activity relationships of structurally diverse mixed σ1R/σ2R ligands that showed promising antitumor profiles towards a variety of cancer cell lines.

Sand Flies and Pathogens in the Lowlands of Emilia-Romagna (Northern Italy).

Cases of sand fly-borne diseases in the Emilia-Romagna region, such as meningitis caused by Toscana virus and human leishmaniasis, are reported annually through dedicated surveillance systems. Sand flies are abundant in the hilly part of the region, while the lowland is unsuitable habitat for sand flies, which are found in lower numbers in this environment with respect to the hilly areas. In this study, we retrieved sand flies collected during entomological surveillance of the West Nile virus (from 2018 to 2021) to assess their abundance and screen them for the presence of pathogens. Over the four-year period, we collected 3022 sand flies, more than half in 2021. The most abundant sand fly species was Phlebotomus (Ph.) perfiliewi, followed by Ph. perniciosus; while more rarely sampled species were Ph. papatasi, Ph. mascittii and Sergentomyia minuta. Sand flies were collected from the end of May to the end of September. The pattern of distribution of the species is characterized by an abundant number of Ph. perfiliewi in the eastern part of the region, which then falls to almost none in the western part of the region, while Ph. perniciosus seems more uniformly distributed throughout. We tested more than 1500 female sand flies in 54 pools to detect phleboviruses and Leishmania species using different PCR protocols. Toscana virus and Leishmania infantum, both human pathogens, were detected in 5 pools and 7 pools, respectively. We also detected Fermo virus, a phlebovirus uncharacterized in terms of relevance to public health, in 4 pools. We recorded different sand fly abundance in different seasons in Emilia-Romagna. During the season more favorable for sand flies, we also detected pathogens transmitted by these insects. This finding implies a health risk linked to sand fly-borne pathogens in the surveyed area in lowland, despite being considered a less suitable habitat for sand flies with respect to the hilly areas.

Novel Tyrosine Kinase Inhibitors to Target Chronic Myeloid Leukemia.

This paper reports on a novel series of tyrosine kinase inhibitors (TKIs) potentially useful for the treatment of chronic myeloid leukemia (CML). The newly designed and synthesized compounds are structurally related to nilotinib (NIL), a second-generation oral TKI, and to a series of imatinib (IM)-based TKIs, previously reported by our research group, these latter characterized by a hybrid structure between TKIs and heme oxygenase-1 (HO-1) inhibitors. The enzyme HO-1 was selected as an additional target since it is overexpressed in many cases of drug resistance, including CML. The new derivatives 1a-j correctly tackle the chimeric protein BCR-ABL. Therefore, the inhibition of TK was comparable to or higher than NIL and IM for many novel compounds, while most of the new analogs showed only moderate potency against HO-1. Molecular docking studies revealed insights into the binding mode with BCR-ABL and HO-1, providing a structural explanation for the differential activity. Cytotoxicity on K562 CML cells, both NIL-sensitive and -resistant, was evaluated. Notably, some new compounds strongly reduced the viability of K562 sensitive cells.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells.

The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study's purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO's effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO's implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO's contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.

Non-prep veneer technique: an analytical laboratory model approach.

There is an ever-increasing patient demand for an esthetic and ultraconservative approach in the restoration of anterior teeth. No-prep veneers are one of the most conservative methods of rehabilitation in esthetic dentistry. To implement the no-prep veneer technique successfully, it is essential to adhere to an analytical treatment concept. In the present case report, despite the fact that some of the veneers were very thin, they could be designed in a nature-identical manner in terms of light dynamics and color. The laboratory technique presented in this article opens up the possibility of modifying and harmonizing tooth shapes and gingival margin contours, and makes it possible to position the prosthetic termination line at different levels without affecting the marginal and interproximal adaptation of the restoration.

Identification of Toscana virus in natural population of sand flies (Diptera: Psychodidae) from Moroccan leishmaniasis foci.

BACKGROUND: Phlebotomine sand flies are known as vectors of various pathogens such as Leishmania sp parasite and Toscana virus (TOSV). Leishmaniasis is endemic in Morocco, and TOSV is increasingly reported. Our objective is to analyze the specific composition of the natural population of sand flies in endemic and non endemic area of leishmaniasis in Morocco, thus evaluated their infection by Toscana virus. METHODS: Sand flies were collected by CDC miniature light traps from seven different localities with an altitude range from 399 m to 1496 m. Synanthropic index was calculated for each sand fly species. The collected female sand flies were grouped in 73 pools, with a maximum of 50 specimens per pool, and submitted to real time PCR for TOSV detection. RESULTS: 8 sand fly species were identified morphologically: 5 of the Phlebotomus genus and 3 of the Sergentomyia genus. Phlebotomus sergenti was the most abundant species comprising of 43,12% of identified sand flies, followed by P. papatasi (18,89%) and P. longicuspis (13,43%). Estimated synanthropic indices for these species were between + 1.1 and + 12.6 suggesting a high preference to anthropogenic environments. A total of 3558 sand fly females were grouped in 73 pools (up to 50 sand flies per pool) for TOSV detection. TOSV was detected in one pool (out of 6 tested) from Lalla Laaziza locality (Chichaoua Province) where P. sergenti was the most abundant sand fly species. CONCLUSION: We reported the TOSV for the first time in a central Morocco, where cutaneous leishmaniasis by L. tropica is endemic. This result has epidemiological importance for both researchers and health authorities to monitor circulation of TOSV and implement a surveillance plan of sand fly-borne phleboviruses in Morocco.

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use.

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42-28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

Host preference and Leishmania infantum natural infection of the sand fly Phlebotomus perfiliewi in northern Italy.

The host preference of hematophagous insects is important in determining the cycle of pathogens that they potentially transmit; for example, sand flies are competent vectors of Leishmania parasites. In this work, we evaluated the host preference of sand flies collected in the Emilia-Romagna region of Italy in 2018 and 2019 in an area in which Leishmania infantum circulates actively. Out of about 30,000 sampled sand flies, we obtained 252 engorged females, which were processed to identify the sources of blood meals. Sampling data collected confirmed a positive phototropism of Phlebotomus (Ph.) perfiliewi respect to Ph. perniciosus and the enhanced efficiency of light traps in collecting engorged females compared with traps baited with carbon dioxide. We identified blood source in 185 females (183 Ph. perfiliewi, two Ph. pernicious). The most bitten animal was the roe deer (49.5%), followed by humans (29.2%), hare (7.1%) and cow (4.7%). Other animals, including wild boar, horse, donkey, porcupine, chicken and red fox, were less represented (<2%), while the blood of dogs and rodents were not detected. In addition, we singly screened engorged females for Leishmania founding 5 positive specimens, fed on roe deer (4) and man (1), providing evidence of parasite circulation in a sylvatic environment, where presence of dogs was not common. These findings suggest the existence of an uncharacterized Leishmania reservoir in the surveyed area.

Discovery of Novel Acetamide-Based Heme Oxygenase-1 Inhibitors with Potent In Vitro Antiproliferative Activity.

Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Accordingly, compounds 7i and 7l-p emerged for their potency against HO-1 and were investigated for their anticancer activity against prostate (DU145), lung (A549), and glioblastoma (U87MG, A172) cancer cells. The selected compounds showed the best activity toward U87MG cells. Compound 7l was further investigated for its in-cell enzymatic HO-1 activity, expression levels, and effects on cell invasion and vascular endothelial growth factor (VEGF) extracellular release. The obtained data suggest that 7l can reduce cell invasivity acting through modulation of HO-1 expression.

Co-Circulation of Phleboviruses and Leishmania Parasites in Sand Flies from a Single Site in Italy Monitored between 2017 and 2020.

Sand flies transmit Leishmania infantum, which is responsible for causing leishmaniasis, as well as many phleboviruses, including the human pathogenic Toscana virus. We screened sand flies collected from a single site between 2017 and 2020 for the presence of both phleboviruses and Leishmania. The sand flies were sampled with attractive carbon dioxide traps and CDC light traps between May and October. We collected more than 50,000 sand flies; 2826 were identified at the species level as Phlebotomus perfiliewi (98%) or Phlebotomus perniciosus (2%). A total of 16,789 sand flies were tested in 355 pools, and phleboviruses were found in 61 pools (6 Toscana virus positive pools, 2 Corfou virus positive pools, 42 Fermo virus positive pools, and 7 Ponticelli virus positive pools, and 4 unidentified phlebovirus positive pools). Leishmania was found in 75 pools and both microorganisms were detected in 16 pools. We isolated nine phleboviruses from another 2960 sand flies (five Ponticelli viruses and for Fermo viruses), not tested for Leishmania; the complete genome of a Fermo virus isolate was sequenced. The simultaneous detection in space and time of the Fermo virus and L. infantum is evidence that supports the co-circulation of both microorganisms in the same location and partial overlap of their cycles. A detailed characterization of the epidemiology of these microorganisms will support measures to limit their transmission.

Lipid Nanoparticles Traverse Non-Corneal Path to Reach the Posterior Eye Segment: In Vivo Evidence.

Lipid-based nanocarriers (LNs) have made it possible to prolong corneal residence time and improve the ocular bioavailability of ophthalmic drugs. In order to investigate how the LNs interact with the ocular mucosa and reach the posterior eye segment, we have formulated lipid nanocarriers that were designed to bear a traceable fluorescent probe in the present work. The chosen fluorescent probe was obtained by a conjugation reaction between fluoresceinamine and the solid lipid excipient stearic acid, forming a chemically synthesized adduct (ODAF, N-(3',6'-dihydroxy-3-oxospiro [isobenzofuran-1(3H),9'-[9H] xanthen]-5-yl)-octadecanamide). The novel formulation (LN-ODAF) has been formulated and characterized in terms of its technological parameters (polydispersity index, mean particle size and zeta potential), while an in vivo study was carried out to assess the ability of LN-ODAF to diffuse through different ocular compartments. LN-ODAF were in nanometric range (112.7 nm ± 0.4), showing a good homogeneity and long-term stability. A TEM (transmission electron microscopy) study corroborated these results of characterization. In vivo results pointed out that after ocular instillation, LN ODAF were concentrated in the cornea (two hours), while at a longer time (from the second hour to the eighth hour), the fluorescent signals extended gradually towards the back of the eye. From the results obtained, LN-ODAF demonstrated a potential use of lipid-based nanoparticles as efficient carriers of an active pharmaceutical ingredient (API) involved in the management of retinal diseases.

Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs.

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the "mutual prodrug" approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity.

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1-4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.