@article{%a1.%Yb_29,

title = {Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase},

author = {Joseph CR and Dusi S and Giannattasio M and Branzei D},

url = {https://www.nature.com/articles/s41467-022-30215-9},

doi = {10.1038/s41467-022-30215-9},

year  = {2022},

date = {2022-08-25},

journal = {Nature communications},

volume = {13},

issue = {1},

pages = {2480},

abstract = {DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_28,

title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies},

author = {Gorski M and Rasheed H and Teumer A and Thomas LF and Graham SE and Sveinbjornsson G and Winkler TW and Gunther F and Stark KJ and Chai JF and Tayo BO and Wuttke M and Li Y and Tin A and Ahluwalia TS and Ärnlöv J and Åsvold BO and Bakker SJL and Banas B and Bansal N and Biggs ML and Biino G and {et al}},

url = {https://www.sciencedirect.com/science/article/pii/S0085253822004549?via%3Dihub},

doi = {10.1016/j.kint.2022.05.021},

year  = {2022},

date = {2022-08-25},

journal = {Kidney international},

volume = {102},

issue = {3},

pages = {624-639},

abstract = {Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_36,

title = {Editorial: Novel Insights Into Female Post-Mating Physiology in Insects},

author = {Scolari F and Khamis FM and Perez-Staples D},

url = {https://www.frontiersin.org/articles/10.3389/fphys.2022.877222/full},

doi = {10.3389/fphys.2022.877222},

year  = {2022},

date = {2022-08-24},

journal = {Frontiers in physiology},

volume = {13},

pages = {877222},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybz,

title = {epg5 knockout leads to the impairment of reproductive success and courtship behaviour in a zebrafish model of autophagy-related diseases},

author = {Fontana CM and Locatello L and Sabatelli P and Facchinello N and Lidron E and Maradonna F and Carnevali O and Rasotto MB and Dalla Valle L},

url = {https://www.sciencedirect.com/science/article/pii/S2319417021000342?via%3Dihub},

doi = {10.1016/j.bj.2021.04.002},

year  = {2022},

date = {2022-08-24},

journal = {Biomedical journal},

volume = {45},

issue = {2},

pages = {377-386},

abstract = {Background: Dysregulation of the autophagic flux is linked to a wide array of human diseases, and recent findings highlighted the central role of autophagy in reproduction, as well as an association between impairment of autophagy and behavioural disorders. Here we deepened on the possible multilevel link between impairment of the autophagic processes and reproduction at both the physiological and the behavioural level in a zebrafish mutant model. Methods: Using a KO epg5 zebrafish line we analysed male breeding success, fertility rate, offspring survival, ejaculate quality, sperm and testes morphology, and courtship behaviour. To this aim physiological, histological, ultrastructural and behavioural analyses on epg5+/+ and mutant epg5-/- males coupled to WT females were applied. Results: We observed an impairment of male reproductive performance in mutant epg5-/- males that showed a lower breeding success with a reduced mean number of eggs spawned by their WT female partners. The spermatogenesis and the ability to produce fertilising ejaculates were not drastically impaired in our mutant males, whereas we observed a reduction of their courtship behaviour that might contribute to explain their lower overall reproductive success. Conclusion: Collectively our findings corroborate the hypothesis of a multilevel link between the autophagic process and reproduction. Moreover, by giving a first glimpse on behavioural disorders associated to epg5 KO in model zebrafish, our results open the way to more extensive behavioural analyses, also beyond the reproductive events, that might serve as new tools for the molecular screening of autophagy-related multisystemic and neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yby,

title = {Development of a Short Questionnaire for the Screening for Vitamin D Deficiency in Italian Adults: The EVIDENCe-Q Project},

author = {{De Giuseppe R} and Tomasinelli CE and Cena H and Braschi V and Giampieri F and Preatoni G and Centofanti D and Princis MP and Bartoletti E and Biino G},

url = {https://www.mdpi.com/2072-6643/14/9/1772},

doi = {10.3390/nu14091772},

year  = {2022},

date = {2022-08-23},

journal = {Nutrients},

volume = {14},

issue = {9},

pages = {1772},

abstract = {Background: To develop and validate a questionnaire for the screening of Vitamin D in Italian adults (Evaluation Vitamin D dEficieNCy Questionnaire, EVIDENCe-Q). Methods: 150 participants, attending the 11Clinical Nutrition and Dietetics Operative Unit, Internal Medicine and Endocrinology, Istituti Clinici Scientifici Maugeri IRCCS, of Pavia were enrolled. Demographic variables and serum levels of vitamin D were recorded. The EVIDENCe-Q included information regarding factors affecting the production, intake, absorption and metabolism of Vitamin D. The EVIDENCe-Q score ranged from 0 (the best status) to 36 (the worst status). Results: Participants showed an inadequate status of Vitamin D, according to the current Italian reference values. A significant difference (p < 0.0001) in the EVIDENCe-Q score was found among the three classes of vitamin D status (severe deficiency, deficiency and adequate), being the mean score higher in severe deficiency and lower in the adequate one. A threshold value for EVIDENCe-Q score of 23 for severe deficiency, a threshold value of 21 for deficiency and a threshold value of 20 for insufficiency were identified. According to these thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 22%, 35.3% and 43.3% of the study population, respectively. Finally, participants with EVIDENCe-Q scores <20 had adequate levels of vitamin D. Conclusions: EVIDENCe-Q can be a useful and easy screening tool for clinicians in their daily practice at a reasonable cost, to identify subjects potentially at risk of vitamin D deficiency and to avoid unwarranted supplementation and/or costly blood testing},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_38,

title = {Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability},

author = {Ticli G and Cazzalini O and Stivala LA and Prosperi E},

url = {https://www.mdpi.com/resolver?pii=ijms23137058},

doi = {10.3390/ijms23137058},

year  = {2022},

date = {2022-08-19},

journal = {International journal of molecular sciences},

volume = {23},

issue = {13},

pages = {7058},

abstract = {The p21 protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_30,

title = {The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer},

author = {Mazzeschi M and Sgarzi M and Romaniello D and Gelfo V and Cavallo C and Ambrosi F and Morselli A and Miano C and Laprovitera N and Girone C and Ferracin M and Santi S and Rihawi K and Ardizzoni A and Fiorentino M and D'Uva G and Győrffy B and Palmer R and Lauriola M},

url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02309-1},

doi = {10.1186/s13046-022-02309-1},

year  = {2022},

date = {2022-08-19},

journal = {Journal of experimental & clinical cancer research},

volume = {41},

issue = {1},

pages = {113},

abstract = {Background: In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods: In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results: ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions: Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_40,

title = {Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature},

author = {Valenti AC and Albini A and Imberti JF and Vitolo M and Bonini N and Lattanzi G and Schnabel RB and Boriani G},

url = {https://www.mdpi.com/2079-7737/11/4/530},

doi = { doi: 10.3390/biology11040530},

year  = {2022},

date = {2022-08-18},

journal = {Biology (Basel)},

volume = {11},

issue = {4},

abstract = {Cardiolaminopathies are a heterogeneous group of disorders which are due to mutations in the genes encoding for nuclear lamins or their binding proteins. The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias. Despite the prognostic significance of cardiac involvement in this setting, the current recommendations lack strong evidence. The aim of our work was to systematically review the current data on the main cardiovascular outcomes in cardiolaminopathies. We searched PubMed/Embase for studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality). In total, 11 studies were included (1070 patients, mean age between 26-45 years, with follow-up periods ranging from 2.5 years up to 45 ± 12). When available, data on the EMD-mutated population were separately reported (40 patients). The incidence rates (IR) were individually assessed for the outcomes of interest. The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year. The IR of atrial standstill ranged between 0 and 2 events/100 pts-year. The IR for malignant ventricular arrhythmias reached 10.2 events/100 pts-year and 15.6 events/100 pts-year for appropriate implantable cardioverter-defibrillator (ICD) interventions. The IR for advanced conduction disturbances ranged between 3.2 and 7.7 events/100 pts-year. The IR of thromboembolic events reached up to 8.9 events/100 pts-year. Our results strengthen the need for periodic cardiological evaluation focusing on the early recognition of atrial arrhythmias, and possibly for the choice of preventive strategies for thromboembolic events. The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_37,

title = {DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective},

author = {Secchi M and Lodola C and Garbelli A and Bione S and Maga G},

url = {https://www.mdpi.com/2072-6694/14/15/3820},

doi = {10.3390/cancers14153820},

year  = {2022},

date = {2022-08-18},

journal = {Cancers (Basel)},

volume = {14},

issue = {15},

pages = {3820},

abstract = {RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_35,

title = {A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids},

author = {Ramdas S and Judd J and {………} and Biino G and {……..} and {et al.}},

url = {https://www.sciencedirect.com/science/article/pii/S0002929722002658?via%3Dihub},

doi = {10.1016/j.ajhg.2022.06.012},

year  = {2022},

date = {2022-08-18},

journal = {American journal of human genetics},

volume = {109},

issue = {8},

pages = {1366-1387},

abstract = {A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_34,

title = {Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells},

author = {Piazzi M and Bavelloni A and Cenni V and Salucci S and Bartoletti Stella A and Tomassini E and Scotlandi K and Blalock WL and Faenza I},

url = {https://www.mdpi.com/1420-3049/27/9/2742},

doi = {10.3390/molecules27092742},

year  = {2022},

date = {2022-08-18},

journal = {Molecules},

volume = {27},

issue = {9},

pages = {2742},

abstract = {Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_32,

title = {MCD Diet Rat Model Induces Alterations in Zinc and Iron during NAFLD Progression from Steatosis to Steatohepatitis},

author = {Palladini G and Di Pasqua LG and Cagna M and Croce AC and Perlini S and Mannucci B and Profumo A and Ferrigno A and Vairetti M},

url = {https://www.mdpi.com/1422-0067/23/12/6817},

doi = {10.3390/ijms23126817},

year  = {2022},

date = {2022-08-18},

journal = {International journal of molecular sciences},

volume = {23},

issue = {12},

pages = {6817},

abstract = {We evaluate the effects of the methionine-choline-deficient (MCD) diet on serum and hepatic zinc (Zn) and iron (Fe) and their relationships with matrix metalloproteinases (MMPs) and their modulators (TIMPs and RECK) as well as hepatic fatty acids using male Wistar rats fed 2-, 4- and 8-week MCD diets. Serum and hepatic Zn decrease after an 8-week MCD diet. Serum Fe increases after an 8-week MCD diet and the same occurs for hepatic Fe. An increase in hepatic MMP activity, associated with a decrease in RECK and TIMPs, is found in the MCD 8-week group. Liver Fe shows a positive correlation versus MMPs and RECK, and an inverse correlation versus TIMPs. A positive correlation is found comparing liver Zn with stearic, vaccenic and arachidonic acids, and an inverse correlation is found with linolenic and docosatetraenoic acids. An opposite trend is found between liver Fe versus these fatty acids. During NAFLD progression from steatosis to steatohepatitis, MCD rats exhibit an increase in Zn and a decrease in Fe levels both in serum and tissue associated with alterations in hepatic MMPs and their inhibitors, and fatty acids. The correlations detected between Zn and Fe versus extracellular matrix modulators and fatty acids support their potential role as therapeutic targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_27,

title = {Ambra1 deficiency impairs mitophagy in skeletal muscle},

author = {Gambarotto L and Metti S and Chrisam M and Cerqua C and Sabatelli P and Armani A and Zanon C and Spizzotin M and Castagnaro S and Strappazzon F and Grumati P and Cescon M and Braghetta P and Trevisson E and Cecconi F and Bonaldo P.},

url = {https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13010},

doi = {10.1002/jcsm.13010},

year  = {2022},

date = {2022-08-18},

journal = {Journal of cachexia, sarcopenia and muscle},

volume = {13},

issue = {4},

pages = {2211-2224},

abstract = {Background: Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency. Methods: To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux. Results: Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle. Conclusions: Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybu,

title = {Multiple lipid nanoparticles as antimicrobial drug delivery systems},

author = {{Ben Khalifa R} and Cacciatore I and Dimmito MP and  Ciulla M and Grande R and Puca V and Robuffo I and De Laurenzi V and Chekir-Ghedira L and Di Stefano A and Marinelli L},

url = {https://www.sciencedirect.com/science/article/pii/S1773224721005670?via%3Dihub},

doi = {10.1016/j.jddst.2021.102887},

year  = {2022},

date = {2022-08-17},

journal = {Journal of drug delivery science and technology},

volume = {67},

pages = {102887},

abstract = {The present work aimed at investigating formulations based on multiple lipid nanoparticles (MLNs) containing carvacrol (CAR) and vancomycin hydrochloride (VAN) co-loaded (CAR-VAN-MLNs) as therapeutical strategy useful to improve the antibiotic activity of VAN. Drug-loaded MLNs were prepared by the ultra-sonication technique and investigated for both physico-chemical and antimicrobial properties. Results revealed that all the formulations possessed particle size lower than 150 nm and negatively charged surfaces, as suggested by the ?-potential values. The encapsulation efficiencies were higher than 70% and 21% for CAR and VAN, respectively. Moreover, differential scanning calorimetry analysis confirmed the effective drug loading, while stability studies indicated that the prepared formulations remained stable for about one month when stored at 4 oC. Finally, in vitro studies revealed a sustained drug release during the time. The morphological MLNs characterization, performed by transmission electron microscopy analysis, showed a spherical shape of the produced nanoparticles. Antimicrobial studies suggested that the co-encapsulation improved VAN antibiotic activity against Staphylococcus aureus with a possible greater advantage during systemic therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybv,

title = {Small Extracellular Vesicles from Inflamed Adipose Derived Stromal Cells Enhance the NF-κB-Dependent Inflammatory/Catabolic Environment of Osteoarthritis. },

author = {Cavallo C and Merli G and Zini N and {D'Adamo} S and Cattini L and Guescini M and Grigolo B and Di Martino A and Santi S and Borzì RM and Filardo G},

url = {https://www.hindawi.com/journals/sci/2022/9376338/},

doi = {10.1155/2022/9376338},

year  = {2022},

date = {2022-08-11},

urldate = {2022-08-11},

journal = {Stem cells international},

volume = {2022},

pages = {9376338},

abstract = {The last decade has seen exponentially growing efforts to exploit the effects of adipose derived stromal cells (ADSC) in the treatment of a wide range of chronic degenerative diseases, including osteoarthritis (OA), the most prevalent joint disorder. In the perspective of developing a cell-free advanced therapy medicinal product, a focus has been recently addressed to the ADSC secretome that lends itself to an allogeneic use and can be further dissected for the selective purification of small extracellular vesicles (sEVs). sEVs can act as "biological drug carriers" to transfer information that mirror the pathophysiology of the providing cells. This is important in the clinical perspective where many OA patients are also affected by the metabolic syndrome (MetS). ADSC from MetS OA patients are dysfunctional and "inflammatory" primed within the adipose tissue. To mimic this condition, we exposed ADSC to IL-1β, and then we investigated the effects of the isolated sEVs on chondrocytes and synoviocytes, either cultured separately or in co-culture, to tease out the effects of these "IL-1β primed sEVs" on gene and protein expression of major inflammatory and catabolic OA markers. In comparison with sEVs isolated from unstimulated ADSC, the IL-1β primed sEVs were able to propagate NF-κB activation in bystander joint cells. The effects were more prominent on synoviocytes, possibly because of a higher expression of binding molecules such as CD44. These findings call upon a careful characterization of the "inflammatory fingerprint" of ADSC to avoid the transfer of an unwanted message as well as the development of in vitro "preconditioning" strategies able to rescue the antiinflammatory/anticatabolic potential of ADSC-derived sEVs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybt,

title = {In Vitro Neurotoxicity of Flumethrin Pyrethroid on SH-SY5Y Neuroblastoma Cells: Apoptosis Associated with Oxidative Stress},

author = {Barrios-Arpi L and Arias Y and Lopez-Torres B and Ramos-Gonzalez M and Ticli G and Prosperi E and Rodríguez J-L},

url = {https://www.mdpi.com/2305-6304/10/3/131#cite},

doi = {10.3390/toxics10030131},

year  = {2022},

date = {2022-07-20},

journal = {Toxics},

volume = {10},

issue = {3},

pages = {131},

abstract = {Pyrethroids are neurotoxicants for animals, showing a pattern of toxic action on the nervous system. Flumethrin, a synthetic pyrethroid, is used against ectoparasites in domestic animals, plants, and for public health. This compound has been shown to be highly toxic to bees, while its effects on other animals have been less investigated. However, in vitro studies to evaluate cytotoxicity are scarce, and the mechanisms associated with this effect at the molecular level are still unknown. This study aimed to investigate the oxidative stress and cell death induction in SH-SY5Y neuroblastoma cells in response to flumethrin exposure (1–1000 µM). Flumethrin induced a significant cytotoxic effect, as evaluated by MTT and LDH leakage assays, and produced an increase in the biomarkers of oxidative stress as reactive oxygen species and nitric oxide (ROS and NO) generation, malondialdehyde (MDA) concentration, and caspase-3 activity. In addition, flumethrin significantly increased apoptosis-related gene expressions (Bax, Casp-3, BNIP3, APAF1, and AKT1) and oxidative stress and antioxidative (NFκB and SOD2) mediators. The results demonstrated, by biochemical and gene expression assays, that flumethrin induces oxidative stress and apoptosis, which could cause DNA damage. Detailed knowledge obtained about these molecular changes could provide the basis for elucidating the molecular mechanisms of flumethrin-induced neurotoxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybs,

title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},

author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E},

url = {https://www.mdpi.com/1422-0067/23/7/3607},

doi = {10.3390/ijms23073607},

year  = {2022},

date = {2022-07-20},

journal = {International journal of molecular sciences},

volume = {23},

issue = {7},

pages = {3607},

abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells},

author = {Corradi G and Bassani B and Simonetti G and Sangaletti S and Vadakekolathu J and Fontana MC and Pazzaglia M and Gulino A and Tripodo C and Cristiano G and Bandini L and Ottaviani E and Ocadlikova D and Piccioli M and Martinelli G and Colombo MP and Rutella S and Cavo M and Ciciarello M and Curti A},

url = {https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-21-3594/694419/Release-of-IFN-by-Acute-Myeloid-Leukemia-Cells?redirectedFrom=fulltext},

doi = {10.1158/1078-0432.CCR-21-3594},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Clinical cancer research},

volume = {Clincanres.359},

pages = {2021},

abstract = {Purpose: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. Experimental design: BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. Results: IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. Conclusions: IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybr,

title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},

author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},

url = {https://www.nature.com/articles/s41419-022-04729-5},

doi = {10.1038/s41419-022-04729-5},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Cell death & disease},

volume = {13},

issue = {4},

pages = {346},

abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybq,

title = {Sex disparities in DNA damage response pathways: Novel determinants in cancer formation and therapy},

author = {Cardano M and Buscemi G and Zannini L},

url = {https://www.sciencedirect.com/science/article/pii/S2589004222001456?via%3Dihub},

doi = {10.1016/j.isci.2022.103875},

year  = {2022},

date = {2022-05-30},

journal = {iScience},

volume = {25},

issue = {3},

pages = {103875},

abstract = {Cancer incidence and survival are different between men and women. Indeed, females have a lesser risk and a better prognosis than males in many tumors unrelated to reproductive functions. Although the reasons for these disparities are still unknown, they constitute an important starting point for the development of personalized cancer therapies. One of the mechanisms that fuels carcinogenesis is the accumulation of defects in DNA damage response (DDR) pathways, a complex signaling cascade that senses DNA lesions and, depending on the severity, coordinates transient cell-cycle arrest, DNA replication, repair, apoptosis, and senescence, preventing genomic instability and cancer. Recently, evidence of sexual dimorphisms is emerging in these pathways, therefore providing new opportunities for precision medicine. Here, we will discuss current knowledge about sexual disparities in the DDR, their role in tumorigenesis and cancer progression, and the importance of considering sex contribution in both research and cancer therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybo,

title = {Peptides Regulating Proliferative Activity and Inflammatory Pathways in the Monocyte/Macrophage THP-1 Cell Line},

author = {Avolio F and Martinotti S and Khavinson VK and Esposito JE and Giambuzzi G and Marino A and Mironova E and Pulcini R and Robuffo I and Bologna G and Simeone P and Lanuti P and Guarnieri S and Trofimova S and Procopio AD and Toniato E.},

url = {https://www.mdpi.com/1422-0067/23/7/3607

},

doi = {10.3390/ijms23073607},

year  = {2022},

date = {2022-05-30},

journal = {International journal of molecular sciences},

volume = {23},

issue = {7},

pages = {3607},

abstract = {This study evaluates the effects of five different peptides, the Epitalon® tetrapeptide, the Vilon® dipeptide, the Thymogen® dipeptide, the Thymalin® peptide complex, and the Chonluten® tripeptide, as regulators of inflammatory and proliferative processes in the human monocytic THP-1, which is a human leukemia monocytic cell line capable of differentiating into macrophages by PMA in vitro. These peptides (Khavinson Peptides®), characterized by Prof. Khavinson from 1973 onwards, were initially isolated from animal tissues and found to be organ specific. We tested the capacity of the five peptides to influence cell cultures in vitro by incubating THP-1 cells with peptides at certain concentrations known for being effective on recipient cells in culture. We found that all five peptides can modulate key proliferative patterns, increasing tyrosine phosphorylation of mitogen-activated cytoplasmic kinases. In addition, the Chonluten tripeptide, derived from bronchial epithelial cells, inhibited in vitro tumor necrosis factor (TNF) production of monocytes exposed to pro-inflammatory bacterial lipopolysaccharide (LPS). The low TNF release by monocytes is linked to a documented mechanism of TNF tolerance, promoting attenuation of inflammatory action. Therefore, all peptides inhibited the expression of TNF and pro-inflammatory IL-6 cytokine stimulated by LPS on terminally differentiated THP-1 cells. Lastly, by incubating the THP1 cells, treated with the peptides, on a layer of activated endothelial cells (HUVECs activated by LPS), we observed a reduction in cell adhesion, a typical pro-inflammatory mechanism. Overall, the results suggest that the Khavinson Peptides® cooperate as natural inducers of TNF tolerance in monocyte, and act on macrophages as anti-inflammatory molecules during inflammatory and microbial-mediated activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb_63,

title = {Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population},

author = {Bacalini MG and Palombo F and Garagnani P and Giuliani C and Fiorini C and Caporali L and Stanzani Maserati M and Capellari S and Romagnoli M and De Fanti S and Benussi L and Binetti G and Ghidoni R and Galimberti D and Scarpini E and Arcaro M and Bonanni E and Siciliano G and Maestri M and Guarnieri B and {Italian Multicentric Group on clock genes and actigraphy in AD} and Martucci M and Monti D and Carelli V and Franceschi C and La Morgia C and Santoro A},

url = {https://link.springer.com/article/10.1007%2Fs11357-021-00477-0},

doi = {10.1007/s11357-021-00477-0},

year  = {2022},

date = {2022-04-29},

urldate = {2022-04-29},

journal = {Geroscience},

volume = {44},

number = {881},

issue = {2},

pages = {896},

abstract = {Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Dynamic susceptibility MR perfusion imaging of the brain: not a question of contrast agent molarity},

author = {Panara V and Chiacchiaretta P and Rapino M and Maruotti V and Parenti M and Piccirilli E and Pizzi AD and Caulo M},

url = {https://link.springer.com/article/10.1007%2Fs00234-021-02807-7},

doi = {10.1007/s00234-021-02807-7},

year  = {2022},

date = {2022-04-13},

urldate = {2022-04-13},

journal = {Neuroradiology},

volume = {64},

issue = {4},

pages = {685-692},

abstract = {Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s. Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists. Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values. Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_65,

title = {Platelet-Derived Extracellular Vesicles Stimulate Migration through Partial Remodelling of the Ca2+ Handling Machinery in MDA-MB-231 Breast Cancer Cells},

author = {Vismara M and Negri S and Scolari F and Brunetti V and Trivigno SMG and Faris P and Galgano L and Soda T and Berra-Romani R and Canobbio I and Torti M and Guidetti GF and Moccia F},

url = {https://www.mdpi.com/2073-4409/11/19/3120},

doi = {10.3390/cells11193120},

year  = {2022},

date = {2022-03-31},

journal = {Cells},

volume = {11},

issue = {19},

pages = {3120},

abstract = {Background: Platelets can support cancer progression via the release of microparticles and microvesicles that enhance the migratory behaviour of recipient cancer cells. We recently showed that platelet-derived extracellular vesicles (PEVs) stimulate migration and invasiveness in highly metastatic MDA-MB-231 cells by stimulating the phosphorylation of p38 MAPK and the myosin light chain 2 (MLC2). Herein, we assessed whether the pro-migratory effect of PEVs involves the remodelling of the Ca2+ handling machinery, which drives MDA-MB-231 cell motility. Methods: PEVs were isolated from human blood platelets, and Fura-2/AM Ca2+ imaging, RT-qPCR, and immunoblotting were exploited to assess their effect on intracellular Ca2+ dynamics and Ca2+-dependent migratory processes in MDA-MB-231 cells. Results: Pretreating MDA-MB-231 cells with PEVs for 24 h caused an increase in Ca2+ release from the endoplasmic reticulum (ER) due to the up-regulation of SERCA2B and InsP3R1/InsP3R2 mRNAs and proteins. The consequent enhancement of ER Ca2+ depletion led to a significant increase in store-operated Ca2+ entry. The larger Ca2+ mobilization from the ER was required to potentiate serum-induced migration by recruiting p38 MAPK and MLC2. Conclusions: PEVs stimulate migration in the highly metastatic MDA-MB-231 breast cancer cell line by inducing a partial remodelling of the Ca2+ handling machinery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_63,

title = {Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation},

author = {Salucci S and Bartoletti-Stella A and Bavelloni A and Aramini B and Blalock WL and Fabbri F and Vannini I and Sambri V and Stella F and Faenza I},

url = {https://www.mdpi.com/2072-6643/14/17/3567},

doi = {10.3390/nu14173567},

year  = {2022},

date = {2022-03-31},

journal = {Nutrients},

volume = {14},

issue = {17},

pages = {3567},

abstract = {Aging results in a progressive decline in skeletal muscle mass, strength and function, a condition known as sarcopenia. This pathological condition is due to multifactorial processes including physical inactivity, inflammation, oxidative stress, hormonal changes, and nutritional intake. Physical therapy remains the standard approach to treat sarcopenia, although some interventions based on dietary supplementation are in clinical development. In this context, thanks to its known anti-inflammatory and antioxidative properties, there is great interest in using extra virgin olive oil (EVOO) supplementation to promote muscle mass and health in sarcopenic patients. To date, the molecular mechanisms responsible for the pathological changes associated with sarcopenia remain undefined; however, a complete understanding of the signaling pathways that regulate skeletal muscle protein synthesis and their behavior during sarcopenia appears vital for defining how EVOO might attenuate muscle wasting during aging. This review highlights the main molecular players that control skeletal muscle mass, with particular regard to sarcopenia, and discusses, based on the more recent findings, the potential of EVOO in delaying/preventing loss of muscle mass and function, with the aim of stimulating further research to assess dietary supplementation with EVOO as an approach to prevent or delay sarcopenia in aging individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_62,

title = {MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets},

author = {Qiu X and Boufaied N and Hallal T and Feit A and de Polo A and Luoma AM and Alahmadi W and Larocque J and Zadra G and Xie Y and Gu S and Tang Q and Zhang Y and Syamala S and Seo JH and Bell C and O'Connor E and Liu Y and Schaeffer EM and Jeffrey Karnes R and Weinmann S and Davicioni E and Morrissey C and Cejas P and Ellis L and Loda M and Wucherpfennig KW and Pomerantz MM and Spratt DE and Corey E and Freedman ML and Shirley Liu X and Brown M and Long HW and Labbé DP},

url = {https://www.nature.com/articles/s41467-022-30257-z},

doi = {10.1038/s41467-022-30257-z},

year  = {2022},

date = {2022-03-31},

journal = {Nature communications},

volume = {13},

issue = {1},

pages = {2559},

abstract = {c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_61,

title = {Obeticholic Acid Reduces Kidney Matrix Metalloproteinase Activation Following Partial Hepatic Ischemia/Reperfusion Injury in Rats},

author = {Palladini G and Cagna M and Di Pasqua LG and Adorini L and Croce AC and Perlini S and Ferrigno A and Berardo C and Vairetti M},

url = {https://www.mdpi.com/1424-8247/15/5/524},

doi = {10.3390/ph15050524},

year  = {2022},

date = {2022-03-31},

journal = {Pharmaceuticals (Basel)},

volume = {15},

issue = {5},

pages = {524},

abstract = {We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The present study investigated the capacity of OCA to modulate MMPs in distant organs such as the kidney. Male Wistar rats were dosed orally with 10 mg/kg/day of OCA (5 days) and were subjected to 60-min partial hepatic ischemia. After 120-min reperfusion, kidney biopsies (cortex and medulla) and blood samples were collected. Serum creatinine, kidney MMP-2, and MMP-9-dimer, tissue inhibitors of MMPs (TIMP-1, TIMP-2), RECK, TNF-alpha, and IL-6 were monitored. MMP-9-dimer activity in the kidney cortex and medulla increased after hepatic I/R and a reduction was detected in OCA-treated I/R rats. Although not significantly, MMP-2 activity decreased in the cortex of OCA-treated I/R rats. TIMPs and RECK levels showed no significant differences among all groups considered. Serum creatinine increased after I/R and a reduction was detected in OCA-treated I/R rats. The same trend occurred for tissue TNF-alpha and IL-6. Although the underlying mechanisms need further investigation, this is the first study showing, in the kidney, beneficial effects of OCA by reducing TNF-alpha-mediated expression of MMPs after liver I/R.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_60,

title = {Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.},

author = {Okbay A and Wu Y and Wang N and Jayashankar H and Bennett M and Nehzati SM and …... and Biino G and …..... and et al},

url = {https://www.nature.com/articles/s41588-022-01016-z},

doi = {10.1038/s41588-022-01016-z},

year  = {2022},

date = {2022-03-31},

journal = {Nature genetics},

volume = {54},

issue = {4},

pages = {437-449},

abstract = {We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of  about 3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_59,

title = {GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells},

author = {Negri S and Scolari F and Vismara M and Brunetti V and Faris P and Terribile G and Sancini G and Berra-Romani R and Moccia F},

url = {https://www.mdpi.com/2073-4409/11/23/3860},

doi = {10.3390/cells11233860},

year  = {2022},

date = {2022-03-31},

urldate = {2022-03-31},

journal = {Cells},

volume = {11},

issue = {23},

pages = {3860},

abstract = {Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_52,

title = {Curcumin-based-fluorescent probes targeting ALDH1A3 as a promising tool for glioblastoma precision surgery and early diagnosis},

author = {Gelardi ELM and Caprioglio D and Colombo G and Del Grosso E and Mazzoletti D and Mattoteia D and Salamone S and Ferraris DM and Aronica E and Nato G and Buffo A and Rizzi M and Magrassi L and Minassi A and Garavaglia S},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437101/},

doi = {10.1038/s42003-022-03834-7},

year  = {2022},

date = {2022-03-31},

journal = {Communications biology},

volume = {5},

issue = {1},

abstract = {Glioblastoma (GBM) is the most aggressive primary brain tumour for which both effective treatments and efficient tools for an early-stage diagnosis are lacking. Herein, we present curcumin-based fluorescent probes that are able to bind to aldehyde dehydrogenase 1A3 (ALDH1A3), an enzyme overexpressed in glioma stem cells (GSCs) and associated with stemness and invasiveness of GBM. Two compounds are selective versus ALDH1A3, without showing any appreciable interaction with other ALDH1A isoenzymes. Indeed, their fluorescent signal is detectable only in our positive controls in vitro and absent in cells that lack ALDH1A3. Remarkably, in vivo, our Probe selectively accumulate in glioblastoma cells, allowing the identification of the growing tumour mass. The significant specificity of our compounds is the necessary premise for their further development into glioblastoma cells detecting probes to be possibly used during neurosurgical operations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_51,

title = {Innate Immunity: A Balance between Disease and Adaption to Stress},

author = {Faenza I and Blalock W},

url = {https://www.mdpi.com/2218-273X/12/5/737},

doi = {10.3390/biom12050737},

year  = {2022},

date = {2022-03-31},

journal = {Biomolecules},

volume = {12},

issue = {5},

pages = {737},

abstract = {Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_47,

title = {TGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration},

author = {Chen L and Roake CM and Maccallini P and Bavasso F and Dehghannasiri R and Santonicola P and Mendoza-Ferreira N and Scatolini L and Rizzuti L and Esposito A and Gallotta I and Francia S and Cacchione S and Galati A and Palumbo V and Kobin MA and Tartaglia GG and Colantoni A and Proietti G and Wu Y and Hammerschmidt M and De Pittà C and Sales G and Salzman J and Pellizzoni L and Wirth B and Schiavi ED and Gatti M and Artandi SE and Raffa GD},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac659/6659874?login=true},

doi = {10.1093/nar/gkac659},

year  = {2022},

date = {2022-03-31},

journal = {Nucleic acids research},

volume = {50},

number = {12400},

issue = {21},

pages = {12424},

abstract = {Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5'-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_44,

title = {The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment},

author = {Capanni C and Schena E and Di Giampietro ML and Montecucco A and Mattioli E and Lattanzi G},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2022.1018102/full},

doi = {10.3389/fcell.2022.1018102},

year  = {2022},

date = {2022-03-31},

journal = {Frontiers in cell and developmental biology},

volume = {10},

abstract = {Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_66,

title = {Collagen VI ablation in zebrafish causes neuromuscular defects during developmental and adult stages},

author = {Tonelotto V and Consorti C and Facchinello N and Trapani V and Sabatelli P and Giraudo C and Spizzotin M and Cescon M and Bertolucci C and Bonaldo P},

url = {https://www.sciencedirect.com/science/article/pii/S0945053X22000981?via%3Dihub},

doi = {10.1016/j.matbio.2022.08.004},

year  = {2022},

date = {2022-03-30},

urldate = {2022-03-30},

journal = {Matrix biology},

volume = {112},

pages = {39-61},

abstract = {Collagen VI (COL6) is an extracellular matrix protein exerting multiple functions in different tissues. In humans, mutations of COL6 genes cause rare inherited congenital disorders, primarily affecting skeletal muscles and collectively known as COL6-related myopathies, for which no cure is available yet. In order to get insights into the pathogenic mechanisms underlying COL6-related diseases, diverse animal models were produced. However, the roles exerted by COL6 during embryogenesis remain largely unknown. Here, we generated the first zebrafish COL6 knockout line through CRISPR/Cas9 site-specific mutagenesis of the col6a1 gene. Phenotypic characterization during embryonic and larval development revealed that lack of COL6 leads to neuromuscular defects and motor dysfunctions, together with distinctive alterations in the three-dimensional architecture of craniofacial cartilages. These phenotypic features were maintained in adult col6a1 null fish, which displayed defective muscle organization and impaired swimming capabilities. Moreover, col6a1 null fish showed autophagy defects and organelle abnormalities at both embryonic and adult stages, thus recapitulating the main features of patients affected by COL6-related myopathies. Mechanistically, lack of COL6 led to increased BMP signaling, and direct inhibition of BMP activity ameliorated the locomotor col6a1 null embryos. Finally performance of, treatment with salbutamol, a beta2-adrenergic receptor agonist, elicited a significant amelioration of the neuromuscular and motility defects of col6a1 null fish embryos. Altogether, these findings indicate that this newly generated zebrafish col6a1 null line is a valuable in vivo tool to model COL6-related myopathies and suitable for drug screenings aimed at addressing the quest for effective therapeutic strategies for these disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_53,

title = {Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis},

author = {Kanoni S and Graham SE and Wang Y and Surakka I and …. and Biino G and ….. and Deloukas P and Willer CJ and Assimes TL and Peloso GM},

url = {https://genomebiology.biomedcentral.com/articles/10.1186/s13059-022-02837-1},

doi = {10.1186/s13059-022-02837-1},

year  = {2022},

date = {2022-03-30},

urldate = {2022-03-30},

journal = {Genome biology},

volume = {23},

issue = {1},

pages = {268},

abstract = {Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_50,

title = {Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment. },

author = {Di Maria S and Picarazzi F and Mori M and Cianciusi A and Carbone A and Crespan E and Perini C and Sabetta S and Deplano S and Poggialini F and Molinari A and Aronne R and Maccioni E and Maga G and Angelucci A and Schenone S and Musumeci F and Dreassi E},

url = {https://www.sciencedirect.com/science/article/pii/S0045206822004771?via%3Dihub},

doi = {10.1016/j.bioorg.2022.106071},

year  = {2022},

date = {2022-03-30},

journal = {Bioorganic chemistry},

volume = {128},

pages = {106071},

abstract = {The Bcr-Abl tyrosine kinase (TK) is the molecular hallmark of chronic myeloid leukemia (CML). Src is another TK kinase whose involvement in CML was widely demonstrated. Small molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds 9a-n were screened as dual Src/Bcr-Abl inhibitors. The antiproliferative activity on K562 CML cells and the ADME profile were determined for the most promising compounds. Molecular modeling studies elucidated the binding mode of the inhibitors into the Bcr-Abl (wt) catalytic pocket. Compounds 8j and 8k showed nanomolar activities in enzymatic and cellular assays, together with favorable ADME properties, emerging as promising candidates for CML therapy. Finally, derivatives 9j and 9k, emerging as valuable inhibitors of the most aggressive Bcr-Abl mutation, T315I, constitute a good starting point in the search for compounds able to treat drug-resistant forms of CML. Overall, this study allowed us to identify more potent compounds than those previously reported by the group, marking a step forward in searching for new antileukemic agents.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_67,

title = {Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals},

author = {Winkler TW and Rasheed H and Teumer A and Gorski M and Rowan BX and Stanzick KJ and Thomas LF and Tin A and Hoppmann A and Chu AY and Tayo B and Thio CHL and Cusi D and Chai JF and Sieber KB and Horn K and Li M and Scholz M and Cocca M and Wuttke M and van der Most PJ and Yang Q and Ghasemi S and Nutile T and Li Y and ……. and Biino G and ……. {et al}},

url = {https://www.nature.com/articles/s42003-022-03448-z},

doi = {Communications biology},

year  = {2022},

date = {2022-03-26},

journal = {Communications biology},

volume = {5},

issue = {1},

pages = {580},

abstract = {Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_56,

title = {TFIIH stabilization recovers the DNA repair and transcription dysfunctions in thermo-sensitive trichothiodystrophy},

author = {Lanzafame M and Nardo T and Ricotti R and Pantaleoni C and D'Arrigo S and Stanzial F and Benedicenti F and Thomas MA and Stefanini M and Orioli D and Botta E},

url = {https://onlinelibrary.wiley.com/doi/10.1002/humu.24488},

doi = {10.1002/humu.24488},

year  = {2022},

date = {2022-03-25},

journal = {Human mutation},

volume = {43},

issue = {12},

pages = {2222},

abstract = {Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the ERCC2/XPD gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel ERCC2/XPD mutations affecting proper protein folding, which generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever. In patient cells, the newly identified XPD variants result in thermo-instability of the whole TFIIH complex and consequent temperature-dependent defects in DNA repair and transcription. Improving the protein folding process by exposing patient cells to low temperature or to the chemical chaperone glycerol allowed rescue of TFIIH thermo-instability and a concomitant recovery of the complex activities. Besides providing a rationale for the peculiar thermo-sensitive clinical features of these new cases, the present findings demonstrate how variations in the cellular concentration of mutated TFIIH impact the cellular functions of the complex and underlie how both quantitative and qualitative TFIIH alterations contribute to TTD clinical features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}