@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}

}

@article{%a1.%Yb_46,

title = {Privileged Scaffold Decoration for the Identification of the First Trisubstituted Triazine with Anti-SARS-CoV-2 Activity},

author = {Cesarini S and Vicenti I and Poggialini F and Secchi M and Giammarino F and Varasi I and Lodola C and Zazzi M and Dreassi E and Maga G and Botta L and Saladino R},

url = {https://www.mdpi.com/1420-3049/27/24/8829},

doi = {10.3390/molecules27248829},

year  = {2022},

date = {2022-03-25},

journal = {Molecules},

volume = {27},

issue = {24},

pages = {8829},

abstract = {Current therapy against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are based on the use of Remdesivir 1, Molnupiravir 2, and the recently identified Nirmatrelvir 3. Unfortunately, these three drugs showed some limitations regarding potency and possible drug-drug interactions. A series of derivatives coming from a decoration approach of the privileged scaffold s-triazines were synthesized and evaluated against SAR-CoV-2. One derivative emerged as the hit of the series for its micromolar antiviral activity and low cytotoxicity. Mode of action and pharmacokinetic in vitro preliminary studies further confirm the role as candidates for a future optimization campaign of the most active derivative identified with this work.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_43,

title = {Screening Questionnaire for Vitamin D Insufficiency in Children with Obesity},

author = {Calcaterra V and Cena H and Biino G and Grazi R and Bortoni G and Braschi V and Tomasinelli CE and Schneider L and Zuccotti G},

url = {https://www.mdpi.com/2227-9067/9/11/1685},

doi = {https://www.mdpi.com/2227-9067/9/11/1685},

year  = {2022},

date = {2022-03-25},

urldate = {2022-03-25},

journal = {Children (Basel)},

volume = {9},

issue = {11},

pages = {1685},

abstract = {"Non-invasive screening tools to identify children at high risk of vitamin D (VitD) deficiency are proactive measures in preventive care. Recently, a validated questionnaire (Evaluation dEficieNCy Questionnaire, EVIDENCe-Q) for identifying newly diagnosed VitD-insufficient adults has been developed. We tested the EVIDENCe-Q modified for children with obesity and evaluated the correlation between VitD and questionnaire scores to adapt this tool to the pediatric population. We enrolled 120 children with obesity (BMI ≥ 2). Clinical evaluation and VitD levels were considered. The modified EVIDENCe-Q included information regarding factors affecting control of VitD, with scores ranging between 0 (best) and 36 (worst). VitD and adiposity indices were inversely correlated. The threshold values for identifying severe deficiency (<10 mg/dL), deficiency (<20 mg/dL) and insufficiency (<30 mg/dL) were scores of 21, 19 and 23, respectively. According to those thresholds, the prevalence of severe deficiency, deficiency and insufficiency was 47.5%, 69.2% and 23.3%, respectively; the best accuracy was obtained with a questionnaire score cut-off of 19 for the VitD deficiency level. A novel simple screening tool such as the modified EVIDENCe-Q would be useful in clinical practice to identify potential cases of hypovitaminosis D and select at-risk patients. Considering the limited accuracy and specificity of our results, for the pediatric population a dedicated tool should be created. Phases of childhood and the role of adipose tissue could be considered in the definition of a questionnaire intended for pediatric patients with obesity.

"},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_66,

title = {A saturated map of common genetic variants associated with human height},

author = {Yengo L and Vedantam S and Marouli E and Sidorenko J and Bartell E and Sakaue S and Graff M and Eliasen AU and Jiang Y and Raghavan S and Miao J and Arias JD and Graham SE and Mukamel RE and Spracklen CN and Yin X and Chen SH and Ferreira T and Highland HH and Ji Y and Karaderi T and Lin K and Lüll K and Malden DE and Medina-Gomez C and Machado and ……. and Biino G and ….. and {et al}},

url = {https://www.nature.com/articles/s41586-022-05275-y},

doi = {10.1038/s41586-022-05275-y.},

year  = {2022},

date = {2022-03-24},

journal = {Nature},

volume = {610},

issue = {7933},

pages = {704-712},

abstract = {Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_57,

title = {Cell-Autonomous Processes That Impair Xenograft Survival into the Cerebellum},

author = {Magrassi L and Nato G and Delia D and Buffo A},

url = {https://link.springer.com/article/10.1007/s12311-022-01414-3},

doi = {10.1007/s12311-022-01414-3},

year  = {2022},

date = {2022-03-24},

journal = {Cerebellum},

volume = {21},

issue = {5},

abstract = {In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_55,

title = {Combined alteration of lamin and nuclear morphology influences the localization of the tumor-associated factor AKTIP},

author = {{La Torre M} and Merigliano C and Maccaroni K and Chojnowski A and Goh WI and Giubettini M and Vernì F and Capanni C and Rhodes D and Wright G and Burke B and Soddu S and Burla R and Saggio I},

url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02480-5},

doi = {10.1186/s13046-022-02480-5},

year  = {2022},

date = {2022-03-24},

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

volume = {41},

issue = {1},

pages = {273},

abstract = {Background: Lamins, key nuclear lamina components, have been proposed as candidate risk biomarkers in different types of cancer but their accuracy is still debated. AKTIP is a telomeric protein with the property of being enriched at the nuclear lamina. AKTIP has similarity with the tumor susceptibility gene TSG101. AKTIP deficiency generates genome instability and, in p53-/- mice, the reduction of the mouse counterpart of AKTIP induces the exacerbation of lymphomas. Here, we asked whether the distribution of AKTIP is altered in cancer cells and whether this is associated with alterations of lamins. Methods: We performed super-resolution imaging, quantification of lamin expression and nuclear morphology on HeLa, MCF7, and A549 tumor cells, and on non-transformed fibroblasts from healthy donor and HGPS (LMNA c.1824C > T p.Gly608Gly) and EDMD2 (LMNA c.775 T > G) patients. As proof of principle model combining a defined lamin alteration with a tumor cell setting, we produced HeLa cells exogenously expressing the HGPS lamin mutant progerin that alters nuclear morphology. Results: In HeLa cells, AKTIP locates at less than 0.5 µm from the nuclear rim and co-localizes with lamin A/C. As compared to HeLa, there is a reduced co-localization of AKTIP with lamin A/C in both MCF7 and A549. Additionally, MCF7 display lower amounts of AKTIP at the rim. The analyses in non-transformed fibroblasts show that AKTIP mislocalizes in HGPS cells but not in EDMD2. The integrated analysis of lamin expression, nuclear morphology, and AKTIP topology shows that positioning of AKTIP is influenced not only by lamin expression, but also by nuclear morphology. This conclusion is validated by progerin-expressing HeLa cells in which nuclei are morphologically altered and AKTIP is mislocalized. Conclusions: Our data show that the combined alteration of lamin and nuclear morphology influences the localization of the tumor-associated factor AKTIP. The results also point to the fact that lamin alterations per se are not predictive of AKTIP mislocalization, in both non-transformed and tumor cells. In more general terms, this study supports the thesis that a combined analytical approach should be preferred to predict lamin-associated changes in tumor cells. This paves the way of next translational evaluation to validate the use of this combined analytical approach as risk biomarker.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_54,

title = {CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing},

author = {Kerschbamer E and Arnoldi M and Tripathi T and Pellegrini M and Maturi S and Erdin S and Salviato E and Di Leva F and Sebestyén E and Dassi E and Zarantonello G and Benelli M and Campos E and Basson MA and Gusella JF and Gustincich S and Piazza S and Demichelis F and Talkowski ME and Ferrari F and Biagioli M},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac1134/6947080?login=false},

doi = {10.1093/nar/gkac1134},

year  = {2022},

date = {2022-03-24},

journal = {Nucleic acids research},

volume = {50},

issue = {22},

pages = {12809-12828},

abstract = {Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in 'regulation of RNA splicing' and 'mRNA catabolic process'. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_45,

title = {3D ECM-rich environment sustains the identity of naive human iPSCs},

author = {Cesare E and Urciuolo A and Stuart HT and Torchio E and Gesualdo A and Laterza C and Gagliano O and Martewicz S and Cui M and Manfredi A and Di Filippo L and Sabatelli P and Squarzoni S and Zorzan I and Betto RM and Martello G and Cacchiarelli D and Luni C and Elvassore N},

url = {https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00458-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590922004581%3Fshowall%3Dtrue},

doi = {10.1016/j.stem.2022.11.011},

year  = {2022},

date = {2022-03-24},

urldate = {2022-03-24},

journal = {Cell stem cell},

volume = {29},

issue = {12},

pages = {1703-1717},

abstract = {The establishment of in vitro naive human pluripotent stem cell cultures opened new perspectives for the study of early events in human development. The role of several transcription factors and signaling pathways have been characterized during maintenance of human naive pluripotency. However, little is known about the role exerted by the extracellular matrix (ECM) and its three-dimensional (3D) organization. Here, using an unbiased and integrated approach combining microfluidic cultures with transcriptional, proteomic, and secretome analyses, we found that naive, but not primed, hiPSC colonies are characterized by a self-organized ECM-rich microenvironment. Based on this, we developed a 3D culture system that supports robust long-term feeder-free self-renewal of naive hiPSCs and also allows direct and timely developmental morphogenesis simply by modulating the signaling environment. Our study opens new perspectives for future applications of naive hiPSCs to study critical stages of human development in 3D starting from a single cell.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_64,

title = {Imaging and spectral analysis of autofluorescence patterns in larval head structures of mosquito vectors},

author = {Scolari F and Girella A and Croce AC},

url = {https://www.ejh.it/index.php/ejh/article/view/3462},

doi = {10.4081/ejh.2022.3462},

year  = {2022},

date = {2022-03-23},

journal = {European journal of histochemistry},

volume = {66},

issue = {4},

pages = {3462},

abstract = {Autofluorescence (AF) in mosquitoes is currently poorly explored, despite its great potential as a marker of body structures and biological functions. Here, for the first time AF in larval heads of two mosquitoes of key public health importance, Aedes albopictus and Culex pipiens, is studied using fluorescence imaging and spectrofluorometry, similarly to a label-free histochemical approach. In generally conserved distribution patterns, AF shows differences between mouth brushes and antennae of the two species. The blue AF ascribable to resilin at the antennal bases, more extended in Cx. pipiens, suggests a potential need to support different antennal movements. The AF spectra larger in Cx. pipiens indicate a variability in material composition and properties likely relatable to mosquito biology, including diverse feeding and locomotion behaviours with implications for vector control.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_58,

title = {Clinical Significance and Regulation of ERK5 Expression and Function in Cancer},

author = {Monti M and Celli J and Missale F and Cersosimo F and Russo M and Belloni E and Di Matteo A and Lonardi S and Vermi W and Ghigna C and Giurisato E},

url = {https://www.mdpi.com/2072-6694/14/2/348},

doi = {10.3390/cancers14020348},

year  = {2022},

date = {2022-03-23},

journal = {Cancers (Basel)},

volume = {14},

issue = {2},

pages = {348},

abstract = {Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybm,

title = {Novel Perceptions on Chemical Profile and Biopharmaceutical Properties of Mentha spicata Extracts: Adding Missing Pieces to the Scientific Puzzle},

author = {Zengin G and Ak G and Ceylan R and Uysal S and Llorent-Martínez E and Di Simone SC and Rapino M and Acquaviva A and Libero ML and Chiavaroli A and Recinella L and Leone S and Brunetti L and Cataldi A and Orlando G and Menghini L and Ferrante C and Balaha M and di Giacomo V},

url = {https://www.mdpi.com/2223-7747/11/2/233},

doi = {10.3390/plants11020233},

year  = {2022},

date = {2022-03-21},

journal = {Plants (Basel)},

volume = {11},

issue = {2},

pages = {233},

abstract = {Mentha spicata is one of the most popular species in the genus, and it is of great interest as a gastrointestinal and sedative agent in the folk medicine system. In this study, different M. spicata extracts, obtained by the use of four solvents (hexane, chloroform, acetone and acetone/water) were chemically characterized using HPLC-ESI-MS n, which allowed for identification of 27 phenolic compounds. The extracts' antioxidant and enzyme inhibitory properties were investigated. In addition, neuroprotective effects were evaluated in hypothalamic HypoE22 cells, and the ability of the extracts to prevent the hydrogen peroxide-induced degradation of dopamine and serotonin was observed. The best antioxidant effect was achieved for all the extraction methods using acetone/water as a solvent. These extracts were the richest in acacetin, eriodictyol, hesperidin, sagerinic acid, naringenin, luteolin, chlorogenic acid, chrysoeriol and apigenin. The intrinsic antioxidant and enzyme inhibition properties of the acetone/water extract could also explain, albeit partially, its efficacy in preventing prostaglandin E2 overproduction and dopamine depletion (82.9% turnover reduction) in HypoE22 cells exposed to hydrogen peroxide. Thus, our observations can provide a scientific confirmation of the neuromodulatory and neuroprotective effects of M. spicata.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybl,

title = {Early Morphological Changes of the Rectus Femoris Muscle and Deep Fascia in Ullrich Congenital Muscular Dystrophy},

author = {Sabatelli P and Merlini L and Di Martino A and Cenni V and Faldini C},

url = {https://www.mdpi.com/1660-4601/19/3/1252},

doi = {International journal of environmental research and public health},

year  = {2022},

date = {2022-03-21},

journal = {International journal of environmental research and public health},

volume = {19},

issue = {3},

pages = {1252},

abstract = {Ullrich congenital muscular dystrophy (UCMD) is a severe form of muscular dystrophy caused by the loss of function of collagen VI, a critical component of the muscle-tendon matrix. Magnetic resonance imaging of UCMD patients' muscles shows a peculiar rim of abnormal signal at the periphery of each muscle, and a relative sparing of the internal part. The mechanism/s involved in the early fat substitution of muscle fiber at the periphery of muscles remain elusive. We studied a muscle biopsy of the rectus femoris/deep fascia (DF) of a 3-year-old UCMD patient, with a homozygous mutation in the COL6A2 gene. By immunohistochemical and ultrastructural analysis, we found a marked fatty infiltration at the interface of the muscle with the epimysium/DF and an atrophic phenotype, primarily in fast-twitch fibers, which has never been reported before. An unexpected finding was the widespread increase of interstitial cells with long cytoplasmic processes, consistent with the telocyte phenotype. Our study documents for the first time in a muscle biopsy the peculiar pattern of outside-in muscle degeneration followed by fat substitution as already shown by muscle imaging, and an increase of telocytes in the interstitium of the deep fascia, which highlights a potential involvement of this structure in the pathogenesis of UCMD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybk,

title = {Telomere dysfunction in ageing and age-related diseases},

author = {Rossiello F and Jurk D and Passos JF and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/s41556-022-00842-x},

doi = {10.1038/s41556-022-00842-x},

year  = {2022},

date = {2022-03-21},

volume = {24},

issue = {2},

pages = {135-147},

abstract = {Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybj,

title = {Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response},

author = {Pesce E and Manfrini N and Cordiglieri C and Santi S and Bandera A and Gobbini A and Gruarin P and Favalli A and Bombaci M and Cuomo A and Collino F and Cricri' G and Ungaro R and Lombardi A and Mangioni D and Muscatello A and Aliberti S and Blasi F and Gori A and Abrignani S and De Francesco R and Biffo S and Grifantini R},

url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-85123854300&partnerID=q2rCbXpz},

doi = {10.3389/fimmu.2021.785941},

year  = {2022},

date = {2022-03-21},

journal = {Frontiers in immunology},

volume = {12},

pages = {7859},

abstract = {Coronavirus disease 2019 (COVID-19) is an infectious disease caused by beta-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has rapidly spread across the globe starting from February 2020. It is well established that during viral infection, extracellular vesicles become delivery/presenting vectors of viral material. However, studies regarding extracellular vesicle function in COVID-19 pathology are still scanty. Here, we performed a comparative study on exosomes recovered from the plasma of either MILD or SEVERE COVID-19 patients. We show that although both types of vesicles efficiently display SARS-CoV-2 spike-derived peptides and carry immunomodulatory molecules, only those of MILD patients are capable of efficiently regulating antigen-specific CD4+ T-cell responses. Accordingly, by mass spectrometry, we show that the proteome of exosomes of MILD patients correlates with a proper functioning of the immune system, while that of SEVERE patients is associated with increased and chronic inflammation. Overall, we show that exosomes recovered from the plasma of COVID-19 patients possess SARS-CoV-2-derived protein material, have an active role in enhancing the immune response, and possess a cargo that reflects the pathological state of patients in the acute phase of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybi,

title = {Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4},

author = {Kannan A and Cuartas J and Gangwani P and Branzei D and Gangwani L},

url = {https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab464/6511590},

doi = {10.1093/brain/awab464},

year  = {2022},

date = {2022-03-21},

journal = {Brain},

abstract = {Mutation in the Senataxin (SETX) gene causes an autosomal dominant neuromuscular disorder, amyotrophic lateral sclerosis 4 (ALS4), characterized by degeneration of motor neurons, muscle weakness and atrophy. SETX is an RNA-DNA helicase that mediates resolution of co-transcriptional RNA-DNA hybrids (R-loops). The process of R-loop resolution is essential for the normal functioning of cells, including neurons. The molecular basis of ALS4 pathogenesis and the mechanism of R-loop resolution are unclear. We report that the zinc finger protein ZPR1 binds to RNA-DNA hybrids, recruits SETX onto R-loops and is critical for R-loop resolution. ZPR1 deficiency disrupts the integrity of R-loop resolution complexes (RLRC) containing SETX and causes increased R-loop accumulation throughout gene transcription. We uncover that SETX is a downstream target of ZPR1 and that overexpression of ZPR1 can rescue RLRC assembly in SETX-deficient cells but not vice versa. To uncover the mechanism of R-loop resolution, we examined the function of SETX-ZPR1 complexes using two genetic motor neuron disease models with altered R-loop resolution. Notably, chronic low levels of SETX-ZPR1 complexes onto R-loops result in a decrease of R-loop resolution activity causing an increase in R-loop levels in spinal muscular atrophy (SMA). ZPR1 overexpression increases recruitment of SETX onto R-loops, decreases R-loops and rescues the SMA phenotype in motor neurons and patient cells. Strikingly, interaction of SETX with ZPR1 is disrupted in ALS4 patients that have heterozygous SETX (L389S) mutation. ZPR1 fails to recruit the mutant SETX homodimer but recruits the heterodimer with partially disrupted interaction between SETX and ZPR1. Interestingly, disruption of SETX-ZPR1 complexes causes increase in R-loop resolution activity leading to fewer R-loops in ALS4. Modulation of ZPR1 levels regulates R-loop accumulation and rescues the pathogenic R-loop phenotype in ALS4 patient cells. These findings originate a new concept, "opposite alterations in a cell biological activity (R-loop resolution) result in similar pathogenesis (neurodegeneration) in different genetic motor neuron disorders". We propose that ZPR1 collaborates with SETX and may function as a molecular brake to regulate SETX-dependent R-loop resolution activity critical for the normal functioning of motor neurons.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Ybh,

title = {The wide and growing range of lamin B-related diseases: from laminopathies to cancer. },

author = {Evangelisti C and Rusciano I and Mongiorgi S and Ramazzotti G and Lattanzi G and Manzoli L and Cocco L and Ratti S and},

url = {https://link.springer.com/article/10.1007/s00018-021-04084-2},

doi = {10.1007/s00018-021-04084-2},

year  = {2022},

date = {2022-03-21},

journal = {Cellular and molecular life sciences},

volume = {79},

number = {126},

issue = {2},

abstract = {B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybg,

title = {Parental histone deposition on the replicated strands promotes error-free DNA damage tolerance and regulates drug resistance},

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

url = {http://genesdev.cshlp.org/content/early/2022/02/01/gad.349207.121.long},

doi = {10.1101/gad.349207.121},

year  = {2022},

date = {2022-03-21},

urldate = {2022-03-21},

journal = {Genes & development},

volume = {36},

issue = {1-4},

pages = {167-179},

abstract = {Ctf4 is a conserved replisome component with multiple roles in DNA metabolism. To investigate connections between Ctf4-mediated processes involved in drug resistance, we conducted a suppressor screen of ctf4delta sensitivity to the methylating agent MMS. We uncovered that mutations in Dpb3 and Dpb4 components of polymerase ε result in the development of drug resistance in ctf4Δ via their histone-binding function. Alleviated sensitivity to MMS of the double mutants was not associated with rescue of ctf4delta defects in sister chromatid cohesion, replication fork architecture, or template switching, which ensures error-free replication in the presence of genotoxic stress. Strikingly, the improved viability depended on translesion synthesis (TLS) polymerase-mediated mutagenesis, which was drastically increased in ctf4 dpb3 double mutants. Importantly, mutations in Mcm2-Ctf4-Polα and Dpb3-Dpb4 axes of parental (H3-H4)2 deposition on lagging and leading strands invariably resulted in reduced error-free DNA damage tolerance through gap filling by template switch recombination. Overall, we uncovered a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Three dimensional spheroid cell culture of human MSC-derived neuron-like cells: new in vitro model to assess magnetite nanoparticle-induced neurotoxicity effects},

author = {{De Simone U} and Croce AC and Pignatti P and Buscaglia E and Caloni F and Coccini T},

url = {https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jat.4292},

doi = {10.1002/jat.4292},

year  = {2022},

date = {2022-03-21},

urldate = {2022-03-21},

journal = {Journal of applied toxicology},

volume = {42},

issue = {7},

pages = {1230-1252},

abstract = {As nanoparticles (NPs) can access the brain and impact on CNS function, novel in vitro models for the evaluation of NPs-induced neurotoxicity are advocated. 3D-spheroids of primary neuron-like cells (hNLCs) of human origin have been generated, from differentiation of human umbilical cord mesenchymal stem cells (MSCs). The study evaluated Fe3 O4 NP impact on the differentiation process by applying the challenge at complete 3D hNLC spheroid formation (after 4 days-T4) or at beginning of neurogenic induction/simultaneously 3D forming (T0). Different endpoints were monitored over time (up to 10 days): spheroid growth, size, morphology, ATP, cell death, neuronal markers (β-Tub III, MAP-2, NSE), NP-uptake. At T0-application, a marked concentration- and time-dependent cell mortality occurred: effect started early (day 2) and low concentration (1 μg/ml) and exacerbated (80% mortality) after prolonged time (day 6) and increased concentrations (50 μg/ml). ATP was strikingly affected. All neuronal markers were downregulated and spheroid morphology altered in a concentration-dependent manner (from ≥ 5μg/ml) after day 2. Fe3 O4 NPs applied at complete 3D formation (T4) still induced adverse effects although less severe: cell mortality (20-60%) and ATP content decrease (10-40%) were observed in a concentration-dependent manner (from ≥ 5 μg/ml). A neuronal-specific marker effect and spheroid size reduction from 25 μg/ml without morphology alteration were evidenced. This finding provides additional information on neurotoxic effects of Fe3 O4 NPs in a new 3D hNLC spheroid model derived from MSCs, that could find a consistent application as in a testing strategy serving in first step hazard identification for correct risk assessment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybd,

title = {Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy},

author = {Czapiewski R and Batrakou DG and de Las Heras JI and Carter RN and Sivakumar A and Sliwinska M and Dixon CR and Webb S and Lattanzi G and Morton NM and Schirmer EC},

url = {https://www.nature.com/articles/s41467-021-27869-2},

doi = {10.1038/s41467-021-27869-2},

year  = {2022},

date = {2022-02-25},

urldate = {2022-02-25},

journal = {Nature communications},

volume = {13},

number = {321},

issue = {1},

abstract = {Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a-/- mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybc,

title = {The Bright Side of the Tiger: Autofluorescence Patterns in Aedes albopictus (Diptera, Culicidae) Male and Female Mosquitoes. },

author = {Croce AC and Scolari F},

url = {https://www.mdpi.com/1420-3049/27/3/713},

doi = {10.3390/molecules27030713},

year  = {2022},

date = {2022-02-25},

journal = {Molecules},

volume = {27},

issue = {3},

pages = {713},

abstract = {Light-based events in insects deserve increasing attention for various reasons. Besides their roles in inter- and intra-specific visual communication, with biological, ecological and taxonomical implications, optical properties are also promising tools for the monitoring of insect pests and disease vectors. Among these is the Asian tiger mosquito, Aedes albopictus, a global arbovirus vector. Here we have focused on the autofluorescence characterization of Ae. albopictus adults using a combined imaging and spectrofluorometric approach. Imaging has evidenced that autofluorescence rises from specific body compartments, such as the head appendages, and the abdominal and leg scales. Spectrofluorometry has demonstrated that emission consists of a main band in the 410-600 nm region. The changes in the maximum peak position, between 430 nm and 500 nm, and in the spectral width, dependent on the target structure, indicate the presence, at variable degrees, of different fluorophores, likely resilin, chitin and melanins. The aim of this work has been to provide initial evidence on the so far largely unexplored autofluorescence of Ae. albopictus, to furnish new perspectives for the set-up of species- and sex-specific investigation of biological functions as well as of strategies for in-flight direct detection and surveillance of mosquito vectors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybb,

title = {BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1},

author = {Chen D and Gervai JZ and Poti A and Nemeth E and Szeltner Z and Szikriszt B and Gyure Z and Zamborszky J and Ceccon M and {d'Adda di Fagagna F} and Szallasi Z and Richardson AL and Szuts D},

url = {https://www.nature.com/articles/s41467-021-27872-7},

doi = {10.1038/s41467-021-27872-7},

year  = {2022},

date = {2022-02-25},

journal = {Nature communications},

volume = {13},

issue = {1},

pages = {226},

abstract = {Defects in BRCA1, BRCA2 and other genes of the homology-dependent DNA repair (HR) pathway cause an elevated rate of mutagenesis, eliciting specific mutation patterns including COSMIC signature SBS3. Using genome sequencing of knock-out cell lines we show that Y family translesion synthesis (TLS) polymerases contribute to the spontaneous generation of base substitution and short insertion/deletion mutations in BRCA1 deficient cells, and that TLS on DNA adducts is increased in BRCA1 and BRCA2 mutants. The inactivation of 53BP1 in BRCA1 mutant cells markedly reduces TLS-specific mutagenesis, and rescues the deficiency of template switch-mediated gene conversions in the immunoglobulin V locus of BRCA1 mutant chicken DT40 cells. 53BP1 also promotes TLS in human cellular extracts in vitro. Our results show that HR deficiency-specific mutagenesis is largely caused by TLS, and suggest a function for 53BP1 in regulating the choice between TLS and error-free template switching in replicative DNA damage bypass.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb,

title = {Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production},

author = {Bolognesi F and Fazio N and Boriani F and Fabbri VP and Gravina D and Pedrini FA and Zini N and Greco M and Paolucci M and Re MC and Asioli S and Foschini MP and D'Errico A and Baldini N and Marchetti C},

url = {https://www.mdpi.com/1422-0067/23/3/1530},

doi = {10.3390/ijms23031530},

year  = {2022},

date = {2022-02-25},

urldate = {2022-02-25},

journal = {International journal of molecular sciences},

volume = {23},

issue = {2},

pages = {1530},

abstract = {Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze-thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}