Analyzing RNA data with scVelo: identifiability issues and a Bayesian implementation

The analysis of RNA data plays a crucial role in understanding cellular differentiation. One widely-used methodology for analyzing RNA data is scVelo. However, in this paper, we show that, among other issues of scVelo, the current model formalization suffers from identifiability problems. We propose a Bayesian version of scVelo with modifications that address these issues

Evaluation of effectiveness of an innovative semen extender (Formula®) comparing with a traditional extender (Lepus®) for artificial insemination in rabbits does

This study aimed to investigate the preservability and viability of the rabbit spermatozoa diluted in a new semen extender Formula® in comparison with Lepus® at 17 °C of storage. The main characteristic of the new extender formulation is the use of an enzymatic agent associated to a polysaccharide as energy source precursor, added with gentamycin. During eight trials, ejaculates from 70 bucks were collected and diluted at 1:10 ratio with both the extenders, after 24 h of storage the semen doses were used for the artificial insemination (AI). Aliquots of the semen doses for each trial were stored at 17 °C, the total and progressive motility were checked at 0, 4, 12, 18, 24, 36, 48, 60, 72, 84, 96, 108 h of storage. A total of 1267 and 1525 does were inseminated, respectively with Formula® and Lepus®. During storage the mean total and progressive motility (77.23% and 72.854%, respectively) were significantly higher for Formula® (p < .01) and the progressive motility at almost 70% was maintained for at least 60 h vs the 24 h of storage for Lepus® with significant differences after 12 h of storage (p < .05). The new extender reported a higher pregnancy rate (p < .05) and an average of 9.25 rabbits born per litter vs 8.83 for the traditional extender (p < .05), while the mean of the newborn alive was 9.08 using Formula® vs 8.51 with Lepus® (p < .05). In conclusion, the use of Formula® is recommended for rabbit semen AI programmes

Zerovalent Fe, Co and Ni nanoparticle toxicity evaluated on SKOV-3 and U87 cell lines

ABSTRACT:We have considered nanoparticles (NPs) of Fe, Co and Ni, three transition metals sharing similar chemical properties. NP dissolution, conducted by radioactive tracer method and inductively coupled plasmamass spectrometry, indicated that NiNPs and FeNPs released in the medium a much smaller amount of ions than that released by Co NPs. The two considered methodological approaches, however, gave comparable but not identical results. All NPs are readily internalized by the cells, but their quantity inside the cells is less than 5%. Cytotoxicity and gene expression experimentswere performed on SKOV-3 and U87 cells. In both cell lines, CoNPs and NiNPs were definitely more toxic than FeNPs. Real-time polymerase chain reaction experiments aimed to evaluatemodifications of the expression of genes involved in the cellular stress response (HSP70, MT2A), or susceptible to metal exposure (SDHB1 and MLL), or involved in specific cellular processes (caspase3, IQSEC1 and VMP1), gave different response patterns in the two cell lines. HSP70, for example, was highly upregulated by CoNPs and NiNPs, but only in SKOV-3 cell lines. Overall, this work underlines the difficulties in predicting NP toxicological properties based only on their chemical characteristics. We, consequently, think that, at this stage of our knowledge, biological effects induced by metal-based NPs should be examined on a case-by-case basis following studies on different in vitro models. Moreover, with the only exception of U87 exposed to Ni, our results suggest thatmetallic NPs have caused, on gene expression, similar effects to those caused by their cor- Q2 responding ions

miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models

Palbociclib is in early-stage clinical testing in advanced hepatocellular carcinoma (HCC). Here, we investigated whether the anti-tumor activity of palbociclib, which prevents the CDK4/6-mediated phosphorylation of RB1 but simultaneously activates AKT signaling, could be improved by its combination with a PI3K/AKT/mTOR inhibitor in liver cancer models. The selective pan-AKT inhibitor, MK-2206, or the microRNA-199a-3p were tested in combination with palbociclib in HCC cell lines and in the TG221 HCC transgenic mouse model. The combination palbociclib/MK-2206 was highly effective, but too toxic to be tolerated by mice. Conversely, the combination miR-199a-3p mimics/palbociclib not only induced a complete or partial regression of tumor lesions, but was also well tolerated. After 3&nbsp;weeks of treatment, the combination produced a significant reduction in number and size of tumor nodules in comparison with palbociclib or miR-199a-3p mimics used as single agents. Moreover, we also reported the efficacy of this combination against sorafenib-resistant cells in&nbsp;vitro and in&nbsp;vivo. At the molecular level, the combination caused the simultaneous decrease of the phosphorylation of both RB1 and of AKT. Our findings provide pre-clinical evidence for the efficacy of the combination miR-199a-3p/palbociclib as anti-HCC treatment or as a new approach to overcome sorafenib resistance

Immunotoxicity and Sensitizing Capacity of Metal Compounds Depend on Speciation

Immunotoxicity of metal compounds is an issue of great importance due to the recent industrial application of metals with unknown toxicity on the immune system and the discovery of metal intermediary compounds not sufficiently studied yet. In this report we show results of our study on the immunotoxicity of the following metals: the Platinum group elements (Platinum, Palladium, Rhodium), Titanium and Arsenic. We applied functional and non functional assays and investigated both innate and adaptive immune systems, in particular, cell proliferation, cytokine production by PBMCs and O−2 production by neutrophils. We obtained the following results: only some Ti compounds (Titanocene, Ti ascorbate and Ti oxalate) show immunotoxicity. Trivalent As compounds (Sodium arsenite and tetraphenyl arsonium chloride) are more immunotoxic than the other investigated As compounds. Genotoxicity of Pt group compounds is in the following order: Pt < Rh < Pd. Immunotoxicity of Pt group compounds is in the following order: Pd < Pt < Rh. Lymphocytes and macrophages show a different reaction of neutrophils to metal toxicity. We can conclude that these studies show that metal immunotoxicity depends on speciation. In general speciation provides additional and often essential information in evaluating metal toxicity. However, there are many difficulties in applying speciation in investigating toxico-kinetic aspects to many metals, mainly due to the lack of information about the existence and significance of species and to the lack of analytical methods for measuring species in biological samples

"In vitro" comparative immune effects of different titanium compounds.

Exposure to Ti compounds is today an occupational and environmental health hazard. Object of this study was to determine "in vitro" effects of different Ti salts on cultured human peripheral blood mononuclear cells (PBMC) proliferation and cytokine release. 10−4 and 10−7 M Ti compounds did not modify spontaneous PBMC proliferation. Ti dioxide (a biocompatible material and sunscreen component) did not exert effects on phytoemagglutinin (PHA) stimulated PBMC proliferation and on PHA stimulated IFN-γ and TNF-α release from PBMC. On the other hand, 10−4 M Ti oxalate (with wide industrial applications) and Ti ascorbate (used mainly in agriculture) inhibited about 70 % the PHA stimulated PBMC proliferation; both these Ti compounds at 10−4 and 10−7 M concentrations significantly inhibited TNF-α release, while only Ti oxalate inhibited that of IFN-γ. Titanocene (used in chemotherapy) did not exert effects on PBMC proliferation but markedly inhibited IFN-γ and TNF-α release. On the whole, this study demonstrates that Ti dioxide is not immunotoxic; Ti oxalate shows marked immunotoxicity; titanocene exerts selective toxicity on cytokine release but not on PBMC proliferation, while Ti ascorbate affects TNF-α release from PBMC but not IFN-γ release. In conclusion, these data show that immunotoxicity of Ti depends on speciation

Redox active Double Wall Carbon Nanotubes show intrinsic anti-proliferative effects and modulate autophagy in cancer cells

In Double-Walled-Carbon-Nanotubes (DWCNTs) the outer shell screens the inner one from the external environment. As a consequence, the electronic properties of the smaller tube are enhanced and DWCNTs have therefore been advocated for a number of uses. In their raw form theymay contain small metallic clusters, left over from the catalytic process, that can give them a redox activity characterized by redox potentials in the range of one hundred millivolts and able to affect biological systems. Indeed, we find that redox active raw-DWCNTs inhibit rat colorectal cancer cell proliferation by blocking cells in the G2 phase through ROS generation by tumor cells. We show that raw-DWCNTs could also modulate autophagy in tumor cells through induction of intracellular acidification. To the best of our knowledge, this is the first time that DWCNTs have been found to inhibit proliferation and modulate autophagy in cancer cells. Our work further supports previous studies that provided promising results on the possibility of future applications of Carbon Nanotubes (CNTs) in nanomedicine

Exploring the Italian equine gene pool via high-throughput genotyping

Introduction: The Italian peninsula is in the center of the Mediterranean area, and historically it has been a hub for numerous human populations, cultures, and also animal species that enriched the hosted biodiversity. Horses are no exception to this phenomenon, with the peculiarity that the gene pool has been impacted by warfare and subsequent “colonization”. In this study, using a comprehensive dataset for almost the entire Italian equine population, in addition to the most influential cosmopolitan breeds, we describe the current status of the modern Italian gene pool.Materials and Methods: The Italian dataset comprised 1,308 individuals and 22 breeds genotyped at a 70 k density that was merged with publicly available data to facilitate comparison with the global equine diversity. After quality control and supervised subsampling to ensure consistency among breeds, the merged dataset with the global equine diversity contained data for 1,333 individuals from 54 populations. Multidimensional scaling, admixture, gene flow, and effective population size were analyzed.Results and Discussion: The results show that some of the native Italian breeds preserve distinct gene pools, potentially because of adaptation to the different geographical contexts of the peninsula. Nevertheless, the comparison with international breeds highlights the presence of strong gene flow from renowned breeds into several Italian breeds, probably due to historical introgression. Coldblood breeds with stronger genetic identity were indeed well differentiated from warmblood breeds, which are highly admixed. Other breeds showed further peculiarities due to their breeding history. Finally, we observed some breeds that exist more on cultural, traditional, and geographical point of view than due to actual genetic distinctiveness

Serum IgG against Simian Virus 40 antigens are hampered by high levels of sHLA-G in patients affected by inflammatory neurological diseases, as multiple sclerosis

Background: Many investigators detected the simian polyomavirus SV40 footprints in human brain tumors and neurologic diseases and recently it has been indicated that SV40 seems to be associated with multiple sclerosis (MS) disease. Interestingly, SV40 interacts with human leukocyte antigen (HLA) class I molecules for cell entry. HLA class I antigens, in particular non-classical HLA-G molecules, characterized by an immune-regulatory function, are involved in MS disease, and the levels of these molecules are modified according with the disease status. Objective: We investigated in serum samples, from Italian patients affected by MS, other inflammatory diseases (OIND), non-inflammatory neurological diseases (NIND) and healthy subjects (HS), SV40-antibody and soluble sHLA-G and the association between SV40-prevalence and sHLA-G levels. Methods: ELISA tests were used for SV40-antibodies detection and sHLA-G quantitation in serum samples. Results: The presence of SV40 antibodies was observed in 6 % of patients affected by MS (N = 4/63), 10 % of OIND (N = 8/77) and 15 % of NIND (N = 9/59), which is suggestive of a lower prevalence in respect to HS (22 %, N = 18/83). MS patients are characterized by higher sHLA-G serum levels (13.9 \ub1 0.9 ng/ml; mean \ub1 St. Error) in comparison with OIND (6.7 \ub1 0.8 ng/ml), NIND (2.9 \ub1 0.4 ng/ml) and HS (2.6 \ub1 0.7 ng/ml) subjects. Interestingly, we observed an inverse correlation between SV40 antibody prevalence and sHLA-G serum levels in MS patients. Conclusion: The data obtained showed a low prevalence of SV40 antibodies in MS patients. These results seems to be due to a generalized status of inability to counteract SV40 infection via antibody production. In particular, we hypothesize that SV40 immune-inhibitory direct effect and the presence of high levels of the immune-inhibitory HLA-G molecules could co-operate in impairing B lymphocyte activation towards SV40 specific peptides

Vanadium Effect on the Activity of Horseradish Peroxidase, Catalase, Glutathione Peroxidase and Superoxide Dismutase in Vitro

Abstract not availableNA-NOT AVAILABL