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[beta].sub.2 -microglobulin ([beta].sub.2 -m), a 11.8 kDa protein, pairs non-covalently with the [alpha]3 domain of the major histocompatibility class (MHC) I [alpha]-chain and is essential for the conformation of the MHC class I protein complex. Shed [beta].sub.2 -m is measurable in circulation, and various disorders are accompanied by increases in [beta].sub.2 -m levels, including several viral infections. Therefore, we explored whether [beta].sub.2 -m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum [beta].sub.2 -m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean [beta].sub.2 -m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean [beta].sub.2 -m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean [beta].sub.2 -m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean [beta].sub.2 -m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression [beta].sub.2 -m levels were the only significant predictor of disease severity. Our findings suggest that higher [beta].sub.2 -m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of [beta].sub.2 -m measurements. The role of [beta].sub.2 -m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.

[beta].sub.2 -microglobulin ([beta].sub.2 -m), a 11.8 kDa protein, pairs non-covalently with the [alpha]3 domain of the major histocompatibility class (MHC) I [alpha]-chain and is essential for the conformation of the MHC class I protein complex. Shed [beta].sub.2 -m is measurable in circulation, and various disorders are accompanied by increases in [beta].sub.2 -m levels, including several viral infections. Therefore, we explored whether [beta].sub.2 -m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum [beta].sub.2 -m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean [beta].sub.2 -m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean [beta].sub.2 -m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean [beta].sub.2 -m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean [beta].sub.2 -m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression [beta].sub.2 -m levels were the only significant predictor of disease severity. Our findings suggest that higher [beta].sub.2 -m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of [beta].sub.2 -m measurements. The role of [beta].sub.2 -m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.

Genome-wide genetic screens are powerful tools to identify genes that act as host factors of viruses. We have applied this technique to analyze the infection of HeLa cells by Vaccinia virus, in an attempt to find genes necessary for infection. Infection of cell populations harboring single gene inactivations resulted in no surviving cells, suggesting that no single gene knock-out was able to provide complete resistance to Vaccinia virus and thus allow cells to survive infection. In the absence of an absolute infection blockage, we explored if some gene inactivations could provide partial protection leading to a reduced probability of infection. Multiple experiments using modified screening procedures involving replication restricted viruses led to the identification of multiple genes whose inactivation potentially increase resistance to infection and therefore cell survival. As expected, significant gene hits were related to proteins known to act in virus entry, such as ITGB1 and AXL as well as genes belonging to their downstream related pathways. Additionally, we consistently found [beta].sub.2 -microglobulin, encoded by the B2M gene, among the screening top hits, a novel finding that was further explored. Inactivation of B2M resulted in 54% and 91% reduced VV infection efficiency in HeLa and HAP1 cell lines respectively. In the absence of B2M, while virus binding to the cells was unaffected, virus internalization and early gene expression were significantly diminished. These results point to [beta].sub.2 -microglobulin as a relevant factor in the Vaccinia virus entry process.

Several [beta]2-microglobulin (B2M) -bound protein complexes undertake key roles in various immune system pathways, including the neonatal Fc receptor (FcRn), cluster of differentiation 1 (CD1) protein, non-classical major histocompatibility complex (MHC), and well-known MHC class I molecules. Therefore, the duplication of B2M may lead to an increase in the biological competence of organisms to the environment. Based on the pig genome assembly SSC10.2, a segmental duplication of ~45.5 kb, encoding the entire B2M protein, was identified in pig chromosome 1. Through experimental validation, we confirmed the functional duplication of the B2M gene with a completely identical coding sequence between two copies in pigs. Considering the importance of B2M in the immune system, we performed the phylogenetic analysis of B2M duplication in ten mammalian species, confirming the presence of B2M duplication in cetartioldactyls, like cattle, sheep, goats, pigs and whales, but non-cetartiodactyl species, like mice, cats, dogs, horses, and humans. The density of long interspersed nuclear element (LINE) at the edges of duplicated blocks (39 to 66%) was found to be 2 to 3-fold higher than the average (20.12%) of the pig genome, suggesting its role in the duplication event. The B2M mRNA expression level in pigs was 12.71 and 7.57 times (2.sup.-[DELTA][DELTA]Ct values) higher than humans and mice, respectively. However, we were unable to experimentally demonstrate the difference in the level of B2M protein because species specific anti-B2M antibodies are not available. We reported, for the first time, the functional duplication of the B2M gene in animals. The identification of partially remaining duplicated B2M sequences in the genomes of only cetartiodactyls indicates that the event was lineage specific. B2M duplication could be beneficial to the immune system of pigs by increasing the availability of MHC class I light chain protein, B2M, to complex with the proteins encoded by the relatively large number of MHC class I heavy chain genes in pigs. Further studies are necessary to address the biological meaning of increased expression of B2M.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and cisplatin (CDDP) is a critical chemical drug for the treatment of BC. However, CDDP-resistance seriously limits the therapeutic efficacy of this drug for clinical utilization. Thus, identification of pivotal molecule targets that regulate CDDP-resistance in BC become urgent and necessary. In this study, we firstly identified a novel BC-associated circular RNA circ₀058063 that participates in the regulation of CDDP-resistance in BC. Specifically, circ₀058063 was significantly overexpressed in CDDP-resistant tissue and cells, in contrast with the corresponding CDDP-sensitive counterparts. Further loss-of-function experiments validated that downregulation of circ₀058063 suppressed cell proliferation and tumor growth, whereas induced cell apoptosis in the CDDP-resistant BC cells in vitro and in vivo. In addition, we disclosed that circ₀058063 acts as a sponge for miR-335-5p to positively regulate B2M expression, and further rescuing experiments verified that the enhancing effects of sh-circ₀058063 on CDDP-sensitivity in the CDDP-resistant BC cells were abrogated by silencing miR-335-5p. Taken together, our results demonstrated that circ₀058063 contributed to CDDP resistance of bladder cancer cells via sponging miR-335-5p, and B2M might be the downstream effector gene. This study firstly evidenced that targeting circ₀058063 might be an effective strategy to improve CDDP-sensitivity in BC.

Background The major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status. Results Somatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients’ respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity. Conclusions Our findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and cisplatin (CDDP) is a critical chemical drug for the treatment of BC. However, CDDP-resistance seriously limits the therapeutic efficacy of this drug for clinical utilization. Thus, identification of pivotal molecule targets that regulate CDDP-resistance in BC become urgent and necessary. In this study, we firstly identified a novel BC-associated circular RNA circ_0058063 that participates in the regulation of CDDP-resistance in BC. Specifically, circ_0058063 was significantly overexpressed in CDDP-resistant tissue and cells, in contrast with the corresponding CDDP-sensitive counterparts. Further loss-of-function experiments validated that downregulation of circ_0058063 suppressed cell proliferation and tumor growth, whereas induced cell apoptosis in the CDDP-resistant BC cells in vitro and in vivo . In addition, we disclosed that circ_0058063 acts as a sponge for miR-335-5p to positively regulate B2M expression, and further rescuing experiments verified that the enhancing effects of sh-circ_0058063 on CDDP-sensitivity in the CDDP-resistant BC cells were abrogated by silencing miR-335-5p. Taken together, our results demonstrated that circ_0058063 contributed to CDDP resistance of bladder cancer cells via sponging miR-335-5p, and B2M might be the downstream effector gene. This study firstly evidenced that targeting circ_0058063 might be an effective strategy to improve CDDP-sensitivity in BC.

Canine babesiosis may cause several hematological and biochemical changes, but only limited studies are available regarding the possible differences of changes in animals infected by different Babesia parasites. The study focused on the evaluation of the differences in serum protein electrophoretic pattern between dogs naturally infected with B. gibsoni (17 dogs) and B. canis (40 dogs). The mean values of total proteins, β 1 -, β 2 - and γ-globulins were in dogs infected with B. gibsoni significantly higher ( P  < 0.05 and P  < 0.001) than in dogs infected with B. canis . The relative concentrations of albumin, α 1 -, α 2 -globulins and the A/G ratios were in the B. gibsoni infected dogs significantly lower ( P  < 0.001), no significant differences were found in the relative concentrations of β 1 - and β 2 -globulins. Significant differences were found in most of the evaluated parameters when comparing the results in relation to the form of B. canis infection to B. gibsoni infection. Hematological indices showed significant differences between dogs infected with B. gibsoni and the complicated form of B. canis infection. In conclusion, the obtained results suggest differences in the changes of serum protein electrophoretic pattern between dogs infected with both Babesia species and thus, in the response to the infection caused by various Babesia parasites.

In dairy cows the period of transition from late gestation to early lactation is recognized as inducing considerable metabolic adaptation. The aim of this study was to analyse modifications in serum protein values occurring during the dry and the transition period and during lactation in a group of five Holstein cows of high average milk production. For all subjects, selected on the basis of their pregnancy status, blood samples were collected at different physiological phases: dry period (−60, −30 d to calving), transition period (almost 7 d to calving, 7 d after calving), and lactation (weeks 2, 5 and 15 after calving), for a total of eight blood samples for each cow. On each blood sample total proteins and electrophoresis analysis were performed. On the data obtained, normally distributed (P<0·05, Kolmogorov-Smirnov's test), one-way Repeated Measure Analysis of Variance (ANOVA), was applied to evaluate the influence of different stages of gestation and lactation on the considered parameters. Results showed a significant effect on total proteins, α1-globulins, β-globulins, γ-globulins and albumin/globulin ratio. Most of the detected modifications were related to the transition from gestation to lactation, indicating that it is a period of great metabolic stress for cows. On the basis of the obtained results we can affirm that the pattern of serum protein fraction rn could give information about dehydration, plasma volume expansion and hepatic function occurring during the peripartum period in dairy cows.