Deubiquitinase USP1 regulates sarbecovirus ORF6 protein function.

SARS-CoV-2 belongs to the subgenus Sarbecovirus, which universally encodes the accessory protein ORF6. SARS-CoV-2 ORF6 is an antagonist of the interferon (IFN)-mediated antiviral response and plays an important role in viral infections. However, the mechanism by which the host counteracts the function of ORF6 to restrict viral replication remains unclear. In this study, we found that most ORF6 proteins encoded by sarbecoviruses could be ubiquitinated and subsequently degraded via the proteasome pathway. Through extensive screening, we identified that the deubiquitinase USP1, which effectively and broadly deubiquitinates sarbecovirus ORF6 proteins, stabilizes ORF6 proteins, resulting in enhanced viral replication. Therefore, ubiquitination and deubiquitination of ORF6 are important for antagonizing IFN-mediated antiviral signaling and influencing the virulence of SARS-CoV-2. These findings highlight an essential molecular mechanism and may provide a novel target for therapeutic interventions against viral infections.IMPORTANCEThe ORF6 proteins encoded by sarbecoviruses are essential for effective viral replication and infection and are important targets for developing effective intervention strategies. In this study, we confirmed that sarbecovirus ORF6 proteins are important antagonists of the host immune response and identified the regulatory mechanisms of ubiquitination and deubiquitination of most sarbecovirus ORF6 proteins. Moreover, we revealed that DUB USP1 prevents the proteasomal degradation of all ORF6 proteins, thereby promoting the virulence of SARS-CoV-2. Thus, impeding ORF6 function is helpful for attenuating the virulence of sarbecoviruses. Therefore, our findings provide a deeper understanding of the molecular mechanisms underlying sarbecovirus infections and offer potential new therapeutic targets for the prevention and treatment of these infections.

Characterization and analysis of linear epitopes corresponding to SARS-CoV-2 outbreak in Jilin Province, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants have caused hundreds of thousands of deaths and shown serious social influence worldwide. Jilin Province, China, experienced the first wave of the outbreak from December 2020 to February 2021. Here, we analyzed the genomic characteristics of the SARS-CoV-2 outbreak in Jilin province using a phylogeographic tree and found that clinical isolates belonged to the B.1 lineage, which was considered to be the ancestral lineage. Several dominant SARS-CoV-2 specific linear B cell epitopes that reacted with the convalescent sera were also analysed and identified using a peptide microarray composed of S, M, and E proteins. Moreover, the serum of convalescent patients infected with SARS-CoV-2 showed neutralizing activity against four widely spreading SARS-CoV-2 variants; however, significant differences were observed in neutralizing activities against different SARS-CoV-2 variants. These data provide important information on genomic characteristics, linear epitopes, and neutralizing activity of SARS-CoV-2 outbreak in Jilin Province, China, which may aid in understanding disease patterns and regional aspects of the pandemic.

A case report of infantile parkinsonism-dystonia-2 caused by homozygous mutation in the SLC18A2 gene.

Background: The monoamine neurotransmitter disorders are neurometabolic syndromes caused by disturbances in the synthesis, transport and metabolism of the biogenic amines (the catecholamines dopamine, norepinephrine and epinephrine; serotonin), which are increasingly recognized as an expanding group of inherited neurometabolic syndromes.Case Description: A 6-month-old male infant who presented with developmental delay and suspected cerebral palsy was diagnosed with infantile parkinsonism-dystonia-2 (MIM: 618049). The whole-exome sequencing identified a homozygous c.710C > T (p.Pro237His) transition in the monoamine transporter gene SLC18A2, which was due to paternal uniparental disomy (UPD) of chromosome 10p15.3q26.3, resulting in brain dopamine-serotonin vesicular transport disease. Sanger sequencing confirmed that his unaffected father carried the same mutation in the heterozygous state, while his mother did not carry the same mutation. Autosomal recessive gene mutations in SLC18A2 has been identified in three families in different countries. The infant was treated with pramipexole, a dopamine agonist, and the static tremor was better compared with that before treatment, but the movement disorder was not significantly improved.Conclusion: This case confirmed the causal mutation of SLC18A2 gene and brain dopamine-serotonin vesicular transport disease, which suggested the mechanism of UPD homozygous formation, and confirmed that dopamine agonist treatment could improve some symptoms in affected individuals.

Bifurcations of an SIRS epidemic model with a general saturated incidence rate.

This paper is concerned with the bifurcations of a susceptible-infectious-recovered-susceptible (SIRS) epidemic model with a general saturated incidence rate $ k I^p/(1+\alpha I^p) $. For general $ p > 1 $, it is shown that the model can undergo saddle-node bifurcation, Bogdanov-Takens bifurcation of codimension two, and degenerate Hopf bifurcation of codimension two with the change of parameters. Combining with the results in [1] for $ 0 < p\leq 1 $, this type of SIRS model has Hopf cyclicity $ 2 $ for any $ p > 0 $. These results also improve some previous ones in [2] and [3], which are dealt with the special case of $ p = 2 $.

Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners.

BACKGROUND: Ubiquitination plays an essential role in many biological processes, including viral infection, and can be reversed by deubiquitinating enzymes (DUBs). Although some studies discovered that DUBs inhibit or enhance viral infection by various mechanisms, there is lack of information on the role of DUBs in virus regulation, which needs to be further investigated. METHODS: Immunoblotting, real-time polymerase chain reaction, in vivo / in vitro deubiquitination, protein immunoprecipitation, immunofluorescence, and co-localization biological techniques were employed to examine the effect of ubiquitin-specific protease 3 (USP3) on APOBEC3G (A3G) stability and human immunodeficiency virus (HIV) replication. To analyse the relationship between USP3 and HIV disease progression, we recruited 20 HIV-infected patients to detect the levels of USP3 and A3G in peripheral blood and analysed their correlation with CD4 + T-cell counts. Correlation was estimated by Pearson correlation coefficients (for parametric data). RESULTS: The results demonstrated that USP3 specifically inhibits HIV-1 replication in an A3G-dependent manner. Further investigation found that USP3 stabilized 90% to 95% of A3G expression by deubiquitinating Vif-mediated polyubiquitination and blocking its degradation in an enzyme-dependent manner. It also enhances the A3G messenger RNA (mRNA) level by binding to A3G mRNA and stabilizing it in an enzyme-independent manner. Moreover, USP3 expression was positively correlated with A3G expression ( r  = 0.5110) and CD4 + T-cell counts ( r  = 0.5083) in HIV-1-infected patients. CONCLUSIONS: USP3 restricts HIV-1 viral infections by increasing the expression of the antiviral factor A3G. Therefore, USP3 may be an important target for drug development and serve as a novel therapeutic strategy against viral infections.

Study on the Mechanism of Action of Different Acupuncture Regimens on Premature Ovarian Failure Model Rats.

Objective: To study the mechanism of acupuncture on premature ovarian failure (POF) through the apoptosis pathway mediated by Bcl-2/Bax. Methods: POF rats were successfully obtained by cyclophosphamide. They were divided into five groups. After that, acupuncture was performed. The blank group and model group were not treated. The routine acupuncture group was acupuncture at Guanyuan, Sanyinjiao, Zhongji, and Guilai four points. The Neck-seven-acupuncture group was selected from Fengchi, Fengfu, Tianzhu, and Wangu four acupoints; the three-viscera simultaneous treatment group selected Guanyuan, Shenshu, Sanyinjiao, Taichong, and Baihui five points; and the data mining group selected Guanyuan and Sanyinjiao two points for 14 days of treatment. During the treatment, some rats were shed one after another due to the side effects of bone marrow suppression caused by mold-making. After treatment, serum estradiol (E2), follicle forming hormone (FSH), and luteinizing hormone (LH) were detected by radioimmunoassay, Bcl-2 and Bax proteins were analyzed by Western blot method, and Bcl-2 and Bax RNA were analyzed by PCR method. Results: Bcl-2 increased and Bax decreased in rats with premature ovarian failure treated with acupuncture. It shows that acupuncture can affect the secretion of ovarian-related hormones and the expression of apoptosis-related proteins, which is more significant in the conventional acupuncture point group. Conclusion: Acupuncture can inhibit the apoptosis of granulosa cells in ovarian tissue of rats with premature ovarian failure and improve ovarian function. The mechanism of its effect is to promote Bcl-2 gene expression and protein synthesis and inhibit Bax gene expression and protein synthesis. The conventional treatment group works best. This provides an experimental basis for the clinical use of acupuncture to intervene in the treatment of premature ovarian failure.

Voice and Touch Based Error-tolerant Multimodal Text Editing and Correction for Smartphones.

Editing operations such as cut, copy, paste, and correcting errors in typed text are often tedious and challenging to perform on smartphones. In this paper, we present VT, a voice and touch-based multi-modal text editing and correction method for smartphones. To edit text with VT, the user glides over a text fragment with a finger and dictates a command, such as "bold" to change the format of the fragment, or the user can tap inside a text area and speak a command such as "highlight this paragraph" to edit the text. For text correcting, the user taps approximately at the area of erroneous text fragment and dictates the new content for substitution or insertion. VT combines touch and voice inputs with language context such as language model and phrase similarity to infer a user's editing intention, which can handle ambiguities and noisy input signals. It is a great advantage over the existing error correction methods (e.g., iOS's Voice Control) which require precise cursor control or text selection. Our evaluation shows that VT significantly improves the efficiency of text editing and text correcting on smartphones over the touch-only method and the iOS's Voice Control method. Our user studies showed that VT reduced the text editing time by 30.80%, and text correcting time by 29.97% over the touch-only method. VT reduced the text editing time by 30.81%, and text correcting time by 47.96% over the iOS's Voice Control method.

BackSwipe: Back-of-device Word-Gesture Interaction on Smartphones.

Back-of-device interaction is a promising approach to interacting on smartphones. In this paper, we create a back-of-device command and text input technique called BackSwipe, which allows a user to hold a smartphone with one hand, and use the index finger of the same hand to draw a word-gesture anywhere at the back of the smartphone to enter commands and text. To support BackSwipe, we propose a back-of-device word-gesture decoding algorithm which infers the keyboard location from back-of-device gestures, and adjusts the keyboard size to suit the gesture scales; the inferred keyboard is then fed back into the system for decoding. Our user study shows BackSwipe is feasible and a promising input method, especially for command input in the one-hand holding posture: users can enter commands at an average accuracy of 92% with a speed of 5.32 seconds/command. The text entry performance varies across users. The average speed is 9.58 WPM with some users at 18.83 WPM; the average word error rate is 11.04% with some users at 2.85%. Overall, BackSwipe complements the extant smartphone interaction by leveraging the back of the device as a gestural input surface.

The functional properties and application of gelatin derived from the skin of channel catfish (Ictalurus punctatus).

The objective of this work was to extract gelatin from skin of channel catfish (Ictalurus punctatus) and to study its functional properties and application in ice-cream and beer. SDS-PAGE patterns showed that channel catfish gelatin (CCG) had more high molecular weight components (ß and γ chains) than had calf bone gelatin (CBG). The viscosity of CCG was 42mPa.s at 10°C, which was three times more than that of CBG. Compared to CBG, CCG presented higher emulsion capacity and stability, as well as higher foaming stability. CCG conferred the ice-cream samples and beer with better mouth feel and clarification effect, respectively. The results indicated that CCG had great potential to be utilized in the food industry.