Nucleic acid-induced NADase activation of a short Sir2-associated prokaryotic Argonaute system.

Inhibition of nucleic acid targets is mediated by Argonaute (Ago) proteins guided by RNA or DNA. Although the mechanisms underpinning the functions of eukaryotic and "long" prokaryotic Ago proteins (pAgos) are well understood, those for short pAgos remain enigmatic. Here, we determine two cryoelectron microscopy structures of short pAgos in association with the NADase-domain-containing protein Sir2-APAZ from Geobacter sulfurreducens (GsSir2/Ago): the guide RNA-target DNA-loaded GsSir2/Ago quaternary complex (2.58 Å) and the dimer of the quaternary complex (2.93Å). These structures show that the nucleic acid binding causes profound conformational changes that result in disorder or partial dissociation of the Sir2 domain, suggesting that it adopts a NADase-active conformation. Subsequently, two RNA-/DNA-loaded GsSir2/Ago complexes form a dimer through their MID domains, further enhancing NADase activity through synergistic effects. The findings provide a structural basis for short-pAgo-mediated defense against invading nucleic acids.

The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction.

SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A's ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.

Lattice Strained Induced Spin Regulation in Co-N/S Coordination-Framework Enhanced Oxygen Reduction Reaction.

Oxygen reduction reaction (ORR) is the bottleneck of metal-air batteries and fuel cells. Strain regulation can change the geometry and adjust the surface charge distribution of catalysts, which is a powerful strategy to optimize the ORR activity. The introduction of controlled strain to the material is still difficult to achieve. Herein, we present a temperature-pressure-induced strategy to achieve the controlled lattice strain for metal coordination polymers. Through the systematic study of the strain effect on ORR performance, the relationship between geometric and electronic effects is further understood and confirmed. The strained Co-DABDT (DABDT=2,5-diaminobenzene-1,4-dithiol) with 2 % lattice compression exhibits a superior half-wave potential of 0.81 V. Theoretical analysis reveals that the lattice strain changes spin-charge densities around S atoms for Co-DABDT, and then regulates the hydrogen bond interaction with intermediates to promote the ORR catalytic process. This work helps to understand the catalytic mechanism from the atomic level.

Nucleic-acid-triggered NADase activation of a short prokaryotic Argonaute.

Argonaute (Ago) proteins mediate RNA- or DNA-guided inhibition of nucleic acids1,2. Although the mechanisms used by eukaryotic Ago proteins and long prokaryotic Ago proteins (pAgos) are known, that used by short pAgos remains elusive. Here we determined the cryo-electron microscopy structures of a short pAgo and the associated TIR-APAZ proteins (SPARTA) from Crenotalea thermophila (Crt): a free-state Crt-SPARTA; a guide RNA-target DNA-loaded Crt-SPARTA; two Crt-SPARTA dimers with distinct TIR organization; and a Crt-SPARTA tetramer. These structures reveal that Crt-SPARTA is composed of a bilobal-fold Ago lobe that connects with a TIR lobe. Whereas the Crt-Ago contains a MID and a PIWI domain, Crt-TIR-APAZ has a TIR domain, an N-like domain, a linker domain and a trigger domain. The bound RNA-DNA duplex adopts a B-form conformation that is recognized by base-specific contacts. Nucleic acid binding causes conformational changes because the trigger domain acts as a 'roadblock' that prevents the guide RNA 5' ends and the target DNA 3' ends from reaching their canonical pockets; this disorders the MID domain and promotes Crt-SPARTA dimerization. Two RNA-DNA-loaded Crt-SPARTA dimers form a tetramer through their TIR domains. Four Crt-TIR domains assemble into two parallel head-to-tail-organized TIR dimers, indicating an NADase-active conformation, which is supported by our mutagenesis study. Our results reveal the structural basis of short-pAgo-mediated defence against invading nucleic acids, and provide insights for optimizing the detection of SPARTA-based programmable DNA sequences.

Efficacy and safety of 13 surgical techniques for the treatment of complex anal fistula, non-Crohn CAF: a systematic review and network meta-analysis.

BACKGROUND: Considering the difficulty of treating complex anal fistula (CAF), various surgical techniques exist in clinical work. However, none are ideal. Evidence on the efficacy and safety of different surgical treatments is scarce. The authors aimed to compare the outcomes of the 13 surgical techniques and tried to find the best surgical method for treating CAF. MATERIALS AND METHODS: The authors searched worldwide databases, including Pubmed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, VIP, and SinoMed, from inception to March 2023. All randomized controlled trials comparing the outcomes of 13 surgical techniques were included according to the PICO principles. The indicators of the cure rate, the recurrence rate, the complication rate, the operating time, the postoperative pain on day 1 (VAS), and the postoperative incontinence in month 1 (Wexner) were extracted and analyzed using STATA software 15.1, Review Manager 5.4, and GeMTC14.3. RESULTS: Twenty-eight randomized controlled trials with a total of 2274 patients were included in the network meta-analysis. There was no statistically significant difference in the comparison among any surgical interventions in terms of the cure rate ( P >0.05 Table 2) and recurrence rate ( P >0.05 Table 3). However, in terms of complication rate, fistulectomy was lower than FPS (Median: 0.14; 95% CI: 0.02-0.70) or fistulotomy (Median: 0.09; 95% CI: 0.01-0.55), and fistulotomy was lower than EAFR (Median: 0.24; 95% CI: 0.05-0.84), LIFT (Median: 0.17; 95% CI: 0.02-0.66) or LIFT-EAFR (Median: 0.11; 95% CI: 0.01-0.69) ( P >0.05 Table 4). The surface estimated the advantages and disadvantages under the cumulative ranking (SUCRA). The ranking results indicated that fistulectomy might have the lowest complication rate (SUCRA=7.9%). Because the network results of the operating time, the postoperative pain, and the postoperative incontinence contained no closed loops, the results of their probability ranking could only be referenced, demonstrating that fistulectomy might have the shortest operating time (SUCRA=23.4%), video-assisted modified ligation of the intersphincteric fistula tract (VAMLIFT) might have the lowest postoperative pain on day 1 (VAS) (SUCRA=0.4%) and LIFT might have the lowest postoperative incontinence in month 1(Wexner) (SUCRA=16.2%). CONCLUSION: Fistulectomy might have the lowest complication rate, which might be the relatively superior surgical technique for treating CAF.

The efficacy and safety of Chinese herbal medicine for reducing wound complications after anal fistula surgery: A protocol for systematic review and meta-analysis.

BACKGROUND: Anal fistula is one of the most common diseases in anorectal surgery. The wound healing after surgery can affect the prognosis of patients. We conducted a protocol for systematic review and meta-analysis to assess the efficacy and safety of Chinese herbal medicine for reducing wound complications after anal fistula surgery. METHODS: We have prepared this protocol in accordance with the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA-P) statement. We will search the following databases: the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biomedical Literature Database, Pubmed, Embase, Web of Science, and the Cochrane library. Two authors will independently assess the risk of bias of the included studies based on the bias risk assessment tool recommended in the Cochrane "Risk of bias" assessment tool. All calculations are carried out with STATA13.0 software. RESULTS: A synthesis of current evidence of Chinese herbal medicine for wound management after anal fistula surgery will be shown in this protocol. CONCLUSION: This study may provide more convincing evidence to help clinicians make decisions when dealing with anal fistula patients after surgery.

Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport.

The emergence of heavily mutated SARS-CoV-2 variants of concern (VOCs) place the international community on high alert. In addition to numerous mutations that map in the spike protein of VOCs, expression of the viral accessory proteins ORF6 and ORF9b also elevate; both are potent interferon antagonists. Here, we present the crystal structures of Rae1-Nup98 in complex with the C-terminal tails (CTT) of SARS-CoV-2 and SARS-CoV ORF6 to 2.85 Å and 2.39 Å resolution, respectively. An invariant methionine (M) 58 residue of ORF6 CTT extends its side chain into a hydrophobic cavity in the Rae1 mRNA binding groove, resembling a bolt-fitting-hole; acidic residues flanking M58 form salt-bridges with Rae1. Our mutagenesis studies identify key residues of ORF6 important for its interaction with Rae1-Nup98 in vitro and in cells, of which M58 is irreplaceable. Furthermore, we show that ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport correlate with the binding affinity between ORF6 and Rae1-Nup98. Finally, binding of ORF6 to Rae1-Nup98 is linked to ORF6-induced interferon antagonism. Taken together, this study reveals the molecular basis for the antagonistic function of Sarbecovirus ORF6, and implies a strategy of using ORF6 CTT-derived peptides for immunosuppressive drug development.

A Synchronous Magnitude Estimation with P-Wave Phases' Detection Used in Earthquake Early Warning System.

How to estimate an earthquake's magnitude rapidly and accurately is a challenge for any earthquake early warning system. In order to reach a balance between accuracy and timeliness, a synchronous magnitude estimation method with P-wave phases' detection is proposed. In this method, the P-wave phases are detected by the changes of the signal-to-noise ratio (SNR) of the seismic records, where the SNRs are calculated by the short-term power and long-term power ratio (STP/LTP). Meanwhile, the variations of the SNR are applied to estimate the magnitude of the earthquake. By the statistics of some earthquake cases, a synchronous magnitude estimation model of the variation of the P-wave phases' SNR, the earthquake magnitude, and the hypocentral distance was built. Compared with some other magnitude estimation methods, the suggested method inherits the robustness of the STP/LTP method and is more accurate and rapid than the peak displacement (Pd) method.

Perineal burn injury with hidradenitis suppurativa: A case report.

RATIONALE: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease which usually presents with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas. Severe HS has interconnecting sinus tracts and when it occurs in the perianal region, perianal fistulas can form. Obesity and smoking are 2 risk factors for the development of HS. PATIENT CONCERNS: We report a case of a 33-year-old male diagnosed with perianal HS and perianal fistula following a burn injury to the area that occurred during childhood. DIAGNOSIS: Through integration of the clinical signs and imaging results, the patient was diagnosed with HS, Hurley stage III with perianal fistulas. INTERVENTIONS: The patient accepted surgical therapy. Performed under the general anesthesia, the procedure comprised sinus tracts excision and drainage. OUTCOMES: The patient was discharged from the hospital 6 weeks after surgery. LESSONS: The pathogenesis of the HS in this case was the burn injury interfering with sweat gland formation around the anus. Moreover, the scar from the burn made surgical treatment difficult.

Feasibility of therapeutic plasma exchange-based combination therapy in the treatment of acquired hemophilia A: A retrospective 6 case series.

ABSTRACT: Poor availability and a lack of affordability of bypassing agents (recombinant activated factor VII and activated prothrombin complex concentrate) in west China prompted us to investigate an alternative cost-effective combination therapy. We aimed to explore the feasibility of therapeutic plasma exchange (TPE)-based combination therapy in the treatment of acquired hemophilia A (AHA).We retrospectively investigated the clinical features of AHA in 6 patients who were treated with a combination of TPE, corticosteroids, and rituximab in our department for 9 years between January, 2011 and December, 2019.We examined 1 male and 5 female patients. The median age at diagnosis of AHA was 51 years (18-66 years). In all patients, FVIII activity levels were low (median: 1.5%; 1-3%), FVIII inhibitor titers were high (median: 24.5 BU/mL; 13.2-48.6 BU/mL), and activated partial thromboplastin time was markedly prolonged (median: 99.4 s; 60.9-110.1 s). They underwent 2 to 8 cycles of plasma exchange and were given varying combinations of dexamethasone, methylprednisolone, prednisone, and rituximab. After TPE bleeding gradually stopped, and activated partial thromboplastin time decreased. After 3 months of treatment, FVIII inhibitors completely disappeared.TPE when combined with corticosteroids and rituximab, as adjunctive immunosuppressive agents, may be an effective and reliable treatment for AHA. When there is no alternative, intensive first-line treatment including TPE may be lifesaving.

Tacrolimus ointment in the treatment of hormone-dependent dermatitis: A protocol of systematic review.

BACKGROUND: Long-term use of corticosteroid ointment for external using or skin management products and cosmetics containing corticosteroid will produce a hormone-dependent effect on facial skin and destroy the barrier function of the skin. It is easy to cause repeated attacks of facial skin inflammation after drug withdrawal because corticosteroid hormones can cause the expression of inflammatory factors in the body, which has a serious impact on patients. The general treatment method is to stop using hormone drugs for psychotherapy and inform patients of the basic knowledge of hormone-dependent dermatitis and daily facial care, but the effect is not good. At present, non-steroidal ointment tacrolimus (a calcineurin inhibitor) is widely used in the treatment of hormone-dependent dermatitis. Tacrolimus ointment is effective for corticosteroid-dependent dermatitis, but adverse events can also occur. METHODS: We plan to searched all randomized controlled trials (RCTs) fortacrolimus ointment therapy of hormone-dependent dermatitis in: MEDLINE, PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Springer and Web of Science, China Biomedical Literature Database (CBM), China Science Journal Database (VIP database) and Wanfang Database, China National Knowledge Infrastructure (CNKI), without the limitation of publication status and language until September 1, 2020. The systematic review will also search will also search for identify publications, meeting minutes, and grey literature (including unpublished meeting articles). DISCUSSION: The systematic review mainly to access the safety and efficacy of tacrolimus ointment for hormone-dependent dermatitis (facial corticosteroid addiction dermatitis and facial steroid dermatitis). The results of our research will facilitate evidence-based management of patients with facial corticosteroid-dependent dermatitis and provide clinical advice on their treatment options. REGISTRATION: PROSPERO CRD42020171813.

Analysis of the Metabolic Characteristics of Serum Samples in Patients With Multiple Myeloma.

Aims: This study aimed to identify potential, non-invasive biomarkers for diagnosis and monitoring of the progress in multiple myeloma (MM) patients. Methods: MM patients and age-matched healthy controls (HC) were recruited in Discovery phase and Validation phase, respectively. MM patients were segregated into active group (AG) and responding group (RG). Serum samples were collected were conducted to non-targeted metabolomics analyses. Metabolites which were significantly changed (SCMs) among groups were identified in Discovery phase and was validated in Validation phase. The signaling pathways of these SCMs were enriched. The ability of SCMs to discriminate among groups in Validation phase was analyzed through receiver operating characteristic curve. The correlations between SCMs and clinical features, between SCMs and survival period of MM patients were analyzed. Results: Total of 23 SCMs were identified in AG compared with HC both in Discovery phase and Validation phase. Those SCMs were significantly enriched in arginine and proline metabolism and glycerophospholipid metabolism. 4 SCMs had the discriminatory ability between MM patients and healthy controls in Validation phase. Moreover, 12 SCMs had the ability to discriminate between the AG patients and RG patients in Validation phase. 10 out of 12 SCMs correlated with advanced features of MM. Moreover, 8 out of 12 SCMs had the negative impact on the survival of MM. 5'-Methylthioadenosine may be the only independent prognostic factor in survival period of MM. Conclusion: 10 SCMs identified in our study, which correlated with advanced features of MM, could be potential, novel, non-invasive biomarkers for active disease in MM.