Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs
, especially in the central nervous system (CNS). Despite antiretroviral therapy (ART), low-level ...persistent HIV replication in these reservoirs remains detectable, which contributes to neuroinflammation and neurological disorders in HIV-infected patients. New approaches complementary to ART to repress residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces the epigenetic suppression of HIV. Here, we examined the effects of this compound on HIV in human myeloid cells. We found that ZL0580 induces potent and durable suppression of both induced and basal HIV transcription in microglial cells (HC69) and monocytic cell lines (U1 and OM10.1). Pretreatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating an epigenetic reprogramming effect of ZL0580 on HIV long terminal repeat (LTR) in microglia. We also demonstrate that ZL0580 induces repressive effect on HIV in human primary monocyte-derived macrophages (MDMs) by promoting HIV suppression during ART treatment. Mechanistically, ZL0580 inhibits Tat transactivation in microglia by disrupting binding of Tat to CDK9, a process key to HIV transcription elongation. High-resolution micrococcal nuclease mapping showed that ZL0580 induces a repressive chromatin structure at the HIV LTR. Taken together, our data suggest that ZL0580 represents a potential approach that could be used in combination with ART to suppress residual HIV replication and/or latent HIV reactivation in CNS reservoirs, thereby reducing HIV-associated neuroinflammation.
Brain-resident microglia and perivascular macrophages are important HIV reservoirs in the CNS. Persistent viral replication and latent HIV reactivation in the CNS, even under ART, are believed to occur, causing neuroinflammation and neurological disorders in HIV-infected patients. It is critical to identify new approaches that can control residual HIV replication and/or latent HIV reactivation in these reservoirs. We here report that the BRD4-selective small molecule modulator, ZL0580, induces potent and durable suppression of HIV in human microglial and monocytic cell lines. Using an
HIV-infected, ART-treated MDM model, we show that ZL0580 also induces suppressive effect on HIV in human primary macrophages. The significance of our research is that it suggests a potential new approach that has utility in combination with ART to suppress residual HIV replication and/or HIV reactivation in CNS reservoirs, thereby reducing neuroinflammation and neurological disorders in HIV-infected individuals.
Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been ...reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai.
Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia.
Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.
Surface nanocrystallization is a highly effective approach for enhancing the surface wear resistance of stainless steel. However, the attainment of fast nanocrystallization on stainless steel ...surfaces remains a significant obstacle. Thus, a novel form for high-voltage electron beam radiation with a rapid response time of 50 ms is proposed to break through this bottleneck. The results revealed the presence of significant quantities of nanocrystals and an amorphous structure in the modified layer of stainless-steel surfaces. A large number of dislocation lines resulted in an interplane distance increase in the (110) planes of Fe-Cr. In addition, the dislocation walls can inhibit the growth of the crystal, contributing to a remarkable enhancement in their surface wear resistance. Significantly, the wear volume of the modified layer decreased from 0.0124 mm3 to 0.0013 mm3, a remarkable reduction of 90 % compared to the initial state due to surface nanocrystallization, dispersion strengthening, and dislocation walls. This study provides novel concepts for the production of surface nanocrystals in ultra-wear-resistant stainless steel.
Display omitted
•A novel form for high-voltage electron beam radiation with a rapid response time of 50 ms•Stainless steel with ultra-wear-resistant was fabricated by EB irradiation.•The process of nanograins generation and the underlying mechanism of strengthening have been elucidated.•Rapid fabrication via EB irradiation advances the wear resistance to 9.5 times higher than that of matrix
Background. Recently, hyaluronic acid dissolving microneedles (HA-DMNs) have been widely used in antiwrinkle research studies. However, the comparison of HA-DMNs with nonablative fractional laser ...(NAFL), which is regarded as the gold standard in the treatment of facial wrinkles, is still lacking. Objective. The purpose was to compare the therapeutic effects and adverse effects of HA-DMNs and NAFL on infraorbital wrinkles. Methods. A prospective, randomized, split-face trial was performed with HA-DMNs on one side and NAFL on the other. The wrinkle numbers, photo-numeric scores, and VISIA assessment scores were compared at baseline and 2, 4, 8, and 12 weeks post-treatment. Reflectance confocal microscopy (RCM) was used to monitor collagen fibers. Adverse effects and subjects’ satisfaction scores were evaluated using scales. Results. The final analysis included 28 patients. The wrinkle numbers and photo-numeric scores decreased on both the HA-DMNs side and the NAFL side in week-2, 4, 8, and 12. The VISIA scores decreased on the HA-DMNs side in week-8 and on the NAFL side in week-2. There were no significant differences in these indexes between the two sides. The RCM images demonstrated a similar increase in collagen density on the two sides. Burning, erythema, edema, and crust scores were higher on the NAFL side than on the HA-DMNs side. There was no significant difference in the subjects’ satisfaction scores of the two sides. Conclusion. HA-DMNs are effective treatment options for infraorbital rejuvenation. From the change of wrinkle numbers and scores, HA-DMNs provided comparable efficacy as NAFL in an observation period of 12 weeks. Meanwhile, HA-DMNs offered a more favorable adverse effect profile than NAFL therapy. Mild but persistent pain, erythema, and edema during the HA-DMNs therapy are noteworthy and require improvement.
Accurately predicting neurosyphilis prior to a lumbar puncture (LP) is critical for the prompt management of neurosyphilis. However, a valid and reliable model for this purpose is still lacking. This ...study aimed to develop a nomogram for the accurate identification of neurosyphilis in patients with syphilis. The training cohort included 9,504 syphilis patients who underwent initial neurosyphilis evaluation between 2009 and 2020, while the validation cohort comprised 526 patients whose data were prospectively collected from January 2021 to September 2021. Neurosyphilis was observed in 35.8% (3,400/9,504) of the training cohort and 37.6% (198/526) of the validation cohort. The nomogram incorporated factors such as age, male gender, neurological and psychiatric symptoms, serum RPR, a mucous plaque of the larynx and nose, a history of other STD infections, and co-diabetes. The model exhibited good performance with concordance indexes of 0.84 (95% CI, 0.83–0.85) and 0.82 (95% CI, 0.78–0.86) in the training and validation cohorts, respectively, along with well-fitted calibration curves. This study developed a precise nomogram to predict neurosyphilis risk in syphilis patients, with potential implications for early detection prior to an LP.
It remains a popular question whether rare earth oxides encourage reinforcing phases to the uniform distribution in cermet coating to improve the mechanical properties. This study applied laser ...cladding to prepare the TiAl/WC/CeOsub.2 MMC cermet coatings on the TC21 alloy substrate. The effects of CeOsub.2 content on the phase composition, microstructure formation, evolution mechanism, and properties of cermet coatings were investigated. Results show that the incorporation of CeOsub.2 did not change the phase of composite coating, but the shape of the TiC phase has a close relation to the CeOsub.2 content. CeOsub.2 enhanced the fluidity of the molten pool, which further encouraged the TiC/Tisub.2AlC core-shell reinforcement phase. With the increase in CeOsub.2 content, the optimized coating contributed to homogenous microstructure distribution and fine grain size. Owing to the hard phases strengthening and dispersion strengthening effects of CeOsub.2, the microhardness of the composite coatings was all significantly higher (almost 1.6 times) than that of the substrate. Importantly, the addition of CeOsub.2 significantly improved the wear resistance of the composite coating. This work provides a certain reference value for the study of surface strengthening of key parts in the aerospace field.
It remains a popular question whether rare earth oxides encourage reinforcing phases to the uniform distribution in cermet coating to improve the mechanical properties. This study applied laser ...cladding to prepare the TiAl/WC/CeO2 MMC cermet coatings on the TC21 alloy substrate. The effects of CeO2 content on the phase composition, microstructure formation, evolution mechanism, and properties of cermet coatings were investigated. Results show that the incorporation of CeO2 did not change the phase of composite coating, but the shape of the TiC phase has a close relation to the CeO2 content. CeO2 enhanced the fluidity of the molten pool, which further encouraged the TiC/Ti2AlC core-shell reinforcement phase. With the increase in CeO2 content, the optimized coating contributed to homogenous microstructure distribution and fine grain size. Owing to the hard phases strengthening and dispersion strengthening effects of CeO2, the microhardness of the composite coatings was all significantly higher (almost 1.6 times) than that of the substrate. Importantly, the addition of CeO2 significantly improved the wear resistance of the composite coating. This work provides a certain reference value for the study of surface strengthening of key parts in the aerospace field.
•A pilot study for the environmental source of B. pseudomallei in Hainan.•1080 soil samples were screened using culture and molecular identification methods.•10.2% soil samples and 13.3% sampling ...sites were positive.•The positive sites covered all coastal counties in Hainan Island.
Melioidosis is an infectious disease caused by Burkholderia pseudomallei, mainly found in Southeast Asia and northern Australia. In Hainan, sporadic cases were first described in 1990; since then, more cases have been identified. No systematic study has yet been done to detect the environmental source of the organism and its true extent in Hainan. This study is aimed to confirm the prevalence of B. pseudomallei in soil samples in Hainan. 1080 soil samples from 18 different counties were collected from 3 sampling points of 360 sites. They were screened for the presence of B. pseudomallei by Ashdown selective media. Suspected colonies of B. pseudomallei were confirmed by biochemical test and a specific PCR assay. 48 of 360 sites (13.3%) were positive for B. pseudomallei, including all coastal counties in Hainan Island. This study revealed the prevalence and distribution of B. pseudomallei in the soil environment in Hainan Island of southern China and may be helpful to understand the distribution of B. pseudomallei and to access its epidemiological importance.
We investigated Chlamydia trachomatis strains from Nanjing, China, and whether these strains differed from Amsterdam, the Netherlands. C. trachomatis type was determined with multilocus sequence ...typing. Most strains were specific to Nanjing, but some clustered with strains from Amsterdam. This demonstrates a geographical variation in C. trachomatis previously left undetected.
PDF
