Lenalidomide potentially reduced the level of cell- associated HIV RNA and improved persistent inflammation in patients with HIV-associated cryptococcal meningitis a pilot study

BackgroundThe HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV.MethodsLenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model.ResultsThirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P = 0.007, P = 0.014, respectively). C-reactive protein/IL-6/TNF-α and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-α and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P = 0.004, P < 0.0001, respectively) while IL-10 levels increased significantly on lenalidomide compared to no-lenalidomide treatment (P < 0.0001).ConclusionsLenalidomide was preliminarily confirmed to reduce the level of cell- associated HIV RNA and improve persistent inflammation in patients with HIV-Associated cryptococcal meningitis, which was a potential intervention for clinical use to inhibit viral transcription of the HIV-1 reservoir and reduced HIV-related inflammation in HIV-1 patients during ART

ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells

An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia

Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation

Joint Character-Level Word Embedding and Adversarial Stability Training to Defend Adversarial Text

Text classification is a basic task in natural language processing, but the small character perturbations in words can greatly decrease the effectiveness of text classification models, which is called character-level adversarial example attack. There are two main challenges in character-level adversarial examples defense, which are out-of-vocabulary words in word embedding model and the distribution difference between training and inference. Both of these two challenges make the character-level adversarial examples difficult to defend. In this paper, we propose a framework which jointly uses the character embedding and the adversarial stability training to overcome these two challenges. Our experimental results on five text classification data sets show that the models based on our framework can effectively defend character-level adversarial examples, and our models can defend 93.19% gradient-based adversarial examples and 94.83% natural adversarial examples, which outperforms the state-of-the-art defense models

Enhancement of focusing properties by interfering spatial bending beams

In this study, two slits were designed symmetrically on a metal film to excite surface plasmon polaritons (SPPs), and two groups of parallel dielectric rectangles were designed over a metal film to convert the SPPs into double mirror-symmetric spatial bending beams. The high-energy far-field focused beams were achieved by interfering double mirror-symmetric spatial bending beams using the finite-element method The focusing properties of the proposed structure are enhanced compared with the conventional metal grating structures. Furthermore, the effects of the structural parameters on the focusing properties were investigated Results show that the focusing properties of the proposed structure rely on the structural parameters of dielectric rectangles and on the distance between the dielectric rectangles and the metal film. The position of the focusing spot relies on the distance between two slits. These findings can be applied in the fields of biology imaging, nanolithography, optical data storage and photo-biomedical detection

Stable propagation of the Poincaré polarization solitons in strongly nonlocal media

We report the first experimental observation of spatial solitons with complex polarization states, called the Poincaré polarization solitons (PPSs) in lead glass with strongly nonlocal nonlinearity. The formations of PPSs with topological charge of l  = 1, including the cylindrical elliptical-polarization soliton (CEPS) and the angularly-hybrid polarization soliton (AHPS), were observed. We showed that the annular profiles and the complex polarization distributions of the first-order PPSs can be remained. Based on the linear stability analysis, we proved that the first-order PPSs are fully stable and the second-order PPS can survive only when one of the two component vortices dominates