AUF1 is involved in splenic follicular B cell maintenance

<p>Abstract</p> <p>Background</p> <p>The adenosine/uridine-rich element (ARE)-binding protein AUF1 functions to regulate the inflammatory response through the targeted degradation of cytokine and other mRNAs that contain specific AREs in their 3' noncoding region (3' NCR). To investigate the role of AUF1 in the immune system, we characterized the lymphoid compartments of AUF1-deficient mice.</p> <p>Results</p> <p>Mice lacking AUF1 exhibit an altered proportion and size of splenic B cell subsets. We show prominent apoptosis in splenic B cell follicles and reduced expression of Bcl-2, A1, and Bcl-X_Lcorrelate with increased turnover and significant reduction in the number and proportion of splenic FO B cells in AUF1-deficient mice. In addition, AUF1-deficient mice exhibit a sharp decrease in splenic size and lymphocyte cellularity. Bone marrow transfer studies demonstrate that AUF1 deficiency induces cell-autonomous defects in mature B cell subsets but not in the overall number of splenocytes. Reconstitution of irradiated adult AUF1-deficient mice with wild-type bone marrow restores the proportion of FO and marginal zone (MZ) B cells, but does not rescue the decrease in the number of splenocytes. Functionally, AUF1-deficient mice mount an attenuated response to T cell-independent (TI) antigen, which correlates with impaired MZ B cell function.</p> <p>Conclusion</p> <p>These data indicate that AUF1 is important in the maintenance of splenic FO B cells and adequate humoral immune responses.</p

Outcome of Blunt Abdominal Traumas with Stable Hemodynamic and Positive FAST Findings

Introduction: Focused assessment with sonography for trauma (FAST) is a highly effective first screening tool for initial classification of abdominal trauma patients. The present study was designed to evaluate the outcome of patients with blunt abdominal trauma and positive FAST findings. Methods: The present prospective cross-sectional study was done on patients over 7 years old with normal abdominal examination, positive FAST findings, and available abdominopelvic computed tomography (CT) scan findings. The frequency of need for laparotomy as well as its probable risk factors were calculated. Results: 180 patients were enrolled (mean age: 28.0 ± 11.5 years; 76.7% male). FAST findings were confirmed by abdominopelvic CT scan in only 124 (68.9%) cases. Finally, 12 (6.6%) patients needed laparotomy. Mean age of those in need of laparotomy was significantly higher than others (36.75 ± 11.37 versus 27.34 ± 11.37, p = 0.006). Higher grading of spleen (p = 0.001) and hepatic (p = 0.038) ruptures increased the probability of need for laparotomy. Conclusion: 68.9% of the positive FAST findings in patients with blunt abdominal trauma and stable hemodynamics was confirmed by abdominopelvic CT scan and only 6.6% needed laparotomy. Simultaneous presence of free fluid and air in the abdominal area, old age, and higher grading o solid organ injuries were factors that had a significant correlation with need for laparotomy

Experimental investigation of energy storage properties and thermal conductivity of a novel organic phase change material/MXene as A new class of nanocomposites

Energy storage is a global critical issue and important area of research as most of the renewable sources of energy are intermittent. In this research work, recently emerged inorganic nanomaterial (MXene) is used for the first time with paraffin wax as a phase change material (PCM) to improve its thermo-physical properties. This paper focuses on preparation, characterization, thermal properties and thermal stability of new class of nanocomposites induced with MXene nanoparticles in three different concentrations. Acquired absorbance (UV-Vis) for nanocomposite with loading concentration of 0.3 wt.% of MXene achieved ~39% enhancement in comparison with the pure paraffin wax. Thermal conductivity measurement for nanocomposites in a solid state is performed using a KD2 PRO decagon. The specific heat capacity (cp) of PCM based MXene is improved by introducing MXene. The improvement of cp is found to be 43% with 0.3 wt.% of MXene loaded in PCM. The highest thermal conductivity increment is found to be 16% at 0.3 wt.% concentration of MXene in PCM. Decomposition temperature of this new class of nanocomposite with 0.3 wt.% mass fraction is increased by ~6%. This improvement is beneficial in thermal energy storage and heat transfer applications

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients

Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression

Auf1/Hnrnpd-Deficient Mice Develop Pruritic Inflammatory Skin Disease

Mice lacking heterogenous nuclear ribonuclear protein D (Hnrnpd), also known as Auf1, a regulator of inflammatory cytokine mRNA stability, develop chronic dermatitis with age that is characterized by pruritis and excoriations. Histological analysis showed marked epidermal acanthosis and spongiosis, neovascularization, and elevated number of inflammatory cells, including T cells, macrophages, neutrophils, mast cells, and eosinophils. Hnrnpd-deficient (Hnrnpdtm1Rjsc) mice with dermatitis display elevated serum IgE levels. Lesions in Hnrnpdtm1Rjsc mice were associated with a shift towards a Th2 immune environment. Evaluation of T-cell-mediated skin inflammation by assaying contact hypersensitivity indicated an increased response in Hnrnpdtm1Rjsc mice. T cells and macrophages from Hnrnpdtm1Rjsc mice demonstrate a number of abnormalities associated with dermatitis, including increased IL2, tumor-necrosis factor-α (TNFα), and IL1β production. Finally, many features of spontaneous dermatitis could be recapitulated in experimentally induced lesions by subcutaneous injection of CCL27 and TNF in unaffected Hnrnpdtm1Rjsc mice. Collectively, these data highlight the importance of HNRNPD and proper regulation of mRNA stability in the intricate processes of leukocyte recruitment and inflammatory activation within the skin

Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs

Excessive production of proinflammatory cytokines, particularly tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia). Precise control of cytokine expression depends on rapid degradation of cytokine mRNAs, mediated by an AU-rich element (ARE) in the 3′ noncoding region and by interacting ARE-binding proteins, which control the systemic inflammatory response. To understand the function of the ARE-binding protein AUF1, we developed an AUF1 knockout mouse. We show that AUF1 normally functions to protect against the lethal progression of endotoxemia. Upon endotoxin challenge, AUF1 knockout mice display symptoms of severe endotoxic shock, including vascular hemorrhage, intravascular coagulation, and high mortality, resulting from overproduction of TNFα and IL-1β. Overexpression of these two cytokines is specific, and shown to result from an inability to rapidly degrade these mRNAs in macrophages following induction. Neutralizing antibodies to TNFα and IL-1β protect AUF1 knockout mice against lethal endotoxic shock. These and other data describe a novel post-transcriptional mechanism whereby AUF1 acts as a crucial attenuator of the inflammatory response, promoting the rapid decay of selective proinflammatory cytokine mRNAs following endotoxin activation. Defects in the AUF1 post-transcriptionally controlled pathway may be involved in human inflammatory disease