/pdf/fatigue-and-fracture-of-thin-metallic-foils-with-aerospace-2lp7jv0oil.pdf

Fatigue and Fracture of Thin Metallic Foils with Aerospace Applications

Approximately five million dengue virus-infected patients, particularly children, progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the FcγR, CD64 on myeloid cells, yet diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage vs. enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics

Severe dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million of the 400 million people infected with dengue virus (DENV) annually. To define DENV target cells and immunological hallmarks of SD progression in children’s blood, we integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion, and cell-cell communications point towards increased migration and inflammation in SD progressors (SDp). Concurrently, antigen presenting cells from SDp demonstrate intact uptake, yet impaired interferon responses and antigen presentation, in part DENV-modulated. Increased activation, regulation, and exhaustion of effector responses and expansion of HLA-DR-expressing, possibly compensatory, adaptive-like NK cells also characterize SDp. These findings reveal DENV target cells in the human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

Global and cell type-specific immunological hallmarks of severe dengue progression

Dengue is a mosquito-borne infection caused by dengue virus (DENV) of the Flaviviridae family. There are four distinct serotypes, DENV-1,-2,-3,-4, which cause outbreaks globally. Infection is often self-resolving, and lifelong immunity against the infecting serotype can be achieved after exposure. However, in some individuals, homologous infection may still result in symptomatic dengue [1]. There is usually limited protection against heterotypic infections by three other DENV serotypes, as cross-protection is short-lived [2]. After this window of “protection”, subsequent infection with a different serotype may increase the risk of develop-ing severe dengue [3,4]. Antibody-dependent enhancement (ADE) in dengue, a process mainly mediated by immunoglobulin G (IgG), is believed to be one of the major underlying mechanisms leading to increased severity in secondary DENV infection. ADE was shown to enhance viral entry into immune cells via their Fc γ receptors (Fc γ R), which promotes viral replication, leading to increased viremia and pro-inflammatory responses. These contribute to disease pathologies including vascular hyperpermeability, a common cause

Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.

https://www.biorxiv.org/content/biorxiv/early/2023/04/03/2023.04.01.535210.full.pdf

DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection

https://doi.org/10.1016/j.isci.2022.104384

Contrasting behavior between the three human monocyte subsets in dengue pathophysiology

Meteoroid/Orbital Debris Risk Assessment for Resuseable Launch Vehicles Using Metallic TPS

Increasing use of joint replacement for various conditions has led to a new group of fractures- the periprosthetic fractures. Periprosthetic fractures are considered which are associated with an orthopaedic implant. Worldwide incidence of Periprosthetic fractures is increasing due to increased number of primary joint arthroplasties and other revision surgeries. Periprosthetic femoral fracture can be classified as intraoperative & post-operative. The intraoperative periprosthetic fractures usually occur during the insertion of the femoral stem, often preceded by an area of increased cortical thickness. The management of these fractures are complex and usually needs application of basic principles to fit an individual situation rather than having a fixed set of rules. Standard treatment protocol includes use of locking plate with encirclage wires. In this study, we provide a case of periprosthetic femur fracture pain. A 75-year-old woman presented to us with pain in her right hip and thigh. The patient was a homemaker who had cemented total hip replacement surgery due to a femoral neck fracture 27 days back. After the primary replacement surgery, the patient appeared to be doing well and adhering to the hip precautions. While getting out of bed, she tripped and fell carelessly in the morning & complained of severe pain in her right hip. After assessment of all her medical conditions and physical examination, she was advised for revision surgery. An open reduction and internal fixation of the fracture with revision of the femoral component was planned. Risks, benefits, and alternatives were discussed at length with her and her family. The patient and her family agreed to the operative plan.

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Raf Ahmed

Papers

Contrasting behavior between the three human monocyte subsets in dengue pathophysiology

Meteoroid/Orbital Debris Risk Assessment for Resuseable Launch Vehicles Using Metallic TPS

Periprosthetic Femur Fracture in a 73-Year-Old Female: A Case Report