Lamin A/C: Function in Normal and Tumor Cells

This review is focused on lamin A/C, a nuclear protein with multiple functions in normal and diseased cells. Its functions, as known to date, are summarized. This summary includes its role in maintaining a cell’s structural stability, cell motility, mechanosensing, chromosome organization, gene regulation, cell differentiation, DNA damage repair, and telomere protection. As lamin A/C has a variety of critical roles within the cell, mutations of the lamin A/C gene and incorrect processing of the protein results in a wide variety of diseases, ranging from striated muscle disorders to accelerated aging diseases. These diseases, collectively termed laminopathies, are also touched upon. Finally, we review the existing evidence of lamin A/C’s deregulation in cancer. Lamin A/C deregulation leads to various traits, including genomic instability and increased tolerance to mechanical insult, which can lead to more aggressive cancer and poorer prognosis. As lamin A/C’s expression in specific cancers varies widely, currently known lamin A/C expression in various cancers is reviewed. Additionally, Lamin A/C’s potential as a biomarker in various cancers and as an aid in more accurately diagnosing intermediate Gleason score prostate cancers is also discussed.

The synapse in traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and is a risk factor for dementia later in life. Research into the pathophysiology of TBI has focused on the impact of injury on the neuron. However, recent advances have shown that TBI has a major impact on synapse structure and function through a combination of the immediate mechanical insult and the ensuing secondary injury processes, leading to synapse loss. In this review, we highlight the role of the synapse in TBI pathophysiology with a focus on the confluence of multiple secondary injury processes including excitotoxicity, inflammation and oxidative stress. The primary insult triggers a cascade of events in each of these secondary processes and we discuss the complex interplay that occurs at the synapse. We also examine how the synapse is impacted by traumatic axonal injury and the role it may play in the spread of tau after TBI. We propose that astrocytes play a crucial role by mediating both synapse loss and recovery. Finally, we highlight recent developments in the field including synapse molecular imaging, fluid biomarkers and therapeutics. In particular, we discuss advances in our understanding of synapse diversity and suggest that the new technology of synaptome mapping may prove useful in identifying synapses that are vulnerable or resistant to TBI.

Panniculitis at the Site of Injection: Infection or Foreign Body Reaction?

Introduction/Objective A 63 year old diabetic female presented to the dermatology clinic with painful abdominal nodules. The nodules seemed to wax and wane every 1–2 weeks and appeared in different locations on the abdomen. The lesions were subcutaneous, tender, firm, and mobile with no discoloration. The patient had diabetes treated with injectable exenatide but no other significant medical or travel history. Methods The differential diagnoses included mycobacterial infection, mechanical insult from injectable diabetes medication, erythema nodosum, erythema induratum, and lupus panniculitis. Ultrasound was indicative of panniculitis. A biopsy of the active lesion was performed. Results The biopsy showed septal and lobular panniculitis with mixed inflammation and multinucleated giant cells. Small, circular, non-polarizable pink amphorous material was associated with the infiltrate. The amphorous material was strongly acid fast. The patient had a negative quantiferon-TB test. Scanning electron microscopy with energy dispersive x-ray analysis showed that the material contained more oxygen and less carbon than surrounding tissue, but no abnormal elements were identified. Infrared spectroscopy of the foreign material most closely matched poly(L- lactide-co-glycolide). Conclusion The diagnosis of exenatide induced granulomatous panniculitis was made. The patient had recently started using this injectable glucagon-like peptide-1 receptor agonist, which has been associated with panniculitis. The injectable formulation is loaded onto microspheres composed of poly (DL-lactic-co-glycolic acid), which is closely related to poly(L-lactide-co-glycolide). This material has been shown to stain strongly acid fast. This case of granulomatous panniculitis due to injectable diabetic medication highlights an important potential pitfall that pathologists should be aware of, especially in cases where mycobacterial infection is in the differential.

Maskne: Exacerbation or Eruption of Acne During the COVID-19 Pandemic

Although the COVID-19 outbreak has decreased dermatology outpatient clinic visits, acne remains the most common condition among patients requesting an appointment. The widespread use of face masks may be a contributing factor to acne mechanica and folliculitis mechanica, where stopping the mechanical insult is essential to treatment. However, COVID-19 poses a unique challenge as mask wearing is crucial to limiting viral exposure. Although reported cases of mask-associated facial dermatoses are largely documented in healthcare workers, the general population is being affected by “maskne”. Pathogenesis and treatment options are discussed and the importance of counseling patients on proper skin hygiene is highlighted. As mask use increases, dermatologists should anticipate this trend in acne flare-ups.

Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice

Spinal cord injury (SCI) is caused by an initial mechanical insult followed by a series of deleterious events that promote the progressive damage of affected tissues. Fibrinolysis, the process by which plasmin degrades cross-linked fibrin clots, has numerous functions in the central nervous system. However, the roles of the fibrinolytic system in SCI pathophysiology remain unknown. We investigated the roles of fibrinolysis in SCI, and explored therapeutic applications targeting fibrinolysis. Plasminogen-deficient (Plg−/−) mice exhibited significantly improved locomotor function in the early phase of SCI (the first 7 days post injury), with significant inhibition of bleeding and vascular permeability, but failed to demonstrate conclusive functional recovery. Consistent with these findings, the short-term administration of tranexamic acid (TXA) in wild-type mice over the first 3 days post injury significantly improved locomotor function after SCI, whereas prolonged TXA administration did not. Prolonged TXA administration resulted in significantly lower levels of matrix metalloproteinase activities in the spinal cord, suggesting that inhibition of the fibrinolytic system impaired tissue remodeling. Our results indicate that the fibrinolytic system has time-dependent biphasic actions following SCI. The temporally optimised modulation of fibrinolytic activity may thus be a novel therapeutic strategy to improve functional outcomes after SCI.

Axons Embedded in a Tissue May Withstand Larger Deformations Than Isolated Axons Before Mechanoporation Occurs

Diffuse axonal injury (DAI) is the pathological consequence of traumatic brain injury (TBI) that most of all requires a multiscale approach in order to be, first, understood and then possibly prevented. While in fact the mechanical insult usually happens at the head (or macro) level, the consequences affect structures at the cellular (or microlevel). The quest for axonal injury tolerances has so far been addressed both with experimental and computational approaches. On one hand, the experimental approach presents challenges connected to both temporal and spatial resolution in the identification of a clear axonal injury trigger after the application of a mechanical load. On the other hand, computational approaches usually consider axons as homogeneous entities and therefore are unable to make inferences about their viability, which is thought to depend on subcellular damages. Here, we propose a computational multiscale approach to investigate the onset of axonal injury in two typical experimental scenarios. We simulated single-cell and tissue stretch injury using a composite finite element axonal model in isolation and embedded in a matrix, respectively. Inferences on axonal damage are based on the comparison between axolemma strains and previously established mechanoporation thresholds. Our results show that, axons embedded in a tissue could withstand higher deformations than isolated axons before mechanoporation occurred and this is exacerbated by the increase in strain rate from 1/s to 10/s.

Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut

Epithelia are exposed to diverse types of stress and damage from pathogens and the environment, and respond by regenerating. Yet, the proximal mechanisms that sense epithelial damage remain poorly understood. Here we report that p38 signaling is activated in adult Drosophila midgut enterocytes in response to diverse stresses including pathogenic bacterial infection and chemical and mechanical insult. Two upstream kinases, Ask1 and Licorne (MKK3), are required for p38 activation following infection, oxidative stress, detergent exposure and wounding. Ask1-p38 signaling in enterocytes is required upon infection to promote full intestinal stem cell (ISC) activation and regeneration, partly through Upd3/Jak-Stat signaling. Furthermore, reactive oxygen species (ROS) produced by the NADPH oxidase Nox in enterocytes, are required for p38 activation in enterocytes following infection or wounding, and for ISC activation upon infection or detergent exposure. We propose that Nox-ROS-Ask1-MKK3-p38 signaling in enterocytes integrates multiple different stresses to induce regeneration.

Optimized Impact Mitigation Barriers for Insensitive Munitions Compliance of a 120mm Warhead

The U.S. Army Combat Capabilities Development Command (CCDC) Armaments Center at Picatinny Arsenal, NJ is working to develop technologies to mitigate the violent reaction of a 120 mm warhead, loaded with an aluminized HMX-based enhanced blast explosive, when subjected to the NATO Insensitive Munitions (IM) Fragment Impact (FI) test. As per NATO STANAG 4496, FI testing is conducted at 8300±300 ft/s with a 0.563” diameter, L/D~1, 160˚ conical nosed mild steel fragment. Reaction violence resulting from FI can be mitigated by the use of liners or barriers applied to the munition itself or its packaging, commonly referred to as a Particle Impact Mitigation Sleeves (PIMS). Previous development efforts for this item focused on a lightweight plastic warhead support which was able to reduce the severity of the input shock sufficiently to prevent high order detonation. However, violent sub-detonative responses were still observed which occurred over several hundred microseconds, consumed part of the explosive charge, and ejected hazardous debris over large distances. These responses are driven by rapid combustion coupled with damage to the explosive as well as mechanical confinement. Quantitative modeling of these scenarios is a challenging active research area. Prior experimental results and modeling guidance have shown that mitigation of these reactions requires a more substantial reduction in the overall mechanical insult to the explosive. In particular, steel and aluminum PIMS have been able to efficiently provide the necessary fragment velocity reduction, breakup and dispersion in typical packaging applications. Packaged warheads were tested at the GD-OTS Rock Hill facility with several PIMS designs incorporated into the ammunition containers. Several designs were demonstrated to provide benign reactions with minimal added weight. Future iterations will attempt to further improve the design using advanced lightweight barrier materials.