"Why couldn't we do this more often?": exploring the feasibility of virtual and distributed work in product design engineering.

Lower costs and higher employee satisfaction are some of the benefits driving organizations to adopt dispersed and virtual working arrangements. Despite these advantages, product design engineering teams-those who develop physical products-have not widely adopted this working style due to perceived critical dependence on physical facilities and the belief that it is ineffective to communicate technical details virtually. This paper uses the mass shift in working conditions caused by the COVID-19 pandemic to explore the feasibility of virtual and distributed work in product design engineering. We conducted 20 semi-structured interviews with product design engineers working virtually to uncover current challenges of, and the beginning of promising strategies for, effective virtual engineering work. We categorize and analyze Tangible Design activities, Intangible Design activities, and Communication and Project Management activities throughout the product design process. Contrary to present opinions, we found that much of a product design engineer's work is realizable in a virtual and distributed setting. However, there are still many challenges, especially when attempting Tangible Design activities-those that require physical products and tools-from home. These challenges, missing from existing virtual product design engineering literature, include but are not limited to individuals' lessened sense of accountability, fewer de-risking opportunities before product sign-off, and limited supervision of production staff. Product design engineers described novel strategies that emerged organically to mitigate these challenges, such as creating digital alternatives for engineering reviews and sign-offs and leveraging rapid prototyping. Recent advances in technology, an increased commitment to reducing environmental impact, and better work-life balance expectations from new generations of workers will only push society faster towards a distributed working model. Thus, it is critical that we use this opportunity to understand the existing challenges for distributed product design engineers, so that organizations can best prepare and become resilient to future shocks.

Enrichment of NPC1-deficient cells with the lipid LBPA stimulates autophagy, improves lysosomal function, and reduces cholesterol storage.

Niemann-Pick C (NPC) is an autosomal recessive disorder characterized by mutations in the NPC1 or NPC2 genes encoding endolysosomal lipid transport proteins, leading to cholesterol accumulation and autophagy dysfunction. We have previously shown that enrichment of NPC1-deficient cells with the anionic lipid lysobisphosphatidic acid (LBPA; also called bis(monoacylglycerol)phosphate) via treatment with its precursor phosphatidylglycerol (PG) results in a dramatic decrease in cholesterol storage. However, the mechanisms underlying this reduction are unknown. In the present study, we showed using biochemical and imaging approaches in both NPC1-deficient cellular models and an NPC1 mouse model that PG incubation/LBPA enrichment significantly improved the compromised autophagic flux associated with NPC1 disease, providing a route for NPC1-independent endolysosomal cholesterol mobilization. PG/LBPA enrichment specifically enhanced the late stages of autophagy, and effects were mediated by activation of the lysosomal enzyme acid sphingomyelinase. PG incubation also led to robust and specific increases in LBPA species with polyunsaturated acyl chains, potentially increasing the propensity for membrane fusion events, which are critical for late-stage autophagy progression. Finally, we demonstrated that PG/LBPA treatment efficiently cleared cholesterol and toxic protein aggregates in Purkinje neurons of the NPC1I1061T mouse model. Collectively, these findings provide a mechanistic basis supporting cellular LBPA as a potential new target for therapeutic intervention in NPC disease.

Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid.

Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.

Primary cutaneous Nocardia brasiliensis infection isolated in an immunosuppressed patient: a case report.

Cutaneous nocardiosis is a rare infection that may manifest as a superficial skin lesion, lymphocutaneous infection, mycetoma, or diffuse cutaneous infection from a disseminated systemic infection. We report a case of a 65-year-old immunocompromised man with persistent primary cutaneous Nocardia brasiliensis infection following a motor vehicle collision. A high degree of suspicion is needed to diagnose Nocardia infection because of its resemblance to other bacterial infections. Nocardiosis should be included in the differential diagnosis of chronic cutaneous infections, especially when the response to antibiotics is inadequate or when the patient is immunocompromised. Because Nocardia may take several weeks to grow in standard bacterial culture media, laboratories should be notified of the suspicion so that culture plates are held for longer time periods. Long-term therapy, usually with sulfonamides, often is necessary.

Medical and surgical approaches to vulvar intraepithelial neoplasia.

Vulvar intraepithelial neoplasia (VIN) is a precursor to invasive vulvar carcinoma. The two major types of VIN, usual and differentiated, differ in epidemiology, pathogenesis, clinical manifestations, pathology, and malignant potential. Usual VIN commonly occurs in younger women. It is associated with human papillomavirus and tends to have multifocal and multicentric involvement. Differentiated VIN is frequently associated with benign vulvar dermatoses such as lichen sclerosus and lichen simplex chronicus. It occurs in older women and typically is unifocal and unicentric. Clinicians must have a high suspicion for VIN, which is diagnosed by biopsy. Surgical excision has been the standard treatment in order to prevent progression to invasive disease. The objectives of treatment have expanded to include preservation of normal vulvar function and anatomy. Therefore, management options are being investigated, including topical therapy, laser excision and vaporization, and photodynamic therapy. All can be effective in both eliminating disease and maintaining relatively normal-appearing and functioning anatomy.

Aphthous vulvar ulcers in adolescent girls: case report and review of the literature.

BACKGROUND: Aphthous vulvar ulcers are painful ulcerations on the genital mucosa frequently accompanied by systemic symptoms. They are most commonly reported in young women and adolescents without a history of sexual contact. Diagnosis is made by exclusion of more common causes, and treatment for this self-limited condition is mainly symptomatic. OBJECTIVE: Clinicians should be aware of this rare condition to avoid misdiagnoses and unwarranted investigations into sexual abuse or false accusations of sexual activity. METHODS: We report a case of an 11-year-old girl with systemic symptoms and vulvar ulcers of unknown etiology. RESULTS: The patient's illness was consistent with previous reports that vulvar ulcers can occur without sexual transmission or a documented infectious cause. CONCLUSION: A lack of general knowledge regarding this entity may lead to its exclusion from the differential diagnosis of vulvar ulcers in this patient population. Aphthous ulcers should be strongly considered in any adolescent with vulvar ulcers.

Nodular amyloidosis: differentiation from colloid milium by electron microscopy.

Nodular amyloidosis is a primary cutaneous amyloidosis characterized by the deposition of amyloid L-type fibril proteins in the dermis. Clinical history and routine histology may not be sufficient to differentiate nodular amyloidosis from colloid milium. We present a case of a 45-year-old man with nodular amyloidosis, whose diagnosis was confirmed by the characteristic appearance of filaments on electron microscopy.