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Sphingolipids play important signaling and structural roles in cells. Here, we find that during de novo sphingolipid biosynthesis, a toxic metabolite is formed with critical implications for cancer cell survival. The enzyme catalyzing the first step in this pathway, serine palmitoyltransferase complex (SPT), is upregulated in breast and other cancers. SPT is dispensable for cancer cell proliferation, as sphingolipids can be salvaged from the environment. However, SPT activity introduces a liability as its product, 3-ketodihydrosphingosine (3KDS), is toxic and requires clearance via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). In cancer cells, but not normal cells, targeting KDSR induces toxic 3KDS accumulation leading to endoplasmic reticulum (ER) dysfunction and loss of proteostasis. Furthermore, the antitumor effect of KDSR disruption can be enhanced by increasing metabolic input (via high-fat diet) to allow greater 3KDS production. Thus, de novo sphingolipid biosynthesis entails a detoxification requirement in cancer cells that can be therapeutically exploited.

Introduction: Since the COVID-19 pandemic, many individuals have turned to peer-led online depression support groups (DSGs) to cope with depressive symptoms. However, relatively little research has articulated how use of DSGs may relate to specific behaviors associated with depression. This study assessed healthy behaviors (healthy support-seeking, healthy normalization, problem-solving) and unhealthy behaviors (unhealthy support-seeking, adverse normalization, co-rumination) associated with the use of peer-led DSGs. Method: Participants (N = 525) were recruited through the Qualtrics platform, and measures of depressive symptoms, self-reported social media use, DSG use, and healthy/unhealthy DSG behaviors were administered online. Path analysis estimated the relations of DSG use to each of the six behaviors. Results: Results showed that all six DSG behaviors were positively associated with DSG use (ps <.001). Standardized coefficients ranged from 0.18 to 0.49 for healthy outcomes and from 0.28 to 0.36 for the unhealthy outcomes. Greater use of DSGs was associated with higher levels of all healthy and unhealthy behaviors. Education level moderated the relation of DSG use to the three unhealthy behaviors, with higher education leading to stronger relations between DSG use and all three unhealthy behaviors. Discussion: These findings suggest that DSGs may be associated with both healthy and unhealthy effects on their users. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor‐T (CAR‐T) therapies represent a major breakthrough in cancer medicine, given the ex vivo‐based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B‐cell lymphomas. Although more than a decade has passed since the initial introduction of CAR‐T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR‐T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time‐honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR‐T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR‐T cell exhaustion. We highlight solutions including point‐of‐care CAR‐T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR‐T deployment for B‐cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first‐in‐class anti‐CD3/CD20 bispecific antibodies—mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024. [ABSTRACT FROM AUTHOR]

This paper describes the design, fabrication, and operational characteristics of a MEMS milliactuator designed for servo tracking in a hard-disk drive (HDD). The actuator is designed to increase the bandwidth of an HDD tracking servo and pack more recording tracks on a disk. An Invar (low thermal expansion metal) electrode position process was developed to meet the thermal stability requirement. The electroplated Invar's thermal coefficient of expansion is as low as 6.3 x [10.sup.-6]/K, which is almost half of that of pure nickel. For the plating mold pattern definition, a high-aspect-ratio polymer etching technique was developed. A high-aspect-ratio structure line-and-gap definition is required to achieve both a high directional stiffness ratio and electrode efficiency for the actuator. The etching technique described can etch through a thick ( Index Terms - Hard-disk drives, high-aspect-ratio structure, high-bandwidth tracking servo, Invar plating, microactuator.

Issue: The physiological effects of urban parks on stress relief and the factors that contribute to the effects are not well understood. Students from both occupational therapy (OT) and medical laboratory science (MLS) programs collaborated to explore the answers. Method: A one-group pretest-posttest research design was employed in this study. OT students worked in urban parks to recruit participants, administer a questionnaire about the subjective wellbeing (SWB) and collect a small amount of saliva before and after their park visits. MLS students worked in laboratories to test the Cortisol and DHEA concentrations in the salivary samples using a sensitive and specific enzyme-linked immunosorbent assay. The data collected from questionnaires and assays were merged and analyzed by both professional students. Outcomes: The levels of all biomarkers in saliva decreased, and SWB scores increased after the park visit. The duration of park visit was a key variable and a duration of 21.8 min had the predictive ability to discriminate Cortisol reductions in park visitors from those in non-park visitors. Conclusion: It is recommended that design of a park space should attract visitors to stay for at least 20 min. [ABSTRACT FROM AUTHOR]

Sputter deposited, equiatomic Pt-Mn thin films used in giant magnetoresistive spin valves are found not to exist in the antiferromagnetic state required for device operation. Therefore, an annealing step is needed to induce a phase transformation from the as-deposited, paramagnetic A1 (fcc) phase to the antiferromagnetic L1[SUB0] phase. The L1[SUB0] phase is the thermodynamically stable configuration, but favorable kinetics for the transformation were only found above 260°C. The A1 to L1[SUB0] phase transformation was studied by x-ray diffraction, transmission electron microscopy and differential scanning calorimetry (DSC). The nucleation and growth conditions were evaluated and an exothermic transformation enthalpy of -12.1 kJ/mol of atoms was determined. The kinetics of the reaction were simulated using the Johnson-Mehl-Avrami analysis, where the necessary parameters were determined by the Kissinger and Ozawa methods from constant scanning rate DSC experiments [H. Yinnon and D. R. Uhlmann, J. Non-Cryst. Solids 54, 253 (1983)]. The resulting simulations were compared to DSC data as well as isothermal x-ray peak shift data and a reasonable agreement was obtained. [ABSTRACT FROM AUTHOR]

During embryonic development, tissues undergo dramatic deformations as functional morphologies are stereotypically sculpted from simple rudiments. Formation of healthy, functional organs therefore requires tight control over the material properties of embryonic tissues during development, yet the biological basis of embryonic tissue mechanics is poorly understood. The present study investigates the mechanics of the embryonic small intestine, a tissue that is compactly organized in the body cavity by a mechanical instability during development, wherein differential elongation rates between the intestinal tube and its attached mesentery create compressive forces that buckle the tube into loops with wavelength and curvature that are tightly conserved for a given species. Focusing on the intestinal tube, we combined micromechanical testing with histologic analyses and enzymatic degradation experiments to conclude that elastic fibers closely associated with intestinal smooth muscle layers are responsible for the bending stiffness of the tube, and for establishing its pronounced mechanical anisotropy. These findings provide insights into the developmental role of elastic fibers in controlling tissue stiffness, and raise new questions on the physiologic function of elastic fibers in the intestine during adulthood.