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Ferroptosis is an iron-dependent form of cell death driven by oxidation of polyunsaturated fatty acid (PUFA) phospholipids. Large-scale genetic screens have uncovered a specialized role for PUFA ether phospholipids (ePLs) in promoting ferroptosis. Understanding of the enzymes involved in PUFA-ePL production, however, remains incomplete. Here we show, using a combination of pathway mining of genetic dependency maps, AlphaFold-guided structure predictions and targeted lipidomics, that the uncharacterized transmembrane protein TMEM164—the genetic ablation of which has been shown to protect cells from ferroptosis—is a cysteine active center enzyme that selectively transfers C20:4 acyl chains from phosphatidylcholine to lyso-ePLs to produce PUFA ePLs. Genetic deletion of TMEM164 across a set of ferroptosis-sensitive cancer cell lines caused selective reductions in C20:4 ePLs with minimal effects on C20:4 diacyl PLs, and this lipid profile produced a variable range of protection from ferroptosis, supportive of an important but contextualized role for C20:4 ePLs in this form of cell death.

A recent study evaluated the effectiveness of 3 direct oral anticoagulants and warfarin in patients with atrial fibrillation. So which agents came out on top? PRACTICE CHANGER Use direct oral [...]

LPCAT3 is an integral membrane acyltransferase in the Lands cycle responsible for generating C20:4 phospholipids and has been implicated in key biological processes such as intestinal lipid absorption, lipoprotein assembly, and ferroptosis. Small-molecule inhibitors of LPCAT3 have not yet been described and would offer complementary tools to genetic models of LPCAT3 loss, which causes neonatal lethality in mice. Here, we report the discovery by high-throughput screening of a class of potent, selective, and cell-active inhibitors of LPCAT3. We provide evidence that these compounds inhibit LPCAT3 in a biphasic manner, possibly reflecting differential activity at each subunit of the LPCAT3 homodimer. LPCAT3 inhibitors cause rapid rewiring of polyunsaturated phospholipids in human cells that mirrors the changes observed in LPCAT3-null cells. Notably, these changes include not only the suppression of C20:4 phospholipids but also corresponding increases in C22:4 phospholipids, providing a potential mechanistic explanation for the partial but incomplete protection from ferroptosis observed in cells with pharmacological or genetic disruption of LPCAT3.

EVIDENCE-BASED ANSWER A / NO. Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms (VMS) in perimenopausal and postmenopausal women (strength of recommendation: A, systematic review of randomized [...]

PHARC (polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and cataract) is a human neurological disorder caused by deleterious mutations in the ABHD12gene, which encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase. Pharmacological or genetic disruption of ABHD12 leads to higher levels of lyso-PS lipids in human cells and the central nervous system (CNS) of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting in selective increases in the level of arachidonoyl (C20:4) PS and decreases in the levels of other PS species. The biochemical basis for ABHD12-dependent PS remodeling and its pathophysiological significance remain unknown. Here, we show that genetic deletion of the lysophospholipid acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice lacking ABHD12 and concurrently produces hyper-increases in the level of lyso-PS in these animals. These lipid changes correlate with exacerbated auditory dysfunction and brain microgliosis in mice lacking both ABHD12 and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3 coordinately regulate lyso-PS and C20:4 PS content in the CNS and point to lyso-PS lipids as the likely bioactive metabolites contributing to PHARC-related neuropathologies.

Byline: Alex Reed With sustainable operation and construction becoming nearly standard practice in K-12 and higher education, indoor air quality (IAQ) sometimes takes a back seat to energy efficiency. But, [...]

ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lysophosphatidylserine (lyso-PS) and lysophosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP) guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways.

ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12–/–mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo–active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12–/–mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12–/–mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo.

Indulgent comfort food the toastie is well-established as a student staple and a treat for kid's holidaying in Spain. Anyone growing up in the seventies will also remember how a [...]

The use of reception meetings is helping to ease the psychological impact of admission to psychiatric hospitals. Issues surrounding admission and hospital routines are discussed at the meetings, which are attended by the patient and close friends or family. The meetings provide an opportunity for hospital staff to discuss the patient's previous mental health, while sharing information regarding care planning. It may be important for some minority groups to know certain procedures are being carried out according to their cultural or religious teachings.

Like the state of technology worldwide, the construct of mobile learning is constantly evolving. Mobile learning and remote teaching are gaining momentum and popularity in higher education, but little research has been done to examine their efficacy. With the use of mobile devices both in and out of the classroom becoming more prevalent, it is essential to examine the effectiveness of their use. This study compared the use of mobile learning and remote teaching (teaching content to students outside traditional face-to-face settings) with that of traditional teaching methods. Using mobile devices and social media, this study examined whether social work curriculum could be taught effectively to students outside static online or classroom environments.

The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Automatic continuous online monitoring of polymerization reactions (ACOMP) was applied to free radical copolymerization of acrylic comonomers, whose spectral characteristics are very similar. Determination of the instantaneous concentration of each comonomer during the reaction was made possible by incorporating a full spectrum UV spectrophotometer into the detector train. The working assumption was that a UV spectrum at any instant during conversion is a linear combination of the normalized basis spectra of the comonomers and the copolymer, and that the unknown comonomer concentrations can be found by minimizing the error between measured and computed spectra over many wavelengths, even when spectral differences are small at any given wavelength. Here, the copolymerization of butyl acrylate (BA) and methyl methacrylate (MMA) was monitored under different starting composition ratios. Continuous conversion kinetics, composition drift, and average composition distribution are all found from the data, in addition to the evolution of weight-average intrinsic viscosity and molar mass Mw. Reactivity ratios, rmma 0.40 ± 0.05 and rba 2.58 ±0.1, are close to the averages found from a literature survey over a wide range of conditions. Comonomer conversion results were independently cross-checked by GPC. Increasing the content of BA in the copolymer was found to increase Mw, while also leading to a significant increase in chain stiffness. This work sets the stage for extension to copolymerization of three and more comonomers.

A quiz about one's emotional balance is presented.