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We have investigated the effect of electron doping on the superconducting properties of MgB2. For the purpose we have synthesized several samples along the Mg1−xScxB2 section. The X-ray diffraction measurements reveal small changes in the lattice parameters suggesting that the Sc doping could be considered to simply fill the boron σ bands. Radio frequency surface resistivity measurements has been used to obtain the variation of Tc with Sc doping. Increasing the Sc content, the experimental Tc diverges from the Tc predicted by the BCS single band theory showing the key role of interchannel pairing near a shape resonance. [Copyright &y& Elsevier]

Towards comprehensively investigating the genotype-phenotype relationships governing the human pluripotent stem cell state, we generated an expressed genome-scale CRISPRi Perturbation Cell Atlas in KOLF2.1J human induced pluripotent stem cells (hiPSCs) mapping transcriptional and fitness phenotypes associated with 11,739 targeted genes. Using the transcriptional phenotypes, we created a minimum distortion embedding map of the pluripotent state, demonstrating rich recapitulation of protein complexes, such as strong co-clustering of MRPL, BAF, SAGA, and Ragulator family members. Additionally, we uncovered transcriptional regulators that are uncoupled from cell fitness, discovering potential novel pluripotency (JOSD1, RNF7) and metabolic factors (ZBTB41). We validated these findings via phenotypic, protein-interaction, and metabolic tracing assays. Finally, we propose a contrastive human-cell engineering framework (CHEF), a machine learning architecture that learns from perturbation cell atlases to predict perturbation recipes that achieve desired transcriptional states. Taken together, our study presents a comprehensive resource for interrogating the regulatory networks governing pluripotency., Competing Interests: DECLARATION OF INTERESTS P.M. is a scientific co-founder of Shape Therapeutics, Boundless Biosciences, Navega Therapeutics, Pi Bio, and Engine Biosciences. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan Krogan has a financially compensated consulting agreement with Maze Therapeutics. Nevan Krogan is the President and is on the Board of Directors of Rezo Therapeutics, and he is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, GEn1E Lifesciences, and Interline Therapeutics.

Recent advancements in technology, especially the emergence of single-cell technologies, genomic sequencing, metabolomics, and artificial intelligence, have enabled us to understand the distinct metabolic changes in different cell types, tissues, genders, disease states, ages, and populations. Six scientists whose work intersects with metabolism in various capacities tell us about their vision for human metabolic heterogeneity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Compound lipids comprise a diverse group of metabolites present in living systems, and metabolic- and environmentally-driven structural distinctions across this family is increasingly linked to biological function. However, methods for deconvoluting these often isobaric lipid species are lacking or require specialized instrumentation. Notably, acyl-chain diversity within cells may be influenced by nutritional states, metabolic dysregulation, or genetic alterations. Therefore, a reliable, validated method of quantifying structurally similar even-, odd-, and branched-chain acyl groups within intact compound lipids will be invaluable for gaining molecular insights into their biological functions. Here we demonstrate the chromatographic resolution of isobaric lipids containing distinct combinations of straight-chain and branched-chain acyl groups via ultra-high-pressure liquid chromatography (UHPLC)-mass spectrometry (MS) using a C30 liquid chromatography column. Using metabolically-engineered adipocytes lacking branched-keto acid dehydrogenase A (Bckdha), we validate this approach through a combination of fatty acid supplementation and metabolic tracing using monomethyl branched-chain fatty acids and valine. We observe resolution of numerous isobaric triacylglycerols and other compound lipids, demonstrating the resolving utility of this method. This approach strengthens our ability to quantify and characterize the inherent diversity of acyl chains across the lipidome.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, causing joint-swelling and pain. International literature highlights that patients with RA are more likely to report high levels of alexithymia, adverse childhood events (ACEs) and stress, but studies investigating the association between these dimensions are lacking. The general aim of the present study is to investigate the association between alexithymia, ACEs, and stress in RA patients and to highlight possible predictors of greater perceived stress. One hundred and thirty-seven female patients with RA (mean age = 50.74; SD = 10.01) participated in an online survey between April and May 2021. Participants completed a questionnaire for the collection of sociodemographic and clinical information, the 20-item Toronto Alexithymia Scale, the Adverse Childhood Events questionnaire and the 10-item Perceived Stress Scale. The correlational analysis highlighted several significant associations between the dimensions evaluated. Regression analyses showed that alexithymia, ACEs and the perceived health status have a predictive effect on the perceived stress of RA patients. More specifically, the role of difficulty in identifying feelings, and the physical and emotional neglect, has been highlighted. ACEs and high levels of alexithymia are common in RA clinical populations and seem to affect the wellbeing of these patients. The use of a biopsychosocial approach to RA treatment appears essential in achieving a better quality of life and illness control in this specific clinical population.

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.

Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase ( SDH ) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH -mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH- mutant tumors, including GIST, has limited molecular characterization and drug discovery., Experimental Design: We describe methods for establishing novel patient-derived SDH -mutant (m SDH ) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with m SDH GIST., Results: Molecular and metabolic characterization of our patient-derived m SDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our m SDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH -mutant GIST treated with temozolomide ( n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST., Conclusions: We report the first methods to establish patient-derived m SDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with m SDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic. See related commentary by Blakely et al., p. 3 ., (©2021 American Association for Cancer Research.)

Deconstructing tissue-specific effects of genes and variants on proliferation is critical to understanding cellular transformation and systematically selecting cancer therapeutics. This requires scalable methods for multiplexed genetic screens tracking fitness across time, across lineages, and in a suitable niche, since physiological cues influence functional differences. Towards this, we present an approach, coupling single-cell cancer driver screens in teratomas with hit enrichment by serial teratoma reinjection, to simultaneously screen drivers across multiple lineages in vivo. Using this system, we analyzed population shifts and lineage-specific enrichment for 51 cancer associated genes and variants, profiling over 100,000 cells spanning over 20 lineages, across two rounds of serial reinjection. We confirmed that c-MYC alone or combined with myristoylated AKT1 potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. Additionally, mutant MEK1 S218D/S222D provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful platform for multi-lineage longitudinal study of oncogenesis., Competing Interests: P.M. is a scientific co-founder of Shape Therapeutics, Boundless Biosciences, Navega Therapeutics, and Engine Biosciences, which have no commercial interests related to this study. K.Z. is a cofounder, equity holder, and paid consultant of Singlera Genomics, which has no commercial interests related to this study. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies., (© 2021 The Author(s).)

PI5P4Ks are a class of phosphoinositide kinases that phosphorylate PI-5-P to PI-4,5-P 2 . Distinct localization of phosphoinositides is fundamental for a multitude of cellular functions. Here, we identify a role for peroxisomal PI-4,5-P 2 generated by the PI5P4Ks in maintaining energy balance. We demonstrate that PI-4,5-P 2 regulates peroxisomal fatty acid oxidation by mediating trafficking of lipid droplets to peroxisomes, which is essential for sustaining mitochondrial metabolism. Using fluorescent-tagged lipids and metabolite tracing, we show that loss of the PI5P4Ks significantly impairs lipid uptake and β-oxidation in the mitochondria. Further, loss of PI5P4Ks results in dramatic alterations in mitochondrial structural and functional integrity, which under nutrient deprivation is further exacerbated, causing cell death. Notably, inhibition of the PI5P4Ks in cancer cells and mouse tumor models leads to decreased cell viability and tumor growth, respectively. Together, these studies reveal an unexplored role for PI5P4Ks in preserving metabolic homeostasis, which is necessary for tumorigenesis., Competing Interests: Declaration of interests C.P. is a scientific advisor for SEngine Precision Medicine and is currently a study pathologist for the CUPISCO trial, which is sponsored by Roche. C.P. receives reimbursement for study-related travels and remuneration for her work as a study pathologist for the benefit of her employer. C.F. is a co-founder of Mirimus., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average dietary intake (1.52-5.20 g/d) needs to be vetted., Objectives: We aimed to determine the tolerance to graded dosages of histidine in a healthy adult population., Methods: Healthy adults aged 21-50 y completed graded dosages of histidine supplement (4, 8, and 12 g/d, Study 1) (n = 20 men and n = 20 women) and/or a 16-g/d dosage of histidine (Study 2, n = 21 men and n = 19 women); 27 participants (n = 12 men and n = 15 women) completed both studies. After study enrollment and baseline measures, participants consumed encapsulated histidine for 4 wk followed by a 3-wk recovery period. Primary outcomes included vitals, select biochemical analytes, anthropometry, serum zinc, and body composition (via DXA)., Results: No changes in vitals or body composition occurred with histidine supplementation in either study. Plasma histidine (measured in subjects who completed all dosages for Studies 1 and 2) was elevated at the 12- and 16-g/d dosages (compared with 0-8 g/d, P < 0.05) and blood urea nitrogen increased with dosage (P = 0.013) and time (P < 0.001) in Study 1 and with time in Study 2 (P < 0.001). In Study 1, mean ferritin concentrations were lower in 12 g/d (46.0 ng/mL; 95% CI: 34.8, 60.9 ng/mL) than in 4 g/d (51.6 ng/mL; 95% CI: 39.0, 68.4 ng/mL; P = 0.038). In Study 2, 16 g/d increased mean aspartate aminotransferase from baseline (19 U/L; 95% CI: 17, 22 U/L) to week 4 (24 U/L; 95% CI: 21, 27 U/L; P < 0.001) and mean serum zinc decreased from baseline (0.75 μg/dL; 95% CI: 0.71, 0.80 μg/dL) to week 4 (0.70 μg/dL; 95% CI: 0.66, 0.74 μg/dL; P = 0.011)., Conclusions: Although values remained within the normal reference ranges for all analytes measured, in all dosages tested, the human no-observed adverse effect level was determined to be 8 g/d owing to changes in blood parameters at the 12-g/d dosage.This trial was registered at clinicaltrials.gov as NCT04142294., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Most animals can successfully travel across cluttered, uneven environments and cope with enormous changes in surface friction, deformability and stability. However, the mechanisms used to achieve such remarkable adaptability and robustness are not fully understood. Even more limited is the understanding of how soft, deformable animals such as tobacco hornworm Manduca sexta (caterpillars) can control their movements as they navigate surfaces that have varying stiffness and are oriented at different angles. To fill this gap, we analyzed the stepping patterns of caterpillars crawling on two different types of substrate (stiff and soft) and in three different orientations (horizontal and upward/downward vertical). Our results show that caterpillars adopt different stepping patterns (i.e. different sequences of transition between the swing and stance phases of prolegs in different body segments) based on substrate stiffness and orientation. These changes in stepping pattern occur more frequently in the upward vertical orientation. The results of this study suggest that caterpillars can detect differences in the material properties of the substrate on which they crawl and adjust their behavior to match those properties., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A., (Copyright © 2019 Elsevier Inc. All rights reserved.)