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Efficient semi‐transparent solar cells can extend the adoption of photovoltaics beyond standard utility‐scale, commercial, or residential applications. Halide perovskites are particularly suitable in this respect owing to their tunable bandgap. The main drawbacks in the development of transparent perovskite solar cells are the high open‐circuit voltage (Voc) deficit and the difficulties in depositing high‐quality thin films over large area substrates, given the low solubility of bromide and chloride precursors. In this work, passivation strategies are developed for the high bandgap Br perovskite able to reduce charge recombination and consequently improve the Voc. The study demonstrates 1 cm2 perovskite solar cells with Voc up to 1.73 V (1.83 eV Quasi Fermi Level Splitting) and a PCE of 8.1%. The average visible transmittance (AVT) exceeds 70% by means of a bifacial light management and a record light utilization efficiency (LUE) of 5.72 is achieved. Moreover, the potential use of the technology is evaluated toward Internet of Things (IoT) application owing to a bifaciality factor of 87% along with 17% PCE under indoor lighting. Finally, the up‐scaling is demonstrated by fabricating 20 cm2 active area modules with PCE of 7.3% and Voc per cell up to 1.65 V. [ABSTRACT FROM AUTHOR]

The development of industrially relevant deposition processes for efficient, stable, and inexpensive charge extracting layers is crucial for the commercialization of perovskite solar cells (PSCs). This work demonstrates, for the first time, the deposition of copper thiocyanate (CuSCN) as a low‐cost and reliable hole‐transport layer using slot‐die coating. Methyl ethyl sulfide is thereby used as an asymmetric cosolvent to significantly increase the solubility of CuSCN in the utilized slot‐die ink compared to traditional pure diethyl sulfide‐based solutions. Optimized CuSCN inks allow for the deposition of CuSCN layers on 5 × 10 cm2 substrates with a wide range of thicknesses. Multidimensional imaging photoluminescence techniques are used to investigate the uniformity of the CuSCN thin films deposition as well as the influence of the solvent on charge losses. Finally, the CuSCN slot‐die deposition is integrated into a fully upscalable PSC fabrication process showing 19.1% power conversion efficiency for small laboratory cells and 14.7% for 9 cm2 minimodules. Furthermore, semitransparent minimodules retain 80% of their initial efficiency after 500 h of constant illumination. [ABSTRACT FROM AUTHOR]

In this study, the electronic band structure and the dynamics of the excited carriers in the formamidinium lead bromide (FAPbBr3) perovskite are investigated by combining the information obtained from steady‐state absorption, photoluminescence, femtosecond transient absorption spectroscopy, photoelectron spectroscopy, and density functional theory calculations. A detailed description of the electronic transitions in the UV–vis energy range has been provided, giving an estimation of the exciton binding energy (40 ± 5 meV), the transition energy from the first valence band (VB1) to the conduction band (CB1) (electronic bandgap at 2.37 ± 0.01 eV) and assigning the broad peak at ≈3.4 eV to the transition from the second innermost valence band (VB2) to CB1. The temporal dynamics of the excited carriers involved in these transitions are investigated using different excitation energies and carrier densities. Different trends are observed in the dynamics of the transient signals associated with the VB1→CB1 (PB1) and VB2→CB1 (PB2) transitions. As the carrier density increased, PB1 exhibited a slowing down of its rise time, while PB2 showed an acceleration attributed to the thermalization of the excited holes in VB2. These valuable findings have the potential to unlock new strategies aimed at maximizing the efficiencies and performance of perovskite‐based solar cell devices. [ABSTRACT FROM AUTHOR]

Understanding the effects of X‐rays on halide perovskite thin films is critical for accurate and reliable characterization of this class of materials, as well as their use in detection systems. In this study, advanced optical imaging techniques are employed, both spectrally and temporally resolved, coupled with chemical characterizations to obtain a comprehensive picture of the degradation mechanism occurring in the material during photoemission spectroscopy measurements. Two main degradation pathways are identified through the use of local correlative physico‐chemical analysis. The first one, at low X‐Ray fluence, shows minor changes of the surface chemistry and composition associated with the formation of electronic defects. Moreover, a second degradation route occurring at higher fluence leads to the evaporation of the organic cations and the formation of an iodine‐poor perovskite. Based on the local variation of the optoelectronic properties, a kinetic model describing the different mechanisms is proposed. These findings provide valuable insight on the impact of X‐rays on the perovskite layers during investigations using X‐ray based techniques. More generally, a deep understanding of the interaction mechanism of X‐rays with perovskite thin films is essential for the development of perovskite‐based X‐ray detectors and solar for space applications. [ABSTRACT FROM AUTHOR]

The extensive use of perovskites as light absorbers calls for a deeper understanding of the interaction of these materials with light. Here, the evolution of the chemical and optoelectronic properties of formamidinium lead tri‐bromide (FAPbBr3) films is tracked under the soft X‐ray beam of a high‐brilliance synchrotron source by photoemission spectroscopy and micro‐photoluminescence. Two contrasting processes are at play during the irradiation. The degradation of the material manifests with the formation of Pb0 metallic clusters, loss of gaseous Br2, decrease and shift of the photoluminescence emission. The recovery of the photoluminescence signal for prolonged beam exposure times is ascribed to self‐healing of FAPbBr3, thanks to the re‐oxidation of Pb0 and migration of FA+ and Br− ions. This scenario is validated on FAPbBr3 films treated by Ar+ ion sputtering. The degradation/self‐healing effect, which is previously reported for irradiation up to the ultraviolet regime, has the potential of extending the lifetime of X‐ray detectors based on perovskites. [ABSTRACT FROM AUTHOR]

In this paper, we derived a new method to map various optoelectronic parameters of solar cells from voltage-dependent electroluminescence imaging. To get quantitative data, we show how the voltage dependence of electroluminescence mimics a local diode current–voltage behavior, and we propose a way to measure the absolute electroluminescence flux. We therefore introduce a calibration factor generally left unknown in the literature. Example is shown on the Al-BSF silicon solar cell for which we map several parameters: diffusion lengths, dark saturation current, local voltages, and lumped series resistances with good accuracy. Comparison with other electroluminescence imaging methods is also shown. Preliminary knowledge about the sample are the spectral reflection coefficient, average dopant concentration, and back surface recombination. This method can also be derived for other kinds of solar cells by using an appropriate carrier collection model depending on their structure. [ABSTRACT FROM AUTHOR]

Observation of robust hot carrier effects in quantum-well structures has prompted hopes to increase the efficiency of solar cells beyond the Shockley–Queisser limit (33% for single junction solar cells at AM1.5G). One of the main studies in hot carrier effects is the determination of carrier temperature, which provides information on the thermalization mechanisms of hot carriers in semiconductor materials. Here, we investigate the spatial distribution of photo-generated hot carriers in a InGaAs multi-quantum-well structure via hyperspectral luminescence imaging. We discuss proper methods of extracting the temperature of carriers from a photoluminescence spectrum. Robust hot carrier effects are observed at the center of the laser spot at various lattice temperatures. In addition, it is seen that the local carrier temperature scales linearly with the local laser intensity as long as the illumination exceeds a threshold power; the carrier temperature at regions with local intensities below the threshold drops to the lattice temperature, i.e., experiences no hot carrier effects. Moreover, at large distances from the concentrated light, where the level of illumination is negligible, evidence of carrier radiative recombination is observed, which is attributed to carrier diffusion in the planar structure. The results of this study can be applied to investigate the influence of carrier diffusion and thermoelectric effects on the thermalization of hot carriers. [ABSTRACT FROM AUTHOR]

We demonstrate the use of the D1/D2 defect luminescence spectral range (1400 nm < λ < 1700 nm) of dislocations in cast-mono silicon to access geometrical tilt and opto-electronic recombination properties in their vicinity. The angle between dislocation and surface was determined thanks to the spatial asymmetry of the PL intensity in the regions close to the dislocations. Our optical model relies on the classical recombination–diffusion continuity equation as well as simple optical absorption and light propagation properties. It takes advantage of the optical transparency of silicon for wavelengths above 1400 nm. Carrier transport properties such as nonradiative lifetime around that location are also investigated. The model is discussed with a parameter study and the unicity of the extracted parameter set has been confirmed. As an example, we find out an angle of a selected dislocation pattern of about 25.4° with respect to the surface and an effective lifetime of 0.8–0.9 μs. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) and Niemann‐Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile‐onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N‐palmitoyl‐O‐phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1‐CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N‐(3β,5α,6β‐trihydroxy‐cholan‐24‐oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1‐, ALG1‐, ALG8‐, and PMM2‐CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Photoluminescence imaging has become a standard method to characterize solar cells. However, performing some quantitative analysis of this technique requires the assumption of uniform local absorptivity, which cannot be directly measured using traditional methods. This study presents a novel approach to measure the local relative absorptivity over a broad spectral range for a perovskite absorber deposited on a charge extraction layer and an electrode. By analyzing the photoluminescence intensity as a function of the incident photon energy, we were able to determine the relative absorptivity of the incident light above the bandgap energy. Additionally, luminescence spectra allow us to accurately assess the absorptivity near the bandgap energy from the reciprocity between absorption and emission. Reflectivity measurements were also performed to further understand the possible limitations of our experiment and to discuss our results. Finally, this method was able to distinguish between variations in the photoluminescence response caused by slight differences in the local film thickness and changes in the local carrier lifetime. [ABSTRACT FROM AUTHOR]

In this article, we introduce time-resolved fluorescence imaging as an optical characterization method for optoelectronic devices. Under wide-field illumination, it allows obtaining time-resolved photoluminescence maps with a temporal resolution of 500 ps and a micrometric spatial resolution. An experiment on a GaAs-based solar cell is presented here as a proof of concept. Thanks to a model including diffusion and recombination of minority charge carriers, we fit the experimental photoluminescence transients and extract key optoelectronic properties for the considered device. For various fluence levels, we determine an intrinsic bulk recombination lifetime τn =75 ns, a constant effective diffusion length Leff =190 μm, which is characteristic for the lateral transport inside the solar cell, and an injection-dependent contact recombination velocity Sn, taking its values between 7 x 104 and 3 x 105 cm/s, which is explained by the saturation of defects. The wide-field illumination notably avoids lateral diffusion artefacts leading to a significant underestimation of τn. [ABSTRACT FROM AUTHOR]

Interface engineering through passivating agents, in the form of organic molecules, is a powerful strategy to enhance the performance of perovskite solar cells. Despite its pivotal function in the development of a rational device optimization, the actual role played by the incorporation of interfacial modifications and the interface physics therein remains poorly understood. Here, we investigate the interface and device physics, quantifying charge recombination and charge losses in state-of-the-art inverted solar cells with power conversion efficiency beyond 23% - among the highest reported so far - by using multidimensional photoluminescence imaging. By doing that we extract physical parameters such as quasi-Fermi level splitting (QFLS) and Urbach energy enabling us to assess that the main passivation mechanism affects the perovskite/PCBM ([6,6]-phenyl-C61-butyric acid methyl ester) interface rather than surface defects. In this work, by linking optical, electrical measurements and modelling we highlight the benefits of organic passivation, made in this case by phenylethylammonium (PEAI) based cations, in maximising all the photovoltaic figures of merit. In this work, charge recombination and losses in inverted solar cells with dual organic cations interfacial passivation are quantified by mapping physical parameters obtained via continuous wave and time resolved photoluminescence imaging techniques. [ABSTRACT FROM AUTHOR]

Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor–stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting the need for an in vitro system that permits understanding the cellular mechanisms underlying neuronal loss and identifying appropriate therapies. This study reports the development of a novel human iPSC-derived, inducible neuronal model of Niemann-Pick disease, type C1 (NPC1). Results: We generated a null i3Neuron (inducible × integrated × isogenic) (NPC1−/− i3Neuron) iPSC-derived neuron model of NPC1. The NPC1−/− and the corresponding isogenic NPC1+/+ i3Neuron cell lines were used to efficiently generate homogenous, synchronized neurons that can be used in high-throughput screens. NPC1−/− i3Neurons recapitulate cardinal cellular NPC1 pathological features including perinuclear endolysosomal storage of unesterified cholesterol, accumulation of GM2 and GM3 gangliosides, mitochondrial dysfunction, and impaired axonal lysosomal transport. Cholesterol storage, mitochondrial dysfunction, and axonal trafficking defects can be ameliorated by treatment with 2-hydroxypropyl-β-cyclodextrin, a drug that has shown efficacy in NPC1 preclinical models and in a phase 1/2a trial. Conclusion: Our data demonstrate the utility of this new cell line in high-throughput drug/chemical screens to identify potential therapeutic agents. The NPC1−/− i3Neuron line will also be a valuable tool for the NPC1 research community to explore the pathological mechanisms contributing to neuronal degeneration. [ABSTRACT FROM AUTHOR]

Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity. Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice. [ABSTRACT FROM AUTHOR]

Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann‐Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4‐phosphate (PtdIns4P) countertransport cycle between Golgi‐endoplasmic reticulum (ER), as well as lysosome‐ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4‐kinases—PI4KIIα and PI4KIIIβ—which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease. Synopsis: The lysosomal Niemann‐Pick Type C1 (NPC1) transporter is essential for the egress of cholesterol from the lysosome to other cellular membranes. This study shows that NPC1 tunes the composition of Golgi‐endoplasmic reticulum (ER) and lysosome‐ER membrane contact sites (MCS) to regulate intracellular trafficking and growth signaling in mammalian cells.Phosphatidylinositol 4‐phosphate (PtdIns4P) levels are increased at Golgi and lysosomal membranes in NPC1 patient‐derived cells and in the brain of an NPC1 mouse model.High levels of PtdIns4P are due to increased recruitment of PI4KIIα and PI4KIIIβ kinases at Golgi and lysosomal membranes.Palmitoyl acyltransferase DHHC3 and multi‐functional adaptor protein ACBD3 mediate recruitment of PI4KIIα and PI4KIIIβ to Golgi‐ER and lysosome‐ER MCS.PtdIns4P increases anterograde secretion from the Golgi, and mTORC1 recruitment to lysosomes. [ABSTRACT FROM AUTHOR]

Background: We determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community‐based sample. Methods: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results: During a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions: Higher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults. [ABSTRACT FROM AUTHOR]

Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix–loop–helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30–dependent manner, also demonstrated increased mortality with starvation–refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation–refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation–refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival. [ABSTRACT FROM AUTHOR]

A nanoreporter noninvasively detects endolysosomal lipids, revealing that short-term changes in diet have enduring effects on hepatic macrophages. Enlightening endolysosomal lipids: Lipid accumulation contributes to multiple diseases including atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and lysosomal storage diseases. To noninvasively measure lipids in vivo, Galassi et al. engineered a carbon nanotube optical reporter for endolysosomal organelle uptake. In mouse models of lysosomal storage disease and NAFLD, the nanoreporter's near-infrared fluorescence tracked lipid accumulation within Kupffer cells (liver macrophages) and revealed that switching mice from a high-fat, high-fructose diet to standard chow only partially reversed liver lipid accumulation. This optical imaging agent could help to elucidate mechanisms of lipid accumulation in disease or be useful for drug development testing. The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube–based optical reporter that noninvasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. The reporter detected lipid accumulation in Niemann-Pick disease, atherosclerosis, and NAFLD models in vivo. By applying the reporter to the study of NAFLD, we found that elevated lipid quantities in hepatic macrophages caused by a high-fat diet persist long after reverting to a normal diet. The reporter dynamically monitored endolysosomal lipid accumulation in vivo over time scales ranging from minutes to weeks, indicating its potential to accelerate preclinical research and drug development processes. [ABSTRACT FROM AUTHOR]

Abstract: Deficiencies of galactosylceramidase and glucocerebrosidase result in the accumulation of galactosylsphingosine (GalSph) and glucosylsphingosine (GluSph) in Krabbe and Gaucher diseases, respectively. GalSph and GluSph are useful biomarkers for both diagnosis and monitoring of treatment effects. We have developed and validated a sensitive, accurate, high‐throughput assay for simultaneous determination of the concentration of GalSph and GluSph in mouse serum. GalSph and GluSph and their deuterated internal standards were extracted by protein precipitation in quantitative recoveries, baseline separated by hydrophilic interaction chromatography and detected by positive‐ion electrospray mass spectrometry in multiple reaction monitoring mode. Total run time was 7 min. The lower limit of quantification was 0.2 ng/mL for both GalSph and GluSph. Sample stability, assay precision and accuracy, and method robustness were demonstrated. This method has been successfully applied to measurement of these lipid biomarkers in a natural history study in twitcher (Krabbe) mice. [ABSTRACT FROM AUTHOR]

Objective: To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF).Methods: A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22).Results: After surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo-derived e' increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate.Conclusions: Surgery-induced weight loss in women with HFpEF and obesity was associated with improved symptoms, reverse cardiac remodeling, and improved relaxation. Although weight loss was associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. The results of this study suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63. Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids. Design: A randomized controlled trial, the Lulun ("egg" in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry. Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA. Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. [ABSTRACT FROM AUTHOR]

The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing cholesterol accumulation in NPC cells is uncertain and its molecular target is unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog of HPβCD, restored impaired macroautophagy/autophagy flux in Niemann-Pick disease, type C1 (NPC1) cells. This effect was mediated by a direct activation of AMP-activated protein kinase (AMPK), an upstream kinase in the autophagy pathway, through MβCD binding to its β-subunits. Knockdown ofPRKAB1orPRKAB2(encoding the AMPK β1 or β2 subunit) expression and an AMPK inhibitor abolished MβCD-mediated reduction of cholesterol storage in NPC1 cells. The results demonstrate that AMPK is the molecular target of MβCD and its activation enhances autophagy flux, thereby mitigating cholesterol accumulation in NPC1 cells. The results identify AMPK as an attractive target for drug development to treat NPC. [ABSTRACT FROM PUBLISHER]

Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MβCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications. [ABSTRACT FROM AUTHOR]

Methyl-b-cyclodextrin (MbCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MbCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MbCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MbCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MbCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MbCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications. [ABSTRACT FROM AUTHOR]

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the "SOAR" mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders. [ABSTRACT FROM AUTHOR]

Dietary fat promotes pathological insulin resistance through chronic inflammation. The inactivation of inflammatory proteins produced by macrophages improves diet-induced diabetes, but how nutrient-dense diets induce diabetes is unknown. Membrane lipids affect the innate immune response, which requires domains that influence high-fat-diet-induced chronic inflammation and alter cell function based on phospholipid composition. Endogenous fatty acid synthesis, mediated by fatty acid synthase (FAS), affects membrane composition. Here we show that macrophage FAS is indispensable for diet-induced inflammation. Deleting Fasn in macrophages prevents diet-induced insulin resistance, recruitment of macrophages to adipose tissue and chronic inflammation in mice. We found that FAS deficiency alters membrane order and composition, impairing the retention of plasma membrane cholesterol and disrupting Rho GTPase trafficking-a process required for cell adhesion, migration and activation. Expression of a constitutively active Rho GTPase, however, restored inflammatory signalling. Exogenous palmitate was partitioned to different pools from endogenous lipids and did not rescue inflammatory signalling. However, exogenous cholesterol, as well as other planar sterols, did rescue signalling, with cholesterol restoring FAS-induced perturbations in membrane order. Our results show that the production of endogenous fat in macrophages is necessary for the development of exogenous-fat-induced insulin resistance through the creation of a receptive environment at the plasma membrane for the assembly of cholesterol-dependent signalling networks. [ABSTRACT FROM AUTHOR]

In this letter, we investigate the origin of the spatial inhomogeneity of the photoluminescence (PL) intensity maps obtained on thin-film solar cells. Based on a hyperspectral imager setup, we record an absolute map of the quasi-Fermi level splitting Δμ by applying the generalized Planck's law. Then, using scanning confocal microscopy, we perform spatially and time-resolved photoluminescence measurements. This allowed us to quantify and map the micrometric fluctuations of the trapping defect density within these solar cells. Finally, we demonstrate the existence of a direct correlation between the spatial fluctuations of the quasi-Fermi level splitting and the trapping defect density. The latter was found to be correlated with the frequently reported spatially inhomogeneous PL maps of thin-film solar cells. Based on the observed correlation, we can quantify the local losses in quasi-Fermi level splitting induced by the spatial distribution of the trapping defects. [ABSTRACT FROM AUTHOR]

Among the known genetic risk factors for Parkinson disease, mutations in GBAl, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of a-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced α-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease. [ABSTRACT FROM AUTHOR]

The article offers information on a study which aims to develop a bile acid-based newborn screen for Niemann-Pick disease type C (NPC), a fatal, neurodegenerative, cholesterol storage disorder. It discussses the need to improve diagnostics and facilitate early intervention as well as the application of metabolomic profiling to identify potential markers and to determine three unknown bile acids.

Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol-sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1I1061T, encodes a misfolded protein with a reduced half-life caused by ER-associated degradation. Therapies directed at stabilization of the mutant NPC1 protein reduce cholesterol storage in fibroblasts but have not been tested in vivo because of lack of a suitable animal model. Whereas the prominent features of human NPC1 disease are replicated in the null Npc1-/- mouse, this model is not amenable to examining proteostatic therapies. The objective of the present study was to develop an NPC1 I1061T knock-in mouse in which to test proteostatic therapies. Compared with the Npc1-/- mouse, this Npc1tm(I1061T)Dso model displays a less severe, delayed form of NPC1 disease with respect to weight loss, decreased motor coordination, Purkinje cell death, lipid storage, and premature death. The murine NPC1I1061T protein has a reduced half-life in vivo, consistent with protein misfolding and rapid ER-associated degradation, and can be stabilized by histone deacetylase inhibition. This novel mouse model faithfully recapitulates human NPC1 disease and provides a powerful tool for preclinical evaluation of therapies targeting NPC1 protein variants with compromised stability. [ABSTRACT FROM AUTHOR]

Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations. [ABSTRACT FROM AUTHOR]

The article focuses on a research on prevention of cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease by intracisternal cyclodextrin. Topics discussed include hepatic disease and progressive neurological disease due to increase in unesterified cholesterol and several sphingolipids; subcutaneous administration 2-hydroxypropyl-b-cyclodextrin (HPbCD) to cats; and efficacy and safety of drug administration directly into the central nervous system.

UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an α2β2γ2 hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the α/β subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III α/β), while mutations in the γ subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III γ). Here we report neurologic consequences of mouse models of ML II and ML III γ. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III γ mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III γ mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6-phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments. [ABSTRACT FROM AUTHOR]