Bimodal Effect Research Articles

Application of the network scale-up method to estimate the sizes of key populations for HIV in Singapore using online surveys.

Singapore lacks robust data on the sizes of the key populations that are most at risk for HIV. Using the network scale-up method for hidden or hard-to-reach populations, we estimate the sizes of five key populations-male clients of female sex workers (MCFSW), men who have sex with men (MSM), female sex workers (FSW), people who inject drugs (PWID) and transgender people-and profile the ages and ethnicities of respondents with the high-risk contacts they report knowing. We conducted a cross-sectional online survey between March and May 2019 (n = 2802) using a network scale-up instrument previously developed for Singapore. Participants were recruited using an existing panel and online advertising, and the sample reweighted by age, sex, ethnicity and education attained to represent the general adult population. We built a Bayesian hierarchical model to estimate the sizes of the five key populations for HIV in Singapore. After adjustment, the sizes of the at-risk populations are estimated to be: 76,800 (95% credible interval [CI]: 64,200-91,800) MCFSW; 139,000 (95% CI: 120,000-160,000) MSM; 8030 (95% CI: 3980-16,200) FSW; 3470 (95% CI: 1540-7830) PWID and 18,000 (95% CI: 14,000-23,200) transgender people. Generally, men reported knowing more people in all the high-risk groups; older people reported knowing more MCFSW, FSW and transgender people; and younger people reported knowing more MSM. There was a bimodal effect of age on those who reported knowing more PWIDs: people in their 20s and 60s reported more contacts. This study demonstrates that a size estimation study of hidden populations is quickly and efficiently scalable through using online surveys in a socially conservative society, like Singapore, where key populations are stigmatized or criminalized. The approach may be suitable in other countries where stigma is prevalent and where barriers to surveillance and data collection are numerous.

The Mechanism of Bimodal Effect of DL-Butyonine Sulfoximine on Constitutive Androstane and Pregnane X Receptors In Vitro

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are nuclear receptors that are involved in the regulation of gene transcription of enzymes that are responsible for biotransformation and excretion of endo- and xenobiotics. The goal of the work was to study the effect of DL-butyonine sulfoximine (BSO, gamma-glutamylcysteine synthetase inhibitor) on the relative amounts of CAR and PXR in Caco-2 cells and to clarify its mechanisms. BSO was used at concentrations of 1-500 μM for 24 and 72 h. The generation of reactive oxygen species (ROS) has been evaluated using the MitoTracker Red CM-H2 XRos fluorescent probes. Cytotoxicity was analyzed by the MTT test. The relative amount of CAR and PXR was assessed by the Western blot method. It has been shown that BSO caused an increase in ROS formation at concentrations of 10, 50, and 100 μM for 24 h and at concentrations of 50 and 100 μM for 72 h. However, 500 μM BSO reduced the viability of cells during all periods of exposure. The relative amount of CAR increased in 24 h at the BSO concentrations of 50 and 100 μM and in 72 h at its concentrations of 10 and 50 μM. The amount of PXR increased in 72 h during incubation with BSO at the concentration of 50 μM and in 24 and 72 h at its concentrations of 100 and 500 μM. The combined use of BSO (50 μM, 24 h; 10 and 50 μM, 72 h) and glutathione inhibited CAR induction, whereas 50 and 100 μM BSO inhibited PXR formation for 72 h. The addition of 1 mM glutathione to the nutrient medium with BSO (100 and 500 μM, 24 h; 500 μM, 72 h) did not affect the relative amount of PXR. No effect on CAR was observed when 1 mM glutathione was used together with BSO (100 μM, 24 h; 50 and 100 μM, 72 h). Thus, BSO can induce CAR and PXR formation by both increasing the production of free radicals, thus developing oxidative stress, and by acting independently as a xenobiotic.

Taurine rescues pancreatic β-cell stress by stimulating α-cell transdifferentiation.

The semi-essential ubiquitous amino acid taurine has been shown to alleviate obesity and hyperglycemia in humans; however, the pathways underlying the antidiabetic actions have not been characterized. We explored the effect of chronic taurine exposure on cell biology of pancreatic islets, in degenerative type 1-like diabetes. The latter was modeled by small dose of streptozotocin (STZ) injection for 5 days in mice, followed by a 10-day administration of taurine (2% w/v, orally) in the drinking water. Taurine treatment opposed the detrimental changes in islet morphology and β-/α-cell ratio, induced by STZ diabetes, coincidentally with a significant 3.9 ± 0.7-fold enhancement of proliferation and 40 ± 5% reduction of apoptosis in β-cells. In line with these findings, the treatment counteracted an upregulation of antioxidant (Sod1, Sod2, Cat, Gpx1) and downregulation of islet expansion (Ngn3, Itgb1) genes induced by STZ, in a pancreatic β-cell line. At the same time, taurine enhanced the transdifferentiation of α-cells into β-cells by 2.3 ± 0.8-fold, echoed in strong non-metabolic elevation of cytosolic Ca2+ levels in pancreatic α-cells. Our data suggest a bimodal effect of dietary taurine on islet β-cell biology, which combines the augmentation of α-/β-cell transdifferentiation with downregulation of apoptosis. The dualism of action, stemming presumably from the intra- and extracellular modality of the signal, is likely to explain the antidiabetic potential of taurine supplementation.

Bimodal effect on mass transport of proton exchange membrane fuel cells by regulating the content of whisker-like carbon nanotubes in microporous layer

The excellent microporous layers (MPLs) in the gas diffusion layer requires superior mass transfer capacity, which is essential to high-performance proton exchange membrane fuel cells. However, the correspondence between MPL structure and mass transfer performance is ambiguous. Here, we design efficient mass transfer channels in MPLs with evolutionary structures by adjusting the content of whisker-like carbon nanotubes (WCNTs). The cell power density exhibits a bimodal shape with the increase of WCNTs in MPLs, which verifies that the perforated cracks of 5–10 μm in the MPL provide the separated channels for water and gas transport, and the optimal hydrophobic mesopores (34.87%) promote the mass transfer efficiency by elevating the capillary force of water transport. At 100% relative humidity (RH), the peak power densities of cells with the two MPLs are increased to 2.321 W cm−2 and 2.117 W cm−2, respectively. The electrochemical impedance spectroscopy confirms that the impedance of both MPLs are 109.35 mΩ cm2 and 63.55 mΩ cm2 at 100% RH and 3 A cm−2. The simple and scalable strategy provides a novel idea to relieve the mass transport loss of fuel cells.

Mechanisms of polyphosphate-induced amyloid fibril formation triggered by breakdown of supersaturation.

Much effort has been devoted to elucidate mechanisms of amyloid fibril formation using various kinds of additives, such as salts, metals, detergents, and biopolymers. Here, we review the effects of additives with a focus on polyphosphate (polyP) on amyloid fibril formation of β2-microglobulin (β2m) and α-synuclein (αSyn). PolyP, consisting of up to 1,000 phosphoanhydride bond-linked phosphate monomers, is one of the most ancient, enigmatic, and negatively charged molecules in biology. Amyloid fibril formation of both β2m and αSyn could be accelerated by counter anion-binding and preferential hydration at relatively lower and higher concentrations of polyP, respectively, depending on the chain length of polyP. These bimodal concentration-dependent effects were also observed in salt- and heparin-induced amyloid fibril formation, indicating the generality of bimodal effects. We also address the effects of detergents, alcohols, and isoelectric point precipitation on amyloid fibril formation, in comparison with the effects of salts. Because polyP is present all around us, from cellular components to food additives, clarifying its effects and consequent biological roles will be important to further advance our understanding of amyloid fibrils. This review article is an extended version of the Japanese article, Linking Protein Folding to Amyloid Formation, published in SEIBUTSU BUTSURI Vol. 61, p. 358-365 (2021).

In Situ Construction of TiC-Ti3SiC2 Gradient Hybrid Interphase Coated SiC Fibers for Suppression of Specular Reflection and Non-Specular Scattering

TiC-Ti3SiC2 gradient hybrid interphase on the surface of SiC fibers was successfully obtained through the molten salt method. The electromagnetic parameters of the prepared samples can be accurately controlled by adjusting the reaction temperature. A significant bimodal effect is observed in electromagnetic parameters patterns, corresponding to the double interface layer. TiC-Ti3SiC2 gradient hybrid interphase plays a dominant role in impedance matching, as well as in the attenuation layer through multi-interfacial polarization and conduction loss. Through the co-evaluation of the suppression of specular reflection and non-specular scattering properties of the samples, the SiC fiber with the TiC-Ti3SiC2 gradient hybrid interphase is expected to be a high temperature resistant radar absorbing material for future stealth aircraft.

Endocannabinoid receptors are involved in enhancing food intake in rainbow trout

SummaryThe mechanisms involved in hedonic regulation of food intake, including endocannabinoid system (ECs) are scarcely known in fish. We recently demonstrate in rainbow trout the presence of a rewarding response mediated by ECs in hypothalamus and telencephalon when fish fed a lipid-enriched diet, and that central administration of main agonists of ECs namely AEA or 2-AG exert a bimodal effect on feed intake in fish with low doses inducing an increase that disappears with the high dose of both endocannabinoids (EC). To assess the precise involvement of the different receptors of the ECs (CNR1, TRPV1, and GPR55) in this response we injected intracerebroventricularly AEA or 2-AG in the absence/presence of specific receptor antagonists (AM251, capsazepine, and ML193; respectively). The presence of antagonists clearly counteracts the effect of EC supporting the specificity of EC action inducing changes not only in ECs but also in GABA and glutamate metabolism ultimately leading to the increase observed in food intake response.

Mechanisms of P-Glycoprotein Regulation Under Exogenous and Endogenous Oxidative Stress In Vitro.

We investigated the mechanisms of P-glycoprotein (P-gp) transporter regulation in Caco-2 cells under exogenous and endogenous oxidative stress (OS). Exogenous OS was modeled by exposure of the growth medium to hydrogen peroxide at concentrations of 0.1, 0.5, and 1 μM for 24 h or 10 μM for 72 h. Endogenous OS was modeled by incubating cells with DL-buthionine sulfoximine (BSO, gamma-glutamylcysteine synthetase inhibitor) at a concentration of 10, 50, and 100 μM for 24 h. The levels of intracellular reactive oxygen species (ROS) were assessed using MitoTracker Red CM-H2XRos fluorescent probes. Relative P-gp contents were analyzed using Western blot. Exogenous and endogenous OS was shown to increase relative to P-gp contents. An important role played by the Nrf2-Keap1 signaling pathway in increasing the P-gp contents under H2O2-induced exogenous OS was revealed using specific inhibitors. The transcription factor HIF1 is involved in the regulation of the P-gp levels under 24-hour exogenous OS, and the transcription factor CAR is involved in the regulation of transporter levels under 72-hour OS. All tested transcription factors and signaling pathways are involved in P-gp induction under endogenous OS. Most likely, this is associated with the bimodal effect of BSO on Pgp. On the one hand, BSO induces the development of OS; on the other, BSO, as a xenobiotic, is able to stimulate PXR and CAR, which, in turn, increase the P-gp contents.

Testing phaeophytinization as an index of ozone stress in trees

Ground-level ozone pollution is a menace for vegetation in the northern hemisphere, limiting photosynthetic pigments and suppressing photosynthesis in trees and other types of plants. Phaeophytinization is the process of converting chlorophylls into phaeophytins, for example by acidification. Ozone is a highly oxidizing molecule and well known to degrade chlorophylls; however, the effect of ozone on phaeophytinization in leaves of higher plants is largely unknown. To reveal ozone effect on phaeophytinization and evaluate the potential of phaeophytinization as an index of ozone stress in trees, the absorbance at the optical density of 665 nm was measured before (OD665) and after (OD665a) acidification in three independent experiments with nearly 30 conditions of ozone exposure. Both current ambient and elevated ozone widely affected phaeophytinization, as indicated by decreases or increases in the phaeophytinization quotient OD665/OD665a. These effects were commonly moderate to large in magnitude and practically significant, and occurred even in ozone-asymptomatic leaves. It emerges that the ozone effect on phaeophytinization is bimodal, likely depending on the intensity of ozone stress. These results indicate a promising feature of OD665/OD665a as a thorough index of ozone stress in the future, but further studies are needed to reveal the underlying biochemical mechanisms of the bimodal effect on phaeophytinization.

A method to soothe and promote sleep in crying infants utilizing the transport response

Approximately 20%-30% of infants cry excessively and exhibit sleep difficulties for no apparent reason, causing parental stress and even triggering impulsive child maltreatment in a small number of cases.1-8 While several sleep training methods or parental education programs may provide long-term improvement of infant cry and sleep problems, there is yet to be a conclusive recommendation for on-site behavioral interventions.9-13 Previously we have reported that brief carrying of infants transiently reduces infant cry via the transport response, a coordinated set of vagal activation and behavioral calming conserved in altricial mammals.14-18 In this study, we disentangled complex infant responses to maternal holding and transport by combining subsecond-scale, event-locked physiological analyses with dynamic mother-infant interactions. Infant cry was attenuated either by maternal carrying or by reciprocal motion provided by a moving cot, but not by maternal holding. Five-minute carrying promoted sleep for crying infants even in the daytime when these infants were usually awake, but not for non-crying infants. Maternal laydown of sleeping infants into a cot exerted bimodal effects, either interrupting or deepening the infants' sleep. During laydown, sleeping infants were alerted most consistently by the initiation of maternal detachment, then calmed after the completion of maternal detachment in a successful laydown. Finally, the sleep outcome after laydown was associated with the sleep duration before the laydown onset. These data propose a "5-min carrying, 5- to 8- min sitting" scheme for attending to infant cry and sleep difficulties, which should be further substantiated in future studies. VIDEO ABSTRACT.

Less is more: Enterobactin concentration dependency in copper tolerance and toxicity.

The ability of siderophores to play roles beyond iron acquisition has been recently proven for many of them and evidence continues to grow. An earlier work showed that the siderophore enterobactin is able to increase copper toxicity by reducing Cu2+ to Cu+, a form of copper that is more toxic to cells. Copper toxicity is multifaceted. It involves the formation of reactive oxygen species (ROS), mismetallation of enzymes and possibly other mechanisms. Given that we previously reported on the capacity of enterobactin to alleviate oxidative stress caused by various stressors other than copper, we considered the possibility that the siderophore could play a dual role regarding copper toxicity. In this work, we show a bimodal effect of enterobactin on copper toxicity (protective and harmful) which depends on the siderophore concentration. We found that the absence of enterobactin rendered Escherichia coli cells more sensitive to copper, due to the reduced ability of those cells to cope with the metal-generated ROS. Consistently, addition of low concentrations of the siderophore had a protective effect by reducing ROS levels. We observed that in order to achieve this protection, enterobactin had to enter cells and be hydrolyzed in the cytoplasm. Further supporting the role of enterobactin in oxidative stress protection, we found that both oxygen and copper, induced the expression of the siderophore and also found that copper strongly counteracted the well-known downregulation effect of iron on enterobactin synthesis. Interestingly, when enterobactin was present in high concentrations, cells became particularly sensitive to copper most likely due to the Cu2+ to Cu+ reduction, which increased the metal toxicity leading to cell death.

Involvement of neurosteroids in the control of prolactin secretion in sheep under basal, stressful and pregnancy conditions

Prolactin (PRL) secretion by the anterior pituitary (AP) is responsive to changes in physiological conditions and many external factors that also affect brain neurosteroid levels. This study tested the hypothesis that neurosteroids can affect PRL secretion in sheep under basal, stressful and advanced pregnancy conditions. In Experiment 1, luteal-phase sheep were subjected to a three-day series of intracerebroventricular (icv.) control (n = 12) or allopregnanolone (AL, 4 × 15 μg/60 μL/30 min at 30-min intervals, n = 12) infusions. Acute stressful stimuli, isolation and partial movement restriction were applied on the third day of infusion to half of the animals in each group. In Experiment 2, pregnant sheep were subjected to a three-day series of icv. control (n = 6) or finasteride (4 × 25 μg/60 μL/30 min at 30-min intervals, n = 6) infusions during the 16th week of pregnancy. As a result, the relative abundance of PRL transcript increased in the AP of luteal-phase sheep treated with stress, AL and AL in combination with stress (P < 0.05 - P < 0.01) compared to controls. The level of PRL mRNA in stressed-AL-treated sheep was higher (P < 0.01) than in sheep only subjected to stress. The PRL protein content in the AP decreased in stressed-only sheep compared to controls (P < 0.05) and increased in stressed-AL-treated sheep compared to controls and other groups (P < 0.05 - P < 0.01). Plasma PRL concentration increased (P < 0.05 - P < 0.01) in stressed-only sheep compared to controls; AL infusion counteracted the stress-induced increase in PRL levels (P < 0.05 - P < 0.01) and had no effect in non-stressed animals. Inhibition of neurosteroid synthesis in the brain of pregnant sheep by finasteride caused transient increases (P < 0.05 - P < 0.001) in plasma PRL concentration compared to controls. In conclusion, the presented results indicate a bimodal effect of AL on PRL secretion in sheep: first at the molecular level – stimulation of PRL mRNA expression; second – inhibition of hormone release from pituitary lactotrophs. Both AL activities may involve various mechanisms regulating PRL secretion. In general, cerebral neurosteroids can affect the supply of pituitary PRL in the body under certain conditions, such as stress and pregnancy.

Improving broadband absorption and transparent properties for microwave metamaterial via stimulating bimodal effect with induced water substrate

In this paper, a frequency selective microwave absorber is designed and demonstrated with water as the substrate layer, which realizes >90% absorption in the frequency range of 7.3–20 GHz and 73.6% light transparent in the spectrum range of 400–800 nm. The improved absorption is believed to be attributed to the synergy between the intrinsic resonance of the ITO metasurface and the new resonance excited by the substrate water layer. Particularly, the light transparence of the absorber is improved with the introduced water layer. Therefore, the proposed absorber shows excellent comprehensive performances for high optical transparent microwave broadband absorbers.

Acoustic analysis of tone production in Mandarin-speaking bimodal cochlear implant users

The benefit of using a hearing aid with a cochlear implant (bimodal hearing) has been demonstrated for tone perception under certain conditions. The present study evaluated bimodal effects for tone production by comparing performance between a bimodal and a unimodal implant group. Results showed that acoustic differentiation of tones produced by the bimodal group was better than the unimodal implant group, and performance was dependent on the subject's acoustic thresholds but not related to implant experience or age at implantation. The findings support the use of amplified acoustic hearing in conjunction with the implant for better development of pitch production.

Emotion-modulated Recall: Congruency Effects of Nonverbal Facial and Vocal Cues on Semantic Recall

The current study had two main goals: First, to replicate the ‘bimodal integration’ effect (i.e. the automatic integration of crossmodal stimuli, namely facial emotions and emotional prosody); and second, to investigate whether this phenomenon facilitates or impairs the intake and retention of unattended verbal content. The study borrowed from previous bimodal integration designs and included a two-alternative forced-choice (2AFC) task, where subjects were instructed to identify the emotion of a face (as either ‘angry’ or ‘happy’) while ignoring a concurrently presented sentence (spoken in an angry, happy, or neutral prosody), after which a surprise recall was administered to investigate effects on semantic content retention. While bimodal integration effects were replicated (i.e. faster and more accurate emotion identification under congruent conditions), congruency effects were not found for semantic recall. Overall, semantic recall was better for trials with emotional (vs. neutral) faces, and worse in trials with happy (vs. angry or neutral) prosody. Taken together, our findings suggest that when individuals focus their attention on evaluation of facial expressions, they implicitly integrate nonverbal emotional vocal cues (i.e. hedonic valence or emotional tone of accompanying sentences), and devote less attention to their semantic content. While the impairing effect of happy prosody on recall may indicate an emotional interference effect, more research is required to uncover potential prosody-specific effects. All supplemental online materials can be found on OSF (https://osf.io/am9p2/).

Development and Reversal of Discolouration in Roots Filled with Ledermix or Doxymix Pastes Stored in the Dark for Three Months then Daylight for Twenty Four Months.

To explore the long-term effects on discolouration by demeclocycline HCl (Ledermix, LED) or doxycycline hyclate (Doxymix, DOX) pastes placed in extracted human teeth over a 27-month period under different storage conditions. The canals in 38 teeth were prepared carefully, to minimize exposure to contamination from irrigants, then either LED (Lederle Pharmaceuticals, Germany) or DOX (Ozdent, Australia) were placed. Samples were stored in the dark for 3 months followed by daylight for 24 months. The storage conditions varied as follows: Group 1: Open access, dry storage (OD); Group 2: Closed access, dry storage (CD); Group 3: Open access, wet storage (OW); Group 4: Closed access, wet storage (n=4 for each material). Additional teeth were used as controls: Polyethylene glycol only in a closed canal; and saline only irrigation with LED paste in a closed canal. Standardised digital photographs were taken over 27 months and evaluated for changes in luminosity. Darkening of tooth structure occurred in all LED groups and in the two DOX groups that were stored wet, during exposure to light, with a faster rate with LED. The most rapid staining occurred with LED in moist conditions with an open access cavity. The least staining occurred with DOX in samples stored dry. With prolonged exposure to light, a reversal in staining occurred with DOX at 3 months and LED at 9 months. Staining of tooth structure is influenced by the choice of medicament, and by exposure to moisture and air. Light has a bimodal effect, first driving staining, but later reversing it. This can be explained by different wavelengths of light causing photodegradation and photo-oxidation of tetracyclines and their complexes with tooth mineral.

Strain-, Sex-, and Time-Dependent Antidepressant-like Effects of Cannabidiol.

Cannabidiol (CBD) is a non-intoxicating compound extracted from Cannabis sativa, showing antidepressant-like effects in different rodent models. However, inconsistent results have been described depending on the species and the strain used to assess depressive-like behavior. Moreover, only a few studies investigated the effect of CBD in female rodents. Therefore, we aimed to (i) investigate the effects of CBD in two different strains of mice (Swiss and C57BL/6) and a rat model of depression based on selective breeding (Flinders Sensitive and Resistant Lines, FSL and FRL) subjected to tests predictive of antidepressant-like effects and (ii) investigate the influence of sex in the effects of CBD in both mice and rats. CBD induced an antidepressant-like effect in male Swiss but not in female Swiss or C57BL/6 mice in the tail suspension test (TST). In male FSL rats, CBD produced an antidepressant-like effect 1 h post injection. However, in female FSL, CBD induced a bimodal effect, increasing the immobility time at 1 h and decreasing it at 2 h. In conclusion, strain, sex, and administration time affect CBD’s behavioral response to rodents exposed to tests predictive of antidepressant effects.

Bone Marrow Adipocytes Induce Metabolic Reprogramming of Multiple Myeloma Cells

Obesity-induced increases in bone marrow adipocyte (BMAd) numbers and volume are associated with an increased risk of multiple myeloma (MM). We analyzed gene expression from previously published public datasets and found that 11 out of 47 genes associated with fatty acid (FA) metabolism showed increasing trend from MGUS (monoclonal gammopathy of undetermined significance), MM, to plasma cell leukemia. These genes included ACC1, the first and rate-limiting step of de novo fatty acid biosynthesis and ECHS1, the second step of the mitochondrial fatty acid beta-oxidation pathway. We have previously shown that adipocytes support the growth of MM cells. However, the molecular mechanisms of interaction between MM cells and BMAd remain largely unknown. Here, we hypothesize that BMAd support MM cells through metabolic reprogramming.Here we sought to identify the molecular pathways involved in MM/ BMAd interaction. BM aspirates of MGUS, smoldering MM (SMM), and newly diagnosed MM (NDMM) patients were used to isolate fat-enriched BM fraction and BM stromal cells (BMSCs). Murine BMSC cell-line OP9, murine MM cell-line 5TGM1, and human MM cell lines MM.1S and OPM2 were obtained from ATCC or provided by collaborators and cultured as their respective standard procedures. In-vitro adipogenesis was induced in OP9 cells or BMSCs by supplementing media with dexamethasone, indomethacin, insulin, and IBMX. MM cells were co-cultured directly with pre- or mature adipocytes. Cell proliferation was assessed using CyQUANT NF Cell Proliferation Assay. Lipolysis was assessed by High Sensitivity Lipolysis Assay Kit (Sigma). Lipid uptake in MM cells was assessed by flow-cytometry analysis of the incorporation of fluorescent 12- or 16-carbon long-chain fatty acids BODIPY-FL-C12 and BODIPY-FL-C16, respectively, or LipidTox labelled FA from co-cultured adipocytes. In-vivo effects of excess FA on MM cell growth were assessed using a plasmacytoma model in CB17 SCID mice.In-vitro co-culture revealed that BMSC-derived adipocytes (Ad) from MGUS, SMM and NDMM donors increased the proliferation of MM.1S MM cells significantly. Similarly, mature murine OP9 Ad cells also increased the proliferation of 5TGM1 murine MM cells. Interestingly, co-cultures showed dramatic decrease in LipidTox-stained lipid-droplet size distribution, suggesting increased lipolysis in Ad. In the process of lipolysis, various lipase enzymes hydrolyze stored triglycerides into free fatty acids (FFA) and glycerol. Co-culture of 5TGM1 or OPM2 cells with OP9 mature Ad increased glycerol secretion in the conditioned media by more than 3-fold indicating that MM induce lipolysis in Ad. Consequently, BMAd from MGUS, SMM, and NDMM patients showed increased expression of genes responsible for lipolysis (NR1H3) and increased FA desaturation (SCD1, FASD2). Although MM cells lacked intracellular lipid storage, OPM2 and 5TGM1 MM cells rapidly took up BODIPY-C12 and -C16 FAs. The FA secreted from Ad were directly taken up by MM cells as shown by transfer of LipidTox-labeled lipids from OP9 Ad to unstained 5TGM1 or OPM2 MM cells as assessed by flow cytometry. The addition of Acipomox, a small-molecule inhibitor of lipolysis, decreased LipidTox signal in MM cells compared to untreated OP9 cells. FA are primarily transported into cells through FATP (1-6) or CD36 receptors. Bioinformatic analysis of public database showed that FATP1 and FATP4 were highly expressed in 21 human MM cell lines. Indeed, MM cells from NDMM patients expressed high levels of FATP1 and FATP4. The uptake of BODIPY-C12 and -C16 by 5TGM1 or OPM2 MM cells was significantly reduced in the presence of Lipofermata, a pharmacological small-molecule inhibitor of FATP. Lipidomic analysis of BM aspirates from MM patients showed altered expression of various FA, including arachidonic acid (AA). Low doses of AA (0.125 - 2 µM) increased the proliferation and viability of MM cells whereas high doses (25- 100µM) dramatically decreased it, indicating a bimodal cellular effect of AA. Peritumoral AA treatment in a plasmacytoma model in CB17 SCID mice using MM.1S cells dramatically decreased tumor volume along with the markers of proliferation.In summary, we show that MM cells induce lipolysis in BMAd and that the released FFA are then taken up by MM cells through FATPs. Inhibition of either BMAd lipolysis or FFA transporter into MM cells could be a potential novel strategy to prevent MM progression. DisclosuresFulzele: Constellation Pharma: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other.

OAB-029: Bone marrow adipocytes induce metabolic reprogramming of multiple myeloma cells

<h3>Background</h3> Obesity-induced increases in bone marrow adipocyte (BMAd) numbers and volume are associated with an increased risk of MM. However, the associated molecular mechanisms have remained largely unknown. We hypothesize that BMAd support MM cells through metabolic reprogramming. <h3>Methods</h3> BM aspirates of MGUS, SMM, and NDMM patients were used to obtain mature BMAd or stromal cells (BMSCs). Murine BMSC cell-line OP9, MM cell-line 5TGM1, and human-origin MM cell-lines MM.1S, OPM2 were obtained from ATCC. Cell proliferation was assessed by CyQUANT Assay; lipolysis by Lipolysis Assay (Sigma); lipid uptake by flow cytometry (FCM) of fluorescent fatty acids (FA) BODIPY-C12 and -C16, or LipidTox. In-vivo efficacy of FA treatment was assessed in a MM CB17 SCID mouse plasmacytoma model. <h3>Results</h3> In-vitro co-culture revealed that BMSC-derived adipocytes (Ad) from MGUS/SMM and NDMM donors significantly increased the proliferation of MM.1S MM cells. Similarly, mature murine OP9 Ad cells also increased the proliferation of 5TGM1 murine MM cells. Interestingly, co-cultures showed dramatic decrease in LipidTox-stained lipid-droplet size distribution, suggesting increased lipolysis in Ad, further confirmed by increased glycerol content in conditioned media in the presence of MM cells. Moreover, BMAd from MGUS, SMM, and NDMM patients showed increased expression of genes responsible for lipolysis (NR1H3) and increased FA desaturation (SCD1, FASD2). Although MM cells lacked intracellular lipid storage, OPM2 and 5TGM1 MM cells rapidly took up BODIPY-C12 and -C16 FAs. The FA secreted from Ad were directly taken up by MM cells as shown by transfer of LipidTox-labeled lipids from OP9 Ad to unstained 5TGM1 or OPM2 MM cells as assessed by FCM. The addition of acipomox, a small-molecule inhibitor of lipolysis, decreased LipidTox signal in MM cells compared to untreated OP9 cells. FA are transported into cells through FATP (1-6) or CD36 receptors. Bioinformatics analysis of public Oncomine database showed that FATP1 and FATP4 were highly expressed in 21 human MM cell lines. MM cells from NDMM patients expressed high levels of FATP1 and FATP4. The uptake of BODIPY-C12 and -C16 by 5TGM1 or OPM2 MM cells was significantly reduced in the presence of Lipofermata, a pharmacological small-molecule inhibitor of FATP. Lipidomic analysis of BM aspirates from MM patients showed altered expression of various FA, including arachidonic acid (AA). Low doses of AA (0.125 - 2 µM) increased the proliferation and viability of MM cells whereas high doses (25- 100µM) dramatically decreased it, indicating a bimodal cellular effect of AA. Peritumoral AA treatment in a plasmacytoma model decreased tumor volume significantly. <h3>Conclusion</h3> We show that MM cells induce lipolysis in BMAd and that the released FFA are then taken up by MM cells through FATPs. Inhibition of either BMAd lipolysis or FFA transporter into MM cells could be a potential novel strategy to prevent MM progression.

Tissue-specific functional interaction between apolipoproteins A1 and E in cold-induced adipose organ mitochondrial energy metabolism.

Background and Aims: White (WAT) and brown (BAT) adipose tissue, are respectively responsible for lipid storage and non-shivering thermogenesis, a process mediated by mitochondrial uncoupling protein 1 (UCP1) which uncouples oxidative phosphorylation from ATP production, leading to heat production. This process can be triggered by cold exposure, caloric excess, and the immune system. Recently thermogenesis has been associated with plasma lipoprotein transport system. Specifically, APOE3 is shown to have a bimodal effect on WAT thermogenesis while APOE2 and APOE4 differentially affect BAT and WAT thermogenesis in processes highly modulated by APOA1. Furthermore, APOA1 deficiency is associated with no measurable UCP1 levels in WAT of mice fed high fat diet.