Decompression with or without Fusion in Degenerative Lumbar Spondylolisthesis.

BACKGROUND: In patients with lumbar spinal stenosis and degenerative spondylolisthesis, it is uncertain whether decompression surgery alone is noninferior to decompression with instrumented fusion. METHODS: We conducted an open-label, multicenter, noninferiority trial involving patients with symptomatic lumbar stenosis that had not responded to conservative management and who had single-level spondylolisthesis of 3 mm or more. Patients were randomly assigned in a 1:1 ratio to undergo decompression surgery (decompression-alone group) or decompression surgery with instrumented fusion (fusion group). The primary outcome was a reduction of at least 30% in the score on the Oswestry Disability Index (ODI; range, 0 to 100, with higher scores indicating more impairment) during the 2 years after surgery, with a noninferiority margin of -15 percentage points. Secondary outcomes included the mean change in the ODI score as well as scores on the Zurich Claudication Questionnaire, leg and back pain, the duration of surgery and length of hospital stay, and reoperation within 2 years. RESULTS: The mean age of patients was approximately 66 years. Approximately 75% of the patients had leg pain for more than a year, and more than 80% had back pain for more than a year. The mean change from baseline to 2 years in the ODI score was -20.6 in the decompression-alone group and -21.3 in the fusion group (mean difference, 0.7; 95% confidence interval [CI], -2.8 to 4.3). In the modified intention-to-treat analysis, 95 of 133 patients (71.4%) in the decompression-alone group and 94 of 129 patients (72.9%) in the fusion group had a reduction of at least 30% in the ODI score (difference, -1.4 percentage points; 95% CI, -12.2 to 9.4), showing the noninferiority of decompression alone. In the per-protocol analysis, 80 of 106 patients (75.5%) and 83 of 110 patients (75.5%), respectively, had a reduction of at least 30% in the ODI score (difference, 0.0 percentage points; 95% CI, -11.4 to 11.4), showing noninferiority. The results for the secondary outcomes were generally in the same direction as those for the primary outcome. Successful fusion was achieved with certainty in 86 of 100 patients (86.0%) who had imaging available at 2 years. Reoperation was performed in 15 of 120 patients (12.5%) in the decompression-alone group and in 11 of 121 patients (9.1%) in the fusion group. CONCLUSIONS: In this trial involving patients who underwent surgery for degenerative lumbar spondylolisthesis, most of whom had symptoms for more than a year, decompression alone was noninferior to decompression with instrumented fusion over a period of 2 years. Reoperation occurred somewhat more often in the decompression-alone group than in the fusion group. (NORDSTEN-DS ClinicalTrials.gov number, NCT02051374.).

Online-Monitoring of the Enantiomeric Ratio in Microfluidic Chip Reactors Using Chiral Selector Ion Vibrational Spectroscopy.

A novel experimental approach for the rapid online monitoring of the enantiomeric ratio of chiral analytes in solution is presented. The charged analyte is transferred to the gas phase by electrospray. Diastereomeric complexes are formed with a volatile chiral selector in a buffer-gas-filled ion guide held at room temperature, mass-selected, and subsequently spectrally differentiated by cryogenic ion trap vibrational spectroscopy. Based on the spectra of the pure complexes in a small diastereomer-specific spectral range, the composition of diastereomeric mixtures is characterized using the cosine similarity score, from which the enantiomeric ratio in the solution is determined. The method is demonstrated for acidified alanine solutions and using three different chiral selectors (2-butanol, 1-phenylethanol, 1-amino-2-propanol). Among these, 2-butanol is the best choice as a selector for protonated alanine, also because the formation ratio of the corresponding diastereomeric complexes is found to be independent of the nature of the enantiomer. Subsequently, a microfluidic chip is implemented to mix enantiomerically pure alanine solutions continuously and determine the enantiomeric ratio online with minimal sample consumption within one minute and with competitive accuracy.

Vibrational wave-packet dynamics of the silver pentamer probed by femtosecond NeNePo spectroscopy.

Vibrational wave-packet dynamics on the ground electronic state of the neutral silver pentamer (Ag5) are studied by femtosecond (fs) pump-probe spectroscopy using the 'negative ion - to neutral - to positive ion' (NeNePo) excitation scheme. A vibrational wave packet is prepared on the 2A1 state of Ag5via photodetachment of mass-selected, cryogenically cooled Ag5- anions using a fs pump pulse. The temporal evolution of the vibrational wave packet is then probed by an ultrafast probe pulse via resonant multiphoton ionization to Ag5+. Frequency analysis of the fs NeNePo transients for pump-probe delay times from 0.2 to 8 ps reveals three primary beating frequencies at 157 cm-1, 101 cm-1 and 56 cm-1 as well as four weaker features. A comparison of these experimentally obtained beating frequencies to harmonic normal mode frequencies calculated from electronic structure calculations confirms that Ag5 in the gas phase adopts a planar trapezoidal geometry, similar to that previously observed in solid argon. The dependence of the ionization yield on the laser polarization indicates a s-d wave electron photodetachment from a 'p-type' occupied molecular orbital of Ag5. Franck-Condon analysis shows that both processes, photodetachment and subsequent photoionization determine the beating frequencies probed in the time-dependent cation yield. The present study extends the applicability of fs NeNePo spectroscopy to characterize the vibrational spectra in the far-IR frequency range in the absence of perturbations from a medium or a messenger atom to mass-selected neutral metal clusters with more than three atoms in the ground electronic states.

Binding Properties of Small Electrophilic Anions [B6 X5 ]- and [B10 X9 ]- (X=Cl, Br, I): Activation of Small Molecules Based on π-Backbonding.

Superelectrophilic anions constitute a special class of molecular anions that show strong binding of weak nucleophiles despite their negative charge. In this study, the binding characteristics of smaller gaseous electrophilic anions of the types [B6 X5 ]- and [B10 X9 ]- (with X=Cl, Br, I) were computationally and experimentally investigated and compared to those of the larger analogues [B12 X11 ]- . The positive charge of vacant boron increases from [B6 X5 ]- via [B10 X9 ]- to [B12 X11 ]- , as evidenced by increasing attachment enthalpies towards typical σ-donor molecules (noble gases, H2 O). However, this behavior is reversed for σ-donor-π-acceptor molecules. [B6 Cl5 ]- binds most strongly to N2 and CO, even more strongly than to H2 O. Energy decomposition analysis confirms that the orbital interaction is responsible for this opposite trend. The extended transition state natural orbitals for chemical valence method shows that the π-backdonation order is [B6 X5 ]- >[B10 X9 ]- >[B12 X11 ]- . This predicted order explains the experimentally observed red shifts of the CO and N2 stretching fundamentals compared to those of the unbound molecules, as measured by infrared photodissociation spectroscopy. The strongest red shift is observed for [B6 Cl5 N2 ]- : 222 cm-1 . Therefore, strong activation of unreactive σ-donor-π-acceptor molecules (commonly observed for cationic transition metal complexes) is achieved with metal-free molecular anions.

Dinitrogen Activation in the Gas Phase: Spectroscopic Characterization of C-N Coupling in the V3 C+ +N2 Reaction.

We report on cluster-mediated C-N bond formation in the gas phase using N2 as a nitrogen source. The V3 C+ +N2 reaction is studied by a combination of ion-trap mass spectrometry with infrared photodissociation (IRPD) spectroscopy and complemented by electronic structure calculations. The proposed reaction mechanism is spectroscopically validated by identifying the structures of the reactant and product ions. V3 C+ exhibits a pyramidal structure of C1 -symmetry. N2 activation is initiated by adsorption in an end-on fashion at a vanadium site, followed by spontaneous cleavage of the N≡N triple bond and subsequent C-N coupling. The IRPD spectrum of the metal nitride product [NV3 (C=N)]+ exhibits characteristic C=N double bond (1530 cm-1 ) and V-N single bond (770, 541 and 522 cm-1 ) stretching bands.

Self-reported lower extremity lymphedema and quality of life after surgical staging of endometrial carcinoma: A population based cross-sectional study.

OBJECTIVES: Sentinel lymph node biopsy (SLN) has replaced lymphadenectomy in staging of endometrial carcinoma. The aims of the study were to explore the prevalence of self-reported lymphedema (LEL), identify factors associated with LEL, compare quality of life (QoL) scores using thresholds of clinical importance, and assess correlation between different questionnaires. METHODS: Women who underwent staging for endometrial carcinoma from 2006 to 2021 were invited to complete the Lower Extremity Lymphedema Screening Questionnaire (LELSQ), EORTC QLQ-C30, QLQ-EN24 and EQ-5D-5L. RESULTS: Of 2156 invited survivors, 61% participated in the study, whereof 1127 were evaluable by LELSQ. The LEL prevalence was 51%, 36% and 40% after lymphadenectomy, SLN and hysterectomy, respectively (p < 0.001). Higher BMI, undergoing lymphadenectomy and receiving adjuvant chemotherapy were associated with LEL; odds ratios 1.07 (95% CI 1.05-1.09), 1.42 (95% CI 1.03-1.97) and 1.43 (95% CI 1.08-1.89) respectively. QoL was lower for women with LEL compared to those without. In women with musculoskeletal complaints the prevalence of LEL was 59%, 50% and 53% after lymphadenectomy, SLN and hysterectomy (p = 0.115), respectively, compared to 39%, 17% and 18% (p < 0.001) in women without musculoskeletal complaints. Spearman's correlation was moderate to strong between the questionnaires. CONCLUSION: SLN implementation is not associated with increased LEL prevalence compared to hysterectomy alone, but is associated with a significantly lower prevalence compared to lymphadenectomy. LEL is associated with lower QoL. Our study demonstrates moderate to strong correlation between self-reported LEL and QoL scores. Available questionnaires may not distinguish between symptoms caused by LEL and musculoskeletal disease.

Nuclear quantum dynamics on the ground electronic state of neutral silver dimer 107Ag109Ag probed by femtosecond NeNePo spectroscopy.

The nuclear quantum dynamics on the ground electronic state of the neutral silver dimer 107Ag109Ag are studied by femtosecond (fs) pump-probe spectroscopy using the 'negative ion - to neutral - to positive ion' (NeNePo) excitation scheme. A vibrational wave packet is prepared on the X1Σ+g state of Ag2via photodetachment of mass-selected, cryogenically cooled Ag2- using a first ultrafast pump laser pulse. The temporal evolution of the wave packet is then probed by an ultrafast probe pulse via resonant multiphoton ionization to Ag2+. Frequency analysis of the fs-NeNePo spectra obtained for a single isotopologue and pump-probe delay times up to 60 ps yields the harmonic (ωe = 192.2 cm-1), quadratic anharmonic (ωexe = 0.637 cm-1) and cubic anharmonic (ωeye = 3 × 10-4 cm-1) constants for the X1Σ+g state of neutral Ag2. The fs-NeNePo spectra obtained at different pump wavelengths provide insight into the excitation mechanism. At a pump wavelength of 510 nm instead of 1010 nm, resonant excitation of a short-lived electronically excited state of the anion followed by autodetachment results in population of higher-energy vibrational levels of the neutral ground state. In contrast, at 1140 nm dynamics with a slightly shorter beating period and different relative phase are observed. The present study demonstrates that isotopologue-specific fs-NeNePo spectroscopy provides accurate vibrational constants of mass-selected neutral clusters in their electronic ground state in the terahertz spectral region, which remains difficult to obtain directly in the frequency domain with any other type of spectroscopy of comparable sensitivity.

Vibrational spectroscopy of Cu+(H2)4: about anharmonicity and fluxionality.

The vibrational spectra of the copper(I) cation-dihydrogen complexes Cu+(H2)4, Cu+(D2)4 and Cu+(D2)3H2 are studied using cryogenic ion trap vibrational spectroscopy in combination with quantum chemical calculations. The infrared photodissociation (IRPD) spectra (2500-7300 cm-1) are assigned based on a comparison to IR spectra calculated using vibrational second-order perturbation theory (VPT2). The IRPD spectra exhibit ≈60 cm-1 broad bands that lack rotational resolution, indicative of rather floppy complexes even at an ion trap temperature of 10 K. The observed vibrational features are assigned to the excitations of dihydrogen stretching fundamentals, combination bands of these fundamentals with low energy excitations as well as overtone excitations of a minimum-energy structure with Cs symmetry. The three distinct dihydrogen positions present in the structure can interconvert via pseudorotations with energy barriers less than 10 cm-1, far below the zero-point vibrational energy. Ab initio Born-Oppenheimer molecular dynamics (BOMD) simulations confirm the fluxional behavior of these complexes and yield an upper limit for the timeframe of the pseudorotation on the order of 10 ps. For Cu+(D2)3H2, the H2 and D2 loss channels yield different IRPD spectra indicating non-ergodic behavior.

High-Resolution Photoelectron Spectroscopy of Vibrationally Excited Vinoxide Anions.

High-resolution photoelectron spectra of vibrationally pre-excited vinoxide anions (CH2CHO-) are reported using the recently developed IR-cryo-SEVI technique. This method is combined with a newly developed implementation of vibrational perturbation theory that can readily identify relevant anharmonic couplings among nearly degenerate vibrational states. IR-cryo-SEVI spectra are obtained by resonant infrared excitation of vinoxide anions via the fundamental C-O (ν4, 1566 cm-1) or isolated C-H (ν3, 2540 cm-1) stretching vibrations prior to photodetachment. Excitation of the ν4 mode leads to a well-resolved photoelectron spectrum that is in excellent agreement with a harmonic Franck-Condon simulation. Excitation of the higher-energy ν3 mode results in a more complicated spectrum that requires consideration of the calculated anharmonic resonances in both the anion and the neutral. From this analysis, information about the zeroth-order states that contribute to the nominal ν3 wave function in the anion is obtained. In the neutral, we observe anharmonic splitting of the ν3 fundamental into a polyad feature with peaks at 2737(22), 2 835(18), and 2910(12) cm-1, for which only the center frequency has been previously reported. Overall, 9 of the 12 fundamental frequencies of the vinoxy radical are extracted from the IR-cryo-SEVI and ground-state cryo-SEVI spectra, most of which are consistent with previous measurements. However, we provide a new estimate of the ν5 (CH2 scissoring) fundamental frequency at 1395(11) cm-1 and attribute the discrepancy with previously reported values to a Fermi resonance with the 2ν11 overtone (CH2 wagging).

Thermal Methane Conversion to Formaldehyde Mediated by NiAlO3+ in the Gas Phase.

Understanding the active sites and reaction mechanisms of Ni-based catalysts, such as Ni/Al2O3, toward methane is a prerequisite for improving their rational design. Here, the gas-phase reactivity of NiAlO3+ cations toward CH4 is studied using mass spectrometry combined with density functional theory. Similar to our previous study on NiAl2O4+, we find evidence for the formation of both the methyl radical (CH3•) and formaldehyde (CH2O). The first step for methane activation is hydrogen atom abstraction by the terminal oxygen radical Ni(O)2AlO• from methane forming a [Ni(O)2AlOH+, •CH3] complex and leaving the Ni-oxidation state unchanged. The second C-H bond is subsequently activated by the association of a bridged Ni-O2--Al. The oxidation state of the Ni atom is reduced from +3 to +1 during the formation of formaldehyde. Compared to Al2O3+/CH4 and YAlO3+/CH4 systems, the Ni-atom substitution increases the overall reaction rate by roughly an order of magnitude and yields a CH3•/CH2O branching ratio of 0.62/0.38. The present study provides molecular-level insights into the highly efficient gas-phase reaction mechanism contributing to an improved understanding of methane conversion by Ni/Al2O3 catalysts.

The Self-Rated Effects of Alcohol Are Related to Presystemic Metabolism of Alcohol.

AIMS: A high number of alcohol units required to feel a subjective effect of alcohol predicts future alcohol use disorders (AUDs). The subjective response to alcohol can be measured using the validated retrospective self-rated effects of alcohol (SRE) questionnaire. Few studies have investigated the specific relationship between SRE and blood alcohol concentration (BAC) in an experimental setting. METHODS: Twenty healthy young adult male volunteers who had experience with binge drinking, but did not have AUD, filled out the SRE-questionnaire and were served with a fixed amount of alcohol per body weight. BACs were measured throughout a 12-hour period, reaching a maximum BAC of ~0.13%. Median split of SRE-scores was utilized to compare BACs among participants with relatively high effects (low SRE) and relatively low effects (high SRE) of alcohol. RESULTS: Participants reporting a relatively low SRE-score had a statistically significant higher measured BAC at all time points until alcohol was eliminated. This was especially pronounced during the first 2 hours after alcohol (P = 0.015) without a significant difference in the alcohol elimination rate being detected. CONCLUSION: The study indicates that a self-ated SRE-score is related to BACs after the ingestion of a standardized amount of alcohol per body weight. Reporting a higher number of alcohol units before feeling an effect was related to a lower BAC. As the differences in BAC between relatively high and low self-rated effects appeared rapidly after intake, this could be interpreted as an effect of presystemic metabolism of alcohol.

Direct functionalization of C-H bonds by electrophilic anions.

Alkanes and [B12X12]2- (X = Cl, Br) are both stable compounds which are difficult to functionalize. Here we demonstrate the formation of a boron-carbon bond between these substances in a two-step process. Fragmentation of [B12X12]2- in the gas phase generates highly reactive [B12X11]- ions which spontaneously react with alkanes. The reaction mechanism was investigated using tandem mass spectrometry and gas-phase vibrational spectroscopy combined with electronic structure calculations. [B12X11]- reacts by an electrophilic substitution of a proton in an alkane resulting in a B-C bond formation. The product is a dianionic [B12X11CnH2n+1]2- species, to which H+ is electrostatically bound. High-flux ion soft landing was performed to codeposit [B12X11]- and complex organic molecules (phthalates) in thin layers on surfaces. Molecular structure analysis of the product films revealed that C-H functionalization by [B12X11]- occurred in the presence of other more reactive functional groups. This observation demonstrates the utility of highly reactive fragment ions for selective bond formation processes and may pave the way for the use of gas-phase ion chemistry for the generation of complex molecular structures in the condensed phase.

Soat2 ties cholesterol metabolism to ß-oxidation and glucose tolerance in male mice.

BACKGROUND: Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins. OBJECTIVES: We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice. METHODS: Soat2-/- and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed. RESULTS: Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2-/- mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2-/- mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice. CONCLUSION: Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.

Infrared photodissociation spectroscopy of (Al2O3)2-5FeO+: influence of Fe-substitution on small alumina clusters.

The infrared photodissociation spectra of He-tagged (Al2O3)nFeO+ (n = 2-5), are reported in the Al-O and Fe-O stretching and bending spectral region (430-1200 cm-1) and assigned based on calculated harmonic IR spectra from density functional theory (DFT). The substitution of Fe for an Al center occurs preferentially at 3-fold oxygen coordination sites located at the cluster rim and with the Fe atom in the +III oxidation state. The accompanying elongation of metal oxygen bonds leaves the Al-O network structure nearly unperturbed (isomorphous substitution). Contrary to the Al2FeO4+ (n = 1), valence isomerism is not observed, which is attributed to a smaller M:O ratio (M = Al, Fe) and consequently decreasing electron affinities with increasing cluster size.

Binding of saturated and unsaturated C6-hydrocarbons to the electrophilic anion [B12Br11]-: a systematic mechanistic study.

The highly reactive gaseous ion [B12Br11]- is a metal-free closed-shell anion which spontaneously forms covalent bonds with hydrocarbon molecules, including alkanes. Herein, we systematically investigate the reaction mechanism for binding of [B12Br11]- to the five hexane isomers yielding [B12Br11(C6H14)]-, as well as to cyclohexane and several hexene isomers (yielding [B12Br11(C6H12)]-) using collision-induced dissociation (CID), infrared photodissociation spectroscopy (IRPD) and computational methods. CID of the different [B12Br11(C6H14)]- ions results in distinct fragmentation patterns dependent on the structure of the hexane isomer. The observed fragmentation reactions provide insights into the addition mechanism of [B12Br11]- to hexane. Based on the observed CID patterns, we identified that either B-C bond formation through heterolytic C-C or C-H bond cleavages or B-H bond formation through heterolytic C-H cleavage occur dependent on the structure of the hexane isomer. Meanwhile, we observe identical CID spectra of adducts originating from isomers of C6H12. Spectroscopic investigations of adducts of 1-hexene and cyclohexane indicate the same product structure with an open C6 chain. Computational investigations evidenced that low lying transition states are present, which enable a ring opening reaction of cyclohexane when binding to [B12Br11]-.

Rational design of an argon-binding superelectrophilic anion.

Chemically binding to argon (Ar) at room temperature has remained the privilege of the most reactive electrophiles, all of which are cationic (or even dicationic) in nature. Herein, we report a concept for the rational design of anionic superelectrophiles that are composed of a strong electrophilic center firmly embedded in a negatively charged framework of exceptional stability. To validate our concept, we synthesized the percyano-dodecoborate [B12(CN)12]2-, the electronically most stable dianion ever investigated experimentally. It serves as a precursor for the generation of the monoanion [B12(CN)11]-, which indeed spontaneously binds Ar at 298 K. Our mass spectrometric and spectroscopic studies are accompanied by high-level computational investigations including a bonding analysis of the exceptional B-Ar bond. The detection and characterization of this highly reactive, structurally stable anionic superelectrophile starts another chapter in the metal-free activation of particularly inert compounds and elements.

Identification of a Two-Coordinate Iron(I)-Oxalate Complex.

Exotic oxidation states of the first-row transition metals have recently attracted much interest. In order to investigate the oxidation states of a series of iron-oxalate complexes, an aqueous solution of iron(III) nitrate and oxalic acid was studied by infrared free liquid matrix-assisted laser desorption/ionization as well as ionspray mass spectrometry. Here, we show that iron is not only detected in its common oxidation states +II and +III, but also in its unusual oxidation state +I, detectable in both positive-ion and in negative-ion modes, respectively. Vibrational spectra of the gas phase anionic iron oxalate complexes [FeIII (C2 O4 )2 ]- , [FeII (C2 O4 )CO2 ]- , and [FeI (C2 O4 )]- were measured by means of infrared photodissociation spectroscopy and their structures were assigned by comparison to anharmonic vibrational spectra based on second-order perturbation theory.

Gas-Phase Mechanism of O.- /Ni2+ -Mediated Methane Conversion to Formaldehyde.

The gas-phase reaction of NiAl2 O4 + with CH4 is studied by mass spectrometry in combination with vibrational action spectroscopy and density functional theory (DFT). Two product ions, NiAl2 O4 H+ and NiAl2 O3 H2 + , are identified in the mass spectra. The DFT calculations predict that the global minimum-energy isomer of NiAl2 O4 + contains Ni in the +II oxidation state and features a terminal Al-O.- oxygen radical site. They show that methane can react along two competing pathways leading to formation of either a methyl radical (CH3 ⋅) or formaldehyde (CH2 O). Both reactions are initiated by hydrogen atom transfer from methane to the terminal O.- site, followed by either CH3 ⋅ loss or CH3 ⋅ migration to an O2- site next to the Ni2+ center. The CH3 ⋅ attaches as CH3 + to O2- and its unpaired electron is transferred to the Ni-center reducing it to Ni+ . The proposed mechanism is experimentally confirmed by vibrational spectroscopy of the reactant and two different product ions.

Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner.

The initiation and progression of autoimmune disorders such as multiple sclerosis (MS) is linked to aberrant cholesterol metabolism and overt inflammation. Liver X receptors (LXR) are nuclear receptors that function at the crossroads of cholesterol metabolism and immunity, and their activation is considered a promising therapeutic strategy to attenuate autoimmunity. However, despite clear functional heterogeneity and cell-specific expression profiles, the impact of the individual LXR isoforms on autoimmunity remains poorly understood. Here, we show that LXRα and LXRß have an opposite impact on immune cell function and disease severity in the experimental autoimmune encephalomyelitis model, an experimental MS model. While Lxrα deficiency aggravated disease pathology and severity, absence of Lxrß was protective. Guided by flow cytometry and by using cell-specific knockout models, reduced disease severity in Lxrß-deficient mice was primarily attributed to changes in peripheral T cell physiology and occurred independent from alterations in microglia function. Collectively, our findings indicate that LXR isoforms play functionally non-redundant roles in autoimmunity, potentially having broad implications for the development of LXR-based therapeutic strategies aimed at dampening autoimmunity and neuroinflammation.

Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans.

BACKGROUND AND AIMS: Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. APPROACH AND RESULTS: Fah-/- , Rag2-/- , and Il2rg-/- knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. CONCLUSIONS: LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.